Pyrimidine heterocyclic compounds, their preparation and medicinal uses

Abstract

A pyrimidine heterocyclic compound, its preparation method and medical use. Specifically, a pyrimidine heterocyclic compound having a structure represented by formula (A) or a pharma- ceutical acceptable salt thereof. The definitions of each group are as defined in the specification. A pharmaceutical composition containing the compound, and use of the compound in the treatment of cell proliferative diseases (cancer, etc.) and the like.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The present invention claims priority to Chinese patent application CN202111583828.0 filed on December 22, 2021, Chinese patent application CN202210098381.6 filed on January 27, 2022, Chinese patent application CN202210562007.7 filed on May 23, 2022, and Chinese patent application CN202211568373.X filed on December 7, 2022. This application cites some or all of the above Chinese patent applications. [Background technology]

[0002] The present invention relates to the pharmaceutical field, specifically to pyrimidine heterocyclic compounds, their preparation methods and pharmaceutical uses.

[0003] Cyclin-dependent kinase (CDK) / cyclin complexes have been identified as conserved components of the RNA polymerase II transcription machinery. Currently, 20 mammalian CDKs are known. Among mammalian CDKs, CDK7 possesses robust kinase activity, and it is the only one with dual functions regulating cell cycle progression and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to function as a CDK1 / 2 / 4 / 6-activating kinase (CAK). Therefore, phosphorylation of conserved residues in CDK1 / 2 / 4 / 6 by CDK7 is required for full catalytic activity of CDKs and cell cycle progression. In the cell nucleus, CDK7 forms the kinase core of the RNA polymerase II transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNA polymerase II, a necessary step in the initiation of gene transcription. The dual functions of CDK7 (i.e., CAK and CTD phosphorylation) support important aspects of cell proliferation, cell cycle, and transcription.

[0004] As a global transcriptional regulator, CDK7 can serve as a therapeutic target for many diseases and syndromes. CDK7 can regulate transcription by interacting with multiple transcription factors, cofactors, chromatin regulators, and non-coding RNAs in the transcriptional regulatory region. Mutations in these transcription factors, cofactors, chromatin regulators, or non-coding RNAs can cause diseases such as cancer, autoimmune diseases, neurological disorders, developmental syndromes, diabetes, cardiovascular disease, and obesity. Some of these transcription factors can control RNA polymerase II-mediated transcription initiation and elongation, and alterations in their expression or function can lead to aggressive tumor cells (e.g., c-Myc-mediated) or certain forms of autoimmunity (e.g., AIRE-mediated). Therefore, CDK7 kinase can promote the aberrant expression of specific tumor-related transcription factors by regulating the global transcription process and promote tumor development by regulating the phosphorylation of key cell cycle kinases. More importantly, CDK7 regulates the expression of oncogenic transcription factors more significantly than other housekeeping genes in cancer cells. CDK7 inhibition can differentially affect the transcription of specific oncogenes and housekeeping genes, providing a therapeutic window. Regulation of CDK7-mediated phosphorylation, through transcriptional and cell cycle regulation, can be used to treat hyperproliferative diseases, including cancer. As a global regulator of transcription, CDK7 can also function as a therapeutic target for treating diseases such as inflammation, viral replication (e.g., HIV and EBV), cancer, and cardiac hypertrophy.

[0005] The high sequence and structural similarity of the kinase domains of CDK family members hinders the discovery of selective CDK7 inhibitors, and therefore the development of selective CDK7 inhibitors would be of great value for clinical application. Summary of the Invention

[0006] A first aspect of the present invention provides a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0007] [ka] (however,

[0008] [ka] and Ring A is absent, or ring A is a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, a 5- to 12-membered heteroaryl group, C 5-12 aryl groups, wherein ring A is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, the 3- to 14-membered heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 12-membered heteroaryl group has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L3 is none, C 1-6 Alkylene group, C 2-6 Alkenylene group or ring B (structure

[0009] [ka] ) and said C 1-6 1, 2, 3, 4, or 5 hydrogen atoms of the alkylene group are each independently R 13 may be substituted with C 2-6 1, 2, 3, 4, or 5 hydrogen atoms of the alkenylene group are each independently R 13 may be substituted with Ring B is a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, a 5- to 12-membered heteroaryl group, C 5-12 aryl groups, wherein ring B is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from group S1, wherein the 3- to 14-membered heterocyclic ring has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 12-membered heteroaryl group has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L1 is None, C 1-6 Alkylene group, C 2-6Alkenylene group, -O-, -NR 10 -, -C=N-, C 5-12 Aryl group, 5- to 12-membered heteroaryl group, -C(O)-, -C(O)-NR 10 -or-NR 10 -C(O)-, 1-6 1, 2, 3, 4, or 5 hydrogen atoms of the alkylene group are each independently R 13 may be substituted with C 2-6 1, 2, 3, 4, or 5 hydrogen atoms of the alkenylene group are each independently R 13 wherein the 5- to 12-membered heteroaryl group has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein the C 5-12 The aryl group and the 5- to 12-membered heteroaryl group are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; L2 is -(O) m2 -(CR 13 R 14 ) m1 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 ) m1 -(NR 12 ) m3 -, -(O) m2 -(CR 13 R 14 ) m5 -(3- to 7-membered carbocyclic ring) m4 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 ) m5 -(3- to 7-membered carbocyclic ring) m4 -(CR 13 R 14 ) m6 -(NR12 ) m3 -, -(O) m2 -(CR 13 R 14 ) m5 -(3- to 7-membered heterocycle) m4 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 ) m5 -(3- to 7-membered heterocycle) m4 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(O) m2 -(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(O) m2 -(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 )m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -(NR 12 ) m3 -、 -(O) m2 -(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -、 -(NR 11 ) m2 -(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -、 -(O) m2 -(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -(NR 12 ) m3 -、 -(NR 11 ) m2 -(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -(NR 12 ) m3 -、 -(O) m2 -(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -(NR 12 ) m3 -、 -(NR 11 ) m2 -(CR13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(O) m2 -(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(O) m2 -(CR 13 R 14 ) m5 -(CH=CH) m7 -(CR 13 R 14 ) m6 -(NR 12 ) m3 -, -(NR 11 ) m2 -(CR 13 R 14 ) m5 -(CH=CH) m7 -(CR 13 R 14 ) m6 -(NR 12 ) m3 - selected from the group consisting of R 10 are each independently hydrogen, C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, -3 to 7-membered carbocyclic group, -C(O)-C 1-6 Alkyl group, -C(O)-C 1-4 Alkyl-C 1-6Alkoxy group, -C(O)-3 to 7-membered carbocyclic group, -C 1-4 Alkyl-hydroxy group, -C 1-4 Alkyl-cyano group, -C 1-4 Alkyl-C 1-6 Alkoxy group, -C 1-4 Alkyl-NHC(O)-C 1-6 Alkyl group, -C 1-4 Alkyl-NHC(O)-C 1-4 Alkyl-C 1-6 Alkoxy group, -C 1-4 Alkyl-NHC(O)-3 to 7-membered carbocyclic group or -C 1-4 alkyl-NRR′, each 3- to 7-membered heterocyclic group independently has 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 3- to 7-membered carbocyclic ring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; each 3- to 7-membered carbocyclic group is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; R 11 are each independently hydrogen, C 1-6 Alkyl group or deuterated C 1-6 is an alkyl group, R 12 are each independently hydrogen, C 1-6 Alkyl group or deuterated C 1-6 is an alkyl group, R 13 are each independently hydrogen, a cyano group, a hydroxy group, a halogen, or C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, -3 to 7-membered carbocyclic group, -C 0-6 Alkylene-NRR', -C 1-6 Alkylene-hydroxy group or -C 0-6 an alkylene-cyano group, R 14 are each independently hydrogen, a cyano group, a hydroxy group, a halogen, or C 1-6 Alkyl group, C1-6 Alkoxy group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, -3 to 7-membered carbocyclic group, -C 0-6 Alkylene-NRR', -C 1-6 Alkylene-hydroxy group or -C 0-6 an alkylene-cyano group, m1 is independently 1, 2, 3, 4, 5, or 6; Each m2 is independently 0 or 1; Each m3 is independently 0 or 1; Each m4 is independently 1 or 2; m5 is independently 0, 1, 2, 3, 4, 5 or 6; m6 is independently 0, 1, 2, 3, 4, 5, or 6; m7 is independently 1 or 2; R1 is hydrogen, halogen, cyano group, C 1-6 is an alkyl group or a 3- to 14-membered carbocyclic group, 1-6 The alkyl group and the 3- to 14-membered carbocyclic group are independently unsubstituted or substituted with an oxo group, a hydroxy group, a halogen, or a C 1-6 Alkyl groups, halogenated C 1-6 substituted with 1, 2, 3, 4, or 5 groups selected from the group consisting of alkyl groups; R2 is hydrogen, halogen, cyano group, C 1-6 is an alkyl group or a 3- to 14-membered carbocyclic group, 1-6 The alkyl group and the 3- to 14-membered carbocyclic group are independently unsubstituted or substituted with an oxo group, a hydroxy group, a halogen, or a C 1-6 Alkyl groups, halogenated C 1-6 substituted with 1, 2, 3, 4, or 5 groups selected from the group consisting of alkyl groups; X2 is N or C(R3); X1 is N or C(R4), Y is N or C(R4); Z is N or C(R3); Each R3 is independently hydrogen, halogen, cyano, C1-6 Alkyl or halogenated C 1-6 is an alkyl group, Each R4 is independently hydrogen, halogen, a hydroxy group, a cyano group, -C 2-4 Alkenylene-phenyl group, -C 2-4 Alkynylene-phenyl group, -S(O)-OH, -S(O)2-OH, -S-(C 1-6 alkyl group), C 1-6 Alkyl group, -OC 1-6 Alkyl group, -C 1-6 Alkylene-OC 1-6 Alkyl group, -OC 1-6 Alkylene-OC 1-6 Alkyl group, -C 0-6 Alkylene-NRR', -C 0-6 Alkylene -C(O)OH, -C 0-6 Alkylene-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-C(O)-NRR', -C 0-6 Alkylene-NR-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -S(O)2-NRR', -C 0-6 Alkylene-NR-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -NR-S(O)2-NR-R', -C 0-6 Alkylene-P(O)O-(C 1-6 alkyl group)2, -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)(OC 1-6 alkyl group), -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)2, -C 0-6 Alkylene-3 to 14-membered carbocyclic group, -C 0-6 alkylene-3 to 14-membered heterocyclic group, -C 0-6 alkylene-5 to 12-membered heteroaryl group, -C 0-6 Alkylene-C 5-12 Aryl group, -C 0-6alkylene-C(O)-3 to 14-membered heterocyclic group, -C 0-6 Alkylene-C(O)-5 to 12-membered heteroaryl group, -OC 0-6 Alkylene-OC 1-6 Alkyl group, -OC 0-6 Alkylene-3 to 14-membered carbocyclic group, -OC 0-6 Alkylene-3 to 14-membered heterocyclic group, -OC 0-6 Alkylene-5 to 12-membered heteroaryl group, -OC 0-6 Alkylene-C 5-12 Aryl group, -S(O)-C 1-6 is an alkyl group, 1-6 Alkyl group, C 0-6 Alkylene group, C 2-4 Alkenylene group, 3- to 14-membered carbocyclic group, 3- to 14-membered heterocyclic group, 5- to 12-membered heteroaryl group, C 5-12 the aryl group is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; the 3- to 14-membered heterocycle has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and the 5- to 12-membered heteroaryl group has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The groups in the S1 group include an oxo group, a halogen, a hydroxy group, a cyano group, C 1-6 Alkyl group, -OC 1-6 Alkyl group, -C 1-6 Alkylene-OC 1-6 Alkyl group, -OC 1-6 Alkylene-OC 1-6 Alkyl group, -C 0-6 Alkylene-NRR', -C 0-6 Alkylene -C(O)OH, -C 0-6 Alkylene-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-C(O)-NRR', -C 0-6 Alkylene-NR-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -S(O)2-NRR', -C0-6 Alkylene-NR-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -NR-S(O)2-NR-R', -C 0-6 Alkylene-P(O)O-(C 1-6 alkyl group)2, -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)(OC 1-6 alkyl group), -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)2, -C 0-6 Alkylene-3 to 14-membered carbocyclic group, -C 0-6 alkylene-3 to 14-membered heterocyclic group, -C 0-6 alkylene-5 to 12-membered heteroaryl group, -C 0-6 Alkylene-C 5-12 Aryl group, -C 0-6 alkylene-C(O)-3 to 14-membered heterocyclic group, -C 0-6 Alkylene-C(O)-5 to 12-membered heteroaryl group, -OC 0-6 Alkylene-OC 1-6 Alkyl group, -OC 0-6 Alkylene-3 to 14-membered carbocyclic group, -OC 0-6 Alkylene-3 to 14-membered heterocyclic group, -OC 0-6 Alkylene-5 to 12-membered heteroaryl group, -OC 0-6 Alkylene-C 5-12 Aryl group, -S(O)-C 1-6 containing an alkyl group, R and R' are each independently hydrogen, C 1-6 Alkyl group or deuterated C 1-6 R and R' may be alkyl groups, or R and R' may form a 3- to 14-membered heterocyclic group or a 5- to 12-membered heteroaryl group together with the nitrogen atom bonded thereto, and the heterocyclic group and heteroaryl group each independently contain, in addition to the existing nitrogen atom, 0, 1 or 2 heteroatoms selected from N, O and S; In each of the above groups, 0-6 Any two hydrogen atoms on the same carbon atom of the alkylene group may be simultaneously replaced by a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic spiro ring; In each of the above groups, 1-6 Any two hydrogen atoms on the same carbon atom of the alkylene group may be simultaneously replaced by a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic spiro ring.

[0010] In some embodiments, R is hydrogen, halogen, cyano, C 1-4 is an alkyl group or a 3- to 7-membered carbocyclic group, 1-4 The alkyl group and the 3- to 7-membered carbocyclic group are independently unsubstituted or substituted with an oxo group, a hydroxy group, a halogen, or C 1-3 Alkyl groups, halogenated C 1-3 It is substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of alkyl groups.

[0011] In some embodiments, R is hydrogen, halogen, cyano, C 1-4 Alkyl groups (e.g., methyl groups), halogenated C 1-4 It is an alkyl group (such as a trifluoromethyl group), a 3- to 7-membered carbocyclic group, or a halogenated 3- to 7-membered carbocyclic group.

[0012] In some embodiments, R2 is hydrogen, halogen, cyano, C 1-4 is an alkyl group or a 3- to 7-membered carbocyclic group, 1-4 The alkyl group and the 3- to 7-membered carbocyclic group are independently unsubstituted or substituted with an oxo group, a hydroxy group, a halogen, or C 1-3 Alkyl groups, halogenated C 1-3 It is substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of alkyl groups.

[0013] In some embodiments, R2 is hydrogen, halogen, cyano, C 1-4 Alkyl groups (e.g., methyl groups), halogenated C 1-4 It is an alkyl group (such as a trifluoromethyl group), a 3- to 7-membered carbocyclic group, or a halogenated 3- to 7-membered carbocyclic group.

[0014] In some embodiments, X 1 is N.

[0015] In some embodiments, X1 is C(R4), and R4 is hydrogen, halogen, a hydroxy group, a cyano group, -C 2-4 Alkenylene-phenyl group, -C 2-4 Alkynylene-phenyl group, -S(O)-OH, -S(O)2-OH, -S-(C 1-6 alkyl group) or R8, where R8 is C 1-6 Alkyl group, -OC 1-6 Alkyl group, -C 1-6 Alkylene-OC 1-6 Alkyl group, -OC 1-6 Alkylene-OC 1-6 Alkyl group, -C 0-6 Alkylene-NRR', -C 0-6 Alkylene -C(O)OH, -C 0-6 Alkylene-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-C(O)-NRR', -C 0-6 Alkylene-NR-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -S(O)2-NRR', -C 0-6 Alkylene-NR-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -NR-S(O)2-NR-R', -C 0-6 Alkylene-P(O)O-(C 1-6 alkyl group)2, -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)(OC 1-6 alkyl group), -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)2, -C 0-6 Alkylene-3 to 14-membered carbocyclic group, -C 0-6 alkylene-3 to 14-membered heterocyclic group, -C 0-6 alkylene-5 to 12-membered heteroaryl group, -C 0-6 Alkylene-C 5-12 Aryl group, -C 0-6 alkylene-C(O)-3 to 14-membered heterocyclic group, -C 0-6Alkylene-C(O)-5 to 12-membered heteroaryl group, -OC 0-6 Alkylene-OC 1-6 Alkyl group, -OC 0-6 Alkylene-3 to 14-membered carbocyclic group, -OC 0-6 Alkylene-3 to 14-membered heterocyclic group, -OC 0-6 Alkylene-5 to 12-membered heteroaryl group, -OC 0-6 Alkylene-C 5-12 Aryl group, -S(O)-C 1-6 is an alkyl group, 1-6 Alkyl group, C 0-6 Alkylene group, C 2-4 Alkenylene group, 3- to 14-membered carbocyclic group, 3- to 14-membered heterocyclic group, 5- to 12-membered heteroaryl group, C 5-12 The aryl group is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, the 3- to 14-membered heterocycle has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the 5- to 12-membered heteroaryl group has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R, R', and the groups in Group S1 are as defined above.

[0016] In some embodiments, X1 is C(R4), and R4 is -C 0-6 Alkylene-NRR', -C 0-6 Alkylene -C(O)OH, -C 0-6 Alkylene-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-C(O)-NRR', -C 0-6 Alkylene-NR-C(O)-C 1-6 Alkyl group, -C 0-6 Alkylene-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -S(O)2-NRR', -C 0-6 Alkylene-NR-S(O)2-C 1-6 Alkyl group, -C 0-6 Alkylene -NR-S(O)2-NR-R', -C 0-6 Alkylene-P(O)O-(C 1-6alkyl group)2, -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)(OC 1-6 alkyl group) or -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)2, 1-6 Alkyl group, C 0-6 The alkylene groups are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, where R, R', and the groups in Group S1 are as defined above.

[0017] In some embodiments, X1 is C(R4), and R4 is -C 0-6 Alkylene-P(O)O-(C 1-6 alkyl group)2, -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)(OC 1-6 alkyl group) or -C 0-6 Alkylene-P(O)-(C 1-6 alkyl group)2, 1-6 Alkyl group, C 0-6 The alkylene groups are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, where Group S1 is as defined above.

[0018] In some embodiments, X is C(R), and R is —P(O)O—(C 1-6 alkyl group)2, -P(O)-(C 1-6 alkyl group)(OC 1-6 alkyl group) or -P(O)-(C 1-6 alkyl group)2, 1-6 The alkyl groups are independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from Group S1, where Group S1 is as defined above.

[0019] In some embodiments, X1 is C(R4), and R4 is hydrogen, halogen, or a cyano group.

[0020] In some embodiments, X1 is C(R4) and R4 is -P(O)O-(CH3)2, -P(O)-(CH3)(O-CH3), or -P(O)-(CH3)2. In some embodiments, X2 is C(R3) and R3 is hydrogen. In some embodiments, Y is C(R4) and R4 is hydrogen. In some embodiments, Z is C(R3) and R3 is hydrogen.

[0021] As referred to herein, C 0-6 Alkylene group or C 0-6 In an alkylene group, two hydrogen atoms on the same carbon atom are simultaneously replaced with a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic spiro ring, meaning that after the two hydrogen atoms on the carbon atom are replaced with a divalent substituent, the divalent substituent forms a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring together with the carbon atom. For example, when two hydrogen atoms on the carbon atom of -CH2- are replaced with a cyclopropyl spiro ring, it means that after the two hydrogen atoms on the carbon atom of -CH2- are replaced with a divalent ethyl group (i.e., an ethylidene group), the ethylidene group forms a cyclopropyl group together with the carbon atom. The same applies hereinafter.

[0022] In some embodiments, The compound of formula (A) is a compound of formula (IA),

[0023] [ka] wherein X1, Y, Z, X2, R1, R2, L1, L2, ring A, and ring B are as defined above, or The compound of formula (A) is a compound of formula (IB),

[0024] [ka] However, X1, Y, Z, X2, R1, R2, L1, L2, ring A, R 13, R 14 are each as defined above, and m0 is 1, 2, 3, 4, 5, or 6; or The compound of formula (A) is a compound of formula (A1),

[0025] [ka] wherein X1, Y, Z, X2, R1, R2, L1, L2, ring A, and ring B are as defined above, or The compound of formula (A) is a compound of formula (A2),

[0026] [ka] However, X1, Y, Z, X2, R1, R2, L1, L2, ring A, R 13 , R 14 are each as defined above, and m0 is 1, 2, 3, 4, 5, or 6. In some embodiments, the compound of Formula (A) is a compound of Formula (Ia), a compound of Formula (Ib), a compound of Formula (Ic), a compound of Formula (Id), a compound of Formula (Ie), or a compound of Formula (If),

[0027] [ka] wherein X1, Y, Z, X2, R1, R2, L1, L2, ring A, and ring B are as defined above. In some embodiments, The compound of formula (A) is a compound of formula (II-A),

[0028] [ka] wherein R1, R2, L1, L2, ring A, ring B, and X1 are as defined above, or The compound of formula (A) is a compound of formula (II-B),

[0029] [ka] However, X1, R1, R2, L1, L2, ring A, R 13 , R 14 are each as defined above, and m0 is 1, 2, 3, 4, 5, or 6; or The compound of formula (A) is a compound of formula (A3),

[0030] [ka] wherein X1, R1, R2, L1, L2, ring A, and ring B are as defined above, or The compound of formula (A) is a compound of formula (A4),

[0031] [ka] However, X1, R1, R2, L1, L2, ring A, R 13 , R 14 are each as defined above, and m0 is 1, 2, 3, 4, 5, or 6.

