Nitrogen-containing heterocyclic compound dual-target inhibitor and use thereof

Abstract

The present disclosure provides a compound represented by formula (I), which has good PCSK9 and / or LPA inhibitory activity and can be used as a PCSK9 and / or LPA target inhibitor for lowering blood lipids.

Description

Nitrogen-containing heterocyclic compound dual-target inhibitors and their applications

[0001] This application requests the following:

[0002] The priority right of the prior application filed with the China National Intellectual Property Administration on January 27, 2025, with patent application number 202510126140.1 and entitled "Dual-target inhibitor of lipid-lowering PCSK9 and LPA and its preparation method and application";

[0003] Priority rights to the earlier application filed with the China National Intellectual Property Administration on May 30, 2025, with patent application number 202510720234.1 and title "Dual-target inhibitor of lipid-lowering PCSK9 and LPA and its preparation method and application";

[0004] The priority right of the prior application filed with the China National Intellectual Property Administration on October 17, 2025, with patent application number 202511489340.X and entitled "Dual-target inhibitor of lipid-lowering PCSK9 and LPA and its preparation method and application";

[0005] The priority right of the prior application filed with the China National Intellectual Property Administration on December 26, 2025, with patent application number 202511995339.4 and title "Dual-target inhibitor of lipid-lowering PCSK9 and LPA and its preparation method and application";

[0006] The full text of the prior application is incorporated herein by reference. Technical Field

[0007] This invention belongs to the field of medicine, specifically relating to a dual-target inhibitor of nitrogen-containing heterocyclic compounds and its application. Background Technology

[0008] PCSK9 is a liver-derived secretory protein that binds to the extracellular domain of LDLR; however, PCSK9's degradation of LDLR is intracellular. PCSK9 does not require kinase catalytic activity to influence LDLR conversion; kinase catalytic activity cannot guide the receptor-carrying complex to the lysosomes where the complex is degraded or inhibit the complex's circulation. As a neuronal apoptosis-regulating enzyme, PCSK9 not only participates in liver regeneration and regulates neuronal apoptosis but also affects LDL internalization by reducing the amount of LDLR on hepatocytes, leading to impaired LDL clearance from the blood and resulting in hypercholesterolemia. Studies have shown that PCSK9 levels are significantly correlated with cholesterol, ox-LDL, and triglycerides. As a serine protease, PCSK9, in addition to degrading LDLR and increasing blood LDL levels, has various other biological functions, such as participating in nervous system development, neuronal apoptosis, and regulating sodium channels and pancreatic islet cell function. The process of PCSK9 production begins with the synthesis of PCSK9 proenzyme in the endoplasmic reticulum. PCSK9 proenzyme then undergoes an autocatalytic reaction in the endoplasmic reticulum or Golgi apparatus, cleaving to release a propeptide, forming a mature protease, which is immediately secreted into the blood. By regulating LDLR, it maintains the homeostasis of plasma lipids and can affect plasma cholesterol levels.

[0009] LPA stands for lipoprotein(a), a specialized lipoprotein particle. LPA is composed of low-density lipoprotein (LDL) and apolipoprotein(a), and its structure is highly homologous to plasminogen. Elevated LPA levels are associated with various cardiovascular diseases, including atherosclerosis, coronary artery disease, and aortic stenosis. Because LPA levels are primarily determined by genetic factors, there are significant differences between different races and individuals. In recent years, treatment strategies targeting lower LPA levels have been continuously researched and developed.

[0010] PCSK9 inhibitors may cause abnormal liver function, manifesting as elevated transaminases, jaundice, ascites, and in severe cases, may develop into cirrhosis or even liver failure. They may also affect the number and activity of low-density lipoprotein receptors, leading to elevated serum total cholesterol and low-density lipoprotein cholesterol levels, increasing the risk of cardiovascular disease. LPA inhibitors can cause adverse reactions such as abnormal liver function and muscle pain, requiring regular monitoring of liver function and creatine kinase levels; they are also prone to causing gastrointestinal discomfort, rashes, and may cause headaches, heartburn, and abdominal pain. Therefore, there is a need to develop more effective and safer dual-target lipid-lowering drugs. Summary of the Invention

[0011] To address the aforementioned technical problems, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0012] U is selected from single bonds, CH2, or C(O);

[0013] Gp1 is -E2-L-E1-XAYG;

[0014] A is selected from unsubstituted or arbitrarily assigned to one, two or more R. a The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R a They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl;

[0015] X does not exist or is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R x They may be the same or different, and are independently selected from H, halogens, OH, CN, and C. 1-10 Alkyl group; when X is absent, A and E1 are screwed together to form a helical ring;

[0016] Y is selected from S, without substitution, or optionally by one, two, or more R. y The following groups are substituted: NH, NHC(O), NHC(O)O, -CH2NH-, -CH2CH2NH-; each R y They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 Alkyl; or, two Rs y The atoms connected to it form C 3-10 cycloalkyl;

[0017] E1 is selected from unsubstituted or optionally by one, two or more R... E1 The following groups are substituted: 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R E1 They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl;

[0018] E2 is selected from OH, unsubstituted, or optionally surrounded by one, two, or more R groups. E2 The following groups are substituted: C 1-10 Alkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), OH, CN, C(O)OH, C 1-10 Alkyl, Halogenated C 1-10 Alkyl, C6-10 Aryl;

[0019] L is selected from single bond, -N(R) L )-、-C(O)C(R L (R) L )-、-C(O)N(R L )-、-C(R L (R) L -; each R L They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. L1 The following groups are substituted: C 1-10 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic; each R L1 They are either the same or different, and are independently selected from halogens, oxygen (=O), and carbon. 1-10 alkyl;

[0020] Or, two Rs L The atoms connected to it form C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups;

[0021] G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 10 Aryl, 5-10 quinone heteroaryl; each R g They are either the same or different, and are independently selected from H, halogens, OH, CN, oxo (=O), C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 3-10 cycloalkyl, C 1-10 Alkyl-NH-, C 3-10 cycloalkyl-NH-, C 1-10 Alkyl-NHC(O)-, C 1-10 Alkyl-C(O)NH-;

[0022] Gp2 is -MQZ; n is 1 or 2;

[0023] M is selected from single bonds, unsubstituted bonds, or optionally bonds formed by one, two, or more Rs. M Replacement C 1-10 Alkyl; each R M Whether the two are the same or different, they are independently selected from H, oxo (=O), and C. 1-10 Alkyl, C 3-10 cycloalkyl;

[0024] Q is selected from unsubstituted or arbitrarily selected by one, two or more R. Q The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 10 Aryl, 5-10 quinone heteroaryl; each R Q They are either the same or different, and are independently selected from H, halogens, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy;

[0025] Z is selected from unsubstituted or optionally by one, two or more R. Z Replacement C 1-10 Alkyl; each R Z They are either identical or different, and are independently selected from H, oxo (=O), C(O)OR Z1 C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; R Z1 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl;

[0026] J1 is selected from a single bond, without substitution, or optionally by one, two, or more R bonds. J1 The following groups are substituted: NH-C(O), C(O)-NH, C 1- 10 Alkyl, -C 1-10 Alkyl-O-, -C 1-10 Alkyl-NH-, 5-10-membered heteroaryl, 3-10-membered heterocyclic, C 1-10 Alkyl-NH-C(O), C(O)-NH-C 1-10 Alkyl, C 1-10 Alkoxy-5-10 heteroaryl, C 1-10 Alkoxy-C(O)-5-10 heteroaryl, C 1-10 Alkyl-NHC(O)-5-10-membered heteroaryl, NHC(O)-5-10-membered heteroaryl; each R J1 Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl;

[0027] J2 is selected from N, NH or -VTW-; V is connected to Gp2, and W is connected to U;

[0028] V is selected from O, S, N, unsubstituted, or optionally replaced by one, two, or more R. V The following groups are substituted: NH, CH2; each R V Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 3-10 cycloalkyl;

[0029] T is selected from a single bond, without substitution, or optionally by one, two, or more Rs. T Replacement C 1-10 Alkyl; each R T Whether the two are the same or different, they are independently selected from H, oxo (=O), and C. 1-10 Alkyl, C 3-10 cycloalkyl;

[0030] W is selected from O, S, N, unsubstituted, or optionally replaced by one, two, or more R. W The following groups are substituted: NH, CH2, C 6-10 Aryl, 5-10 quinone heteroaryl; each R W Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 3-10 Cycloalkyl.

[0031] According to embodiments of this disclosure, A is selected from unsubstituted or optionally replaced by one, two or more R. a The following groups are substituted: C 3-8 Cycloalkyl, 5-8 membered heterocyclic groups, C 6-8 Aryl, 5-6 quinone heteroaryl;

[0032] According to embodiments of this disclosure, A is selected from unsubstituted or optionally replaced by one, two or more R. a The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, bicyclo[3.2.0]heptyl, 2-azaspiro[3.4]octyl, phenyl, pyridyl, 2,3-dihydro-1H-indenyl;

[0033] According to the implementation scheme of this disclosure, each R a They may be the same or different, and are independently selected from halogens (e.g., F), OH, CN, C. 1-6 alkyl;

[0034] According to the embodiments of this disclosure, A is selected from And when X does not exist, A is selected from

[0035] According to the implementation scheme of this disclosure, A is selected from... And when X does not exist, A is selected from

[0036] According to the embodiments of this disclosure, X is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R x They are either the same or different, and are independently selected from H, OH, CN, and C. 1-6 Alkyl groups (e.g., methyl groups);

[0037] According to the embodiments of this disclosure, X is selected from single bonds, NH, S, (For example ), (For example ).

[0038] According to the implementation scheme of this disclosure, Y is selected from NH, S, NHC(O), NHC(O)O,

[0039] According to the implementation scheme of this disclosure, each R y Same or different, selected independently from C 1-6 Alkyl (e.g., methyl); or, two Rs y The atoms connected to it form C 3-6 Cycloalkyl groups (e.g., cyclopropyl);

[0040] According to the implementation scheme of this disclosure, Y is selected from NH, S, NHC(O), NHC(O)O, (For example ),

[0041] According to embodiments of this disclosure, E1 is selected from unsubstituted or optionally replaced by one, two or more R. E1 The following groups are substituted: 6-9 membered heterocyclic groups, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl;

[0042] According to embodiments of this disclosure, E1 is selected from unsubstituted or optionally replaced by one, two or more R. E1 The following groups may be substituted: pyridinyl, pyridazinyl, thiazolyl, oxazolyl, phenyl, benzimidazolyl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl, indolinel;

[0043] According to the implementation scheme of this disclosure, E1 is selected from... (For example ), (For example ); and when X does not exist, E1 is selected from

[0044] According to embodiments of this disclosure, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: C 1-6 Alkyl, 4-8 membered heterocyclic group, C 6-8 Aryl, 5-6 quinary heteroaryl, 8-10 quinary heteroaryl;

[0045] According to embodiments of this disclosure, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: methyl, ethyl, 1,2-dihydropyridyl, pyrrolyl, imidazole, phenyl, 2,3-dihydro-1H-imidazolyl, aziridine, aziridine-butenyl, tetrahydropyrrolyl, indolinel, Indole, 1H-pyrrolo[3,2-b]pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 2H-indazoleyl, thiazolyl, triazolyl, dihydropyrrolyl, 1H-pyrazolo[3,4-b]pyridyl, 7H-pyrrolo[2,3-c]pyridazinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl;

[0046] According to the implementation scheme of this disclosure, each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), C(O)OH, CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-8 Aryl;

[0047] According to the implementation scheme of this disclosure, each R E2 They are either the same or different, and are independently selected from F, oxo (=O), C(O)OH, CN, methyl, difluoromethyl, and phenyl.

[0048] According to the implementation scheme of this disclosure, E2 is selected from... Preferably, The N and L terminals are connected. The methylene group in the middle is connected to the L-terminus.

[0049] According to the embodiments of this disclosure, L is selected from single bonds, NH, -C(O)C(R) L (R) L )-、-C(O)N(RL )-、-C(R L (R) L )-;

[0050] According to the implementation scheme of this disclosure, each R L They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. L1 The following groups are substituted: C 1-6 Alkyl, C 6-8 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclic; or, two R groups L The atoms connected to it form C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups;

[0051] According to the implementation scheme of this disclosure, each R L1 They may be the same or different, and are independently selected from halogens (e.g., F, C). 1-6 Alkyl groups (e.g., methyl groups);

[0052] According to the implementation scheme of this disclosure, each R L Same or different, selected independently from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-8 Aryl, Halogenated C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl, C 1-6 Alkyl-5-6-membered heteroaryl, 3-6-membered heterocyclic; or, two R L It forms cyclopropyl, cyclobutyl, and oxecyclobutane groups with the atoms it is attached to.

[0053] According to the implementation scheme of this disclosure, each R L They may be the same or different, and are independently selected from methyl, trifluoromethyl, difluoromethyl, 3-fluorophenyl, 4-fluorophenyl, imidazolyl, etc. Triazolyl, pyrimidinyl, thiazolyl, phenyl, oxacyclobutyl, pyridinyl, indoleyl; or, two Rs L The atoms connected to each other form

[0054] According to the embodiments of this disclosure, L is selected from single bonds, NH,

[0055] According to embodiments of this disclosure, G is selected from unsubstituted or optionally replaced by one, two or more R. g The following groups are substituted: C 3-6 Cycloalkyl, 5-6 membered heterocyclic, 9-10 membered heterocyclic, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl;

[0056] According to embodiments of this disclosure, G is selected from unsubstituted or optionally replaced by one, two or more R. g The following groups may be substituted: thiazolyl, 2-oxabicyclohexyl, phenyl, cyclopropyl, triazine, oxadiazole, oxazole, thiazolyl, triazolyl, pyrimidinyl,

[0057] According to the implementation scheme of this disclosure, G is selected from...

[0058] According to the implementation scheme of this disclosure, each R g Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl-NH-, C 1-6 Alkyl-NHC(O)-, C 1-6 Alkyl-C(O)NH-;

[0059] According to the implementation scheme of this disclosure, each R g They may be the same or different, and are independently selected from methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, cyclopropyl,

[0060] According to the implementation scheme of this disclosure, G is selected from...

[0061] According to the implementation scheme of this disclosure, Gp1 is or

[0062] According to the implementation scheme of this disclosure, Gp1 is

[0063] According to the implementation scheme of this disclosure, M is selected from C. 1-6 Alkyl groups, such as methylene.

[0064] According to the embodiments of this disclosure, Q is selected from unsubstituted or optionally replaced by one, two or more R. Q The following groups are substituted: C 6-8 Aryl, such as phenyl (e.g.) like ), or 5-9 membered heteroaryl, such as thiazolyl (e.g. ), thiophene group (such as ).

[0065] According to the implementation scheme of this disclosure, each R Q Selected independently of H, halogen, C, whether identical or different 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0066] According to the implementation scheme of this disclosure, each R Q The same or different from each other are independently selected from H, F, methyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0067] According to embodiments of this disclosure, Z is selected from unsubstituted or optionally replaced by one, two or more R. Z Replacement C 1-6 alkyl;

[0068] According to embodiments of this disclosure, Z is selected from unsubstituted or optionally replaced by one, two or more R. Z The following groups are substituted: methylene, ethylene;

[0069] According to the implementation scheme of this disclosure, each R Z Whether the two are the same or different, they are selected independently from C(O)OR Z1 ; Each R Z1 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl).

[0070] According to the implementation scheme of this disclosure, each R Z They are either the same or different, and are independently selected from H, C(O)OH, and C(O)OC. 1-6 Alkyl groups, 3-8 membered heterocyclic groups;

[0071] According to the implementation scheme of this disclosure, each R Z They may be the same or different, and are independently selected from H, C(O)OH, 3-6 membered heterocyclic groups (e.g., tetrahydropyrrole, such as...). For example ).

[0072] According to the implementation scheme of this disclosure, Gp2 is (like ), (like ), For example For example For example

[0073] According to embodiments of this disclosure, J1 is selected from single bonds, unsubstituted bonds, or optionally bonds formed by one, two, or more R bonds. J1 The following groups are substituted: NH-C(O), C(O)-NH, C 1-10 Alkyl, -C 1-10 Alkyl-O-, -C 1-10 Alkyl-NH-, 5-10-membered heteroaryl, C 1-10 Alkyl-NH-C(O), C(O)-NH-C 1-10 Alkyl, C 1-10 Alkoxy-5-10 heteroaryl, C 1-10 Alkoxy-C(O)-5-10 heteroaryl, C 1-10 Alkyl-NHC(O)-5-10-membered heteroaryl, NHC(O)-5-10-membered heteroaryl; each R J1 Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl;

[0074] According to the embodiments of this disclosure, J1 is selected from single bonds, NH-C(O), C(O)-NH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-OC 1-6 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, C 1-6 Alkyl-NH-C(O), C 1-6 alkoxy-5-6-membered heteroaryl, C 1-6 alkoxy-C(O)-5-6-membered heteroaryl, C 1-6 Alkyl-NHC(O)-5-6-membered heteroaryl, NHC(O)-5-6-membered heteroaryl; preferably, J1 is selected from C 1-6 When alkyl-O-, the O end is connected to U.

[0075] According to the embodiments of this disclosure, J1 is selected from single bonds, NH-C(O), C(O)-NH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-OC 1-6 Alkyl, 5-6 membered heteroaryl, C 1-6Alkyl-NH-C(O), C 1-6 alkoxy-5-6-membered heteroaryl, C 1-6 alkoxy-C(O)-5-6-membered heteroaryl, C 1-6 Alkyl-NHC(O)-5-6-membered heteroaryl, NHC(O)-5-6-membered heteroaryl; preferably, J1 is selected from C 1-6 When alkyl-O-, the O end is connected to U.

[0076] According to the embodiments of this disclosure, J1 is selected from single bonds, NH-C(O), C(O)-NH, CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2-O, CH2-O-CH2, CH2CH2-O-CH2, CH2NH-C(O), pyrrole (e.g.) ), tetrahydropyrrole (e.g.) ), imidazole group (e.g. ),

[0077] According to the embodiments of this disclosure, J1 is selected from single bonds, NH-C(O), C(O)-NH, CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2-O, CH2-O-CH2, CH2CH2-O-CH2, CH2NH-C(O), pyrrole (e.g.) ),

[0078] According to the embodiments of this disclosure, V is selected from O, S, N, NH, CH2;

[0079] According to embodiments of this disclosure, T is selected from unsubstituted or optionally replaced by one, two or more R. T Replacement C 1-6 Alkyl groups, such as ethylene, propyleneene, butylene, pentylene, and hexylene;

[0080] According to the embodiments of this disclosure, T is selected from C(O), methylene, Preferably, The carbonyl group in the figure is attached to V;

[0081] According to the embodiments of this disclosure, W is selected from O, S, N, NH, CH2, C 6-10 Aryl, halophenyl, haloC 1-6 Alkylphenyl, 5-6 membered heteroaryl (e.g., pyridyl), 9-10 membered heteroaryl (e.g., quinolinyl);

[0082] According to the embodiments of this disclosure, W is selected from O, S, N, NH, CH2,

[0083] According to the implementation scheme of this disclosure, J2 is selected from N, NH,

[0084] According to the implementation scheme of this disclosure, Selected from O,

[0085] According to the implementation scheme of this disclosure, Selected from

[0086] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0087] Wherein, Gp1, Gp2, J1, J2, and n independently have the definitions described above. According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0088] Among them, Gp1, Gp2, J1, J2, Rg, R T R Z1 , n, U, and Q are independently defined as described above.

[0089] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0090] Among them, J1, J2, U, R Z1 Q and Q are independently defined as described above.

[0091] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0092] The present invention also provides a pharmaceutical composition comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0093] According to embodiments of this disclosure, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0094] This disclosure also provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of drugs for the treatment and / or prevention of diseases associated with PCSK9 and / or LPA targets, such as cardiovascular diseases:

[0095] According to the embodiments of this disclosure, the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease.

[0096] According to the embodiments of this disclosure, the cardiovascular disease is familial hypercholesterolemia.

[0097] According to the embodiments of this disclosure, the cardiovascular disease is autosomal dominant hypercholesterolemia.

[0098] This disclosure also provides a method for treating cardiovascular disease, comprising administering to a patient a therapeutically effective amount of at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] According to embodiments of this disclosure, the method further includes the combined administration of one or more additional therapeutic agents.

[0100] According to embodiments of this disclosure, the therapeutic agent may be selected from alizumab, evokulumab, beroxizumab, RG7652, LY3015014, mAb316P, berberine, quercetin, ezetimibe, prilol, BMS-962476, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0101] According to embodiments of this disclosure, the therapeutic agent may be selected from HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, HMG-CoA synthase gene expression inhibitors, MTP / Apo B secretion inhibitors, CETP inhibitors, bile acid absorption inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, squalene synthase inhibitors, squalene epoxide inhibitors, squalene cyclase inhibitors, combinations of squalene epoxide / squalene cyclase inhibitors, fibrates, niacin, combinations of niacin and lovastatin, ion exchange resins, antioxidants, ACAT inhibitors, bile acid chelators, and PCSK9 translation inhibitors. Beneficial effects

[0102] This disclosure provides a compound of formula (I) which has good PCSK9 and / or LPA inhibitory activity, and also has binding activity and biological effects on LPA, and can be used as a PCSK9 and / or LPA target inhibitor for lowering blood lipids.

[0103] Terminology Definitions and Explanations

[0104] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0105] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0106] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0107] The context of this disclosure is used Represents a chemical bond.

[0108] Term "C" 1-10 "alkyl" refers to a straight-chain or branched monovalent or polyvalent saturated hydrocarbon group, preferably a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The alkyl group includes C... 1-3 Alkyl, C 1-6 Alkyl, C 3-6Alkyl, C 1-10 Alkyl groups, etc. "C" 1- 10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, methylene, ethyl, ethylene, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0109] Term "C" 3-10 "Cycloalkyl" refers to a saturated monovalent or polyvalent monocyclic, bicyclic (e.g., fused ring, bridged ring, spiro ring) hydrocarbon ring or tricyclic alkane, preferably having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group includes C... 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, C 3-10 Cycloalkyl groups, etc. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0110] The term "3-10 membered heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system (preferably 3-8 membered heterocyclic group) containing 1-5 heteroatoms independently selected from N, O, and S, with monovalent or polyvalent rings of 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. For example, a 3-8 membered heterocyclic group can be a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system containing 3, 4, 5, 6, 7, or 8 ring atoms, wherein the 3-8 membered heterocyclic group contains 1-5 heteroatoms independently selected from N, O, and S. The bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic rings, or bridged rings. The 3-10 membered heterocyclic group includes 3-8 membered heterocyclic groups and 5-6 membered heterocyclic groups. The 3-10 membered heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The 3-10 membered heterocyclic groups may include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic groups may include, but are not limited to: 3-membered rings, such as azirropropyl or oxacyclopropyl; 4-membered rings, such as azirrobutyl or oxacyclobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl. Alternatively, it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclic group is linked to other groups to form the compounds of this disclosure, the carbon atom on the 3-10 membered heterocyclic group can be linked to other groups, or a heterocyclic atom (such as a nitrogen atom) on the ring of the 3-10 membered heterocyclic group can be linked to other groups. For example, when the 3-10 membered heterocyclic group is selected from piperazineyl or tetrahydropyrroleyl, the nitrogen atom or carbon atom on the piperazineyl group can be linked to other groups. Alternatively, when the 3-10 membered heterocyclic group is selected from piperidinyl, it can be the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta or para position connected to other groups.

[0111] Term "C" 6-10"Aryl" should preferably be understood to refer to a monocyclic, bicyclic (such as fused ring, bridged ring, spirocyclic) or tricyclic hydrocarbon ring having monovalent or polyvalent aromaticity or partial aromaticity with 6 to 10 carbon atoms. It can be a monoaromatic ring or a polyaromatic ring fused together. The term "C" 6-10 "Aryl" should be understood to preferably represent a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, or 10 carbon atoms, exhibiting monovalent or polyvalent aromaticity or partial aromaticity ("C"). 6-10 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. When the C 6-10 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0112] The term "5-10-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms, wherein the ring atoms comprise 1-5 heteroatoms independently selected from N, O, and S, and the bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic, or bridged rings (preferably 5-9-membered heteroaryl). The 5-9-membered heteroaryl contains 1-5 heteroatoms, preferably 1-3. Additionally, in each case, the 5-10-membered heteroaryl can be benzofused. The 5-10-membered heteroaryl includes 5-8-membered heteroaryl, 5-9-membered heteroaryl, 5-10-membered heteroaryl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, 6-membered heteroaryl, etc. Examples of heteroaryl groups include, but are not limited to: 5-membered rings, such as oxazolyl, pyrazolyl, thiophene, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group may be bicyclic, including but not limited to: 5,5-membered rings, such as tetrahydrocyclopentanopyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisoxazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptazothiazole, tetrahydrocycloheptazofuran. The heterocyclic group can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-10 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom bonded to the carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom bonded to the heteroatom on the heteroaryl ring can be substituted.

[0113] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0114] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0115] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0116] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0117] "Halogenation" refers to the substitution of a substance by one or more halogens.

[0118] Unless otherwise stated, the definitions of terms in this document also apply to groups that contain the term; for example, the definition of alkyl also applies to the definition of alkyl-containing groups such as alkoxy (i.e., alkyloxy).

[0119] Unless otherwise stated, the term "compound" in the context of this disclosure shall be understood to include the compound itself and its tautomers, stereoisomers, solvates or isotopic labels.

[0120] Crystallization often produces solvates of the compounds disclosed herein. As used herein, a solvate is a combination of one or more molecules of the compounds disclosed and one or more solvent molecules.

[0121] The solvent can be water, in which case the solvate is a hydrate; alternatively, it can be an organic solvate.

[0122] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it does not have a lasting harmful effect on the overall health of the subject of treatment.

[0123] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds disclosed herein and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition.

[0124] Those skilled in the art will understand that the compounds of this disclosure can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0125] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0126] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0127] In this application, "pharmaceutical composition" refers to a formulation of the disclosed compound and a medium conventionally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0128] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0129] In this application, the term "prodrug" refers to a compound of this disclosure that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of this disclosure are prepared by modifying functional groups in the compound; such modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group in the compound of this disclosure. When a prodrug of the compound of this disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0130] "Isotope" refers to all isotopes of atoms appearing in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds disclosed herein are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 31 P, 32 P, 35 S, 18 F and 36 C1. The isotopically labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically labeled reagents instead of non-isotopically labeled preparations. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0131] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0132] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0133] (ii) To suppress a disease or symptom, that is, to curb its development;

[0134] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0135] (iv) To alleviate the symptoms caused by the disease or condition.

[0136] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0137] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0138] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0139] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0140] Synthesis of intermediate INT-1

[0141] Under nitrogen atmosphere, at 25°C, trifluoroacetic acid (1 mL) was added dropwise to 3 mL of dichloromethane containing (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) under stirring. The resulting mixture was stirred at 25°C for 2 hours. The crude product was purified by pre-high performance liquid chromatography to give a white solid (2S)-3-(3-bromophenyl)-2-[(3R)-pyrrolidine-3-yl]propionate (10.2 mg).

[0142] LCMS(ESI,m / z):[M+H]+=298.0

[0143] 1H NMR(400MHz,D2O)δ7.39(d,J=3.3Hz,2H),7.25–7.11(m,2H),3.52(d,J=11.8Hz,1H),3.37(d,J=12.1Hz,1H),3.20(d,J=11.9Hz, 1H),3.00(d,J=11.8Hz,1H),2.89–2.78(m,2H),2.69(t,J=9.4Hz,1H),2.56–2.41(m,1H),2.20–2.05(m,1H),1.80–1.60(m,1H).

[0144] Synthesis of intermediate INT-2

[0145] Sodium borohydride (16 mg, 0.4 mmol) was added to a stirred solution of methyl 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylate (100 mg, 0.2 mmol) in methanol (3 mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The crude product (100 mg) was purified by pre-high performance liquid chromatography to obtain 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-[1,3'-bipyridine]-2-one (14.0 mg), which was a white solid.

[0146] LCMS(ESI,m / z):[M+H]+=223.10

[0147] 1 H NMR(400MHz,MeOD-d4)δ8.19(d,J=0.8Hz,2H),7.99–7.94(m,1H),7.60–7.45(m,2H),6.91–6.53(m,3H),6.47–6 .41(m,1H),4.56(d,J=1.4Hz,2H),4.46–4.32(m,2H),2.33–2.24(m,2H),2.10–1.99(m,2H),1.70–1.60(m,2H).

