Cyclin K degrading agent and use thereof

Abstract

Cyclin K degrading compounds, methods for their preparation and uses are provided. Specifically, there is provided the use of compounds having the structure of formula (I) and pharmaceutical compositions thereof in the prevention and / or treatment of cyclin K-associated diseases. JPEG2026501188000135.jpg71145

Description

[Technical Field]

[0001] The present invention relates to compounds that degrade cyclin K and methods of using same to treat / prevent cyclin K-associated disorders. [Background technology]

[0002] Tumors are the second leading cause of death in humans, accounting for approximately 10 million deaths worldwide each year. Because aberrant expression of cellular proteins is believed to be a key factor leading to tumor development and progression, most drugs target these aberrantly expressed proteins. Compared with traditional inhibitor-based drug development, drug-induced protein degradation is a novel strategy to target these tumor-associated proteins. Based on their mechanism of action, protein degrons can be classified into three categories: proteolysis-targeting chimeras (PROTACs), monovalent degrons, and molecular glue degrons (Burslem, GM & Crews, CM Chem. Rev. 117, 11269-11301 (2017)).

[0003] PROTACs are currently the most widely used protein degradation technology and typically consist of a protein-targeting binding domain, an E3 ubiquitin ligase recruitment domain, and a linker. PROTAC molecules bind to target proteins and recruit E3 ligases, which ubiquitinate the target protein, ultimately leading to its degradation. Due to their large molecular weight (typically 700–1200), PROTACs have poor membrane permeability and oral bioavailability. Monovalent degrons and molecular glues have much smaller molecular weights than PROTACs, which is more consistent with Lipinski's five principles (den Besten, W. et al. Nat Chem Biol 16, 1157–1158 (2020)). Monovalent degrons induce protein degradation by binding to proteins and altering their conformation or other changes. Molecular glues induce interactions between Culin-RING E3 ligases and target proteins, ultimately leading to their degradation. Molecular glue-mediated degradation of target proteins may be independent of the target protein's ligand pocket. Previously reported thalidomide analogues (Simonetta, KR et al. Nat Commun 10, 1402 (2019)) and arylsulfonamide analogues (Baek, K. et al. Nat Chem Biol 16, 2-3 (2020)) have been developed based on this mechanism. Therefore, molecular glue may bring new hope to targets that have previously been difficult to drug due to the lack of a suitable ligand pocket. Cyclin K (also known as CCNK) is the most important cyclin of the cyclin-dependent kinase 12 / 13 (CDK12 / 13) family (Pawel Lukasik, et al. Int J Mol Sci. 2021 Mar;22(6)):2935). By forming a complex with CDK12 / 13, it can participate in the regulation of multiple biological processes, including transcription, post-transcriptional modifications, cell cycle, and cell proliferation. Initial studies have shown that CDK12 / 13 forms a complex with cyclin K and phosphorylates the C-terminal domain of RNA polymerase II, regulating its activity and thereby regulating the expression of DNA damage repair genes such as BRCA1, ATR, and FANC1 (Malgorzata Krajewska et al. Nat Commun. 2019 Apr 15;10(1):1757). CDK12 / 13 is considered a potential target for tumor therapy (Cells 2020, 9 (6), 1483;). Designing degrons targeting cyclin K has provided a novel approach to inhibiting the function of CDK12 / 13 by affecting the formation of a complex between CDK12 / 13 and cyclin K proteins. In 2020, Benjamin L. Ebert et al. reported that the CDK inhibitor CR8 induces cyclin K protein degradation through a molecular glue degrader mechanism (Nature 2020, 585, 293-297.). However, there are currently few molecular glue-based degraders for cyclin K, and these are unsatisfactory. Therefore, there is an urgent need to discover compounds with good degrading activity against cyclin K. Currently, there are very few molecular glue degraders targeting cyclin K, and it is therefore urgent to discover more compounds with high degrading activity against cyclin K and use them for drug discovery. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention provides the use of compounds having excellent Cyclin K degradation activity, their stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, metabolites, isotopic derivatives, N-oxides or prodrugs, and pharmaceutical compositions containing the compounds in the treatment or prevention of Cyclin K-related diseases. [Means for solving the problem]

[0005] In one aspect of the present invention, there are provided compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, prodrug, isotopic derivative, stereoisomer, tautomer, N-oxide, solvate, prodrug, or metabolite thereof:

[0006] JPEG2026501188000002.jpg71145

[0007] where: JPEG2026501188000003.jpg94149W 1 each independently represents CR, N, or a bond; W 2 are each independently CR 0 , N, NR a , S or O; W 3 each independently represents C or N, and W 3 At most two can be N at the same time; W 4 are each independently CR 1 , N, NR a , S or O;

[0008] R, R 0 and R 1 are each independently hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a Rb , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)NR a R b , -P(O)R a R b , C1-C6 alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, wherein the alkyl, alkenyl, or alkynyl is each -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)NR a R b , -P(O)R a R b wherein the —NR a C(O)R b R in b is -(C0-C3 alkylene) OR a , -(C0-C3 alkylene)SR a , -(C0-C3 alkylene) NR a R b optionally substituted with 0, 1 or 2 substituents selected from:

[0009] R L and R L’ each independently represents hydrogen, fluorine, C1-C6 alkyl, or C3-C6 cycloalkyl; R L and R L’ can form a 3- to 6-membered ring together with the carbon atoms to which they are attached;

[0010] R 2 is halogen, -R a , -ORa , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)NR a R b , -P(O)R a R b , (C2-C6) alkenyl, (C2-C6) alkynyl;

[0011] R 3 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl group, 5-10 membered heteroaryl, -NR M R N , -NHR M , -OR M , -SR M represents;

[0012] R 3 represents a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, a C3-C10 cycloalkyl group, or a 3- to 10-membered heterocycloalkyl group, the group may be substituted with oxo, nitro, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b, -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2 or 3 substituents selected from:

[0013] R 3 C6~C 10 When representing an aryl group or a 5- to 10-membered heteroaryl, the group may be substituted with nitro, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2, 3 substituents selected from:

[0014] R 3 Ha-NR M R N , -NHR M , -OR M , -SR M When R represents M and R N are each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10cycloalkyl), -(C0-C6 alkylene)(3-10 membered heterocycloalkyl), -(C0-C6 alkylene)(C6-C 10 -(C0-C6 alkylene)(5-10 membered heteroaryl); R M and R N are each optionally oxo, nitro, halogen, cyano, -R a , -(4-8 membered heterocycloalkyl), -(C0-C6 alkylene)OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b wherein R M or R N represents a -(C0-C6 alkylene)(3-10 membered heterocycloalkyl) containing a nitrogen atom, and when a substituent is located on the nitrogen atom, the carbon atom adjacent to the nitrogen atom in the substituent may be further substituted with an oxo group;

[0015] where R a , R b each independently represent hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein said alkyl or cycloalkyl may each independently be substituted with 0, 1, 2, or 3 halogen atoms.

[0016] In some embodiments of the present invention, JPEG2026501188000004.jpg73170W here 1 each independently represents CR or N; W 2 , W 3 and W 4 is as defined in formula (I) above.

[0017] In some embodiments of the present invention, JPEG2026501188000005.jpg234170JPEG2026501188000006.jpg214170JPEG2026501188000007.jpg105170Here, X is NR independently. a , O or S; W 1 each independently represents CR or N; W 2 are each independently CR 0 or N;W 4 are each independently CR 1 Or represents N.

[0018] In some preferred embodiments of the present invention, JPEG2026501188000008.jpg102170 where X is independently NR a , O or S; W 1 each independently represents CR or N; W 2 are each independently CR 0 or N;W 4 are each independently CR 1 Or represents N.

[0019] In some embodiments of the present invention, W 1 each independently represents CR or N; where each R is independently hydrogen, halogen, cyano, -R a -OR a Preferably, each R is independently hydrogen, halogen or -R a more preferably, each R independently represents hydrogen or C1-C6 alkyl.

[0020] In some embodiments of the present invention, W 2 are each independently CR 0 or N; where R 0 are each independently hydrogen, halogen, cyano, -R a -OR a preferably R 0 are each independently hydrogen, halogen, cyano, or -R a more preferably, each R independently represents hydrogen, cyano, or C1-C6 alkyl.

[0021] In some embodiments of the present invention, W 4 are each independently CR 1 or N; where R 1 are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a wherein each C1-C6 alkyl is independently a halogen, -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a wherein said -NR a C(O)R b R in b is optionally -(C0-C3 alkylene)ORa , -(C0-C3 alkylene)SR a , -(C0-C3 alkylene) NR a R b and preferably, the —NR a C(O)R b R in b is optionally substituted with 0, 1 or 2 substituents selected from -(C0-C3 alkylene)OH, -(C0-C3 alkylene)SH, -(C0-C3 alkylene)NH; more preferably, said -NR a C(O)R b R in b is optionally substituted with 0, 1 or 2 substituents selected from -CH2OH, -CH2SH, -CH2NH2.

[0022] In some preferred embodiments of the present invention, W 4 are each independently, CR 1 or N; where R 1 are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a wherein each C1-C6 alkyl is independently optionally halogen, OR a , S.R. a , N.R. a R b , N.R. a C(O)R b wherein said —NR a C(O)R b R in b is optionally -(C0-C3 alkylene)OR a , -(C0-C3 alkylene)SR a, -(C0-C3 alkylene) NR a R b and preferably, the —NR a C(O)R b R in b is optionally substituted with 0, 1 or 2 substituents selected from -(C0-C3 alkylene)OH, -(C0-C3 alkylene)SH, -(C0-C3 alkylene)NH; more preferably, said -NR a C(O)R b R in b is optionally substituted with 0, 1 or 2 substituents selected from -CH2OH, -CH2SH, -CH2NH2.

[0023] In some more preferred embodiments of the present invention, W 4 are each independently CR 1 or N; where R 1 each independently represents hydrogen, halogen, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, -(C0-C6 alkylene)OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene) NR a C(O)R b Represents.

[0024] In some embodiments of the present invention, R L and R L’ each independently represents hydrogen or fluorine; preferably, R L and R L’ are both hydrogen.

[0025] In some embodiments of the present invention, R 2 is halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)Rb preferably R 2 is halogen or -R a more preferably, R 2 is -CF3.

[0026] In some embodiments of the present invention, R 3 is C1-C6 alkyl, C3-C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl each independently represent oxo, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b may be substituted by 0, 1, 2, or 3 substituents selected from:

[0027] In some embodiments of the present invention, R 3 represents a C6-C10 aryl or a 5- to 10-membered heteroaryl, and the aryl and heteroaryl each independently represent a halogen, a cyano, or -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b, -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b It may be substituted by 0, 1, 2 or 3 substituents selected from:

[0028] In some embodiments of the present invention, R 3 Ha-NR M R N , -NHR M , -OR M , -SR M where R M and R N are each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 cycloalkyl), -(C0-C6 alkylene)(3-10 membered heterocycloalkyl), -(C0-C6 alkylene)(C6-C 10 -(C0-C6 alkylene)(5-10 membered heteroaryl); R M and R N are oxo, nitro, halogen, cyano, and -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a, -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b wherein R M or R N represents -(C0-C6 alkylene)(3-10 membered heterocycloalkyl) containing an N atom, and when a substituent is located on the N atom, the carbon atom adjacent to the N atom in the substituent may be further substituted with an oxo group.

[0029] In some embodiments of the present invention, R 3 Ha-NR M R N , -NHR M , -OR M , -SR M represents R M and R N are each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 cycloalkyl), -(C0-C6 alkylene)(3-10 membered heterocycloalkyl), -(C0-C6 alkylene)(C6-C 10 aryl), -(C0-C6 alkylene)(5-10 heteroaryl); M and R N are oxo, nitro, halogen, cyano, and -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)ORa , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b It may be optionally substituted with 0, 1, 2 or 3 substituents selected from:

[0030] In some embodiments of the present invention, R 3 Ha-NR M R N , -NHR M , -OR M , -SR M represents R M and R N are each independently hydrogen or C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 cycloalkyl), -(C0-C6 alkylene)(3-10 membered heterocycloalkyl), -(C0-C6 alkylene)(C6-C 10 aromatic group), -(C0-C6 alkylene)(5-10 membered heteroaryl); M and R N are each independently oxo, nitro, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)Ra , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b It may be substituted with 0, 1, 2 or 3 substituents selected from:

[0031] In some preferred embodiments of the present invention, R 3 Ha-NHR M , -OR M , -SR M represents R M are each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 -(C0-C6 alkylene)(3-10 membered heterocycloalkyl); R M are each independently oxo, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R b It may be substituted with 0, 1, 2 or 3 substituents selected from:

[0032] In some preferred embodiments of the present invention, R 3 Ha-NHR M , -OR M , -SR M represents R Mare each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 -(C0-C6 alkylene)(3-10 membered heterocycloalkyl); R M is optionally oxo, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)NR a R b , -S(O)2R a , - S(O)R a , -S(O)NR a R b , -P(O)R a R b and more preferably, R M are each independently, R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -C(O)NR a R b It may be substituted with 0, 1, 2 or 3 substituents selected from:

[0033] In some preferred embodiments of the present invention, R 3 Ha-NHR M , -OR M , -SR M represents R M are each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 -(C0-C6 alkylene)(3-10 membered heterocycloalkyl); R M is optionally oxo, halogen, cyano, -R a , -OR a, -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)NR a R b , -S(O)2R a , - S(O)R a , -S(O)NR a R b , -P(O)R a R b and more preferably, R M are each independently -R a , -OR a , -SR a , -NR a R b , -C(O)NR a R b It may be substituted with 0, 1, 2 or 3 substituents selected from:

[0034] In some preferred embodiments of the present invention, R 3 Ha-NHR M , -OR M , -SR M represents R M are each independently C1-C6 alkyl, -(C0-C6 alkylene)(C3-C 10 -(C0-C6 alkylene)(3-10 membered heterocycloalkyl); R M is optionally oxo, halogen, cyano, -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)NR a R b , -S(O)2R a , - S(O)R a , -S(O)NR a R b , -P(O)R a Rb and more preferably, R M are each independently -OR a , -SR a , -NR a R b , -C(O)NR a R b It may be substituted with 0, 1, 2 or 3 substituents selected from:

[0035] In some embodiments of the present invention, R 3 Ha-NR M R N , -NHR M , -OR M , -SR M Preferably, R 3 Ha-NHR M , -OR M , -SR M, represents R M and R N each independently represents a nitrogen-containing -(C0-C6 alkylene)(3-10 membered heterocycloalkyl), which structure may further include nitro, halogen, cyano, -R a , -(C0-C6 alkylene) OR a , -(C0-C6 alkylene)SR a , -(C0-C6 alkylene)NR a R b , -(C0-C6 alkylene)NR a C(O)R b , -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkylene)C(O)NR a R b , -(C0-C6 alkylene)S(O)2R a , -(C0-C6 alkylene)S(O)R a , -(C0-C6 alkylene)S(O)2NR a R b , -(C0-C6 alkylene)P(O)R a R bwherein the substituents are located on the nitrogen atom, and the carbon atom adjacent to the nitrogen atom in the substituent may be further substituted with oxo.

[0036] In some embodiments of the present invention, R a and R b each independently represents hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl may be optionally substituted with 0, 1, 2, or 3 halogen atoms.

[0037] In some preferred embodiments of the present invention, R a and R b each independently represents hydrogen or C1-C3 alkyl, said alkyl optionally being substituted with 0, 1, 2, or 3 halogen atoms.

[0038] The present invention encompasses any combination of the above embodiments.

[0039] More preferably, in some embodiments of the present invention, the compound represented by formula (I) is any of the compounds shown below.

[0040] JPEG2026501188000009.jpg220170JPEG2026501188000010.jpg220170JPEG2026501188000011.jpg219170JPEG202650118 8000012.jpg222170JPEG2026501188000013.jpg220170JPEG2026501188000014.jpg219170JPEG2026501188000015.jpg220 170JPEG2026501188000016.jpg219170JPEG2026501188000017.jpg153170Another aspect of the present invention relates to a pharmaceutical composition comprising: a compound according to the present invention, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[0041] Another aspect of the present invention relates to the use of a compound represented by formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a disease or disorder associated with Cyclin K protein, particularly, the disease or disorder is selected from tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases.

[0042] Another aspect of the present invention relates to a method for treating a disease or disorder associated with Cyclin K protein, the method comprising administering to a mammal in need thereof a compound of the present invention, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention. [Brief explanation of the drawings]

[0043] [Figure 1]showed that compounds 12, 17, and 18 at different concentrations induced the degradation of Cyclin K after treatment of HEK293 cells for 6 hours. DETAILED DESCRIPTION OF THE INVENTION

[0044] It should be noted that when a "compound" having a particular structural formula is referred to, this generally also encompasses its stereoisomers, diastereoisomers, enantiomers, racemic mixtures and isotopic derivatives, as well as alternative forms thereof, including pharmaceutically acceptable salts, solvates and hydrates.

[0045] Those skilled in the art are familiar with the fact that salts, solvates, and hydrates of a compound are alternative forms of the compound, and all of these can be converted into the compound under certain conditions. Furthermore, when a compound having a specific structural formula is mentioned, its pharmaceutically acceptable salts are generally included, and solvates and hydrates thereof are also included.

[0046] Similarly, a reference herein to a compound generally includes its prodrugs, metabolites, and nitroxides.

[0047] The "stereoisomer" of the compound of formula (I) of the present invention refers to a symmetric isomer formed when the compound of formula (I) has an asymmetric carbon atom. Furthermore, when the compound has a carbon-carbon double bond or a cyclic structure, an antistereoisomer is formed, and when the compound has a ketone, oxime, or the like, a tautomer is formed. All symmetric isomers, asymmetric isomers, racemates, antistereoisomers, tautomers, geometric isomers, stereoisomers, rotational isomers, and mixtures thereof of the compound of formula (I) are included within the scope of the present invention.

[0048] In the present invention, "pharmaceutically acceptable salts" refer to medicinal acid and base addition salts or solvates thereof. Such medicinal salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and chain fatty acids (e.g., acetic acid, HOOC-(CH)-COOH (where n is 0 to 4)). Base salts also include sodium salts, potassium salts, calcium salts, ammonium salts, and the like. Many non-toxic medicinal addition salts known to those skilled in the art are also included.