[0032] In some embodiments, the compound of Formula (A) is a compound of Formula (IIa), a compound of Formula (IIb), a compound of Formula (IIc), a compound of Formula (IId), a compound of Formula (IIe), or a compound of Formula (IIf),

[0033] [ka] wherein X1, R1, R2, L1, L2, ring A, and ring B are as defined above. In some embodiments, The compound of formula (A) is a compound of formula (III-A),

[0034] [ka] wherein L1, L2, ring A, ring B, and X1 are as defined above, or The compound of formula (A) is a compound of formula (III-B),

[0035] [ka] However, X1, L1, L2, ring A, R 13 , R 14 are each as defined above, and m0 is 1, 2, 3, 4, 5, or 6; or The compound of formula (A) is a compound of formula (A5),

[0036] [ka] wherein X1, L1, L2, ring A, and ring B are as defined above, or The compound of formula (A) is a compound of formula (A6),

[0037] [ka] However, X1, L1, L2, ring A, R 13 , R 14 are each as defined above, and m0 is 1, 2, 3, 4, 5, or 6. In some embodiments, the compound of Formula (A) is a compound of Formula (III-1) or a compound of Formula (III-2):

[0038] [ka] wherein L1, L2, ring A, ring B, and X1 are as defined above. In some embodiments, the compound of Formula (A) is a compound of Formula (III-a), a compound of Formula (III-b), a compound of Formula (III-c), or a compound of Formula (III-d),

[0039] [ka] wherein L1, L2, ring A, ring B, and X1 are as defined above. In some embodiments, the compound of Formula (A) is a compound of Formula (IV-a), a compound of Formula (IV-b), or a compound of Formula (IV-c):

[0040] [ka] wherein L1, L2, ring B, and X1 are as defined above. In some embodiments, ring A is absent or selected from the group consisting of a 3- to 6-membered carbocyclic ring, a 3- to 6-membered heterocyclic ring, a 5- to 6-membered heteroaryl group, and a phenyl group, and said ring A is unsubstituted or selected from the group consisting of OH, C 1-6 It is substituted with 1, 2, or 3 selected from alkyl groups, halogens, and the remainder of the variables are as defined herein.

[0041] In some embodiments, ring A is absent, or ring A is selected from the group consisting of a cyclobutane ring, a cyclopentyl ring, a cyclohexane ring, a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a pyrazole ring, and an imidazole ring, wherein ring A is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, and the remaining variables are as defined herein.

[0042] In some embodiments, ring A is absent, or ring A is selected from the group consisting of a cyclobutane ring, a cyclopentyl ring, a cyclohexane ring, a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a pyrazole ring, and an imidazole ring, and ring A is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, which groups include hydroxy, methyl, and halogen, and the remaining variables are as defined herein.

[0043] In some embodiments, ring A is absent, or ring A is

[0044] [ka] and the remainder of the variables are as defined herein. In some embodiments, ring A is absent, or ring A is

[0045] [ka] and the remainder of the variables are as defined herein. In some embodiments, Ring B is selected from the group consisting of a 3- to 6-membered carbocyclic ring, a 3- to 6-membered heterocyclic ring, and said Ring B is unsubstituted or is selected from the group consisting of OH, C 1-6 It is substituted with 1, 2, or 3 selected from alkyl groups, halogens, and the remainder of the variables are as defined herein.

[0046] In some embodiments, Ring B is selected from the group consisting of a cyclobutane ring, a cyclopentyl ring, a cyclohexane ring, a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a pyrazole ring, and an imidazole ring, wherein Ring B is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1, and the remaining variables are as defined herein. In some embodiments, ring B is

[0047] [ka] and the remainder of the variables are as defined herein. In some embodiments, ring B is

[0048] [ka] and the remainder of the variables are as defined herein.

[0049] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m1 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and each R 13 , R 14 is independently hydrogen, halogen, or a methyl group; m1 is 1, 2, 3, 4, 5, or 6; and the remainder of the variables are as defined herein.

[0050] In some embodiments, L2 is -O-(CR 13 R 14 ) m1 -NR 12 - and R 12 is hydrogen or a methyl group, and each R 13 , R 14 is independently hydrogen, halogen, or a methyl group; m1 is 1, 2, 3, 4, 5, or 6; and the remainder of the variables are as defined herein.

[0051] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m1 - and R 11 is hydrogen or a methyl group, and each R 13 , R 14is independently hydrogen, halogen, or a methyl group; m1 is 1, 2, 3, 4, 5, or 6; and the remainder of the variables are as defined herein.

[0052] In some embodiments, L2 is -(CR 13 R 14 ) m1 -NR 12 - and R 12 is hydrogen or a methyl group, and each R 13 , R 14 is independently hydrogen, halogen, or a methyl group; m1 is 1, 2, 3, 4, 5, or 6; and the remainder of the variables are as defined herein.

[0053] In some embodiments, L2 is -(CR 13 R 14 ) m1 - and each R 13 , R 14 is independently hydrogen, halogen, or a methyl group; m1 is 1, 2, 3, 4, 5, or 6; and the remainder of the variables are as defined herein.

[0054] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -3~7-membered carbocycle-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; the 3- to 7-membered carbocyclic ring is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; and the remainder of the variables are as defined herein.

[0055] In some embodiments, L2 is -O-(CR 13 R 14 )m5 -3~7-membered carbocycle-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; the 3- to 7-membered carbocyclic ring is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; and the remainder of the variables are as defined herein.

[0056] In some embodiments, L2 is -(CR 13 R 14 ) m5 -3~7-membered carbocycle-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or methyl, m5 is 0, 1, 2, 3, or 4, m6 is 0, 1, 2, 3, or 4, and the 3- to 7-membered carbocyclic ring is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1. In some embodiments, the 3- to 7-membered carbocyclic ring is a cyclobutyl, cyclopentyl, or cyclohexyl group, and the remaining variables are as defined herein.

[0057] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -3 to 7-membered heterocycle-(CR 13 R 14 ) m6 -NR 12 and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; the 3- to 7-membered heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; and the remaining variables are as defined herein.

[0058] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -3 to 7-membered heterocycle-(CR 13 R 14 ) m6 -NR 12 and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; the 3- to 7-membered heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; and the remaining variables are as defined herein.

[0059] In some embodiments, L2 is -(CR 13 R 14 ) m5 -3 to 7-membered heterocycle-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; the 3- to 7-membered heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1; and the remaining variables are as defined herein.

[0060] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -NR 10-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0061] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0062] In some embodiments, L2 is -(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0063] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0064] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0065] In some embodiments, L2 is -(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0066] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0067] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0068] In some embodiments, L2 is -(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -NR 12- and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; R 10 is hydrogen or a methyl group, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remainder of the variables are as defined herein.

[0069] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0070] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0071] In some embodiments, L2 is -(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -NR 12 - and R12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0072] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0073] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0074] In some embodiments, L2 is -(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0075] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0076] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0077] In some embodiments, L2 is -(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0078] In some embodiments, L2 is -NR 11 -(CR 13 R 14 ) m5 -CH=CH-(CR 13 R 14 ) m6 -NR 12 - and R 11 , R 12 are independently hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0079] In some embodiments, L2 is -O-(CR 13 R 14 ) m5 -CH=CH-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14 are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0080] In some embodiments, L2 is -(CR 13 R 14 ) m5 -CH=CH-(CR 13 R 14 ) m6 -NR 12 - and R 12 is hydrogen or a methyl group, and R 13 , R 14are each independently hydrogen, halogen, or a methyl group; m5 is 0, 1, 2, 3, or 4; m6 is 0, 1, 2, 3, or 4; and the remainder of the variables are as defined herein.

[0081] In some embodiments, the groups in the S1 group include oxo, hydroxy, cyano, halogen, methyl, ethyl, and propyl, with the remainder of the variables being as defined herein.

[0082] In some embodiments, the 3- to 7-membered carbocyclic ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, and the remaining variables are as defined herein.

[0083] In some embodiments, the 3- to 7-membered heterocycle is an azetidinyl group, an oxetanyl group, a tetrahydropyrrolyl group, a tetrahydrofuryl group, a piperidinyl group, or a piperazinyl group, and the remaining variables are as defined herein.

[0084] In some embodiments, L2 is

[0085] [ka]

[0086] [ka] and the remaining variables are as defined herein. In some embodiments, L2 is

[0087] [ka] and the remainder of the variables are as defined herein.

[0088] In some embodiments, L1 is none, -O-, -N(CH3)-, -CH=CH-, -C=N-, -CH2-, -CH(CH3), -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH2CH(CH3)-, -C(O)-, -NH-C(O)-, -N(CH3)-C(O)-, -C(O)-N(CH3)--C(O)-NH-CH2-, or -C(O)-NH-, and the remainder of the variables are as defined herein.

[0089] In some embodiments, L1 is -N(CD3)-, -CH(CD3), -N(CD3)-C(O)-, or -C(O)-N(CD3), and the remaining variables are as defined herein.

[0090] In some embodiments, X1 is N or C(R4), where R4 is hydrogen, halogen, cyano, -S(O)2CH3, or -P(O)(CH3)2, and the remaining variables are as defined herein.

[0091] In some embodiments, the compound of formula (A) is selected from one of the compounds in Table (I) below.

[0092] [Table 1-1]

[0093] [Table 1-2]

[0094] [Table 1-3]

[0095] [Table 1-4]

[0096] [Table 1-5]

[0097] A second aspect of the present invention provides a pharmaceutical composition comprising a compound according to the first aspect, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0098] As used herein, the term "active agent of the invention" or "compound of the invention" refers to a compound according to the first aspect, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.

[0099] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of an active agent of the present invention, does not interfere with the biological activity of the active agent, and does not cause adverse side effects to the host or subject. Exemplary carriers include water, oils, vegetable and mineral bases, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0100] The pharmaceutical compositions may be administered orally, by aerosol inhalation, rectally, nasally, buccally, topically, or parenterally, for example, by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an implanted reservoir, with oral, intraperitoneal, or intravenous administration being preferred. For oral administration, the compounds of the present invention may be prepared in any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, or aqueous suspensions. Carriers used in tablets typically include lactose and cornstarch, and lubricants such as magnesium stearate may be added. Diluents used in capsule formulations typically include lactose and dried cornstarch. Aqueous suspension formulations are typically prepared by mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or coloring agents may be added to the above oral dosage forms. For topical administration, particularly when treating neurological disorders of easily accessible surfaces or organs such as the eye, skin, or lower intestine, the compounds of the present invention may be prepared in various dosage forms for topical administration depending on the affected surface or organ. For topical administration to the eye, the compounds of the present invention may be prepared in the form of a micronized suspension or solution, and the carrier used is isotonic sterile saline with a specific pH, with or without the addition of a preservative such as chlorobenzyl alkoxide. For use in the eye, the compounds may be prepared in an ointment, such as petrolatum ointment. For topical administration to the skin, the compounds of the present invention may be prepared in a suitable ointment, lotion, or cream, with the active ingredient suspended or dissolved in one or more carriers. Carriers that can be used for ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polypropylene oxide, emulsifying wax, and water. Carriers that can be used for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, hexadecane aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the present invention may also be administered in sterile injectable form, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.Usable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils such as monoglycerides or diglycerides can also be used as solvents or suspending media.

[0101] In another aspect, the present invention provides the use of a compound according to the first aspect, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a CDK7-related disease.

[0102] In another aspect, the present invention provides the use of a compound according to the first aspect, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer.

[0103] In another aspect, the present invention provides a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first aspect, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, or any combination thereof, or a pharmaceutical composition according to the second aspect.

[0104] In another aspect, the present invention provides the use of a compound according to the first aspect, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of a CDK7 inhibitor.

[0105] In some embodiments, the CDK7-associated disease is a proliferative disease (such as a tumor or cancer), an infectious disease, an immune disease, an autoimmune disease, or an inflammatory disease.

[0106] In some embodiments, the tumor or cancer comprises a solid tumor or a hematological tumor. In some embodiments, the tumor or cancer comprises melanoma, bone cancer (e.g., osteosarcoma, Ewing's sarcoma), breast cancer (e.g., hormone receptor positive (HR+) breast cancer (e.g., estrogen receptor positive (ER+) or progesterone receptor positive (PR+) breast cancer), hormone receptor negative breast cancer, triple negative breast cancer (TNBC, ER- / PR- / HER2-)), colon cancer, brain cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), pancreatic cancer, ovarian cancer, endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, bile duct cancer, prostate cancer, liver cancer, renal cell carcinoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), lymphoma, multiple myeloma, glioblastoma, neuroblastoma.

[0107] In some embodiments, the infectious disease comprises AIDS, cholera, conjunctivitis, dengue fever, encephalitis, enterovirus infection (e.g., acute poliomyelitis, non-acute poliomyelitis), E. coli infection, foot and mouth disease, hepatitis, shingles, influenza, measles, and the like.

[0108] In some embodiments, the immune and / or autoimmune diseases include asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary disease, osteoporosis, ulcerative colitis, lupus erythematosus, allergies, rheumatoid arthritis, myasthenia gravis, Crohn's disease, psoriasis, and the like.

[0109] In some embodiments, the inflammatory disease is selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory diseases of uveitis, and inflammatory diseases of the pharynx.

[0110] As used herein, the term "subject" refers to an animal, particularly a mammal, preferably a human.

[0111] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of a drug or agent sufficient to achieve a desired effect. In an embodiment of the present invention, when treating a patient according to the present invention, the amount of a given drug will depend on various factors, such as the specific administration regimen, the type and severity of the disease or condition, and the specific characteristics (e.g., body weight) of the subject or host requiring treatment. However, the dosage may be routinely determined by methods known in the art, depending on the specific circumstances, such as the specific drug used, the administration method, the condition being treated, and the subject or host being treated. For dosages typically used in adult treatment, dosages typically range from 0.02 to 5000 mg / day, e.g., about 1 to 1500 mg / day. The required dose can be administered as a single dose, simultaneously (or closely spaced), or in divided doses at appropriate intervals, e.g., two, three, four, or more times per day, depending on convenience. Those skilled in the art will understand that, although dosage ranges are described above, the specific effective amount can be appropriately adjusted in conjunction with a physician's diagnosis depending on the patient's condition.

[0112] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. This type of salt includes acid addition salts with inorganic acids (such as nitric acid, phosphoric acid, and carbonic acid) or organic acids (such as propionic acid, caproic acid, cypionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, and muconic acid), salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion or an alkaline earth metal ion, or a compound formed by coordination with an organic base, such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid or base group by conventional chemical methods. Generally, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The compounds according to the present invention exist in the form of prodrugs in addition to salts. The prodrugs of the compounds described herein are easily converted into the compounds of the present invention under physiological conditions by chemical changes. Furthermore, the prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0113] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, and configurational isomers primarily include cis-trans isomers and optical isomers. The compounds described herein may exist in stereoisomeric forms, and therefore include all possible stereoisomeric forms, including, but not limited to, cis-trans isomers, tautomers, enantiomers, diastereoisomers, atropisomers, and the like. The compounds described herein may exist in any combination or mixture of the above stereoisomers, such as mesomers, racemates, or mixtures of equal amounts of atropisomers. Examples include single enantiomers, single diastereoisomers, or mixtures thereof, or single atropisomers or mixtures thereof. When a compound described herein contains an olefinic double bond, it includes cis- and trans-isomers, as well as any combination thereof, unless otherwise specified. The atropisomers of the present invention are structural isomers based on axial or planar chirality resulting from restricted internal molecular rotation. The compound of formula (A) has optical isomers due to asymmetric carbons, axial asymmetry, etc., and, if necessary, single isomers can be obtained by separation using methods known in the art, such as crystallization or chiral chromatography.

[0114] As used herein, the term "hydrocarbon group" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. 1-6 The term "hydrocarbon group" refers to a straight or branched chain hydrocarbon group having 1 to 6 carbon atoms. For example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and the like are included.

[0115] As used herein, "C 1-6 The term "alkyl group" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. 1-4 alkyl group, more preferably C 1-3Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof.

[0116] As used herein, the term "alkenyl group" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain, and includes "C 2-6 The term "alkenyl group" refers to an alkenyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. Preferably, C 2-4 Alkenyl groups (i.e., alkenyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds) include, but are not limited to, vinyl groups, 1-propenyl groups, 2-propenyl groups, 1-butenyl groups, 2-butenyl groups, 3-butenyl groups, pentenyl groups, hexenyl groups, and butadienyl groups.

[0117] As used herein, the term "alkynyl group" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position in the chain, and includes "C 2-6 The term "alkynyl group" refers to an alkynyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. More preferably, C 2-4Alkynyl groups (i.e., alkynyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0118] As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0119] As used herein, the term "halo" refers to fluoro, chloro, bromo or iodo.

[0120] As used herein, the term "halogenated hydrocarbon group" refers to a hydrocarbon group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms have been replaced with halogen, and the hydrocarbon group is as defined above. 1-6 The term "alkyl group" refers to a haloalkyl group having 1 to 6 carbon atoms. Preferably, the halogenated C 1-4 alkyl group, more preferably halogenated C 1-3 It is an alkyl group. Specific examples include, but are not limited to, a monochloromethyl group, a dichloromethyl group, a trichloromethyl group, a monochloroethyl group, a 1,2-dichloroethyl group, a trichloroethyl group, a monobromoethyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, and a trifluoroethyl group.

[0121] As used herein, the term "deuterated alkyl group" refers to a hydrocarbon group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms have been replaced with deuterium atoms, where hydrocarbon group is as defined above. 1-6 The term "alkyl group" refers to a deuterated alkyl group having 1 to 6 carbon atoms. Preferably, a deuterated C 1-4 alkyl group, more preferably deuterated C 1-3Specific examples include, but are not limited to, monodeuterated methyl groups, deuterated methyl groups, tritiated methyl groups, and the like.

[0122] As used herein, the terms "carbocyclic group" and "carbocycle" are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon groups. 3-14 The term "carbocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 14 carbon atoms. For example, a monocyclic carbocyclic group (e.g., a 3- to 7-membered carbocyclic group or "C 3-7 carbocyclic groups) or polycyclic carbocyclic groups (e.g., spirocarbocyclic groups, fused carbocyclic groups, bridged carbocyclic groups, etc.).

[0123] "3- to 7-membered carbocyclic group" or "C 3-7 The term "carbocyclic group" is used interchangeably and refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group having 3 to 7 ring carbon atoms. A 3- to 6-membered monocyclic carbocyclic group is preferred, a 4- to 6-membered monocyclic carbocyclic group is preferred, and a 3-, 4-, 5-, or 6-membered monocyclic carbocyclic group is more preferred. Specific examples of monocyclic carbocyclic groups include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.

[0124] The terms "spirocarbocyclic group" and "spirocarbocyclyl ring" refer to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (called a spiro atom). Depending on the number of spiro atoms shared between the rings, spirocarbocyclic groups are classified into monospirocarbocyclic groups, bisspirocarbocyclic groups, and polyspirocarbocyclic groups. The term "6- to 12-membered spirocarbocyclic group" refers to a polycyclic hydrocarbon group having 6 to 12 ring carbon atoms, and the monocyclic rings sharing the spiro atom are 3- to 7-membered monocyclic carbocyclic rings. A 7- to 12-membered spirocarbocyclic group is preferred, and a 7- to 12-membered monospirocarbocyclic group is more preferred. More preferred are 7-membered (4-membered monocyclic carbocyclyl ring / 4-membered monocyclic carbocyclyl ring), 8-membered (4-membered monocyclic carbocyclyl ring / 5-membered monocyclic carbocyclyl ring), 9-membered (4-membered monocyclic carbocyclyl ring / 6-membered monocyclic carbocyclyl ring, 5-membered monocyclic carbocyclyl ring / 5-membered monocyclic carbocyclyl ring), 10-membered (5-membered monocyclic carbocyclyl ring / 6-membered monocyclic carbocyclyl ring) or 11-membered (6-membered monocyclic carbocyclyl ring / 6-membered monocyclic carbocyclyl ring) monospirocarbocyclyl groups. Specific examples of spirocarbocyclyl groups include:

[0125] [ka] These spirocarbocyclic groups can be attached to the rest of the molecule through any one of the ring atoms.

[0126] The terms "fused carbocyclic group" and "fused carbocyclyl ring" refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing a pair of adjacent carbon atoms. Depending on the number of rings formed, the group can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused carbocyclic group. The term "5- to 12-membered fused carbocyclic group" refers to a polycyclic cyclic hydrocarbon group having 5 to 12 ring carbon atoms, and the monocyclic rings sharing a pair of adjacent carbon atoms are 3- to 7-membered monocyclic carbocyclic rings. A 7- to 12-membered fused carbocyclic group is preferred. A 7- to 10-membered bis-fused carbocyclic group is more preferred. Most preferred are 8-membered (a 5-membered monocyclic carbocyclyl ring fused with a 5-membered monocyclic carbocyclyl ring), 9-membered (a 5-membered monocyclic carbocyclyl ring fused with a 6-membered monocyclic carbocyclyl ring), or 10-membered (a 6-membered monocyclic carbocyclyl ring fused with a 6-membered monocyclic carbocyclyl ring) bis-fused carbocyclyl groups. Specific examples of fused carbocyclyl groups include:

[0127] [ka] These fused carbocyclic groups can be attached to the remainder of the molecule through any one of the ring atoms.

[0128] The terms "bridged carbocyclic group" and "bridged carbocyclyl ring" refer to a polycyclic cyclic hydrocarbon group formed by sharing two carbon atoms that are not directly bonded to two or more monocyclic rings. Depending on the number of rings formed, the group can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged carbocyclic group. The term "5- to 12-membered bridged carbocyclic group" refers to a polycyclic cyclic hydrocarbon group having 5 to 12 ring carbon atoms, and any two rings share two carbon atoms that are not directly bonded to each other. A 7- to 12-membered bridged carbocyclic group is preferred. Specific examples of bridged carbocyclic groups include:

[0129] [ka] These bridged carbocyclic groups can be attached to the remainder of the molecule through any one of the ring atoms.

[0130] The carbocyclyl ring can be fused to an aryl group, a heteroaryl group, or a heterocyclyl ring, and the ring attached to the parent structure is a carbocyclyl ring, non-limiting examples of which include an indane group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. In the present invention, the various carbocyclic groups described above may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the substituents described herein.