[0148] Example 1

[0149] 1. Synthesis of compound a

[0150] Under nitrogen atmosphere and at 25°C, pyridine (10.0 g, 130.6 mmol) was added dropwise to a mixture of methyl 6'-oxo-1H-pyridine-3-carboxylate (10.0 g, 65.3 mmol) and copper acetate (23.0 g, 130.6 mmol) in 100 mL of dichloromethane. The resulting mixture was stirred at 25°C for 16 hours. The residue was purified by reversed-phase flash chromatography to give methyl 6'-bromo-6-oxo-[1,3'-bipyridine]-3-carboxylate (5.0 g), a white solid. LCMS (ESI, m / z): [M+H]+=310.1

[0151] 2. Synthesis of compound b

[0152] Cesium carbonate (59.0 g, 183.8 mmol) was added in portions to a stirred mixture of 2-chloropyrimidin-5-ol (20.0 g, 153.2 mmol) and ethyl 2-chloro-2,2-difluoroacetate (72.0 g, 459.6 mmol) in N,N-dimethylformamide (200 mL). The resulting mixture was stirred at 100 °C for 12 hours. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give 2-chloro-5-(difluoromethoxy)pyrimidine (6.0 g) as a colorless oil. LCMS (ESI, m / z): [M+H] + =181.5

[0153] 3. Synthesis of compound c

[0154] Under nitrogen atmosphere, N,N-diisopropylethylamine (12.0 g, 99.7 mmol) was added dropwise to a solution of 2-chloro-5-(difluoromethoxy)pyrimidine (6.0 g, 33.2 mmol) and N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (6.0 g, 33.2 mmol) in dimethyl sulfoxide (60 mL) at 25 °C. The resulting mixture was stirred at 110 °C for 16 hours. The residue was purified by reversed-phase flash chromatography to give N-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]carbamate tert-butyl ester (10.0 g). LCMS (ESI, m / z): [M+H] + =345.1

[0155] 4. Synthesis of compound d

[0156] Under nitrogen atmosphere at 25°C, 1,4-dioxane hydrochloride (4.0 M) (50 mL) was added dropwise to a mixture of N-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]carbamate tert-butyl ester (10.0 g, 29.0 mmol) and dioxane (100 mL). The resulting mixture was stirred at 25°C for 2 hours. The mixture was then concentrated under reduced pressure to give (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (7.0 g). LCMS (ESI, m / z): [M+H] + =245.1

[0157] 5. Synthesis of compound e

[0158] Under nitrogen atmosphere, at 25°C, cuprous iodide (0.3 g, 1.7 mmol), potassium carbonate (7.9 g, 57.3 mmol), and N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (0.3 g, 1.1 mmol) were added to a stirred solution of (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (7.0 g, 28.6 mmol) and methyl 6'-bromo-6-oxo-[1,3'-bipyridine]-3-carboxylate (8.8 g, 28.6 mmol) in dimethyl sulfoxide (80 mL). The resulting mixture was stirred overnight at 110°C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography to give methyl 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylate (6.0 g). LCMS (ESI, m / z): [M+H] + =473.1

[0159] 6. Synthesis of compound f

[0160] Under nitrogen atmosphere and at 25°C, lithium hydroxide (0.6 g, 22.9 mmol) and water (10 mL) were added to a stirred mixture of vanadium methyl 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (vanadium methyl ester, 6.0 g, 11.4 mmol) in methanol (10 mL). The resulting mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (5.0 g). LCMS (ESI, m / z): [M+H] + =459.1

[0161] 7. Synthesis of compound g

[0162] Under a nitrogen atmosphere, at 25 °C, tert-butyl pyrrolidine-1-carboxylate (5.0 g, 12.3 mmol) and N,N-dimethylformamide (50 mL) of 6'-{[1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (5.6 g, 12.3 mmol) were added to N,N-diisopropylethylamine (4.7 g, 37.1 mmol) and HATU (7.1 g, 18.5 mmol). The resulting mixture was stirred at 25 °C for 1 hour under a nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography to give (R)-3-((S)-1-(tert-butoxy)-3-(4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g). LCMS (ESI, m / z): [M+H] + =845.4

[0163] 8. Synthesis of Compound 1

[0164] Under nitrogen atmosphere and at 25°C, 1,4-dioxane hydrochloride (4.0 M) (1 mL) was added dropwise to a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)carbamate]methyl}phenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) dioxane (1 mL). The resulting mixture was stirred at 25°C for 2 hours. The crude product was purified by pre-high performance liquid chromatography to obtain (2S)-3-(4-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridin]-3-yl)carbamate]methyl}phenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (12.7 mg). LCMS (ESI, m / z): [M+H]+=689.4

[0165] 1H NMR(400MHz,D2O)δ8.15(s,2H),8.06(s,1H),7.91(dd,J=9.2,2.5Hz,1H),7.83(s,1H),7.39(d,J=9.1Hz, 1H),7.20–7.06(m,4H),6.70–6.53(m,3H),4.41(s,2H),4.17(d,J=6.1Hz,2H),3.41(dd,J=11.8,6.7Hz,1 H),3.36–3.25(m,1H),3.19–3.07(m,1H),2.94–2.82(m,1H),2.68(s,2H),2.47–2.30(m,2H),2.16(dd,J= 12.3, 6.4Hz, 2H), 2.01 (d, J = 20.0Hz, 1H), 1.91 (d, J = 5.6Hz, 2H), 1.66 (d, J = 9.4Hz, 1H), 1.58–1.45 (m, 2H).

[0166] Example 2

[0167] 1. Synthesis of compound a

[0168] Under nitrogen atmosphere and at 0°C, lithium bis(trimethylsilylaminolithium) (10.3 g, 61.7 mmol) was added dropwise to a mixture of (R)-3-(2-((S)-4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20.0 g, 51.4 mmol) in tetrahydrofuran (200 mL). After stirring for 5 minutes, 1-bromo-3-(bromomethyl)benzene (14.1 g, 56.6 mmol) was added. The resulting mixture was stirred at 25°C for 2 hours. The reaction was quenched with water at 0°C. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography to give (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (19.0 g) as a colorless oil. LCMS (ESI, m / z): [M+H]+=557.1.

[0169] 2. Synthesis of compound b

[0170] Under nitrogen atmosphere, at 0°C, lithium hydroxide (1.2 g, 51.1 mmol) was added to a mixture of (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazoline-3-yl]-3-(3-bromophenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (19.0 g, 34.1 mmol) and hydrogen peroxide (1.7 g, 51.1 mmol) in tetrahydrofuran (200 mL). The resulting mixture was stirred at 25°C for 2 hours. The reaction was quenched at 0°C with saturated sodium sulfite, and the residue was alkalized with sodium hydroxide to pH 12. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layer was acidified with concentrated hydrochloric acid to pH 3. The resulting mixture was concentrated under reduced pressure to give (S)-3-(3-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (18.0 g) as a colorless oil. LCMS (ESI, m / z): [M+H] + =398.1.

[0171] 3. Synthesis of compound c

[0172] Under nitrogen atmosphere and at 25°C, (E)-N,N'-diisopropyltert-butoxymethylimine (19.4 g, 97.1 mmol) was added dropwise to (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propionic acid (12.9 g, 32.3 mmol) in 100 mL of 2-methyltetrahydrofuran. The resulting mixture was stirred at 65°C for 16 hours. The residue was purified by silica gel column chromatography to give (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (11.0 g) as a colorless oil. LCMS (ESI, m / z): [M+H] + =454.1.

[0173] 4. Synthesis of compound d

[0174] Under a carbon monoxide and hydrogen atmosphere at room temperature, bis(adamantane-1-yl)(butyl)phosphine (3.4 g, 9.6 mmol) and palladium acetate (2.1 g, 9.6 mmol) were added in portions to a stirred mixture of (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (11.0 g, 24.2 mmol) and [2-(dimethylamino)ethyl]dimethylamine (11.2 g, 96.8 mmol) in toluene (100 mL). The resulting mixture was stirred at 105 °C for 3 days under a carbon monoxide and hydrogen atmosphere. The residue was purified by reversed-phase flash chromatography to give a white solid (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g). LCMS (ESI, m / z): [M+H] + =404.2.

[0175] 5. Synthesis of compound e

[0176] A mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 7.4 mmol) and hydroxylamine hydrochloride (0.6 g, 8.9 mmol) in ethanol and water was stirred overnight at 90 °C under nitrogen. The resulting mixture was concentrated under reduced pressure to give (R)-3-((S)-1-(tert-butoxy)-3-(3-((E)-(hydroxyimino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g). LCMS (ESI, m / z): [M+H] + =419.2.

[0177] 6. Synthesis of compound f

[0178] Under hydrogen atmosphere at 25°C, Pd / C (100 mg, 0.9 mmol) was added to 25 mL of methanol containing (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(1E)-(hydroxyimino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 5.9 mmol). After the addition was complete, the mixture was stirred for 1 hour, and the resulting mixture was filtered. The filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to obtain (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g). LCMS (ESI, m / z): [M+H] + =405.2.

[0179] 7. Synthesis of compound g

[0180] Under nitrogen atmosphere and at 25°C, 100 mg (0.2 mmol) of tert-butyl pyrrolidine-1-carboxylate (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate and 1 mL of N,N-dimethylformamide (6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid (113 mg, 0.2 mmol) were added in portions to N,N-dimethylformamide (1 mL) under stirring. The residue was purified by reversed-phase flash chromatography to give (R)-3-((S)-1-(tert-butoxy)-3-(3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg). LCMS (ESI, m / z): [M+H] + =845.4

[0181] 8. Synthesis of Compound 2

[0182] Under nitrogen atmosphere and at 25°C, 1,4-dioxane hydrochloride (4.0 M) (1 mL) was added dropwise to a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)carbamate]methyl}phenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) and 1 mL of 1,4-dioxane (4.0 M) (1 mL). The resulting mixture was stirred at 25°C for 2 hours. The crude product was purified by pre-high performance liquid chromatography to obtain (2S)-3-(3-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)carbamoyl]methyl}phenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (53.7 mg).

[0183] LCMS(ESI,m / z):[M+H]+=689.45

[0184] 1H NMR(400MHz,D2O)δ8.31(s,1H),8.02(s,3H),7.85–7.72(m,2H),7.40(s,1H),7.15–7.05(m,4H),6.50(s,2H),4. 60–3.80(m,4H),3.30(s,2H),3.12(s,1H),2.90–2.60(m,3H),2.39(s,2H),2.20–1.80(m,5H),1.80–1.10(m,3H).

[0185] Example 3

[0186] 1. Synthesis of compound a

[0187] Triethylamine (72.2 mL, 519 mmol) was added to a stirred solution of [(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]acetic acid (50.0 g, 218 mmol) in tetrahydrofuran (600 mL) at 0 °C in air. The resulting mixture was stirred at 0 °C for 5 minutes under nitrogen atmosphere. 2,2-Dimethylpropionyl chloride (31.3 g, 259.6 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 5 minutes. The resulting mixture was stirred at 0 °C for another 15 minutes. Lithium chloride (11.0 g, 259.6 mmol) and (4S)-4-benzyl-1,3-oxazoline-2-one (36.8 g, 207.7 mmol) were added to the mixture, and the mixture was stirred at 0 °C for 10 minutes. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with ethyl acetate. The resulting mixture was washed with hydrochloric acid solution. The resulting mixture was washed with 500 mL of brine. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with methanol / water (200 / 400 mL). The resulting mixture was stirred overnight in air at room temperature. The precipitated solid was collected by filtration. The resulting mixture was concentrated under reduced pressure to give (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazoline-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylic acid tert-butyl ester (61.2 g). LCMS (ESI, m / z): [M+H]+ = 389.25.

[0188] 2. Synthesis of compound b

[0189] Under nitrogen atmosphere at 0°C, lithium bis(trimethylsilylaminolithium) (56.6 mL, 56.6 mmol) was added to a stirred solution of (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazoline-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate (20.0 g, 51.5 mmol) in tetrahydrofuran (200 mL). The resulting mixture was stirred at 0°C under nitrogen atmosphere for 30 minutes. 1-Bromo-4-(bromomethyl)benzene (14.2 g, 56.6 mmol) was added to the above mixture at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 18.0 g of (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazoline-3-yl]-3-(4-bromophenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester was obtained. LCMS (ESI, m / z): [M+H]+=557.25.

[0190] 3. Synthesis of compound c

[0191] Under nitrogen atmosphere, tert-butyl pyrrolidine-1-carboxylate (20.0 g, 35.9 mmol) and water (61.2 mL, 53.8 mmol) were stirred, and lithium hydroxide (2.3 g, 53.8 mmol, 30%) was added to tetrahydrofuran (200 mL) under nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was quenched with saturated sodium bisulfite solution at 0 °C, and alkalized to pH 12 with sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain (2S)-3-(4-bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propionic acid (16.3 g), which was a yellow oil. LCMS (ESI, m / z): [M+H]+=398.25.

[0192] 4. Synthesis of compound d

[0193] To a mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propionic acid (2.0 g, 5.0 mmol) and (E)-N,N'-diisopropyltert-butoxymethylamine (2.5 g, 12.6 mmol) under air atmosphere, at room temperature, (E)-(tert-butoxy)-N',N-bis(propyl-2-yl)formamidin (1.0 g, 5.0 mmol) was added to 2-methyltetrahydrofuran (20 mL). The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (8:1) to give (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g). LCMS (ESI, m / z): [M+H]+=454.25.

[0194] 5. Synthesis of compound e

[0195] To a mixture of (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (9.0 g, 19.8 mmol) and [2-(dimethylamino)ethyl]dimethylamine (9.2 g, 79.2 mmol) in toluene (36 mL), bis(adamantane-1-yl)(butyl)phosphine (2.8 g, 7.9 mmol) and palladium acetate (1.8 g, 7.9 mmol) were added at room temperature and in air. The resulting mixture was stirred at 105 °C for 3 days under a carbon monoxide-hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (8:1) to give (R)-3-((S)-1-(tert-butoxy)-3-(4-formylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (7.1 g), a brown oil. LCMS (ESI, m / z): [M+H]+=404.25.

[0196] 6. Synthesis of compound f

[0197] To a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-formylphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate tert-butyl ester (500 mg, 1.2 mmol) and water (1 mL) in 5 mL of ethanol, hydroxylamine hydrochloride (129.2 mg, 1.9 mmol) was added at room temperature and in air. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The final product was (400 mg) colorless solid of (3R)-3-[(2S)-3-[4-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate. LCMS (ESI, m / z): [M+H]+=405.25.

[0198] 7. Synthesis of compound g

[0199] Compound g was obtained by referring to step 6 of Example 2.

[0200] 8. Synthesis of compound h

[0201] To a stirred mixture of (3R)-3-[(2S)-3-[4-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (113.3 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.7 mmol) and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (187.9 mg, 0.5 mmol) were added in portions under air at room temperature. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-liquid chromatography (dichloromethane / methanol 10:1) to give (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)carbamate]methyl}phenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (90 mg) as a colorless oil.

[0202] LCMS (ESI, m / z): [M+H]+=845.45

[0203] 9. Synthesis of Compound 3

[0204] 1 mL of hydrochloric acid in 1,4-dioxane (4.0 M) was added to a stirred mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carbamate]methyl}phenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.1 mmol). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The resulting mixture was then concentrated under reduced pressure. The crude product (80 mg) was purified by liquid chromatography to obtain (2S)-3-(4-{[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)carbamoyl]methyl}phenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (24.9 mg).

[0205] LCMS(ESI,m / z):[M+H]+=345.20

[0206] 1 H NMR(400MHz,D2O)δ8.19–8.14(m,2H),7.90–7.84(m,1H),7.61(d,J=7.2Hz,1H),7.43(d,J=9.2Hz,1H),7 .26–7.14(m,4H),6.92–6.87(m,1H),6.79–6.59(m,3H),4.51–4.41(m,2H),4.26–4.13(m,2H),3.49–3.4 1(m,1H),3.40–3.30(m,1H),3.24–3.13(m,1H),2.95–2.85(m,1H),2.72(d,J=6.4Hz,2H),2.41(d,J=7.8 Hz,2H),2.25–2.13(m,2H),2.11–2.03(m,1H),2.00–1.89(m,2H),1.74–1.64(m,1H),1.61–1.49(m,2H).

[0207] Example 4

[0208] 1. Synthesis of compound a

[0209] To a stirred mixture of (3R)-3-[(2S)-3-[4-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) and 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylic acid (113.3 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.7 mmol) and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (187.9 mg, 0.5 mmol) were added in portions at room temperature and in air. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-liquid chromatography to give (R)-3-((S)-1-(tert-butoxy)-3-(3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg) as a colorless oil. LCMS (ESI, m / z): [M+H]+=845.35.

[0210] 2. Synthesis of Compound 4

[0211] 1 mL of hydrochloric acid in 1,4-dioxane (4.0 M) was added to (R)-3-((S)-1-(tert-butoxy)-3-(3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.1 mmol). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by liquid chromatography to obtain (S)-3-(3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (37.2 mg).

[0212] LCMS(ESI,m / z):[M+H]+=345.30

[0213] 1 H NMR (400MHz, MeOD-d4) δ8.42–8.32(m,1H),8.22–8.17(m,2H),7.98(d,J=2.6Hz,1H),7.74–7.68(m,1H),7. 51–7.45(m,1H),7.32–7.16(m,4H),7.03–6.98(m,1H),6.91–6.52(m,3H),4.59–4.51(m,2H),4.48–4.33(m, 2H),3.43–3.36(m,2H),3.23–3.16(m,1H),3.08–2.96(m,2H),2.85–2.76(m,1H),2.71–2.61(m,1H),2.56–2 .44(m,1H),2.36–2.24(m,2H),2.23–2.14(m,1H),2.09–1.99(m,2H),1.97–1.85(m,1H),1.70–1.57(m,2H).

[0214] Example 5

[0215] 1. Synthesis of compound a

[0216] To a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-formylphenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 1.487 mmol) and ethylenediamine (89.4 mg, 1.5 mmol) in methanol (6 mL), sodium cyanoborohydride (280.3 mg, 4.5 mmol) and acetic acid (89 mg, 1.5 mmol) were added in portions under air at room temperature. The resulting mixture was stirred at room temperature for 2 hours under nitrogen. The reaction was quenched with water at room temperature. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (1 x 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give (3R)-3-[(2S)-3-(4-{[(2-aminoethyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg), as a colorless oil. LCMS (ESI, m / z): [M+H]+=448.35.

[0217] 2. Synthesis of compound b

[0218] A solution of 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (120 mg, 0.3 mmol) and (3R)-3-[(2S)-3-(4-{[(2-aminoethyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (117.2 mg, 0.3 mmol) in N,N-dimethylformamide (2 mL) was mixed with 1-hydroxybenzotriazole (70.7 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81.3 mg, 0.5 mmol). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative plate (dichloromethane / methanol 10:1) to give (3R)-3-[(2S)-1-(tert-butoxy)-3-{4-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)carbamate]ethyl}amino)methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg) as a pale yellow solid. LCMS (ESI, m / z): [M+H]+=888.30.

[0219] 3. Synthesis of Compound 5

[0220] To a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-{4-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridin]-3-yl)carbamate]ethyl}amino)methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) and 1,4-dioxane (0.5 mL), 0.5 mL of hydrochloric acid in 1,4-dioxane (4.0 M) was added at room temperature and under air atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by pre-liquid chromatography to obtain (2S)-3-{4-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)carbamoyl]ethyl}amino)methyl]phenyl}-2-[(3R)-pyrrolidine-3-yl]propionic acid; bis(formic acid) (23.1 mg).

[0221] LCMS(ESI,m / z):[M+H]+=366.80

[0222] 1 H NMR(400MHz,MeOD-d4)δ8.62–8.44(m,2H),8.25(d,J=2.6Hz,1H),8.22–8.15(m,2H),8.03–7.97(m,2H), 7.52–7.46(m,1H),7.41–7.29(m,4H),6.76–6.51(m,3H),4.47–4.34(m,2H),4.15–4.11(m,2H),3.68–3. 59(m,2H),3.53–3.41(m,2H),3.24–3.13(m,3H),3.07–2.94(m,2H),2.77–2.70(m,1H),2.54–2.43(m,2H ),2.34–2.25(m,2H),2.15(d,J=13.1=2Hz,1H),2.08–1.99(m,2H),1.96–1.86(m,1H),1.71–1.59(m,2H).

[0223] Example 6

[0224] 1. Compound a

[0225] Under nitrogen atmosphere at 0°C, acetic acid (7 mg, 0.1 mmol) and sodium cyanoborohydride (116 mg, 1.8 mmol) were added to methanol (5 mL) containing (R)-3-((2S)-3-(3-{[(2-aminoethyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg). The mixture was stirred at 25°C for 2 hours. The residue was purified by reversed-phase flash chromatography to give (3R)-3-[(2S)-3-(3-{[(2-aminoethyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS (ESI, m / z): [M+H]+=448.3.

[0226] 2. Compound b

[0227] Under nitrogen atmosphere and at 25°C, tert-butyl pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (102 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL) were added, along with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.3 mmol) and 1-hydroxybenzotriazole (45 mg, 0.3 mmol). The resulting mixture was stirred at 25°C for 2 hours. The residue was purified by reversed-phase flash chromatography to give (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridin]-3-yl)carbamate]ethyl}amino)methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (120 mg). LCMS (ESI, m / z): [M+H] + =888.4.

[0228] 3. Synthesis of Compound 6

[0229] Under nitrogen atmosphere and at 25°C, 1,4-dioxane hydrochloride (4.0 M) (1 mL) was added to a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)carbamate]ethyl}amino)methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.1 mol) and 1,4-dioxane (4.0 M) (1 mL). The resulting mixture was stirred at 25°C for 2 hours. The crude product was purified by pre-high performance liquid chromatography to obtain (S)-3-(3-((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxamido)ethyl)amino)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (11.6 mg).

[0230] LCMS(ESI,m / z):[M+H] + =732.4

[0231] 1 H NMR(400MHz,D2O)δ8.16(s,2H),8.06(s,1H),7.88(d,J=3.3Hz,2H),7.80–7.60(m,1H),7.44(d,J=9. 0Hz,1H),7.18(s,2H),7.10(s,1H),6.69–6.36(m,3H),4.19(d,J=8.1Hz,2H),3.70(s,2H),3.41(t,J= 6.1Hz,3H),3.34–3.25(m,1H),3.24–3.08(m,1H),2.88(t,J=10.3Hz,1H),2.75(t,J=6.1Hz,2H),2.65 (d,J=4.8Hz,2H),2.36(d,J=6.4Hz,2H),2.19(d,J=13.2Hz,2H),2.10–1.80(m,3H),1.70–1.29(m,3H)

[0232] Example 7

[0233] 1. Synthesis of compound a

[0234] A solution of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxylic acid (120 mg, 0.3 mmol) and (3R)-3-[(2S)-3-(4-{[(2-aminoethyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (117.2 mg, 0.3 mmol) in N,N-dimethylformamide (2 mL) was mixed with 1-hydroxybenzotriazole (70.7 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81.3 mg, 0.5 mmol). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative plate to give (R)-3-((S)-1-(tert-butoxy)-3-(4-(((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H[1,3'-bipyridine]-4-carboxamido)ethyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (100 mg). LCMS (ESI, m / z): [M+H]+=889.35.

[0235] 2. Synthesis of Compound 7

[0236] To a mixture of (R)-3-((S)-1-(tert-butoxy)-3-(4-(((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H[1,3'-bipyridine]-4-carboxamido)ethyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) and 1,4-dioxane (0.5 mL), 0.5 mL of hydrochloric acid in 1,4-dioxane (4.0 M) was added at room temperature and under air atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by pre-liquid chromatography to obtain (S)-3-(4-(((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)ethyl)amino)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (14.7 mg).

[0237] LCMS(ESI,m / z):[M+H]+=244.80

[0238] 1 H NMR(400MHz,MeOD-d4)δ8.23–8.16(m,2H),8.00–7.95(m,1H),7.76–7.71(m,1H),7.52–7.44(m,1H),7 .42–7.32(m,4H),7.03–6.98(m,1H),6.90–6.54(m,3H),4.45–4.32(m,2H),4.16–4.11(m,2H),3.73–3 .62(m,2H),3.51–3.39(m,2H),3.24–3.15(m,3H),3.06–2.95(m,2H),2.78–2.71(m,1H),2.58–2.46(m ,2H),2.32–2.23(m,2H),2.20–2.12(m,1H),2.08–2.01(m,2H),1.98–1.88(m,1H),1.69–1.56(m,2H).

[0239] Example 8

[0240] 1. Synthesis of compound a

[0241] Under nitrogen atmosphere and at 25°C, tert-butyl pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (102 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL) were added, along with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.3 mmol) and 1-hydroxybenzotriazole (45 mg, 0.3 mmol). The resulting mixture was stirred at 25°C for 2 hours. The residue was purified by reversed-phase flash chromatography to give (R)-3-((S)-1-(tert-butoxy)-3-(3-((2-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)ethyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (100 mg). LCMS (ESI, m / z): [M+H] + =888.4.

[0242] 2. Synthesis of Compound 7

[0243] Under nitrogen atmosphere and at 25°C, 1,4-dioxane hydrochloride (4.0 M) (1 mL) was added dropwise to a mixture of (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carbamate]ethyl}amino)methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (80 mg, 0.09 mmol) and 1,4-dioxane (1 mL). The resulting mixture was stirred at 25°C for 2 hours. The crude product was purified by pre-high performance liquid chromatography to obtain (2S)-3-{3-[({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)formamido]ethyl}amino)methyl]phenyl}-2-[(3R)-pyrrolidine-3-yl]propionic acid; formic acid (18.1 mg).

[0244] LCMS(ESI,m / z):[M+H] + =732.45

[0245] 1 H NMR(400MHz,D2O)δ8.37(s,1H),8.17(s,2H),7.89(d,J=2.6Hz,1H),7.65(d,J=7.1Hz,1H),7.70–7.40(m,1H),7.33 (d,J=8.5Hz,1H),7.28–7.18(m,3H),6.93(d,J=1.9Hz,1H),6.81–6.58(m,3H),4.20(s,4H),3.66(t,J=5.9Hz,2H), 3.54(d,J=11.7Hz,1H),3.43–3.30(m,1H),3.26(t,J=5.9Hz,3H),3.03–2.91(m,1H),2.84–2.63(m,2H),2.41(t,J= 5.1Hz,2H),2.29–2.10(m,2H),2.11–2.00(m,1H),1.96(t,J=6.6Hz,2H),1.74–1.62(m,1H),1.56(d,J=11.2Hz,2H).

[0246] Example 9

[0247] 1. Synthesis of compound a

[0248] At room temperature and in air, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (373 mg, 0.9 mmol) and N,N-diisopropylethylamine (253 mg, 1.9 mmol) were added to a dichloromethane solution of 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (300 mg, 0.6 mmol) and ethyl aminoethyl (67 mg, 0.6 mmol) The residue was purified by silica gel column chromatography to give ethyl acetate (300 mg) as a yellow oil, which is 2-[(6′-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3′-bipyridine]-3-yl)methylamino]. LCMS (ESI, m / z): [M+H]+=544.30.

[0249] 2. Synthesis of compound b

[0250] At room temperature and in air, 360 mg (0.6 mmol) of ethyl acetate (3-(6′-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3′-bipyridine]-3-yl)methylamino]acetic acid (3-6-oxo-[1,3′-bipyridine]-3-yl)formamide]acetic acid (180 mg) was added to a tetrahydrofuran (4 mL) solution of ethyl acetate (360 mg, 0.6 mmol) at room temperature and in air. The resulting mixture was stirred at room temperature for another 2 hours. The mixture was then subjected to reduced pressure to give 180 mg (1-(6′-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3′-bipyridine]-3-yl)formamide]acetic acid. LCMS (ESI, m / z): [M+H]+ = 516.20.

[0251] 3. Synthesis of compound c

[0252] At room temperature and in air, N,N,N-dimethylformamide (1 mL) was added to a solution of tert-butyl(3R)-3-[(2S)-3-[4-(aminomethyl)phenyl]-1-(tert-butyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (90 mg, 0.2 mmol) and [(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridin]-3-yl)methylamino]acetic acid (114 mg, 0.222 mmol) and N,N,N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (126 mg, 0.3 mmol) and N,N-diisopropylethylamine (86 mg, 0.6 mmol) at room temperature and in air. The resulting mixture was stirred at room temperature for another 2 hours. The resulting mixture was subjected to reduced pressure to yield tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-[4-(2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)methylamino]acetamido}methyl)phenyl]-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (120 mg) as an orange oil. LCMS (ESI, m / z): [M+H]+=902.30.

[0253] 4. Synthesis of Compound 9

[0254] 100 mg (0.1 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butyl))-3-[4-(2-[(6′-{(1S,3S))-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3′-bipyridine]-3-yl)methylamino]acetamido}methyl)phenyl]-1-oxopropyl-2-yl]pyridine-1-carboxylate was dissolved in 1,4-dioxane hydrochloric acid (4.0 M) (1 mL) under air and at room temperature. The resulting mixture was stirred at room temperature and at air for 2 hours. The resulting mixture was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography to obtain (2S)-3-[4-({2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)methylamino]acetamido}methyl)phenyl]-2-[(3R)pyridin-3-yl]propionic acid (9.1 mg, yield 11.01%).

[0255] LCMS (ESI, m / z): [M+H]+=746.45

[0256] 1 H NMR(400MHz, DMSO-d6)δ8.70(t,J=6.0Hz,1H),8.41(t,J=6.1Hz,1H),8.35–8.28(m,1H),8.24(s,2H),8.00( d,J=2.7Hz,1H),7.92(dd,J=9.6,2.6Hz,1H),7.50–7.43(m,2H),7.28–6.83(m,6H),6.53(dd,J=20.3,9.2Hz ,2H),4.32(q,J=6.9Hz,2H),4.24(d,J=5.9Hz,2H),3.85(d,J=5.7Hz,2H),3.21–3.02(m,4H),2.89–2.80(m, 3H),2.59(d,J=5.3Hz,1H),2.15–2.05(m,3H),1.88–1.76(m,3H),1.66(d,J=10.5Hz,1H),1.52–1.39(m,2H).

[0257] Example 10

[0258] 1. Synthesis of compound a

[0259] At room temperature and in air, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol) were added to a solution of [(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)methylamine]acetic acid (70 mg, 0.1 mmol) and tert-butyl(3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (54 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol). The resulting mixture was stirred at room temperature and in air for 2 hours. The resulting mixture was concentrated under reduced pressure to give (3R)-3-[(2S)-1-(tert-butyl)-3-[3-(2-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)methylamino]acetamido}methyl)phenyl]-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (100 mg) as an orange oil. LCMS (ESI, m / z): [M+H]+=902.30

[0260] 2. Synthesis of Compound 10

[0261] At room temperature and in air, 100 mg (0.1 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-[3-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)methylamino]acetamido}methyl)phenyl]-1-oxopropyl-2-yl]pyridine-1-carboxylate was dissolved in 0.5 mL of 1,4-dioxane, and 0.5 mL of 4.0 M hydrochloric acid was added. The resulting mixture was stirred at room temperature in air for 1 hour. The resulting mixture was then concentrated under reduced pressure. Purified by reversed-phase flash chromatography, (2S)-3-[3-({2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)methylamino]acetamido}methyl)phenyl]-2-[(3R)pyridin-3-yl]propionic acid (14.2 mg).

[0262] LCMS (ESI, m / z): [M+H]+=746.45

[0263] 1H NMR(400MHz, DMSO-d6)δ9.15(s,1H),δ8.82(t,J=5.9Hz,1H),8.44(d,J=6.3Hz,1H),8.35–8.30(m,1H),8.24(s,2H ),8.00(d,J=2.6Hz,1H),7.94(dd,J=9.6,2.6Hz,1H),7.51–7.39(m,2H),7.25–6.81(m,6H),6.53(dd,J=20.6,9.2 Hz,2H),4.32(m,J=6.9Hz,2H),4.25(d,J=6.0Hz,2H),3.87(d,J=5.7Hz,2H),3.15(m,9.6Hz,2H),3.02–2.80(m,3H ),2.52(m,2H),2.47(d,J=7.8Hz,1H),2.26–2.04(m,3H),1.96–1.81(m,3H),1.71–1.62(m,1H),1.59–1.44(m,2H).

[0264] Example 11

[0265] 1. Synthesis of compound a

[0266] At room temperature, N,N-diisopropylethylamine (0.5 mL, 2.6 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (663 mg, 1.7 mmol) were added in portions to a stirred solution of 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (400 mg, 0.9 mmol) and glycine ethyl ester hydrochloride (121 mg, 0.9 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The residue was purified by preparative plate to give ethyl acetate (330 mg) of 2-[6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)formamido], as a green oil. LCMS (ESI, m / z): [M+H]+=544.25.

[0267] 2. Synthesis of compound b

[0268] Ethyl 2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)formamido]ethyl acetate (320 mg, 0.6 mmol) and lithium hydroxide (28 mg, 1.2 mmol) were added to a mixture of ethanol (5 mL) and water (5 mL) and stirred for one hour. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly for the next step. LCMS (ESI, m / z): [M+H]+ = 516.35.

[0269] 3. Synthesis of compound c

[0270] At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.3 mmol) were added in portions to a solution of (6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)formamido]acetic acid (70 mg, 0.14 mmol) and (3R)-3-[(2S)-3-[4-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was stirred in air at room temperature for 1 hour. The reaction solution was purified by reversed-phase flash chromatography to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-[4-({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carbamate]acetamido}methyl)phenyl]-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (50 mg, 40.82% yield) as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=904.20.