[0049] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (acetone, methanol, ethanol, acetonitrile, etc.) and adding an excess of an organic solvent thereto, precipitating the salt from the resulting mixture using an acid or aqueous inorganic acid solution, removing the solvent and remaining free acid therefrom, and then isolating the precipitated salt.

[0050] The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as they are converted into compounds through in vivo metabolism. For example, a "prodrug" refers to a prodrug of a compound of the present invention that, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., exhibits a reasonable benefit / risk ratio, and is effective for its intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo, for example, by metabolism in the body, to produce the parent compound of the above formula.

[0051] term Unless otherwise noted, the terms used in this application (including the specification and claims) are defined as follows: It should be noted that throughout this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. It should be noted that throughout this specification and the appended claims, the singular form "one" includes the plural reference unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology were employed unless otherwise indicated. In this application, the use of "or" or "and" means "and / or" unless stated otherwise.

[0052] In the specification and claims, a given chemical formula or name is intended to encompass all stereoisomers and optical isomers, as well as racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like may also be present in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, which can be separated into mixtures of isomers or into separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All processes for preparing the compounds of the present invention and intermediates prepared therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, such as chromatography or fractional crystallization. Depending on the process conditions, the final products of the present invention may be obtained in free (neutral) or salt form. Both the free form and the salts of these final products are within the scope of the present invention. If necessary, one form of a compound can be converted to another form. A free base or acid can be converted to a salt, and the salt can be converted to the free compound or another salt, and a mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts, can exist in various tautomeric forms in which hydrogen atoms are transferred to other parts of the molecule, thereby rearranging the chemical bonds between the atoms of the molecule. It should be understood that all possible tautomers are included in the present invention.

[0053] In the present invention, when the linking direction of a described linking group is not specified, the linking direction is arbitrary.

[0054] JPEG2026501188000018.jpg47170 Combinations of such linking groups and linked groups are permissible only if stable compounds are formed.

[0055] The definitions of the substituents in the present invention are independent of each other unless otherwise specified. For example, Ra (or R b ) is independent of the definition of different substituents. Specifically, R a (or R b ) is chosen, it is the same as R a (or R b ) have the same definition. More specifically, for example (but not exhaustively), a R b About R a (or R b When the definition of ) is selected from hydrogen, it is -C(O)-NR a R b In R a (or R b ) must be hydrogen. On the other hand, multiple R a (or R b ), if there are R a (or R b ) are also independent. For example, the substituent -(CR a R b )mO-(CR a R b )n-, if m+n is 2 or more, then m+n's R a (or R b ) are independent and can have the same or different meanings.

[0056] Unless otherwise defined, when a substituent is designated as "optionally substituted," that substituent can be, for example, alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (wherein the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arolylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio group, arylthio group, arylalkylthio group, arylthiocarbonyl group, arylalkylthiocarbonyl group, alkylsulfonyl group, arylsulfonyl group, arylalkylsulfonyl group, sulfonamido group such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH2, -CONHalkyl, substituted carbamoylaryl such as -CONH, -CONH Arylalkyl, or when there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, are selected from substituents such as alkoxycarbonyl, aryl, substituted aryl, guanidyl, heterocyclyl such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, homopiperazinyl, and substituted heterocyclyl.

[0057] In the present invention, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, and the like. Preferred alkyls in the present invention include C1-C6 alkyl or C1-C4 alkyl. Alkyl can be unsubstituted or substituted. When substituted, it can be substituted at any available attachment point, and the substituent is preferably one or more selected from duttalium, halogen, hydroxy, amino, cyano, alkyl, alkyloxy, halogenated alkyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl.

[0058] As used herein, the term "aralkyl" includes branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and refers to a residue formed by removing two hydrogen atoms from the same carbon atom or two different carbon atoms from a parent alkane. For example, "C0-C6 aralkyl" refers to an aralkyl having 0 to 6 carbon atoms, with C0 aralkyl being absent (indicating one bond). Examples of aralkyl include, but are not limited to, methylene (-CH2-), 1,1-ethoxy (-CH(CH3)-), 1,2-ethoxy (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-adane (-CH2CH2CH2CH2-), and the like. Preferred aralkyl groups in the present invention include C0-C6 aralkyl.

[0059] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and generally consisting of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains 2 to 6 carbon atoms. Alkenyl includes, but is not limited to, an ethylene group, a propylene group, a butene group, a 1-methyl-2-butene-1- group, and the like. Preferred alkenyls for the present invention include C2-C6 alkenyl.

[0060] In the present invention, the term "alkyne group" refers to a straight-chain or branched-chain hydrocarbon group containing one or more triple bonds and generally consisting of 2 to 20 carbon atoms. For example, a "C2-C6 alkyne group" contains 2 to 6 carbon atoms. Representative alkyne groups include, but are not limited to, ethyne, 1-propyne, 1-butyne, and the like. Preferred alkyne groups in the present invention include C2-C6 alkyne groups.

[0061] In the present invention, the term "alkoxy group" or "alkyloxy group" refers to -O-alkyl. A "C1-C6 alkoxy group" (or alkyloxy group) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (such as n-propoxy and i-propoxy), t-butyloxy, and the like. Similarly, an "alkylthio group" or "thioalkoxy group" refers to an alkyl as defined above attached through a sulfur bridge having the specified number of carbon atoms; for example, methyl-S- and ethyl-S- are included. Preferred alkoxy groups in the present invention include C1-C6 alkoxy groups or C1-C4 alkoxy groups.

[0062] In the present invention, the term "carbonyl" refers to an organic functional group in which two atoms, carbon and oxygen, are joined by a double bond (C=O).

[0063] As used herein, the term "aryl," whether alone or as part of a larger term such as "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members. At least one ring in the system is aromatic, where each ring in the system contains 3 to 7 ring members. In some embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, benzene, biphenyl, indane, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like. The term "arylalkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenylethyl, and the like. An appended aryl can be attached to the cyclic alkyl ring or aromatic ring at any suitable position to form a separate group. The imaginary dotted line extending from the ring system indicates a key that can be attached to any suitable ring atom. The aryl can be unsubstituted or substituted. When substituted, the substituents may be at any available point of attachment, and are preferably one or more selected from duttalium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, alkyl halide, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl.

[0064] In the present invention, the term "halogen" or "halogenated" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, heptachloropropyl, and the like. Examples of halogenated alkyls also include "fluoroalkyl," which includes branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0065] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms, e.g., trifluoromethyl-S- and pentafluoroethyl-S-.

[0066] In this disclosure, C x1 ~C x2 The expression "x" is used when referring to several substituents, which means that the number of carbon atoms in the substituent can be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms, and C4-C8 means that the group contains 4, 5, 6, 7, or 8 carbon atoms. 8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0067] In the present disclosure, the expression "x1-x2-membered ring" is used when referring to a cyclic group (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), meaning that the number of ring atoms in the group can be x1 to x2. For example, a 3- to 12-membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10-, 11-, or 12. A 3- to 6-membered ring means that the cyclic group can be a 3-, 4-, 5-, or 6-membered ring, and the number of ring atoms can be 3, 4, 5, or 6. A 3- to 8-membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, or 8. A 3-9 membered ring means that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, or 9. A 4- to 7-membered ring means that the cyclic group can be a 4-, 5-, 6-, or 7-membered ring, and the number of ring atoms can be 4, 5, 6, or 7. A 5- to 8-membered ring means that the cyclic group can be a 5-, 6-, 7-, or 8-membered ring, and the number of ring atoms can be 5, 6, 7, or 8. A 5- to 12-membered ring means that the cyclic group can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms can be 5, 6, 7, 8, 9, 10-, 11-, or 12. By 6-12 membered ring, it is meant that the cyclic group can be a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocyclic ring, the heterocyclic ring can contain 1, 2, 3, or 4 ring heteroatoms, for example, selected from N, O, and S heteroatoms.

[0068] In the present invention, the one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0069] In the present invention, the term "heteroaryl group" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and fused bicyclic or polycyclic ring systems having at least one heteroaromatic ring (i.e., an aromatic ring system containing at least one heteroatom). The ring system may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, for example, 5 to 10 ring atoms. The heteroatom may be oxygen, nitrogen, or sulfur. The carbon atoms and heteroatoms on the heteroaryl group may be optionally substituted with an oxo group (e.g., C=O, S(=O), or S(=O)2). The heteroaryl group may be unsubstituted or substituted, and if substituted, the substitution may occur at any available position. The substituent may be one or more selected from deuterium, halogen, a hydroxy group, an amino group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group.

[0070] As used herein, the term "heterocycloalkyl group" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocycloalkyl system in which one, two, three, or four ring atoms are composed of heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), with the remaining ring atoms being carbon atoms. The nitrogen atom may optionally be quaternized, and the nitrogen and sulfur atoms may optionally be oxidized (i.e., NO, SO, or SO). This definition includes monocyclic heterocycles, fused bicyclic heterocycles, and tricyclic heterocycles, and fused bicyclic and tricyclic systems include spirocyclic heterocycles, fused ring heterocycles, and bridged heterocycles. Heterocycloalkyl groups may be unsubstituted or substituted, and if substituted, may be substituted at any available bonding position. The substituents may be one or more selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups.

[0071] As used herein, the term "3- to 10-membered heterocycloalkyl" or "3- to 10-membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocycloalkyl system consisting of 3 to 10 ring atoms. In the ring structure, 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), with the remaining ring atoms being carbon atoms. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO, or SO). Note that when the total number of S and O atoms exceeds 1, the heteroatoms are not adjacent to one another. This definition includes monocyclic heterocycles, fused bicyclic heterocycles, and tricyclic heterocycles, including spiro, fused, and bridged heterocyclic structures. As used herein, the term "3- to 10-membered heterocyclic group" includes 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycles. Specific examples include azacyclobutyl, oxacyclobutane, pyrrolidinyl (including 2-pyrrolidinyl and 3-pyrrolidinyl), piperidinyl (2-, 3-, 4-piperidinyl), piperazinyl, hexahydro-1,2-diazine, morpholino, dioxanyl, azacycloheptane, 1,4-diazacycloheptane, cyclopentyl-fused pyrrolidinyl, pyrrolidinyl-fused pyrrolidinyl, cyclopropylspiropiperazine, cyclobutylspiroazacyclobutyl, azacyclobutylspiroazacyclobutyl, cyclobutylspiroazacyclopentyl, azacyclobutylspirocyclopentyl, and azacyclobutyl. Examples of cycloazacyclopentyl include, but are not limited to, cyclopentylspiroazacyclopentyl, cyclobutylspiroazacyclohexyl, azacyclobutylspirocyclohexyl, azacyclobutylspiroazacyclohexyl, cyclopentylspiroazacyclopentyl, azacyclopentylspiroazacyclopentyl, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, and the like.

[0072] In the present invention, the term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic carbocyclic ring system, in which all ring atoms of the ring system are carbon atoms. This includes monocyclic cycloalkyl, fused cycloalkyl (solid ring), spirocycloalkyl, and bridged cycloalkyl. The cycloalkyl group may be unsubstituted or substituted. When substituted, it may be substituted at any available bonding position. Preferably, it is substituted with one or more substituents selected from deuterium, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, haloalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group.

[0073] In the present invention, "C3 to C 10 "Cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cycloalkyl system of 3 to 10 carbon atoms. This includes single rings, fused rings, spiro rings, and bridged rings. Furthermore, a "C3-C12 cycloalkyl group" may be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-fused cyclopentyl, spirocyclobutyl, bicyclo[1.1.1]pentyl, and the like.

[0074] In the present invention, the term "fused ring" or "polycyclic ring" refers to a polycyclic group formed by two or more ring structures sharing two adjacent atoms with each other.

[0075] In the present invention, the term "aromatic dense ring" refers to a dense ring structure having aromaticity, and the aromaticity can be determined by methods well known to those skilled in the art, for example, by Huckel's rule. When the number of π-conjugated electrons is 4n+2, the ring structure is determined to have aromaticity.

[0076] In the present invention, the term "bridged ring" refers to a polycyclic group in which two rings have two or more ring atoms in common.

[0077] In the present invention, the term "spiro ring" refers to a polycyclic group in which two rings have one carbon atom (spiro atom) in common.

[0078] As used herein, "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen substituent, provided that the correct valence is maintained and a stable compound is obtained. As used herein, a "cyclic double bond" refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0079] When nitrogen atoms (e.g., amines) are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass the nitrogen atoms shown and their N-oxides to provide derivatives of the invention.

[0080] When any variable occurs more than one time in any composition or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, that group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definitions of R. Further, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0081] As used herein, the term "patient" refers to an organism treated by the methods of the present invention, preferably, but not limited to, a mammal (e.g., rodent, ape / monkey, horse, cow, pig, dog, cat, etc.), and most preferably, a human.

[0082] As used herein, the term "effective amount" refers to an amount of a drug or agent (i.e., a compound of the present invention) that elicits the biological or medical response desired, for example, in a tissue, system, animal, or human, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to an amount that results in the treatment, cure, prevention, or improvement of amelioration of a disease, disorder, or side effect, or a reduction in the risk of a disease, disorder, or side effect, compared to a corresponding subject not receiving such an amount or compared to the rate at which symptoms progress. An effective amount can be administered in one or more administrations, doses, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also encompasses within its scope amounts effective to enhance normal physiological function.

[0083] In the present invention, the term "treatment" is used in its broadest sense to encompass therapeutic and / or prophylactic treatment of a subject. Specifically, a given "treatment" includes any treatment that results in the alleviation, suppression, elimination, improvement, and / or prevention of a condition, disease, disorder, etc. For example, it includes alleviating, reducing, regulating, improving, eliminating, preventing, or ameliorating symptoms.

[0084] Routine therapeutic treatments include alleviating, inhibiting, or ameliorating the symptoms or condition of a disease; inhibiting the occurrence of complications; ameliorating underlying metabolic syndrome; inhibiting the occurrence of a disease or condition (including controlling the progression of a disease or condition); alleviating a disease or condition; attenuating a disease or condition; reducing complications caused by a disease or condition, or treating symptoms caused by a disease or condition. Routine prophylactic treatments include proactive treatments to prevent, inhibit, or delay the onset or progression of a disease or condition, or to reduce the severity of a disease or condition.

[0085] Similarly, a "therapeutic agent" includes a drug or reagent that has therapeutic and / or prophylactic treatment for a subject.

[0086] The terms "pharmaceutically useful" or "pharmaceutically acceptable" are used herein to refer to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals, without undue toxicity, irritation, allergic response, and / or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0087] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, zinc stearate, or stearic acid, etc.), or solvent encapsulating material, which carries or transports the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0088] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes (i.e.,) adjuvants, excipients, or vehicles (e.g., diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, aromatic substances, antibacterial agents, antifungal agents, lubricants, dispersing agents, and the like), which will vary depending on the method of administration and the nature of the dosage form.

[0089] Certain pharmaceutical and medical terms As used herein, the term "acceptable" means that the formulation ingredients or active ingredients do not have excessive adverse effects on the health of the typical treated subject.

[0090] The term "cancer," as used herein, refers to an abnormal growth of cells that is uncontrolled and may metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (bladder, intestine, brain, breast, uterus, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organs (e.g., thyroid), prostate, skin (melanoma), or blood tumors (e.g., non-leukemic leukemia).

[0091] As used herein, the term "administration in combination" or similar terms refers to the administration of several selected therapeutic agents to a patient at the same or different times, in the same or different modes of administration.

[0092] As used herein, the terms "enhance" or "potentiable" mean that a desired result is increased or prolonged, either in potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "potentiable" refers to the ability of a drug to increase or prolong its potency or duration in a system. As used in this article, "synergy" refers to the ability to maximize the potentiation of another therapeutic agent in an ideal system.

[0093] The term "immune disease" refers to a disease or disorder resulting from an adverse or harmful response to endogenous or exogenous antigens, usually resulting in cellular dysfunction or organ or tissue damage that can lead to immune symptoms.

[0094] As used herein, the terms "kit" and "product package" are synonymous.

[0095] The terms "subject," "test subject," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals (humans, non-human primates, e.g., orangutans, monkeys, and apes), agricultural animals (e.g., cows, horses, goats, sheep, and pigs), livestock (e.g., rabbits and dogs), and laboratory animals (including rodents such as rats, mice, and guinea pigs). Non-mammals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the selected mammal is a human.

[0096] Certain compounds or pharmaceutical compositions described herein, after administration, result in an improvement in a particular disease, symptom, or condition, particularly a reduction in the severity, delay in onset, slowing of disease progression, or shortening of disease duration, whether administered as a fixed dose or punctually, whether administered continuously or intermittently.

[0097] Specific Embodiments The present invention will be better understood by reference to the following specific examples, which are intended for illustrative purposes and not limiting.

[0098] If no manufacturing route is mentioned in the present invention, the relevant raw materials and intermediates are purchased from commercial reagents (e.g., Bidepharm, PharmaBlock, etc.).

[0099] The meanings of the abbreviations used in the present invention are as follows:

[0100] JPEG2026501188000019.jpg201170 In the following examples, unless otherwise specified, the reaction temperature is room temperature (10 to 30°C).

[0101] The compounds of the present invention can be separated and purified by preparative TLC, silica gel column chromatography, preparative HPLC and / or silica gel flash column chromatography (flash column chromatography), and their structures can be determined by 1The reaction was confirmed by 1 H NMR and / or MS. The progress of the reaction was monitored by TLC or LC-MS.

[0102] 1 H-NMR spectra were recorded at 500 MHz on a Bruker instrument. Chemical shifts are reported in ppm (δ values). The following abbreviations are used for NMR signal multiplicities: s = singlet, brs = broad, d = doublet, t = triplet, and m = multiplet. Coupling constants are reported as J values ​​in Hz. LC-MS experimental conditions were as follows: Instrument: Thermo U3000, ALLtech ELSD, MSQ, UV detector (combined with ELSD and MSD, elution ratio 4:1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6 × 50 mm. Column temperature: 30 °C. Gradient (time [min] / % of solvent B in A): 0.00 / 5.0, 1.40 / 95, 2.80 / 95, 2.82 / 5, 3.00 / 5. (Solvent A = 0.01% trifluoroacetic acid in water, Solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214 / 254 / 280 / 300 nm, DAD detection: 210-350 nm, flow rate: 2 mL / min, MS: ESI, 100-1500 m / z.