[0131] As used herein, the terms "heterocyclic group" and "heterocycle" are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. The ring carbon atoms of the heterocyclic groups described in the present invention may be optionally substituted with one, two, or three oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. The term "3- to 14-membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 14 ring atoms, provided that one or more (preferably 1, 2, 3, or 4) ring atoms are nitrogen, oxygen, or S(=O). m’ (wherein m' is an integer of 0 to 2), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the other ring atom is carbon. When a ring atom is a nitrogen atom, it may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents defined herein). The 3- to 14-membered heterocyclic groups described in the present invention include monocyclic heterocyclic groups (e.g., 3- to 7-membered heterocyclic groups), spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0132] The terms "3- to 7-membered heterocyclic group" and "3- to 7-membered heterocyclyl ring" refer to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group having 3 to 7 ring atoms, provided that 1, 2, or 3 of the ring atoms are nitrogen, oxygen, or S(=O). m’(wherein m' is an integer of 0 to 2). Preferably, it is a 4- to 7-membered monocyclic heterocyclic group having 4 to 7 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferably, it is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be oxidized (i.e., S(=O) m’(wherein m' is an integer of 0 to 2). The ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted with 1, 2, or 3 oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. Specific examples of the monocyclic heterocyclic group include aziridine, ethylene oxide, azetidine, azetidin-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidin-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrolyl, and 1,3-dioxolane-2-one. , oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxacyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1 H-Pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2 (1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,Examples include, but are not limited to, 3-dihydro-2H-pyrrol-2-one, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, and the like.

[0133] Two ring atoms linked to the above-mentioned monocyclic heterocyclyl ring, e.g., CC and NC, may be fused to a carbocyclic, heterocyclic, aryl or heteroaryl group, such as a monocyclic carbocyclyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, a 5- or 6-membered monocyclic heteroaryl ring, any of which is defined herein, to form a fused polycyclic ring system. The two ring atoms linked to a monocyclic heterocyclic group that forms a fused ring with another ring are preferably CC.

[0134] The terms "spiroheterocyclic group" and "spiroheterocyclyl ring" refer to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing one carbon atom (called a spiro atom), provided that one or more (e.g., 1, 2, or 3) ring atoms are not nitrogen, oxygen, or S(=O). m’(where m' is an integer of 0 to 2), and the other ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents defined herein). Each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between rings, spiroheterocyclic groups are divided into monospiroheterocyclic groups, bisspiroheterocyclic groups, and polyspiroheterocyclic groups. The term "7- to 14-membered spiroheterocyclic group" refers to a spiroheterocyclic group having 7 to 14 ring atoms, one or two of which are heteroatoms. Preferred are 7-membered (4-membered monocyclic heterocyclyl ring / 4-membered monocyclic heterocyclyl ring or 4-membered monocyclic heterocyclyl ring / 4-membered monocyclic carbocyclic group or 4-membered monocyclic carbocyclyl ring / 4-membered monocyclic heterocyclyl ring), 8-membered (4-membered monocyclic heterocyclyl ring / 5-membered monocyclic heterocyclyl ring), 9-membered (4-membered monocyclic heterocyclyl ring / 6-membered monocyclic heterocyclyl ring, 5-membered monocyclic heterocyclyl ring / 5-membered monocyclic heterocyclyl ring), 10-membered (5-membered monocyclic heterocyclyl ring / 6-membered monocyclic heterocyclyl ring), or 11-membered (6-membered monocyclic heterocyclyl ring / 6-membered monocyclic heterocyclyl ring) monospiroheterocyclic groups. Specific examples of spiroheterocyclic groups include:

[0135] [ka] Including but not limited to:

[0136] These spiroheterocyclic groups can be attached to the remainder of the molecule via any one suitable ring atom.

[0137] The terms "fused heterocyclic group" and "fused heterocyclyl ring" refer to a polycyclic heterocyclic group formed by sharing adjacent pairs of ring atoms between two or more saturated or partially unsaturated monocyclic rings, provided that one or more (e.g., 1, 2, or 3) ring atoms are nitrogen, oxygen, or S(=O). m’(where m' is an integer of 0 to 2), and the other ring atom is carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents defined herein). Each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π-electron system. A pair of adjacent shared ring atoms may be CC or NC. Depending on the number of rings formed, fused heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. The term "5- to 14-membered fused heterocyclic group" refers to a fused heterocyclic group having 5 to 14 ring atoms. Preferably, it is a 6- to 10-membered fused heterocyclic group having 6 to 10 ring atoms, one or two of which are heteroatoms. More preferably, it is an 8- to 10-membered fused heterocyclic group having 8 to 10 ring atoms, one or two of which are heteroatoms. Most preferred are 8-membered (a 5-membered monocyclic heterocyclyl ring fused with a 5-membered monocyclic heterocyclyl ring), 9-membered (a 5-membered monocyclic heterocyclyl ring fused with a 6-membered monocyclic heterocyclyl ring), or 10-membered (a 6-membered monocyclic heterocyclyl ring fused with a 6-membered monocyclic heterocyclyl ring) bicyclic fused heterocyclic groups. Specific examples of fused heterocyclic groups include:

[0138] [ka] Including but not limited to:

[0139] These fused heterocyclic groups can be attached to the remainder of the molecule through any one suitable ring atom.

[0140] The terms "bridged heterocyclic group" and "bridged heterocyclyl ring" refer to a polycyclic heterocyclic group formed by sharing two or more saturated or partially unsaturated monocyclic rings that are not directly bonded to each other, provided that one or more (e.g., 1, 2, or 3) ring atoms are not nitrogen, oxygen, or S(=O). m’(where m' is an integer of 0 to 2), and the other ring atoms are carbon. Depending on the number of rings formed, they can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged carbocyclic groups. The term "5- to 14-membered bridged heterocyclic group" refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 14 ring atoms, in which any two rings share two ring atoms that are not directly bonded, and each single ring may contain one or more double bonds, but there is no ring with a completely conjugated π-electron system. A 5- to 10-membered bridged heterocyclic group is preferred. Specific examples of bridged heterocyclic groups include:

[0141] [ka] Including but not limited to:

[0142] These bridged heterocyclic groups can be attached to the remainder of the molecule through any one suitable ring atom.

[0143] In the present invention, the various heterocyclic groups described above may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituents described herein.

[0144] As used herein, the terms "aryl group," "aryl ring," and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic (the rings are covalently bonded and not fused), or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group in which at least one ring is aromatic, i.e., has a conjugated π-electron system. 5-12 The term "aryl group" refers to an aryl group having 5 to 12 ring atoms, preferably C 6-10 C in the present invention is an aryl group. 5-12 Aryl groups include monocyclic aryl groups (eg, phenyl groups), non-fused polycyclic aryl groups (eg, biphenyl groups), and aromatic fused polycyclic groups.

[0145] In some embodiments, C 5-12 When the aryl group is an aromatic fused polycyclic group, the aromatic fused polycyclic group may be a polycyclic group formed by condensing a monoaryl ring with one or more monoaryl rings, non-limiting examples of which include a naphthyl group, an anthranyl group, etc.

[0146] In some embodiments, C 5-12 When the aryl group is an aromatic fused polycyclic group, the aromatic fused polycyclic group may be a polycyclic group formed by condensing a monoaryl ring (e.g., a phenyl group) with one or more non-aromatic rings, and the ring bonded to the parent structure may be an aromatic ring or a non-aromatic ring. The non-aromatic ring may include, but is not limited to, a 3- to 7-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, whose ring carbon atoms may be substituted with one or two oxo groups to form a cyclic lactam or cyclic lactone structure) or a 3- to 7-membered monocyclic carbocyclyl ring (preferably a 5- or 6-membered monocyclic carbocyclyl ring, whose ring carbon atoms may be substituted with one or two oxo groups to form a cyclic ketone structure). The polycyclic group formed by condensing a monoaryl ring with one or more non-aromatic rings may be bonded to another group or the parent structure via a nitrogen atom or a carbon atom, and the ring bonded to the parent structure may be a monoaryl ring or a non-aromatic ring.

[0147] As used herein, the terms "heteroaryl group," "heteroaryl ring," and "heteroaromatic ring" are used interchangeably and refer to monocyclic or fused polycyclic (i.e., adjacent pairs of ring atoms are shared, and the shared adjacent pair of ring atoms may be CC or NC) groups in which ring atoms are independently substituted with at least one heteroatom selected from nitrogen, oxygen, or sulfur, and the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heteroaryl group has 6, 10, or 14 shared π-electrons, and at least one ring in the group is aromatic. The term "5- to 12-membered heteroaryl group" refers to a heteroaryl group having 5 to 12 ring atoms, of which 1, 2, 3, or 4 ring atoms are nitrogen, oxygen, or S(=O). m’(where m' is an integer of 0 to 2). Preferably, it is a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. The heteroaryl group herein may be a monocyclic heteroaryl group (e.g., a 5- or 6-membered monocyclic heteroaryl group), a fused bicyclic heteroaryl group (e.g., an 8- to 10-membered bicyclic heteroaryl group), or a fused tricyclic heteroaryl group.

[0148] As used herein, the term "5- or 6-membered monocyclic heteroaryl group" or "5- or 6-membered heteroaryl" refers to a heterocyclic group having 5 or 6 ring atoms, of which 1, 2, or 3 ring atoms are nitrogen, oxygen, or S(=O). m’ (wherein m' is an integer of 0 to 2). Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0149] As used herein, the term "8-10 membered bicyclic heteroaryl group" refers to a heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are nitrogen, oxygen, or S(=O). m’(wherein m' is an integer of 0 to 2). The fused bicyclic heteroaryl group may be a bicyclic group formed by fusing a monoaryl ring (e.g., a phenyl group) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or a bicyclic group formed by fusing a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).

[0150] Any two ring atoms optionally linked to the monocyclic heteroaryl ring, e.g., CC, NC, NN, may be fused to a carbocyclic, heterocyclic, aryl, or heteroaryl group, such as a monocyclic carbocyclyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, or a 5- or 6-membered monocyclic heteroaryl ring, as defined herein, to form a fused polycyclic ring system. Non-limiting examples of the 8- to 10-membered bicyclic heteroaryl group include benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazolo[1,2-b]pyridazine, and the like.

[0151] The above-mentioned monocyclic heteroaryl groups, bicyclic heteroaryl groups formed by fusing a benzene ring with a monocyclic heteroaryl ring, or bicyclic heteroaryl groups formed by fusing a monocyclic heteroaryl ring with a monocyclic heteroaryl ring can be bonded to other groups or parent structures via a nitrogen atom or a carbon atom. Specific examples of bicyclic heteroaryl groups include:

[0152] [ka] These groups can be attached to the remainder of the molecule through any suitable ring atom. The ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.

[0153] In some embodiments, the fused bicyclic heteroaryl group or fused tricyclic heteroaryl group may be a polycyclic group formed by fusing a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with one or more non-aromatic rings, and the ring bonded to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. Examples of the non-aromatic ring include, but are not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring whose ring carbon atoms may be substituted with 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic carbocyclyl ring (preferably a 5- or 6-membered monocyclic carbocyclyl ring whose ring carbon atoms may be substituted with 1 to 2 oxo groups to form a cyclic ketone structure), and the like. The polycyclic group formed by fusing the above-mentioned monocyclic heteroaryl ring with one or more non-aromatic rings can be bonded to other groups or to a parent structure through a nitrogen atom or a carbon atom, and the ring bonded to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. For example, the term "8- to 10-membered heteroaryl heterocyclic group" or "8- to 10-membered heteroaryl heterocyclyl ring" refers to an 8- to 10-membered fused bicyclic heteroaryl group formed by fusing a 5- or 6-membered monocyclic heteroaryl ring with a 5- or 6-membered monocyclic heterocyclyl ring, i.e., two adjacent substituents on the 5- or 6-membered monocyclic heteroaryl group and the ring atoms bonded thereto form a fused 5- or 6-membered monocyclic heterocyclyl ring, and the 5- or 6-membered monocyclic heterocyclyl ring is as defined above. Also, for example, as used herein, the term "8- to 10-membered heteroarylcarbocyclyl group" or "8- to 10-membered heteroarylcarbocyclyl ring" refers to an 8- to 10-membered fused bicyclic heteroaryl group formed by fusing a 5- or 6-membered monocyclic heteroaryl ring with one 5- or 6-membered monocyclic carbocyclyl ring, i.e., two adjacent substituents on the 5- or 6-membered monocyclic heteroaryl group and the ring atoms bonded thereto form a fused 5- or 6-membered monocyclic carbocyclyl ring, wherein the 5- or 6-membered monocyclic carbocyclyl ring is as defined above. Non-limiting examples of "8- to 10-membered heteroaryl heterocyclic group" or "8- to 10-membered heteroarylcarbocyclyl group" include:

[0154] [ka] The above groups can be attached to the rest of the molecule through any one of the suitable ring atoms. In the present invention, the various heteroaryl groups described above may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituents described herein.

[0155] As used herein, the term "hydroxy group" refers to --OH. As used herein, the term "amino group" refers to -NH2. As used herein, the term "cyano" refers to -CN. As used herein, the term "nitro group" refers to -NO2. As used herein, the term "benzyl group" refers to -CH2-benzene. As used herein, the term "oxo group" refers to =O.

[0156] As used herein, the term "alkylene group" refers to a divalent form of an alkyl group. For example, "C 0-6 An "alkylene group" refers to an alkylene group having 0 to 6 carbon atoms. For example, a "C1 alkylene group" refers to an alkylene group having 1 carbon atom, such as -CH2-. For example, a "C2 alkylene group" refers to an alkylene group having 2 carbon atoms, such as -CH2CH2-. The same applies below.

[0157] As used herein, the term "alkenylene group" refers to a divalent bonded form of an alkenyl group. For example, "C 2-6 An "alkenylene group" refers to an alkenylene group having 2 to 6 carbon atoms. For example, a "C2 alkenylene group" refers to an alkenylene group having 2 carbon atoms, such as -CH=CH-. The same applies hereinafter.

[0158] As used herein, the term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable, and includes deuterium and hydrogen variants. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo group substitution does not occur in aryl groups. The terms "optionally substituted" or "optionally substituted" refer to whether or not substitution is required, and unless otherwise specified, the type and number of substituents are optional as long as it is chemically feasible.

[0159] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group may be substituted with at most 2 R, and at each occurrence, R is an independent option. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0160] As used herein, the term "none" refers to a direct bond between the two groups to which it connects, e.g.,

[0161] [ka] In the above formula, when ring A is not present, L1 and L2 are directly bonded to each other, forming "L1-L2".

[0162] If the atom through which a recited substituent is bonded to the group it substituted is not indicated, then such substituent can be bonded through any of those atoms; for example, a pyridyl group as a substituent can be bonded to the group it substituted through any one of the carbon atoms in the pyridine ring.

[0163] When the linking direction is not indicated for the linking group, the linking direction is arbitrary, for example,

[0164] [ka] In the above formula, when L is -C(O)-NH-, -C(O)-NH- connects the benzene ring and the cyclopentane in the same direction as reading from left to right,

[0165] [ka] It is also possible to construct a benzene ring and a cyclopentane in the opposite direction to the left-to-right reading order.

[0166] [ka] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0167] The compounds of formula (A) of the present invention can be prepared using synthetic methods known in the art, or by combining methods known in the art with the methods described in the present invention. The solvents, temperatures, and other reaction conditions given in the present invention are all exemplary and can be varied according to methods known in the art. Depending on their specific structures, the compounds in the examples described in the present invention can be synthesized using appropriate starting materials according to the methods described in the examples, or can be synthesized using methods similar to those described in the examples. The starting materials for synthesizing the compounds in the examples of the present invention can be prepared by known synthetic methods or similar methods described in the literature, or can be obtained from commercial sources. If necessary, the compounds can be further resolved to obtain their stereoisomers by methods known in the art, such as crystallization or chromatography, and the resolution conditions can be easily obtained by those skilled in the art through routine means or limited experimentation. More specifically, the compounds of formula (A) of the present invention can be synthesized by the following methods. The solvents, temperatures, and other reaction conditions in each step can be the same as or similar to those described in the examples below, and reaction conditions known in the art can also be used. DETAILED DESCRIPTION OF THE INVENTION

[0168] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments obtained by combining these with other chemical synthetic methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0169] The present invention will be described in detail below with reference to examples, but is not intended to be limiting. This specification describes the present invention in detail, but specific examples thereof are disclosed, and it will be obvious to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Specific conditions not specified in the examples are carried out according to standard conditions or conditions provided by the manufacturer. Unless the manufacturer is specified, the reagents or equipment used are all commercially available, commonly available products.

[0170] [ka]

[0171] Step 1: Benzyl [2-(2-hydroxyethoxy)ethyl]carbamate (5.0 g, 20.92 mmol) and dichloromethane (25 mL) were added to a three-neck flask and stirred. Triethylamine (6.34 g, 62.76 mmol) and 4-dimethylaminopyridine (510 mg, 4.18 mmol) were added. The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (3.97 g, 20.92 mmol) was added slowly. The reaction was stirred at room temperature for 2 hours and monitored by LC-MS for the completion of the reaction of the raw material. The mixture was poured into saturated sodium bicarbonate (100 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (ethyl acetate / petroleum ether: 20% to 50%) to give 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (3.84 g, yield 46.7%) as an oily product. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.42 - 7.28 (m, 7H), 5.10 (s, 3H), 4.35 - 4.07 (m, 2H), 3.68 - 3.58 (m, 2H), 3.47 (t, J = 5.0 Hz, 2H), 3.32 (dd, J = 10.4, 5.2 Hz, 2H), 2.41 (s, 3H).

[0172] Step 2: To a solution of 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (1000 mg, 2.542 mmol) and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (394 mg, 2.12 mmol) in N,N-dimethylformamide (15.0 mL) was added potassium iodide (0.056 mL, 0.508 mmol) and potassium carbonate (702.54 mg, 5.083 mmol) at room temperature. The reaction mixture was stirred at 70°C for 16 hours. After the reaction was complete, the mixture was poured into ice water (100 mL) and extracted several times with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 10% to 100%) to give (S)-(2-(2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)ethoxy)ethyl)carbamic acid benzyl ester (630 mg, 1.314 mmol, 51.70% yield) as a yellow oil. LCMS m / z (ESI): [M+H] + =408.2.

[0173] Step 3: At room temperature, trifluoroacetic acid (4.0 mL, 53.85 mmol) was added to a solution of (S)-(2-(2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)ethoxy)ethyl)carbamic acid benzyl ester (730 mg, 1.791 mmol) in dichloromethane (6.0 mL). The reaction mixture was stirred at room temperature for 3 hours, and the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (50 mL x 3) and saturated sodium bicarbonate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane: 0-10%) to obtain (S)-(2-(2-(3-aminopyrrolidin-1-yl)ethoxy)ethyl)carbamic acid benzyl ester (520 mg, 1.66 mmol, 92.55% yield) as a yellow oily product. LCMS m / z (ESI): [M+H] + =308.2.

[0174] Step 4: At room temperature, aluminum trichloride (12.9 g, 85.62 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (7.44 g, 34.29 mmol) in 1,2-dichloroethane (30.0 mL). The temperature was raised to 90°C and the reaction was continued for 30 minutes. A solution of 6-methylformate indole (5.0 g, 28.54 mmol) in 1,2-dichloroethane (30.0 mL) was slowly added dropwise to the reaction solution. The reaction mixture was continued at 90°C for 18 hours. The mixture was cooled, poured into ice water (200 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane: 0-10%) to give 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (2.5 g, 6.26 mmol, 21.92% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.08 (d, J = 3.4 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H), 8.20 (t, J = 6.4 Hz, 1H), 7.89 - 7.77 (m, 1H), 3.89 (s, 3H).

[0175] Step 5: Under a nitrogen atmosphere, N,N-diisopropylethylamine (1.56 ml, 9.4 mmol) was added to a solution of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (450 mg, 1.27 mmol) and (S)-(2-(2-(3-aminopyrrolidin-1-yl)ethoxy)ethyl)carbamic acid benzyl ester (583 mg, 1.9 mmol) in dioxane (6 mL) at room temperature. The reaction mixture was heated to 120 °C and reacted for 4 hours. The mixture was cooled, poured into ice water (50 mL), and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (methanol / dichloromethane: 0-10%) to give methyl (R)-3-(2-((1-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (286 mg, 0.32 mmol, 25.25% yield) as a yellow oil. LCMS m / z (ESI): [M+H] + =627.3.

[0176] Step 6: At room temperature, 10% palladium on carbon (100 mg, 0.945 mmol) was added to a solution of the compound methyl (R)-3-(2-((1-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (660 mg, 1.05 mmol) in methanol (50 mL). The reaction mixture was stirred under a hydrogen atmosphere for about 4 hours and allowed to react. After filtration and concentration, the crude product was purified on a silica gel column (methanol / dichloromethane: 0-20%) to give (R)-3-(2-((1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (460 mg, 0.65 mmol, 62.08% yield) as a gray-black oil. LCMS m / z (ESI): [M+H] + =493.0.

[0177] Step 7: Under a nitrogen atmosphere, lithium hydroxide (197.3 mg, 4.7 mmol) was added to a solution of the compound (R)-3-(2-((1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (386 mg, 0.76 mmol) in methanol / water (10 / 5 mL) at room temperature. The reaction mixture was heated to 70° C. and reacted for 3 hours. The mixture was cooled and concentrated. The crude product was purified by reverse-phase column chromatography (acetonitrile / water: 0-70%) to give (R)-3-(2-((1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (106 mg, 0.19 mmol, 24.03% yield) as a white solid. LCMS m / z (ESI): [M+H] + =479.2.