[0271] 4. Synthesis of Compound 11

[0272] At room temperature, tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-[4-({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carbamoyl]acetamido}methyl)phenyl]-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (35 mg, 0.04 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (4.0 M) (1.5 mL) and stirred for one hour. The resulting mixture was concentrated under reduced pressure. The crude product (20 mg) was purified by pre-liquid chromatography to obtain (S)-3-(4-((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)acetamido)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (23.4 mg).

[0273] LCMS (ESI, m / z): [M+H]+=746.45

[0274] 1 H NMR (400MHz, DMSO-d6) δ9.05(t,J=5.8Hz,1H),8.47(t,J=6.0Hz,1H),8.24(s,2H),7.95(d,J=2.7Hz,1H),7.72(d,J=7.1Hz,1H),7 .48(d,J=7.2Hz,1H),7.42(dd,J=8.9,2.7Hz,1H),7.28–6.77(m,7H),6.62(dd,J=7.1,1.9Hz,1H),6.54(d,J=8.9Hz,1H),4.38–4. 20(m,4H),3.89(d,J=5.9Hz,2H),3.25(d,J=8.6Hz,2H),3.18(d,J=10.6Hz,2H),2.94(d,J=19.9Hz,2H),2.85(dd,J=13.6,8.9Hz, 1H),2.62(dd,J=13.5,5.6Hz,1H),2.30–2.10(m,1H),2.19-2.04(m,2H),1.97–1.82(m,3H),1.80–1.60(m,1H),1.58–1.44(m,2H).

[0275] Example 12

[0276] 1. Synthesis of compound a

[0277] At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.3 mmol) were added in portions to a solution of [(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)formamido]acetic acid (70 mg, 0.14 mmol) and (R)-3-((S)-3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred in air at room temperature for 1 hour. The residue was purified by reversed-phase flash chromatography to give tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((2-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)acetamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (20 mg, yield 16.32%), as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=904.20

[0278] 2. Synthesis of Compound 12

[0279] (R)-3-((S)-1-(tert-butoxy)-3-(3-((2-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carboxamido)acetamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (20 mg, 0.02 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (4.0 M) (1.5 mL) and stirred for one hour. The resulting mixture was concentrated under reduced pressure. The crude product (20 mg) was purified by high performance liquid chromatography to obtain (2S)-3-[3-({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carbamoyl]acetamido}methyl)phenyl]-2-[(3R)-pyrrolidine-3-yl]propionic acid (3.3 mg, yield 19.96%).

[0280] LCMS (ESI, m / z): [M+H]+=746.40

[0281] 1 H NMR (400MHz, DMSO-d6) δ9.07(t,J=6.0Hz,1H),8.46(t,J=5.9Hz,1H),8.25(d,J=6.4Hz,2H),7.95(d,J=2.7Hz,1H),7.73(d ,J=7.1Hz,1H),7.48(d,J=7.2Hz,1H),7.42(dd,J=8.9,2.7Hz,1H),7.30–7.18(m,1H),7.16–6.78(m,6H),6.63(dd,J=7.1,2 .0Hz,1H),6.54(d,J=9.0Hz,1H),4.41–4.20(m,4H),3.90(d,J=5.8Hz,2H),3.20(d,J=3.2Hz,2H),3.03–2.80(m,4H),2.74– 2.63(m,2H),2.26(q,J=8.1Hz,1H),2.17-2.08(m,2H),1.97–1.84(m,3H),1.66(dd,J=12.6,8.8Hz,1H),1.58–1.45(m,2H).

[0282] Example 13

[0283] 1. Synthesis of compound a

[0284] Triethylamine (0.5 mL, 4.0 mmol) and sodium triacetoxyborohydride (630 mg, 3.0 mmol) were added in portions to a stirred solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-formylphenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 2.0 mmol) and ammonium carbonate (285 mg, 3.0 mmol) in dichloromethane (10 mL) at room temperature. The resulting mixture was stirred in a nitrogen atmosphere at room temperature for two hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The crude product was used directly for the next step. LCMS (ESI, m / z): [M+H] + =790.50.

[0285] 2. Synthesis of compound b

[0286] (3R)-3-[(2S)-1-(tert-butoxy)-3-{4-[(1E)-[({4-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)imino]methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 0.9 mmol) and sodium borohydride (67 mg, 1.78 mmol) were stirred in methanol (5 mL) for one hour at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly for the next step. LCMS (ESI, m / z): [M+H]+=792.50

[0287] 3. Synthesis of compound c

[0288] Under nitrogen protection at room temperature, potassium carbonate (138 mg, 1.0 mmol) and potassium iodide (6 mg, 0.03 mmol) were added in portions to a stirred solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-(4-{[[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (265 mg, 0.3 mmol) and N-(2-bromoethyl)phthalimide (94 mg, 0.4 mmol) in acetonitrile (5 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give 3,3'-((2S,2'S)-((((2-(1,3-dioxoisoindoline-2-yl)ethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (130 mg) as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=965.75.

[0289] 4. Synthesis of compound d

[0290] 3,3'-((2S,2'S)-((((2-(1,3-dioxoisoindoline-2-yl)ethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (125 mg, 0.1 mmol) and hydrazine hydrate (98 mg, 0.3 mmol) were added to an ethanol (5 mL) solution at room temperature. The resulting mixture was stirred at room temperature for two hours. The mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain 3,3'-((2S,2'S)-((((2-aminoethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (90 mg), LCMS (ESI, m / z): [M+H]+=835.50.

[0291] 5. Synthesis of compound e

[0292] At room temperature, N,N-diisopropylethylamine was added in portions to a solution of 3,3'-((2S,2'S)-((((2-aminoethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (50 mg, 0.06 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (33 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL). The residues of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (34 mg, 0.09 mmol) were purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) ester (28 mg, 36.66% yield), LCMS (ESI, m / z): [M+H]+=1275.95.

[0293] 6. Synthesis of Compound 13

[0294] Di-tert-butyl 3,3'-((2S,2'S)-((((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) ester (35 mg, 0.04 mmol) in 1,4-dioxane hydrochloride (4.0 M) (1. Stir in 5 mL for one hour. Concentrate the reaction solution under reduced pressure. The crude product (20 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,((R)-pyrrolidine-3-yl)propionic acid) (23.4 mg).

[0295] LCMS(ESI,m / z):[M+H]+=963.60

[0296] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.37–8.17(m,4H),8.17–7.96(m,2H),7.86(dd,J=9.6,2.6Hz,1H),7.53–7.42(m,2H),7.2 5(d,J=7.8Hz,4H),7.18–7.03(m,4H),7.03–6.84(m,2H),6.54(dd,J=25.0,9.2Hz,2H),4.32(q,J=6.8Hz,2H),3.54(s,4H),3.3 2–3.21(m,6H),3.09(dt,J=11.1,7.9Hz,2H),2.89(dd,J=11.5,9.4Hz,2H),2.76(d,J=7.3Hz,4H),2.69–2.55(m,4H),2.33(q,J =8.4Hz,3H),2.22–2.06(m,2H),2.04-1.93(m,2H),1.93-1.83(m,2H),1.78–1.59(m,2H),1.58–1.44(m,2H),1.33–1.23(m,1H).

[0297] Example 14

[0298] 1. Synthesis of compound a

[0299] At room temperature, (3R)-3-[(2S)-3-(4-{[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (90 mg, 0.1 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoro In a solution of N,N-dimethylformamide (1 mL) containing 59 mg (0.1 mmol) of methoxypyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid, 1-hydroxybenzotriazole (22 mg, 0.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.2 mmol) were added in portions. The reaction mixture was stirred at room temperature for one hour. The residue was purified by vacuum distillation and reversed-phase flash chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-((((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) ester (70 mg), a pale yellow oil. LCMS (ESI, m / z): [M+H]+=1275.75

[0300] 2. Synthesis of Compound 13-2

[0301] Di-tert-butyl-di-tert-butyl 3,3'-((2S,2'S)-((((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) ester (80 mg, 0.06 mmol)) was stirred for one hour in 1,4-dioxane hydrochloric acid (4.0 M) (1.5 mL). The reaction solution was concentrated under reduced pressure. Crude product The compound was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((2-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbamate)ethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (8.2 mg, yield 13.58%).

[0302] LCMS(ESI,m / z):[M+H]+=963.60

[0303] 1H NMR (400MHz, D2O) δ8.37(s,1H),8.16(s,2H),7.89(d,J=2.6Hz,1H),7.63(d,J=7.1Hz,1H),7.46(dd,J=9. 3,2.6Hz,1H),7.32(d,J=7.7Hz,4H),7.21(d,J=7.7Hz,4H),6.81–6.42(m,4H),4.32(s,4H),4.19(t,J=6.6 Hz,2H),3.56–3.26(m,8H),3.26–3.11(m,2H),2.92(t,J=9.2Hz,2H),2.68(d,J=6.2Hz,4H),2.39(d,J=9. 2Hz,4H),2.17(dt,J=9.4,7.1Hz,2H),2.04(s,2H),1.98–1.87(m,2H),1.67(t,J=9.2Hz,2H),1.55(s,2H).

[0304] Example 15

[0305] 1. Synthesis of compound a

[0306] Triethylamine (66 mg, 0.6 mmol) was added to a solution of tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-(4-{{4-[(2S)-3-(tert-butyl))-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenylmethyl)amino]methylphenyl)-1-oxopropyl]pyrrolidine-1-carboxylate (260 mg, 0.3 mmol) in dichloromethane (3 mL). The resulting mixture was stirred at 0°C for 10 minutes in air. (1,3-dioxoisoindol-2-yl)acetyl chloride (146 mg, 0.6 mmol) was added dropwise to the mixture at 0°C in air. The resulting mixture was stirred for another 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. Purified by reversed-phase flash chromatography, tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-(4-{N-({4-[(2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)-2-(1,3-dioxoisoindol-2-yl)acetamido]methyl)-1-oxopropyl]pyrrolidine-1-carboxylate (220 mg) was obtained. LCMS (ESI, m / z): [M+H]+=979.50

[0307] 2. Synthesis of compound b

[0308] Hydrazine hydrate (0.02 mL, 0.4 mmol) was added to a 2 mL solution of tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-(4-{N-({2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenylmethyl)-2-(1,3-dioxoisoindol-2-yl)acetyl]methylphenyl)-1-oxopropyl]pyrrolidine-1-carboxylate (220 mg, 0.2 mmol) in ethanol. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. Purified by reversed-phase flash chromatography, (3R)-3-[(2S)-3-(4-{2-amino-n-({4-[(2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenylmethyl)acetamide]methyl}phenyl)-1-(tert-butyl)-1-oxopropyl]pyrrolidine-1-carboxylic acid ester (107 mg, yield 56.09%) was obtained. LCMS (ESI, m / z): [M+H]+=849.50

[0309] 3. Synthesis of compound c

[0310] At room temperature and in air, tert-butyl(3R)-3-[(2S)-3-(4-{2-amino-n-({2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenylmethyl)acetamide]methyl}phenyl)-1-(tert-butyl)-1-oxopropyl]pyrrolidine-1-carboxylate (50 mg, 0.05 mmol) and 6'-{[(1S,3S)-3-{[ N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (33 mg, 0.08 mmol) and N,N-diisopropylethylamine (22 mg, 0.17 mmol) were added to a solution of 5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (26 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at room temperature in air for 2 hours. The resulting mixture was concentrated under reduced pressure to give tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-(4-[N-(4-[(2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrronyl-3-yl]-3-oxopropyl]phenyl}methyl)-2-[(6′-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]aminocyclopentyl]amino}-6-oxo-[1,3′-bipyridine]-3-yl)formyl]methyl]phenyl)-1-oxopropyl]pyrronyl-1-carboxylate (70 mg) as an orange oil. LCMS (ESI, m / z): [M+H]+=1289.50

[0311] 4. Synthesis of Compound 14

[0312] 60 mg (0.04 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-(4-[N-[(2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)-2-[(6′-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]aminocyclopentyl]amino}-6-oxo-[1,3′-bipyridine]-3-yl]methyl]phenyl)-1-oxopropyl]pyrrolidine-1-carboxylate (1 mL) was dissolved in 1,4-dioxane hydrochloric acid (4.0 M). The resulting mixture was stirred at room temperature in air for 2 hours. The resulting mixture was concentrated under reduced pressure. Purified by reversed-phase flash chromatography, (2S)-3-(4-{(N-{4-[(2S)-2-carboxy-2-[(3R)-pyridin-3-yl]ethyl]phenyl}methyl)-2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridin-3-yl)methylamine]acetamido]methyl}phenyl)-2-[(3R)-pyridin-3-yl]propionic acid (16.4 mg).

[0313] LCMS (ESI, m / z): [M+H]+=977.60

[0314] 1 H NMR(400MHz,D2O)δ8.29(s,1H),8.02(s,2H),7.99–7.94(m,1H),7.84–7.71(m,2H),7.39( d,J=9.2Hz,1H),7.12–6.89(m,8H),6.75–6.31(m,3H),4.31(s,4H),4.12–3.93(m,4H),3.3 9(s,2H),3.30(q,J=6.1,3.1Hz,2H),3.20–3.05(m,2H),2.86(t,J=10.4Hz,2H),2.64(d,J= 17.2Hz,4H),2.55–2.30(m,4H),2.03(s,4H),1.80(s,2H),1.80–1.55(m,2H),1.43(s,2H).

[0315] Example 16

[0316] 1. Synthesis of compound a

[0317] Triethylamine (102 mg, 1.0 mmol) was added to a stirred solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 0.5 mmol) and (1,3-dioxoisoindol-2-yl)acetyl chloride (135 mg, 0.6 mmol) in dichloromethane (5 mL) under room temperature protection. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain di-tert-butyl 3,3'-((2S,2'S)-((((2-(1,3-dioxoisoindoline-2-yl)acetyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid)di-tert-butyl ester (260 mg) as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=1074.80.

[0318] 2. Synthesis of compound b

[0319] Di-tert-butyl 3,3'-((2S,2'S)-((((2-(1,3-dioxoisoindoline-2-yl)acetyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (260 mg, 0.3 mmol) and hydrazine hydrate (33 mg, 0.5 mmol, 80%) were added to an ethanol (5 mL) solution at room temperature. The resulting mixture was stirred at room temperature for two hours. The mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-(((glycylazinediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (130 mg). LCMS (ESI, m / z): [M+H]+=849.60

[0320] 3. Synthesis of compound c

[0321] At room temperature, di-tert-butyl 3,3'-((2S,2'S)-(((glycylazinediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (130 mg, 0.1 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidine- In a solution of 2-[2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (36 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (18 mg, 0.1 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (40 mg, 0.1 mmol) were added in portions. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was then distilled under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]5-carbonyl)glycyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) ester (55 mg, 60.36% yield). LCMS (ESI, m / z): [M+H]+=1289.75

[0322] 4. Synthesis of Compound 14-1

[0323] Di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]5-carbonyl)glycyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) ester (80 mg, 0.1 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (70 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonyl)glycyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (29.4 mg).

[0324] LCMS(ESI,m / z):[M+H]+=977.55

[0325] 1 H NMR(400MHz,D2O)δ8.01–7.88(m,3H),7.87–7.65(m,2H),7.18–6.22(m,12H),4.60–3.60(m,8H),3.40–3.10(m,4H),3.10–2. 98(m,2H),2.97–2.55(m,4H),2.55–2.42(m,2H),2.41–2.25(m,4H),2.20–1.80(m,4H),1.80–1.40(m,4H),1.40–1.01(m,2H)

[0326] Example 17

[0327] 1. Synthesis of compound a

[0328] At room temperature and in air, tert-butyl(3R)-3-[(2S)-3-(4-{2-amino-n-({2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenylmethyl)acetamide]methyl}phenyl)-1-(tert-butyl)-1-oxopropyl]pyrrolidine-1-carboxylate (40 mg, 0.04 mmol) and 6'-{[(1S,3S)-3-{[5 N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (26 mg, 0.07 mmol) and N,N-diisopropylethylamine (18 mg, 0.14 mmol) were added to a solution of N,N-dimethylformamide (1 mL) containing 21 mg (21 mg, 0.04 mmol) of 2-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid. The resulting mixture was stirred at room temperature in air for 2 hours. The resulting mixture was concentrated under reduced pressure to give (3R)-3-[(2S)-1-(tert-butyl)-3-(4-{N-({2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)-2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)formamide]acetamido]methyl]phenyl-1-oxopropyl]pyrrolidine-1-carboxylate (60 mg) as an orange oil. LCMS (ESI, m / z): [M+H]+=1289.50

[0329] 2. Synthesis of Compound 14-2

[0330] (3R)-3-[(2S)-1-(tert-butyl)-3-(4-{N-({2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)-2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)carboxamide]acetamido]methyl]phenyl-1-oxopropyl]pyrrolidine-1-carboxylate (55 mg, 0.04 mmol) was dissolved in 1,4-dioxane hydrochloric acid (4.0 M) (1 mL). The resulting mixture was stirred at room temperature in air for 2 hours. The resulting mixture was concentrated under reduced pressure. Purified by reversed-phase flash chromatography, (2S)-3-(4-{(N-{4-[(2S)-2-carboxy-2-[(3R)-pyridin-3-yl]ethyl]phenyl}methyl)-2-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methylamine]acetamido]methyl}phenyl)-2-[(3R)-pyridin-3-yl]propionic acid (9.0 mg).

[0331] LCMS (ESI, m / z): [M+H]+=977.45

[0332] 1 H NMR(400MHz,MeOD-d4)δ8.57(d,J=1.6Hz,2H),8.16(d,J=2.4Hz,1H),8.07–7.75(m,2H),7.31(d,J=7.9Hz, 2H),7.27–7.19(m,7H),7.08–6.65(m,3H),4.60(d,J=7.4Hz,5H),4.43(t,J=6.1Hz,1H),4.35(s,2H),3.57– 3.48(m,2H),3.43–3.36(m,2H),3.30–3.22(m,2H),3.13–3.02(m,2H),3.01–2.87(m,4H),2.79–2.70(m,2H ),2.58(q,J=10.8,7.8Hz,2H),2.51–2.39(m,2H),2.36–2.27(m,2H),2.22–2.14(m,2H),1.88–1.77(m,4H).

[0333] Example 18

[0334] 1. Synthesis of compound a

[0335] At room temperature, di-tert-butyl 3,3'-((2S,2'S)-(((glycylazine)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (80 mg, 0.1 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidine-2 [-yl]amino]cyclopentyl]amino]-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (50 mg, 0.1 mmol) was added in portions to a solution of N,N-dimethylformamide (1 mL) containing 24 mg, 0.2 mmol, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (54 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was then distilled under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)glycyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (50 mg). LCMS (ESI, m / z): [M+H]+=1289.85

[0336] 2. Synthesis of Compound 14-3

[0337] Di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)glycyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (80 mg, 0.06 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (75 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,2-((R)-pyrrolidine-3-yl)propionic acid) (19.5 mg).

[0338] LCMS(ESI,m / z):[M+H]+=977.60

[0339] 1H NMR(400MHz,D2O)δ8.30–7.82(m,2H),7.82–6.02(m,15H),4.72–3.74(m,7H),3.60–3.10(m,4H),3.10–3. 00(m,2H),2.98–2.64(m,6H),2.40–2.22(m,5H),2.20–1.80(m,4H),1.80–1.40(m,4H),1.40–1.00(m,2H).

[0340] Example 19

[0341] 1. Synthesis of compound a

[0342] At room temperature, 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (80 mg, 0.1 mmol) and 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (58 mg, 0.2 mmol) and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added in portions to a solution of N,N-dimethylformamide (2 mL) containing 2-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid (55 mg, 0.1 mmol). The reaction solution was stirred at room temperature for one hour. The residue was purified by vacuum distillation and reversed-phase flash chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2-hydro-[1,3'-bipyridine]-5-carbonyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg), a pale yellow oil. LCMS (ESI, m / z): [M+H]+=1233.00

[0343] 2. Synthesis of Compound 29

[0344] Di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2-hydro-[1,3'-bipyridine]-5-carbonyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 0.04 mmol) was stirred for one hour in 2.0 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (70 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (18.2 mg).

[0345] LCMS(ESI,m / z):[M+H]+=920.55

[0346] 1 H NMR(400MHz,D2O)δ8.10(s,2H),7.67–7.56(m,2H),7.44(d,J=2.4Hz,1H),7.23–7.01 (m,7H),6.93(s,2H),6.79–6.39(m,3H),4.72–4.43(m,4H),4.15–4.05(m,2H),3.44-3 .43–3.33(m,4H),3.22–3.10(m,2H),2.86–2.80(m,2H),2.80–2.60(m,4H),2.40–2.3 0(m,4H),2.19–1.94(m,4H),1.91–1.76(m,2H),1.75–1.58(m,2H),1.50–1.30(m,2H).

[0347] Example 20

[0348] 1. Synthesis of compound a

[0349] At room temperature, 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (50 mg, 0.06 mmol) and 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (36 mg, 0.1 mmol) and N,N-diisopropylethylamine (16 mg, 0.1 mmol) were added in portions to a solution of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (36 mg, 0.1 mmol) and N,N-diisopropylethylamine (16 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for one hour. The residue was purified by vacuum distillation and reversed-phase flash chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H[1,3'-bipyridine]-5-carbonyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (50 mg), a pale yellow oil. LCMS (ESI, m / z): [M+H]+=1232.80

[0350] 2. Synthesis of Compound 29-1

[0351] Di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H[1,3'-bipyridine]-5-carbonyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (50 mg, 0.04 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (40 mg) was purified by high performance liquid chromatography to obtain (2R,2'R)-3,3'-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(2-((S)-pyrrolidine-3-yl)propionic acid) (18.8 mg).

[0352] LCMS(ESI,m / z):[M+H]+=920.60

[0353] 1 H NMR(400MHz,D2O)δ8.11(s,2H),7.66(dd,J=9.5,2.4Hz,1H),7.58(d,J=2.6Hz,1H),7.45(d,J=2.4Hz,1H ),7.29–6.95(m,7H),6.81(d,J=31.1Hz,2H),6.65–6.37(m,3H),4.64(s,2H),4.52(s,2H),4.24-4.01(m, 2H),3.41–3.24(m,4H),3.20–3.06(m,2H),2.82(t,J=10.1Hz,2H),2.76-2.47(m,4H),2.34(s,4H),2.13 (dd,J=11.7,5.9Hz,2H),2.02(s,2H),1.93–1.77(m,J=6.5Hz,2H),1.74–1.58(m,2H),1.57–1.38(m,2H).

[0354] Example 21

[0355] 1. Synthesis of compound a

[0356] At room temperature, 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (50 mg, 0.06 mmol) and 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (36 mg, 0.1 mmol) and N,N-diisopropylethylamine (16 mg, 0.1 mmol) were added in portions to a solution of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (36 mg, 0.1 mmol) and N,N-diisopropylethylamine (16 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for one hour. The residue was purified by vacuum distillation and reversed-phase flash chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (30 mg), a pale yellow oil. LCMS (ESI, m / z): [M+H]+=1232.75

[0357] 2. Synthesis of compound 29-2

[0358] Di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (30 mg, 0.02 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (14.8 mg).

[0359] LCMS(ESI,m / z):[M+H]+=920.60

[0360] 1 H NMR(400MHz,D2O)δ8.43(s,1H),8.06(s,2H),7.77(s,1H),7.42(s,2H),7.14(d,J=7.6Hz,2H) ,7.08(d,J=7.4Hz,3H),6.92(d,J=7.6Hz,2H),6.74–6.34(m,4H),4.49(s,2H),4.31(s,2H),4. 10–4.00(m,2H),3.44–3.32(m,4H),3.20–3.00(m,2H),3.00–2.80(m,2H),2.80–2.60(m,4H),2 .50–2.30(m,4H),2.19–1.95(m,4H),1.90–1.80(m,2H),1.80–1.60(m,2H),1.60–1.20(m,2H).

[0361] Example 22

[0362] 1. Synthesis of compound a

[0363] At room temperature, di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (100 mg, 0.1 mmol) and 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentanyl ester were synthesized. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (72 mg, 0.2 mmol) and N,N-diisopropylethylamine (32 mg, 0.2 mmol) were added in portions to a solution of N,N-dimethylformamide (2 mL) containing (68 mg, 0.1 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. The reaction mixture was stirred at room temperature for one hour. The residue was purified by vacuum distillation and reversed-phase flash chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2-hydro-[1,3'-bipyridine]-4-carbonyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg). LCMS (ESI, m / z): [M+H]+=1232.75

[0364] 2. Synthesis of compound 29-3

[0365] Di-tert-butyl 3,3'-((2S,2'S)-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2-hydro-[1,3'-bipyridine]-4-carbonyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 0.04 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (65 mg) was purified by high performance liquid chromatography to obtain (2R,2'R)-3,3'-((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(2-((S)-pyrrolidine-3-yl)propionic acid) (24.9 mg).

[0366] LCMS(ESI,m / z):[M+H]+=920.60

[0367] 1 H NMR(400MHz,D2O)δ7.93(s,2H),7.69(s,1H),7.32(s,1H),7.22–6.94(m,7H),6.84–6.72(d,m,2H),6.60–6.53(m,1H),6.46–6.22(m,3H),4 .70–4.11(m,4H),3.97(s,2H),3.29(s,4H),3.12(s,2H),2.82–2.48( m,6H),2.51–2.34(m,4H),2.0–1.93(m,4H),1.67(s,4H),1.30(s,2H).

[0368] Example 23

[0369] 1. Synthesis of compound a

[0370] Di-tert-butyl 3,3'-((2S,2'S)-(((glycylazinediyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (125 mg, 0.1 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)] N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (84 mg, 0.2 mmol) and N,N-diisopropylethylamine (56 mg, 0.4 mmol) were added to a solution of N,N-dimethylformamide (2 mL) containing 65 mg of pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid. The resulting mixture was stirred at room temperature in air for 2 hours. The resulting mixture was concentrated under reduced pressure to give di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H--[1,3'-bipyridine]-4-carbonyl)glycyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (130 mg), LCMS (ESI, m / z): [M+H]+=1289.50.

[0371] 2. Synthesis of Compound 14-2

[0372] Di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H--[1,3'-bipyridine]-4-carbonyl)glycyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (125 mg, 0.1 mmol) was dissolved in 1,4-dioxane hydrochloric acid (4.0 M) (2 mL) at room temperature and air. The resulting mixture was stirred at room temperature and air for 2 hours. The resulting mixture was concentrated under reduced pressure. Purified by reversed-phase flash chromatography, (2S,2'S)-3,3'-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)glycyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid (35.8 mg) was obtained.

[0373] LCMS(ESI,m / z):[M+H]-=975.50

[0374] 1 H NMR (400MHz, Methanol-d4) δ8.60(s,2H),8.17(d,J=2.2Hz,1H),8.11(s,1H),8.04(d,J=9.5Hz,1H),7.79(d,J=7.0Hz, 1H),7.31(d,J=7.8Hz,2H),7.24(dt,J=8.0,3.1Hz,5H),7.20(d,J=7.9Hz,2H),7.11–6.71(m,3H),4.59(s,5H),4.43(q, J=6.2Hz,1H),4.35(s,2H),3.58–3.47(m,2H),3.46–3.37(m,2H),3.27(td,J=10.8,8.4Hz,2H),3.08(t,J=10.7Hz,2H) ,3.02–2.85(m,4H),2.84–2.72(m,2H),2.57(d,J=9.7Hz,2H),2.52–2.27(m,4H),2.26–2.16(m,2H),1.93–1.78(m,4H).

[0375] Example 24

[0376] 1. Synthesis of compound a

[0377] Under nitrogen protection at room temperature, sodium borohydride acetate (80 mg, 0.4 mmol) and acetic acid (2 mg, 0.03 mmol) were added to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azadimethyl)bis(1,4-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(1-pyrrolidinyl carboxylate) (200 mg, 0.3 mmol) and chloroacetaldehyde (30 mg, 0.4 mmol) in dichloromethane (5 mL). The resulting mixture was stirred under nitrogen at room temperature for three hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroethyl)azonide)bis(methylene))bis(4,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate (160 mg), LCMS (ESI, m / z): [M+H]+=854.55.

[0378] 2. Synthesis of compound b

[0379] At room temperature, sodium hydroxide (0.1 mL, 0.3 mmol, 5 mol / L) and tetrabutylammonium iodide (4 mg) were added to a mixed solution of di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroethyl)azonidyl)bis(methylene))bis(4,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate (100 mg, 0.1 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-2H-[1,3'-bipyridine]-2-one (42 mg, 0.1 mmol) in toluene (1 mL) and 1,4-dioxane (2 mL). 0.01 mmol). The reaction mixture was stirred at 60 °C for 24 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl3,3'-((2S,2'S)-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)ethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (50 mg), as a yellow oil. LCMS (ESI, m / z): [M+H]+=1262.75

[0380] 3. Synthesis of compound 31-2

[0381] Di-tert-butyl 3,3'-((2S,2'S)-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)ethyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (50 mg, 0.04 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (60 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)ethyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (8.6 mg).

[0382] LCMS(ESI,m / z):[M+H]+=950.65

[0383] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.46(s,2H),9.40–9.21(m,2H),8.26(s,2H),8.09(s,1H),7.90(d,J=10.2H z,1H),7.68(d,J=7.1Hz,1H),7.58(d,J=7.7Hz,5H),7.31(d,J=7.9Hz,4H),7.26–6.84(m,2H),6.45(s,1H),6.35–6 .25(m,1H),4.48–4.25(m,8H),3.82(t,J=5.4Hz,2H),3.41–3.29(m,2H),3.28–3.15(m,4H),3.14–3.03(m,2H),3.0 1–2.75(m,6H),2.78–2.65(m,2H),2.38(q,J=8.5Hz,2H),2.31–2.04(m,3H),2.03–1.93(m,3H),1.71–1.54(m,4H).

[0384] Example 25

[0385] 1. Synthesis of compound a

[0386] Under nitrogen protection at room temperature, sodium borohydride acetate (96 mg, 0.4 mmol) and acetic acid (2 mg, 0.03 mmol) were added to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (250 mg, 0.3 mmol) and chloroacetaldehyde (35 mg, 0.4 mmol) in dichloromethane (5 mL). The resulting mixture was stirred under nitrogen at room temperature for three hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroethyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (205 mg), LCMS (ESI, m / z): [M+H]+=854.55.

[0387] 2. Synthesis of compound b

[0388] At room temperature, di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroethyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (150 mg, 0.15 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy) Sodium hydroxide (0.2 mL, 0.7 mmol, 4.3 eq., 5 mol / L) and tetrabutylammonium iodide (6 mg, 0.02 mmol) were added to a mixed solution of toluene (1 mL) and 1,4-dioxane (2 mL) containing 63 mg (0.15 mmol) of pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-2H-[1,3'-bipyridine]-2-one (2 H-H ... The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((2-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)ethyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg). LCMS (ESI, m / z): [M+H]+=1262.75

[0389] 3. Synthesis of compound 31-3

[0390] Di-tert-butyl 3,3'-((2S,2'S)-((((2-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)ethyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 0.05 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (60 mg) was purified by high performance liquid chromatography to obtain (2R,2'R)-3,3'-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine])-(4-yl)methoxy)ethyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(2-((S)-pyrrolidine-3-yl)propionic acid) (9.8 mg, yield 25.53%).