[0103] Preparative HPLC was typically performed using either the alkaline or acidic method (alkaline mobile phase: acetonitrile / 0.05% aqueous ammonium bicarbonate solution, acid mobile phase: acetonitrile / 0.05% aqueous formic acid solution) on a Thermo U3000 AFC-3000 system using a Globalsil C-18 12 nm, 250 × 20 mm, 10 μm, or equivalent column at a flow rate of 20 mL / min, with gradient elution.

[0104] Example 1: 3-Oxetanol (1.26 g, 17.0 mmol) and 2,4-dichloro-5-trifluoromethylpyrimidine (3.50 g, 16.1 mmol) were dissolved in tetrahydrofuran (50 mL), and lithium bis(trimethylsilyl)amide (1 M in THF, 17.7 mL) was added dropwise at 0 °C. After stirring at 0 °C for 3 h, 50 mL of ammonium chloride solution was added and the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phase was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 1-a (1.10 g, 26.9% yield).

[0105] 3-Bromocarbazole (1 g, 4.06 mmol) was dissolved in N-methylpyrrolidone (5 mL) and copper cyanide (761 mg, 8.13 mmol) was added. The mixture was stirred at 170 °C for 5 hours under microwave conditions. After the reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added and the mixture was filtered through Celite. The filtrate was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 1-b (500 mg, 64.0% yield). ESI-MS (m / z): 193.4 [M+H] + . Compound 1-b (500 mg, 2.60 mmol) was dissolved in methanol (10 mL) and Raney nickel (100 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through Celite and concentrated. The residue was purified by flash column chromatography to give 1-c (180 mg, 35.3% yield). ESI-MS (m / z): 197.5 [M+H] + . Compound 1-c (30 mg, 152 μmol) and compound 1-a (38.9 mg, 152 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (59 mg, 458 μmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to obtain compound 1 (20 mg, 31.5% yield). ESI-MS (m / z): 415.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.81 - 8.33 (m, 2H), 8.18 - 7.95 (m, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.19 - 7.05 (m, 2H), 5.73 - 5.46 (m, 1H), 4.95 - 4.41 (m, 6H).

[0106] Example 2: 2-Chloro-3-nitropyridine (500 mg, 3.15 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (1.05 g, 3.15 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (231 mg, 315 μmol) and potassium carbonate (872 mg, 6.31 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction solution was cooled to room temperature, added with 30 mL of ethyl acetate, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 2-a (600 mg, yield 57.8%). ESI-MS (m / z): 330.4 [M+H] + . 2-a (600 mg, 1.82 mmol) and 1,2-bis(diphenylphosphino)ethane (2.18 g, 5.47 mmol) were added to a flask. The mixture was reacted at 180 °C for 0.5 h. The mixture was cooled to room temperature and purified by column chromatography to give compound 2-b (150 mg, 27.6% yield). ESI-MS (m / z): 298.3 [M+H] + . Compound 2-b (150 mg, 504 μmol) was dissolved in dichloromethane (10 mL) and a dioxane hydrochloride solution (4 M, 2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give 2-c (118 mg, 100% yield). ESI-MS (m / z): 198.4 [M+H] + . Compound 2-c (30 mg, 128 μmol) and compound 1-a (32.7 mg, 128 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (49.8 mg, 385 μmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to obtain compound 2 (15 mg, 28.1% yield). ESI-MS (m / z): 416.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.47 - 11.30 (m, 1H), 8.83 - 8.39 (m, 3H), 8.21 - 8.09 (m, 1H), 7.94 - 7.81 (m, 1H), 7.47 - 7.19 (m, 3H), 5.73 - 5.51 (m, 1H), 4.94 - 4.43 (m, 6H).

[0107] Example 3: Compound 2 (20 mg, 48 μmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (31.4 mg, 96.3 μmol) and iodomethane (8.9 mg, 63 μmol) were added. The mixture was stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to give compound 3 (5 mg, 24.2% yield). ESI-MS (m / z): 430.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.35 (m, 3H), 8.22 - 8.10 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.50 - 7.37 (m, 1H), 7.35 - 7.22 (m, 1H), 5.71 - 5.56 (m, 1H), 4.97 - 4.43 (m, 6H), 3.96 - 3.85 (m, 3H).

[0108] Example 4: JPEG2026501188000023.jpg791582,4-Dichloro-5-trifluoromethylpyrimidine (20 g, 92 mmol) and zinc chloride (16.3 g, 112 mmol) were dissolved in tetrahydrofuran (200 mL), and 20% aqueous sodium thiomethoxide solution (48.5 g, 138 mmol) was added dropwise under ice cooling. The mixture was stirred at 45 °C for 16 hours. The reaction solution was cooled to room temperature, and 300 mL of ethyl acetate was added. The mixture was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain compound 4-a (7.0 g, 33.2% yield).

[0109] Compound 4-a (900 mg, 3.94 mmol) and (R)-2-aminobutanamide hydrochloride (813 mg, 7.97 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (1.53 g, 11.8 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate was added. The mixture was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 4-b (1.0 g, 86.3% yield). ESI-MS (m / z): 295.5 [M+H] + .

[0110] Compound 4-b (277 mg, 0.94 mmol) was dissolved in dichloromethane (10 mL) and m-chloroperbenzoic acid (325 mg, 1.88 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography to give compound 4-c (150 mg, 48.9% yield). ESI-MS (m / z): 327.3 [M+H] + .

[0111] Compound 2-c (30 mg, 128 μmol) and compound 4-c (42 mg, 128 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (50 mg, 385 μmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to obtain compound 4 (20 mg, 35.1% yield). ESI-MS (m / z): 444.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.80 - 8.40 (m, 4H), 8.30 - 8.11 (m, 1H), 7.84 (s, 1H), 7.75 - 7.60 (m, 2H), 7.48 - 7.31 (m, 2H), 4.83 - 4.72 (m, 2H), 4.60 (d, J = 6.5 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.86 - 1.69 (m, 2H), 0.89 - 0.62 (m, 4H).

[0112] Example 5: JPEG2026501188000024.jpg30162

[0113] Compound 5-a was obtained by replacing (R)-2-aminobutanamide hydrochloride with (2R,3R)-2-aminobutane-1,3-diol and following the synthesis of compound 4-c. Compound 5 was obtained by replacing compound 4-c with compound 5-a and following the synthesis of compound 4. ESI-MS (m / z): 447.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.74 - 12.32 (m, 1H), 8.86 - 8.68 (m, 2H), 8.60 - 8.45 (m, 2H), 8.34 - 8.11 (m, 1H), 7.93 - 7.83 (m, 1H), 7.78 - 7.01 (m, 3H), 4.82 - 4.74 (m, 2H), 4.12 - 3.97 (m, 2H), 0.95 - 0.81 (m, 3H).

[0114] Example 6: JPEG2026501188000025.jpg24164Compound 6-a was obtained by replacing 2-chloro-3-nitropyridine with 2-chloro-4-methyl-3-nitropyridine and following the synthesis of compound 2-c. Compound 6 was obtained by replacing compound 2-c with compound 6-a and following the synthesis of compound 2. ESI-MS (m / z): 430.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.82 - 8.41 (m, 2H), 8.39 - 8.29 (m, 1H), 8.16 - 8.07 (m, 1H), 7.51 - 7.41 (m, 1H), 7.23 - 7.17 (m, 2H), 5.70 - 5.53 (m, 1H), 5.35 - 4.89 (m, 1H), 4.78 - 4.57 (m, 4H), 4.45 - 4.41 (m, 1H), 2.57 (s, 3H).

[0115] Example 7: Compound 7-a was obtained by replacing compound 2-c with compound 7-a, but using (2-chloro-3-nitropyridin-4-yl)methanol instead of 2-chloro-3-nitropyridine. Compound 7 was obtained by replacing compound 2-c with compound 7-a, but using the synthesis method of compound 2 as a reference. ESI-MS (m / z): 446.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.80 - 8.37 (m, 3H), 8.16 - 8.01 (m, 1H), 7.51 - 7.15 (m, 3H), 5.68 - 5.47 (m, 2H), 4.92 - 4.67 (m, 5H), 4.65 - 4.40 (m, 3H).

[0116] Example 8: JPEG2026501188000027.jpg39148 Compound 8 was obtained by following the synthesis of compound 2, except that 2-chloro-6-methyl-3-nitropyridine was used instead of 2-chloro-3-nitropyridine. ESI-MS (m / z): 430.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.81 - 8.32 (m, 2H), 8.14 - 7.12 (m, 5H), 5.72 - 5.43 (m, 1H), 4.94 - 4.34 (m, 6H), 2.61 (s, 3H).

[0117] Example 9: Compound 9 was obtained by replacing compound 1-c with benzofuran[3,2-b]pyridine-7-methylamine and following the synthesis of compound 1. ESI-MS (m / z): 417.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.81 - 8.49 (m, 2H), 8.48 - 8.39 (m, 1H), 8.22 - 8.09 (m, 2H), 7.70 (s, 1H), 7.59 - 7.51 (m, 1H), 7.51 - 7.43 (m, 1H), 5.70 - 5.52 (m, 1H), 4.95 - 4.35 (m, 6H).

[0118] Example 10: JPEG2026501188000029.jpg37134 Compound 10 was obtained by replacing tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate with tert-butyl ((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate. ESI-MS (m / z): 417.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.78 - 8.40 (m, 4H), 7.95 - 7.86 (m, 1H), 7.49 - 7.42 (m, 1H), 7.27 - 7.21 (m, 1H), 5.76 - 5.36 (m, 1H), 5.35 - 4.65 (m, 3H), 4.64 - 4.53 (m, 2H), 4.32 - 4.29 (m, 1H).

[0119] Example 11: JPEG2026501188000030.jpg66136

[0120] Compound 4-a (1 g, 4.37 mmol) and (2R,3R)-2,3-butanediol (473 mg, 5.25 mmol) were dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (589 mg, 5.25 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate was added. The mixture was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 11-a (400 mg, 32.4% yield). ESI-MS (m / z): 283.1 [M+H] + .

[0121] Compound 11-a (400 mg, 1.42 mmol) was dissolved in dichloromethane (10 mL) and m-chloroperbenzoic acid (318 mg, 1.84 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography to give compound 11-b (250 mg, 56.1% yield). ESI-MS (m / z): 315.3 [M+H] + .

[0122] Compound 11 was obtained by replacing compound 4-c with compound 11-b and following the synthesis method of compound 4. ESI-MS (m / z): 432.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.49 - 11.29 (m, 1H), 8.67 - 8.38 (m, 2H), 8.38 - 8.28 (m, 1H), 8.16 - 8.08 (m, 1H), 7.90 - 7.82 (m, 1H), 7.52 - 7.43 (m, 1H), 7.41 - 7.33 (m, 1H), 7.28 - 7.18 (m, 1H), 5.32 - 5.13 (m, 1H), 4.87 - 4.57 (m, 3H), 3.85 - 3.72 (m, 1H), 1.24 - 0.97 (m, 6H);

[0123] Example 12: JPEG2026501188000031.jpg30155

[0124] Compound 12 was obtained by replacing compound 2-c with compound 7-a and compound 4-c with compound 11-b, following the synthesis of compound 4. ESI-MS (m / z): 462.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.74 - 7.02 (m, 7H), 5.57 - 5.45 (m, 1H), 5.30 - 5.12 (m, 1H), 4.91 - 4.57 (m, 5H), 3.85 - 3.69 (m, 1H), 1.24 - 1.20 (m, 1H), 1.12 - 0.94 (m, 5H).

[0125] Example 13: JPEG2026501188000032.jpg28155

[0126] Compound 13 was obtained by replacing compound 2-c with compound 7-a and compound 4-c with compound 5-a, following the synthesis of compound 4. ESI-MS (m / z): 477.0 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.45 - 7.08 (m, 7H), 5.72 - 5.41 (m, 2H), 5.07 - 4.58 (m, 6H), 4.13 - 3.97 (m, 2H), 3.49 - 3.43 (m, 2H), 1.08 - 0.87 (m, 3H).

[0127] Example 14: JPEG2026501188000033.jpg31129

[0128] Compound 14 was obtained by replacing compound 1-c with (4H-thiazo[4,5-b]indol-6-yl)methanamine and following the synthesis of compound 1. ESI-MS (m / z): 422.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.08 - 11.97 (m, 1H), 9.07 (s, 1H), 8.74 - 8.38 (m, 2H), 7.79 - 7.71 (m, 1H), 7.46 - 7.39 (m, 1H), 7.16 - 7.09 (m, 1H), 5.66 - 5.55 (m, 1H), 4.90 - 4.73 (m, 2H), 4.71 - 4.54 (m, 3H), 4.46 - 4.43 (m, 1H).

[0129] Example 15: JPEG2026501188000034.jpg28133

[0130] Compound 15 was synthesized by following the procedure for compound 2, replacing tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate with tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate. ESI-MS (m / z): 441.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.83 - 8.57 (m, 2H), 8.47 - 8.42 (m, 1H), 8.04 - 7.98 (m, 1H), 7.83 - 7.79 (m, 1H), 7.77 - 7.68 (m, 1H), 7.55 - 7.49 (m, 1H), 5.68 - 5.55 (m, 1H), 5.00 - 4.87 (m, 1H), 4.78 - 4.40 (m, 6H).

[0131] Example 16: Compound 16 was synthesized by following the procedure for compound 2, replacing tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate with tert-butyl(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate. ESI-MS (m / z): 430.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.49 - 11.06 (m, 1H), 8.83 - 6.98 (m, 7H), 5.78 - 5.36 (m, 1H), 5.04 - 4.17 (m, 6H), 2.58 - 2.54 (m, 3H).

[0132] Example 17: JPEG2026501188000036.jpg32137

[0133] Compound 17 was obtained by replacing compound 2-c with compound 7-a and following the synthesis method of compound 4. ESI-MS (m / z): 474.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.52 - 8.41 (m, 1H), 8.31 - 8.12 (m, 3H), 7.75 - 7.24 (m, 5H), 6.44 - 6.27 (m, 1H), 5.73 - 5.53 (m, 1H), 5.01 - 4.92 (m, 2H), 4.84 - 4.63 (m, 3H), 2.01 - 1.67 (m, 2H), 0.91 - 0.71 (m, 3H).

[0134] Example 18: JPEG2026501188000037.jpg54162

[0135] Compound 18-a was obtained by replacing (R)-2-aminobutanamide hydrochloride with (2R,3R)-3-aminobutan-2-ol and following the synthesis of compound 4-c. Compound 18 was obtained by replacing compound 4-c with compound 18-a and compound 2-c with compound 7-a and following the synthesis of compound 4. ESI-MS (m / z): 461.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.39 (d, J = 4.7 Hz, 1H), 8.17 - 7.89 (m, 3H), 7.51 - 7.44 (m, 1H), 7.40 - 7.32 (m, 1H), 7.24 - 7.13 (m, 1H), 5.80 - 5.63 (m, 1H), 5.62 - 5.46 (m, 1H), 5.11 - 4.94 (m, 1H), 4.94 - 4.84 (m, 2H), 4.74 - 4.55 (m, 2H), 4.17 - 3.99 (m, 1H), 3.83 - 3.57 (m, 1H), 1.21 - 0.86 (m, 6H).

[0136] Example 19: JPEG2026501188000038.jpg59158

[0137] Compound 19-a was obtained by following the synthesis of compound 2-b, except that (2-chloro-3-nitropyridin-4-yl)methanol was used instead of 2-chloro-3-nitropyridine.

[0138] Compound 19-a (1.08 g, 3.29 mmol) was dissolved in tetrahydrofuran (20 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (601 mg, 3.95 mmol) and diphenylphosphoryl azide (1.09 g, 3.95 mmol) were added. The mixture was stirred at room temperature for 5 hours. 50 mL of ethyl acetate was added, and the mixture was washed once with water, once with 5% dilute hydrochloric acid, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 19-b (1.1 g, 94.9% yield). ESI-MS (m / z): 353.4 [M+H] + Compound 19-b (280 mg, 795 μmol) was dissolved in dichloromethane (5 mL) and a solution of dioxane-HCl (4 M, 2 mL) was added. The mixture was stirred at room temperature for 5 hours and concentrated to give compound 19-c (229 mg, 99.9% yield). ESI-MS (m / z): 253.7 [M+H] + .

[0139] Compound 19-c (50 mg, 173 μmol) and compound 1-a (44.1 mg, 173 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (112 mg, 865 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 19-d (50 mg, 61.4% yield). ESI-MS (m / z): 471.3 [M+H] + .

[0140] Compound 19-d (50 mg, 106 μmol) was dissolved in tetrahydrofuran (20 mL), and triphenylphosphine (83.6 mg, 319 μmol) and water (0.1 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 19 (10 mg, 21.1% yield). ESI-MS (m / z): 445.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.87 - 8.34 (m, 4H), 8.15 - 8.05 (m, 1H), 7.49 - 7.38 (m, 2H), 7.26 - 7.16 (m, 1H), 5.68 - 5.53 (m, 1H), 4.94 - 4.39 (m, 7H), 4.16 (s, 2H).

[0141] Example 20: JPEG2026501188000039.jpg42170

[0142] Compound 20 was obtained by replacing compound 1-c with (4H-thieno[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)methanamine and following the synthesis of compound 1. ESI-MS (m / z): 422.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.56 - 11.47 (m, 1H), 8.79 - 8.52 (m, 1H), 8.52 - 8.41 (m, 1H), 8.37 - 8.28 (m, 1H), 7.94 - 7.76 (m, 1H), 7.22 - 7.15 (m, 2H), 5.76 - 5.60 (m, 1H), 4.95 - 4.79 (m, 3H), 4.76 - 4.73 (m, 1H), 4.60 - 4.52 (m, 2H).