[0178] Step 8: Under a nitrogen atmosphere, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (126 mg, 0.33 mmol) was added to a solution of N,N-dimethylformamide (15 mL) at room temperature. While stirring the mixture, a solution of (R)-3-(2-((1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (106 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was allowed to react at room temperature for 30 minutes. The mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was purified (chromatography column: Waters Xbridge C18 10um OBD 19*250mm, mobile phase: water / acetonitrile (0.1% ammonium bicarbonate), flow rate: 20mL / min, detection wavelength: 254nm / 214nm, column temperature: room temperature) to give the product (4 3 S)-2 5 -(trifluoromethyl)-1 1 H-7-Oxa-3,10-diaza-1(3,6)-indole-2(4,2)-pyrimidin-4(3,1)-pyrrolidinecycloundecaphan-11-one ((4 3 S)-2 5 -(trifluoromethyl)-1 1 The product was obtained as H-7-oxa-3,10-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-pyrrolidinacycloundecaphan-11-one (Z1, 2.3 mg, 2.25% yield). LCMS m / z (ESI): [M+H] + =461.2. 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.58 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.61 (s, 2H), 7.39 (s, 1H), 4.08 (s, 1H), 3.57 (s, 3H), 3.25 (s, 3H), 3.08 (s, 2H), 2.71 (d, J = 82.0 Hz, 3H), 2.00 (d, J = 90.2 Hz, 3H). 19 F NMR (400 MHz, DMSO) δ -56.63.

[0179] [ka]

[0180] Step 1: To a solution of 4-amino-1-butanol (3.0 g, 33.7 mmol) in ethanol (30 mL) was added di-tert-butyl dicarbonate (3.67 g, 16.856 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the crude product was extracted with ethyl acetate (100 mL x 3) and sodium bicarbonate (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (ethyl acetate / petroleum ether: 0-100%) to afford (4-hydroxybutyl)carbamic acid tert-butyl ester (5.8 g, 30.69 mmol, 91% yield) as a colorless oil.

[0181] Step 2: Under a nitrogen atmosphere, oxalyl chloride (13 mL, 23 mmol, 2 M dichloromethane) was added dropwise to a reaction solution of dimethyl sulfoxide (3.7 mL) and dichloromethane (50 mL) at -70°C, and stirring was continued for 5 minutes. A solution of (4-hydroxybutyl)carbamic acid tert-butyl ester (4.1 g, 21.6 mmol) in dichloromethane (35.0 mL) was added dropwise at -70°C. The reaction mixture was gradually warmed to 0°C and stirred for 25 minutes. After the reaction was complete, the mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column (ethyl acetate / petroleum ether: 0-50%) to give (4-oxobutyl)carbamic acid tert-butyl ester (4.0 g, 24.59 mmol, 84.55% yield) as a yellow oil.

[0182] Step 3: Under a nitrogen atmosphere, N,N-diisopropylethylamine (2.78 mL, 16.78 mmol) was added to a solution of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (2.0 g, 5.62 mmol) and ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (1.02 g, 5.06 mmol) in N-methylpyrrolidone (30 mL) at room temperature. The reaction mixture was heated to 140 °C and reacted for 0.5 hours. The mixture was cooled, poured into ice water, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (methanol / dichloromethane: 0-10%) to give 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (2.0 g, 3.84 mmol, 68.47% yield) as a gray solid. LCMS m / z (ESI): [M+H] + =519.2. 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.64 - 8.51 (m, 1H), 8.48 - 8.31 (m, 1H), 8.15 (d, J = 5.8 Hz, 1H), 8.01 (d, J = 21.1 Hz, 2H), 7.88 - 7.69 (m, 1H), 7.06 - 6.83 (m, 1H), 4.44 (s, 1H), 4.07 - 3.81 (m, 4H), 2.16 - 1.77 (m, 4H), 1.51 (d, J = 33.4 Hz, 2H), 1.41 - 1.34 (m, 9H).

[0183] Step 4: At room temperature, trifluoroacetic acid (1.0 mL, 13.56 mmol) was added to a solution of the compound 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (520 mg, 1.0 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (50 mL x 3) and saturated sodium bicarbonate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give crude yellow oily product methyl 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (520 mg, 1.66 mmol, 92.55% yield), which was used directly in the next step reaction without purification. LCMS m / z (ESI): [M+H] + =419.1.

[0184] Step 5: At room temperature, to a solution of methyl 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (480 mg, 1.0 mmol) in tetrahydrofuran (5 mL) was added (4-oxobutyl)carbamic acid tert-butyl ester (192.86 mg, 1.03 mmol). The mixture was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (143.84 mg, 2.29 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (50 mL x 3) and saturated sodium bicarbonate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol / dichloromethane: 0-10%) to give methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (356 mg, 0.6 mmol, 52.66% yield) as a yellow solid compound. LCMS m / z (ESI): [M+H] + =590.2.

[0185] Step 6: At room temperature, trifluoroacetic acid (0.5 mL, 6.75 mmol) was added to a solution of the compound methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (356 mg, 0.76 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was complete. The reaction mixture was concentrated and extracted with ethyl acetate (50 mL x 3) and saturated sodium bicarbonate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude yellow oily compound 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (387 mg, 0.47 mmol, 78.54%), which was used directly in the next step reaction without purification. LCMS m / z (ESI): [M+H] + =490.2.

[0186] Step 7: Under a nitrogen atmosphere, lithium hydroxide (98.54 mg, 2.35 mmol) was added to a solution of the compound 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (384 mg, 0.78 mmol) in tetrahydrofuran / water (10 mL / 5 mL) at room temperature. The reaction mixture was stirred for 0.5 h. The mixture was cooled and concentrated. The crude product was purified by reverse-phase column chromatography (acetonitrile / water: 0-70%) to give 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (208 mg, 0.44 mmol, 55.76% yield) as a white solid. LCMS m / z(ESI):[M+H] + =476.2.

[0187] Step 8: Under a nitrogen atmosphere, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (239 mg, 0.63 mmol) was added to a solution of N,N-dimethylformamide (5 mL) at room temperature. While stirring the mixture, a solution of 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (106 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was allowed to react at room temperature for 30 minutes. The mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified (chromatography column: Waters Xbridge C18 10 um OBD 19*250 mm, mobile phase: water / acetonitrile (0.1% ammonium bicarbonate), flow rate: 20 mL / min, detection wavelength: 254 nm / 214 nm, column temperature: 25 °C) and (4 1 S,4 3 S)-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one ((4 1 S,4 3 S)-2 5 -(trifluoromethyl)-1 1 The product was obtained as H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z2, 1.02 mg, 0.35% yield). LCMS m / z (ESI): [M+H] + =458.2. 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.79 (s, 1H), 7.47 (s, 1H), 7.34 - 7.24 (m, 1H), 7.23 - 7.07 (m, 1H), 2.95 (s, 2H), 2.27 (d, J = 23.4 Hz, 2H), 2.08 (d, J = 8.5 Hz, 2H), 1.41 (m, 4H), 1.19 (m, 6H). 19 F NMR (377 MHz, CD3OD) δ -59.28 (s).

[0188] [ka]

[0189] Step 1: Under a nitrogen atmosphere, at -30°C, allylmagnesium chloride (60.739 mL, 121.48 mmol, 2 M / L) was slowly added dropwise to a solution of 3-N-tert-butoxycarbonyl-6-oxa-3-azabicyclo[3.1.0]hexane (5 g, 26.99 mmol) and copper(I) bromide dimethyl sulfide complex (60.739 mL, 121.48 mmol) in tetrahydrofuran (150 mL). The reaction mixture was stirred at -10°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with 10% aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL) and then stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 55 / 45) to give (3R,4S)-3-hydroxy-4-allylpyrrolidine-1-carboxylic acid tert-butyl ester (1.55 g, 25.26% yield) as a yellow oil. LCMS m / z (ESI): [M+H-56] + =172.

[0190] Step 2: Under a nitrogen atmosphere, sodium hydride (0.32 g, 7.92 mmol, 60% purity) was added to a solution of (3R,4S)-3-hydroxy-4-allylpyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.60 mmol) in N,N-dimethylformamide (8 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours under a nitrogen atmosphere. Benzyl bromide (0.947 mL, 7.92 mmol) was added, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 9 / 1) to give (3R,4S)-3-benzyloxy-4-allylpyrrolidine-1-carboxylic acid tert-butyl ester (0.9 g, 42.96% yield) as a yellow oil. LCMS m / z (ESI): [M+H-56] + =262, [M+H-100] + =218. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.25 (m, 5H), 5.82 - 5.66 (m, 1H), 5.11 - 4.97 (m, 2H), 4.60 - 4.44 (m, 2H), 3.83 - 3.72 (m, 1H), 3.64 - 3.49 (m, 2H), 3.42 - 3.32 (m, 1H), 3.20 - 3.03 (m, 1H), 2.37 - 2.25 (m, 1H), 2.24 - 2.14 (m, 1H), 2.09 - 1.93 (m, 1H), 1.45 (s, 9H).

[0191] Step 3: To a solution of (3R,4S)-3-benzyloxy-4-allylpyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 2.52 mmol) and sodium periodate (1.62 g, 7.56 mmol) in acetonitrile (15 mL) and water (6 mL), potassium osmate (92.86 mg, 0.25 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 55 / 45) to afford (3R,4S)-3-benzyloxy-4-(2-acetaldehyde)pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 62.11% yield) as a yellow oil. LCMS: MS m / z(ESI):[M+H-56] + =264, [M+H-100] + =220.

[0192] Step 4: To a solution of (3R,4S)-3-benzyloxy-4-(2-acetaldehyde)pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg, 1.50 mmol) and 3-(2-(((1S,3S)-3-amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (630 mg, 1.50 mmol) in 1,2-dichloroethane (15 mL), a small amount of acetic acid (0.086 mL, 1.50 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. Sodium borohydride acetate (951 mg, 4.51 mmol) was added, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was added (20 mL) and extracted with water and ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 95 / 5) to give 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (460 mg, 42.37% yield) as a yellow oil. LCMS:MS m / z (ESI): [M+H] + =723.

[0193] Step 5: To a solution of 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)-1-(tert-butyloxycarbonyl)pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (480 mg, 0.66 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of lithium hydroxide (139 mg, 3.32 mmol) in water (2 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 0.5 M aqueous hydrochloric acid to pH=3-4 and extracted with ethyl acetate (5 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 85 / 15) to give 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (460 mg, 98.2% yield) as a yellow oil. LCMS:MS m / z (ESI): [M+H] + =709.

[0194] Step 6: At 0° C., 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)-1-(tert-butyloxycarbonyl)pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (390 mg, 0.55 mmol) was added hydrochloric acid / dioxane (10 mL, 4N) solution and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to give 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (320 mg, yield 95.55%) as a yellow solid. LCMS:MS m / z(ESI):[M+H] + =609.

[0195] Step 7: To a solution of 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (320 mg, 0.53 mmol) in N,N-dimethylformamide (180 mL), pentafluorophenol (194 mg, 1.05 mmol) and N,N'-dicyclohexylcarbodiimide (217 mg, 1.05 mmol) were added in that order, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and the resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 90 / 10) to give (4 1 S,4 3 S,8 3 S,8 4 R)-8 4 -(benzyloxy)-2 5 -(trifluoromethyl)-1 1 H-3,5-diaza-1(3,6)-indole-2(4,2)-pyrimidine-8(3,1)-pyrrolidine-4(1,3)-cyclopentanecyclononan-9-one (100 mg, 32.26% yield) was obtained as a brown solid. LCMS: MS m / z (ESI): [M+H]+ =591.

[0196] Step 8: At 0°C, (4 1 S,4 3 S,8 3 S,8 4 R)-8 4 -(benzyloxy)-2 5 -(trifluoromethyl)-1 1 To a solution of H-3,5-diaza-1(3,6)-indole-2(4,2)-pyrimidine-8(3,1)-pyrrolidine-4(1,3)-cyclopentanecyclononan-9-one (30 mg, 0.05 mmol) in dichloromethane (2 mL) was slowly added a solution of boron trichloride (0.25 mL, 1 M) dropwise, and the reaction mixture was stirred at 0°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was quenched with methanol (0.1 mL) and concentrated to dryness. The resulting crude product was purified by preparative HPLC (chromatography column: Xbridge Prep C18 10 μm OBO TM 19*250nm, mobile phase: acetonitrile / water (0.05% ammonia water), flow rate: 20ml / min), (4 1 S,4 3 S,8 3 S,8 4 R)-8 4 -(hydroxy)-2 5 -(trifluoromethyl)-1 1 H-3,5-diaza-1(3,6)-indole-2(4,2)-pyrimidine-8(3,1)-pyrrolidine-4(1,3)-cyclopentanecyclononan-9-one ((4 1 S,4 3 S,8 3 S,8 4 R)-8 4 -hydroxy-2 5 -(trifluoromethyl)-1 1 H-3,5-diaza-1(3,6)-indola-2(4,2)-pyrimidina-8(3,1)-pyrrolidina-4(1,3)-cyclopentanacyclononaphan-9-one) (Z3, 2.6 mg, 8.0% yield). LCMS: MS m / z (ESI): [M+H]+ =501. 1 H NMR (400 MHz, CD3OD) δ 8.79 - 8.19 (m, 2H), 7.86 (d, J = 76.7 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.25 - 7.15 (m, 1H), 4.64 - 4.48 (m, 1H), 4.29 - 4.18 (m, 1H), 4.15 - 3.87 (m, 2H), 3.58 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.86 - 2.67 (m, 1H), 2.59 - 2.47 (m, 1H), 2.29 - 2.19 (m, 2H), 2.13 - 1.96 (m, 2H), 1.88 - 1.74 (m, 1H), 1.70 - 1.58 (m, 2H), 1.56 - 1.44 (m, 1H), 1.36 - 1.09 (m, 2H).

[0197] [ka]

[0198] Step 1: To a solution of tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (1 g, 5.0 mmol) in tetrahydrofuran (25 mL), N,N-diisopropylethylamine (2.61 g, 20.0 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.10 g, 5.0 mmol) were added, and the reaction mixture was stirred at 25° C. for 14 hours. After the completion of the reaction was detected by LCMS, the reaction mixture was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 15 / 1) to obtain N-[(1S,3S)-3-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]carbamic acid tert-butyl ester (0.76 g, 40% yield). LCMS: MS m / z (ESI): [M+H] + =381.2,t R =1.56min.

[0199] Step 2: To a solution of 1H-indole-6-carboxylic acid methyl ester (3.00 g, 17.12 mmol) in N,N-dimethylformamide (30 mL) was added 1-iodo-pyrrolidine-2,5-dione (4.62 g, 20.55 mmol) at 0 °C. The reaction was stirred at room temperature for 3 hours. TLC (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The mixture was extracted with ethyl acetate (200 mL x 3) and water (60 mL). The mixture was then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 3-iodo-1H-indole-6-carboxylic acid methyl ester (3.5 g, 67.89% yield).

[0200] Step 3: To a solution of 3-iodo-1H-indole-6-carboxylic acid methyl ester (3.50 g, 11.62 mmol) in dichloromethane (35 mL), triethylamine (3.23 mL, 23.25 mmol) and 4-dimethylaminopyridine (0.36 g, 2.91 mmol) were added. At 0 °C, di-tert-butyl dicarbonate (2.99 mL, 13.95 mmol) was added. The reaction was stirred at room temperature for 18 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed the reaction was complete. The reaction mixture was extracted with dichloromethane (200 mL × 3) and water (60 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to obtain the compound 1-(tert-butyl) 6-methyl 3-iodo-1H-indole-1,6-dicarboxylic acid ester (3.8 g, yield 81.48%).

[0201] Step 4: To a solution of 1-(tert-butyl) 6-methyl-3-iodo-1H-indole-1,6-dicarboxylate (3.60 g, 8.97 mmol) in dioxane (36 mL), potassium acetate (1.76 g, 17.95 mmol), palladium dichloride (0.66 g, 0.91 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborinane (1.95 mL, 13.46 mmol) were added and stirred at 70 °C for 3 h. TLC (petroleum ether:ethyl acetate = 5:1) showed the reaction was complete. The mixture was collected and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain 1-(tert-butyl) 6-methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-1,6-dicarboxylic acid ester (2.5 g, yield 69.43%).

[0202] Step 5: To a solution of 1-(tert-butyl) 6-methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-1,6-dicarboxylic acid ester (2.3 g, 5.73 mmol) in dioxane and water (23 mL) was added potassium carbonate (1.58 g, 11.46 mmol), palladium dichloride (0.28 g, 0.38 mmol), and N-[(1S,3S)-3-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]carbamic acid tert-butyl ester (1.46 g, 3.82 mmol), and the reaction was stirred at 100 °C for 3 h. TLC (petroleum ether:ethyl acetate = 3:1) indicated the reaction was complete. The mixture was collected and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate elution=3:1) to obtain 1-(tert-butyl) 6-methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-1,6-dicarboxylic acid ester (2.2 g, yield 90%).

[0203] Step 6: To a flask containing 1-(tert-butyl) 6-methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-1,6-dicarboxylic acid ester (2.20 g, 3.55 mmol) was added dioxane (15 mL, 3.55 mmol), followed by hydrogen chloride (15 mL, 3.55 mmol). The mixture was stirred at 25° C. for 2 hours. TLC (dichloromethane:methanol=10:1) showed the reaction was complete. After concentration, the resulting solid was dissolved in methyl tert-butyl ether and filtered to give 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (2.6 g, crude product, hydrochloride salt) as a pale yellow solid compound. ES-API: [M+H] + = 419.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.60 (d, J = 15.4 Hz, 1H), 8.38 (d, J = 30.4 Hz, 1H), 8.05 (s, 2H), 7.78 (d, J = 24.6 Hz, 1H), 4.53 (d, J = 6.1 Hz, 1H), 3.88 (s, 3H), 3.56 (s, 2H), 2.16 (s, 2H), 2.00 (d, J = 9.2 Hz, 3H), 1.63 (s, 2H), 1.23 (s, 2H).

[0204] Step 7: To a solution of 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (1.00 g, 2.38 mmol) in 1,2-dichloroethane (10 mL) was added sodium borohydride (0.39 mL, 11.92 mmol), tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.54 g, 2.38 mmol), and the reaction was stirred at room temperature overnight. The reaction was extracted with dichloromethane (60 mL x 3) and saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography (dichloromethane:methanol=30:1) to give methyl 3-(2-(((1S,3S)-3-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (300 mg, 19.46% yield). ES-API: [M+H] += 630.31.

[0205] Step 8: To a solution of methyl 3-(2-(((1S,3S)-3-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (150 mg, 0.24 mmol) in tetrahydrofuran / methanol / water (1:1:1), lithium hydroxide (0.02 mL, 0.71 mmol) was added and the reaction was stirred at room temperature overnight. The pH value of the reaction was adjusted to acidic with dilute hydrochloric acid. The reaction was diluted with ethyl acetate (6 mL × 3) and water (2 ml), followed by the addition of saturated sodium chloride solution and separation. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated to give compound 3-(2-(((1S,3S)-3-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (150 mg, yield 98.79%). 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (d, J = 14.1 Hz, 1H), 9.16 (s, 3H), 8.85 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 8.16 - 7.98 (m, 3H), 7.76 (d, J = 17.5 Hz, 1H), 4.52 (s, 1H), 3.21 (d, J = 12.1 Hz, 4H), 2.84 (d, J = 29.6 Hz, 5H), 2.19 (d, J = 6.3 Hz, 3H), 1.78 (s, 3H), 1.60 (s, 4H), 1.28 (d, J = 40.2 Hz, 9H).

[0206] Step 9: To a flask containing 3-(2-(((1S,3S)-3-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (330 mg, 0.52 mmol) was added dioxane (3 mL, 0.52 mmol), followed by hydrogen chloride (3 mL). The mixture was stirred at 25° C. for 2 hours. TLC (dichloromethane:methanol=7:1) showed the reaction was complete. The organic layer was concentrated in vacuo. The resulting solid was dissolved in methyl tert-butyl ether and filtered to give 3-(2-(((1S,3S)-3-((2-(piperidin-4-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (350 mg, yield 126.00%) as a pale yellow solid compound. ES-API: [M+H] + =517.4. 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.39 (d, J = 41.9 Hz, 3H), 9.13 (s, 1H), 8.59 (d, J = 12.7 Hz, 1H), 8.37 (dd, J = 40.4, 8.0 Hz, 1H), 8.07 (d, J = 60.1 Hz, 3H), 7.76 (dd, J = 33.4, 8.0 Hz, 1H), 4.51 (s, 1H), 3.18 (d, J = 11.9 Hz, 3H), 2.91 - 2.71 (m, 4H), 2.20 (dd, J = 13.6, 6.8 Hz, 3H), 1.79 (d, J = 8.9 Hz, 3H), 1.66 (d, J = 19.7 Hz, 4H), 1.37 (d, J = 9.5 Hz, 2H).

[0207] Step 10: To a solution of 3-(2-((1S,3S)-3-((2-(piperidin-4-yl)ethyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (90 mg, 0.17 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) and N,N-diisopropylethylamine (88 mg, 0.68 mmol) in sequence, and the reaction was stirred at room temperature for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated to dryness, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XBC18, 50*250 mm, 10 μm (PARP-06), flow rate: 70 mL / min, mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), column temperature: 25°C). 1 S,4 3 S)-2 5 -(trifluoromethyl)-1 1 H-3,5-diaza-1(3,6)-indole-2(4,2)-pyrimidine-8(4,1)-piperidine-4(1,3)-cyclopentanecyclononan-9-one ((4 1 S,4 3 S)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5-diaza-1(3,6)-indola-2(4,2)-pyrimidina-8(4,1)-piperidina-4(1,3)-cyclopentanacyclononaphan-9-one (Z4) (1.7 mg, 1.3% yield) was obtained. LCMS: MS m / z (ESI): [M+H] + =499.2,t R =1.22 min. 11H NMR (400 MHz, CD3OD): δ 8.64 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.53 - 4.50 (m, 1H), 4.48 - 4.37 (m, 1H), 3.72 (s, 1H), 3.26 - 3.19 (m, 1H), 3.09 - 2.97 (m, 1H), 2.80 - 2.55 (m, 3H), 2.42 - 2,40 (m, 2H), 2.11 - 1.97 (m, 2H), 1.92 - 1.60 (m, 8H), 1.36 - 1.29 (m, 1H).