[0391] LCMS(ESI,m / z):[M+H]+=950.65

[0392] 1 H NMR (400MHz, DMSO-d6) δ9.66–9.45(m,1H),8.28(s,2H),8.15(s,2H),7.97(d,J=9.1Hz,1H),7.68(d,J=7.1Hz ,1H),7.61–7.46(m,4H),7.43–7.27(m,4H),7.25–6.87(m,2H),6.50(s,1H),6.38–6.25(m,1H),4.49–4.27(m, 9H),3.89(d,J=5.0Hz,2H),3.42–3.31(m,2H),3.30–3.16(m,4H),3.16–3.06(m,2H),2.99–2.85(m,4H),2.84 –2.67(m,4H),2.43–2.35(m,2H),2.35–2.23(m,2H),2.20–2.07(m,2H),2.04–1.92(m,3H),1.72–1.51(m,4H).

[0393] Example 26

[0394] 1. Synthesis of compound a

[0395] Under room temperature protection, chloroacetyl chloride (43 mg, 0.4 mmol) was added to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (200 mg, 0.3 mmol) and triethylamine (0.2 mL, 0.3 mmol) in dichloromethane (5 mL). The resulting mixture was stirred overnight under nitrogen atmosphere at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroacetyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (140 mg, 63.84% yield), LCMS (ESI, m / z): [M+H]+=868.50.

[0396] 2. Synthesis of compound b

[0397] Cesium carbonate (98 mg, 0.3 mmol) was added to a solution of di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroacetyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (130 mg, 0.15 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-[1,3'-bipyridine]-2-one (63 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl3,3'-((2S,2'S)-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2-hydro-[1,3'-bipyridine]-4-yl)methoxy)acetyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (80 mg, 41.87% yield), as a yellow oil, LCMS (ESI, m / z): [M+H]+=1276.80

[0398] 3. Synthesis of compound 32-2

[0399] Di-tert-butyl 3,3'-((2S,2'S)-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2-hydro-[1,3'-bipyridine]-4-yl)methoxy)acetyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (80 mg, 0.1 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (70 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((2-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)acetyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (5.8 mg, yield 9.60%).

[0400] LCMS(ESI,m / z):[M+H]+=962.65

[0401] 1 H NMR(400MHz,D2O)δ8.11(s,2H),7.75(s,1H),7.31(t,J=8.2Hz,2H),7.20–7.01(m,6H),6.97(d, J=7.8Hz,2H),6.79–6.51(m,2H),6.46(s,1H),6.41–6.31(m,1H),4.45(d,J=11.1Hz,4H),4.30( d,J=9.9Hz,4H),4.14(s,2H),3.41–3.30(m,4H),3.14(d,J=10.5Hz,2H),2.83(q,J=9.4Hz,2H), 2.75-2.50(m,4H),2.39–2.30(m,4H),2.15–2.05(m,4H),1.88(s,2H),1.65(s,2H),1.49(s,2H).

[0402] Example 27

[0403] 1. Synthesis of compound a

[0404] Under room temperature protection, chloroacetyl chloride (43 mg, 0.4 mmol) was added to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (200 mg, 0.3 mmol) and triethylamine (0.2 mL, 0.3 mmol) in dichloromethane (5 mL). The resulting mixture was stirred overnight under nitrogen atmosphere at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroacetyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (132 mg, 61.59% yield) as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=868.50.

[0405] 2. Synthesis of compound b

[0406] Cesium carbonate (98 mg, 0.3 mmol) was added to a solution of di-tert-butyl 3,3'-((2S,2'S)-((((2-chloroacetyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (130 mg, 0.15 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-[1,3'-bipyridine]-2-one (63 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)acetyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (95 mg, 49.69% yield), as a yellow oil. LCMS (ESI, m / z): [M+H]+=1276.80.

[0407] 3. Synthesis of compound c

[0408] Di-tert-butyl 3,3'-((2S,2'S)-((((2-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)acetyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (80 mg, 0.1 mmol) was stirred for one hour in 1.5 mL of 1,4-dioxane hydrochloric acid (4.0 M). The reaction solution was concentrated under reduced pressure. The crude product (70 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((2-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)acetyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (25.2 mg, yield 43.90%).

[0409] LCMS(ESI,m / z):[M+H]+=962.65

[0410] 1 H NMR(400MHz, DMSO-d6)δ9.46–9.43(m,2H),8.27(s,2H),8.10(s,1H),8.02–7.89(m,1H),7.65(d,J= 7.1Hz,1H),7.39–7.10(m,5H),7.10–6.82(m,5H),6.45(s,1H),6.38–6.25(m,1H),4.58–4.29(m,10H ),3.34(q,J=6.2Hz,3H),3.27–3.19(m,2H),3.18–3.05(m,3H),2.93(q,J=9.5Hz,2H),2.86–2.75(m, 4H),2.75–2.62(m,2H),2.44–2.23(m,3H),2.22–2.05(m,2H),2.04–1.90(m,3H),1.72–1.54(m,4H).

[0411] Example 28

[0412] 1. Synthesis of compound a

[0413] Under room temperature protection, fractionally added sodium triacetoxyborohydride (120 mg, 0.6 mmol) and acetic acid (2 mg, 0.04 mmol) to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (300 mg, 0.4 mmol) and 3-chloropropanal (53 mg, 0.6 mmol) in dichloromethane (5 mL). The resulting mixture was stirred for three hours under nitrogen atmosphere at room temperature. The reaction solution was quenched with water at room temperature. The mixture was extracted with dichloromethane (2 x 20 mL), the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((3-chloropropyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (150 mg) as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=868.55.

[0414] 2. Synthesis of compound b

[0415] At room temperature, under nitrogen protection, sodium hydroxide (200 mg, 0.2 mmol) and tetrabutylammonium iodide (87 mg, 0.2 mmol) were added in portions to a tetrahydrofuran (5 mL) solution of di-tert-butyl 3,3'-((2S,2'S)-((((3-chloropropyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (200 mg, 0.2 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-[1,3'-bipyridine]-2-one (81 mg, 0.2 mmol) with 0.7 mmol and 0.2 mmol respectively. The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (50 mg), which is a yellow oil.

[0416] LCMS(ESI,m / z):[M+H] + =1276.80

[0417] 3. Synthesis of compound 33-2

[0418] Di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (50 mg, 0.005 mmol, 16%) was stirred for one hour in 1,4-dioxane hydrochloric acid (4.0 M) (1.5 mL). The reaction solution was concentrated under reduced pressure. The crude product (60 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid (0.5 mg).

[0419] LCMS(ESI,m / z):[M+H]-=962.55

[0420] 1 H NMR(400MHz,D2O)δ8.12(s,2H),7.79(s,1H),7.34(s,2H),7.13(d,J=7.9 Hz,8H),6.81–6.22(m,4H),4.30–4.15(m,4H),3.47(s,6H),3.29(s,4H),3 .12(d,J=10.1Hz,2H),2.85–2.70(m,4H),2.60(s,2H),2.37(s,6H),2.14 (s,2H),2.02(s,2H),1.91(s,2H),1.73(s,2H),1.64(s,2H),1.50(s,2H).

[0421] Example 29

[0422] 1. Synthesis of compound a

[0423] Under room temperature protection, 3-bromopropionyl chloride (78 mg, 0.5 mmol) was added to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (300 mg, 0.4 mmol) and potassium carbonate (104 mg, 0.8 mmol) in acetonitrile (5 mL). The resulting mixture was stirred under nitrogen atmosphere at room temperature for two hours. The mixture was filtered, and the filter cake was washed with MeCN (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain di-tert-butyl 3,3'-((2S,2'S)-((((3-bromopropionyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (230 mg) as a pale yellow oil.

[0424] LCMS(ESI,m / z):[M+H]+=926.40

[0425] 2. Synthesis of compound b

[0426] At room temperature, under nitrogen protection, sodium hydroxide (200 mg, 0.2 mmol) and tetrabutylammonium iodide (87 mg, 0.2 mmol) were added in portions to a tetrahydrofuran (5 mL) solution of di-tert-butyl 3,3'-((2S,2'S)-((((3-bromopropionyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (200 mg, 0.2 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-[1,3'-bipyridine]-2-one (81 mg, 0.2 mmol) iodide (5 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl3,3'-((2S,2'S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propionyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg). LCMS (ESI, m / z): [M+H] + =1291.00

[0427] 3. Synthesis of compound 34-2

[0428] Di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propionyl)azodiyl)bis(methylene))bis(4,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.01 mmol, 15%) was stirred for one hour in 1,4-dioxane hydrochloric acid (4.0 M) (1.5 mL). The reaction solution was concentrated under reduced pressure. The crude product (60 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propionyl)azodimethyl)bis(methylene))bis(4,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid (3.8 mg).

[0429] LCMS(ESI,m / z):[M+H]-=976.50

[0430] 1 H NMR(400MHz,D2O)δ8.17(s,2H),7.82(d,J=2.6Hz,1H),7.42–7.35(m,2H),7.13(d,J=8.0Hz,2H),7.06( d,J=6.4Hz,6H),6.81–6.38(m,4H),4.55–4.41(m,4H),4.40(s,2H),4.25–4.15(m,2H),3.84(t,J=5.7Hz ,2H),3.42–3.26(m,4H),3.21–3.09(m,2H),2.88–2.61(m,8H),2.37(h,J=9.2Hz,4H),2.25–2.13(m,2H ),2.08–1.98(m,2H),1.94(p,J=6.8Hz,2H),1.65(dt,J=12.9,9.1Hz,2H),1.54(dt,J=11.4,5.9Hz,2H).

[0431] Example 30

[0432] 1. Synthesis of compound a

[0433] Under room temperature protection, 3-bromopropionyl chloride (78 mg, 0.5 mmol) was added to a stirred solution of di-tert-butyl 3,3'-((2S,2'S)-((azodimethylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (300 mg, 0.4 mmol) and potassium carbonate (104 mg, 0.8 mmol) in acetonitrile (5 mL). The resulting mixture was stirred under nitrogen atmosphere at room temperature for two hours. The mixture was filtered, and the filter cake was washed with MeCN (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl 3,3'-((2S,2'S)-((((3-bromopropionyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (220 mg) as a pale yellow oil. LCMS (ESI, m / z): [M+H]+=926.40

[0434] 2. Synthesis of compound b

[0435] At room temperature, under nitrogen protection, sodium hydroxide (200 mg, 0.2 mmol) and tetrabutylammonium iodide (87 mg, 0.2 mmol) were added in portions to a tetrahydrofuran (5 mL) solution of di-tert-butyl 3,3'-((2S,2'S)-((((3-bromopropionyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert-butyl ester (200 mg, 0.2 mmol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(hydroxymethyl)-[1,3'-bipyridine]-2-one (81 mg, 0.2 mmol) iodide (5 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give di-tert-butyl3,3'-((2S,2'S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propionyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg). LCMS (ESI, m / z): [M+H] + =1291.00

[0436] 3. Synthesis of compound 34-3

[0437] Di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propionyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.01 mmol, 15%) was stirred for one hour in 1,4-dioxane hydrochloric acid (4.0 M) (1.5 mL). The reaction solution was concentrated under reduced pressure. The crude product (60 mg) was purified by high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)propionyl)azodimethyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid (3.7 mg).

[0438] LCMS(ESI,m / z):[M+H]-=976.50

[0439] 1 H NMR(400MHz,D2O)δ8.18(s,2H),7.86(d,J=2.7Hz,1H),7.46–7.36(m,2H),7.28–7.12(m,2H),7.11–7 .03(m,2H),7.08–6.95(m,4H),6.82–6.33(m,4H),4.66–4.50(m,4H),4.40(s,2H),4.22(t,J=6.5Hz,2 H),3.85(t,J=5.8Hz,2H),3.43–3.26(m,4H),3.15(t,J=10.4Hz,2H),2.92–2.74(m,4H),2.72–2.53(m ,4H),2.43–2.26(m,4H),2.25–2.15(m,2H),2.09–1.90(m,4H),1.72–1.60(m,2H),1.61–1.51(m,2H).

[0440] Example 31

[0441] Compound 14-3 (8 mg) was purified by pre-high performance liquid chromatography to give di-tert-butyl 3,3'-((2S,2'S)-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-carbonyl)glycyl)azodiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate)pentahydrochloride (1.3 mg, purity 96.5%).

[0442] LCMS(ESI,m / z):[M+H]+=977.45

[0443] 1 H NMR (400MHz, DMSO-d6) δ9.54–9.22(m,5H),9.09(t,J=5.8Hz,1H),8.27(s,2H),8.17(d,J=2.4Hz,1H),7.97( dd,J=9.4,2.4Hz,1H),7.81(d,J=7.1Hz,1H),7.58(s,1H),7.32(t,J=7.8Hz,1H),7.30–6.83(m,10H),6.71( dd,J=7.1,1.9Hz,1H),4.52(d,J=6.1Hz,2H),4.49–4.29(m,4H),4.22(d,J=5.8Hz,2H),3.39–3.03(m,10H), 3.00–2.63(m,9H),2.37(t,J=7.9Hz,2H),2.29(dd,J=8.9,3.7Hz,1H),2.23–1.94(m,5H),1.78–1.55(m,4H).

[0444] Example 32

[0445] 1. Synthesis of Compound 2

[0446] 4.7 g (10.3 mmol) of tert-butyl(3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate, 947.16 mg (1.034 mmol) of tris(dibenzylacetone)palladium, 439.23 mg (1.0 mmol) of 2-di-tert-butylphospho-2,4,6-triisopropylbiphenyl, and 1160.61 mg (20.6 mmol) of potassium hydroxide were dissolved in dioxane (50 mL) and water (10 mL) and stirred at 110 °C for 2 hours under a nitrogen atmosphere. The target product was detected by liquid chromatography-mass spectrometry. The residue was purified by silica gel column chromatography, eluting with PE / EA (7:1) to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (3.4 g, yield 83.96%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=392.24.

[0447] 2. Synthesis of Compound 3

[0448] 4-(bromomethyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-dipyridin]-2-one (300 mg, 0.6 mol), tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid (277.81 mg, 0.7 mol), and potassium carbonate (163.45 mg) were dissolved in 3 mL of N,N-dimethylformamide and stirred at 60 °C in air for 2 hours. The target product was detected by liquid chromatography (LCMS). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid (100 mg). LCMS (ESI, m / z): [M+H]+=818.40.

[0449] 3. Synthesis of Compound 204

[0450] 100 mg (0.1 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid was mixed with hydrochloric acid in dioxane (0.5 mL) and stirred in air at room temperature for 1 hour. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by pre-column high-performance liquid chromatography to obtain (2S)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}-2-[(3R)-pyrrolidine-3-yl]propionic acid (6.3 mg, yield 7.79%).

[0451] LCMS(ESI,m / z):[M+H] + =662.35

[0452] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,2H),7.93(d,J=2.7Hz,1H),7.61(d,J=7.0Hz,1H),7.48(d,J=7.2Hz,1H),7.40(d d,J=8.9,2.7Hz,1H),7.24–6.84(m,4H),6.81(dd,J=8.3,2.6Hz,2H),6.52(d,J=8.9Hz,1H),6.48(d,J=1.8Hz,1H) ,6.30(dd,J=7.1,1.9Hz,1H),5.00(s,2H),4.43–4.21(m,2H),3.24(d,J=10.7Hz,2H),3.02–2.97(m,3H),2.80(q, J=9.4Hz,1H),2.49–2.38(m,2H),2.25–2.04(m,3H),1.91–1.88(m,3H),1.70(h,J=9.6Hz,1H),1.55–1.52(m,2H).

[0453] Example 33

[0454] 1. Synthesis of Compound 3

[0455] (2S)-3-(3-bromo-5-fluorophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propionic acid (10.4 g, 25.0 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL) and reacted with 2-tert-butyl-1,3-diisopropylisourea (12.5 g, 62.458 mmol) at 70 °C under air for 3 hours. Then, 2-tert-butyl-1,3-diisopropylisourea (5.0 g, 25.0 mmol) was added at 70 °C. The resulting mixture was stirred overnight at 70 °C under air. The residue was purified by silica gel column chromatography, eluting with PE / EA (3 / 1) to give tert-butyl(3R)-3-[(2S)-3-(3-bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (6.4 g). LCMS (ESI, m / z): [M+H]+=401.0.

[0456] 2. Synthesis of Compound 4

[0457] A mixture of tert-butyl(3R)-3-[(2S)-3-(3-bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (2.0 g, 4.2 mmol), tris(dibenzylideneacetone)dipalladium (0.39 g, 0.4 mmol), 2-di-tert-butylphospho-2,4,6-triisopropylbiphenyl (0.18 g, 0.4 mmol) and potassium hydroxide (0.48 g, 8.4 mmol) was placed in dioxane (20 mL) / water (4 mL) and stirred at 105 °C for 3 hours under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-fluoro-5-hydroxyphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (1.0 g, yield 57.68%), as a white solid.

[0458] 3. Synthesis of Compound 6

[0459] 4-(bromomethyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (200 mg, 0.4 mol), tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-fluoro-5-hydroxyphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (161.4 mg, 0.4 mol), KI (98.2 mg, 0.6 mol), and potassium carbonate (108.9 mg, 0.8 mol) were dissolved in acetone (2 mL) and stirred at 60 °C under air for 2 hours. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed twice with methanol (6 mL each time). 200 mg of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]-5-fluorophenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester was obtained as a yellow oil. The filtrate was concentrated under reduced pressure. The crude product was used directly for the next step. LCMS (ESI, m / z): [M+H]+=836.93

[0460] 4. Synthesis of Compound 205

[0461] 180.0 mg (0.2 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]-5-fluorophenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid was reacted with hydrochloric acid in dioxane (2.0 mL) and stirred in air at room temperature for 1 hour. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by pre-column high-performance liquid chromatography to obtain (2S)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]-5-fluorophenyl}-2-[(3R)-pyrrolidine-3-yl]propionic acid (8.1 mg, yield 5.53%).

[0462] LCMS(ESI,m / z):[M+H] + =680.30

[0463] 1H NMR (400MHz, DMSO-d6) δ8.24(s,2H),7.93(d,J=2.6Hz,1H),7.62(d,J=7.1Hz,1H),7.48(d,J=7.1Hz,1 H),7.40(dd,J=8.9,2.7Hz,1H),7.25–6.90(m,2H),6.80–6.63(m,3H),6.52(d,J=9.0Hz,1H),6.48(s,1 H),6.29(dd,J=7.0,1.9Hz,1H),5.02(s,2H),4.31(q,J=7.0Hz,2H),3.34–3.30(m,1H)3.12–2.99(m,4H ),2.82(d,J=9.1Hz,1H),2.47(d,2H),2.13(m,3H),1.90(m,3H),1.87–1.84(d,1H),1.56–1.51(m,2H).

[0464] Example 34

[0465] 1. Synthesis of Compound 2

[0466] A mixture of tert-butyl(3R)-3-[(2S)-3-[3-bromo-5-(trifluoromethyl)phenyl]-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (2.5 g, 4.8 mmol), tris(dibenzylideneacetone)dipalladium (0.44 g, 0.5 mmol), 2-di-tert-butylphospho-2,4,6-triisopropylbiphenyl (0.20 g, 0.5 mmol) and potassium hydroxide (0.54 g, 9.6 mmol) was placed in dioxane (50 mL) / water (10 mL) and stirred at 105 °C for 3 hours under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-[3-hydroxy-5-(trifluoromethyl)phenyl]-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (1.0 g). LCMS (ESI, m / z): [M+H] + =460.22

[0467] 2. Synthesis of Compound 3

[0468] A solution (10 mL) of 4-(bromomethyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (600.0 mg, 1.2 mmol) in acetone was stirred at 60 °C for 2 hours under air atmosphere with tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-[3-hydroxy-5-(trifluoromethyl)phenyl]-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (543.4 mg, 1.2 mmol), potassium iodide (294.5 mg, 1.8 mmol), and potassium carbonate (326.9 mg, 2.4 mmol). The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]-5-(trifluoromethyl)phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (160 mg). LCMS (ESI, m / z): [M+H] + =886.38

[0469] 3. Synthesis of Compound 206

[0470] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]-5-(trifluoromethyl)phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid (180.0 mg, 0.2 mmol) and hydrochloric acid in dioxane (1.5 mL) was stirred in air at room temperature for 1 hour. The desired product was detected by liquid chromatography-mass spectrometry (LC-MS). The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative high performance liquid chromatography to obtain (2S)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]-5-(trifluoromethyl)phenyl}-2-[(3R)-pyrrolidine-3-yl]propionic acid (7.0 mg, yield 4.72%).

[0471] LCMS(ESI,m / z):[M+H] + =730.30

[0472] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.92(d,J=2.7Hz,1H),7.62(d,J=7.0Hz,1H),7.47(d,J =7.2Hz,1H),7.39(dd,J=8.9,2.7Hz,1H),7.25–6.81(m,5H),6.57–6.48(m,2H),6.31(dd,J= 7.1,1.9Hz,1H),5.08(s,2H),4.40–4.21(m,2H),3.31–3.10(m,2H),3.02(m,3H),2.89–2.74 (m,1H),2.70–2.55(m,2H),2.46–2.00(m,3H),1.88(d,3H),1.71(m,1H),1.60–1.40(m,2H).

[0473] Example 35

[0474] 1. Synthesis of Compound 2

[0475] A solution of (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]propionic acid (30.0 g, 75.3 mmol) was dissolved in DMF (300 mL). Potassium carbonate (52.0 g, 376.6 mmol) was added at room temperature and stirred for 30 min. Then, iodoethane (23.4 g, 150.6 mmol) was added in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine (3 × 500 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1), yielded (3R)-3-[(2S)-3-(3-bromophenyl)-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl (11 g) in butter-like condition. LCMS (ESI, m / z): [M+H]+=426.12

[0476] 2. Synthesis of Compound 4

[0477] tert-butyl(3R)-3-[(2S)-3-(3-bromophenyl)-1-ethoxy-1-oxopropane-2-yl]pyridine-1-carboxylic acid ester (11 g, 25.8 mmol), n-butylbis(1-adamantyl)phosphine (7.4 g, 20.6 mmol), palladium acetate (2.3 g, 10.3 mmol), and N,N,N',N'-tetramethylenediamine (1.2 g, 10.3 mmol) were added to toluene (100 mL) and stirred for 3 days at 105 °C under a hydrogen:carbon monoxide = 1:1 (40 atm) atmosphere. The desired product was detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give (3R)-3-[(2S)-1-ethoxy-3-(3-formylphenyl)-1-oxopropyl]pyrrolidine-1-carboxylic acid tert-butyl (7.5 g) butter. LCMS (ESI, m / z): [M+H]+=376.20

[0478] 3. Synthesis of Compound 5

[0479] tert-butyl(3R)-3-[(2S)-1-ethoxy-3-(3-formylphenyl)-1-oxopropyl-2-yl]pyridine-1-carboxylic acid ester (2.0 g, 5.3 mmol), ammonium carbonate (767.7 mg, 8.0 mmol), triethylamine (1.1 g, 10.6 mmol), and sodium triacetoxyborohydride (1.7 g, 8.0 mmol) were stirred overnight at 40 °C under a nitrogen atmosphere in dichloromethane (15 mL). The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine (2 × 30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. 1.8 g of (3R)-3-[(2S)-3-(3)-{(E)-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methylphenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid ester was obtained. LCMS (ESI, m / z): [M+H]+=734.43

[0480] 4. Synthesis of Compound 6

[0481] 3.8 g (5.2 mmol) of tert-butyl(3R)-3-[(2S)-3-(3)-{(E)-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenylmethylmethylene)amino]methylphenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylate (5.2 mmol) and sodium borohydride (391.7 mg, 10.3 mmol) were added to methanol (40 mL) and stirred for 2 hours at room temperature under a nitrogen atmosphere. The desired product was detected by LCMS. The reaction was quenched by adding 10 mL of saturated ammonium chloride at 0 °C. The resulting mixture was extracted with ethyl acetate (2 × 20 mL). The bound organic layer was washed with brine (2 × 50 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. (3R)-3-[(2S)-3-(3-{(3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid ester (3.5 g) of butter was obtained. LCMS (ESI, m / z): [M+H]+=736.45

[0482] 5. Synthesis of Compound 8

[0483] tert-butyl(3R)-3-[(2S)-3-(3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenylmethyl)amino]methylphenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylate (3.5 g, 4.8 mmol), 9H-fluorene-9-ylmethyl N-(2-chloro-2-oxoethyl)carbamate (1.8 g, 5.7 mmol), and triethylamine (1.0 g, 9.5 mmol) were added sequentially to DCM (50 mL), and stirred for 6 hours at room temperature under a nitrogen atmosphere. The desired product was detected by LCMS. The reaction was quenched by adding water (50 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine (2 × 10 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography to obtain (3R)-3-[(2S)-3-(3-{N-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)-2-[(9H-fluorene-9-ylmethoxy)carbonyl]amino]methyl}phenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid ester (2.5 g) of butter. LCMS (ESI, m / z): [M+H]+=1015.54

[0484] 6. Synthesis of Compound 9

[0485] 2.5 g (2.5 mmol) of tert-butyl(3R)-3-[(2S)-3-(3-{N-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)-2-[(9H-fluorene-9-ylmethoxy)carbonyl]aminoacetyl]methylphenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylate (2.5 g, 2.5 mmol) and piperidine (1.0 g, 12.3 mmol) were stirred in N,N-dimethylformamide (25 mL) at room temperature under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The product was purified by reversed-phase flash chromatography to obtain (3R)-3-[(2S)-3-(3-{2-amino-N-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)ethoxy]methyl}phenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid ester (1.2 g) butter. LCMS (ESI, m / z): [M+H]+=793.47.

[0486] 7. Synthesis of Compound 10

[0487] 100 mg (0.126 mmol) of tert-butyl(3R)-3-[(2S)-3-(3-{2-amino-n-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)ethoxy-1-oxopropyl]pyrrolidine-1-carboxylate and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy) Pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (57.81 mg, 0.126 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (71.92 mg, 0.189 mmol), N,N-diisopropylethylamine (32.60 mg, 0.252 mmol) were added to N, The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere in N-dimethylformamide (1 mL). The desired product was detected by LCMS. Purification by reversed-phase flash chromatography yielded tert-butyl(3R)-3-[(2S)-3-(3-{N-(3-[(2S)-2-[(3R)-1-(tert-butylmethoxy)pyrrolidone-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)-2-[(6 '-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]aminocyclopentyl]amino}-2-oxy-[1,3'-bipyridine]-4-yl)methylamino]acetamido]methyl]phenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylate (95 mg, yield 61.08%) is a yellow solid. LCMS (ESI, m / z): [M+H]+=1233.61.

[0488] 8. Synthesis of compound 35-3

[0489] tert-butyl(3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)formamide]methyl}phenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (85 mg, 0.069 mmol) was mixed with hydrochloric acid in dioxane (0.9 mL, 3.4 mmol) and then with dioxane (1 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by pre-column high-performance liquid chromatography to give ethyl(2S)-3-[3-({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin-4-yl)carboxamide]-N-({3-[(2S)-3-ethoxy-3-oxo-2-((3R)-pyrrolidine-3-yl)propyl]phenyl}methyl)acetamide}methyl)phenyl]-2-((3R)-pyrrolidine-3-yl)propionate (4.3 mg, yield 6.04%).

[0490] LCMS(ESI,m / z):[M+H] + =1033.35

[0491] 1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.36(s,2H),8.22(s,2H),7.97-7.96(m,1H),7.74-7.72(m,1H),7.49-7.44(m,1H),7.44-7.4 0(m,1H),7.32-7.26(m,1H),7.25-7.19(m,1H),7.13-6.80(d,9H),6.61-6.57(m,1H),6.55-6.51(m,1H),4.51-4.45(s,2H),4.44- 4.38(m,2H),4.33-4.26(m,2H),4.21-4.15(m,2H),3.99-3.88(m,4H),3.28-3.25(m,2H),3.11-3.02(m,2H),3.01-2.94(m,2H),2. 89-2.73(m,5H),2.72-2.65(m,3H),2.35-2.24(m,2H),2.17-2.07(m,2H),1.93-1.82(m,4H),1.57-1.43(m,4H),1.04-0.96(m,6H).

[0492] Example 36

[0493] Compound 36-3 was prepared using a method similar to that in Example 35.

[0494] LCMS (ESI, m / z): [M+H]+=1061.35. 1H NMR (400MHz, DMSO-d6) δ9.04(t,J=5.7Hz,1H),8.39(s,2H),8.24(s,2H),7.97(d,J=2.7Hz,1H),7.74(d,J=7.1Hz,1H),7.49(d,J=7.2Hz, 1H),7.45–7.42(m,1H),7.31(t,J=7.5Hz,1H),7.29–7.22(m,1H),7.16–6.84(m,9H),6.63–6.60(m,1H),6.55(d,J=8.9Hz,1H),4.81–4.74 (m,2H),4.53–4.38(m,3H),4.35–4.30(m,3H),4.21(d,J=5.8Hz,2H),3.28(s,2H),3.12(s,2H),3.01(d,J=9.2Hz,2H),2.90–2.82(m,4H), 2.80–2.62(m,4H),2.40–2.27(m,2H),2.20–2.07(m,2H),1.96–1.84(m,4H),1.60–1.43(m,4H),1.10–1.09(m,6H),0.93(d,J=6.2Hz,6H).

[0495] Example 37

[0496] 1. Synthesis of Compound 3

[0497] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)amino]methyl}-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (9.5 g, 11.5 mmol), 9H-fluorene-9-ylmethyl N-(2-chloro-2-oxoethyl)carbamate (4.3 g, 13.7 mmol), and triethylamine (2.3 g, 22.9 mmol) in dichloromethane (100 mL) was stirred in air at room temperature for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was extracted with dichloromethane (2 × 100 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[N-({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)-2-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}acetamido]methyl}-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g). LCMS (ESI, m / z): [M+H] + =1107.58.

[0498] 2. Synthesis of Compound 4

[0499] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[N-({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)-2-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}acetamide]methyl}-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (5.0 g, 4.5 mmol) and piperidine (10 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature in air for 2 hours. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-3-(3-{[2-amino-N-({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)acetamide]methyl}-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (1.6 g). LCMS (ESI, m / z): [M+H] +=885.51

[0500] 3. Synthesis of Compound 5

[0501] 400 mg, 0.5 mmol of tert-butyl(3R)-3-[(2S)-3-(3-{[2-amino-N-({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)acetamide]methyl}-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (400 mg, 0.5 mmol) was mixed with 6'-{[(1S,3S)-3-{[5-(difluoro) Methoxypyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (207.2 mg, 0.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (257.7 mg, 0.75 mmol), and N,N-diisopropylethylamine (116.8 mg, 0.1 mmol) were stirred in N,N-dimethylformamide (4 mL) at room temperature under air for 2 hours. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography to obtain (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[N-({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)formamide]acetamide]methyl}-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg). LCMS (ESI, m / z): [M+H] + =1325.65.