[0143] Example 21: JPEG2026501188000040.jpg37133

[0144] Compound 21 was obtained by replacing tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate with tert-butyl (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate, following the synthesis of compound 2. ESI-MS (m / z): 430.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.40 - 11.30 (m, 1H), 8.76 - 8.39 (m, 3H), 7.88 - 7.80 (m, 1H), 7.37 - 7.31 (m, 1H), 7.30 - 7.24 (m, 1H), 7.04 - 6.95 (m, 1H), 5.69 - 5.55 (m, 1H), 4.92 - 4.71 (m, 2H), 4.69 - 4.42 (m, 4H), 2.98 - 2.91 (m, 3H).

[0145] Example 22: Compound 22 was obtained by replacing compound 2-c with (4H-thiazo[4,5-b]indol-6-yl)methanamine and compound 4-c with compound 11-b. The synthesis of compound 4 was described in detail below. 1 H NMR (500 MHz, DMSO-d6) δ 12.08 - 11.98 (m, 1H), 9.07 (s, 1H), 8.61 - 8.37 (m, 1H), 8.36 - 8.27 (m, 1H), 7.80 - 7.71 (m, 1H), 7.51 - 7.41 (m, 1H), 7.18 - 7.10 (m, 1H), 5.28 - 5.16 (m, 1H), 4.83 - 4.74 (m, 1H), 4.72 - 4.54 (m, 2H), 3.82 - 3.73 (m, 1H), 1.22 - 0.98 (m, 6H); ESI-MS (m / z): 438.3 [M+H] + .

[0146] Example 23: JPEG2026501188000042.jpg53157

[0147] Compound 23-a was obtained by replacing (R)-2-aminobutanamide hydrochloride with (2R,3R)-3-aminopentan-2-ol and following the synthesis of compound 4-c. Compound 23 was obtained by replacing compound 4-c with compound 23-a and compound 2-c with compound 7-a and following the synthesis of compound 4. ESI-MS (m / z): 475.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.33 - 11.19 (m, 1H), 8.45 - 8.36 (m, 1H), 8.17 - 7.73 (m, 3H), 7.50 - 7.43 (m, 1H), 7.42 - 7.33 (m, 1H), 7.25 - 7.15 (m, 1H), 5.69 - 5.57 (m, 1H), 5.57 - 5.49 (m, 1H), 5.05 - 4.84 (m, 3H), 4.75 - 4.53 (m, 2H), 4.06 - 3.90 (m, 1H), 3.89 - 3.69 (m, 1H), 2.03 - 1.39 (m, 3H), 0.85 - 0.80 (m, 2H), 0.69 - 0.62 (m, 3H).

[0148] Example 24: JPEG2026501188000043.jpg67152

[0149] 6-Chloropyridine-2-carbonitrile (1 g, 7.22 mmol) and tert-butyl (3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (3.00 g, 7.94 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (528 mg, 722 μmol) and potassium carbonate (2.99 g, 21.7 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction solution was cooled to room temperature, 80 mL of ethyl acetate was added, washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 24-a (2 g, 78.2% yield). ESI-MS (m / z): 355.3 [M+H] + .

[0150] Compound 24-a (2 g, 5.64 mmol) and 1,2-bis(diphenylphosphino)ethane (6.75 g, 16.9 mmol) were added to a flask. The mixture was reacted at 180 °C for 0.5 h. The mixture was cooled to room temperature and purified by column chromatography to give compound 24-b (200 mg, 11.0% yield). ESI-MS (m / z): 323.3 [M+H] + .

[0151] Compound 24-b (200 mg, 620 μmol) was dissolved in dichloromethane (10 mL) and a dioxane hydrochloride solution (4 M, 2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give 24-c (160 mg, 100% yield). ESI-MS (m / z): 223.3 [M+H] + .

[0152] Compound 24-c (30.5 mg, 118 μmol) and compound 1-a (30 mg, 118 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (45.7 mg, 353 μmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to give compound 24 (12 mg, 23.1% yield). ESI-MS (m / z): 441.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.85 - 8.51 (m, 2H), 8.45 - 8.11 (m, 3H), 7.83 - 7.24 (m, 3H), 5.71 - 5.45 (m, 1H), 4.93 - 4.65 (m, 4H), 4.63 - 4.35 (m, 2H).

[0153] Example 25: JPEG2026501188000044.jpg44153

[0154] Compound 25 was obtained by replacing 6-chloropyridinecarbonitrile with 2-chloroisonicotinonitrile and following the synthesis method of compound 24. ESI-MS (m / z): 441.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.27 - 9.09 (m, 2H), 8.86 - 8.24 (m, 3H), 7.84 - 7.29 (m, 3H), 5.77 - 5.41 (m, 1H), 4.92 - 4.65 (m, 4H), 4.61 - 4.36 (m, 2H).

[0155] Example 26: JPEG2026501188000045.jpg51151

[0156] Compound 26 was obtained by replacing 6-chloropyridinecarbonitrile with 6-chloropyridine-2-methanol and following the synthesis method of compound 24. ESI-MS (m / z): 446.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.80 - 8.48 (m, 1H), 8.44 - 8.34 (m, 2H), 8.29 - 8.20 (m, 1H), 7.66 - 7.41 (m, 3H), 7.23 - 7.15 (m, 1H), 5.90 - 5.80 (m, 1H), 5.68 - 5.48 (m, 1H), 5.13 - 5.03 (m, 2H), 4.92 - 4.63 (m, 4H), 4.61 - 4.33 (m, 2H).

[0157] Example 27: JPEG2026501188000046.jpg50158

[0158] Compound 27 was obtained by replacing compound 1-a with compound 11-b and following the synthesis method of compound 19. ESI-MS (m / z): 461.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.13 - 11.57 (m, 1H), 8.74 - 8.04 (m, 4H), 7.56 - 7.16 (m, 3H), 5.36 - 5.16 (m, 1H), 4.80 - 4.38 (m, 4H), 3.85 - 3.68 (m, 2H), 1.23 - 0.95 (m, 6H).

[0159] Example 28:

[0160] Compound 24 (10 mg, 23 μmol) was dissolved in methanol (2 mL) and Raney nickel (10 mg) was added. The mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through Celite and concentrated. The residue was purified by preparative liquid chromatography to give compound 28 (3 mg, 30% yield). ESI-MS (m / z): 445.3 (M+H) + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.82 - 8.14 (m, 6H), 7.72 - 7.45 (m, 3H), 7.25 - 7.16 (m, 1H), 5.71 - 5.50 (m, 1H), 4.94 - 4.84 (m, 1H), 4.76 - 4.58 (m, 4H), 4.41 - 4.32 (m, 3H).

[0161] Example 29: JPEG2026501188000048.jpg37166

[0162] Compound 29 was obtained by replacing compound 1-c with (4H-thiazo[5,4-b]indol-6-yl)methanamine and following the synthesis of compound 1. ESI-MS (m / z): 422.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.87 - 8.32 (m, 3H), 7.87 - 7.76 (m, 1H), 7.50 - 7.38 (m, 1H), 7.19 - 7.09 (m, 1H), 5.69 - 5.54 (m, 1H), 4.93 - 4.71 (m, 2H), 4.70 - 4.42 (m, 4H).

[0163] Example 30: JPEG2026501188000049.jpg35165

[0164] Compound 30 was obtained by replacing compound 1-c with (benzo[4,5]thieno[3,2-b]pyridin-7-yl)methanamine and following the synthesis of compound 1. ESI-MS (m / z): 433.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.81 - 8.70 (m, 2H), 8.54 - 8.49 (m, 1H), 8.47 - 8.41 (m, 1H), 8.40 - 8.34 (m, 1H), 8.06 - 7.98 (m, 1H), 7.57 - 7.49 (m, 2H), 5.71 - 5.53 (m, 1H), 4.92 - 4.37 (m, 6H).

[0165] Example 31: JPEG2026501188000050.jpg37161

[0166] Compound 31 was obtained by replacing compound 1-c with (benzo[h]quinolin-8-yl)methanamine and following the synthesis of compound 1. ESI-MS (m / z): 427.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.20 - 9.11 (m, 1H), 9.03 - 8.98 (m, 1H), 8.82 - 8.53 (m, 1H), 8.47 - 8.39 (m, 2H), 7.98 - 7.85 (m, 3H), 7.75 - 7.70 (m, 1H), 7.70 - 7.65 (m, 1H), 5.74 - 5.50 (m, 1H), 4.90 - 4.31 (m, 6H).

[0167] Example 32: JPEG2026501188000051.jpg41140

[0168] Compound 32 was obtained by replacing compound 1-c with (thieno[3,2-H]quinolin-2-yl)methanamine and following the synthesis of compound 1. ESI-MS (m / z): 433.4 [M+H] +; 1 H NMR (500 MHz, DMSO-d6) δ 8.92 - 8.42 (m, 4H), 7.99 - 7.92 (m, 1H), 7.88 - 7.81 (m, 1H), 7.62 - 7.55 (m, 1H), 7.55 - 7.48 (m, 1H), 5.73 - 5.61 (m, 1H), 4.92 - 4.79 (m, 4H), 4.62 - 4.47 (m, 2H).

[0169] Example 33: JPEG2026501188000052.jpg30135

[0170] Compound 33 was obtained by replacing compound 1-a with compound 4-c and following the synthesis method of compound 19. ESI-MS (m / z): 473.7 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 4.8 Hz, 1H), 8.30 (s, 1H), 8.18 - 8.11 (m, 1H), 8.11 - 8.06 (m, 1H), 7.68 - 7.62 (m, 2H), 7.52 - 7.43 (m, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.26 - 7.15 (m, 1H), 6.26 (d, J = 6.9 Hz, 1H), 4.78 - 4.55 (m, 3H), 4.16 (s, 2H), 2.06 - 1.61 (m, 2H), 0.84 - 0.62 (m, 3H).

[0171] Example 34: JPEG2026501188000053.jpg39157

[0172] Compound 34 was obtained by replacing compound 1-a with compound 18-a and following the synthesis of compound 19. ESI-MS (m / z): 460.6 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 4.7 Hz, 1H), 8.10 (br.s, 1H), 8.08 - 8.02 (m, 2H), 7.45 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.23 - 7.11 (m, 1H), 5.75 - 5.65 (m, 1H), 5.04 (br.s, 1H), 4.73 - 4.52 (m, 2H), 4.15 - 3.96 (m, 3H), 3.78 - 3.57 (m, 1H), 1.48 - 0.78 (m, 6H).

[0173] Example 35: JPEG2026501188000054.jpg26159

[0174] Compound 35-a was obtained by replacing 2-chloro-3-nitropyridine with 2-chloro-4-methoxy-3-nitropyridine and following the synthesis of compound 2-c. Compound 35 was obtained by replacing compound 2-c with compound 35-a and following the synthesis of compound 2. ESI-MS (m / z): 446.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.54 - 11.39 (m, 1H), 8.80 - 8.47 (m, 1H), 8.45 - 8.38 (m, 1H), 8.31 (d, J = 5.3 Hz, 1H), 8.09 - 8.03 (m, 1H), 7.43 (s, 1H), 7.18 (dd, J = 8.5, 4.6 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 5.68 - 5.54 (m, 1H), 4.93 - 4.40 (m, 6H), 4.04 (s, 3H).

[0175] Example 36: JPEG2026501188000055.jpg39150

[0176] Compound 36 was obtained by replacing 6-chloropyrimidine with 2-chloropyrimidine and following the synthesis method of compound 24. ESI-MS (m / z): 417.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.48 - 9.38 (m, 1H), 8.83 - 8.46 (m, 2H), 8.46 - 8.15 (m, 2H), 7.66 (s, 1H), 7.53 - 7.40 (m, 1H), 7.35 - 7.21 (m, 1H), 5.71 - 5.50 (m, 1H), 4.92 - 4.33 (m, 6H).

[0177] Example 37: JPEG2026501188000056.jpg107153

[0178] 6-Bromo-1H-indazol-3-amine (2 g, 9.43 mmol) and 4-[tert-butyl(dimethyl)]silanyl]oxybut-2-ynal (6.2 g, 31.3 mmol) were dissolved in acetonitrile (6 mL), and glacial acetic acid (566 mg, 9.43 mmol) and silver trifluoroacetate (625 mg, 2.83 mmol) were added. The mixture was stirred at room temperature for 16 h. 80 mL of ethyl acetate and 50 mL of water were added, filtered through Celite, the layers were separated, and the organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 37-a (700 mg, 18.9% yield) and compound 37-b (700 mg, 18.9% yield). ESI-MS (m / z): 392.4 [M+H] + .

[0179] Compound 37-a (700 mg, 1.78 mmol) and potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (383 mg, 1.62 mmol) were dissolved in a mixture of 1,4-dioxane (6 mL) and water (1 mL), and SPhos (73.2 mg, 178 μmol), potassium carbonate (740 mg, 5.35 mmol), and palladium acetate (40 mg, 178 μmol) were added. The mixture was stirred at 90 °C for 16 h under nitrogen protection. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 30 mL of water were added. The mixture was filtered through Celite. The organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 37-c (400 mg, 18.9% yield). ESI-MS (m / z): 443.4 [M+H] + .

[0180] Compound 37-c (90 mg, 203 μmol) was dissolved in a mixture of methanol (1 mL) and dichloromethane (5 mL), and dioxane hydrochloride solution (4 M, 1 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to give compound 37-d (53 mg, 98.5% yield). ESI-MS (m / z): 229.4 (M+H). + .

[0181] Compound 37-d (10 mg, 38 μmol) and compound 1-a (9.62 mg, 38 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (24.4 mg, 189 μmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to give compound 37 (3.5 mg, 20.8% yield). ESI-MS (m / z): 447.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.46 - 9.30 (m, 1H), 8.81 - 8.47 (m, 1H), 8.47 - 8.41 (m, 1H), 8.23 ​​- 8.07 (m, 1H), 7.62 (s, 1H), 7.58 - 7.51 (m, 1H), 7.28 - 7.16 (m, 1H), 5.89 - 5.71 (m, 1H), 5.72 - 5.51 (m, 1H), 4.93 - 4.32 (m, 8H).

[0182] Example 38: JPEG2026501188000057.jpg32130

[0183] Compound 38 was obtained by replacing compound 2-c with compound 37-d and following the synthesis method of compound 4. ESI-MS (m / z): 475.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.42 - 9.30 (m, 1H), 8.20 - 7.86 (m, 3H), 7.73 - 7.56 (m, 2H), 7.56 - 7.47 (m, 1H), 7.41 - 7.18 (m, 2H), 6.34 - 6.17 (m, 1H), 5.86 - 5.74 (m, 1H), 4.85 - 4.54 (m, 5H), 1.86 - 1.60 (m, 2H), 0.85 - 0.58 (m, 3H).

[0184] Example 39: JPEG2026501188000058.jpg30157

[0185] Compound 37-b was used instead of compound 37-a to obtain compound 39-a by referring to the synthesis of compound 37-d. Compound 39 was obtained by referring to the synthesis of compound 37. ESI-MS (m / z): 447.6 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.95 - 8.10 (m, 4H), 7.66 (s, 1H), 7.61 - 7.54 (m, 1H), 7.36 - 7.22 (m, 1H), 6.14 - 6.04 (m, 1H), 5.70 - 5.44 (m, 1H), 5.23 - 4.28 (m, 8H).

[0186] Example 40: JPEG2026501188000059.jpg33129

[0187] Compound 40 was obtained by replacing compound 2-c with compound 39-a and following the synthesis method of compound 4. ESI-MS (m / z): 475.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.82 - 8.52 (m, 1H), 8.26 - 7.88 (m, 3H), 7.77 - 7.52 (m, 3H), 7.40 - 7.23 (m, 2H), 6.33 - 6.20 (m, 1H), 5.17 - 5.07 (m, 2H), 4.81 - 4.53 (m, 3H), 1.79 - 1.63 (m, 2H), 0.79 - 0.64 (m, 3H).

[0188] Example 41: JPEG2026501188000060.jpg30142

[0189] Compound 33 (5 mg, 11 μmol) was dissolved in methanol (2 mL) and aqueous formaldehyde (34%, 0.05 mL) was added. The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (1.33 mg, 21.17 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was quenched with water (0.5 mL) and concentrated. The residue was purified by preparative liquid chromatography to give compound 41 (1 mg, 18.3% yield). ESI-MS (m / z): 501.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.36 (d, J = 4.7 Hz, 1H), 8.17 - 8.04 (m, 3H), 7.68 - 7.46 (m, 2H), 7.37 - 7.12 (m, 3H), 6.32 - 6.21 (m, 1H), 4.77 - 4.49 (m, 3H), 3.74 (s, 2H), 2.23 (s, 6H)1.85 - 1.60 (m, 2H), 0.95 - 0.57 (m, 3H).

[0190] Example 42: JPEG2026501188000061.jpg97154

[0191] (R)-2-((tert-Butyloxycarbonyl)amino)-2-cyclopropylacetic acid (200 mg, 929 μmol), N,N-diisopropylethylamine (480 mg, 3.72 mmol), and ammonium chloride (149 mg, 2.79 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), and HATU (530 mg, 1.39 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 42-a (160 mg, 80.4% yield).

[0192] Compound 42-a (160 mg, 746 μmol) was dissolved in dichloromethane (2 mL) and a 4 M solution of dioxane hydrochloride (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 42-b (112 mg, 99.6% yield).

[0193] Compound 42-b (100 mg, 664 μmol) and compound 4-a (152 mg, 664 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (257 mg, 1.99 mmol) was added. The mixture was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, and water (10 mL) was added. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 42-c (154 mg, 75.7% yield). ESI-MS (m / z): 307.3 [M+H] + .

[0194] Compound 42-c (154 mg, 503 μmol) was dissolved in dichloromethane (10 mL) and m-chloroperbenzoic acid (174 mg, 1.01 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography to give compound 42-d (140 mg, 82.3% yield). ESI-MS (m / z): 339.3 [M+H] + .

[0195] Compound 42-d (96.1 mg, 284 μmol) and compound 19-c (71.7 mg, 284 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (110 mg, 852 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 42-e (45 mg, 31.0% yield). ESI-MS (m / z): 511.5 [M+H] + .