[0208]

Chem.

[0209] Step 1: To a solution of 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (270 mg, 0.55 mmol) in N,N-dimethylformamide (5 mL) at room temperature, tert-butyl(4-bromobutyl)carbamate (138 mg, 0.55 mmol) and N,N-diisopropylethylamine (284 mg, 2.20 mmol) were added in that order. The reaction mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, 10% aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to give methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (170 mg, 46% yield) as a white solid. LCMS:MS m / z (ESI): [M+H] + =667.3,t R =1.28min.

[0210] Step 2: To a solution of methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (170 mg, 0.26 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of lithium hydroxide (66.0 mg, 1.56 mmol) in water (2 mL), and the reaction was stirred at 40° C. overnight. After detecting the completion of the reaction by LCMS, the reaction solution was acidified with 1.0 M aqueous hydrochloric acid to pH=3-4 and extracted with dichloromethane (10 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (160 mg, 94% yield) as a white solid, which was used directly in the next step reaction without purification. LCMS: MS m / z (ESI): [M+H] + =653.2,t R =1.12 min.

[0211] Step 3: At 25° C., a solution of 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (160 mg, 0.25 mmol) in methanol (5 mL) was added with a solution of hydrochloric acid / methanol (5 mL, 4N), and the reaction mixture was stirred at 25° C. for 16 hours. After completion of the reaction was detected by LCMS, the reaction mixture was concentrated to give 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (120 mg, 87% yield) as a white solid. LCMS: MS m / z(ESI): 553.2 [M+H]+ ,t R =1.00min.

[0212] Step 4: To a solution of 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (120 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (91.2 mg, 0.24 mmol) and N,N-diisopropylethylamine (114 mg, 0.88 mmol) in sequence, and the reaction was stirred at 80° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XBC18, 50*250 mm, 10 μm (PARP-06), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z5) was obtained (17.2 mg, 17% yield). LCMS: MS m / z (ESI): [M+H] + =535.2,t R =1.55min. 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.61 (s, 1H), 8.53 - 8.31 (m, 3H), 8.18 (d, J = 4.0 Hz, 1H), 8.13 - 8.05 (m, 1H), 8.00 (s, 1H), 7.29-7.26 (m, 1H), 4.34 - 4.20 (m, 1H), 2.85 - 2.75 (m, 1H), 2.73 - 2.57 (m, 4H), 2.20-2.12 (m, 2H), 1.95 - 1.85 (m, 6H), 1.81 - 1.52 (m, 6H), 1.50 - 1.40 (m, 1H).

[0213] [ka]

[0214] Step 1: To a solution of 2-bromo-3-nitrobenzoic acid (10.0 g, 40.6 mmol) in tetrahydrofuran (150 mL) was slowly added a solution of vinylmagnesium bromide in tetrahydrofuran (1 M, 163 mL, 163 mmol) at -78 °C. After the addition was complete, the mixture was stirred at -78 °C under a nitrogen atmosphere for 3 hours, then allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction was confirmed by LCMS, the reaction mixture was quenched by slowly adding saturated aqueous ammonium chloride (300 mL). The pH was adjusted to 4-5 with 1 M hydrochloric acid, and then extracted with dichloromethane (300 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give 7-bromo-1H-indole-6-carboxylic acid (9.4 g, yield 96.5%) as a yellow solid. LCMS: m / z (ESI): 239.8 [M+H] + ,t R =1.21 min.

[0215] Step 2: To a solution of 7-bromo-1H-indole-6-carboxylic acid (9.40 g, 39.2 mmol) in N,N-dimethylformamide (80 mL) at 25 °C, methyl iodide (6.66 g, 46.9 mmol) and potassium carbonate (10.8 g, 78.3 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 7-bromo-1H-indole-6-carboxylic acid methyl ester (3.90 g, 37% yield) as a yellow solid. LCMS: m / z (ESI): 254.0 [M+H] + ,t R =1.46min. 1 H NMR (400 MHz, DMSO-d6): δ 11.63 (s, 1H), 7.62 (dd, J = 13.6, 5.6 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 3.87 (s, 3H).

[0216] Step 3: At 25° C., tris(dibenzylideneacetone)dipalladium (242 mg, 0.393 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthe (455 mg, 0.787 mmol), and 1,4-dioxane (20 mL) were added sequentially to a sealed can and stirred under a nitrogen atmosphere for 30 minutes. Then, 7-bromo-1H-indole-6-carboxylic acid methyl ester (2.0 g, 7.87 mmol), potassium phosphate (1.67 g, 7.87 mmol), and dimethylphosphine oxide (0.61 g, 7.87 mmol) were added sequentially. The reaction mixture was stirred at 110° C. for 14 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was directly concentrated to obtain the product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to pure ethyl acetate) to obtain 7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (1.00 g, 51% yield) as a yellow solid. LCMS: m / z (ESI): [M+H] + =252.0,t R =1.30min. 1 H NMR (400 MHz, DMSO-d6): δ 12.12 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 3.6 Hz, 1H), 7.65 (t, J = 2.8 Hz, 1H), 6.59 (s, 1H), 3.88 (s, 3H), 1.95 (s, 3H), 1.92 (s, 3H).

[0217] Step 4: Under a nitrogen atmosphere, aluminum trichloride (1.06 g, 7.96 mmol) was added to a dry 50 mL three-neck flask, and then a solution of 7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (1.00 g, 3.98 mmol) in 1,2-dichloroethane (10 mL) was added via syringe and stirred at 80°C for 30 minutes. Thereafter, a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.95 g, 4.38 mmol) in 1,2-dichloroethane (1 mL) was added, and the reaction mixture was reacted at 80°C for 16 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 5) to obtain 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (800 mg, 47% yield) as a white solid. LCMS: m / z (ESI): [M+H] + =432.0,t R =1.58min. 1 H NMR (400 MHz, CDCl3): δ 13.15 (s, 1H), 8.83 (s, 1H), 8.77 (dd, J = 8.8, 1.6 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 8.8, 4.0 Hz, 1H), 3.96 (s, 3H), 2.10 (d, J = 14.4 Hz, 6H).

[0218] Step 5: To a 10 mL microwave tube were added 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (770 mg, 1.78 mmol), N-methylpyrrolidone (4 mL), N,N-diisopropylethylamine (0.59 mL, 3.57 mmol), and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (392 mg, 1.96 mmol) in sequence, and the reaction was stirred at 80° C. to clarify and microwaved at 130° C. for 2 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (500 mg, 58% yield) as an off-white solid. LCMS: m / z (ESI): [M+H] + =595.8,t R =1.58min. 1 H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 8.59 (s, 2H), 8.16 (s, 1H), 8.01 - 7.68 (m, 2H), 6.78 (s, 1H), 4.46 (dd, J = 13.8, 6.8 Hz, 1H), 3.94 (s, 3H), 2.23 - 2.10 (m, 2H), 2.00 (d, J = 14.2 Hz, 6H), 1.96 - 1.87 (m, 3H), 1.66 - 1.47 (m, 2H), 1.40 (s, 9H).

[0219] Step 6: At room temperature, methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (400 mg, 0.67 mmol) was dissolved in a mixture of hydrogen chloride / dioxane (5 mL, 4 M) and methanol (2 mL), and the mixture was reacted at 20° C. for 16 hours. After detecting the completion of the reaction by LCMS, saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (dichloromethane / methanol = 30:1) to give 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (160 mg, 48% yield) as a white solid. LCMS: m / z (ESI): 496.2 [M+H] + ,t R =1.40min.

[0220] Step 7: 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (500 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (3 mL), tert-butyl(5-bromopentyl)carbamate (269 mg, 1.0 mmol) and N,N-diisopropylethylamine (0.67 mL, 4.0 mmol) were added sequentially, and the reaction was stirred at 80° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was spun dry and purified by column chromatography (dichloromethane / methanol=100 / 7) to give methyl 3-(2-(((1S,3S)-3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (420 mg, 61% yield) as an off-white solid. LCMS: m / z (ESI): [M+H] + =681.2,t R =1.54min.

[0221] Step 8: Methyl 3-(2-(((1S,3S)-3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (360 mg, 0.53 mmol) was dissolved in a mixture of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL). Lithium hydroxide monohydrate (111 mg, 2.65 mmol) was then added and the mixture was stirred at 40° C. for 16 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added, and the mixture was adjusted to pH 4-5 with hydrochloric acid (1 M), followed by extraction with dichloromethane (20 mL x 9). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(2-(((1S,3S)-3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (320 mg, 91% yield) as a white solid crude product, which was used directly in the next step reaction without purification. LCMS: m / z (ESI): [M+H] + =667.2,t R =1.50min.

[0222] Step 9: 3-(2-(((1S,3S)-3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (320 mg, 0.47 mmol) was dissolved in hydrogen chloride / methanol (5 mL, 4 M), and the system was stirred at 25° C. for 4 hours. After the completion of the reaction was detected by LCMS, the solvent was evaporated to dryness to give 3-(2-(((1S,3S)-3-((5-aminopentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (260 mg, 98% yield) as a white solid, which was used directly in the next step reaction without purification. LCMS: m / z(ESI):[M+H] + =567.3,t R =0.92 min.

[0223] Step 10: To a solution of 3-(2-(((1S,3S)-3-((5-aminopentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (200 mg, 0.35 mmol) in N,N-dimethylformamide (20 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (134 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.41 mmol) in sequence, and the reaction was stirred at 60° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1H-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z6) was obtained (34.3 mg, 15% yield). LCMS: m / z (ESI): [M+H] + =549.2,t R =0.70 min. 1 H NMR (400 MHz, DMSO-d6): δ 11.84 - 11.94 (m, 1H), 8.70 - 8.30 (m, 3H), 8.30 - 8.07 (m, 3H), 7.87 - 8.10 (m, 1H), 7.62 - 7.22 (m, 1H), 4.39 - 4.18 (m, 1H), 3.50 - 3.05 (m, 1H), 3.01 - 2.80 (m, 3H), 2.70 - 2.52 (m, 1H), 2.45 - 2.33 (s, 1H), 2.22 - 2.01 (m, 2H), 2.00 - 1.37 (m, 15H).

[0224] [ka]

[0225] Step 1: At room temperature, to a solution of 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (500 mg, 1.00 mmol) in N,N-dimethylformamide (5 mL), (2-(2-bromoethoxy)ethyl)carbamic acid tert-butyl ester (270 mg, 1.00 mmol) and N,N-diisopropylethylamine (0.67 mL, 4.00 mmol) were added in that order, and the reaction mixture was stirred at 70° C. for 16 hours under a nitrogen atmosphere. After the completion of the reaction was detected by LCMS, 10% aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give methyl 3-(2-(((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (170 mg, 46% yield) as a yellow solid. LCMS:MS m / z (ESI): [M+H] + =683.4,t R =1.18min.

[0226] Step 2: To a solution of methyl 3-(2-(((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (350 mg, 0.51 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of lithium hydroxide (86.0 mg, 2.05 mmol) in water (2 mL), and the reaction was stirred at 40° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was acidified with 1.0 M aqueous hydrochloric acid to pH 3-4 and extracted with dichloromethane / methanol (10:1, 60 mL x 6). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(2-(((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (314 mg, 92% yield) as a yellow solid. The crude product was used directly in the next step without purification. LCMS: MS m / z (ESI): [M+H] + =669.2,t R =1.10 min.

[0227] Step 3: At 25° C., a solution of 3-(2-(((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 0.45 mmol) in methanol (5 mL) was added with a solution of hydrochloric acid / methanol (5 mL, 4 M), and the reaction mixture was stirred at 40° C. for 4 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was directly concentrated to give 3-(2-(((1S,3S)-3-((2-(2-aminoethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (244 mg, 96% yield) as a yellow solid. The crude product was used directly in the next step reaction without purification. LCMS: MS m / z(ESI): [M+H] + =569.2,t R =0.95min.

[0228] Step 4: To a solution of 3-(2-(((1S,3S)-3-((2-(2-aminoethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (220 mg, 0.39 mmol) in N,N-dimethylformamide (8 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (149 mg, 0.39 mmol) and N,N-diisopropylethylamine (182 mg, 1.41 mmol) in sequence, and the reaction was stirred at 60° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), chromatography conditions: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-25 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z7) was obtained (33.5 mg, 16% yield). LCMS: MS m / z (ESI): [M+H] + =551.2,t R =0.69 min. 1 H NMR (400 MHz, DMSO-d6): δ 12.06 - 12.05 (m, 1H), 8.69 (d, J = 8.0 Hz, 2H), 8.64 - 8.48 (m, 2H), 8.13 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.42 (dd, J = 8.0, 3.2 Hz, 1H), 4.32 - 4.18 (m, 1H), 3.82 - 3.72 (m, 5H), 3.46 (t, J = 7.2 Hz, 1H), 3.31 - 3.17 (m, 2H), 3.16 - 3.08 (m, 1H), 2.72 (dd, J = 14.4, 7.2 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.19 - 2.11 (m, 1H), 2.02 - 1.86 (m, 6H), 1.82 - 1.62 (m, 3H).

[0229] [ka]

[0230] Step 1: To a 10 mL microwave tube were added 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (810 mg, 1.88 mmol), N-methylpyrrolidone (5 mL), N,N-diisopropylethylamine (0.93 mL, 5.63 mmol), and tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate (384 mg, 2.06 mmol) in sequence. The reaction was stirred at 80 °C to clarify and then microwaved at 130 °C for 2 h. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give methyl 3-(2-(((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (970 mg, 89% yield) as an off-white solid. LCMS: MS m / z (ESI): [M+H] + =582.2,t R =1.89min.

[0231] Step 2: At room temperature, methyl 3-(2-(((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (500 mg, 0.86 mmol) was dissolved in a mixture of hydrogen chloride / dioxane (5 mL, 4 M) and methanol (2 mL), and the mixture was reacted at 25° C. for 16 hours. After detecting the completion of the reaction by LCMS, saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 10). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 3-(2-(((1r,3r)-3-aminocyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (220 mg, 53% yield) as a white solid. LCMS: MS m / z (ESI): [M+H] + =482.2,t R =1.35min.

[0232] Step 3: At room temperature, tert-butyl (4-bromobutyl)carbamate (157 mg, 0.62 mmol) and N,N-diisopropylethylamine (322 mg, 2.49 mmol) were added sequentially to a solution of 3-(2-(((1r,3r)-3-aminocyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. After the completion of the reaction was detected by LCMS, saturated ammonium chloride solution (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give methyl 3-(2-(((1r,3r)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (225 mg, 55% yield) as a yellow solid. LCMS:MS m / z (ESI): [M+H] + =653.3,t R =1.19 min.

[0233] Step 4: To a solution of methyl 3-(2-(((1r,3r)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (225 mg, 0.35 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of lithium hydroxide monohydrate (72.0 mg, 1.72 mmol) in water (2 mL), and the reaction was stirred at 40° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was acidified with 1.0 M aqueous hydrochloric acid to pH 3-4 and extracted with dichloromethane / methanol (10:1, 60 mL x 6). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(2-(((1r,3r)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 95% yield) as a yellow solid. The crude product was used directly in the next step without purification. LCMS: MS m / z (ESI): [M+H] + =639.2,t R =1.40min.

[0234] Step 5: To a solution of 3-(2-(((1r,3r)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 0.33 mmol) in methanol (5 mL) was added a solution of hydrochloric acid / methanol (5 mL, 4 M), and the reaction mixture was stirred at 40° C. for 16 hours. After completion of the reaction was detected by LCMS, the reaction mixture was concentrated to dryness to give 3-(2-(((1r,3r)-3-((4-aminobutyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (270 mg, 94% yield) as a yellow solid. The crude product was used directly in the next step reaction without purification. LCMS:MS m / z(ESI):[M+H] + =639.2,t R =1.31min.

[0235] Step 6: To a solution of 3-(2-(((1r,3r)-3-((4-aminobutyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (270 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (200 mg, 1.55 mmol) sequentially, and the reaction was stirred at 70° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated to dryness, and the resulting crude product was purified by reverse phase chromatography (70 mL / min, 25 °C, Ultimate XB-C18, 50 x 250 mm, 10 μm (PARP-02), acetonitrile-water (0.1% trifluoroacetic acid)). 1 r,4 3 r)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclobutanecycloundecan-11-one ((4 1 r,4 3 r)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclobutanacycloundecaphan-11-one (Z8) was obtained (3.9 mg, 2.4% yield). LCMS: MS m / z (ESI): [M+H] + =551.3,t R =1.05min. 1 H NMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.29 (d, J = 4.4 Hz, 1H), 8.07 - 7.92 (m, 2H), 7.42 - 7.32 (m, 1H), 4.82 - 4.68 (m, 1H), 4.05 (s, 1H), 2.86 - 2.78 (m, 2H), 2.36 - 2.28 (m, 2H), 2.26 - 2.18 (m, 2H), 2.08 - 1.94 (m, 3H), 1.91 (s, 3H), 1.87 (s, 3H), 1.76 - 1.68 (m, 2H), 1.56 - 1.48 (m, 2H).

[0236] [ka]

[0237] Step 1: To a 10 mL microwave tube were added 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (450 mg, 1.04 mmol), N-methylpyrrolidone (5 mL), N,N-diisopropylethylamine (0.52 mL, 3.13 mmol), and tert-butyl ((1S,3S)-3-aminocyclohexyl)carbamate (235 mg, 1.09 mmol) in sequence, and the reaction was stirred at 80° C. to clarify and microwaved at 130° C. for 2 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (470 mg, 74% yield) as an off-white solid. LCMS: m / z (ESI): [M+H] + =610.2,t R =1.98min.

[0238] Step 2: At room temperature, methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (470 mg, 0.77 mmol) was dissolved in a mixture of hydrogen chloride / dioxane (5 mL, 4 M) and methanol (2 mL), and the mixture was reacted at 25° C. for 16 hours. After detecting the completion of the reaction by LCMS, saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 10). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 3-(2-(((1S,3S)-3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (310 mg, 79% yield) as a white solid. LCMS: m / z (ESI): [M+H] + =510.5,t R =1.42 min.

[0239] Step 3: 3-(2-(((1S,3S)-3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (310 mg, 0.61 mmol) was dissolved in N,N-dimethylformamide (3 mL), tert-butyl (4-bromobutyl)carbamate (153 mg, 0.61 mmol) and N,N-diisopropylethylamine (0.67 mL, 4.0 mmol) were added sequentially, and the reaction was stirred at 80° C. for 16 h. After detecting the completion of the reaction by LCMS, the reaction mixture was spun dry and purified by column chromatography (dichloromethane / methanol=100 / 7) to give methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (200 mg, 48% yield) as an off-yellow solid. LCMS: m / z (ESI): [M+H] + =681.2,t R =1.60min.

[0240] Step 4: Methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (200 mg, 0.29 mmol) was dissolved in a mixture of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL), then lithium hydroxide monohydrate (61.6 mg, 1.47 mmol) was added and the reaction was stirred at 40° C. for 16 hours. After the completion of the reaction was detected by LCMS, the solvent was spun down to give 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (180 mg, 92% yield) as a crude yellow solid, which was used directly in the next step reaction without purification. LCMS: m / z (ESI): [M+H] + =667.2,t R =1.43 min.

[0241] Step 5: 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (180 mg, 0.27 mmol) was dissolved in hydrogen chloride / methanol (5 mL, 4 M), and the system was stirred at 15° C. for 4 hours. After the completion of the reaction was detected by LCMS, the solvent was directly rotovapped to give 3-(2-(((1S,3S)-3-((4-aminobutyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (120 mg, 78% yield) as a yellow solid, which was used directly in the next step reaction without purification. LCMS: m / z(ESI):[M+H] + =567.2,t R =1.43 min.

[0242] Step 6: To a solution of 3-(2-(((1S,3S)-3-((4-aminobutyl)amino))cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (120 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (80.4 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.84 mmol) sequentially, and the reaction was stirred at 60° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate SFC18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclohexanecycloundecane-11-one ((4 1 S,4 3 S)-1 7 -1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclohexanacycloundecaphan-11-one (Z9) was obtained (8.2 mg, 5.8% yield). LCMS: m / z (ESI): [M+H] + =549.2,t R =0.72 min. 1H NMR (400 MHz, DMSO-d6): δ 11.87 (d, 1H), 8.62 (s, 1H), 8.27 - 8.09 (m, 2H), 7.97 (m, 2H), 7.88 - 7.76 (m, 2H), 7.29 (m, 1H), 4.05 (m, 1H), 2.83 (m, 3H), 2.71 - 2.58 (m, 2H), 2.36 (m, 1H), 1.88 (m, 8H), 1.58 (m, 9H).

[0243] [ka]

[0244] Step 1: At room temperature, 3-(tert-butoxycarbonylamino)propyl bromide (144 mg, 0.61 mmol) and N,N-diisopropylethylamine (313 mg, 2.42 mmol) were added sequentially to a solution of 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 0.61 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, 10% aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1 to 15 / 1) to give 3-(2-(((1S,3S)-3-(3-(tert-butoxycarbonylaminopropyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (100 mg, 25% yield) as a yellow solid. LCMS: MS m / z (ESI): [M+H] + =653.6,t R =1.53 min.

[0245] Step 2: To a solution of 3-(2-(((1S,3S)-3-(3-(tert-butoxycarbonylaminopropyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.16 mmol) in a mixture of tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added a solution of lithium hydroxide monohydrate (33 mg, 0.78 mmol) in water (1.5 mL), and the reaction mixture was stirred at 40° C. for 16 hours. After completion of the reaction was detected by LCMS, The reaction mixture was acidified with 1.0 M aqueous hydrochloric acid to pH 3-4 and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(2-(((1S,3S)-3-((3-(tert-butoxycarbonyl)amino)propyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (90 mg, 92% yield) as a white solid, which was used directly in the next step without purification. LCMS: MS m / z (ESI): [M+H] + =639.2,t R =1.10 min.