[0502] 4. Synthesis of Compound 37-1

[0503] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[N-({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)formamide]acetamide]methyl}-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (190 mg, 0.14 mmol) in hydrochloric acid in dioxane (1.90 mL, 7.5 mmol) was stirred at room temperature in air for 1 hour. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC to give (2S)-3-[3-{[N-({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]-5-fluorophenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-yl)formamide]acetamide]methyl}-5-fluorophenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (6.9 mg, 4.75% yield).

[0504] LCMS(ESI,m / z):[M+H] + =1013.40

[0505] 1 H NMR(400MHz, DMSO-d6+DCl)δ8.47(s,2H),8.35(d,J=2.6Hz,1H),8.18(s,1H),8.05–7.93(m,1H),7.33–6.89 (m,7H),6.85(d,J=9.6Hz,1H),6.39(s,1H),4.53(s,2H),4.48–4.32(m,4H),4.13(s,2H),3.35–3.24(m,2H) ,3.23–3.13(m,2H),3.12–3.01(m,2H),2.98–2.86(m,2H),2.80(d,J=9.3Hz,2H),2.75–2.62(m,4H),2.40–2 .29(m,2H),2.28–2.12(m,1H),2.11–2.09(m,2H),2.09-2.01(m,1H),2.00–1.89(m,2H),1.77–1.48(m,4H).

[0506] Example 38

[0507] 1. Synthesis of Compound 3

[0508] 20.0 g (51.5 mol) of tert-butyl(3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylic acid ester was dissolved in tetrahydrofuran (200 mL), and lithium bis(trimethylsilylamino)amine (56.63 mL, 56.6 mol) was added in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 30 minutes. 1-Bromo-3-(bromomethyl)-5-fluorobenzene (15.2 g, 56.6 mol) was added in portions to the above mixture. The resulting mixture was stirred overnight at room temperature. The reaction was terminated at 0 °C by adding saturated aqueous ammonium chloride solution (100 mL). The residue was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give tert-butyl(3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-3-(3-bromo-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (12.0 g), a white oil. LCMS (ESI, m / z): [M+H]+=575.15.

[0509] 2. Synthesis of Compound 4

[0510] 12.0 g (20.9 mmol) of tert-butyl(3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-3-(3-bromo-5-fluorophenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid and 4.7 g (41.7 mmol, 30%) were dissolved in tetrahydrofuran (120 mL), and then lithium hydroxide hydrate (1.8 g, 41.7 mmol) was added to the solution at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched at 0 °C with a saturated sodium hydroxide-sodium hydrosulfide solution. The mixture was alkalized with sodium hydroxide to pH 12. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. (2S)-3-(3-bromo-5-fluorophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propionic acid (16 g) was obtained as a yellow oil. LCMS (ESI, m / z): [M+H]+=416.08.

[0511] 3. Synthesis of Compound 6

[0512] A solution of (2S)-3-(3-bromo-5-fluorophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propionic acid (16.0 g, 38.4 mmol) in dimethylformamide (200 mL) was reacted with potassium carbonate (26.6 g, 192.2 mmol) at room temperature under a nitrogen atmosphere for 0.5 h, followed by the addition of ethyl iodine (12.0 g, 76.8 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was diluted with water (1000 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(3R)-3-[(2S)-3-(3-bromo-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (9.5 g) as a yellow oil. LCMS (ESI, m / z): [M+H]+=444.11.

[0513] 4. Synthesis of Compound 8

[0514] tert-Butyl(3R)-3-[(2S)-3-(3-bromo-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid (9.5 g, 21.4 mol), n-butylbis(1-adamantyl)phosphine (6.13 g, 17.1 mol), palladium acetate (1.9 g, 8.6 mol), and N,N,N',N'-tetramethylethylenediamine (1.0 g, 8.6 mol) were dissolved in toluene (100 mL) and stirred at 105 °C under a carbon monoxide / hydrogen atmosphere (40 atm) for 3 days. The target product was detected by liquid chromatography-mass spectrometry. The residue was purified by silica gel column chromatography to give 7.0 g of tert-butyl(3R)-3-[(2S)-1-ethoxy-3-(3-fluoro-5-formylphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid as a yellow oil. LCMS (ESI, m / z): [M+H]+=394.20.

[0515] 5. Synthesis of Compound 9

[0516] tert-butyl(3R)-3-[(2S)-1-ethoxy-3-(3-fluoro-5-formylphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (2.0 g, 5.1 mol), ammonium carbonate (732.6 mg, 7.6 mol), triethylamine (1.0 g, 10.2 mol), and sodium borohydride acetate (1.6 g, 7.6 mol) were dissolved in dichloromethane (15 mL) and stirred overnight at 40 °C under a nitrogen atmosphere. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl(3R)-3-[(2S)-3-(3-{[(E)-({3-[(2S)-2-(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methylimine)amino]methyl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (1.8 g, crude product) as a yellow oil. LCMS (ESI, m / z): [M+H]+=770.41.

[0517] 6. Synthesis of Compound 10

[0518] 3.9 g (5.1 mol) of tert-butyl(3R)-3-[(2S)-3-(3-{[(E)-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)amino]methyl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester and sodium borohydride (383.3 mg, 10.1 mol) were dissolved in methanol (40 mL) and stirred at room temperature under a nitrogen atmosphere for 1 hour. The target product was detected by LC-MS. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride at 0 °C, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded tert-butyl(3R)-3-[(2S)-3-(3-{[({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)amino]methyl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (3.5 g) as a yellow oil. LCMS (ESI, m / z): [M+H]+=772.43.

[0519] 7. Synthesis of Compound 12

[0520] tert-butyl(3R)-3-[(2S)-3-(3-{[({3-[(2S)-2-(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl}-5-fluorophenyl)methyl]amino}methyl)-5-fluorophenyl]-1-ethoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (3.5 g, 4.5 mmol), N-FMOC-glycyl chloride (1.7 g, 5.4 mmol), and triethylamine (0.92 g, 9.0 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature under a nitrogen atmosphere for 4 hours. The target product was detected by liquid chromatography. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give 1.8 g of 3-tert-butyl(3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl}-5-fluorophenyl}methyl)-2-{[(9H-furan-9-ylmethoxy)carbonyl]amino}acetamido}]methyl)-5-fluorophenyl)-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid as a white oil. LCMS (ESI, m / z): [M+H]+=1051.52

[0521] 8. Synthesis of Compound 13

[0522] 1.8 g (1.7 mol) of 3-tert-butyl(3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)-2-{[(9H-furan-9-ylmethoxy)carbonyl]amino}acetamide})methyl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid (1.8 g, 1.7 mol) was dissolved in dimethylformamide (10 mL). 10 mL (0.1 mol) of piperidine was added in portions at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The target product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography to give 3-tert-butyl(3R)-3-[(2S)-3-(3-{[2-amino-N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)acetamide})methyl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid (900 mg) as a yellow oil. LCMS (ESI, m / z): [M+H]+=829.45.

[0523] 9. Synthesis of Compound 14

[0524] 300 mg, 0.4 mol of tert-butyl(3R)-3-[(2S)-3-(3-{[2-amino-N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)acetamide]yl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid (300 mg, 0.4 mol) and 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidine- [2-yl]amino]cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (165.9 mg, 0.4 mol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (206.4 mg, 0.5 mol), and N,N-diisopropylethylamine (126.1 μL, 0.7 mol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature under a nitrogen atmosphere for 1 hour. The target product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino}-2-oxo-[1,3'-bipyridinin-4-yl)formamide]acetamide]yl}-5-fluorophenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid (290 mg) as a yellow solid. LCMS (ESI, m / z): [M+H]+=1269.59.

[0525] 10. Synthesis of compound 37-3-1

[0526] 100 mg (0.1 mmol) of tert-butyl(3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-fluorophenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyridin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)formamide]acetamide})-5-fluorophenyl)-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylate was mixed with hydrochloric acid in dioxane (1 mL) and stirred at room temperature for 1 hour under a nitrogen atmosphere. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by pre-column high-performance liquid chromatography to obtain ethyl(2S)-3-[3-({2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin-4-yl)carboxamide]-N-({3-[(2S)-3-ethoxy-3-oxo-2-[(3R)-pyrrolidine-3-yl]propyl]-5-fluorophenyl}methyl)acetamide}methyl)-5-fluorophenyl]-2-[(3R)-pyrrolidine-3-yl]propionate (8.0 mg, yield 9.50%).

[0527] LCMS(ESI,m / z):[M+H]+=1069.35

[0528] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.39–8.34(m,2H),8.23(s,2H),7.95(d,J=2.7Hz,1H),7.72(d,J=7.0Hz,1H),7. 47(d,J=7.2Hz,1H),7.42(dd,J=8.9,2.7Hz,1H),7.22–6.83(m,9H),6.59(m,,1H),6.54(d,J=8.9Hz,1H),4.56(s,2H) ,4.51–4.39(m,2H),4.30(d,J=6.7Hz,2H),4.17(d,J=5.9Hz,2H),3.96(q,J=6.9Hz,4H),3.25(s,2H),3.09(s,2H),3. 00(d,J=8.9Hz,2H),2.91–2.65(m,8H),2.38–2.25(m,2H),2.12(m,2H),1.95–1.82(m,4H),1.51(m,4H),1.02(m,6H).

[0529] Example 39

[0530] Synthesis of compound 37-3

[0531] Ethyl(2S)-3-[3-({2-[(6'-{[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)carboxamide]-N-({3-[(2S)-3-ethoxy-3-oxo-2-[(3R)-pyrrolidine-3-yl]propyl]-5-fluorophenyl}methyl)acetamide)]-5-fluorophenyl]-2-[(3R)-pyrrolidine-3-yl]propionate (100.0 mg, 0.1 mmol) and sodium hydroxide (37.41 mg, 1.0 mmol) were dissolved in methanol (0.5 mL) and water (0.5 mL) and stirred overnight in air at room temperature. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by pre-column high-performance liquid chromatography to obtain (2S)-3-(3-{[N-({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]-5-fluorophenyl}methyl)-2-[(6'{-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)carboxamide]acetamide]methyl}-5-fluorophenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (8.3 mg, yield 8.76%).

[0532] LCMS(ESI,m / z):[M+H] + =1013.25

[0533] 1H NMR (400MHz, Methanol-d4) δ8.41(d,J=4.4Hz,2H),7.94(d,J=2.3Hz,1H),7.81(d,J=9.5Hz,1H),7.57(d,J=7.0Hz,1 H),7.02(d,J=10.3Hz,1H),6.91–6.82(m,2H),6.80–6.50(m,7H),4.42(d,J=5.9Hz,2H),4.39(d,J=7.9Hz,3H),4.34 (m,1H),4.27–4.18(m,1H),4.13(s,2H),3.37–3.25(m,2H),3.21-3.15(m,2H),3.08–3.02(m,2H),2.97–2.83(m,2H) ,2.79–2.68(m,4H),2.63-2.57(m,2H),2.43–2.30(m,2H),2.29–2.04(m,2H),2.04–1.93(m,2H),1.89-1.84(m,4H).

[0534] Following the methods described in Examples 38-39, the following compounds were synthesized:

[0535] Compound 38-3-1

[0536] LCMS(ESI,m / z):[M+H]+=1169.15

[0537] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.37 (s, 2H), 8.24 (s, 2H), 7.96 (d, J = 2.7Hz, 1H), 7.73 (d, J = 7.1Hz, 1H), 7.5 1–7.32(m,8H),7.07–6.83(m,3H),6.66–6.52(m,2H),4.72(d,J=5.3Hz,2H),4.65–4.50(m,2H),4.35–4.28(m,2H) ,4.20(d,J=5.7Hz,2H),3.98–3.91(M,4H),3.54–3.46(m,2H),3.29(s,2H),3.12(s,2H),3.03–2.85(m,4H),2.80( d,J=13.2Hz,4H),2.39–2.31(m,2H),2.21-2.07(m,2H),1.96–1.84(m,4H),1.60–1.46(m,4H),1.01–0.97(m,6H).

[0538] Compound 38-3

[0539] LCMS(ESI, m / z): [M + H]+ = 1113.45

[0540] 1 H NMR(400 MHz, DMSO-d6) δ 9.81–9.67(m, 1H), 8.36(s, 2H), 8.16(s, 1H), 8.01(d, J = 9.3 Hz, 1H), 7.81(d, J = 7.2 Hz, 1H), 7.50(s, 2H), 7.45(d, J = 7.0 Hz, 2H), 7.40(d, J = 8.9 Hz, 2H), 7.32–6.86(m, 2H), 6.71–6.59(m, 1H), 4.82–4.65(m, 1H), 4.63–4.47(m, 1H), 4.43(s, 1H), 4.39–4.33(m, 1H), 4.21(s, 2H), 3.39–3.32(m, 2H), 3.22(s, 1H), 3.12(t, J = 10.0 Hz, 1H), 3.03–2.96(m, 1H), 2.94–2.84(m, 1H), 2.83–2.70(m, 1H), 2.43–2.37(m, 1H), 2.35–2.23(m, 1H), 2.21–2.10(m, 1H), 2.07–1.93(m, 2H), 1.70–1.60(m, 3H), 1.22(s, 1H).

[0541] Compound 39-3-1

[0542] LCMS(ESI, m / z): [M + H]+ = 1061.35

[0543] 11H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J = 5.9 Hz, 1H), 8.41 (s, 2H), 8.24 (s, 2H), 7.96 (d, J = 2.7 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.53–7.37 (m, 2H), 7.25–6.77 (m, 9H), 6.58 (dd, J = 12.5, 8.0 Hz, 2H), 4.43 (dd, J = 9.7, 5.1 Hz, 3H), 4.39–4.30 (m, 3H), 4.19 (d, J = 5.8 Hz, 2H), 4.03–3.95 (m, 4H), 3.39–3.26 (m, 2H), 3.13 (d, J = 9.4 Hz, 2H), 3.06–2.99 (m, 2H), 2.96–2.59 (m, 8H), 2.43–2.31 (m, 2H), 2.26 (d, J = 9.6 Hz, 6H), 2.15–2.08 (m, 2H), 1.95–1.88 (m, 4H), 1.58–1.50 (m, 4H), 1.03 (t, J = 7.1 Hz, 6H).

[0544] Compound 39-3

[0545] LCMS (ESI, m / z): [M+H]+ = 1005.30

[0546] 1 1H NMR (400 MHz, Deuterium Oxide) δ 8.09 (s, 1H), 7.82 (s, 1H), 7.59–7.38 (m, 2H), 7.31 (dd, J = 12.9, 7.5 Hz, 3H), 6.88 (d, J = 12.8 Hz, 2H), 6.77 (d, J = 12.7 Hz, 4H), 6.58 (d, J = 19.5 Hz, 2H), 4.56–4.32 (m, 4H), 4.25–4.16 (m, 4H), 3.34 (d, J = 11.4 Hz, 4H), 3.13 (s, 2H), 2.82 (s, 2H), 2.68 (s, 3H), 2.57 (s, 1H), 2.35 (s, 4H), 2.10–1.95 (m, 10H), 1.86 (d, J = 12.3 Hz, 2H), 1.66 (s, 2H), 1.48 (s, 2H).

[0547] Compound 40-3-1

[0548] LCMS (ESI, m / z): [M+H]+ = 1201.20

[0549] 11H NMR (400 MHz, DMSO-d6) δ 9.09 (t, J = 5.8 Hz, 1H), 8.40 (s, 2H), 8.24 (s, 2H), 7.96 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.51–7.40 (m, 2H), 7.32–6.82 (m, 9H), 6.66–6.46 (m, 2H), 4.73–4.58 (m, 2H), 4.56–4.45 (m, 2H), 4.36–4.31 (m, 2H), 4.18 (d, J = 5.8 Hz, 2H), 3.98–3.86 (m, 4H), 3.32–3.24 (m, 2H), 3.17–3.06 (m, 2H), 3.02 (t, J = 8.8 Hz, 2H), 2.95–2.85 (m, 4H), 2.84–2.68 (m, 4H), 2.38–2.27 (m, 2H), 2.19–2.09 (m, 2H), 1.96–1.81 (m, 4H), 1.58–1.47 (m, 4H), 1.08–0.98 (m, 6H).

[0550] Compound 40-3-1

[0551] LCMS (ESI, m / z): [M+H]+ = 1201.20

[0552] 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (t, J = 5.8 Hz, 1H), 8.40 (s, 2H), 8.24 (s, 2H), 7.96 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.51–7.40 (m, 2H), 7.32–6.82 (m, 9H), 6.66–6.46 (m, 2H), 4.73–4.58 (m, 2H), 4.56–4.45 (m, 2H), 4.36–4.31 (m, 2H), 4.18 (d, J = 5.8 Hz, 2H), 3.98–3.86 (m, 4H), 3.32–3.24 (m, 2H), 3.17–3.06 (m, 2H), 3.02 (t, J = 8.8 Hz, 2H), 2.95–2.85 (m, 4H), 2.84–2.68 (m, 4H), 2.38–2.27 (m, 2H), 2.19–2.09 (m, 2H), 1.96–1.81 (m, 4H), 1.58–1.47 (m, 4H), 1.08–0.98 (m, 6H).

[0553] Compound 40-3

[0554] LCMS(ESI,m / z):[M+H]+=1145.25

[0555] 1 H NMR (400MHz, DMSO-d6) δ9.84–9.52(m,1H),8.34(s,2H),8.16(d,J=5.8Hz,1H),8.01(d,J=9.5Hz,1H),7.8 2(d,J=7.1Hz,1H),7.36–7.20(m,2H),7.18–6.86(m,6H),6.70(dd,J=7.2,1.9Hz,1H),4.78–4.60(m,2H),4 .57–4.32(m,4H),4.19(s,2H),3.38–3.27(m,2H),3.25–3.20(m,2H),3.18–3.04(m,2H),3.05–2.92(m,2H ),2.85–2.77(m,11.4Hz,6H),2.45–2.23(m,3H),2.19–2.13(m,2H),2.09–1.93(m,3H),1.69–1.58(m,4H).

[0556] Example 40

[0557] 1. Synthesis of Compound 2

[0558] A solution of tert-butyl(3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (14.5 g, 31.9 mmol) in tetrahydrofuran (180 mL) was reacted with lithium diisopropylamino (6.8 g, 63.8 mmol) at -78 °C for 30 min under a nitrogen atmosphere, followed by dropwise addition of N-fluorobisbenzenesulfonamide (30.2 g, 95.7 mmol) at -78 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched at 0 °C with a saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(3S)-3-(3-(3-bromophenyl)-1-(tert-butoxy)-2-fluoro-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester (10 g, 66.3% yield) as a brown oil. LCMS (ESI, m / z): [M+H]+=472.14.

[0559] 2. Synthesis of Compound 4

[0560] In a stirred mixture of tert-butyl(3S)-3-(3-(3-bromophenyl)-1-(tert-butoxy)-2-fluoro-1-oxopropane-2-yl)pyrrolidine-1-carboxylate (10.0 g, 21.2 mmol) and bis(adamantane-1-yl)(butyl)phosphine (6.1 g, 16.9 mmol) in toluene (150 mL) under room temperature and air atmosphere, N,N,N',N'-tetramethylethylenediamine (1.0 g, 8.5 mmol) and palladium acetate (1.9 g, 8.5 mmol) were added. The resulting mixture was stirred for 3 days at 105 °C with a CO:H2 ratio of 1:1 (40 bar). The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7.6 g of tert-butyl(3S)-3-(1-(tert-butoxy)-2-fluoro-3-(3-carboxyphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate. LCMS (ESI, m / z): [M+H]+=422.23.

[0561] 3. Synthesis of Compound 5

[0562] Under a nitrogen atmosphere, tert-butyl(3S)-3-[1-(tert-butoxy)-2-fluoro-3-(3-carboxymethylphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (4.0 g, 9.5 mmol) and ammonium carbonate (0.68 g, 14.2 mmol) were added to DCM (36 mL). The mixture was then added in two portions, followed by the addition of triethylamine (1.9 g, 18.9 mmol) and sodium triacetoxyborohydride (3.0 g, 14.2 mmol). The mixture was stirred overnight under a nitrogen atmosphere at room temperature. The resulting mixture was diluted with water. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 4.0 g of tert-butyl(3S)-3-(1-(tert-butoxy)-3-(3-((((E)-3-(3-(tert-butoxy)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-fluoro-3-oxopropyl)benzylmethyl)amino)methyl)phenyl)-2-fluoro-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester was obtained as a brown oil. LCMS (ESI, m / z): [M+H]+=826.47.

[0563] 4. Synthesis of Compound 6

[0564] A mixture of tert-butyl(3S)-3-(1-(tert-butoxy)-3-(3-((((E)-3-(3-(tert-butoxy)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-fluoro-3-oxopropyl)benzylmethyl)amino)methyl)phenyl)-2-fluoro-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester (4.0 g, 4.8 mmol) and sodium borohydride (370 mg, 9.7 mmol) was stirred in methanol (30 mL) at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with water. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Di-tert-butyl 3,3'-(((azinediylbis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-2-fluoro-3-oxopropane-1,2-diyl))(3S,3'S)-bis(pyrrolidine-1-carboxylic acid ester) (3.4 g) was obtained as a yellow solid. LCMS (ESI, m / z): [M+H]+=828.49.

[0565] 5. Synthesis of Compound 8

[0566] 3,3'-(((azaalkyldiylbis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-2-fluoro-3-oxopropane-1,2-diyl))bis(tert-butyl)(3S,3'S)-bis(pyrrolidine-1-carboxylic acid ester) (3.4 g, 4.1 mmol) was mixed with 9H-fluorene-9-methyl N-(2-chloro-2-oxoethyl)carbamate (2.6 g, 8.2 mmol) and triethylamine (0.8 g, 8.2 mmol) in dichloromethane (30 mL) under a nitrogen atmosphere at 25 °C for 2 hours. The resulting mixture was diluted with water. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give bis(tert-butyl)3,3'-((((((9H-fluorene-9-methoxy)carbonyl)glycyl)azanyldiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-2-fluoro-3-oxopropane-1,2-diyl))(3S,3'S)-bis(pyrrolidine-1-carboxylic acid ester) (2.3 g, 50% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=1107.58.

[0567] 6. Synthesis of Compound 9

[0568] Di-tert-butyl 3,3'-((((((((9H-fluoren-9-yl)methoxy)carbonyl)glycyl)iminodimethyl)bis(3,1-phenyl))bis(3-(tert-butoxy)-2-fluoro-3-oxopropane-1,2-diyl))(3S,3'S)-bis(pyrrolidine-1-carboxylate) (2.3 g, 2.1 mmol) was stirred in piperidine (5 mL) / dichloromethane (15 mL) at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with water. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give a white solid tert-butyl(3S)-3-[3-(3-{[2-amino-N-({3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-2-fluoro-3-oxopropyl]phenyl}methyl)acetamide]methyl}phenyl)-1-(tert-butoxy)-2-fluoro-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (900 mg, 48.9% yield). LCMS (ESI, m / z): [M+H]+=885.51.

[0569] 7. Synthesis of Compound 41-3

[0570] tert-butyl(3S)-3-[1-(tert-butoxy)-3-(3-{[N-({3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-fluoro-3-oxopropyl]phenyl}methyl)-2-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino} ring [Pentyl]amino]-2-oxo-[1,3'-bipyridine]-4-yl)formamide]acetamide]methyl]phenyl]-2-fluoro-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (100 mg, 0.08 mmol) was stirred in 1,4-dioxane hydrochloride solution (4.0 M, 0.5 mL) in 1,4-dioxane (0.5 mL) at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to obtain 3,3'-(((((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)carbamoyl)glycyl)azadiyl)bis(methylene))bis(3,1-phenyl)bis(2-fluoro-2-((S)-pyrrolidine-3-yl)propionic acid) (9.6 mg, 12.56% yield).

[0571] LCMS(ESI,m / z):[M+H]+=1013.30

[0572] 1 H NMR (400MHz, DMSO-d6) δ9.78–9.55(m,1H),8.33(d,J=1.9Hz,2H),8.17(s,1H),8.01(d,J=9. 6Hz,1H),7.82(d,J=7.1Hz,1H),7.43–6.84(m,11H),6.71(dd,J=7.1,1.9Hz,1H),4.65–4.47( m,3H),4.48–4.30(m,3H),4.20(s,2H),3.25–3.19(m,10H),3.04–2.78(m,4H),2.40–2.27(m ,1H),2.26–2.07(m,4H),2.02(dt,J=13.1,6.6Hz,1H),1.92–1.85(m,2H),1.66–1.62(m,2H).

[0573] Example 41

[0574] 1. Synthesis of Compound 2

[0575] A solution of methyl 2-(2-methoxypyridin-4-yl)acetate (2.0 g, 11.0 mmol) in acetonitrile (20 mL) was reacted with sodium iodide (6.6 g, 44.2 mmol) at room temperature under a nitrogen atmosphere for 2 min, followed by dropwise addition of trimethylchlorosilane (3.6 g, 33.1 mmol) at room temperature. The resulting mixture was stirred at 130 °C for 15 min under a nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate, to give methyl 2-(2-oxo-1H-pyridin-4-yl)acetate (670 mg) as a pale yellow solid. LCMS (ESI, m / z): [M+H]+=168.04

[0576] 2. Synthesis of Compound 4

[0577] 2-(2-oxo-1H-pyridin-4-yl)methyl acetate (670 mg, 4.0 mmol), 6-bromopyridin-3-ylboronic acid (809 mg, 4.0 mmol), copper acetate (1.1 g, 6.0 mmol), and pyridine (634 mg, 8.0 mmol) were added to 10 mL of dichloromethane. The resulting mixture was stirred at room temperature under air for 2 days. The precipitated solid was collected by filtration and washed with 30 mL of dichloromethane. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid column chromatography to give 2-(6'-chloro-2-oxo-[1,3'-bipyridin]-4-yl)methyl acetate (160 mg), as a yellow oil. LCMS (ESI, m / z): [M+H]+=323.05; 325.05.

[0578] 3. Synthesis of Compound 6

[0579] 2-(6'-chloro-2-oxo-[1,3'-bipyridinyl]-4-yl)methyl acetate (280 mg, 1.0 mmol), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (245 mg, 1.0 mmol), N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (10 mg, 0.1 mmol), cuprous iodide (12 mg, 0.1 mmol), and potassium carbonate (417 mg, 3.0 mmol) were dissolved in 5 mL of dimethyl sulfoxide, and the mixture was stirred at 120 °C for 16 hours under nitrogen protection. The precipitated solid was collected by filtration and washed with methanol. The residue was purified by reversed-phase rapid column chromatography to obtain methyl 2-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)acetate (200 mg), as a colorless oil. LCMS (ESI, m / z): [M+H]+=487.30.

[0580] 4. Synthesis of Compound 7

[0581] 2-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)acetic acid methyl ester (190 mg, 0.4 mmol) and lithium hydroxide (28 mg, 1.2 mmol) were dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase rapid column chromatography to obtain the target product (6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)acetic acid (102 mg). LCMS (ESI, m / z): [M+H]+=473.26

[0582] 5. Synthesis of Compound 9

[0583] (3R)-3-[(2S)-3-(3-{[({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.2 mmol) was mixed with (6'-{[(1S,3S)-3-{[5-(difluoro Methoxypyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)acetic acid (103 mg, 0.2 mmol), benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate (124 mg, 0.3 mmol), and N,N-diisopropylethylamine (84 mg, 0.7 mmol) were dissolved in 2 mL of N,N-dimethylformamide and reacted at room temperature for 1 hour under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid column chromatography to obtain (3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)-2-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridinyl]-4-yl)acetamyl]methyl}phenyl)-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (85 mg), an off-white solid. LCMS (ESI, m / z): [M+H]+=1190.39.

[0584] 6. Synthesis of compound 42-3-1

[0585] (3R)-3-[(2S)-3-(3-{[N-({3-[(2S)-2-[(3R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]phenyl}methyl)-2-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)acetamyl]methyl}phenyl)-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.1 mmol) was dissolved in 1,4-dioxane hydrochloride solution (2 mL), and the reaction was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative high-performance liquid chromatography to obtain ethyl (2S)-3-(3-{[2-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)-N-({3-[(2S)-3-ethoxy-3-oxo-2-[(3R)-pyrrolidine-3-yl]propyl]phenyl}methyl)acetamyl]methyl}phenyl)-2-[(3R)-pyrrolidine-3-yl]propionate (8.7 mg, yield 13.1%).

[0586] LCMS(ESI,m / z):[M+H]+=990.30

[0587] 1 H NMR (400MHz, DMSO-d6) δ8.39(s,2H),8.24(s,2H),7.91(d,J=2.6Hz,1H),7.54(d,J=7.0Hz,1H),7.49(d,J=7.2Hz,1H),7.39–7 .36(m,1H),7.33–6.84(m,10H),6.54(d,J=8.9Hz,1H),6.31(d,J=1.9Hz,1H),6.20–6.18(m,1H),4.56–4.48(m,2H),4.48–4.39 (m,2H),4.34–4.27(m,2H),4.00–3.87(m,4H),3.69(s,2H),3.25(s,2H),3.08(s,2H),2.99(s,2H),2.92–2.78(m,4H),2.78–2 .71(m,2H),2.71–2.59(m,2H),2.39–2.23(m,2H),2.20–2.07(m,2H),1.98–1.81(m,4H),1.62–1.45(m,4H),1.03–1.98(m,6H).

[0588] Example 42

[0589] 1. Synthesis of Compound 1

[0590] After stirring 4-bromo-2-methoxypyridine (16.0 g, 85.0 mmol) and ethyl 4-bromobutyrate (21.5 g, 110.6 mmol) in ethylene glycol dimethyl ether (180 mL), aliquots of (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-KN)phenylKC]IRID (0.9 g, 0.8 mmol, 0.01 eq.), 1,1,1,3,3,3-hexamethylene-2-(trimethylsilyl)trisilane (21.1 g, 85.0 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) chloride (0.1 g, 0.4 mmol) and sodium carbonate (18.0 g, 170.1 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere and irradiated with a 450 nm blue LED. The reaction mixture was filtered. The filtrate was diluted with water (800 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. It was purified by reversed-phase flash chromatography to obtain ethyl 4-(2-methoxypyridin-4-yl)butyrate (7.6 g), LCMS (ESI, m / z): [M+H]+=224.09.

[0591] 2. Synthesis of Compound 2

[0592] Ethyl 4-(2-methoxypyridin-4-acyl)butyrate (7.6 g, 34.0 mmol) and pyridine hydrochloride (39.3 g, 340.3 mmol) were stirred at 130 °C for 30 min in N,N-dimethylformamide (100 mL). The mixture was purified by reversed-phase flash chromatography to obtain ethyl 4-(2-oxo-1H-pyridin-4-yl)butyrate (5.7 g), LCMS (ESI, m / z): [M+H]+ = 210.13.

[0593] 3. Synthesis of Compound 3

[0594] A mixture of ethyl 4-(2-oxo-1H-pyridin-4-yl)butyrate (5.6 g, 26.7 mmol), 6-bromo-3-pyridineboronic acid (5.4 g, 26.7 mmol), copper acetate (7.2 g, 40.1 mmol), and pyridine (4.2 g, 53.5 mmol) was placed in 100 mL of dichloromethane and stirred in air at room temperature for 2 days. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The residue was purified by reversed-phase rapid chromatography to give ethyl 4-{6'-bromo-2-oxo-[1,3'-bipyridine]-4-yl}butyrate (5.7 g) as a white solid. LCMS (ESI, m / z): [M+H]+ = 365.10.