[0196] Compound 42-e (45 mg, 88 μmol) was dissolved in tetrahydrofuran (5 mL), and triphenylphosphine (69.4 mg, 264 μmol) and water (0.1 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 42 (15 mg, 35.1% yield). ESI-MS (m / z): 485.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 4.7 Hz, 1H), 8.16 - 7.81 (m, 3H), 7.63 - 7.42 (m, 2H), 7.40 (d, J = 4.8 Hz, 1H), 7.33 - 7.13 (m, 2H), 6.27 - 6.13 (m, 1H), 4.82 - 4.51 (m, 2H), 4.32 - 4.10 (m, 3H), 1.31 - 0.91 (m, 1H), 0.64 - 0.09 (m, 4H).

[0197] Example 43: JPEG2026501188000062.jpg39149

[0198] By using the synthesis method of compound 2 as a reference, 2-chloro-3-nitropyridine was replaced with 3-chloro-4-nitropyridine to obtain compound 43. ESI-MS (m / z): 416.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.28 (s, 1H), 8.79 - 8.45 (m, 1H), 8.41 - 8.36 (m, 1H), 8.24 - 8.11 (m, 2H), 7.49 - 7.41 (m, 2H), 7.28 - 7.18 (m, 1H), 5.67 - 5.51 (m, 1H), 4.93 - 4.84 (m, 1H), 4.75 - 4.68 (m, 2H), 4.66 - 4.56 (m, 2H), 4.44 - 4.41 (m, 1H).

[0199] Example 44: JPEG2026501188000063.jpg40153

[0200] Using the synthesis method of compound 2 as a reference, 2-chloro-3-nitropyridine was replaced with 4-chloro-3-nitropyridine to obtain compound 44. ESI-MS (m / z): 416.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.61 - 11.48 (m, 1H), 8.93 - 8.81 (m, 1H), 8.82 - 8.48 (m, 1H), 8.47 - 8.38 (m, 1H), 8.36 - 8.28 (m, 1H), 8.20 - 8.11 (m, 1H), 8.09 - 8.02 (m, 1H), 7.51 - 7.46 (m, 1H), 7.25 - 7.16 (m, 1H), 5.69 - 5.51 (m, 1H), 4.93 - 4.83 (m, 1H), 4.76 - 4.68 (m, 2H), 4.66 - 4.56 (m, 2H), 4.43 - 4.40 (m, 1H).

[0201] Example 45: JPEG2026501188000064.jpg36160

[0202] By using the synthesis method of compound 2 as a reference, 2-chloro-3-nitropyridine was replaced with 3-chloro-2-nitropyridine to obtain compound 45. ESI-MS (m / z): 416.6 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.76 - 11.67 (m, 1H), 8.81 - 8.48 (m, 1H), 8.14 - 8.06 (m, 1H), 7.78 - 7.73 (m, 1H), 7.60 - 7.46 (m, 2H), 7.44 - 7.37 (m, 1H), 7.25 - 7.14 (m, 2H), 5.71 - 5.50 (m, 1H), 4.93 - 4.84 (m, 1H), 4.76 - 4.67 (m, 2H), 4.65 - 4.55 (m, 2H), 4.46 - 4.39 (m, 1H).

[0203] Example 46: JPEG2026501188000065.jpg53161

[0204] Compound 46-a was obtained by replacing (R)-2-aminobutanamide hydrochloride with (R)-2-aminopropanamide hydrochloride and following the synthesis of compound 4-c. Compound 46 was obtained by replacing compound 4-c with compound 46-a and compound 2-c with compound 7-a and following the synthesis of compound 4. ESI-MS (m / z): 460.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.48 - 8.30 (m, 1H), 8.23 ​​- 7.80 (m, 3H), 7.68 - 7.44 (m, 2H), 7.39 - 7.14 (m, 3H), 6.44 - 6.31 (m, 1H), 5.59 - 5.45 (m, 1H), 4.92 - 4.82 (m, 2H), 4.79 - 4.50 (m, 3H), 1.30 - 1.21 (m, 3H).

[0205] Example 47: JPEG2026501188000066.jpg27148

[0206] Compound 33 (5 mg, 11 μmol) was dissolved in dichloromethane (2 mL), and acetic anhydride (1.1 mg, 11 μmol) and N,N-diisopropylethylamine (2 mg, 16 μmol) were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 47 (3 mg, 55.1% yield). ESI-MS (m / z): 515.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.63 - 8.51 (m, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.19 - 7.86 (m, 3H), 7.66 (s, 1H), 7.53 - 7.41 (m, 1H), 7.37 - 7.12 (m, 3H), 6.38 - 6.16 (m, 1H), 4.87 - 4.36 (m, 5H), 1.94 (s, 3H), 1.91 - 1.59 (m, 2H), 0.90 - 0.55 (m, 3H).

[0207] Example 48: JPEG2026501188000067.jpg31163

[0208] Use (R)-2-amino-3-methylbutanamide hydrochloride instead of (R)-2-aminobutanamide hydrochloride to obtain compound 48-a, refer to the synthesis of compound 4-c; use compound 48-a instead of compound 1-a to obtain compound 48, refer to the synthesis of compound 19. ESI-MS (m / z): 487.7 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.37 (d, J = 4.7 Hz, 1H), 8.17 - 7.79 (m, 3H), 7.65 - 7.41 (m, 2H), 7.38 (d, J = 4.8 Hz, 1H), 7.33 - 7.12 (m, 2H), 6.20 - 5.81 (m, 1H), 4.83 - 4.43 (m, 3H), 4.06 (s, 2H), 2.10 - 1.95 (m, 1H), 0.96 - 0.58 (m, 6H).

[0209] Example 49: JPEG2026501188000068.jpg39160

[0210] Compound 49 was obtained by replacing 6-chloropyridinecarbonitrile with 2-bromopyrazine and following the synthesis method of compound 24. ESI-MS (m / z): 417.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.11 - 9.01 (m, 1H), 8.83 - 8.49 (m, 1H), 8.44 - 8.36 (m, 2H), 8.32 (d, J = 4.6 Hz, 1H), 7.79 (s, 1H), 7.49 - 7.33 (m, 1H), 5.70 - 5.48 (m, 1H), 4.95 - 4.66 (m, 4H), 4.62 - 4.36 (m, 2H).

[0211] Example 50: JPEG2026501188000069.jpg31154

[0212] Compound 50 was obtained by replacing compound 2-c with compound 39-a and compound 4-c with compound 48-a. ESI-MS (m / z): 489.6 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 4.4 Hz, 1H), 8.24 - 7.82 (m, 3H), 7.77 - 7.50 (m, 3H), 7.37 - 7.21 (m, 2H), 6.12 - 5.85 (m, 2H), 5.13 (d, J = 5.8 Hz, 2H), 4.84 - 4.50 (m, 3H), 2.06 - 1.94 (m, 1H), 0.98 - 0.63 (m, 6H).

[0213] Example 51: JPEG2026501188000070.jpg52167

[0214] 3-Pyridazinone (500 mg, 5.20 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (1.14 g, 5.20 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (2.16 g, 15.6 mmol) was added. The reaction solution was stirred at 90 °C for 16 hours. The reaction solution was cooled to room temperature, water (25 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 51-a (390 mg, 25.3% yield). ESI-MS (m / z): 296.1 [M+H] + .

[0215] Compound 51-a (390 mg, 1.32 mmol) was dissolved in tetrahydrofuran (5 mL), and 10% palladium on carbon (14.0 mg, 132 μmol) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 6 hours. The reaction solution was filtered through Celite and concentrated to give compound 51-b (110 mg, 31.4% yield). ESI-MS (m / z): 266.0 [M+H] + .

[0216] Compound 51-b (110 mg, 413 μmol) was dissolved in polyphosphoric acid (1 g). The mixture was reacted at 150° C. for 6 hours. The reaction solution was cooled to room temperature, water was added, and the pH was adjusted to >7 with 2N aqueous sodium hydroxide solution. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 51-c (56 mg, 54.6% yield). ESI-MS (m / z): 248.0 [M+H] + .

[0217] Compound 51-c (56 mg, 225 μmol) and potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (69.6 mg, 293 μmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), and palladium acetate (3.8 mg, 22.6 μmol), sulfos (21 mg, 45 μmol), and cesium carbonate (221 mg, 677 μmol) were added. The mixture was reacted at 90 °C for 16 h under nitrogen protection. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 51-d (55 mg, 82.6% yield). ESI-MS (m / z): 299.2 [M+H] + .

[0218] Compound 51-d (55 mg, 184 μmol) was dissolved in dichloromethane (2 mL) and a dioxane hydrochloride solution (4 M, 0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound 51-f (43 mg, 99.4% yield). ESI-MS (m / z): 199.2 [M+H] + .

[0219] Compound 51 was obtained by replacing compound 1-c with compound 51-f and following the synthesis method of compound 1. ESI-MS (m / z): 417.4 [M+H]+ ; 1 H NMR (500 MHz, DMSO-d6) δ 8.80 - 8.49 (m, 2H), 8.45 - 8.38 (m, 1H), 8.26 - 8.20 (m, 1H), 8.17 - 8.10 (m, 1H), 7.81 (s, 1H), 7.54 - 7.49 (m, 1H), 7.49 - 7.45 (m, 1H), 5.70 - 5.53 (m, 1H), 5.39 - 4.80 (m, 1H), 4.78 - 4.71 (m, 2H), 4.70 - 4.66 (m, 1H), 4.61 - 4.38 (m, 2H).

[0220] Example 52: JPEG2026501188000071.jpg31134

[0221] Compound 52 was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid with (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid and following the synthesis of compound 42. ESI-MS (m / z): 513.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.44 - 8.32 (m, 1H), 8.18 - 7.99 (m, 3H), 7.59 - 7.42 (m, 2H), 7.38 (d, J = 4.8 Hz, 1H), 7.25 - 7.12 (m, 2H), 6.27 - 5.84 (m, 1H), 4.99 - 4.39 (m, 4H), 4.07 (s, 2H), 1.72 - 0.87 (m, 9H).

[0222] Example 53: JPEG2026501188000072.jpg32132

[0223] Compound 53 was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid with (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropionic acid, following the synthesis of compound 42. ESI-MS (m / z): 499.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.46 - 8.28 (m, 1H), 8.21 - 7.86 (m, 3H), 7.58 (s, 1H), 7.46 (s, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.32 - 7.13 (m, 2H), 6.38 - 6.20 (m, 1H), 4.83 - 4.46 (m, 3H), 4.09 (s, 2H), 1.86 - 1.45 (m, 2H), 0.71 - 0.05 (m, 4H), -0.18 - -0.29 (m, 1H).

[0224] Example 54: Compound 54 was obtained by replacing compound 42-b with (R)-2-aminopentanamide hydrochloride and following the synthesis of compound 42. ESI-MS (m / z): 487.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.45 - 8.28 (m, 1H), 8.24 - 7.80 (m, 3H), 7.64 - 7.43 (m, 2H), 7.38 (d, J = 4.7 Hz, 1H), 7.32 - 7.07 (m, 2H), 6.33 - 6.16 (m, 1H), 4.88 - 4.40 (m, 3H), 4.09 (s, 2H), 1.99 - 0.77 (m, 7H).

[0225] Example 55: JPEG2026501188000074.jpg29135

[0226] Compound 55 was obtained by replacing compound 42-b with (R)-2-amino-3,3-dimethylbutanamide hydrochloride and following the synthesis of compound 42. ESI-MS (m / z): 501.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.37 (d, J = 4.8 Hz, 1H), 8.20 - 7.55 (m, 4H), 7.51 - 7.41 (m, 1H), 7.38 (d, J = 4.7 Hz, 1H), 7.32 - 7.08 (m, 2H), 5.98 - 5.64 (m, 1H), 5.00 - 4.42 (m, 3H), 4.07 (s, 2H), 1.06 - 0.70 (m, 9H).

[0227] Example 56: JPEG2026501188000075.jpg32133

[0228] Compound 56 was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid with (R)-2-((tert-butoxycarbonyl)amino)-2-cyclobutylacetic acid and following the synthesis of compound 42. ESI-MS (m / z): 499.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.42 - 8.26 (m, 1H), 8.19 - 7.79 (m, 3H), 7.65 - 7.34 (m, 3H), 7.30 - 7.08 (m, 2H), 6.21 - 5.95 (m, 1H), 4.90 - 3.86 (m, 5H), 2.80 - 2.54 (m, 1H), 2.03 - 1.39 (m, 6H).

[0229] Example 57: JPEG2026501188000076.jpg31159

[0230] Compound 57-a was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid with (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid, with reference to the synthesis of compound 42-d. Compound 57 was obtained by replacing compound 42-d with compound 57-a, with reference to the synthesis procedure of compound 42. ESI-MS (m / z): 503.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.41 - 8.37 (m, 1H), 8.21 - 7.91 (m, 3H), 7.48 - 7.30 (m, 4H), 7.24 - 7.11 (m, 1H), 6.04 - 5.93 (m, 1H), 4.77 - 4.60 (m, 3H), 4.18 - 4.11 (m, 2H), 3.82 - 3.77 (m, 1H), 3.17 - 3.13 (m, 3H), 1.10 - 0.91 (m, 3H).

[0231] Example 58: JPEG2026501188000077.jpg32133

[0232] Compound 58 was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid with (R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid, following the synthesis of compound 42. ESI-MS (m / z): 503.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.44 - 8.20 (m, 1H), 8.18 - 7.91 (m, 3H), 7.85 - 6.73 (m, 6H), 6.17 - 5.95 (m, 1H), 5.18 - 3.80 (m, 6H), 1.33 - 0.97 (m, 6H).

[0233] Example 59: JPEG2026501188000078.jpg65156

[0234] Compound 33 (10 mg, 21 μmol) was dissolved in dichloromethane (2 mL), and acetoxyacetic acid (3 mg, 25 μmol), N,N-diisopropylethylamine (8.2 mg, 64 μmol), and HATU (12 mg, 32 μmol) were added. The mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 59-a (12 mg). ESI-MS (m / z): 573.4 [M+H] + .

[0235] The crude product, compound 59-a (12 mg), was dissolved in methanol (2 mL) and potassium carbonate (8.7 mg, 63 μmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 59 (3 mg, 27.0% yield). ESI-MS (m / z): 531.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.59 - 8.49 (m, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.18 - 7.86 (m, 3H), 7.68 - 7.56 (m, 1H), 7.52 - 7.41 (m, 1H), 7.36 - 7.13 (m, 3H), 6.36 - 6.07 (m, 1H), 5.62 (t, J = 5.8 Hz, 1H), 4.81 - 4.45 (m, 5H), 3.91 (d, J = 5.6 Hz, 2H), 1.97 - 1.56 (m, 2H), 0.88 - 0.58 (m, 3H).

[0236] Example 60: JPEG2026501188000079.jpg29152

[0237] Compound 60 was obtained by replacing compound 2-c with compound 39-a and compound 4-c with compound 18-a, following the synthesis of compound 4. ESI-MS (m / z): 462.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.79 - 8.75 (m, 1H), 8.22 - 8.18 (m, 1H), 8.16 - 7.93 (m, 2H), 7.71 - 7.62 (m, 1H), 7.56 - 7.53 (m, 1H), 7.33 - 7.25 (m, 1H), 6.14 - 6.05 (m, 1H), 5.78 - 5.65 (m, 1H), 5.16 - 5.10 (m, 2H), 5.07 - 4.94 (m, 1H), 4.73 - 4.57 (m, 2H), 4.16 - 3.99 (m, 1H), 3.77 - 3.60 (m, 1H), 1.08 - 0.88 (m, 6H).

[0238] Example 62: JPEG2026501188000080.jpg88153

[0239] Compound 62-a was obtained by replacing compound 37-a with compound 37-b and following the synthesis of compound 37-c.

[0240] Compound 62-a (500 mg, 1.13 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 2.26 mL) was added under ice cooling. The mixture was allowed to react in an ice bath for 10 minutes. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phase was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 62-b (325 mg, 87.6% yield). ESI-MS (m / z): 329.5 [M+H] + .

[0241] Compound 62-b (100 mg, 304 μmol), phthalimide (49.3 mg, 335 μmol), and triphenylphosphine (160 mg, 609 μmol) were dissolved in tetrahydrofuran (10 mL), and diisopropyl azodicarboxylate (123 mg, 609 μmol) was added under ice-cooling. The mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 62-c (113 mg, 81.1% yield). ESI-MS (m / z): 458.3 [M+H] + .

[0242] Compound 62-c (60 mg, 131 μmol) was dissolved in dichloromethane (2 mL) and a dioxane hydrochloride solution (4 M, 0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 62-d (45 mg, 85% yield). ESI-MS (m / z): 358.4 [M+H] + .

[0243] Compound 62-d (45 mg, 111 μmol) and compound 4-c (43 mg, 140 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (59 mg, 458 μmol) was added. The mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 62-f (60 mg, 89% yield). ESI-MS (m / z): 604.2 [M+H] + .

[0244] Compound 62-f (60 mg, 99 μmol) was dissolved in 95% ethanol (5 mL) and 80% hydrazine hydrate (0.5 mL) was added. The mixture was stirred at 80° C. for 6 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by preparative liquid chromatography to give compound 62 (2 mg, 4.2% yield). ESI-MS (m / z): 474.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.95 - 8.71 (m, 1H), 8.26 - 7.71 (m, 4H), 7.71 - 7.55 (m, 2H), 7.41 - 7.22 (m, 2H), 6.34 - 6.16 (m, 1H), 4.81 - 4.55 (m, 3H), 4.42 - 4.27 (m, 2H), 2.00 - 1.60 (m, 2H), 0.83 - 0.63 (m, 3H).

[0245] Example 63: JPEG2026501188000081.jpg35156

[0246] Compound 63 was obtained by replacing compound 4-c with compound 18-a and following the synthesis method of compound 62. ESI-MS (m / z): 461.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.15 - 8.07 (m, 1H), 8.07 - 7.91 (m, 1H), 7.73 - 7.63 (m, 1H), 7.60 (d, J = 4.4 Hz, 1H), 7.32 - 7.22 (m, 1H), 5.76 - 5.63 (m, 1H), 5.10 - 4.90 (m, 1H), 4.78 - 4.55 (m, 2H), 4.33 (s, 2H), 4.17 - 3.96 (m, 1H), 3.79 - 3.58 (m, 1H), 1.46 - 0.71 (m, 6H).