[0246] Step 3: At 25° C., a solution of 3-(2-(((1S,3S)-3-((3-(tert-butoxycarbonyl)amino)propyl)amino)cyclopentyl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (90 mg, 0.14 mmol) in methanol (3 mL) was added with a solution of hydrochloric acid / methanol (6 mL, 4N), and the reaction mixture was stirred at 40° C. for 2 hours. After completion of the reaction was detected by LCMS, the reaction mixture was concentrated to give 3-(2-(((1S,3S)-3-((3-aminopropyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (70 mg, 93% yield) as a white solid. LCMS: MS m / z (ESI): [M+H] + =539.6,t R =1.33 min.

[0247] Step 4: To a solution of 3-(2-(((1S,3S)-3-((3-aminopropyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (65 mg, 0.12 mmol) in N,N-dimethylformamide (8 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (300 mg, 2.32 mmol) sequentially, and the reaction was stirred at 80° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XBC18, 50*250 mm, 10 μm (PARP-06), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, room temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1H-3,5,9-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclodecan-10-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,9-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclodecaphan-10-one (Z10) was obtained (1.6 mg, 3% yield). LCMS: MS m / z (ESI): [M+H] + =521.2,t R =1.26 min.

[0248] [ka]

[0249] Step 1: At -78 °C, a solution of 2-chloro-3-nitrobenzoic acid (10.0 g, 49.6 mmol) in tetrahydrofuran (120 mL) was slowly added dropwise with a solution of vinylmagnesium bromide in tetrahydrofuran (198 mL, 198 mmol, 1 M). After the addition was complete, the mixture was stirred at -78 °C for 3 h under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, the reaction mixture was quenched by slowly adding saturated aqueous ammonium chloride (300 mL). The pH was adjusted to 4-5 with 1 M hydrochloric acid, and then extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-chloro-1H-indole-6-carboxylic acid (8.03 g, 83% yield) as a crude tan solid, which was used directly in the next step without further purification. LCMS: m / z (ESI): [M+H] + =196.0,t R =1.53 min.

[0250] Step 2: To a solution of 7-chloro-1H-indole-6-carboxylic acid (8.00 g, 40.9 mmol) in N,N-dimethylformamide (85 mL) at 25 °C, methyl iodide (6.97 g, 49.1 mmol) and potassium carbonate (11.3 g, 81.9 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by TLC, water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (150 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 7-chloro-1H-indole-6-carboxylic acid methyl ester (5.8 g, 67% yield) as a yellow solid. LCMS: m / z (ESI): [M+H] + =210.1,t R =1.45min. 1 H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40 (m, 1H), 6.62 (dd, J = 3.2, 2.0 Hz, 1H), 3.95 (s, 3H).

[0251] Step 3: In a dry 50 mL three-neck flask, aluminum trichloride (1.27 g, 9.54 mmol) was added, and under a nitrogen atmosphere, a solution of 7-chloro-1H-indole-6-carboxylic acid methyl ester (1.00 g, 4.77 mmol) in 1,2-dichloroethane (10 mL) was added, and the system was stirred at 80° C. for 30 minutes, and then a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.09 g, 5.01 mmol) in 1,2-dichloroethane (1 mL) was added, and the reaction solution was reacted at 80° C. for 16 hours. After detecting the completion of the reaction by TLC, water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 5) to give 7-chloro-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (0.38 g, 20% yield) as a white solid. LCMS: m / z (ESI): [M+H] + =392.0,t R =1.70min. 1 H NMR (400 MHz, DMSO-d6): δ 12.86 (s, 1H), 9.10 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H).

[0252] Step 4: To a 10 mL microwave tube were added 7-chloro-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (420 mg, 1.08 mmol), N-methylpyrrolidone (2 mL), N,N-diisopropylethylamine (0.53 mL, 3.23 mmol) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (237 mg, 1.18 mmol) in sequence, and the reaction was stirred at 80° C. to clarify and microwaved at 130° C. for 2 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylate (430 mg, 72% yield) as an off-white solid. LCMS: m / z (ESI): [M+H] + =554.0,t R =2.05min.

[0253] Step 5: At room temperature, methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylate (430 mg, 0.72 mmol) was dissolved in a mixture of hydrogen chloride / dioxane (4 mL, 4 M) and methanol (2 mL), and the mixture was reacted at 15° C. for 16 hours. After detecting the completion of the reaction by LCMS, saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (dichloromethane / methanol = 30:1) to give 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylic acid methyl ester (320 mg, 89% yield) as a white solid. LCMS: m / z (ESI): [M+H] + =454.0,t R =1.38min.

[0254] Step 6: 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylic acid methyl ester (320 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl (4-bromobutyl)carbamate (178 mg, 0.71 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.53 mmol) were added sequentially, and the reaction was stirred at 80° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was rotovapped and purified by column chromatography (dichloromethane / methanol=100 / 7) to give methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylate (230 mg, 52% yield) as a yellow solid. LCMS: m / z (ESI): [M+H] + =625.4,t R =1.07min.

[0255] Step 7: Methyl 3-(2-((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylate (230 mg, 0.37 mmol) was dissolved in a mixture of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL), then lithium hydroxide monohydrate (77.2 mg, 1.84 mmol) was added and the reaction was stirred at 40° C. for 16 hours. After the completion of the reaction was detected by LCMS, the solvent was spun down to give 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylic acid (lithium salt, 340 mg, 91% yield) as a crude yellow solid, which was used directly in the next step reaction without purification. LCMS: m / z (ESI): [M+H] +=611.4,t R =0.98min.

[0256] Step 8: 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonylamino)pentylamino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (lithium salt, 340 mg) was dissolved in hydrogen chloride / methanol (5 mL, 4 M), and the system was stirred at 25 °C for 4 h. After the completion of the reaction was detected by LCMS, the solvent was evaporated to dryness to give 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylic acid (containing lithium chloride, 300 mg, 88% yield) as a brown solid, which was used directly in the next step reaction without purification. LCMS: m / z (ESI): [M+H] + =511.2,t R =0.61 min.

[0257] Step 9: To a solution of 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylic acid (containing lithium chloride, 290 mg, 0.28 mmol) in N,N-dimethylformamide (10 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (108 mg, 0.28 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.42 mmol) in sequence, and the reaction was stirred at 60° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -chloro-25 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentylcycloundecan-11-one ((4 1 S,4 3 S)-1 7 The trifluoroacetate salt of 11H-3,5,10-triazaz-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z11) was obtained (30.8 mg, 22% yield). LCMS: m / z (ESI): [M+H] + =493.2,t R =1.27min. 1 H NMR (400 MHz, DMSO-d6): δ 12.33 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.34 - 8.04 (m, 3H), 7.99 (s, 1H), 7.78 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 3.60 (s, 2H), 2.88 (s, 1H), 2.55 (s, 1H), 2.47 - 2.38 (m, 1H), 2.30 - 1.95 (m, 3H), 1.83 - 1.41 (m, 6H), 1.30 - 1.25 (m, 2H).

[0258] [ka]

[0259] Step 1: To a solution (10 mL) of 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (750 mg, 1.52 mmol) in methanol at room temperature, tert-butyl ((4-oxocyclohexyl)methyl)carbamate (414 mg, 1.82 mmol) and glacial acetic acid (0.1 mL) were added in sequence, and the reaction mixture was stirred at 25° C. for 16 hours under a nitrogen atmosphere. Sodium cyanoborohydride (287 mg, 4.56 mmol) was then added, and the reaction mixture was stirred at 25° C. for 2 hours. After the completion of the reaction was confirmed by LCMS, saturated ammonium chloride solution (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C) to obtain methyl 3-(2-((1S,3S)-3-((tert-butoxycarbonyl)amino)methylcyclohexylamino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (P1: 340 mg, yield 32%) (LCMS: MS m / z (ESI): 707.4 [M+H]). + ,t R = 7.43 min), methyl 3-(2-((1S,3S)-3-((tert-butoxycarbonyl)amino)methylcyclohexylamino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (P2: 340 mg, 32% yield) (LCMS: MS m / z (ESI): 707.4 [M+H] + ,t R =7.53 min) was obtained as a white solid.

[0260] Step 2: To a solution of methyl 3-(2-(((1S,3S)-3-((4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (P2: 340 mg, 0.48 mmol) in a mixture of tetrahydrofuran (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (101 mg, 2.40 mmol) in water (3 mL), and the reaction was stirred at 40° C. overnight. After detecting the completion of the reaction by LCMS, the reaction mixture was acidified with 1.0 M aqueous hydrochloric acid to pH 3-4 and extracted with dichloromethane (10 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(2-(((1S,3S)-3-((4-(((tert-butoxycarbonyl)amino)methyl))cyclohexyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 90% yield) as a white solid. The crude product was used directly in the next step without purification. LCMS: MS m / z (ESI): [M+H] + =692.6,t R =1.14 min.

[0261] Step 3: At 25° C., to a solution of 3-(2-(((1S,3S)-3-((4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 0.43 mmol) in methanol (3 mL) was added a solution of hydrochloric acid in dioxane (3 mL, 4N) and the reaction was stirred at 25° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated and purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to give 3-(2-(((1S,3S)-3-((4-(aminomethyl)cyclohexyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (140mg, 55% yield) as a white solid. LCMS:MS m / z(ESI):[M+H] + =592.8,t R =0.94 min.

[0262] Step 4: To a solution of 3-(2-(((1S,3S)-3-((4-(aminomethyl)cyclohexyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (30 mg, 0.05 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol) and N,N-diisopropylethylamine (32 mg, 0.25 mmol) sequentially, and the reaction was stirred at 70° C. for 14 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XBC18, 50*250 mm, 10 μm (PARP-06), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,8-triaza-1(3,6)-indole-2(4,2)-pyrimidine-6(1,4)-cyclohexyl-4(1,3)-cyclopentanecyclononan-9-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,8-triaza-1(3,6)-indola-2(4,2)-pyrimidina-6(1,4)-cyclohexana-4(1,3)-cyclopentanacyclononaphan-9-one (Z12) was obtained (2.0 mg, 9% yield). LCMS: MS m / z (ESI): [M+H] + =575.3,t R =1.55min. 1H NMR (400 MHz, CD3OD): δ 11.44 (s, 1H), 8.63 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.80 (s, 1H), 7.21 (dd, J = 8.0, 3.2 Hz, 1H), 3.94 - 3.68 (m, 2H), 3.17 - 2.94 (m, 3H), 2.68-2.63 (m, 1H), 2.48-2.41 (m, 1H), 2.28 (d, J = 12.8 Hz, 1H), 2.16-2.11 (m, 1H), 2.02-1.97 (m, 8H), 1.94-1.85 (m, 1H), 1.78 - 1.53 (m, 6H), 1.37-1.29 (m, 1H), 1.00-0.85 (m, 1H).

[0263] [ka]

[0264] Step 1: Under a nitrogen atmosphere at 25°C, Dess-Martin reagent (843 mg, 2.0 mmol) was added to a solution of tert-butyl((1S,3S)-3-hydroxycyclobutyl)(methyl)aminomethyl (200 mg, 1.0 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at 25°C for 3 hours under a nitrogen atmosphere. After the completion of the reaction was confirmed by LCMS, the reaction mixture was extracted with water (10 mL) and ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to afford {[(3-oxocyclobutyl)methyl]amino}methanoate-2-methylpropan-2-yl (170 mg, 86% yield) as a white solid. LCMS: m / z (ESI): [M+H-56] + =144.2,t R =1.58min.

[0265] Step 2: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (423 mg, 0.85 mmol) and {[(3-oxocyclobutyl)methyl]amino}methanoate-2-methylpropan-2-yl (170 mg, 0.85 mmol) in methanol (3 mL) was added acetic acid (20 mg, 0.33 mmol) and stirred at 25° C. under a nitrogen atmosphere for 16 hours. Sodium cyanoborohydride (268 mg, 4.26 mmol) was then added to the reaction mixture and the mixture was allowed to react at 25° C. under a nitrogen atmosphere for 6 hours. Completion of the reaction was detected by LCMS. The reaction mixture was extracted with water (10 mL) and ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 60 / 1 to 30 / 1) to afford {[(3-{[(1S,3S)-3-[(4-{7-[dimethyl(oxo)-λ5-methylphosphoryl]-6-(methoxycarbonyl)-1H-indol-3-yl}-5-(trifluoromethyl)pyrimidin-2-yl)amino]cyclopentyl]amino}cyclobutyl)methyl]amino}methanoate-2-methylpropan-2-yl (380 mg, 67% yield) as a white solid. LCMS: m / z (ESI): [M+H] + =679.4,t R =1.19 min.

[0266] Step 3: Under a nitrogen atmosphere at 25° C., lithium hydroxide monohydrate (117 mg, 2.8 mmol) was added to a mixed solution of {[(3-{[(1S,3S)-3-[(4-{7-[dimethyl(oxo)-λ5-methylphosphoryl]-6-(methoxycarbonyl)-1H-indol-3-yl}-5-(trifluoromethyl)pyrimidin-2-yl)amino]cyclopentyl]amino}cyclobutyl)methyl]amino}methanoate-2-methylpropan-2-yl in methanol (4 mL), tetrahydrofuran (4 mL), and water (4 mL). The reaction mixture was heated to 40° C. under a nitrogen atmosphere and stirred for 16 hours, and completion of the reaction was detected by LCMS. The reaction mixture was adjusted to pH 4-5 by the slow addition of 2 M hydrochloric acid solution, extracted with ethyl acetate (50 mL x 5). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product, a colorless oil, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-{[3-(2,2-dimethyl-4-oxo-5-aza-3-oxahexan-6-yl)cyclobutyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (400 mg, 70% purity, 75% yield), was used directly in the next step without further purification. LCMS: m / z (ESI): [M+H] + =664.6,t R =1.11 min.

[0267] Step 4: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-{[3-(2,2-dimethyl-4-oxo-5-aza-3-oxahexan-6-yl)cyclobutyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (300 mg, 0.45 mmol) in methanol (5 mL) was added 4 M methanolic hydrogen chloride solution (10 mL). The reaction mixture was heated to 40° C. under a nitrogen atmosphere and stirred for 2 hours. After completion of the reaction was detected by LCMS, saturated sodium bicarbonate solution (30 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was prepared (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), and purified with 7-[dimethyl(oxo)-λ 5 1H-indole-6-carboxylic acid (185 mg, 73% yield) as a white solid. LCMS:MS m / z(ESI):[M+H] + =565.2,t R =1.25min.

[0268] Step 5: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-{[3-(aminomethyl)cyclobutyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (50 mg, 0.089 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.089 mmol) and N,N-diisopropylethylamine (0.059 mL, 0.35 mmol) sequentially, and the reaction was stirred at 60° C. for 2 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,8-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentane-6(1,3)-cyclobutanecyclononan-9-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,8-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentana-6(1,3)-cyclobutanacyclononaphan-9-one (Z13) was obtained (2.43 mg, 5% yield). LCMS: MS m / z (ESI): [M+H] + =547.3,t R =0.83 min. 1H NMR (400 MHz, CD3OD): δ 8.61 (s, 1H), 8.00 - 7.90 (m, 1H), 7.77 (s, 1H), 7.16 (dd, J = 8.0, 2.8 Hz, 1H), 4.00 - 3.90 (m, 1H), 3.70 - 3.65 (m, 1H), 3.61 - 3.52 (m, 1H), 3.25 - 3.15 (m, 1H), 2.90 - 2.80 (m, 1H), 2.65 - 2.56 (m, 2H), 2.40 - 2.30 (m, 3H), 2.15 - 2.05 (m, 1H), 1.99 (s, 3H), 1.96 (s, 3H), 1.84 - 1.75 (m, 1H), 1.73 - 1.61 (m, 2H), 1.56 - 1.40 (m, 2H).

[0269] [ka]

[0270] Step 1: To a solution of benzyl {[(3S)-tetrahydro-1H-pyrrol-3-yl]amino}methanoate (225 mg, 1.02 mmol) in N,N-dimethylmethanamide (6 mL), 2-methylpropan-2-yl [(5-bromopentyl)amino]methanoate (299 mg, 1.12 mmol) and N,N-diisopropylethylenediamine (528 mg, 4.08 mmol) were added in that order, and the reaction mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, the reaction mixture was extracted with water (15 mL) and ethyl acetate (25 mL×3). The combined organic layer was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1 to 10 / 1) to give benzyl {[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)tetrahydro-1H-pyrrol-3-yl]amino}methanoate (373 mg, 90% yield) as a yellow solid. LCMS: m / z (ESI): [M+H] +=406.2,t R =0.80min.

[0271] Step 2: To a solution of benzyl {[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)tetrahydro-1H-pyrrol-3-yl]amino}methanoate (500 mg, 1.23 mmol) in methanol (8 mL) was added palladium on carbon (50 mg, 10% content, 60% water content), and the reaction mixture was stirred at 25 °C for 2 h under a hydrogen atmosphere. LCMS showed completion of the reaction. The reaction mixture was filtered and rotary evaporated to give 2-methylpropan-2-yl ({5-[(3S)-3-aminotetrahydro-1H-pyrrol-1-yl]pentyl}amino)methanoate (370 mg, approximately 85% pure, 94% yield) as a crude product, which was used directly in the next step without further purification. LCMS: m / z (ESI): [M+H] + =272.2,t R =0.46min.

[0272] Step 3: To a solution of ({5-[(3S)-3-aminotetrahydro-1H-pyrrol-1-yl]pentyl}amino)methanoate-2-methylpropan-2-yl (334 mg, 1.23 mmol) in N,N-dimethylmethanamide (8 mL), 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxo)-λ5-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (507 mg, 1.23 mmol) and N,N-diisopropylethylenediamine (477 mg, 3.69 mmol) were added in sequence, and the reaction mixture was heated to 80° C. under a nitrogen atmosphere and stirred for 16 hours, at which time completion of the reaction was detected by LCMS. The reaction mixture was extracted with water (20 mL) and dichloromethane (30 mL × 5). The combined organic layers were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1 to 10 / 1) to afford 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)tetrahydro-1H-pyrrol-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (550 mg, 67% yield) as a yellow solid. LCMS: m / z (ESI): [M+H] + =667.4,t R =0.92 min.

[0273] Step 4: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)tetrahydro-1H-pyrrol-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (550 mg, 0.83 mmol) in a mixture of methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL), lithium hydroxide monohydrate (173 mg, 4.13 mmol) was added. The reaction mixture was heated to 40° C. under a nitrogen atmosphere and stirred for 2 hours. After detecting the completion of the reaction by LCMS, the solvent was removed by concentration under reduced pressure to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)tetrahydro-1H-pyrrol-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (480 mg, approximately 85% purity, 95% yield) as a crude yellow solid. LCMS:MS m / z(ESI):[M+H] + =653.2,t R =0.83 min.

[0274] Step 5: 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)tetrahydro-1H-pyrrol-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (480 mg, 0.70 mmol) was added to 4M 1,4-dioxane hydrogen chloride solution (8 mL). Under a nitrogen atmosphere, the reaction mixture was heated to 40° C. and stirred for 2 hours. After completion of the reaction was detected by LCMS, saturated sodium bicarbonate solution (30 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (40 mL×3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified in the reverse direction (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(5-aminopentyl)tetrahydro-1H-pyrrol-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (300 mg, 77% yield) as a yellow solid. LCMS: MS m / z (ESI): 553.2 [M+H] + ,t R =0.61 min.

[0275] Step 6: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(5-aminopentyl)tetrahydro-1H-pyrrol-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (100 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (69 mg, 0.18 mmol) and N,N-diisopropylethylamine (94 mg, 0.12 mmol) sequentially, and the reaction was stirred at 60° C. for 16 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,10-diaza-1(3,6)-indole-2(4,2)-pyrimidin-4(3,1)-pyrrolidinecycloundecaphan-11-one ((4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,10-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-pyrrolidinacycloundecaphan-11-one (Z14) was obtained (13.8 mg, 14% yield). LCMS: MS m / z (ESI): [M+H] + =535.2,t R =0.63 min. 1H NMR (400 MHz, CD3OD): δ 8.63 (s, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.32 (dd, J = 8.0, 3.6 Hz, 1H), 4.50 - 4.37 (m, 1H), 3.97 - 3.85 (m, 1H), 3.63 - 3.50 (m, 1H), 3.26 - 3.20 (m, 1H), 3.17 - 3.08 (m, 2H), 3.02 - 2.84 (m, 2H), 2.59 - 2.46 (m, 1H), 2.23 - 2.12 (m, 1H), 2.01 (d, J = 3.6 Hz, 3H), 1.98 (d, J = 3.6 Hz, 3H), 1.82 - 1.65 (m, 2H), 1.52 - 1.37 (m, 4H).

[0276] [ka]

[0277] Step 1: To a solution of benzyl {[(3S)-hexahydropyridin-3-yl]amino}methanoate (242 mg, 1.03 mmol) in N,N-dimethylformamide (8 mL) at 25° C., 2-methylpropan-2-yl [(5-bromopentyl)amino]methanoate (250 mg, 0.939 mmol) and N,N-diisopropylethylamine (363 mg, 2.82 mmol) were added, and the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 6 hours. After detecting the completion of the reaction by LCMS, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-methylpropan-2-yl ({5-[(3S)-3-{[(benzyloxy)carbonyl]amino}hexahydropyridin-1-yl]pentyl}amino)methanoate (280 mg, 64% yield) as a colorless oil. LCMS: m / z (ESI): [M+H] + =420.4,t R=0.80min.

[0278] Step 2: ({5-[(3S)-3-{[(benzyloxy)carbonyl]amino}hexahydropyridin-1-yl]pentyl}amino)methanoate-2-methylpropan-2-yl (250 mg, 0.596 mmol) was dissolved in methanol (10 mL), and palladium on carbon (100 mg, 10% content, 60% water content) was added. The reaction mixture was stirred at 25° C. under a hydrogen atmosphere for 3 hours. After the completion of the reaction was detected by LCMS, the reaction mixture was filtered and concentrated to give ({5-[(3S)-3-aminohexahydropyridin-1-yl]pentyl}amino)methanoate-2-methylpropan-2-yl (180 mg, crude product) as a colorless oil. LCMS: m / z (ESI): [M+H] + =286.0,t R =0.80min.