[0595] 4. Synthesis of Compound 4

[0596] A mixture of ethyl 4-{6'-bromo-2-oxo-[1,3'-bipyridine]-4-yl}butyrate (1.0 g, 2.7 mmol), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (668 mg, 2.7 mmol), N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (26 mg, 0.1 mmol), copper iodide (31 mg, 0.1 mmol), and potassium carbonate (756 mg, 5.4 mmol) was placed in 10 mL of dimethyl sulfoxide and stirred at 110 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filter cake was washed with dimethyl sulfoxide (10 mL). The residue was purified by reversed-phase rapid chromatography to obtain ethyl 4-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)butyrate (940 mg), a light brown oil. LCMS (ESI, m / z): [M+H]+=529.35

[0597] 5. Synthesis of Compound 5

[0598] Under a nitrogen atmosphere, a solution of ethyl 4-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)butyrate (900 mg, 1.7 mmol) in 10 mL of tetrahydrofuran was stirred, and then diisobutylaluminum hydride (1210 mg, 8.5 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was terminated by adding water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(4-hydroxybutyl)-[1,3'-bipyridine]-2-one (540 mg). LCMS (ESI, m / z): [M+H]+=487.40

[0599] 6. Synthesis of Compound 6

[0600] Under a nitrogen atmosphere, a stirred solution of 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-4-(4-hydroxybutyl)-[1,3'-bipyridine]-2-one (510 mg, 1.0 mmol) and triphenylphosphine (412 mg, 1.5 mmol) was placed at 0 °C, and carbon tetrabromide (521 mg, 1.5 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 hour under a nitrogen atmosphere. The reaction solution was quenched at 0 °C with a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give 4-(4-bromobutyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (800 mg) as a light brown solid. LCMS (ESI, m / z): [M+H]+=549.18

[0601] 7. Synthesis of Compound 7

[0602] 650 mg, 0.8 mmol of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl}phenyl)methyl]amino}methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (4-(4-bromobutyl)- A solution of 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (541 mg, 0.9 mmol), sodium carbonate (521 mg, 4.9 mmol), and sodium iodide (36 mg, 0.2 mmol, 0.3 eq.) was placed in acetonitrile (7 mL) and stirred overnight at 90 °C in air. The mixture was then cooled to room temperature. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl}phenyl)methyl][4-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)butyl]amino}methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (200 mg, 19.33% yield), as a white solid. LCMS (ESI, m / z): [M+H]+=1261.15.

[0603] 8. Synthesis of compound 43-3

[0604] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)[4-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)butyl]amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (200 mg, 0.1 mmol) was placed in 1,4-dioxane (1 mL) and stirred in air at room temperature for 2 minutes. A 4.0 mol / L solution of hydrochloric acid in 1,4-dioxane was added dropwise to the above mixture at room temperature (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The solution was purified by high performance liquid chromatography to give (2S)-3-[3-{[({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl}methyl)[4-(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)butyl]amino]methyl}phenyl]-2-[(3R)-pyrrolidine-3-yl]propionic acid (12.2 mg, yield 8.11%).

[0605] LCMS(ESI,m / z):[M+H]+=948.50

[0606] 1 H NMR(400MHz, DMSO-d6)δ8.45(dd,J=5.9,3.3Hz,2H),8.11–7.87(m,2H),7.61(d,J=7.0Hz,1H),7.56–7.43 (m,4H),7.41–6.85(m,6H),6.26(dd,J=7.1,1.8Hz,2H),4.47–4.33(m,2H),4.23(dd,J=16.3,9.3Hz,4H), 3.43–3.30(m,2H),3.27–3.15(m,2H),3.14–3.04(m,2H),3.00–2.81(m,6H),2.76(q,J=7.6,5.8Hz,4H),2 .39(q,J=7.2,6.7Hz,4H),2.32–2.10(m,3H),2.07–1.90(m,3H),1.79–1.55(m,6H),1.46(q,J=7.7Hz,2H).

[0607] Example 43

[0608] 1. Synthesis of Compound 1

[0609] Sodium borohydride (320 mg, 8.4 mmol) was added to a methanol (30 mL) solution of methyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-dipyridine]-4-carboxylic acid (2.0 g, 4.2 mmol) in air. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding water (15 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-4-(hydroxymethyl)-2H-[1,3'-dipyridin]-2-one (500 mg, yield 26.58%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=445.18

[0610] 2. Synthesis of Compound 2

[0611] Phosphorus tribromide (292 mg, 1.0 mmol) was added dropwise to a solution of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-4-(hydroxymethyl)-2h-[1,3'-bipyridine]-2-one (400 mg, 0.9 mmol) in dichloromethane (4 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution at 0 °C. The mixture was neutralized to pH 7 with saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This yields 4-(bromoethyl)-6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2h-[1,3'-bipyridine]-2-1 (350 mg). LCMS (ESI, m / z): [M+H] + =507.09

[0612] 3. Synthesis of Compound 3

[0613] Potassium carbonate (136 mg, 1.0 mmol) was added to a mixed solution of 4-(bromomethyl)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2h-[1,3'-bipyridine]-2-one (300 mg, 0.6 mmol) and methyl m-hydroxybenzoate (75 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) at room temperature and air. The resulting mixture was stirred at 60 °C for 2 hours. The resulting mixture was then precipitated with ethyl acetate. Extracted with ethyl methacrylate (3 × 100 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography, eluting with PE / EA (1:1) to give methyl 3-((6′-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3′-bipyridine]-4-yl)methoxybenzoate (150 mg). LCMS (ESI, m / z): [M+H]+=579.21

[0614] 4. Synthesis of Compound 4

[0615] Lithium hydroxide (21 mg, 0.8 mmol) was added to a mixture of methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridin]-4-yl)methoxy)benzoate (100 mg, 0.2 mmol) in methanol (2 mL) and water (0.4 mL) at room temperature and air. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then dissolved in hydrochloric acid (2 M). The solution was acidified to pH 5. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The result was 3-((6'-(((1S,3S))-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-4-yl)methoxy)benzoic acid (102 mg) as a yellow solid. LCMS (ESI, m / z): [M+H]+=565.19

[0616] 5. Synthesis of Compound 5

[0617] At room temperature and in air, 3-[(6'-{[(1S,3S))-3-{[5-(difluoromethoxy)pyrimidin-2-carbonyl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-yl)methoxy]benzoic acid (90 mg, 0.1 mmol) and tert-butyl(3S)-3-[1-(tert-butyl)-3-(3-{(3-[(2R)- 3-(tert-butyl)-3-(tert-butyl)pyrrolidine-3-yl]-2-fluoro-1-oxopropyl]phenyl)-2-fluoro-1-oxopropyl]pyrrolidine-1-carboxylate (132 mg, 0.1 mmol) was added to N,N-dimethylformamide (3 mL) along with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (91 mg, 0.2 mmol). 0.5 mmol) and N,N-diisopropylethylamine (62 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 4 hours. The residue was purified by reversed-phase rapid chromatography to give di-tert-butyl 3,3'-(2S,2S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-4-yl)methoxybenzoyl)azonidyl)di(methylene)di(3,1-phenyl)di(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)di(pyrrolidine-1-carboxylate) (40 mg, yield 18.74%) as a white solid. LCMS (ESI, m / z): [M+H]+=1338.69.

[0618] 6. Synthesis of compound 44-3

[0619] Dioxane hydrochloride (3 mL) was added to di-tert-butyl3,3'-((2S,2S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxy-2h-[1,3'-bipyridine]-4-yl)methoxy)benzoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (30 mg, 0.02 mmol) at room temperature and in air. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain (2S,2S)-3,3'-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)-2-oxo-2h-[1,3'-bipyridine]-4-yl)methoxybenzoyl)azidine)di(methylene)di(3,1-phenyl)di(2-((R)-pyridin-3-yl)propionic acid) (6 mg).

[0620] LCMS(ESI,m / z):[M+H]+=513.90

[0621] 1 H NMR (400MHz, Methanol-d4) δ8.50(s,1H),8.19(s,2H),7.93(s,1H),7.58(d,J=7.0Hz,1H),7.48–7.38(m,2H),7.30(t,J=8.1 Hz,2H),7.18–7.12(m,3H),7.11(s,3H),7.08–6.96(m,2H),6.93–6.57(m,3H),6.55–6.46(m,1H),5.03(s,2H),4.70(d,J=8. 9Hz,1H),4.65(s,3H),4.46–4.25(m,3H),3.27–3.10(m,2H),3.08–2.87(m,4H),2.85–2.77(m,2H),2.76–2.47(m,4H),2.35– 2.21(m,2H),2.20(dd,J=19.4,11.8Hz,2H),2.19–1.99(m,2H),1.87(t,J=7.3Hz,2H),1.81–1.62(m,2H),1.44–1.22(m,4H).

[0622] Example 44

[0623] 1. Synthesis of Compound 1

[0624] Cesium carbonate (104.5 g, 320.8 mmol) was added to a solution of 3-bromo-5-methylphenol (40.0 g, 213.9 mmol) and sodium 2-chloro-2,2-difluoroacetate (97.8 g, 641.6 mmol) in N,N-dimethylformamide (400 mL) at room temperature and in air. The resulting mixture was stirred at 100 °C for 2 hours. The mixture was extracted with ethyl acetate (3 × 700 mL). The bound organic layer was washed with brine (3 × 300 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography, 1-bromo-3-(difluoromethoxy)-5-toluene (26.0 g) was obtained as a colorless oil. LCMS (ESI, m / z): [M+H]+ = 236.95 / 238.95.

[0625] 2. Synthesis of Compound 2

[0626] N-bromosuccinimide (24.0 g, 137.1 mmol, 1.3 eq.) and azobisisobutyronitrile (5.1 g, 31.6 mmol, 0.3 eq.) were added to a solution of 1-bromo-3-(difluoromethoxy)-5-toluene (25.0 g, 105.5 mmol) in carbon tetrachloride (300 mL) at room temperature and air. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (15:1) to give a colorless oil of 1-bromo-3-(bromoethyl)-5-(difluoromethoxy)benzene (18.0 g, 54.02% yield). LCMS (ESI, m / z): [M+H] + =314.85.

[0627] 3. Synthesis of Compound 3

[0628] Under a nitrogen atmosphere, a solution of tert-butyl(R)-3-(2-(S)-4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (14.2 g, 36.5 mmol) in tetrahydrofuran (150 mL) was added and stirred for 30 min. Then, 1-bromo-3-(bromomethyl)-5-(difluoromethoxy)benzene (15.0 g, 47.5 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (5 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine (3 × 200 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography, eluted with PE / EA (1:1), to give a brown oily third butyl(3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-3-[3-bromo-5-(difluoromethoxy)phenyl]-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (13.0 g). LCMS (ESI, m / z): [M+H]+=623.13

[0629] 4. Synthesis of Compound 4

[0630] Hydrogen peroxide (4.7 g, 41.7 mmol) (30%) and lithium hydroxide (1.0 g, 41.7 mmol) were added to a tetrahydrofuran (150 mL) solution of tert-butyl(R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromo-5-(difluoromethoxy)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (13.0 g, 20.9 mmol) (30 mL) at room temperature and air. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate (30 mL) at 0 °C. The mixture was alkalized to pH 12 with sodium hydroxide. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with hydrochloric acid (2 M) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This yielded a white solid (S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (10.0 g). LCMS (ESI, m / z): [M+H]+=464.05.

[0631] 5. Synthesis of Compound 5

[0632] Potassium carbonate (8.9 g, 64.6 mmol) was added to a solution of (S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (10.0 g, 21.5 mmol) and iodoethane (4.4 g, 28.0 mmol) in N,N-dimethylformamide (150 mL) at room temperature and in air. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. After purification by silica gel column chromatography, elution with PE / EA (5:1) yielded a yellow oily tert-butyl(3R)-3-[(2S)-3-[3-bromo-5-(difluoromethoxy)phenyl]-1-ethoxy-1-oxopropane-2-yl]pyrrolidine-1-carboxylic acid ester (6.6 g). LCMS(ESI,m / z):[M+H]+=492.10

[0633] 6. Synthesis of Compound 6

[0634] Palladium acetate (1.2 g, 5.4 mmol) and N,N,N',N'-tetramethylethylenediamine (0.6 g, 5.4 mmol) were added to a toluene (30 mL) solution of tert-butyl(R)-3-((S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-1-ethoxy-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (3.9 g, 10.7 mmol) at room temperature and air. The resulting mixture was stirred for 3 days at 105 °C, 40 atm, and in a carbon monoxide and hydrogen (1:1) atmosphere. The resulting mixture was then concentrated under reduced pressure. Purified by silica gel column chromatography, eluting with PE / EA (1:2), yielded a brown oily tert-butyl(3R)-3-[(2S)-3-[3-(difluoromethoxy)-5-formyl]-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylic acid ester (5.4 g). LCMS (ESI, m / z): [M+H]+=442.20

[0635] 7. Synthesis of Compound 7

[0636] Triethylamine (2.5 g, 24.5 mmol) and sodium triacetoxyborohydride (3.9 g, 18.3 mmol) were added to a solution of (R)-3-(S)-3-(3-(difluoromethoxy)-5-formylphenyl)-1-ethoxy-1-oxopropyl-2-yl)pyridine-1-carboxylic acid tert-butyl (5.4 g, 12.2 mmol) and ammonium carbonate (1.8 g, 18.3 mmol) in dichloromethane (100 mL) at room temperature and in air. The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 16 hours. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This yielded a yellow solid, 4.5 g, of tert-butyl(R)-3-((S)-3-(3-(E)-(3-(S)-2-(R)-1-(tert-butylcarbonyl)pyrrolidine-3-oxypropyl)-5-(difluoromethoxy)benzyl)imino)methyl)-5-(difluoromethoxy)phenyl)-1-ethoxy-1-oxypropyl)pyrrolidine-1-carboxylate. LCMS (ESI, m / z): [M+H]+=866.39.

[0637] 8. Synthesis of Compound 8

[0638] Sodium borohydride (393.2 g, 10.4 mmol) was added to a solution of tert-butyl(R)-3-((E)-(3-(E)-(3-(S)-2-(R)-1-(tert-butyl)-pyrrolidine-3-yl)-3-ethoxy-3-oxopropyl)-5-(difluoromethoxy)benzyl)-imino)methyl)-5-(difluoromethoxy)phenyl)-1-ethoxy-1-oxopropyl)pyrrolidine-1-carboxylate (4.5 g, 5.2 mmol) in methanol (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This yielded a yellow solid, 4.3 g, of di-tert-butyl 3,3'-(2S,2'S)-((azadiylbis(methylene))-(5-(difluoromethoxy)-3,1-phenyl))-(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate). LCMS (ESI, m / z): [M+H]+=868.41.

[0639] 9. Synthesis of Compound 9

[0640] At room temperature and air, (9h-fluorene-9-yl)methyl(2-chloro-2-oxoethyl)carbamate (1.9 g, 5.9 mmol) was added to a solution of di-tert-butyl 3,3'-((2S,2S)-((azadiylbis(methylene))bis(5-(difluoromethoxy)-3,1-phenyl)bis(3-ethoxy-3-oxopropane-1,2-diyl)) (4.3 g, 4.9 mmol) and triethylamine (1.0 g, 9.9 mmol) in dichloromethane (50 mL). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was extracted with dichloromethane (3 × 300 mL). The bound organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purification was performed by reversed-phase flash chromatography to give 1.2 g of tert-butyl(3R)-3-[(2S)-3-(3-{N-({3-[(2S)-2-[(3R)-1-(tert-butylcarbonyl)pyrrolidine-3-yl]-3-ethoxy-3-oxopropyl]-5-(difluoromethoxy)phenyl}methyl)-2-{[(9h-fluorene-9-methoxy)carbonyl]amino}acetamide]methyl}-5-(difluoromethoxy)phenyl)-1-ethoxy-1-oxopropyl]pyrrolidine-1-carboxylate. LCMS (ESI, m / z): [M+H]+=1147.51

[0641] 10. Synthesis of Compound 10

[0642] At room temperature and in air, di-tert-butyl 3,3′-(2S,2S)-(((((((9h-fluorene-9-ylmethoxycarbonylglycolylazidodiyl)bis(methylene)bis(5-(difluoromethoxy)-3,1-phenyl)bis(3-ethoxy-3-oxopropane-1,2-diyl)bis(3R,3′r)bis(pyrrolidine-1-carboxylic acid ester) (1.2 g, 1.0 mmol) and piperidine (3 mL) were reacted in N,N-dimethylformamide (1 Stir for 1 hour in 2 mL of solution. Purify by reversed-phase flash chromatography to obtain di-tert-butyl 3,3'-((2S,2'S)-(((glycyloyldiyl)bis(methylene))bis(5-(difluoromethoxy)-3,1-phenyl))bis(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (300 mg). LCMS (ESI, m / z): [M+H]+=925.42

[0643] 11. Synthesis of Compound 11

[0644] At 25°C and in air, di-tert-butyl 3,3'-((2S,2'S)-(((glyoyldiyl)bis(methylene))bis(5-(difluoromethoxy)-3,1-phenyl))bis(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (300 mg, 0.3 mmol), 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidine- 2-(1,3'-bipyridine)-4-carboxylic acid (149 mg, 0.3 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (185 mg, 0.5 mmol), and N,N-diisopropylethylamine (84 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. Purified by reversed-phase flash chromatography, 3,3′-(2S,2S)-(((((6′-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3′-bipyridine]-4-carbonyl)glycyl)azonidyl)di(methylene)di(5-(difluoromethoxy)-3,1-phenyl)di(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3′r)-di(pyrronane-1-carboxylate) (200 mg) was obtained as a yellow solid. LCMS (ESI, m / z): [M+H]+=1365.58.

[0645] 12. Synthesis of compound 45-3-1

[0646] At room temperature and in air, 70 mg (0.05 mmol) of 3,3'-(2S,2S)-(((((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-4-carbonyl)glycyl)azadiyl)-di(methylene)-di(5-(difluoromethoxy)-3,1-phenyl)-di(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'r)-di(pyridine-1-carboxylate) (2 mL) of dioxane solution was added with hydrochloric acid to dioxane. (2 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to give a yellow solid, 8.5 mg, of diethyl 3,3'-(((((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carbonyl)glycyl)azidine)bis(methylene)bis(5-(difluoromethoxy)-3,1-phenyl))(2S,2S)-bis(2-(((R)-pyridin-3-yl)propionate).

[0647] LCMS(ESI,m / z):[M+H]+=583.45

[0648] 1 H NMR (400MHz, DMSO-d6) δ9.08(d,J=6.2Hz,1H),8.36(s,2H),8.24(s,2H),7.96(d,J=2.7Hz,1H),7.74(d,J=7.0Hz,1H),7.49( d,J=7.2Hz,1H),7.46–7.40(m,1H),7.29–7.13(m,2H),7.07–6.81(m,9H),6.70–6.59(m,1H),6.55(d,J=8.9Hz,1H),4.65–4.5 3(m,2H),4.52–4.41(m,2H),4.39–4.30(m,2H),4.18(d,J=5.7Hz,2H),4.01–3.97(m,4H),3.22(s,2H),3.05(s,2H),3.01–2. 97(m,2H),2.95–2.75(m,8H),2.37–2.23(m,2H),2.19–2.09(m,1H),1.98–1.80(m,4H),1.63–1.42(m,4H),1.14–0.95(m,6H).

[0649] Example 45

[0650] 1. Synthesis of Compound 3

[0651] Under a nitrogen atmosphere, 4-(bromomethyl)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (400 mg, 0.8 mmol) and methyl 3-fluoro-5-hydroxybenzoate (147.6 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (4 mL), stirred, and then potassium carbonate (218 mg, 1.6 mmol) was added. The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The crude white solid product methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoate (380 mg) was obtained. LCMS (ESI, m / z): [M+H]+=597.20.

[0652] 2. Synthesis of Compound 4

[0653] Lithium hydroxide (400 mg, 1.9 mmol) was added to a stirred mixture of methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoate (370 mg, 0.6 mmol) and water (2 mL) in tetrahydrofuran (2 mL). The resulting mixture was stirred at room temperature in air for 1 hour. After the reaction was complete, the mixture was acidified to pH 6 with hydrochloric acid (1 M). The resulting mixture was concentrated under reduced pressure to give 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoic acid (419 mg). LCMS (ESI, m / z): [M+H]+=583.18

[0654] 3. Synthesis of Compound 5

[0655] Under a nitrogen atmosphere, a stirred mixture of 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoic acid (280 mg, 0.5 mmol) and tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (419 mg, 0.5 mmol) was placed in 3 mL Diisopropylethylamine (124 mg, 1.0 mmol) and HATU (274 mg, 0.7 mmol) were added to DMF. The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was complete, the residue was purified by reversed-phase rapid chromatography to give di-tert-butyl3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-fluorobenzoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (72 mg). LCMS (ESI, m / z): [M+H]+=1356.68.

[0656] 4. Synthesis of compound 46-3

[0657] A mixture of di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-fluorobenzoyl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (67 mg, 0.05 mmol) was placed in 1,4-dioxane hydrochloride (4 M, 3 mL) and stirred in air at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to obtain (2S,2'S)-3,3'-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-fluorobenzoyl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (10.4 mg).

[0658] LCMS(ESI,m / z):[M+H]+=1044.45

[0659] 1 H NMR (400MHz, DMSO-d6) δ9.78-9.52(m,1H),8.49(s,2H),8.07(s,1H),7.92(d,J=9.6Hz,1H),7.70(d,J=7.0Hz,1H),7.28–7 .20(m,3H),7.18–7.11(m,2H),7.10(d,J=9.0Hz,2H),7.04–6.87(m,6H),6.51(s,1H),6.34(dd,J=7.1,1.8Hz,1H),5.03(s, 2H),4.62–4.34(m,4H),4.27(s,2H),3.32(t,J=9.5Hz,2H),3.22–3.18(m,2H),3.13–3.01(m,2H),3.01–2.77(m,4H),2.77 –2.61(m,4H),2.43–2.31(m,2H),2.31–2.18(m,2H),2.17–2.12(m,1H),2.08–2.01(m,1H),1.96(s,2H),1.69–1.62(m,4H).

[0660] Example 46

[0661] 1. Synthesis of Compound 2

[0662] A solution of tert-butyl(3R)-3-[(2S)-1-ethoxy-3-(3-carboxymethylphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (4.0 g, 10.6 mmol) in dichloromethane (30 mL) with ammonium carbonate (1.5 g, 16.0 mmol), triethylamine (2.2 g, 21.2 mmol), and sodium triacetoxyborohydride (3.4 g, 16.0 mmol) was stirred overnight at 40 °C under a nitrogen atmosphere. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 3.8 g of tert-butyl(R)-3-((S)-3-(3-((E)-((3-((S)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl)-3-ethoxy-3-oxopropyl)benzyl)imino)methyl)phenyl)-1-ethoxy-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester was obtained as a yellow oil. LCMS (ESI, m / z): [M+H]+=734.43

[0663] 2. Synthesis of Compound 3

[0664] A solution of tert-butyl(R)-3-((S)-3-(3-((E)-((3-((S)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-yl)-3-ethoxy-3-oxopropyl)benzyl)imino)methyl)phenyl)-1-ethoxy-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester (3.8 g, 5.2 mmol) and sodium borohydride (392 mg, 10.4 mmol) was placed in methanol (40 mL) and stirred at room temperature for 2 hours under a nitrogen atmosphere. The desired product was detected by liquid chromatography-mass spectrometry. The mixture was quenched at 0 °C with saturated ammonium chloride aqueous solution. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Di-tert-butyl 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenyl))bis(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (3.6 g) was obtained. LCMS (ESI, m / z): [M+H]+=736.45

[0665] 3. Synthesis of Compound 6

[0666] Under a nitrogen atmosphere, 4-(bromomethyl)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (400 mg, 0.8 mmol) and methyl 3-fluoro-5-hydroxybenzoate (147.6 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (4 mL), stirred, and then potassium carbonate (218 mg, 1.6 mmol) was added. The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The crude white solid product methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoate (380 mg) was obtained. LCMS (ESI, m / z): [M+H]+=597.20.

[0667] 4. Synthesis of Compound 7

[0668] Lithium hydroxide (400 mg, 1.9 mmol) was added to a stirred mixture of methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoate (370 mg, 0.6 mmol) and water (2 mL) in tetrahydrofuran (2 mL). The resulting mixture was stirred at room temperature in air for 1 hour. After the reaction was complete, the mixture was acidified to pH 6 with hydrochloric acid (1 M). The resulting mixture was concentrated under reduced pressure to give a yellow solid, 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoic acid (300 mg). LCMS (ESI, m / z): [M+H]+=583.18

[0669] 5. Synthesis of Compound 8

[0670] Under a nitrogen atmosphere, 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-fluorobenzoic acid (290 mg, 0.5 mmol) and di-tert-butyl3,3'-((2S,2'S)-((iminobis(methylene))bis(3,1-phenyl))bis(3- A mixture of ethoxy-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (403 mg, 0.5 mmol) and N,N-dimethylformamide (3 mL) was mixed with diisopropylethylamine (129 mg, 1.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (284 mg, 0.7 mmol). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was purified by reversed-phase rapid chromatography to obtain di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-fluorobenzoyl)iminobis(methylene))bis(3,1-phenyl))bis(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (68 mg), as a yellow solid. LCMS (ESI, m / z): [M+H]+=1300.62.

[0671] 6. Synthesis of compound 46-3-1

[0672] Di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-fluorobenzoyl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(3-ethoxy-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (58 mg, 0.05 mmol) was placed in 1,4-dioxane hydrochloride (1 mL) and stirred at room temperature in air for 30 minutes. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain diethyl 3,3'-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-fluorobenzoyl)azadiyl)bis(methylene))bis(3,1-phenylene))(2S,2'S)-bis(2-((R)-pyrrolidine-3-yl)propionate) (14.0 mg).

[0673] LCMS(ESI,m / z):[M+H]+=1100.40

[0674] 1H NMR (400MHz, DMSO-d6) δ8.37(s,2H),8.24(s,2H),7.91(d,J=2.7Hz,1H),7.62(d,J=7.0Hz,1H),7.48(d,J=7.2Hz,1H),7.37(dd,J=8.9,2.7Hz,1H), 7.33–7.25(m,2H),7.11(d,J=8.2Hz,3H),7.07(d,J=2.4Hz,2H),7.03(d, J=2.8Hz,1H),7.01–6.90(m,5H),6.52(d,J=8.9Hz,1H),6.48(d,J=1.7Hz, 1H),6.26(dd,J=7.1,1.9Hz,1H),5.04(s,2H),4.62–4.43(m,2H),4.36–4 .25(m,4H),3.98–3.85(m,4H),3.31–3.21(m,2H),3.12–3.01(m,2H),3.02 –2.91(m,2H),2.86–2.72(m,6H),2.72–2.60(m,2H),2.42–2.24(m,2H),2. 16–2.05(m,2H),1.99–1.80(m,4H),1.64–1.40(m,4H),0.99–0.85(m,6H).

[0675] Example 47

[0676] 1. Synthesis of Compound 3

[0677] Under a nitrogen atmosphere, 4-(bromomethyl)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (400 mg, 0.8 mmol) and methyl 3-hydroxy-5-(trifluoromethyl)benzoate (208 mg, 0.9 mmol) were added to DMF (4 mL) at room temperature. Potassium carbonate (218 mg, 1.6 mmol) and potassium iodide (131 mg, 0.8 mmol) were then added to the mixture. The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure. A yellow oily substance, methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-(trifluoromethyl)benzoate (350 mg, crude product) was obtained. The crude product was used directly in the next reaction. LCMS (ESI, m / z): [M+H]+=647.20

[0678] 2. Synthesis of Compound 4

[0679] Methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-(trifluoromethyl)benzoate (350 mg, 0.5 mmol) and lithium hydroxide (26 mg, 1.1 mmol) were added to tetrahydrofuran (2 mL) / water (2 mL) and stirred at room temperature under air for 2 hours. After the reaction was complete, the mixture was acidified to pH 6 with hydrochloric acid (1 M). The resulting mixture was concentrated under reduced pressure. A yellow solid, 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)methoxy)-5-(trifluoromethyl)benzoic acid (300 mg, crude product), was obtained. LCMS (ESI, m / z): [M+H]+=633.18.

[0680] 3. Synthesis of Compound 5

[0681] Under a nitrogen atmosphere, at room temperature, 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-(trifluoromethyl)benzoic acid (290 mg, 0.5 mmol) and tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)]-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)]-3-[(2S)-3-(tert-butoxy)-2-[(3R) ...3-[(3R [1-(tert-Butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (400 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of diisopropylethylamine (119 mg, 0.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (262 mg, 0.7 mmol). The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. After the reaction was complete, the residue was purified by reversed-phase rapid chromatography to obtain a yellow solid, bis(tert-butyl)3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-(trifluoromethyl)benzoyl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (75 mg). LCMS (ESI, m / z): [M+H]+=1046.68

[0682] 4. Synthesis of compound 47-3

[0683] Di-tert-butyl 3,3'-((2S,2'S)-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-(trifluoromethyl)benzoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (70 mg, 0.05 mmol) was stirred in 1,4-dioxane hydrochloride in 4 M, 3 mL at room temperature under air for 3 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain (2S,2'S)-3,3'-((((3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-5-(trifluoromethyl)benzoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(2-((R)-pyrrolidine-3-yl)propionic acid (7.4 mg).

[0684] LCMS(ESI,m / z):[M+H]+=1044.55

[0685] 1 H NMR (400MHz, DMSO-d6) δ9.71–9.43(m,2H),8.31(s,2H),8.11(s,1H),7.95(d,J=9.3Hz,1H),7.72(d, J=7.1Hz,1H),7.46(s,1H),7.39(d,J=11.6Hz,2H),7.33–6.79(m,10H),6.57(s,1H),6.37(d,J=7.1H z,1H),5.11(s,2H),4.31(s,6H),3.36(d,J=12.3Hz,2H),3.21(s,2H),3.10(d,J=9.3Hz,2H),2.93(s ,2H),2.89–2.63(m,6H),2.45–2.26(m,3H),2.22–2.06(m,2H),2.07–1.89(m,3H),1.76–1.51(m,4H).

[0686] Example 48

[0687] 1. Synthesis of Compound 2

[0688] tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (2.0 g, 2.5 mmol), 1-(benzyloxy)-3-(bromomethyl)benzene (0.8 g, 3.0 mmol), and potassium carbonate (0.7 g, 5.0 mmol) were stirred overnight in air at room temperature in N,N-dimethylformamide (20 mL). The desired product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-3-{3-[({[3-(benzyloxy)phenyl]methyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl]phenyl}-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (900 mg, 36.06% yield) as a white oil. LCMS (ESI, m / z): [M+H] + =988.60.