[0247] Example 67: JPEG2026501188000082.jpg84163

[0248] Compound 19-a (1 g, 3.05 mmol) was dissolved in dichloromethane (30 mL), and DMP (1.43 g, 3.36 mmol) was added under ice-cooling. The mixture was slowly warmed to room temperature and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction solution, dichloromethane was evaporated under reduced pressure, and the residue was extracted three times with ethyl acetate (30 mL). The combined organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 67-a (1 g). ESI-MS (m / z): 326.8 [M+H] + .

[0249] The crude product, compound 67-a (1 g), was dissolved in 95% ethanol (20 mL), and sodium acetate (756 mg, 9.22 mmol) and hydroxylamine hydrochloride (320 mg, 4.61 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and water (30 mL) was added to the residue, followed by extraction three times with ethyl acetate (30 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 67-b (1.05 g). ESI-MS (m / z): 341.7 [M+H] + .

[0250] The crude product, compound 67-b (1.05 g), was dissolved in pyridine (10 mL), and trifluoroacetic anhydride (2.57 g, 12.22 mmol) was slowly added under ice-cooling. The mixture was slowly warmed to room temperature and stirred at room temperature for 4 hours. Methanol (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and water (30 mL) was added to the residue, followed by extraction three times with ethyl acetate (30 mL). The combined organic phases were washed once with saturated citric acid solution and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 67-c (400 mg, 40.6% yield). ESI-MS (m / z): 323.7 [M+H] + .

[0251] Compound 67-c (250 mg, 775 μmol) was dissolved in dichloromethane (5 mL) and a dioxane hydrochloride solution (4 M, 1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound 67-d (229 mg, 100% yield). ESI-MS (m / z): 223.5 [M+H] + .

[0252] Compound 67 was obtained by replacing compound 2-c with compound 67-d and compound 4-c with compound 57-a, following the synthesis of compound 4. ESI-MS (m / z): 499.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.49 - 12.28 (m, 1H), 8.67 - 8.46 (m, 1H), 8.28 - 7.96 (m, 3H), 7.83 - 7.77 (m, 1H), 7.58 - 7.50 (m, 1H), 7.45 - 7.28 (m, 3H), 6.05 - 5.94 (m, 1H), 4.80 - 4.59 (m, 3H), 3.95 - 3.73 (m, 1H), 3.31 - 3.12 (m, 3H), 1.13 - 0.88 (m, 3H).

[0253] Example 68: JPEG2026501188000083.jpg27143

[0254] Compound 68 was obtained by replacing compound 2-c with compound 6-a and compound 4-c with compound 18-a, following the synthesis of compound 4. ESI-MS (m / z): 445.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.31 - 8.27 (m, 1H), 8.14 - 7.90 (m, 3H), 7.47 - 7.40 (m, 1H), 7.22 - 7.14 (m, 2H), 5.83 - 5.66 (m, 1H), 5.12 - 4.93 (m, 1H), 4.75 - 4.50 (m, 2H), 4.15 - 3.97 (m, 1H), 3.81 - 3.59 (m, 1H), 2.56 - 2.55 (m, 3H), 1.17 - 0.86 (m, 6H).

[0255] Example 69: JPEG2026501188000084.jpg56136

[0256] Compound 17 (20 mg, 42 μmol) was dissolved in N,N-dimethylformamide (2 mL) and DMP (20 mg, 46 μmol) was added. The mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 69-a (20 mg). ESI-MS (m / z): 472.7 [M+H] + .

[0257] The crude product, compound 69-a (8 mg), was dissolved in N,N-dimethylformamide (2 mL), and a 2M methylamine tetrahydrofuran solution (34 μL) and glacial acetic acid (1 mg, 17 μmol) were added. The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (18 mg, 85 μmol) was added. The reaction was continued at room temperature overnight. Water (0.1 mL) was added to the reaction solution to quench the reaction. The mixture was purified by preparative liquid chromatography to give compound 69 (1.5 mg, 18.2% yield). ESI-MS (m / z): 487.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.55 - 11.16 (m, 1H), 8.41 - 8.36 (m, 1H), 8.19 - 7.88 (m, 4H), 7.69 - 7.60 (m, 1H), 7.53 - 7.45 (m, 1H), 7.40 - 7.29 (m, 2H), 7.25 - 7.14 (m, 1H), 6.32 - 6.22 (m, 1H), 4.76 - 4.55 (m, 3H), 4.14 - 4.02 (m, 2H), 2.40 - 2.38 (m, 3H), 0.83 - 0.76 (m, 2H), 0.69 - 0.62 (m, 3H).

[0258] Example 70: JPEG2026501188000085.jpg34161

[0259] Compound 70 was obtained by replacing compound 2-c with compound 6-a and following the synthesis method of compound 4. ESI-MS (m / z): 458.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.30 (d, J = 4.7 Hz, 1H), 8.20 - 7.84 (m, 3H), 7.73 - 7.58 (m, 1H), 7.49 - 7.42 (m, 1H), 7.40 - 7.30 (m, 1H), 7.26 - 7.14 (m, 2H), 6.37 - 6.18 (m, 1H), 4.83 - 4.54 (m, 3H), 2.56 (s, 3H), 1.91 - 1.61 (m, 2H), 0.85 - 0.56 (m, 3H).

[0260] Example 71: JPEG2026501188000086.jpg69157

[0261] Compound 71-a was obtained by using (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid instead of (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid and following the synthesis of compound 42-c.

[0262] Compound 71-a (100 mg, 308 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic anhydride (194 mg, 925 μmol) and pyridine (244 mg, 3.08 mmol) were added under ice-cooling. The mixture was slowly warmed to room temperature and stirred for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 71-b (94 mg). ESI-MS (m / z): 307.4 [M+H] + .

[0263] The crude product, compound 71-b (94 mg), was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (80 mg, 462 μmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (5 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (10 mL). The combined organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 71-c (99 mg). ESI-MS (m / z): 323.5 [M+H] + .

[0264] Compound 7-a (35.3 mg, 134 μmol) and crude compound 1-a (50 mg) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (200 mg, 1.55 mmol) was added. The mixture was stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to give compound 71 (12 mg, 24.7% yield). ESI-MS (m / z): 486.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.46 - 8.22 (m, 2H), 8.22 - 8.17 (m, 1H), 8.11 - 8.06 (m, 1H), 7.49 - 7.43 (m, 1H), 7.38 - 7.32 (m, 1H), 7.25 - 7.14 (m, 2H), 5.56 - 5.50 (m, 1H), 5.39 - 4.93 (m, 1H), 4.91 - 4.83 (m, 2H), 4.79 - 4.64 (m, 2H), 3.95 - 3.50 (m, 1H), 3.25 - 2.89 (m, 3H), 1.24 - 0.94 (m, 3H).

[0265] Example 72: JPEG2026501188000087.jpg70144

[0266] 2,4-Dichloro-5-cyanopyrimidine (500 mg, 2.87 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (R)-2-aminobutanamide hydrochloride (440 mg, 4.31 mmol) and N,N-diisopropylethylamine (1.11 g, 8.62 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 72-a (151 mg, 21.9% yield).

[0267] Compound 7-a (30 mg, 132 μmol) and compound 72-a (31.64 mg, 132 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (200 mg, 1.55 mmol) was added. The mixture was stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature and purified by preparative liquid chromatography to give compound 72 (10 mg, 17.6% yield). ESI-MS (m / z): 431.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.39 (d, J = 5.0 Hz, 1H), 8.37 - 8.12 (m, 2H), 8.11 - 8.05 (m, 1H), 7.56 - 7.41 (m, 2H), 7.36 (d, J = 4.7 Hz, 1H), 7.25 - 7.13 (m, 2H), 6.97 - 6.79 (m, 1H), 5.56 (s, 1H), 4.88 (s, 2H), 4.74 - 4.56 (m, 2H), 4.51 - 4.42 (m, 1H), 1.87 - 1.60 (m, 2H), 0.90 - 0.66 (m, 3H).

[0268] Example 73: JPEG2026501188000088.jpg31142

[0269] Compound 73 was obtained by replacing compound 2-c with compound 67-d and compound 4-c with compound 5-a, following the synthesis of compound 4. ESI-MS (m / z): 472.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.62 - 12.17 (m, 1H), 8.60 - 8.53 (m, 1H), 8.20 - 7.95 (m, 3H), 7.82 - 7.47 (m, 2H), 7.35 - 7.27 (m, 1H), 5.79 - 5.65 (m, 2H), 5.12 - 4.93 (m, 2H), 4.82 - 4.74 (m, 2H), 4.12 - 3.97 (m, 3H), 0.95 - 0.81 (m, 3H).

[0270] Example 74: JPEG2026501188000089.jpg28163

[0271] Compound 74-a was obtained by referring to the synthesis of compound 42-b, except that (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-methoxybutyric acid was used instead of (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid. Compound 74 was obtained by referring to the synthesis method of compound 72, except that (R)-2-aminobutanamide hydrochloride was replaced with compound 74-a. ESI-MS (m / z): 461.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.32 - 11.20 (m, 1H), 8.49 - 8.21 (m, 3H), 8.10 - 8.05 (m, 1H), 7.57 - 7.42 (m, 2H), 7.38 - 7.34 (m, 1H), 7.31 - 7.27 (m, 1H), 7.22 - 7.13 (m, 1H), 6.36 - 6.20 (m, 1H), 5.69 - 5.48 (m, 1H), 4.96 - 4.83 (m, 2H), 4.75 - 4.51 (m, 3H), 3.98 - 3.75 (m, 1H), 3.23 - 3.11 (m, 3H), 1.12 - 0.95 (m, 3H).

[0272] Example 75: JPEG2026501188000090.jpg68164

[0273] Compound 4-a (105 mg, 459 μmol) was dissolved in N,N-dimethylformamide (3 mL), and (3R,4S)-tert-butyl 3-amino-4-hydroxypiperidine-1-carboxylate (99 mg, 459 μmol) and N,N-diisopropylethylamine (178 mg, 1.38 mmol) were added. The mixture was stirred at 50°C overnight. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 75-a (180 mg, 95.9% yield). ESI-MS (m / z): 409.3 [M+H] + .

[0274] Compound 75-a (154 mg, 503 μmol) was dissolved in dichloromethane (5 mL) and m-chloroperbenzoic acid (152 mg, 881 μmol) was added. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, compound 75-b (190 mg). ESI-MS (m / z): 441.5 [M+H] + .

[0275] Compound 7-a (50 mg, 220 μmol) and crude compound 75-b (97 mg) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (85.3 mg, 660 μmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was purified by column chromatography to give compound 75-c (95 mg, 73.5% yield). ESI-MS (m / z): 588.4 [M+H] + .

[0276] Compound 75-c (95 mg, 161 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 75 (35 mg, 44.4% yield). ESI-MS (m / z): 488.7 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.42 - 8.35 (m, 1H), 8.19 - 7.95 (m, 3H), 7.53 - 7.42 (m, 1H), 7.39 - 7.32 (m, 1H), 7.25 - 7.15 (m, 1H), 5.81 - 5.67 (m, 1H), 5.59 - 5.48 (m, 1H), 5.13 - 4.81 (m, 3H), 4.71 - 4.56 (m, 2H), 4.19 - 4.00 (m, 1H), 3.89 - 3.73 (m, 1H), 2.86 - 2.66 (m, 2H), 2.58 - 2.51 (m, 2H), 1.64 - 1.51 (m, 2H).

[0277] Example 76: JPEG2026501188000091.jpg74154

[0278] Compound 4-a (855 mg, 3.74 mmol) and tert-butyl 3-(1-amino-2-methoxy-2-oxoethyl)azetidine-1-carboxylate (914 mg, 3.74 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (1.45 g, 11.2 mmol) was added. The mixture was stirred at 80 °C for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 76-a (330 mg, 20.2% yield). ESI-MS (m / z): 437.0 [M+H] + .

[0279] Compound 76-a (330 mg, 756 μmol) was dissolved in ammonia methanol solution (7 M, 5 mL). The mixture was stirred at 60 °C overnight. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography to give compound 76-b (240 mg, 75.3% yield). ESI-MS (m / z): 422.0 [M+H]+ .

[0280] Compound 76 was obtained by replacing compound 75-a with compound 76-b and following the synthesis method of compound 75. ESI-MS (m / z): 501.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.78 - 11.18 (m, 1H), 8.43 - 8.34 (m, 1H), 8.27 - 8.14 (m, 1H), 8.14 - 7.94 (m, 2H), 7.67 - 7.44 (m, 2H), 7.42 - 7.21 (m, 3H), 6.83 - 6.31 (m, 1H), 5.88 - 5.33 (m, 1H), 4.91 - 4.85 (m, 2H), 4.82 - 4.64 (m, 2H), 4.66 - 4.48 (m, 1H), 3.82 - 3.47 (m, 4H), 3.19 - 2.92 (m, 1H), 1.51 - 1.28 (m, 1H).

[0281] Example 77: JPEG2026501188000092.jpg34137

[0282] Compound 77 was obtained by replacing (3R,4S)-3-amino-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester and following the synthesis of compound 75. ESI-MS (m / z): 488.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.45 - 8.32 (m, 1H), 8.30 - 7.90 (m, 3H), 7.45 (s, 1H), 7.42 - 7.31 (m, 1H), 7.28 - 7.11 (m, 1H), 5.74 - 5.48 (m, 2H), 5.12 - 4.93 (m, 1H), 4.87 (s, 2H), 4.72 - 4.52 (m, 2H), 4.19 - 3.88 (m, 1H), 3.88 - 3.40 (m, 2H), 2.93 - 2.53 (m, 4H), 1.76 - 1.23 (m, 2H).

[0283] Example 78: JPEG2026501188000093.jpg45168

[0284] Compound 77 was obtained by replacing (3R,4S)-3-amino-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester and following the synthesis of compound 75. ESI-MS (m / z): 474.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.71 - 11.21 (m, 1H), 8.41 - 8.36 (m, 1H), 8.24 - 7.93 (m, 3H), 7.56 - 7.45 (m, 1H), 7.37 - 7.31 (m, 1H), 7.23 - 7.15 (m, 1H), 6.18 - 5.95 (m, 1H), 5.87 - 5.45 (m, 2H), 4.90 - 4.85 (m, 2H), 4.72 - 4.56 (m, 2H), 4.23 - 3.80 (m, 2H), 3.57 - 3.44 (m, 1H), 3.24 - 3.01 (m, 2H), 2.71 - 2.55 (m, 1H), 2.49 - 2.28 (m, 1H).

[0285] Example 79: JPEG2026501188000094.jpg31147

[0286] Compound 79 was obtained by replacing compound 2-c with compound 39-a and compound 4-c with compound 57-a, following the synthesis of compound 4. ESI-MS (m / z): 505.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.81 - 8.75 (m, 1H), 8.25 - 7.96 (m, 3H), 7.75 - 7.62 (m, 1H), 7.58 - 7.53 (m, 1H), 7.45 - 7.26 (m, 3H), 6.19 - 5.91 (m, 2H), 5.19 - 5.07 (m, 2H), 4.82 - 4.60 (m, 3H), 3.96 - 3.75 (m, 1H), 3.20 - 3.10 (m, 3H), 1.11 - 0.91 (m, 3H).

[0287] Example 80: JPEG2026501188000095.jpg29145

[0288] Compound 80 was obtained by replacing compound 7-a with compound 39-a and following the synthesis of compound 75. ESI-MS (m / z): 489.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 4.4 Hz, 1H), 8.22 - 7.96 (m, 3H), 7.76 - 7.61 (m, 1H), 7.56 - 7.53 (m, 1H), 7.34 - 7.24 (m, 1H), 6.08 (s, 1H), 5.80 - 5.67 (m, 1H), 5.15 - 4.99 (m, 3H), 4.73 - 4.55 (m, 2H), 4.20 - 3.98 (m, 1H), 3.89 - 3.71 (m, 1H), 2.85 - 2.50 (m, 4H), 1.63 - 1.50 (m, 2H).

[0289] Example 81: JPEG2026501188000096.jpg29149

[0290] Compound 81 was obtained by replacing compound 7-a with compound 67-d and following the synthesis of compound 75. ESI-MS (m / z): 483.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.25 - 7.95 (m, 3H), 7.79 (d, J = 5.0 Hz, 1H), 7.63 - 7.46 (m, 1H), 7.40 - 7.26 (m, 1H), 5.82 - 5.68 (m, 1H), 5.15 - 4.90 (m, 1H), 4.75 - 4.56 (m, 2H), 4.23 - 3.93 (m, 1H), 3.86 - 3.72 (m, 1H), 2.88 - 2.52 (m, 4H), 1.65 - 1.49 (m, 2H).

[0291] Example 82: JPEG2026501188000097.jpg32155

[0292] Compound 82 was obtained by replacing compound 2-c with compound 7-a and compound 4-c with compound 57-a, following the synthesis of compound 4. ESI-MS (m / z): 504.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.25 - 7.89 (m, 3H), 7.51 - 7.30 (m, 4H), 7.25 - 7.12 (m, 1H), 6.05 - 5.88 (m, 1H), 5.54 (t, J = 5.5 Hz, 1H), 4.88 (d, J = 5.4 Hz, 2H), 4.76 - 4.48 (m, 3H), 3.95 - 3.66 (m, 1H), 3.33 - 3.14 (m, 3H), 1.10 - 0.84 (m, 3H).

[0293] Example 83: JPEG2026501188000098.jpg28147

[0294] Compound 83 was obtained by replacing compound 7-a with compound 6-a and following the synthesis of compound 75. ESI-MS (m / z): 472.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.48 - 11.28 (m, 1H), 8.30 (d, J = 4.7 Hz, 1H), 8.25 - 7.92 (m, 3H), 7.53 - 7.42 (m, 1H), 7.28 - 7.15 (m, 2H), 5.86 - 5.75 (m, 1H), 5.32 - 5.14 (m, 1H), 4.75 - 4.60 (m, 2H), 4.24 - 4.15 (m, 1H), 3.91 - 3.80 (m, 1H), 2.93 - 2.66 (m, 4H), 2.60 - 2.55 (m, 3H), 1.75 - 1.58 (m, 2H).