[0279] Step 3: To a solution of ({5-[(3S)-3-aminohexahydropyridin-1-yl]pentyl}amino)methanoate-2-methylpropan-2-yl (180 mg, 0.63 mmol) in N,N-dimethylformamide (6 mL) at room temperature was added 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxo)-λ 5[-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (272 mg, 0.63 mmol) and N,N-diisopropylethylamine (244 mg, 1.89 mmol) were added in that order, and the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 16 hours. After the completion of the reaction was detected by LCMS, an aqueous solution (50 mL) was added to the reaction mixture, which was then extracted with dichloromethane (50 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 70% yield) as a colorless oil. LCMS:MS m / z (ESI): [M+H] + =681.1,t R =1.11 min.

[0280] Step 4: At room temperature, 7-[dimethyl(oxo)-λ 5To a solution of [2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 0.441 mmol) in methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL) was added lithium hydroxide hydrate (185 mg, 4.41 mmol), and the reaction mixture was stirred at 40° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, the mixture was concentrated to dryness to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (260 mg, crude product) as a white solid. LCMS:MS m / z(ESI):[M+H] + =667.2,t R =0.79 min.

[0281] Step 5: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-10-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (260 mg, 0.390 mmol) in dioxane (4 mL) was added hydrochloric acid in dioxane (1.95 mL, 4 mol / L) at room temperature. Under a nitrogen atmosphere, the reaction mixture was stirred at 40° C. for 3 hours. After detecting the completion of the reaction by LCMS, the mixture was concentrated to remove hydrochloric acid, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C) to obtain 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(5-aminopentyl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (200 mg, 95% yield) as a white solid. LCMS: MS m / z (ESI): 567.2 [M+H] + ,t R =0.82min.

[0282] Step 6: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(5-aminopentyl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (70 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added with 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (56.3 mg, 0.14 mmol) and N,N-diisopropylethylamine (77.4 mg, 0.6 mmol) in that order, and the reaction mixture was reacted at 65° C. for 3 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, the mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (10 mmol NH4HCO3), flow rate: 70 mL / min, column temperature: 25°C) (4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,10-diaza-1(3,6)-indole-2(4,2)-pyrimidin-4(3,1)-piperidinecycloundecan-11-one ((4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,10-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-piperidinacycloundecaphan-11-one) (Z15) (1.2 mg, 1.9% yield). LCMS: MS m / z (ESI): 549.3 [M+H] + ,t R =0.81min. 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.22 - 7.19 (m, 1H), 2.96 - 2.78 (m, 4H), 2.46 - 2.40 (m, 2H), 2.08 - 2.03 (m, 1H), 1.96 (d, J = 14.4 Hz, 3H), 1.83 (d, J = 13.6 Hz, 3H), 1.71 (s, 1H), 1.73 - 1.56 (m, 5H), 1.38 - 1.14 (m, 6H).

[0283] [ka]

[0284] Step 1: 7-[dimethyl(oxo)-λ 5 [-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 0.61 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then [(4-bromobutyl)amino]methanoate-2-methylpropan-2-yl (153 mg, 0.61 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.83 mmol) were added in that order, and the mixture was stirred at 80°C for 16 hours. After detecting the completion of the reaction by LCMS, an appropriate amount of silica gel was directly added, and the sample was mixed by rotary evaporation and purified by column chromatography (dichloromethane / methanol = 100 / 7) to obtain 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (200 mg, 50% yield) as an off-white solid. LCMS: m / z (ESI): [M+H] + =667.2,t R =0.91 min.

[0285] Step 2: 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (150 mg, 0.225 mmol) was dissolved in methanol (3 mL). Paraformaldehyde (45.0 mg, 1.13 mmol), palladium on carbon (10 mg, 10% content, 60% water), and glacial acetic acid (0.1 mL) were added and stirred at 70 °C for 5 hours. After the completion of the reaction was confirmed by LCMS, the palladium on carbon was filtered, and the filtrate was mixed with silica gel and purified by column chromatography (dichloromethane / methanol = 100 / 7) to obtain 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,2-dimethyl-4-oxo-5,10-diaza-3-oxaundecan-10-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (130 mg, 85% yield) was obtained as a white solid. LCMS: m / z (ESI): [M+H] + =681.2,t R =0.93 min.

[0286] Step 3: 7-[dimethyl(oxo)-λ 5

[0047] [-methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,2-dimethyl-4-oxo-5,10-diaza-3-oxaundecan-10-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (130 mg, 0.191 mmol) was dissolved in a mixture of water (1 mL), methanol (1 mL), and tetrahydrofuran (1 mL). Lithium hydroxide monohydrate (40.1 mg, 0.955 mmol) was added and the mixture was stirred at 40°C for 16 hours. After completion of the reaction was detected by LCMS, the reaction mixture was used directly in the next step. LCMS: m / z (ESI): 667.4 [M+H] + =667.4,t R =0.76 min.

[0287] Step 4: To the reaction mixture from the previous step, hydrochloric acid in 1,4-dioxane (5 mL, 4 M) was added, and the mixture was stirred at 10°C for 4 hours. After the completion of the reaction was detected by LCMS, the solvent was directly spun onto a rotary evaporator. The resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% ammonium bicarbonate), flow rate: 70 mL / min, column temperature: 25°C) to obtain 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(4-aminobutyl)(methyl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (20 mg, 13% yield) was obtained as a white solid. LCMS: m / z (ESI): [M+H] + =567.2,t R =0.59min.

[0288] Step 5: 7-[dimethyl(oxo)-λ 5To a solution of [2-(2-methylphosphoryl]-3-{[(1S,3S)-3-[(4-aminobutyl)(methyl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (20 mg, 0.04 mmol) in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14.8 mg, 0.04 mmol) and N,N-diisopropylethylamine (0.03 mL, 0.18 mmol) were added sequentially, and the reaction was stirred at 60° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-5-methyl-2 5 -(trifluoromethyl)-1 1 The trifluoroacetate salt of H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z16) was obtained (5.88 mg, 30% yield). LCMS: m / z (ESI): [M+H] + =549.2,t R =0.67min. 1H NMR (400 MHz, CD3OD): δ 8.57 (s, 1H), 8.53 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.31 (dd, J = 8.4, 3.2 Hz, 1H), 4.25-4.31 (m, 1H), 3.91-4.04 (m, 1H), 3.24 - 3.11 (m, 1H), 2.86-2.91 (m, 2H), 2.78 (s, 1H), 2.72 (s, 2H), 2.52-2.57 (m, 1H), 2.38 - 2.22 (m, 2H), 2.14 - 1.70 (m, 12H), 1.57-1.66 (m, 1H), 1.29-1.37 (m, 1H).

[0289] [ka]

[0290] Step 1: N-[(benzyloxy)carbonyl]glycine (20 g, 95.6 mmol), tetrahydrofuran (130 mL), magnesium chloride (4.55 g, 47.8 mmol), carbonyldiimidazole (15.5 g, 95.6 mmol), and [(3-methoxy-1,3-dioxopropyl)oxy]potassium (12.2 g, 71.7 mmol) were added to a 250 mL three-neck flask in this order, and the reaction mixture was purged with nitrogen and refluxed at 70°C for 4 hours. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated, diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 3) to give benzyl [(1-methoxy-1,3-dioxobutyl-4-yl)amino]methanoate (3.7 g, 15% yield) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 7.42-7.26 (m, 5H), 5.12 (s, 2H), 4.21 (d, J = 5.2 Hz, 2H), 3.74 (s, 3H), 3.50 (s, 2H).

[0291] Step 2: [(1-methoxy-1,3-dioxobutyl-4-yl)amino]benzyl methanate (1.50 g, 5.66 mmol) was dissolved in dichloromethane (30 mL), and then diethylamine sulfur trifluoride (1.00 g, 6.22 mmol) was added dropwise at 0°C and stirred at 15°C for 16 hours. Then, diethylamine sulfur trifluoride (1.00 g, 6.22 mmol) was added at 15°C and stirred at 15°C for 4 hours. After detecting the completion of the reaction by LCMS, the reaction was quenched by adding water (20 mL), then extracted with ethyl acetate (20 mL × 3), dried with anhydrous sodium sulfate, and the concentrated crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50 * 250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25 ° C.) to obtain benzyl (3,3-difluoro-1-methoxy-1-oxobutyl-4-yl)amino]methanoate (0.15 g, 9% yield) as a yellow oil. LCMS: m / z (ESI): [M + H] + =288.0,t R =0.97min.

[0292] Step 3: Benzyl [(3,3-difluoro-1-methoxy-1-oxobutyl-4-yl)amino]methanoate (130 mg, 0.45 mmol) was dissolved in tetrahydrofuran (3 mL). Then, at 0 °C, a solution of lithium aluminum tetrahydrofuran (1 mL, 1 M) was added dropwise, and the reaction was stirred at 10 °C for 2 h. After completion of the reaction was confirmed by LCMS, it was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give benzyl [(2,2-difluoro-4-hydroxybutyl)amino]methanoate (100 mg, 85% yield) as a yellow oily crude product, which was used directly in the next step without purification. LCMS: m / z (ESI): [M+H] + =260.0,t R =0.88min.

[0293] Step 4: Benzyl [(2,2-difluoro-4-hydroxybutyl)amino]methanoate (120 mg, 0.46 mmol) was dissolved in dichloromethane (1 mL), pyridine (1 mL) and p-methylsulfonyl chloride (265 mg, 1.39 mmol) were added, and the mixture was stirred at 10 °C for 3 h. After detecting the completion of the reaction by LCMS, silica gel was directly added, and the mixture was mixed by rotary drying on an oil pump. The mixture was purified by silica gel column chromatography (dichloromethane 100%) to obtain 6,6-difluoro-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl 4-methylbenzenesulfonate (130 mg, 68% yield) as a yellow oil. LCMS: m / z (ESI): [M+H] + =414.0,t R =1.20min.

[0294] Step 5: In a 10 mL single-neck flask, add 7-[dimethyl(oxo)-λ 5 [2-(2-methylphosphoryl)-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (173 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then 4-methylbenzenesulfonate-6,6-difluoro-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl (120 mg, 0.29 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.45 mmol) were added. The system was stirred at 100 °C for 20 h. After the completion of the reaction was detected by LCMS, silica gel was added, and the sample was mixed by rotary drying on an oil pump. The mixture was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 7-[dimethyl(oxo)-λ 5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (81 mg, 38% yield) was obtained as a yellow oil. LCMS: m / z (ESI): [M+H] + =737.2,t R =0.96 min.

[0295] Step 6: 7-[dimethyl(oxo)-λ 5 [-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (90 mg, 0.12 mmol) was dissolved in a mixture of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL), then lithium hydroxide monohydrate (5.13 mg, 0.12 mmol) was added and the reaction was stirred at 40° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was filtered, and the filtrate was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% ammonium bicarbonate), flow rate: 70mL / min, column temperature: 25℃), and purified with 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (30 mg, 34% yield) as a white solid. LCMS: m / z (ESI): [M+H] += 723.2,t R =0.87min.

[0296] Step 7: In a 10 mL single-neck flask, add 7-[dimethyl(oxo)-λ5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (18 mg, 0.03 mmol) and trifluoroacetic acid (3 mL) were added. The mixture was stirred at 60 °C for 1.5 hours, and after completion of the reaction was confirmed by LCMS, the reaction mixture was spun down and 2,2-difluoro-4-{[(1S,3S)-3-[(4-{5-[(Z)-[dimethyl(oxo)-λ 5 -methylphosphoryl]methylene]-4-[(1Z)-ethylidene]-1H-pyrrol-3-yl}-5-(trifluoromethyl)pyrimidin-2-yl)amino]cyclopentyl]amino}butane-1-carbamic acid (14 mg, 96%) was obtained as a crude grey solid which was used directly in the next step without purification. LCMS: m / z (ESI): [M+H] + =589.2,t R =0.62 min.

[0297] Step 8: 2,2-difluoro-4-{[(1S,3S)-3-[(4-{5-[(Z)-[dimethyl(oxo)-λ 5 To a solution of [(1Z)-ethylidene]-1H-pyrrol-3-yl}-5-(trifluoromethyl)pyrimidin-2-yl)amino]cyclopentyl]amino}butane-1-carbamic acid (14 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.95 mg, 0.03 mmol) and N,N-diisopropylethylamine (0.02 mL, 0.12 mmol) in that order. After stirring at 60°C for 16 hours and detecting the completion of the reaction by LCMS, the reaction mixture was concentrated and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C), (41 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z19) (1.22 mg, 9% yield, trifluoroacetate salt) was obtained. LCMS: m / z (ESI): [M+H] + =571.2,t R =0.67min. 1 H NMR (400 MHz, CD3OD): δ 8.57-8.58 (m, 2H), 8.01 (s, 1H), 7.32 (d, J = 5.6 Hz, 1H), 4.16-4.18 (m, 1H), 3.86-3.87 (m, 1H), 3.47-3.49 (m, 1H), 2.89-2.93 (m, 2H), 2.70-2.73 (m, 1H), 2.48-2.27 (m, 4H), 1.98-2.02 (m, 6H), 1.81-1.86 (m, 2H), 1.28-1.29 (m, 2H).

[0298] [ka]

[0299] Step 1: At 25°C, carbon tetrabromide (981 mg, 3.74 mmol) and triphenylphosphine (1.24 g, 3.74 mmol) were added to a solution of 2-methylpropan-2-yl [(1-hydroxybutyl-4-yl)(methyl)amino]methanoate (400 mg, 1.97 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-methylpropan-2-yl [(1-bromobutyl-4-yl)(methyl)amino]methanoate (400 mg, 46% yield) as a colorless oil. LCMS: m / z(ESI):[M+H-56] + =210.0,t R =2.03 min.

[0300] Step 2: [(1-Bromobutyl-4-yl)(methyl)amino]methanoate-2-methylpropan-2-yl (240 mg, 0.90 mmol), 3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-7-[methyl(oxo)-λ5-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (447 mg, 0.90 mmol) were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (349 mg, 2.71 mmol) was added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (220 mg, 36% yield) as a colorless oil. LCMS: m / z (ESI): [M+H] += 681.4,tR =0.96 min.

[0301] Step 3: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (220 mg, 0.32 mmol) in methanol (8 mL) was added paraformaldehyde (145 mg, 1.62 mmol), acetic acid (244 mg, 1.89 mmol), and radium on carbon (20 mg, 10% content, 60% water content) at room temperature. The mixture was stirred at 80°C for 16 hours under a hydrogen atmosphere. After the completion of the reaction was confirmed by LCMS, 50 mL of aqueous solution was added to the reaction mixture, which was then extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to afford 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,2,5-trimethyl-4-oxo-5,10-diaza-3-oxaundecan-10-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (200 mg, 71% yield) as a colorless oil. LCMS: MS m / z (ESI): [M+H] + =695.7,t R =1.19 min.

[0302] Step 4: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,2,5-trimethyl-4-oxo-5,10-diaza-3-oxaundecan-10-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (200 mg, 0.29 mmol) was added to methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL) with lithium hydroxide hydrate (121 mg, 2.88 mmol). The mixture was stirred at 40° C. under a nitrogen atmosphere for 16 hours. After the completion of the reaction was confirmed by LCMS, the mixture was concentrated to dryness and the 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,2,5-trimethyl-4-oxo-5,10-diaza-3-oxaundecan-10-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (180 mg, 83% yield) was obtained as a crude white solid. LCMS:MS m / z(ESI):[M+H] + =681.4,t R =0.93 min.

[0303] Step 5: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,2,5-trimethyl-4-oxo-5,10-diaza-3-oxaundecan-10-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (180 mg, 0.26 mmol) in dioxane (4 mL) was added with dioxane hydrochloride (1.32 mL, 5.29 mmol, 4 mol / L). The mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, the mixture was concentrated and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25℃) with 7-[dimethyl(oxo)-λ 5-methylphosphoryl]-3-(2-{[(1S,3S)-3-(2,7-diazaoct-2-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (80 mg, 50% yield) as a white solid. LCMS: MS m / z (ESI): [M+H] + =581.2,t R =1.00min.

[0304] Step 6: At room temperature, 7-[dimethyl(oxo)-λ 5 To a solution of [[(1S,3S)-3-(2,7-diazaoct-2-yl)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid (70 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55 mg, 0.15 mmol) and N,N-diisopropylethylamine (78 mg, 0.61 mmol) were added in that order. The reaction was carried out at 60°C for 18 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, the mixture was concentrated and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25℃), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-5,10-dimethyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecan-11-one 2,2,2-trifluoroacetic acid (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-5,10-dimethyl-2 5 -(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclodecaphan-11-one(Z27) (26 mg, yield 36%) was obtained. LCMS:MS m / z(ESI):[M+H] + =563.2,t R =1.30min. 1 H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 9.50 - 9.00 (m, 1H), 8.62 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.97 (s, 1H), 7.23 (dd, J = 11.2, 1.2 Hz, 1H), 4.22 - 3.84 (m, 2H), 3.53 (s, 3H), 3.22 - 3.05 (m, 2H), 3.00 (s, 3H), 2.92 - 2.84 (m, 1H), 2.68 - 2.66 (m, 1H), 2.59 (d, J = 4.0 Hz, 2H), 2.45 - 2.37 (m, 1H), 2.17 - 2.08 (m, 2H), 1.91 - 1.49 (m, 11H).

[0305]

change

[0306] Step 1: Under a nitrogen atmosphere, methylmagnesium bromide (15.1 mL, 15.1 mmol) was slowly added dropwise to a solution of 2-methylpropan-2-yl 2-oxotetrahydropyrrole-1-carboxylate (2.00 g, 10.8 mmol) in tetrahydrofuran (30 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h. After detecting the completion of the reaction by spotting, the mixture was quenched by adding water (30 mL). The mixture was then extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-methylpropan-2-yl [(4-oxopentyl)amino]methanoate (1.20 g, 56% yield) as a colorless oil. 1 H NMR (400 MHz, CD3OD): δ 3.02 (t, J = 7.2 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.69 (p, J = 7.2 Hz, 1H), 1.43 (s, 9H).

[0307] Step 2: [(4-oxopentyl)amino]methanoic acid-2-methylpropan-2-yl (122 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL), and then isopropyl titanate (574 mg, 2.0 mmol), 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (250 mg, 0.51 mmol) were added, and the reaction mixture was stirred at 70° C. for 16 hours, then cooled to room temperature, and sodium cyanoborohydride (159 mg, 2.53 mmol) was added thereto, followed by stirring at 25° C. for 6 hours. After detecting the completion of the reaction by LCMS, the reaction solution was filtered to remove solid impurities, and the organic phase was concentrated to obtain the crude product. The crude product was then purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (270 mg, 79% yield) as a yellow oil. LCMS: m / z (ESI): [M+H] + =681.4,t R =0.99min.

[0308] Step 3: 7-[Dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxadecan-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (220 mg, 0.32 mmol) was dissolved in a mixture of water (2 mL), methanol (2 mL), and tetrahydrofuran (2 mL). Lithium hydroxide (1 water of crystallization, 68 mg, 1.62 mmol) was added, and the reaction mixture was stirred at 40° C. for 14 hours. After completion of the reaction was detected by LCMS, the reaction mixture was used directly in the next step. LCMS: m / z (ESI): [M+H]+ =667.4,t R =0.91 min.

[0309] Step 4: To the reaction mixture from Step 3, hydrogen chloride / 1,4-dioxane solution (5 mL, 4 M) was added, and the mixture was stirred at 40 °C for 4 hours. After the completion of the reaction was confirmed by LCMS, the solvent was directly spun onto a rotary evaporator to obtain the crude product. The crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50 x 250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25 °C) to obtain 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(5-aminopentyl-2-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (150 mg, 94% yield) as a white solid. LCMS: m / z(ESI):[M+H] + =567.2,t R =0.87min.

[0310] Step 5: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(5-aminopentyl-2-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (70 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) was added 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (47 mg, 0.12 mmol) and N,N-diisopropylethylamine (64 mg, 0.50 mmol) sequentially, and the reaction was stirred at 80° C. for 18 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,43 S)-1 7 -(dimethylphosphoryl)-6-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-6-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z58) (10.50 mg, 15% yield, trifluoroacetate salt) was obtained. LCMS: m / z (ESI): [M+H] + =549.2,t R =0.69min. 1 H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 8.51 - 8.36 (m, 1H), 7.97 (s, 1H), 7.45 - 7.29 (m, 1H), 4.42 - 4.11 (m, 1H), 3.95 - 3.74 (m, 1H), 3.30 - 3.17 (m, 1H), 3.13 - 2.99 (m, 1H), 2.98 - 2.74 (m, 2H), 2.66 - 2.50 (m, 1H), 2.36 - 2.27 (m, 1H), 2.27 - 2.19 (m, 1H), 2.15 - 2.05 (m, 1H), 2.03 - 1.96 (m, 6H), 1.95 - 1.85 (m, 1H), 1.80 - 1.66 (m, 2H), 1.56 - 1.50 (m, 1H), 1.47 - 1.34 (m, 1H), 1.26 (t, J = 6.0 Hz, 3H).

[0311] [ka]

[0312] Step 1: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (200 mg, 0.71 mmol) in N,N-dimethylformamide (6 mL) was added [(6-bromohexyl)amino]methanoate-2-methylpropan-2-yl (353 mg, 0.71 mmol) and N,N-diisopropylethylamine (460 mg, 3.57 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (180 mg, 33% yield) as a colorless oil. LCMS: m / z (ESI): [M+H] + =694.7,t R =1.33 min.

[0313] Step 2: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (180 mg, 0.26 mmol) in methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL) was added with lithium hydroxide hydrate (109 mg, 2.59 mmol). The mixture was stirred at 40° C. under a nitrogen atmosphere for 16 hours. After completion of the reaction was confirmed by LCMS, the mixture was concentrated to dryness to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (180 mg, crude product) as a white solid crude product. LCMS:MS m / z(ESI):[M+H] + =681.3,t R =0.87min.