[0689] 2. Synthesis of Compound 3

[0690] A solution of tert-butyl(3R)-3-[(2S)-3-{3-[({[3-(benzyloxy)phenyl]methyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl]phenyl}-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (480 mg, 0.5 mmol) and palladium / carbon (51.7 mg, 0.05 mmol, 10%) in ethanol (5 mL) was stirred at room temperature under a hydrogen atmosphere for 5 hours. The desired product was detected by LCMS. The mixture was filtered, and the filter cake was washed with ethanol (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)[(3-hydroxyphenyl)methyl]amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (200 mg, 45.85% yield), as a white oil. LCMS (ESI, m / z): [M+H] + =898.55.

[0691] 3. Synthesis of Compound 4

[0692] 180 mg of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)[(3-hydroxyphenyl)methyl]amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (0. 20 mmol) of 4-(bromomethyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (111.8 mg, 0.2 mmol) and potassium carbonate (55.4 mg, 0.4 mmol) were stirred overnight at 60 °C in air under N,N-dimethylformamide (2 mL). The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl]phenyl}methyl)({3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridinin-4-yl)methoxy]phenyl}methyl)amino]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (90 mg, 33.90% yield), LCMS (ESI, m / z): [M+H] + =1324.71.

[0693] 4. Synthesis of compound 48-3

[0694] 80 mg (0.06 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-(3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl]-3-oxopropyl}phenyl)methyl]({3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridinin]-4-yl)methoxy]phenyl}methyl)amino]methyl}phenyl)-1-oxopropyl]pyrrolidine-1-carboxylic acid was mixed with hydrochloric acid in dioxane (2 mL) and stirred in air at room temperature for 2 hours. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (75 mg) was purified by pre-column high-performance liquid chromatography to obtain (2S)-3-(3-{[({3-[(2S)-2-carboxy-2-(3R)-pyrrolidine-3-yl]ethyl}phenyl)({3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}methyl)amino]methyl}phenyl)-2-(3R)-pyrrolidine-3-yl)propionic acid (8.5 mg).

[0695] LCMS(ESI,m / z):[M+H] + =1012.50

[0696] 1 H NMR(400MHz, DMSO-d6+DCl)δ8.40–8.32(m,2H),8.18(s,1H),7.91(s,1H),7.72–7.71(m,1H),7.47–7.40(m,5H),7.38–7.3 0(m,3H),7.27–7.21(m,3H),7.21–7.19(m,1H),7.07–6.96(m,2H),6.55(s,1H),6.40–6.38(m,1H),5.43(s,1H),5.10(s,2H ),4.45–4.37(m,1H),4.37–4.35(m,1H),4.16(s,5H),3.48–3.37(m,2H),3.26–3.16(m,2H),3.15–3.03(m,2H),2.98–2.84 (m,2H),2.84–2.80(m,2H),2.84–2.70(m,3H),2.39–2.37(m,4H),2.22-2.14(m,2H),2.02–1.99(m,3H),1.64–1.59(m,4H).

[0697] Example 49

[0698] 1. Synthesis of Compound 2

[0699] At room temperature and in an air atmosphere, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (746 mg, 2.0 mmol) and N,N-diisopropylethylamine (507 mg, 3.9 mmol) were added to a solution of 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino) and methyl 3-aminobenzoate (297 mg, 2.0 mmol) in N,N-dimethylformamide (25 mL). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was then concentrated under reduced pressure. Purified by reversed-phase flash chromatography, methyl 3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-5-carboxamine)benzoate (600 mg, yield 77.49%) was obtained as a yellow solid. LCMS (ESI, m / z): [M+H]+=592.21

[0700] 2. Synthesis of Compound 3

[0701] Lithium hydroxide (235 mg, 9.8 mmol) was added to a solution of methyl 3-(6′-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3′-bipyridine]-5-carboxylamine)benzoate (580 mg, 1.0 mmol) in tetrahydrofuran and water (2 mL / 2 mL). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This gave 3-(6′-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3′-bipyridine]-5-carboxyl)benzoic acid (550 mg, crude) as a yellow solid. LCMS(ESI,m / z):[M+H] + =578.20.

[0702] 3. Synthesis of Compound 4

[0703] At room temperature and in an air atmosphere, 3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-oxo-2h-[1,3'-bipyridine]-5-carboxy)benzoic acid (200 mg, 0.3 mmol) and di-tert-butyl3,3′-((2S,2′s)-(azadiyl(methylene))di(3,1-phenyl))di(3-(tert-butyl)-3-oxo) To a solution of propane-1,2-diyl)(3R,3′r)-bis(pyrrolidine-1-carboxylate) (274 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (198 mg, 0.5 mmol) and N,N-diisopropylethylamine (134 mg, 1.0 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. Purified by reversed-phase flash chromatography, di-tert-butyl 3,3'-(2S,2S)-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-5-carboxyl)benzoyl)azonyl)di(methylene)di(3,1-phenyl)di(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)-di(pyridine-1-carboxylate) (150 mg, yield 32.05%) was obtained as a yellow solid. LCMS (ESI, m / z): [M+H]+=1351.70 / 1352.70.

[0704] 4. Synthesis of Compound 49-1

[0705] Dioxane hydrochloride (3 mL) was added to ((2S,2S)-((((3-(6-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3-bipyridine]-5-carboxamino)benzoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(100 mg, 0.1 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was then concentrated under reduced pressure. The solution was purified by preparative high performance liquid chromatography to obtain (2S,2S)-3,3'-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-5-carboxyl)benzoyl)azonid)di(methylene)di(3,1-phenyl)di(2-((R)-pyridin-3-yl)propionic acid) (13.4 mg).

[0706] LCMS(ESI,m / z):[M+H]+=520.50

[0707] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.55–9.08(m,3H),8.64(d,J=2.7Hz,1H),8.33(s,1H),8.27(s,2H),8.15–8.06(m,1 H),8.03(d,J=9.8Hz,1H),7.94(s,1H),7.85(d,J=8.3Hz,1H),7.59(s,1H),7.51–7.39(m,1H),7.35–6.80(m,11H),6.62(d, J=9.6Hz,1H),4.52(d,J=5.4Hz,2H),4.45–4.32(m,4H),3.35(d,J=8.6Hz,2H),3.27–3.17(m,2H),3.15–3.03(m,2H),2.98 –2.90(m,2H),2.88–2.59(m,6H),2.54(s,1H),2.45–2.24(m,2H),2.22–2.05(m,2H),2.04–1.92(m,3H),1.73–1.55(m,4H).

[0708] Example 50

[0709] 1. Synthesis of Compound 2

[0710] At room temperature and in an air atmosphere, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (746 mg, 1.9 mmol) and N,N-diisopropylethylamine (507 mg, 3.9 mmol) were added to a solution of 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-oxo-2h-[1,3'-bipyridine]-4-carboxylic acid (600 mg, 1.3 mmol) and methyl 3-aminobenzoate (198 mg, 1.3 mmol) in N,N-dimethylformamide (3 mL). The resulting mixture was stirred at room temperature for 2 hours. Methyl benzoate (400 mg, 51.66% yield) was purified by reversed-phase flash chromatography to obtain a brown solid, methyl benzoate (500 mg, yield 51.66%). LCMS (ESI, m / z): [M+H]+ = 592.19.

[0711] 2. Synthesis of Compound 3

[0712] A solution of lithium hydroxide (121 mg, 5.1 mmol) in water (6 mL) was added to a solution of methyl 3-(6'-(1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-ylamino)-2-oxy-2h-[1,3'-bipyridine]-4-carboxy)benzoate (300 mg, 0.5 mmol) in tetrahydrofuran (6 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH 6 with hydrochloric acid (1.5 M). The resulting mixture was concentrated under reduced pressure. This yielded 3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-ylamino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxy)benzoic acid (280 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H] + =578.17.

[0713] 3. Synthesis of Compound 4

[0714] At room temperature and in an air atmosphere, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (198 mg, 0.5 mmol) and N,N-diisopropylethylamine (134 mg, 0.3 mmol) were added to a solution of 3-(6'-(5-(difluoromethoxy)pyrimidin-2-ylamino)-2-oxy-2h-[1,3'-bipyridine]-4-carboxylic acid (200 mg, 0.3 mmol) and di-tert-butyl3,3'-((2S,2'S)-((azadiyl(methylene))-bis(3,1-phenyl))(3R,3'r)-di(3-(tert-butyl)-3-oxopropane-1-carboxylic acid) (274 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL). (mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 2 hours. Purification was performed by reversed-phase flash chromatography to give di-tert-butyl 3,3'-(2S,2S)-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-4-carboxylic acid)benzoyl)azadiyl)di(methylene)di(3,1-phenyl)di(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)di(pyrronane-1-carboxylate) (150 mg, yield 32.05%) as a brown solid. LCMS (ESI, m / z): [M+H]+=1351.65 / 1352.65

[0715] 4. Synthesis of compound 49-3

[0716] At room temperature and in an air atmosphere, hydrochloric acid was added to 130 mg (0.1 mmol) of 3′-((2S,2S)-((((3-(6′-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino-cyclopentyl)-2-oxo-2h-[1,3′-bipyridine]-4-carboxyl)benzoylazinediyl)bis(methylene))bis(3,1-phenyl))(3-(tert-butyl)-3-oxopropane-1,2-diyl))(3R,3′r)-bis(pyrronyl-1-carboxylate) in dioxane. 2 mL of the ring was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. It was purified by preparative high performance liquid chromatography to give (2S,2S)-3,3'-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxyl)benzoyl)azonid)di(methylene)di(3,1-phenyl)di(2-((R)-pyridin-3-yl)propionic acid) (16.6 mg).

[0717] LCMS(ESI,m / z):[M+H]+=520.45

[0718] 1 H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), δ8.31 (d, J = 1.6Hz, 2H), 8.20 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H) ,7.93–7.87(m,1H),7.86(s,1H),7.51–7.41(m,1H),7.41–7.25(m,4H),7.24–7.17(m,5H),7.09–6.9 1(m,2H),6.89–6.79(m,1H),5.19(s,3H),4.76–4.08(m,5H),3.41–3.21(m,3H),3.15–2.91(m,3H), 2.89–2.57(m,6H),2.45–2.27(m,5H),2.28–2.11(m,2H),2.09–1.95(m,3H),1.67(d,J=14.0Hz,4H).

[0719] Example 51

[0720] 1. Synthesis of Compound 2

[0721] At room temperature and in an air atmosphere, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (746 mg, 1.9 mmol) and N,N-diisopropylethylamine (507 mg, 3.9 mmol) were added to N,N-dimethylformamide (6 mL) containing 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-3-(aminomethyl)benzoate (216 mg, 1.3 mmol) at room temperature and in an air atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Methyl 3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxamine)methyl benzoate (550 mg, yield 69.39%) was purified by reversed-phase flash chromatography to obtain a yellow solid. LCMS (ESI, m / z): [M+H]+=606.21

[0722] 2. Synthesis of Compound 3

[0723] At room temperature and in an air atmosphere, a solution of lithium hydroxide (198 mg, 8.2 mmol) in water (8 mL) was added to a methanol (8 mL) solution of methyl 3-((6′-((1S,3S))-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-oxo-2h-[1,3′-bipyridine]-4-carboxamine)methyl benzoate (500 mg, 0.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then acidified to pH 1.5 with hydrochloric acid (1.5 M). 6. The resulting mixture was concentrated under reduced pressure. This yielded 3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxamine)methyl)benzoic acid (480 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =592.18

[0724] 3. Synthesis of Compound 4

[0725] At room temperature and in an air atmosphere, 3-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2h-[1,3'-bipyridine]-4-carboxamino)methyl)benzoic acid (200 mg, 0.3 mmol) and di-tert-butyl3,3'-((2S,2S)-((azadiylbis(methylene))bis(3,1- To a solution of 268 mg (0.3 mmol) of bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl) N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (193 mg, 0.5 mmol) and N,N-diisopropylethylamine (131 mg, 1.0 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. Purified by reversed-phase flash chromatography, di-tert-butyl 3,3'-(2S,2S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-4-carboxyl)methyl)benzoyl)azonidyl)di(methylene)di(3,1-phenyl)di(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)-di(pyrronyl-1-carboxylate) (150 mg, yield 32.49%) was obtained as a yellow solid. LCMS (ESI, m / z): [M+H]+=1365.68 / 1366.68.

[0726] 4. Synthesis of Compound 50-3

[0727] At room temperature and in an air atmosphere, dioxane hydrochloride (3m) was added to 3,3'-(2S,2S)-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-(5-(difluoromethoxy)pyrimidin-4-carboxyl)methyl)benzoyl-azadiyl)-(methylene)-(3,1-phenyl)-(3-(tert-butyl)-3-oxopropane-1,2-diyl)-(3R,3'r)-di(pyronyl-1-carboxylate) (130 mg, 0.1 mmol) L). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. It was purified by preparative high performance liquid chromatography to obtain (2S,2S)-3,3'-((((3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxamino)methyl)benzoyl)azonyl)di(methylene)di(3,1-phenyl)di(2-(R)pyridin-3-yl)propionic acid (18.8 mg).

[0728] LCMS(ESI,m / z):[M+H]+=527.45

[0729] 1 H NMR (400MHz, DMSO-d6) δ9.71–9.16(m,2H),8.28(s,2H),8.15(d,J=5.8Hz,2H),8.00(d,J=9.6Hz,1 H),7.81(d,J=7.2Hz,1H),7.49–7.33(m,4H),7.32–6.82(m,11H),6.78–6.65(m,1H),4.43–4.38(m, 3H),4.36(s,2H),4.35(s,3H),3.45–3.31(m,2H),3.28–3.17(m,2H),3.18–3.05(m,2H),2.95(m,2 H),2.90–2.62(m,6H),2.48–2.24(m,3H),2.21–2.04(m,2H),2.06–1.93(m,3H),1.75–1.54(m,4H).

[0730] Example 52

[0731] 1. Synthesis of Compound 2

[0732] Under a nitrogen atmosphere and at room temperature, 4-(bromomethyl)-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (400 mg, 0.80 mmol) and ethyl 4-hydroxy-2-naphthoate (205 mg, 0.9 mmol) were added to N,N-dimethylformamide (4 mL), followed by potassium carbonate (218 mg, 1.6 mmol). The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product ethyl 4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthoic acid (360 mg, crude product) was obtained as a yellow oil.

[0733] LCMS(ESI,m / z):[M+H]+=643.24

[0734] 2. Synthesis of Compound 3

[0735] Ethyl 4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthonic acid (360 mg, 0.6 mmol) was added to a mixture of tetrahydrofuran (2 mL) and water (2 mL) and stirred overnight at room temperature under air. After the reaction was complete, the mixture was acidified to pH 6 with 1 M hydrochloric acid. The mixture was concentrated under reduced pressure to give a yellow solid 4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthonic acid (310 mg, crude). LCMS (ESI, m / z): [M+H]+=615.21.

[0736] 3. Synthesis of Compound 4

[0737] 4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthoic acid (310 mg, 0.5 mmol) and di-tert-butyl3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenyl))bis(3-(tert-butyl) Butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (440 mg, 0.6 mmol) was added to N,N-dimethylformamide (3 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (288 mg, 0.8 mmol) and N,N-diisopropylethylamine (130 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was completed, the residue was purified by reversed-phase rapid chromatography to obtain bis-tert-butyl 3,3'-((2S,2'S)-((((4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (90 mg). LCMS (ESI, m / z): [M+H]+=1388.71

[0738] 4. Synthesis of compound 64-3

[0739] Di-tert-butyl 3,3'-((2S,2'S)-((((4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (80 mg, 0.06 mmol) was stirred in 1,4-dioxane hydrochloride (1 mL) at room temperature for 2 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to obtain (2S,2'S)-3,3'-((((4-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)methoxy)-2-naphthoyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (12.4 mg).

[0740] LCMS(ESI,m / z):[M+H]+=1076.45

[0741] 1 H NMR (400MHz, DMSO-d6) δ9.82–9.51(m,1H),8.38(s,2H),8.33–8.22(m,1H),8.15(s,2H),8.00–7.93(m,2H),7.76(d,J=7.1H z,1H),7.68(s,1H),7.65–7.54(m,2H),7.29(d,J=9.3Hz,2H),7.20(t,J=14.1Hz,6H),7.09(d,J=4.6Hz,1H),7.00–6.89(m,1 H),6.63(s,1H),6.45(dd,J=7.3,1.8Hz,1H),5.18(s,2H),4.62–4.51(m,2H),4.44–4.33(m,4H),3.35(s,2H),3.28–3.16(m ,2H),3.09(d,J=9.8Hz,2H),3.02–2.62(m,8H),2.45–2.26(m,2H),2.19–2.11(m,4H),2.09–1.91(m,2H),1.75–1.56(m,4H).

[0742] Referring to the method of Example 52, the following compounds were synthesized:

[0743] Compound 65-3

[0744] LCMS(ESI,m / z):[M+H]+=1076.40

[0745] 1 H NMR(400MHz,DMSO-d6)δ9.71–9.52(m,2H),8.41(s,2H),8.14(s,1H),8.09(s,1H), 7.95(d,J=9.5Hz,1H),7.86(d,J=8.2Hz,1H),7.70(t,J=9.2Hz,2H),7.52(dd,J=13. 7,6.3Hz,2H),7.43(t,J=7.7Hz,1H),7.32(d,J=7.8Hz,2H),7.26(d,J=9.1Hz,1H), 7.24–7.14(m,4H),7.08(d,J=9.3Hz,1H),6.91(d,J=4.9Hz,1H),6.87(d,J=7.7Hz,1 H),6.60(s,1H),6.42(d,J=7.2Hz,1H),5.16(s,2H),4.88–4.75(m,1H),4.58–4.41 (m,1H),4.42–4.33(m,2H),4.28–4.15(m,1H),4.09(s,1H),3.38–3.31(m,2H),3.22 –3.16(m,2H),3.11–3.02(m,2H),3.01–2.84(m,3H),2.83–2.57(m,5H),2.45–2.36( m,1H),2.32–2.27(m,2H),2.17–2.12(m,2H),2.09–1.90(m,3H),1.66–1.62(m,4H).

[0746] Compound 66-3

[0747] LCMS(ESI,m / z):[M+H]+=1080.40

[0748] 11H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.37 (s, 2H), 8.10 (s, 1H), 7.94 (s, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.34–6.87 (m, 10H), 6.82 (s, 2H), 6.49 (s, 1H), 6.33 (dd, J = 7.1, 1.8 Hz, 1H), 4.90 (s, 2H), 4.61–4.16 (m, 6H), 3.35 (dd, J = 11.5, 7.5 Hz, 2H), 3.27–3.16 (m, 2H), 3.13–3.05 (m, 2H), 2.94 (t, J = 10.3 Hz, 2H), 2.85 (d, J = 12.6 Hz, 2H), 2.68 (d, J = 8.0 Hz, 5H), 2.66 (s, 3H), 2.39 (t, J = 8.4 Hz, 1H), 2.35–2.22 (m, 2H), 2.18–2.11 (m, 2H), 2.07–1.90 (m, 3H), 1.80–1.56 (m, 8H).

[0749] Compound 67-3

[0750] LCMS (ESI, m / z): [M+H]+ = 1080.55

[0751] 1 1H NMR (400 MHz, DMSO-d6) δ 8.58–8.44 (m, 2H), 8.05 (s, 1H), 7.90 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.35–7.23 (m, 2H), 7.14 (dd, J = 13.3, 12.3 Hz, 6H), 6.93 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 10.5 Hz, 1H), 6.80 (s, 2H), 6.47 (s, 1H), 6.33 (d, J = 7.1 Hz, 1H), 4.91 (d, J = 12.8 Hz, 3H), 4.41–4.35 (m, 2H), 4.23–4.00 (m, 3H), 3.35–3.30 (m, 2H), 3.19 (s, 2H), 3.07 (d, J = 9.5 Hz, 2H), 2.90 (t, J = 10.1 Hz, 2H), 2.84–2.71 (m, 3H), 2.69–2.59 (m, 5H), 2.51 (s, 1H), 2.34 (d, J = 8.6 Hz, 4H), 2.27 (s, 1H), 2.16–2.08 (m, 1H), 2.06–2.01 (m, 2H), 1.95 (s, 2H), 1.63–1.59 (m, 8H).

[0752] Example 53

[0753] 1. Synthesis of Compound 2

[0754] At room temperature and in an air atmosphere, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (746 mg, 1.9 mmol) was added to a solution of methyl 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-amino)-2-oxo-2h-[1,3'-bipyridine]-4-carboxylic acid ester (600 mg, 1.3 mmol) and methyl 3-aminobenzoate ester (198 mg, 1.3 mmol) in N,N-dimethylformamide (7 mL). 1,1.5 eq) and N,N-diisopropylethylamine (507 mg, 3.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Purification by reversed-phase flash chromatography yielded methyl 3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxamine)benzoate (350 mg, 45.20% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =592.19.

[0755] 2. Synthesis of Compound 3

[0756] At room temperature and in an air atmosphere, methyl 3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxamine)benzoate (300 mg, 0.5 mmol) was added to a solution of lithium hydroxide (monohydrate of crystallization) (121 mg, 5.1 mmol, 10.0 eq) in tetrahydrofuran (8 mL) and an aqueous solution (8 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH 5 with 1.5 M hydrochloric acid (aq). The resulting mixture was extracted with ethyl acetate (3 × 80 mL). The filtered filtrate was concentrated under reduced pressure. This yielded 3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxyl)benzoic acid (280 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =578.20.

[0757] 3. Synthesis of Compound 4

[0758] At room temperature and in an air atmosphere, benzoic acid (250 mg, 0.4 mmol) and di-tert-butyl-3,3'-((2S,2S)-((azadiylbis(methylene))bis(5-fluoro-3,1-phenyl ... To a mixture of 430 mg (430 mg, 0.5 mmol, 1.2 eq) of DMF (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (247 mg, 0.6 mmol, 1.5 eq) and N,N-diisopropylethylamine (168 mg, 1.3 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours. Purified by reversed-phase flash chromatography, di-tert-butyl 3,3'-(2S,2S)-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridine]-4-carboxylic acid)benzoyl)azadiyl)di(methylene)di(5-fluoro-3,1-phenyl))di(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)-di(pyrronane-1-carboxylate) (180 mg, yield 29.97%) was obtained as a yellow solid. LCMS (ESI, m / z): [M+H] + =1387.65.

[0759] 4. Synthesis of Compound 68-3

[0760] A solution of 1,4-dioxane (4 M, 3 mL) of hydrogen chloride was added to di-tert-butyl 3,3'-((2S,2'S)-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxy-2h-[1,3'-bipyridine]-4-carboxyl)benzoyl)azadiyl)bis(methylene))bis(5-fluoro-3,1-phenyl))bis(3-(tert-butyl)-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.1 mmol) at room temperature and in an air atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) to obtain (2S,2S)-3,3'-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxyl)benzoyl)azadiyl)di(methylene)di(5-fluoro-3,1-phenyl))di(2-((R)-pyridin-3-yl)propionic acid). LCMS (ESI, m / z): [M+H] + =1075.30; 1 H NMR (400MHz, DMSO-d6) δ9.79–9.49(m,1H),8.48(d,J=3.6Hz,2H),8.17(d,J=11.1Hz,1H),8.02(d,J=9.8Hz,1H),7.97(s,1H ),7.98–7.81(m,2H),7.48–7.41(m,1H),7.36–7.24(m,1H),7.21(d,J=7.6Hz,1H),7.13(d,J=1.8Hz,1H),7.09–6.85(m,6H) ,6.81–6.78(m,2H),4.55(s,2H),4.52–4.29(m,4H),3.42–3.32(m,2H),3.29–3.15(m,2H),3.13–3.05(m,2H),3.04–2.84(m ,4H),2.83–2.73(m,4H),2.45–2.32(m,2H),2.21–2.07(m,2H),2.06–1.91(m,3H),1.78–1.60(m,4H),1.22(d,J=6.1Hz,1H).

[0761] Example 54

[0762] 1. Synthesis of Compound 2

[0763] Potassium carbonate (200 mg, 1.5 mmol) and potassium iodide (241 mg, 1.5 mmol) were added to an acetone (8 mL) solution of di-tert-butyl 3,3'-((2S,2S)-((azadiylbis(methylene))bis(5-fluoro-3,1-phenyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylic acid ester) (600 mg, 0.7 mmol) and 1-(bromomethyl)-3-nitrobenzene (157 mg, 0.7 mmol) at room temperature and in an air atmosphere. The resulting mixture was stirred at 60 °C for 16 hours. The product was purified by reversed-phase flash chromatography to obtain di-tert-butyl 3,3'-(2S,2'S)-((((3-nitrobenzylazadiyl)-(methylene)-(5-fluoro-3,1-phenyl))-(3-(tert-butyl)-3-oxopropane-1,2-diyl)-(3R,3'r)-(pyridine-1-carboxylic acid ester) (350 mg, yield 50.15%).

[0764] 2. Synthesis of Compound 3

[0765] Iron (87 mg, 1.6 mmol) and ammonium chloride (83 mg, 1.6 mmol) were added to 3,3′-(2S,2S)-((((3-nitrobenzyl)di-tert-butyl(methylene))-(methylene)-(5-fluoro-3,1-phenyl)-(3-(tert-butyl)-3-oxopropane-1,2-diyl)-(3R,3′r)-(pyridine-1-carboxylic acid ester) (300 mg, 0.3 mmol) in ethanol (5 mL) and water (5 mL) at room temperature and in an air atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give di-tert-butyl 3,3'-((2S,2'S)-((((3-aminophenyl)azadiyl)bis(methylene)bis(5-fluoro-3,1-phenyl)bis(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)-bis(pyridine-1-carboxylic acid ester) (250 mg, yield 86.01%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =933.54.

[0766] 3. Synthesis of Compound 4

[0767] At room temperature and in an air atmosphere, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (122 mg, 0.2 mmol) was added to a solution of di-tert-butyl 3,3'-((2S,2S)-((((3-aminophenyl)azadiyl)bis(methylene))bis(5-fluoro-3,1-phenyl)bis(3-(tert-butyl)-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (200 mg, 0.2 mmol) and 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-carboxylic acid (128 mg, 0.3 mmol, 1.3 eq) in N,N-dimethylformamide (5 mL). g (0.3 mmol, 1.5 eq) and N,N-diisopropylethylamine (83 mg, 0.6 mmol). The resulting mixture was stirred at room temperature for 3 hours. Purification by reversed-phase flash chromatography yielded di-tert-butyl 3,3'-((2S,2'S)-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-oxy-2h-[1,3'-bipyridine]-4-carboxylic acid)benzyl)azadiyl)bis(methylene))bis(5-fluoro-3,1-phenyl))(3-(tert-butyl)-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (180 mg, 61.14% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =1373.69.

[0768] 4. Synthesis of Compound 69-3

[0769] A solution of 1,4-dioxane in hydrogen chloride (4 M, 3 mL) was added to di-tert-butyl3,3'-((2S,2'S)-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxy-2h-[1,3'-bipyridine]-4-carboxylic acid)benzyl)azadiyl)bis(methylene))bis(5-fluoro-3,1-phenyl))bis(3-(tert-butyl)-3-oxopropane-1,2-diyl))(3R,3'r)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.1 mmol) at room temperature and in an air atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain (2S,2S)-3,3'-((((3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2h-[1,3-bipyridine]-4-carboxamido)benzyl)azadiyl)bis(methylene))bis(5-fluoro-3,1-phenyl))bis(2-((R)-pyrrolidin-3-yl)propionic acid).

[0770] LCMS(ESI,m / z):[M+H] + =1061.40; 1 H NMR (400MHz, DMSO-d6) δ9.85–9.50(m,1H),8.51–8.35(m,2H),8.19(s,1H),8.10–7.98(m,2H),7.89(d,J=7.1Hz ,1H),7.78(d,J=8.0Hz,1H),7.61–7.44(m,4H),7.38–7.22(m,3H),7.20–6.95(m,4H),6.93–6.74(m,1H),4.51– 4.41(m,1H),4.39–4.33(m,1H),4.31–4.11(m,6H),3.45–3.31(m,2H),3.29–3.17(m,2H),3.15–3.04(m,2H),2. 98–2.82(m,4H),2.81–2.73(m,4H),2.45–2.31(m,3H),2.25–2.11(m,2H),2.09–1.89(m,3H),1.76–1.49(m,4H).

[0771] Example 55

[0772] 1. Synthesis of Compound 1

[0773] Sodium borohydride (0.6 g, 14.9 mmol) was added to a methanol (30 mL) solution of tert-butyl(R)-3-(S)-1-(tert-butyl)-3-(3-formylphenyl)-1-oxypropyl-2-yl)pyrrolidine-1-carboxylate (3 g, 7.4 mmol) at 0 °C and in air. The resulting mixture was stirred for 2 hours at room temperature and in air. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. Purified by reversed-phase flash chromatography, the product (1.92 g, 63.68% yield) of (R)-3-((S)-1-(tert-butyl)-3-(3-(hydroxymethyl)phenyl)-1-oxypropane-2-yl)pyrrolidine-1-carboxylate was given as a grayish-white oil. LCMS (ESI, m / z): [M+H]+=406.23

[0774] 2. Synthesis of Compound 2

[0775] At 0 °C and in air, carbon tetrabromide (613 mg, 1.8 mmol) and triphenylphosphine (485 mg, 1.8 mmol) were added to a solution of tert-butyl(R)-3-(S)-1-(tert-butyl)-3-(3-(hydroxymethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.2 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at 0 °C for 1 hour. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give a light brown solid (R)-3-(S)-3-(3-(bromoethyl)phenyl)-1-(tert-butyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (480 mg, 83.11% yield). LCMS (ESI, m / z): [M+H] + =468.15 / 470.15

[0776] 3. Synthesis of Compound 3

[0777] At room temperature and in an air atmosphere, potassium carbonate (118 mg, 0.8 mmol) and potassium iodide (142 mg, 0.8 mmol) were added to a solution of tert-butyl(R)-3-(S)-3-(3-(bromoethyl)phenyl)-1-(tert-butyl)-1-oxopropan-2-yl)pyridine-1-carboxylic acid ester (200 mg, 0.4 mmol) and 6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino(cyclopentyl)amino)-4-hydroxy-2H-[1,3'-bipyridine]-2-one (184 mg, 0.4 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at 60 °C. 2 hours. The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The bound organic layer was washed with brine (3 × 30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This yielded (R)-3-((S)-1-(tert-butyl)-3-(3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2H-[1,3'-bipyridine]-4-yl)oxo)methyl)phenyl-1-oxopropane-2-yl)pyridine-1-carboxylic acid ester (180 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H]+=818.39

[0778] 4. Synthesis of Compound 201

[0779] At room temperature and in an air atmosphere, 130 mg (0.16 mmol) of (R)-3-((S)-1-(tert-butyl)-3-(3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridin]-4-yl)oxo-methyl)phenyl-1-oxopropane-2-yl)pyridine-1-carboxylate was added to a solution of dioxane hydrochloride (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to obtain (S)-3-(3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridine]-4-yl)oxo(methyl)phenyl)-2-((R)-pyridin-3-yl)propionic acid (15.5 mg).