[0295] Example 84: JPEG2026501188000099.jpg65166

[0296] Compound 4-a (500 mg, 2.19 mmol) and triethylamine (332 mg, 3.28 mmol) were dissolved in N-methylpyrrolidone, and a solution of (R)-2-hydroxybutyric acid methyl ester (310 mg, 2.62 mmol) in tetrahydrofuran (2 mL) and a solution of sodium tert-butoxide (315 mg, 3.28 mmol) in dimethyl sulfoxide (2 mL) were added under ice cooling. The mixture was reacted overnight at room temperature. Water (20 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 84-a (434 mg, 64.0% yield). ESI-MS (m / z): 311.3 [M+H] + .

[0297] Compound 84-a (360 mg, 1.16 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide monohydrate (97 mg, 2.32 mmol) was added. The mixture was stirred at room temperature for 5 hours. The pH of the reaction solution was adjusted to 4 with dilute hydrochloric acid, and the tetrahydrofuran was evaporated under reduced pressure. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 84-b (343 mg, 99.8% yield). ESI-MS (m / z): 297.1 [M+H] + .

[0298] Compound 84-b (50 mg, 168 μmol) was dissolved in N,N-dimethylformamide (3 mL), and ammonium chloride (18 mg, 337 μmol), HATU (96 mg, 253 μmol), and N,N-diisopropylethylamine (65 mg, 506 μmol) were added. The mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (5 mL). The combined organic phases were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 84-c (49 mg, 98.3% yield). ESI-MS (m / z): 296.6 [M+H]+ .

[0299] Compound 84 was obtained by replacing compound 42-c with compound 84-c and following the synthesis of compound 42. ESI-MS (m / z): 474.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.57 - 8.26 (m, 3H), 8.04 - 7.98 (m, 1H), 7.47 - 7.37 (m, 1H), 7.35 - 7.19 (m, 2H), 7.17 - 7.02 (m, 2H), 5.17 - 5.00 (m, 1H), 4.74 - 4.51 (m, 2H), 4.05 - 3.96 (m, 2H), 1.85 - 1.69 (m, 2H), 0.89 - 0.81 (m, 3H).

[0300] Example 85: JPEG2026501188000100.jpg27157

[0301] Compound 85 was obtained by replacing compound 7-a with compound 67-d and replacing (3R,4S)-3-amino-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (3R,4R)-3-amino-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester. ESI-MS (m / z): 483.7 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.59 - 8.52 (m, 1H), 8.20 - 8.08 (m, 2H), 8.06 - 7.93 (m, 1H), 7.81 - 7.77 (m, 1H), 7.61 - 7.52 (m, 1H), 7.40 - 7.29 (m, 1H), 6.06 - 5.95 (m, 1H), 4.82 - 4.58 (m, 3H), 3.99 - 3.73 (m, 1H), 3.64 - 3.55 (m, 1H), 3.23 - 3.00 (m, 1H), 2.85 (s, 1H), 2.48 - 2.31 (m, 1H), 2.28 - 1.68 (m, 2H), 1.52 - 1.26 (m, 2H).

[0302] Example 86: JPEG2026501188000101.jpg30154

[0303] Compound 86 was obtained by replacing compound 7-a with compound 67-d and replacing (3R,4S)-3-amino-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. ESI-MS (m / z): 469.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.61 - 8.53 (m, 1H), 8.19 - 8.06 (m, 2H), 7.80 (d, J = 5.0 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.36 - 7.19 (m, 2H), 6.22 - 5.96 (m, 1H), 5.79 - 5.43 (m, 1H), 4.76 - 4.64 (m, 2H), 4.28 - 3.99 (m, 2H), 3.14 - 2.99 (m, 3H), 2.70 - 2.57 (m, 1H), 2.40 - 2.28 (m, 1H).

[0304] Example 87: JPEG2026501188000102.jpg38161

[0305] N-(tert-Butyloxycarbonyl)glycine (3.6 mg, 21 μmol) and N-hydroxysuccinimide (2.9 mg, 25 μmol) were dissolved in dichloromethane (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6 mg, 31 μmol) was added. The mixture was stirred at room temperature for 0.5 h, and then compound 83 (10 mg, 21 μmol) and N,N-diisopropylethylamine (2.7 mg, 21 mmol) were added. Water (5 mL) was added to the reaction solution, which was then extracted three times with dichloromethane (10 mL). The combined organic phases were concentrated. The residue was dissolved in dichloromethane (2 mL), and a dioxane hydrochloride solution (4 M, 1 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 87 (3 mg, 22.6% yield). ESI-MS (m / z): 540.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.53 - 8.45 (m, 1H), 8.25 - 7.98 (m, 3H), 7.75 - 7.68 (m, 1H), 7.53 - 7.43 (m, 1H), 7.29 - 7.20 (m, 1H), 5.72 - 5.57 (m, 1H), 5.45 - 5.27 (m, 1H), 4.82 - 4.04 (m, 3H), 3.96 - 3.37 (m, 5H), 3.12 - 2.69 (m, 2H), 1.63 - 1.44 (m, 2H).

[0306] Example 88: JPEG2026501188000103.jpg30156

[0307] Compound 83 (450 mg, 867 μmol) was dissolved in dichloromethane (10 mL) and methanol (3 mL), and aqueous formaldehyde (34%, 213 μL) and glacial acetic acid (52 mg, 867 μmol) were added. The mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (919 mg, 4.34 mmol) was added and stirred at room temperature overnight. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, which was then extracted three times with ethyl acetate (30 mL). The combined organic phases were concentrated. The residue was purified by preparative liquid chromatography to give compound 88 (200 mg, 46.5% yield). ESI-MS (m / z): 497.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.63 - 8.54 (m, 1H), 8.27 - 8.07 (m, 3H), 7.85 - 7.77 (m, 1H), 7.55 (s, 1H), 7.39 - 7.27 (m, 1H), 5.81 - 5.67 (m, 1H), 5.16 - 4.55 (m, 3H), 4.32 - 4.07 (m, 1H), 3.84 - 3.63 (m, 1H), 3.29 - 3.18 (m, 2H), 2.36 - 1.87 (m, 5H), 1.74 - 1.41 (m, 2H).

[0308] Example 89: JPEG2026501188000104.jpg31162

[0309] Compound 89 was obtained by replacing compound 7-a with compound 67-d and replacing (3R,4S)-3-amino-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester. ESI-MS (m / z): 483.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.32 - 8.00 (m, 3H), 7.81 (d, J = 4.9 Hz, 1H), 7.54 (s, 1H), 7.37 - 7.29 (m, 1H), 5.77 - 5.62 (m, 1H), 5.36 - 5.10 (m, 1H), 4.76 - 4.55 (m, 2H), 4.20 - 3.89 (m, 1H), 3.78 - 3.48 (m, 1H), 2.97 - 2.55 (m, 3H), 2.51 - 2.37 (m, 2H), 1.71 - 1.29 (m, 2H).

[0310] Example 90: JPEG2026501188000105.jpg57166

[0311] (2R,3R)-3-Aminobutan-2-ol hydrochloride (1.27 g, 10.1 mmol) and phthalic anhydride (1 g, 6.8 mmol) were added to a glass bottle and heated to 150 °C for 5 hours. The mixture was cooled to room temperature, and dichloromethane (30 mL) was added. The mixture was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound 90-a (126 mg, 8.5% yield).

[0312] Compound 90-a (70 mg, 319 μmol) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (60% in oil, 15 mg, 639 μmol) was added under ice-cooling. After stirring for 15 minutes under ice-cooling, compound 4-a (88 mg, 383 μmol) was added. The reaction solution was heated to 50°C and allowed to react for 5 hours. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give compound 90-b (30 mg, 21.9% yield). ESI-MS (m / z): 430.6 [M+H] + .

[0313] Compound 90-b (30 mg, 70 μmol) was dissolved in ethyl acetate (2 mL), and m-chloroperbenzoic acid (24 mg, 139 μmol) was added. The mixture was stirred at room temperature for 2 hours. Ethyl acetate (5 mL) was added to the reaction solution, and the mixture was filtered. The residue was washed twice with ethyl acetate (5 mL). The combined organic phase was concentrated to give crude compound 90-c (30 mg). ESI-MS (m / z): 462.3 [M+H] + . Compound 90-c (30 mg, 65 μmol) and compound 4-a (17 mg, 65 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (25 mg, 195 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated to give crude product compound 90-d (32 mg). ESI-MS (m / z): 609.8 [M+H] + .

[0314] The crude product, compound 90-d (32 mg), was dissolved in ethanol (5 mL) and 80% hydrazine hydrate (0.1 mL) was added. The mixture was reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by preparative liquid chromatography to give compound 90 (3 mg, 13% yield). ESI-MS (m / z): 461.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.29 - 11.10 (m, 1H), 8.34 - 8.30 (m, 1H), 8.06 - 7.81 (m, 3H), 7.49 - 7.44 (m, 1H), 7.31 - 7.27 (m, 1H), 7.17 - 7.12 (m, 1H), 5.55 - 5.39 (m, 1H), 4.86 - 4.74 (m, 2H), 4.68 - 4.35 (m, 2H), 4.09 - 3.52 (m, 1H), 2.06 - 1.84 (m, 1H), 1.23 - 0.73 (m, 6H).

[0315] Example 91: JPEG2026501188000106.jpg62157

[0316] Compound 91-a was obtained by replacing (2R,3R)-2,3-butanediol with tert-butyl cis-3,4-dihydroxypyrrolidine-1-carboxylate, following the synthesis method of compound 11-b. Compound 91 was obtained by replacing compound 7-a with compound 67-d and compound 75-b with compound 91-a. ESI-MS (m / z): 470.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.77 - 8.40 (m, 2H), 8.38 - 8.29 (m, 1H), 8.22 - 8.16 (m, 1H), 7.84 - 7.78 (m, 1H), 7.61 - 7.54 (m, 1H), 7.39 - 7.29 (m, 1H), 5.36 - 5.09 (m, 1H), 4.85 - 4.54 (m, 3H), 4.28 - 4.01 (m, 1H), 3.24 - 3.19 (m, 1H), 3.11 - 2.80 (m, 2H), 2.71 - 2.55 (m, 2H).

[0317] Example 92: JPEG2026501188000107.jpg35151

[0318] Compound 83 (20 mg, 41 μmol) and 2-hydroxyacetic acid (3 mg, 41 μmol) were dissolved in N,N-dimethylformamide (2 mL), and HATU (17 mg, 45 μmol) and triethylamine (8.4 mg, 82 μmol) were added. The mixture was stirred at room temperature for 2 hours. Water (0.1 mL) was added to the reaction solution, and the mixture was directly purified by preparative liquid chromatography to give compound 92 (6.5 mg, 29% yield). ESI-MS (m / z): 541.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.46 - 12.31 (m, 1H), 8.61 - 8.55 (m, 1H), 8.33 - 8.07 (m, 3H), 7.83 - 7.79 (m, 1H), 7.60 - 7.53 (m, 1H), 7.37 - 7.29 (m, 1H), 5.80 - 5.40 (m, 2H), 4.89 - 4.44 (m, 3H), 4.40 - 3.38 (m, 6H), 3.27 - 2.80 (m, 2H), 1.68 - 1.44 (m, 2H).

[0319] Example 93: JPEG2026501188000108.jpg62162Compound 93-a was obtained by replacing compound 7-a with compound 67-d and following the synthesis of compound 75-c.

[0320] Compound 93-a (20 mg, 34 μmol) was dissolved in N,N-dimethylformamide (2 mL), and iodomethane (7 mg, 51 μmol) and cesium carbonate (26 mg, 80 μmol) were added. The mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (5 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography to give compound 93-b (12 mg, 59% yield). ESI-MS (m / z): 597.3 [M+H] + .

[0321] Compound 93-b (12 mg, 20 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 93 (5.5 mg, 55.1% yield). ESI-MS (m / z): 497.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.60 - 8.54 (m, 1H), 8.26 - 8.09 (m, 2H), 8.08 - 7.95 (m, 1H), 7.86 - 7.80 (m, 1H), 7.78 - 7.69 (m, 1H), 7.45 - 7.34 (m, 1H), 5.85 - 5.69 (m, 1H), 5.14 - 4.95 (m, 1H), 4.81 - 4.59 (m, 2H), 4.19 - 4.02 (m, 4H), 3.87 - 3.75 (m, 1H), 2.86 - 2.52 (m, 4H), 2.05 - 1.44 (m, 3H).

[0322] Example 94: JPEG2026501188000109.jpg67157

[0323] Compound 83 (20 mg, 41 μmol) and 2-(tert-butyldimethylsilyloxy)acetaldehyde (7.2 mg, 41 μmol) were dissolved in dichloromethane (1 mL) and methanol (1 mL), and glacial acetic acid (2.4 mg, 41 μmol) was added. The mixture was stirred at room temperature for 30 minutes, sodium cyanoborohydride (5.2 mg, 82 μmol) was added, and the mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (5 mL). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography to give compound 94-a (20 mg, 75.3% yield). ESI-MS (m / z): 641.3 [M+H] + .

[0324] Compound 94-a (20 mg, 31 μmol) was dissolved in tetrahydrofuran (2 mL) and 1N tetrabutylammonium fluoride in tetrahydrofuran (0.1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to give compound 94 (5 mg, 30.4% yield). ESI-MS (m / z): 527.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.53 - 8.00 (m, 4H), 7.72 - 7.42 (m, 2H), 7.25 - 7.14 (m, 1H), 5.82 - 5.71 (m, 1H), 5.22 - 4.98 (m, 1H), 4.81 - 4.45 (m, 2H), 4.33 - 4.09 (m, 1H), 3.85 - 3.66 (m, 1H), 3.59 - 3.44 (m, 3H), 2.82 - 2.67 (m, 1H), 2.60 - 2.53 (m, 1H), 2.47 - 2.36 (m, 2H), 2.33 - 1.95 (m, 3H), 1.76 - 1.61 (m, 2H).

[0325] Example 95: JPEG2026501188000110.jpg63163

[0326] Compound 95-a was obtained by replacing (R)-2-aminobutanamide hydrochloride with (2S,3R)-2-amino-3-hydroxybutanamide hydrochloride and following the synthesis of compound 4-c. Compound 95 was obtained by replacing compound 2-c with compound 67-d and compound 4-c with compound 95-a and following the synthesis of compound 4. ESI-MS (m / z): 485.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.16 - 7.84 (m, 3H), 7.72 (d, J = 4.9 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.35 - 7.20 (m, 2H), 7.12 (s, 1H), 6.01 (d, J = 7.6 Hz, 1H), 5.27 - 5.05 (m, 1H), 4.74 - 4.52 (m, 2H), 4.46 - 4.35 (m, 1H), 4.21 - 4.03 (m, 1H), 1.08 - 0.84 (m, 3H).

[0327] Example 96: JPEG2026501188000111.jpg27157

[0328] Compound 96-a was obtained by replacing compound 19-a with compound 62-b and by referring to the synthesis of compound 67-d. Compound 96 was obtained by replacing compound 7-a with compound 96-a and by referring to the synthesis of compound 75. ESI-MS (m / z): 484.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 4.4 Hz, 1H), 8.24 - 8.20 (m, 1H), 8.18 (d, J = 4.4 Hz, 1H), 8.15 - 7.94 (m, 2H), 7.82 - 7.68 (m, 1H), 7.43 - 7.33 (m, 1H), 5.76 - 5.61 (m, 1H), 5.04 - 4.90 (m, 1H), 4.71 - 4.56 (m, 2H), 4.16 - 3.89 (m, 1H), 3.84 - 3.60 (m, 1H), 2.76 - 2.44 (m, 5H), 1.60 - 1.45 (m, 2H).

[0329] Example 97: JPEG2026501188000112.jpg30152

[0330] Compound 35-a was used instead of compound 2-c, and compound 57-a was used instead of compound 4-c. Compound 97 was obtained by reference to the synthesis of compound 4. ESI-MS (m / z): 504.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.34 - 8.29 (m, 1H), 8.21 - 7.90 (m, 3H), 7.46 - 7.35 (m, 3H), 7.23 - 7.14 (m, 1H), 7.08 - 7.02 (m, 1H), 6.04 - 5.93 (m, 1H), 4.76 - 4.54 (m, 3H), 4.04 (s, 3H), 3.92 - 3.76 (m, 1H), 3.17 (s, 3H), 1.07 - 0.92 (m, 3H).

[0331] Example 98: JPEG2026501188000113.jpg28153

[0332] Compound 98 was obtained by replacing compound 2-c with compound 67-d and compound 4-c with compound 18-a, following the synthesis of compound 4. ESI-MS (m / z): 456.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.62 - 12.17 (m, 1H), 8.60 - 8.53 (m, 1H), 8.20 - 7.95 (m, 3H), 7.82 - 7.47 (m, 2H), 7.35 - 7.27 (m, 1H), 5.79 - 5.65 (m, 1H), 5.12 - 4.93 (m, 1H), 4.80 - 4.55 (m, 2H), 4.19 - 3.92 (m, 1H), 3.83 - 3.57 (m, 1H), 1.16 - 0.85 (m, 6H).

[0333] Example 99: JPEG2026501188000114.jpg55166

[0334] Compound 99-a was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)butyric acid with (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid and ammonium chloride with methylamine hydrochloride, with reference to the synthesis of compound 42-d. Compound 99 was obtained by replacing compound 4-c with compound 99-a and compound 2-c with compound 7-a, with reference to the synthesis of compound 4. ESI-MS (m / z): 488.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.45 - 8.34 (m, 1H), 8.19 - 7.86 (m, 4H), 7.52 - 7.42 (m, 1H), 7.38 - 7.33 (m, 1H), 7.24 - 7.14 (m, 1H), 6.32 - 6.21 (m, 1H), 5.54 (t, J = 5.5 Hz, 1H), 4.87 (d, J = 5.3 Hz, 2H), 4.72 - 4.52 (m, 3H), 2.67 - 2.52 (m, 3H), 1.94 - 1.56 (m, 2H), 0.83 - 0.63 (m, 3H).