[0780] LCMS(ESI,m / z):[M+H]+=331.75

[0781] 1H NMR(400MHz, DMSO-d6)δ8.23(s,2H),7.87(d,J=2.7Hz,1H),7.61–7.41(m,2H),7.39–7.28(m,1H),7.2 7–6.83(m,2H),7.24–6.83(m,4H),6.51(d,J=8.9Hz,1H),6.10–6.05(m,1H),5.94(d,J=2.7Hz,1H),5.0 6(s,2H),4.41–4.31(m,2H),3.23(s,2H),2.99–2.92(m,3H),2.81(d,J=9.1Hz,1H),2.65–2.54(m,1H), 2.45(d,J=6.8Hz,1H),2.24–2.06(m,3H),1.97–1.85(m,3H),1.72(d,J=9.2Hz,1H),1.60–1.33(m,2H).

[0782] Referring to the method of Example 55, the following compounds were synthesized:

[0783] Compound 202

[0784] LCMS(ESI,m / z):[M+H] + =680.25

[0785] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.88(m,1H),7.52(m,1H),7.48(m,1H),7.34( m,1H),7.24–6.82(m,5H),6.51(m,1H),6.07(m,1H),5.94(m,1H),5.08(s,2H),4.3 9–4.22(m,2H),3.26(s,2H),3.05(m,2H),2.98(m,1H),2.84(m,1H),2.56(m,1H),2 .45(m,1H),2.25–2.04(m,3H),1.97–1.78(m,3H),1.70(m,1H),1.60–1.40(m,2H).

[0786] Compound 203

[0787] LCMS(ESI,m / z):[M+H] + =730.30

[0788] 1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.23(s,2H),7.88(m,1H),7.60(s,2H),7.58–7 .51(m,2H),7.48(m,1H),7.35(m,1H),7.30–6.83(m,2H),6.51(d,1H),6.09(m,1H), 5.97(m,1H),5.16(s,2H),4.37–4.23(m,2H),3.26(m,3H),3.05(m,3H),2.84(m,1H) ,2.70–2.60(m,1H),2.28–2.04(m,3H),1.88(m,3H),1.70(m,1H),1.60–1.42(m,2H).

[0789] Example 56

[0790] 1. Synthesis of Compound 2

[0791] Potassium carbonate (191 mg, 1.4 mmol) was added to a mixture of 4-(bromomethyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (350 mg, 0.7 mmol) and methyl 3-hydroxybenzoate (105 mg, 0.7 mmol) at room temperature and in an air atmosphere. The resulting mixture was stirred at 60 °C for 2 hours. The resulting mixture was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. This yielded methyl 3-[(6'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]benzoate (340 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=579.23.

[0792] 2. Synthesis of Compound 3

[0793] Lithium hydroxide (70.4 mg, 2.9 mmol) was added to a mixture of methyl 3-((6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-oxo-2h-[1,3'-bipyridin]-4-yl)methoxy)benzoate (340 mg, 0.6 mmol) in methanol (2 mL) and water (2 mL) at room temperature and in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was stirred at room temperature for 2 hours. The mixture was then acidified to pH 1.5 with 1.5 M hydrochloric acid solution. 6. The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The bound organic layer was washed with brine (3 × 50 mL) and dried over anhydrous sodium sulfate. The filtrate after extraction was concentrated under reduced pressure. This resulted in 3-((6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridin]-4-yl)methoxy)benzoic acid (250 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H] + =565.16.

[0794] 3. Synthesis of Compound 5

[0795] At room temperature and in an air atmosphere, benzoic acid (250 mg, 0.4 mmol) and a solution of tert-butyl(3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butyl)-1-oxopropyl]pyridine-1-carboxylate (179 mg, 0.4 mmol) in N,N-dimethylformamide (3 mL) were added at room temperature to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (252 mg, 0.7 mmol) and N,N-diisopropylethylamine (172 mg, 1.3 mmol). The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by reversed-phase rapid chromatography to give (3R)-3-[(2S)-1-(tert-butyl)-3-{3-[(3)-[(6)'-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]aminocyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]phenyl}carboxamide methyl]phenyl}-1-oxopropyl-2-yl]pyridine-1-carboxylic acid ester (50 mg, yield 11.87%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=951.43.

[0796] 4. Synthesis of Compound 207

[0797] Dioxane hydrochloride (3 mL) was added to tert-butyl(3R)-3-[(2S)-1-(tert-butyl)-3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)methoxy]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate (50 mg, 0.053 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain (S)-3-(3-(3-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino-2-oxo-2h-[1,3'-bipyridin]-4-yl)methoxy)phenyl)-2-((R)-pyridin-3-yl)propionic acid (9.1 mg, yield 21.78%).

[0798] LCMS(ESI,m / z):[M+H]+=398.25

[0799] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.34(s,1H),8.24(s,2H),7.93(d,J=2.7Hz,1H),7.63(d,J=6.9Hz ,1H),7.59(s,1H),7.55(d,J=7.4Hz,1H),7.52(s,1H),7.48(d,J=7.1Hz,1H),7.45–7.36(m,2H),7.28–7 .19(m,2H),7.17–7.11(m,1H),6.85(s,2H),6.54(s,2H),6.51–6.32(m,1H),5.10(s,2H),4.45(d,J=5.9 Hz,2H),4.41–4.20(m,2H),3.12–2.74(m,4H),2.29–2.15(m,5H),2.19–1.88(m,4H),1.73–1.41(m,4H).

[0800] Example 57

[0801] 1. Synthesis of Compound 3

[0802] HATU (3.7 g, 9.7 mmol) and diisopropylethylamine (2.5 g, 19.2 mmol, 3 eq.) were added in portions to a stirred solution of tert-butyl(3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (2.6 g, 6.4 mmol) and m-bromobenzoic acid (1.3 g, 6.4 mmol) in N,N-dimethylformamide (30 mL) at room temperature under air. The resulting mixture was stirred for 2 hours at room temperature under air. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-3-(3-{[(3-bromophenyl)carbamate]methyl}phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (2.6 g, 68.85%) as a pale white oil.

[0803] LCMS(ESI,m / z):[M+H] + =587.20

[0804] 2. Synthesis of Compound 4

[0805] In an air atmosphere, a stirred solution of tert-butyl(3R)-3-[(2S)-3-(3-{[(3-bromophenyl)carboxamido]methyl}phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (2.6 g, 4.4 mmol) and potassium tert-butoxide (1.49 g, 13.2 mmol, 3 eq.) was placed in dimethylformamide (26 mL), and iodomethane (1.9 g, 13.2 mmol, 3 eq.) was added at 0 °C. The resulting mixture was stirred in an air atmosphere at room temperature for 2 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, methanol in water, 0% to 100% gradient over 20 minutes; detector, 254 nm UV light. Tert-butyl(3R)-3-[(2S)-3-(3-{[1-(3-bromophenyl)-N-methylformamido]methyl}phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (2.4 g, 90.16%) was obtained as a pale white oil.

[0806] LCMS(ESI,m / z):[M+H] + =601.22

[0807] 3. Synthesis of Compound 5

[0808] To a stirred solution of tert-butyl(3R)-3-[(2S)-3-(3-{[1-(3-bromophenyl)-N-methylformamido]methyl}phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (2.4 g, 1.0 mmol) and potassium carbonate (1.10 g, 7.978 mmol) in dioxane (25 mL) / water (5 mL), tris(diphenylphosphine)palladium dichloride (0.4 g, 0.4 mmol) and t-BuXPhos (0.2 g, 0.4 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 105 °C for 3 hours under a nitrogen atmosphere. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[1-(3-hydroxyphenyl)-N-methylformamido]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (1.92 g, 89.34%) as a pale white oil.

[0809] LCMS(ESI,m / z):[M+H] + =539.30

[0810] 4. Synthesis of Compound 6

[0811] 4-(bromomethyl)-6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-dipyridinic]-2-one (300 mg, 0.6 mol), tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[1-(3-hydroxyphenyl)-N-methylarcarboxamide]methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (254.8 mg, 0.5 mol), K₂CO₃ (163.5 mg, 1.2 mol), and potassium iodide (147.2 mg, 0.9 mol) were dissolved in acetone (10 mL) and stirred overnight at 60 °C under air atmosphere. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed with methanol (twice, 5 mL each time). The filtrate was concentrated under reduced pressure. This yielded tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(1-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}-N-methylarcarboxamide)methyl]phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (190 mg, crude product), as a yellow solid. LCMS (ESI, m / z): [M+H] + =965.47.

[0812] 5. Synthesis of Compound 212

[0813] 180 mg (0.2 mmol) of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(1-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}-N-methylarcarboxamide)methyl]phenyl}-1-oxopropane-2-yl]pyrrolidine-1-carboxylate was dissolved in dioxane hydrochloride (1 mL) and stirred in air at room temperature for 1 hour. The target product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by pre-column high-performance liquid chromatography to obtain (2S)-3-{3-[(1-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-dipyridin]-4-yl)methoxy]phenyl}-N-methylarcarboxamide)methyl]phenyl}-2-[(3R)-pyrrolidine-3-yl]propionic acid (8.7 mg, 5.77%). LCMS (ESI, m / z): [M+H] + =809.40.

[0814] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.90(d,J=2.4Hz,1H),7.60(d,J=6.0Hz,1H),7.47(d,J=7. 2Hz,1H),7.37(d,J=6.8Hz,2H),7.28–6.80(m,9H),6.55–6.42(m,2H),6.35–6.22(m,1H),5.24–4 .90(m,2H),4.61(s,1H),4.39(s,1H),4.30(m,2H),3.30–3.12(m,2H),3.06–2.84(m,4H),2.83– 2.59(m,3H),2.46–2.30(m,2H),2.24–2.02(m,3H),1.87(d,3H),1.73(d,1H),1.59–1.38(m,2H).

[0815] Example 58

[0816] 1. Synthesis of Compound 3

[0817] N-(3-bromopropyl)phthalimide (500 mg, 1.9 mmol), tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (876.2 mg, 2.2 mmol), and potassium carbonate (515.48 mg, 3.730 mmol) were stirred in N,N-dimethylformamide (10 mL) at 60 °C in air for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[3-(1,3-dioxoisoindol-2-yl)propoxy]phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (700 mg, 64.86%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =579.30.

[0818] 2. Synthesis of Compound 4

[0819] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[3-(1,3-dioxoisoindol-2-yl)propoxy]phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (550 mg, 0.9 mmol) and hydrazine hydrate (118.9 mg, 1.9 mmol, 80%) was placed in ethanol (5 mL) and stirred in air at room temperature for 2 hours. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(3R)-3-[(2S)-3-[3-(3-aminopropoxy)phenyl]-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (150 mg, 35.18%) as a pale white oil. LCMS (ESI, m / z): [M+H] + =449.29.

[0820] 3. Synthesis of Compound 5

[0821] tert-butyl(3R)-3-[(2S)-3-[3-(3-aminopropoxy)phenyl]-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (140 mg, 0.3 mmol) was mixed with 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (143.1 mg, 0.3 mmol), HATU (178.0 mg, 0.5 mmol), and diisopropylethylamine (80.7 mg, 0.6 mmol) in dimethylformamide (2 mL) and stirred in air at room temperature for 1 hour. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography to obtain tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridinyl]-4-yl)carboxamido]propoxy}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylic acid ester (90 mg, 32.44%), a white oil. LCMS (ESI, m / z): [M+H] + =889.43.

[0822] 4. Synthesis of Compound 213

[0823] A solution of tert-butyl(3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carboxylic acid]propoxy}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (80 mg, 0.1 mmol) was placed in hydrochloric acid in 1 mL of dioxane and stirred at room temperature under air for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative high-performance liquid chromatography (Prep-HPLC) to obtain (2S)-3-(3-{3-[(6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridin]-4-yl)carbamoyl]propoxy}phenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (10.0 mg, 15.16%), as an off-white solid.

[0824] LCMS(ESI,m / z):[M+H] + =733.35

[0825] 1H NMR (400MHz, DMSO-d6) δ8.82(m,1H),8.23(s,2H),7.95(d,J=2.8Hz,1H),7.70(d,J=7.2Hz,1H),7.48(d,J=7.2Hz,1H),7.42(m,1H),7.25–6.83(m, 4H),6.82–6.68(m,3H),6.59(m,1H),6.53(m,1H),4.31(m,2H),4.05–3.9 2(m,2H),3.45–3.32(m,3H),3.28–3.21(m,1H),3.11–2.95(m,2H),2.92(m 1H),2.81(m,1H),2.47–2.34(m,2H),2.22–2.03(m,3H),2.02–1.77(m,5H),1.71(m,1H),1.62–1.42(m,2H).

[0826] Example 59

[0827] 1. Synthesis of Compound 3

[0828] At room temperature and in an air atmosphere, 60% sodium hydride (1.0 g) was added to a solution of ethyl 2-(dioxophosphoryl)acetate (5.6 g, 24.9 mmol) in tetrahydrofuran (100 mL). The resulting mixture was stirred at room temperature for 30 minutes. Benzyl 3-formylpyrrolidine-1-carboxylate (5.0 g) was added to the mixture. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-(3-ethoxy-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylate (5.5 g). LCMS (ESI, m / z): [M+H] + =304.13.

[0829] 2. Synthesis of Compound 4

[0830] At room temperature, palladium hydroxide (20% palladium hydroxide content) (875 mg) was added to a methanol (130 mL) solution of 6.3 g (20.8 mmol) of benzyl 3-(3-ethoxy-3-oxopropyl-1-en-1-yl)pyridine-1-carboxylic acid. The resulting mixture was stirred for 4 hours at 40 °C and under a hydrogen atmosphere (3 atm). The resulting mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give ethyl 3-(pyrrolidine-3-yl)propionate (3.8 g), LCMS (ESI, m / z): [M+H] + =172.11.

[0831] 3. Synthesis of Compound 5

[0832] At room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N,N′,N′-tetramethylurea hexafluorophosphate (1.7 g, 4.4 mmol) and N,N-diisopropylethylamine (1.1 g, 8.8 mmol) were added to a solution of ethyl 3-(pyrrolidone-3-yl)propionate (500 mg, 2.9 mmol) and 2-(6-(((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3-acid (1.1 g, 2.9 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by reversed-phase rapid chromatography to give ethyl 3-(1-(2-(6-((1S,3S))-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)acetylpyridin-3-yl)propionate (400 mg). LCMS (ESI, m / z): [M+H] + =533.24.

[0833] 4. Synthesis of Compound 6

[0834] At room temperature, a solution of ethyl 3-(1-(2-(6-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)acetylpyridin-3-yl)propionate (350 mg, 0.6 mmol) in tetrahydrofuran (5 mL) was added to an aqueous solution of lithium hydroxide (157 mg, 6.6 mmol) (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with 2 mol / L hydrochloric acid (aqueous solution). The resulting mixture was concentrated under reduced pressure to give 3-(1-(2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)acetyl)pyrrolidine-3-yl)propionate (300 mg). LCMS (ESI, m / z): [M+H] + =505.25.

[0835] 5. Synthesis of Compound 7

[0836] At room temperature, 200 mg (0.4 mmol) of 3-(1-(2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)acetyl)pyrrolidine-3-yl)propionic acid and di-tert-butyl-3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenyl))bis(3-tert-butoxy)-3 To a solution of 242 mg (0.3 mmol) of 1,2-dimethylpropane)(3R,3'R)-bis(pyrrolidine-1-carboxylate) in N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (174 mg, 0.5 mmol) and N,N-diisopropylethylamine (118 mg, 0.9 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by reversed-phase rapid chromatography to yield di-tert-butyl 3,3'-((2S,2'S)-(((((3-(1-(2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)acetyl)pyrrolidine-3-yl)propionyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (150 mg), LCMS (ESI, m / z): [M+H + =1279.01.

[0837] 6. Synthesis of Compound 57-3

[0838] At room temperature, a solution of 1,4-dioxane with hydrogen chloride was added to 3,3'-((2S,2's)-((((3-(1-(6-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)acetyl)pyrrolidine-3-yl)propyl)azadiyl)bis(methylene))bis(3,1-phenyl))bis(3-(tert-butyl)-3-oxopropane-1,2-diyl)(3R,3'r)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (2S)-3-(3-{[N-({3-[(2S)-2-carboxy-2-((3R)-pyrrolidine-3-yl]ethyl}phenyl)methyl)-3-{1-[2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl)amino]pyridin-3-yl)acetyl}pyrrolidine-3-yl}propionyl]amino}phenyl)-2-((3R)-pyrrolidine-3-yl)propionic acid (15.2 mg).

[0839] LCMS(ESI,m / z):[M+H] + =483.90

[0840] 1 H NMR(400MHz, Methanol-d4)δ8.40(s,2H),8.18(s,2H),7.85–7.72(m,1H),7.50–7.40(m,1H),7.31–7.21(m,2H),7.19–7.14(m,2H),7.13–7.0 5(m,2H),7.04–6.98(m,1H),6.89(s,1H),6.87–6.58(m,2H),4.67–4.5 1(m,4H),4.39–4.28(m,1H),4.26–4.18(m,1H),3.78–3.64(m,1H),3.6 3–3.57(m,1H),3.56–3.45(m,3H),3.43–3.36(m,2H),3.25–3.14(m,2H ),3.13–3.05(m,1H),3.02–2.88(m,5H),2.87–2.71(m,2H),2.65–2.54 (m,4H),2.52–2.39(m,2H),2.38–2.26(m,3H),2.24–2.08(m,3H),2.06 –1.94(m,3H),1.96–1.87(m,2H),1.86–1.73(m,2H),1.69–1.47(m,3H).

[0841] Example 60

[0842] 1. Synthesis of Compound 2

[0843] At room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N,N′,N′-tetramethylurea hexafluorophosphate (655 mg, 1.7 mmol) and N,N-diisopropylethylamine (445 mg, 3.4 mmol) were added to a solution of pyrrolidine-3-ol (100 mg, 1.1 mmol) and 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)acetic acid (435 mg, 1.1 mmol) in N,N-dimethylformamide (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reversed-phase rapid chromatography to give 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-(3-hydroxypyrrolidone-1-yl)ethane-1-one (140.0 mg). LCMS (ESI, m / z): [M+H] + =449.21.

[0844] 2. Synthesis of Compound 3

[0845] At room temperature, potassium carbonate (62 mg, 0.4 mmol) and potassium iodide (93 mg, 0.6 mmol) were added to a solution of 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-(3-hydroxypyrrolidine-1-yl)ethane-1-one (100 mg, 0.2 mmol) and di-tert-butyl-3,3'-((2S,2'S)-((((2-chloroacetyl)azoniumdiyl)bis(methylene))bis(3,1-styrene))bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (194 mg, 0.2 mmol) in acetone (5 mL). The resulting mixture was stirred at 60 °C for 16 hours. The resulting mixture was filtered, and the filter cake was washed with acetonitrile (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give di-tert-butyl 3,3'-((2S,2'S)-(((((2-(1-(2-(6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)acetyl)pyrrolidine-3-yl)oxy)acetyl)azadiethylene)bis(methylene)bis(3,1-styrene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis...

Claims

1. A compound represented by Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: wherein, U is selected from single bonds, CH2, or C(O); Gp1 is -E2-L-E1-XAYG; A is selected from unsubstituted or arbitrarily assigned to one, two or more R. a The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R a They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl; X is absent or selected from a single bond, N(R x ), S, C(R x )(R x ); each R x is the same or different, independently of each other, selected from H, halogen, OH, CN, C 1-10 alkyl; when X is absent, A is spiro-attached to E1 to form a spirocycle; Y is selected from S, without substitution, or optionally by one, two, or more R. y The following groups are substituted: NH, NHC(O), NHC(O)O, -CH2NH-, -CH2CH2NH-; each R y They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 Alkyl; or, two Rs y The atoms connected to each other form C 3-10 cycloalkyl; E1 is selected from unsubstituted or optionally by one, two or more R... E1 The following groups are substituted: 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R E1 They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl; E2 is selected from OH, unsubstituted, or optionally surrounded by one, two, or more R groups. E2 The following groups are substituted: C 1-10 Alkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), OH, CN, C(O)OH, C 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 6-10 Aryl; L is selected from single bond, -N(R) L )-、-C(O)C(R L (R) L )-、-C(O)N(R L )-、-C(R L (R) L -; each R L They may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more R. L1 The following groups are substituted: C 1-10 Alkyl, C 6- 10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic; each R L1 They are either the same or different, and are independently selected from halogens, oxometalates (=O), and carbon atoms. 1-10 alkyl; Or, two Rs L The atoms connected to each other form C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups; G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R g They are either the same or different, and are independently selected from H, halogens, OH, CN, oxo (=O), C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 3-10 cycloalkyl, C 1-10 Alkyl-NH-, C 3-10 cycloalkyl-NH-, C 1-10 Alkyl-NHC(O)-, C 1-10 Alkyl-C(O)NH-; Gp2 is -MQZ; n is 1 or 2; M is selected from single bonds, unsubstituted bonds, or optionally bonds formed by one, two, or more Rs. M Replacement C 1-10 Alkyl; each R M Whether the two are the same or different, they are independently selected from H, oxo (=O), and C. 1-10 Alkyl, C 3-10 cycloalkyl; Q is selected from unsubstituted or arbitrarily selected by one, two or more R. Q The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R Q Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy groups; each R Q They are either the same or different, and are independently selected from H, halogens, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy; Z is selected from unsubstituted or optionally by one, two or more R. Z Replacement C 1-10 Alkyl; each R Z They are either identical or different, and are independently selected from H, oxo (=O), C(O)OR Z1 C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; R Z1 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; J1 is selected from a single bond, without substitution, or optionally by one, two, or more R bonds. J1 The following groups are substituted: NH-C(O), C(O)-NH, C 1-10 Alkyl, -C 1-10 Alkyl-O-, -C 1-10 Alkyl-NH-, 5-10-membered heteroaryl, 3-10-membered heterocyclic, C 1-10 Alkyl-NH-C(O), C(O)-NH-C 1-10 Alkyl, C 1-10 Alkoxy-5-10 heteroaryl, C 1-10 Alkoxy-C(O)-5-10 heteroaryl, C 1- 10 Alkyl-NHC(O)-5-10-membered heteroaryl, NHC(O)-5-10-membered heteroaryl; each R J1 Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl; J2 is selected from N, NH or -VTW-; V is connected to Gp2, and W is connected to U; V is selected from O, S, N, unsubstituted, or optionally replaced by one, two, or more R. V The following groups are substituted: NH, CH2; each R V Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 3-10 cycloalkyl; T is selected from a single bond, without substitution, or optionally by one, two, or more Rs. T Replacement C 1-10 Alkyl; each R T Whether the two are the same or different, they are independently selected from H, oxo (=O), and C. 1-10 Alkyl, C 3-10 cycloalkyl; W is selected from O, S, N, unsubstituted, or optionally replaced by one, two, or more R. W The following groups are substituted: NH, CH2, C 6-10 Aryl, 5-10 quinone heteroaryl; each R W Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 3-10 Cycloalkyl.

2. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, A is selected from unsubstituted or arbitrarily assigned to one, two or more R. a The following groups are substituted: C 3-8 cycloalkyl, 5-8 membered heterocyclic, C 6-8 Aryl, 5-6 quinone heteroaryl; Preferably, A is selected from unsubstituted or optionally substituted by one, two or more R. a The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, bicyclo[3.2.0]heptyl, 2-azaspiro[3.4]octyl, phenyl, pyridyl, 2,3-dihydro-1H-indenyl; Preferably, each R a They may be the same or different, and are independently selected from halogens (e.g., F), OH, CN, C. 1-6 alkyl; Preferably, A is selected from and when X is absent, A is selected from Preferably, A is selected from and when X is absent, A is selected from Preferably, X is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R x They are either the same or different, and are independently selected from H, OH, CN, and C. 1-6 Alkyl groups (e.g., methyl groups); Preferably, X is selected from a single bond, NH, S, (For example )、 (For example )； Preferably, Y is selected from NH, S, NHC(O), NHC(O)O, Preferably, each R y Same or different, selected independently from C 1-6 Alkyl (e.g., methyl); or, two Rs y The atoms connected to each other form C 3-6 Cycloalkyl groups (e.g., cyclopropyl); Preferably, Y is selected from NH, S, NHC(O), NHC(O)O, (For example )、 3. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, E1 is selected from unsubstituted or optionally by one, two or more R... E1 The following groups are substituted: 6-9 membered heterocyclic groups, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl; Preferably, E1 is selected from unsubstituted or optionally substituted by one, two or more R. E1 The following groups may be substituted: pyridinyl, pyridazinyl, thiazolyl, oxazolyl, phenyl, benzimidazolyl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl, indolinel; Preferably, E1 is selected from (For example )、 (For example ); and when X is absent, E1is selected from Preferably, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: C 1-6 Alkyl, 4-8 membered heterocyclic group, C 6-8 Aryl, 5-6 quinary heteroaryl, 8-10 quinary heteroaryl; Preferably, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: methyl, ethyl, 1,2-dihydropyridyl, pyrrolyl, imidazole, phenyl, 2,3-dihydro-1H-imidazolyl, aziridine, aziridine-butenyl, tetrahydropyrrolyl, indolinel, Indole, 1H-pyrrolo[3,2-b]pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 2H-indazoleyl, thiazolyl, triazolyl, dihydropyrrolyl, 1H-pyrazolo[3,4-b]pyridyl, 7H-pyrrolo[2,3-c]pyridazinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl; Preferably, each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), C(O)OH, CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-8 Aryl; Preferably, each R E2 They are either the same or different, and are independently selected from F, oxo (=O), C(O)OH, CN, methyl, difluoromethyl, and phenyl. Preferably, E2 is selected from Preferably, N in the N-L terminal connection, The methylene group is attached to the L-terminus; Preferably, L is selected from a single bond, NH, -C(O)C(R L )(R L )-, -C(O)N(R L )-, -C(R L )(R L )-; Preferably, each R L They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. L1 The following groups are substituted: C 1-6 Alkyl, C 6-8 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclic; or, two R groups L The atoms connected to it form C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; Preferably, each R L1 are the same or different, independently of each other, selected from halogen (e.g. F), C 1-6 alkyl (e.g. methyl); Preferably, each R L Same or different, selected independently from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-8 Aryl, Halogenated C 6- 8-aryl, 5-6-membered heteroaryl, 9-10-membered heteroaryl, C 1-6 Alkyl-5-6-membered heteroaryl, 3-6-membered heterocyclic; or, two R L It forms cyclopropyl, cyclobutyl, and oxecyclobutane groups with the atoms it is attached to. Preferably, each R L are the same or different, independently of each other, selected from the group consisting of methyl, trifluoromethyl, difluoromethyl, 3-fluorophenyl, 4-fluorophenyl, imidazolyl, triazolyl, pyrimidinyl, thiazolyl, phenyl, oxetanyl, pyridinyl, indolyl; or, two R L with the atom to which each is attached forms a 5- or 6-membered ring Preferably, L is selected from a single bond, NH, 4. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: C 3-6 Cycloalkyl, 5-6 membered heterocyclic, 9-10 membered heterocyclic, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl; Preferably, G is selected from the group consisting of unsubstituted or optionally substituted by one, two or more R g substituted with one, two or more R Preferably, G is selected from Preferably, each R g Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl-NH-, C 1-6 Alkyl-NHC(O)-, C 1-6 Alkyl-C(O)NH-; Preferably, each R g are the same or different, independently of each other, selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, cyclopropyl, Preferably, G is selected from 5. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, Gp1 is Preferably, Gp1 is Preferably, M is selected from C 1-6 alkyl, such as methylene; Preferably, Q is selected from the group consisting of unsubstituted or optionally substituted by one, two or more R Q substituted by one, two or more R 6-8 aryl, for example phenyl (e.g. As ), or 5-9 membered heteroaryl, for example, thiazolyl (such as ), thienyl (e.g. )； Preferably, each R Q Selected independently of H, halogen, C, whether identical or different 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Preferably, each R Q are the same or different and are independently selected from H, F, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy; Preferably, Z is selected from unsubstituted or optionally substituted by one, two or more R Z substituted C 1-6 alkyl; Preferably, Z is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R Z substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substit Preferably, each R Z are the same or different, independently of each other, selected from the group consisting of C(O)OR Z1 ; each R Z1 are the same or different, independently of each other, selected from the group consisting of H, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl); Preferably, each R Z are the same or different, independently of each other, selected from H, C(O)OH, C(O)O-C 1-6 alkyl, 3-8 membered heterocyclyl; Preferably, each R Z are the same or different, independently of each other, selected from H, C(O)OH, 3-6 membered heterocyclyl (e.g. tetrahydropyrrolyl, such as For example )； Preferably, Gp2 is (As )、 (As )、 For example For example For example 6. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein, J1 is selected from single bonds, NH-C(O), C(O)-NH, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-OC 1- 6-alkyl, 5-6-membered heteroaryl, 5-6-membered heterocyclic, C 1-6 Alkyl-NH-C(O), C 1-6 Alkoxy-5-6 heteroaryl, C 1-6 alkoxy-C(O)-5-6-membered heteroaryl, C 1-6 Alkyl-NHC(O)-5-6-membered heteroaryl, NHC(O)-5-6-membered heteroaryl; preferably, J1 is selected from C 1-6 In alkyl-O-, the O end is connected to U; Preferably, J1is selected from a single bond, NH-C(O), C(O)-NH, CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2-O, CH2-O-CH2, CH2CH2-O-CH2, CH2NH-C(O), pyrrolyl (such as ), tetrahydropyrrolyl (e.g. ), imidazole group (e.g. )、 Preferably, V is selected from O, S, N, NH, CH2; Preferably, T is selected from unsubstituted or optionally substituted by one, two or more R T substituted C 1-6 alkyl, for example ethylene, propylene, butylene, pentylene, hexylene; Preferably, T is selected from C(O), methylene, Preferably, The carbonyl group in the figure is attached to V; Preferably, W is selected from O, S, N, NH, CH2, C 6-10 Aryl, halophenyl, haloC 1-6 Alkylphenyl, 5-6 membered heteroaryl (e.g., pyridyl), 9-10 membered heteroaryl (e.g., quinolinyl); Preferably, W is selected from O, S, N, NH, CH2, Preferably, J2is selected from Preferably, selected from O, 7. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, The compound of formula (I) is selected from the following compounds: Wherein, Gp1, Gp2, J1, J2, and n independently have the definitions described in any one of claims 1-6; Preferably, the compound of formula (I) is selected from the following compounds: Among them, Gp1, Gp2, J1, J2, Rg, R T R Z1 , n, U, and Q independently have the definitions described in any one of claims 1-6; Preferably, the compound of formula (I) is selected from the following compounds: wherein J1, J2, U, R Z1 , Q independently of one another have the definitions according to any of claims 1 to 6.

8. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein, The compound is selected from the following structures:

9. A pharmaceutical composition comprising at least one of the compounds of any one of claims 1-8, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

10. The use of the compound of any one of claims 1-8, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of diseases associated with PCSK9 and / or LPA targets, such as cardiovascular diseases; Preferably, the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease. Preferably, the cardiovascular disease is familial hypercholesterolemia; Preferably, the cardiovascular disease is autosomal dominant hypercholesterolemia.

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