[0335] Example 100: JPEG2026501188000115.jpg59165

[0336] Compound 100-a was obtained by replacing (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid with (R)-2-((tert-butoxycarbonyl)amino)butyric acid and ammonium chloride with dimethylamine hydrochloride, with reference to the synthesis of compound 42-d. Compound 100 was obtained by replacing compound 4-c with compound 100-a and compound 2-c with compound 7-a, with reference to the synthesis of compound 4. ESI-MS (m / z): 502.1 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.41 - 8.37 (m, 1H), 8.22 - 7.92 (m, 3H), 7.46 (s, 1H), 7.37 - 7.32 (m, 1H), 7.21 - 7.16 (m, 1H), 6.33 - 6.24 (m, 1H), 5.53 (t, J = 5.6 Hz, 1H), 5.16 - 4.85 (m, 3H), 4.73 - 4.59 (m, 2H), 3.12 - 2.65 (m, 6H), 1.75 - 1.44 (m, 2H), 0.87 - 0.61 (m, 3H).

[0337] Example 101: JPEG2026501188000116.jpg26142

[0338] Compound 75 (15 mg, 30 μmol) was dissolved in dichloromethane (2 mL) and methanol (0.5 mL), and aqueous formaldehyde (34%, 15 μL) and glacial acetic acid (2 mg, 43 μmol) were added. The mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (33 mg, 154 μmol) was added and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction solution, which was then extracted three times with ethyl acetate (15 mL). The combined organic phases were concentrated. The residue was purified by preparative liquid chromatography to give compound 101 (5.2 mg, 34.1% yield). ESI-MS (m / z): 502.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.24 - 7.98 (m, 3H), 7.48 - 7.42 (m, 1H), 7.35 (d, J = 4.7 Hz, 1H), 7.21 - 7.14 (m, 1H), 5.92 - 5.68 (m, 1H), 5.56 - 5.48 (m, 1H), 5.32 - 4.97 (m, 3H), 4.93 - 4.80 (m, 2H), 4.78 - 4.50 (m, 2H), 4.40 - 4.01 (m, 1H), 3.84 - 3.58 (m, 1H), 2.33 - 2.09 (m, 3H), 2.04 - 1.80 (m, 2H), 1.77 - 1.49 (m, 2H).

[0339] Test Example Detection of biological activity in inhibiting HGC27 (human gastric cancer cell) cell proliferation This detection method is used to evaluate the biological activity of the compounds of the present invention at the cellular level.

[0340] HGC27 cells (purchased from the Chinese Academy of Sciences) were collected and resuspended in complete medium to a cell density of 0.2 × 10 per ml. 6Cells were prepared in a 96-well plate. 100 μL of the cell suspension was added to each well and incubated overnight at 37°C in a 5% CO2 incubator. The compounds to be tested were prepared and added to the cell plate at a maximum concentration of 10 μM. Eight concentration points were set up using 3-fold dilutions. A 100% inhibition control well (a well containing an equal volume of complete medium without cells) and a 0% inhibition control well (a well containing cells with 0.1% DMSO) were also set up. The cell plate was cultured at 37°C under 5% CO2 for 24 hours. The cell culture plate was removed, and 25 μL of CellTiter-Glo® Luminescent Cell Viability Reagent (Promega cat# G7573) was added to each well. The plate was incubated in the dark for 10 minutes. 100 μL was then transferred to a white plate, and chemiluminescence was detected using a Molecular Devices SpectraMax i3. For data processing, the inhibition rate was calculated using the following formula: Compound inhibition rate = (0% inhibition control well signal - compound-treated well signal) / (0% inhibition control well signal - 100% inhibition control well signal) * 100%. The calculated data were fitted using graphpad prism software with four parameters to obtain the corresponding IC 50 was calculated.

[0341] JPEG2026501188000117.jpg220170The above results confirmed that the compounds of the present invention have excellent growth inhibitory activity against HGC27 tumor cells.

[0342] Evaluation of biological activity in inhibiting cell proliferation in NCI-N87 (human gastric cancer cells) This evaluation method is used to evaluate the biological activity of the compounds of the present invention at the cellular level.

[0343] NCI-N87 cells (purchased from the Chinese Academy of Sciences) were collected and resuspended in complete medium to a cell density of 0.1 × 10 per ml. 6 Cells were prepared in a 96-well plate. 100 μL of the cell suspension was added to each well and incubated overnight in a 37°C, 5% CO2 incubator. The compounds to be tested were prepared and added to the cell plate at a maximum concentration of 10 μM. Eight concentration points were set up using 3-fold dilutions. A 100% inhibition control well (a well containing an equal volume of complete medium without cells) and a 0% inhibition control well (a cell well containing 0.1% DMSO) were also set up. The cell plate was then cultured at 37°C, 5% CO2 for 72 hours. The cell culture plate was removed, and 25 μL of CellTiter-Glo™ Luminescent Cell Viability Reagent (Promega cat# G7573) was added to each well. The plate was incubated in the dark for 10 minutes. 100 μL was then transferred to a white plate, and chemiluminescence was detected using a Molecular Devices SpectraMax i3. For data processing, the inhibition rate was calculated using the following formula: Compound inhibition rate = (0% inhibition control well signal - compound-treated well signal) / (0% inhibition control well signal - 100% inhibition control well signal) × 100%.

[0344] The calculated data were fitted with a four-parameter fitting using GraphPad Prism software to obtain the corresponding IC 50 was calculated.

[0345] JPEG2026501188000118.jpg197170The above results confirmed that the compounds of the present invention have excellent growth inhibitory activity against NCI-N87 tumor cells.

[0346] Western blot detection of cyclin K (CCNK) degradation Harvest HEK293 cells (ATCC, Cat. No. CRL-1573) and culture at a cell density of 1 x 10 6 The cell suspension was adjusted to cells / mL. 1 mL of cell suspension was poured into a 6-well plate and cultured overnight. Compound stock solutions were diluted to the appropriate concentrations with DMSO. The diluted compounds were added to cell wells at a 1:1000 ratio using medium so that the DMSO concentration in each well was 0.1%. At the same time, negative control wells were set up, containing complete medium containing 0.1% DMSO. After treatment with compounds at the indicated concentrations for various times and fixation, total cellular protein was extracted using RIPA cell lysis buffer (Beyotime, catalog number P0013B) supplemented with PMSF. Protein was quantified using a BCA protein quantification kit (Thermo Fisher, catalog number A53225), and each sample was subsequently subjected to SDS-PAGE and Western blot experiments with a loading volume of 40 μg. The specific conditions were to run the gel at a constant voltage of 120 V for 90 minutes, followed by film transfer at a constant current of 320 mA for 60 minutes. Antibody incubation was performed according to the recommended antibody dilution and incubation time. The antibodies used in the experiment were as follows: Anti-GAPDH antibody (Abcam, cat#ab9485), Anti-Cyclin K antibody (Abcam, cat#ab85854), Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, HRP (Invitrogen, cat#G--21234). Color development was performed using ECL luminescence solution (Thermo Fisher, cat#32209). The final results were analyzed using a gel imaging system.

[0347] Some of the compounds of the present invention were evaluated based on the above detection method.

[0348] Figure 1 shows that after treatment of HEK293 cells with compounds 12, 17, and 18 at different concentrations for 6 hours, cyclin K degradation was significantly induced compared to the control.

[0349] From the above results, it was confirmed that the compounds of the present invention have the ability to effectively decompose cyclin K.

Claims

1. A compound having the structure of Formula (I), or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide, or prodrug thereof: Where: W 1 each independently represents CR, N, or a bond; W 2 are each independently CR 0 , N, NR a , S or O; W 3 each independently represents C or N, W 3 At most two are N at the same time; W 4 are each independently CR 1 , N, NR a , S or O; R, R 0 and R 1 are each independently hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O) 2 R a , -S(O)R a , -S(O) 2 NR a R b , -P(O)R a R b , C 1 -C 6 Alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, wherein the alkyl, alkenyl, or alkynyl is each —OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 R a , -S(O)R a , -S(O) 2 NR a R b , -P(O)R a R b wherein said —NR a C(O)R b R in b is -(C 0 -C 3 alkylene) OR a , -(C 0 -C 3 Alkylene)SR a , -(C 0 -C 3 alkylene) NR a R b optionally substituted with 0, 1 or 2 substituents selected from R L and R L’ are each independently hydrogen, fluorine, or C 1 -C 6 Alkyl or C 3 -C 6 represents cycloalkyl, and R L and R L’ can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R 2 is halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 R a , -S(O)R a , -S(O) 2 NR a R b , -P(O)R a R b , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) represents alkynyl; R 3 is C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -NR M R N , -NHR M , -OR M , -SR M represents; R 3 When represents a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, a C3-C10 cycloalkyl group, or a 3- to 10-membered heterocycloalkyl group, the group may be oxo, nitro, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , - (C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2, or 3 substituents selected from R 3 When represents a C6-C10 aryl group or a 5- to 10-membered heteroaryl, the group may be selected from nitro, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , - (C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2, or 3 substituents selected from R 3 Ha-NR M R N , -NHR M , -OR M , -SR M When R represents M and R N are each independently C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), -(C 0 -C 6 alkylene)(C 6 -C 10 aryl), -(C 0 -C 6 alkylene)(5-10 membered heteroaryl); R M and R N are each optionally oxo, nitro, halogen, cyano, -R a , -(4-8 membered heterocycloalkyl), -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , - (C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b wherein R M or R N contains a nitrogen atom -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), and when a substituent is located on the nitrogen atom, the carbon atom adjacent to the nitrogen atom in the substituent may be further substituted with an oxo group; where R a , R b are independently hydrogen, C 1 -C 6 Alkyl or C 3 -C 8 and represents cycloalkyl, wherein said alkyl or cycloalkyl may each independently be substituted with 0, 1, 2, or 3 halogen atoms.

2. Where W 1 each independently represents CR or N; W 2 , W 3 and W 4 is as defined in formula (I) above, 10. The compound of claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

3. wherein each X is independently NR a , O or S; W 1 each independently represents CR or N; W 2 are each independently CR 0 or N; W 4 are each independently CR 1 or N, 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

4. wherein each X is independently NR a , O or S; W 1 each independently represents CR or N; W 2 are each independently CR 0 or N; W 4 are each independently CR 1 or N, 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

5. W 1 each independently represents CR or N; where each R is independently hydrogen, halogen, cyano, -R a -OR a Preferably, each R is independently hydrogen, halogen or -R a more preferably, each R is independently hydrogen, C 1 -C 6 represents alkyl, 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

6. W 2 are each independently CR 0 or N; where R 0 are each independently hydrogen, halogen, cyano, -R a -OR a preferably R 0 are each independently hydrogen, halogen, cyano or -R a more preferably, R 0 are independently hydrogen, cyano, or C 1 -C 6 represents alkyl, 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

7. W 4 are each independently CR 1 or N; where R 1 are each independently hydrogen, halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O) 2 R a , -S(O)R a where C 1 -C 6 Each alkyl is independently a halogen, -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 R a , -S(O)R a wherein said —NR a C(O)R b R in b is optionally -(C 0 -C 3 alkylene) OR a , -(C 0 -C 3 Alkylene)SR a , -(C 0 -C 3 alkylene) NR a R b and preferably, the —NR a C(O)R b R in b is arbitrarily -(C 0 -C 3 alkylene)OH, -(C 0 -C 3 alkylene)SH, -(C 0 -C 3 alkylene) NH 2 and more preferably, the —NR a C(O)R b R in b is optionally -CH 2 OH,-CH 2 SH, -CH 2 NH 2 optionally substituted with 0, 1 or 2 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

8. W 4 are each independently, CR 1 or N; where R 1 are each independently hydrogen, halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)NR a R b , -NR a C(O)R b , -S(O) 2 R a wherein C represents 1 -C 6 Each alkyl is independently optionally selected from halogen, OR a , S.R. a , N.R. a R b , N.R. a C(O)R b wherein said —NR a C(O)R b R in b is optionally -(C 0 -C 3 alkylene) OR a , -(C 0 -C 3 Alkylene)SR a , -(C 0 -C 3 alkylene) NR a R b and preferably, the —NR a C(O)R b R in b is optionally -(C 0 -C 3 alkylene)OH, -(C 0 -C 3 alkylene)SH, -(C 0 -C 3 alkylene) NH 2 and more preferably, the —NR a C(O)R b R in b is optionally -CH 2 OH,-CH 2 SH, -CH 2 NH 2 optionally substituted with 0, 1 or 2 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

9. W 4 are each independently CR 1 or N; where R 1 are independently hydrogen, halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -(C 0 -C 6 alkylene) NR a C(O)R b characterized in that it represents 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

10. R L and R L’ each independently represents hydrogen or fluorine; preferably, R L and R L’ are both hydrogen; 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

11. R 2 is halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b preferably R 2 is halogen or -R a more preferably, R 2 Ha-CF 3 characterized in that 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

12. R 3 is C 1 -C 6 Alkyl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl each independently represent oxo, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -(C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b and optionally substituted by 0, 1, 2, or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

13. R 3 represents a C6-C10 aryl or a 5- to 10-membered heteroaryl, and each of the aryl and heteroaryl is independently halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -(C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b optionally substituted by 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

14. R 3 Ha-NR M R N , -NHR M , -OR M , -SR M where R M and R N are each independently, C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), -(C 0 -C 6 alkylene)(C 6 -C 10 aryl), -(C 0 -C 6 alkylene)(5-10 membered heteroaryl); R M and R N are oxo, nitro, halogen, cyano, and -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , - (C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b wherein R M or R N represents -(C0-C6 alkylene)(3-10 membered heterocycloalkyl) containing an N atom, and when a substituent is located on the N atom, the carbon atom adjacent to the N atom in the substituent may be further substituted with an oxo group; 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

15. R 3 Ha-NR M R N , -NHR M , -OR M , -SR M represents R M and R N Each one is independently C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), -(C 0 -C 6 alkylene)(C 6 -C 10 aryl), -(C 0 -C 6 alkylene)(5-10 membered heteroaryl); M and R N are oxo, nitro, halogen, cyano, and -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , - (C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

16. R 3 Ha-NR M R N , -NHR M , -OR M , -SR M where R M and R N are each independently hydrogen or C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), -(C 0 -C 6 alkylene)(C 6 -C 10 aryl), -(C 0 -C 6 alkylene)(5-10 membered heteroaryl); M and R N are each independently oxo, nitro, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -(C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

17. R 3 Ha-NHR M , -OR M , -SR M where R M are each independently, C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl); R M are each independently oxo, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -(C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b optionally substituted with 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

18. R 3 Ha-NHR M , -OR M , -SR M where R M are each independently, C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), M is optionally oxo, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)NR a R b , -S(O) 2 R a , - S(O)R a , -S(O) 2 NR a R b , -P(O)R a R b and more preferably, R M are each independently, R a , -(C 0 -C 6 alkylene) OR a , - (C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , -C(O)NR a R b optionally substituted with 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

19. R 3 Ha-NHR M , -OR M , -SR M where R M are each independently, C 1 -C 6 Alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), M is optionally oxo, halogen, cyano, -R a , -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)NR a R b , -S(O) 2 R a , - S(O)R a , -S(O) 2 NR a R b , -P(O)R a R b and more preferably, R M are each independently -R a , -OR a , -SR a , -NR a R b , -C(O)NR a R b optionally substituted with 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

20. R 3 Ha-NHR M , -OR M , -SR M where R M are each independently C 1 -C alkyl, -(C 0 -C 6 alkylene)(C 3 -C 10 cycloalkyl), -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), M is optionally oxo, halogen, cyano, -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)NR a R b , -S(O) 2 R a , - S(O)R a , -S(O) 2 NR a R b , -P(O)R a R b and more preferably, R M are each independently -OR a , -SR a , -NR a R b , -C(O)NR a R b optionally substituted with 0, 1, 2 or 3 substituents selected from 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

21. R 3 Ha-NR M R N , -NHR M , -OR M , -SR M Preferably, R 3 Ha-NHR M , -OR M , -SR M， represents R M and R N are each independently a nitrogen-containing -(C 0 -C 6 alkylene)(3-10 membered heterocycloalkyl), which structure may further include oxo, nitro, halogen, cyano, -R a , -(C 0 -C 6 alkylene) OR a , -(C 0 -C 6 Alkylene)SR a , -(C 0 -C 6 Alkylene)NR a R b , - (C 0 -C 6 Alkylene)NR a C(O)R b , -(C 0 -C 6 alkylene)C(O)R a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkylene)C(O)NR a R b , -(C 0 -C 6 Alkylene)S(O) 2 R a , -(C 0 -C 6 alkylene)S(O)R a , -(C 0 -C 6 Alkylene)S(O) 2 NR a R b , -(C 0 -C 6 alkylene)P(O)R a R b wherein the substituents are located on the nitrogen atom, and the carbon atom adjacent to the nitrogen atom in the substituents may be further substituted with oxo.

10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

22. R a and R b are independently hydrogen, C 1 -C 3 Alkyl or C 3 -C 6 cycloalkyl, wherein said alkyl and cycloalkyl may be optionally substituted with 0, 1, 2, or 3 halogen atoms; 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

23. R a and R b are each independently hydrogen or C 1 -C 3 alkyl, wherein said alkyl is optionally substituted with 0, 1, 2, or 3 halogen atoms; 10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof.

24. The compound is selected from any of the compounds shown in the following table:

10. A compound according to any one of the preceding claims, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof:

25. 25. A pharmaceutical composition comprising a compound of any one of claims 1-24, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

26. Use of a compound according to any one of claims 1-24, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof, or a pharmaceutical composition according to claim 25, in the manufacture of a medicament for the prevention or treatment of a disease or disorder associated with a cyclin K protein.

27. 26. The use according to claim 25, wherein the disease or disorder is selected from tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases.

28. 26. A method for treating a rheumatoid arthritis comprising administering to a mammal in need thereof a compound according to any one of claims 1-24, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, metabolite, isotopic derivative, N-oxide or prodrug thereof, or a pharmaceutical composition according to claim 25. A method of treating a disease or disorder associated with a cyclin K protein.

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