[0314] Step 3: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (160 mg, 0.24 mmol) in methanol (4 mL) was added methanol hydrochloride (1.12 mL, 4 mol / L) at room temperature. The reaction mixture was stirred at 40° C. under a nitrogen atmosphere for 16 hours. After detecting the completion of the reaction by LCMS, the concentrated hydrochloric acid was removed, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to obtain 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6-aminohexyl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (80mg, 56% yield) as a white solid. LCMS:MS m / z(ESI):[M+H] + =581.4,t R =0.68min.

[0315] Step 4: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6-aminohexyl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (70 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added in sequence with 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55.2 mg, 0.15 mmol) and N,N-diisopropylethylamine (78 mg, 0.61 mmol). The reaction was carried out at 60°C for 16 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, the mixture was concentrated and the obtained crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,12-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclotridecan-13-one 2,2,2-trifluoroacetic acid (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,5,12-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclotridecaphan-13-one (Z59) (14 mg, 18% yield) was obtained. LCMS: MS m / z (ESI): [M+H] + =563.0,t R =0.68min. 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.62 (s, 1H), 8.60 - 8.57 (m, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.46 (dd, J = 8.4, 3.2 Hz, 1H), 4.27 - 4.20 (m, 1H), 3.73 - 3.71 (m, 1H), 3.63 - 3.55 (m, 2H), 3.19 - 3.14 (m, 1H), 2.95 - 2.92 (m, 2H), 2.18 - 2.05 (m, 2H), 2.01- 1.89 (m, 7H), 1.82- 1.74 (m, 1H), 1.69 - 1.48 (m, 9H).

[0316] [ka]

[0317] Step 1: At room temperature, (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 To a solution (5 mL) of H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecyclododecan-12-one 2,2,2-trifluoroacetate (20 mg, 0.030 mmol), paraformaldehyde (20 mg, 0.22 mmol) and isopropyl titanate (10.3 mg, 0.036 mmol) were added in this order. The mixture was stirred at 60°C for 14 hours under a nitrogen atmosphere. After the reaction mixture was cooled to 30°C, sodium cyanoborohydride (20 mg, 0.318 mmol) was added and the mixture was kept at this temperature for 4 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (41 S,4 3 S)-1 7 -(dimethylphosphoryl)-5-methyl-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecyclododecan-12-one-2,2,2-trifluoroacetate (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-5-methyl-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z60) (7.8 mg, 38% yield) was obtained. LCMS: MS m / z (ESI): [M+H] + =565.2,t R =0.73min. 1 H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 8.50 - 8.28 (m, 1H), 7.94 - 7.89 (m, 1H), 7.69 - 7.50 (m, 1H), 4.28 - 4.15 (m, 1H), 3.99 - 3.68 (m, 6H), 3.52 - 3.42 (m, 1H), 3.24 - 3.14 (m, 1H), 2.97 - 2.85 (m, 3H), 2.78 - 2.59 (m, 1H), 2.37 - 2.15 (m, 3H), 2.14 - 1.92 (m, 7H), 1.87 - 1.70 (m, 2H).

[0318] [ka]

[0319] Step 1: To a solution of 2-methylpropan-2-yl [(6-bromohexyl)amino]methanoate (300 mg, 1.28 mmol) in N,N-dimethylformamide (8 mL) was added benzyl {[(3S)-hexahydropyridin-3-yl]amino}methanoate (395 mg, 1.41 mmol) and N,N-diisopropylethylamine (662 mg, 5.12 mmol) at 25° C. Under a nitrogen atmosphere, the reaction mixture was stirred at 80° C. for 6 hours. After detecting the completion of the reaction by LCMS, water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1 to 10 / 1) to give benzyl {[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)hexahydropyridin-3-yl]amino}methanoate (555 mg, 92% yield) as a colorless oil. LCMS: m / z (ESI): [M+H] + =434.2,t R =1.57min.

[0320] Step 2: Benzyl {[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)hexahydropyridin-3-yl]amino}methanoate (555 mg, 1.17 mmol) was dissolved in methanol (10 mL), and palladium on carbon (60 mg, 10% content, 60% water content) was added. The reaction mixture was stirred at 25°C for 3 hours under a hydrogen atmosphere. After the completion of the reaction was detected by LCMS, the reaction mixture was filtered and concentrated to give 2-methylpropan-2-yl ({6-[(3S)-3-aminohexahydropyridin-1-yl]hexyl}amino)methanoate (350 mg, crude product) as a colorless oil. LCMS: m / z (ESI): [M+H] + =300.0,t R =0.98min.

[0321] Step 3: At room temperature, 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxo)-λ5-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (404 mg, 0.94 mmol) and N,N-diisopropylethylamine (483 mg, 3.74 mmol) were added sequentially to a solution of {6-[(3S)-3-aminohexahydropyridin-1-yl]hexyl}amino (280 mg, 0.94 mmol) in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, an aqueous solution (40 mL) was added to the reaction mixture, which was then extracted with dichloromethane (50 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1 to 10 / 1) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (473 mg, 72% yield) as a yellow oil. LCMS:MS m / z (ESI): [M+H] + =695.4,t R =1.15min.

[0322] Step 4: At room temperature, to a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (243 mg, 0.35 mmol) in methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL) was added lithium hydroxide hydrate (74 mg, 1.75 mmol), and the reaction mixture was stirred at 40° C. under nitrogen atmosphere for 14 hours. After completion of the reaction was confirmed by LCMS, the mixture was concentrated to dryness to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (320 mg, crude product, purity 90%) as a yellow solid. LCMS:MS m / z(ESI):[M+H] + =680.8,t R =1.21 min.

[0323] Step 5: At room temperature, a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(2,2-dimethyl-4-oxo-5-aza-3-oxaundecan-11-yl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (420 mg, crude product, purity 90%) in methanol (4 mL) was added with hydrogen chloride / methanol solution (6 mL, 4 mol / L). The reaction mixture was stirred at 40° C. under a nitrogen atmosphere for 4 hours. After detecting the completion of the reaction by LCMS, the mixture was concentrated to remove the hydrochloric acid, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to obtain 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(6-aminohexyl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (275mg, 85% yield) as a white solid. LCMS: MS m / z (ESI): [M+H] + =581.4,t R =0.64min.

[0324] Step 6: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(3S)-1-(6-aminohexyl)hexahydropyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (100 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) was added with 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (65.4 mg, 0.17 mmol) and N,N-diisopropylethylamine (88.9 mg, 0.69 mmol) in that order, and the reaction mixture was reacted at 80°C for 16 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, the mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,11-diaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-piperidinecyclododecan-12-one (4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,11-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-piperidinacyclododecaphan-12-one (Z61) (18.90 mg, 19% yield, trifluoroacetate salt) was obtained. LCMS: MS m / z (ESI): [M+H] + =563.2,t R =0.67min. 1H NMR (400 MHz, CD3OD): δ 8.64 (s, 1H), 8.22 (dd, J = 8.4, 1.2 Hz, 1H), 7.91 (s, 1H), 7.65 (dd, J = 8.4, 3.6 Hz, 1H), 4.22 - 4.02 (m, 1H), 4.01 - 3.49 (m, 3H), 3.29 - 3.21 (m, 1H), 3.19 - 3.09 (m, 2H), 2.95 - 2.87 (m, 1H), 2.87 - 2.69 (m, 1H), 2.16 - 1.89 (m, 9H), 1.80 - 1.27 (m, 9H).

[0325] [ka]

[0326] Step 1: To a solution of 2-methylpropan-2-yl {[2-(tetrahydro-1H-pyrrol-3-yl)ethyl]amino}methanoate (200 mg, 0.93 mmol) in N,N-dimethylformamide (6 mL) was added benzyl [(2-bromoethyl)amino]methanoate (241 mg, 0.93 mmol) and N,N-diisopropylethylamine (602 mg, 4.67 mmol) at 25° C. Under a nitrogen atmosphere, the reaction mixture was stirred at 80° C. for 5 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-methylpropan-2-yl ({2-[1-(3-oxo-1-phenyl-4-aza-2-oxahexan-6-yl)tetrahydro-1H-pyrrol-3-yl]ethyl}amino)methanoate (218 mg, 54% yield) as a colorless oil. LCMS: m / z (ESI): [M+H] + =392.4,t R =1.40min.

[0327] Step 2: At room temperature, Pd / C (20 mg, 10% content, 60% water content) was added to ({2-[1-(3-oxo-1-phenyl-4-aza-2-oxahexan-6-yl)tetrahydro-1H-pyrrol-3-yl]ethyl}amino)methanoate-2-methylpropan-2-yl (200 mg, 0.51 mmol) in methanol. The reaction mixture was stirred at 25° C. for 5 hours under a hydrogen atmosphere. After the completion of the reaction was detected by LCMS, the mixture was concentrated to dryness to obtain ({2-[1-(2-aminoethyl)tetrahydro-1H-pyrrol-3-yl]ethyl}amino)methanoate-2-methylpropan-2-yl (100 mg, 53% yield) as a white solid crude product. LCMS: MS m / z (ESI): [M+H] + =258.2,t R =0.47min.

[0328] Step 3: At room temperature, ({2-[1-(2-aminoethyl)tetrahydro-1H-pyrrol-3-yl]ethyl}amino)methanoic acid-2-methylpropan-2-yl (100 mg, 0.39 mmol) in N,N-dimethylformamide (6 mL) was added with 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxo)-λ5-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (168 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 mg, 1.17 mmol). Under a nitrogen atmosphere, the reaction mixture was stirred at 80° C. for 16 hours. After detecting the completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-[2-({2-[3-(2,2-dimethyl-4-oxo-5-aza-3-oxaheptyl-7-yl)tetrahydro-1H-pyrrol-1-yl]ethyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid methyl ester (220 mg, 78% yield) as a colorless oil. LCMS: MS m / z (ESI): [M+H] + =653.2,t R =1.41min.

[0329] Step 4: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-[2-({2-[3-(2,2-dimethyl-4-oxo-5-aza-3-oxaheptyl-7-yl)tetrahydro-1H-pyrrol-1-yl]ethyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid methyl ester (220 mg, 0.34 mmol) in methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL) was added with lithium hydroxide hydrate (141 mg, 3.37 mmol). The mixture was stirred at 40° C. under a nitrogen atmosphere for 16 hours. After the completion of the reaction was confirmed by LCMS, the mixture was concentrated to dryness to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-[2-({2-[3-(2,2-dimethyl-4-oxo-5-aza-3-oxaheptyl-7-yl)tetrahydro-1H-pyrrol-1-yl]ethyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid (200 mg) as a crude white solid. LCMS:MS m / z(ESI):[M+H] + =638.7,t R =1.11 min.

[0330] Step 5: At room temperature, 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-[2-({2-[3-(2,2-dimethyl-4-oxo-5-aza-3-oxaheptyl-7-yl)tetrahydro-1H-pyrrol-1-yl]ethyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid (200 mg, 0.31 mmol) in 1,4-dioxane (4 mL) was added with 1,4-dioxane hydrochloric acid (0.78 mL, 3.13 mmol, 4 mol / L). The mixture was stirred at 40° C. for 3 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, the crude product was concentrated and purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to obtain 3-[2-({2-[3-(2-aminoethyl)tetrahydro-1H-pyrrol-1-yl]ethyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxo)-λ5-methylphosphoryl]-1H-indole-6-carboxylic acid (70mg, 37% yield) as a white solid. LCMS: MS m / z (ESI): [M+H] + =538.8,t R =0.98min.

[0331] Step 6: At room temperature, 3-[2-({2-[3-(2-aminoethyl)tetrahydro-1H-pyrrol-1-yl]ethyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxo)-λ5-methylphosphoryl]-1H-indole-6-carboxylic acid (70 mg, 0.11 mmol) in N,N-dimethylformamide (5 mL) was added with 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51 mg, 0.13 mmol) and N,N-diisopropylethylamine (43 mg, 0.33 mmol) in that order. The reaction was carried out at 65 °C under a nitrogen atmosphere for 3 hours. After detecting the completion of the reaction by LCMS, the mixture was concentrated and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25℃). 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,9-diaza-1(3,6)-indole-2(4,2)-pyrimidin-6(1,3)-pyrrolidinecyclodecan-10-one 1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-3,9-diaza-1(3,6)-indola-2(4,2)-pyrimidina-6(1,3)-pyrrolidinacyclodecaphan-10-one (Z56) (6.0 mg, 10% yield, trifluoroacetate salt) was obtained. LCMS: MS m / z (ESI): [M+H] + =521.3,t R =0.71min. 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.58 - 8.43 (m, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 4.09 - 3.82 (m, 3H), 3.63 - 3.36 (m, 4H), 3.18 - 2.98 (m, 2H), 2.78 - 2.57 (m, 1H), 2.49 - 2.35 (m, 1H), 2.23 - 1.99 (m, 7H), 1.70 - 1.14 (m, 3H).

[0332] [ka]

[0333] Step 1: To a 50 mL one-neck flask, imidazole (140 mg, 2.05 mmol), triphenylphosphine (431 mg, 1.64 mmol), and iodine (521 mg, 2.05 mmol) were added in order to a solution of 2-methylpropan-2-yl (1-hydroxy-6-aza-3-oxaheptyl)methanoate (300 mg, 1.37 mmol) in dichloromethane (10 mL). The mixture was stirred at 5°C under a nitrogen atmosphere for 2 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was diluted with water (20 mL), extracted with dichloromethane (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 2-methylpropan-2-yl (1-iodo-6-aza-3-oxaheptyl-6-yl)methanoate (314 mg, 70% yield) as a pale yellow oil. LCMS: m / z (ESI): [M-100+H] + =230.0,t R =1.20min.

[0334] Step 2: In a 50 mL one-neck flask, add a solution of (1-iodo-6-aza-3-oxaheptyl-6-yl)methanoate-2-methylpropan-2-yl (350 mg, 1.06 mmol) in N,N-dimethylformamide (5 mL) to 7-[dimethyl(oxo)-λ 5[-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (553 mg, 1.12 mmol) and N,N-diisopropylethylamine (0.88 mL, 5.32 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. After the completion of the reaction was confirmed by LCMS, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:6) and purified to obtain 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3,8-dioxadecyl-10-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (610 mg, 82% yield) was obtained as a pale yellow solid. LCMS: m / z (ESI): [M+H] + =697.4,t R =0.97min.

[0335] Step 3: 7-[dimethyl(oxo)-λ 5

[0047] -3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3,8-dioxadecyl-10-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (610 mg, 0.88 mmol) was dissolved in a mixture of water (3 mL), methanol (3 mL), and tetrahydrofuran (3 mL). Lithium hydroxide monohydrate (184 mg, 4.38 mmol) was added, and the mixture was stirred at 40 °C for 16 hours. After the completion of the reaction was confirmed by LCMS, 7-[dimethyl(oxo)-λ 5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3,8-dioxadecyl-10-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid, which was used directly in the next step. LCMS: m / z (ESI): [M+H] + =683.3,t R =0.86min.

[0336] Step 4: To the reaction mixture from the previous step, a solution of hydrochloric acid in methanol (5 mL, 4 M) was added and stirred at 5°C for 5 hours. After completion was confirmed by LCMS, the reaction mixture was concentrated and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C) with 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-(6-aza-3-oxaheptyl-1-ylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (260 mg, 51% yield over two steps) as a white solid. LCMS: m / z (ESI): [M+H] + =582.6,t R =0.92 min.

[0337] Step 5: 7-[dimethyl(oxo)-λ 5To a solution of [2-(2-methylphosphoryl]-3-{[(1S,3S)-3-(6-aza-3-oxaheptyl-1-ylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (260 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (187 mg, 0.49 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.23 mmol) were added in that order. The mixture was stirred at 60°C for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C). 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-11-methyl-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-11-methyl-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z64) (120 mg, 48% yield, trifluoroacetate salt) was obtained as a pale yellow solid. LCMS: m / z (ESI): [M+H] + =564.8,t R =0.97min. 1H NMR (400 MHz, CD3OD): δ 8.57 (s, 1H), 8.43 (br, 1H), 7.96 (s, 1H), 7.44 (dd, J = 8.4, 3.2 Hz, 1H), 4.36-4.39 (m, 1H), 3.88-3.91 (m, 1H), 3.78-3.83 (m, 2H), 3.53-3.72 (m, 3H), 3.67-3.42 (m, 1H), 3.23-3.61 (m, 1H), 3.13 (s, 3H), 2.65-2.71 (m, 1H), 2.32-2.39 (m, 1H), 2.21-2.23 (m, 1H), 2.14 - 1.62 (m, 10H).

[0338] [ka]

[0339] Step 1: In a 10 mL single-neck flask, add (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-11-methyl-2 5 -(trifluoromethyl)-1 1 To a solution of H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one trifluoroacetate (35 mg, 0.06 mmol) in tetrahydrofuran (3 mL), paraformaldehyde (9.30 mg, 0.31 mmol) and tetraisopropyl titanate (35.2 mg, 0.12 mmol) were added in sequence. The reaction mixture was stirred at 70°C for 16 hours, cooled to 35°C, and sodium cyanoborohydride (7.79 mg, 0.12 mmol) was added and stirred at 35°C for 3 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,43 S)-1 7 -(dimethylphosphoryl)-5,11-dimethyl-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one ((4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-5,11-dimethyl-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z63) (2 mg, 6% yield, trifluoroacetate salt). LCMS: m / z (ESI): [M+H] + =579.2,t R =0.77min. 1 H NMR (400 MHz, CD3OD): δ 8.24-8.58 (m, 2H), 7.88-8.01 (m, 1H), 7.41-7.43 (m, 1H), 4.11-4.18 (m, 1H), 3.94-3.97 (m, 1H), 3.79-3.85 (m, 3H), 3.66-3.70 (m, 2H), 3.36-3.41 (m, 1H), 3.13-3.18 (m, 4H), 2.86 (s, 2H), 2.55-2.73 (m, 2H), 2.25-2.32 (m, 3H), 1.82-1.97 (m, 9H).

[0340] [ka]

[0341] Step 1: To a solution of 7-bromo-1H-indole-6-carboxylic acid methyl ester (1.0 g, 3.9 mmol) in N,N-dimethylformamide (10 mL) at 25 °C, tetrakis(triphenylphosphine)palladium (0.45 g, 0.39 mmol) and zinc cyanide (0.46 g, 3.9 mmol) were added. Nitrogen was bubbled through the mixture for 1 minute, and the reaction was performed in a microwave oven at 150 °C for 1 hour. After completion of the reaction was confirmed by LCMS, water (20 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 7-cyano-1H-indole-6-carboxylic acid methyl ester (yellow solid, 800 mg, 81% yield). LCMS: m / z (ESI): 201.2 [M+H] + ,t R =1.22 min.

[0342] Step 2: To a solution of 7-cyano-1H-indole-6-carboxylic acid methyl ester (800 mg, 4.0 mmol) in N,N-dimethylformamide (10 mL) was added N-iodosuccinimide (1.35 g, 6.0 mmol) at 25 °C. The mixture was purged with nitrogen and stirred at 40 °C for 3 hours. The completion of the reaction was confirmed by LCMS. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with saturated brine (40 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 7-cyano-3-iodo-1H-indole-6-carboxylic acid methyl ester (off-white solid, 740 mg, 51% yield). LCMS: m / z (ESI): 327.0 [M+H] + ,t R =1.95min.

[0343] Step 3: To a solution of 7-cyano-3-iodo-1H-indole-6-carboxylic acid methyl ester (740 mg, 2.27 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (871 mg, 6.81 mmol) in tetrahydrofuran (15 mL) was added tris(dibenzylideneacetone)dipalladium (312 mg, 0.34 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (108 mg, 0.227 mmol), and triethylamine (689 mg, 6.81 mmol) in that order at 25 °C. The atmosphere was purged with nitrogen and the reaction was continued at 90 °C for 14 hours. Completion of the reaction was confirmed by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 6-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carbonitrilemethane (yellow solid, 600 mg, 81% yield). LCMS: m / z (ESI): 327.2 [M+H]. + ,t R =1.26 min.

[0344] Step 4: To a solution of 6-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carbonitrilemethane (600 mg, 1.84 mmol) and {[(1S,3S)-3-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl]amino}methanoate-2-methylpropan-2-yl (583 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was added a solution of chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (102 mg, 0.153 mmol) and potassium phosphate (976 mg, 4.6 mmol) in water (2 mL) at 25 °C. The mixture was purged with nitrogen and reacted at 60 °C for 14 hours. The reaction was complete as determined by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 7-cyano-3-(2-{[(1S,3S)-3-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (yellow oil, 580 mg, 69% yield). LCMS: m / z (ESI): 544.8 [M+H] + ,t R =1.66min.

[0345] Step 5: At 25° C., trifluoroacetic acid (2.5 mL) was added to a solution of 7-cyano-3-(2-{[(1S,3S)-3-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (500 mg, 0.92 mmol) in dichloromethane (5 mL). The reaction was continued at 20° C. for 3 hours, and the completion of the reaction was detected by LCMS. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, which was then extracted with a mixture of dichloromethane and methanol (5:1) (50 mL x 6). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-cyano-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (yellow oil, 500 mg, 75% purity, 92% yield) as a crude product. LCMS: MS m / z (ESI): 445.2 [M+H] + ,t R =0.79 min.

[0346] Step 6: To a solution of 7-cyano-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.225 mmol) in N,N-dimethylformamide (2 mL) was added [(4-bromobutyl)amino]methanoate-2-methylpropan-2-yl (56 mg, 0.225 mmol) and N,N-diisopropylethylamine (116 mg, 0.9 mmol) sequentially at room temperature. The mixture was purged with nitrogen and stirred at 80 °C for 16 hours. The completion of the reaction was confirmed by LCMS. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 10 / 1) to give 7-cyano-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (yellow oil, 70 mg, 40% yield). LCMS: MS m / z (ESI): 615.8 [M+H] + ,t R =1.28min.

[0347] Step 7: To a solution of 7-cyano-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (70 mg, 0.09 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (19.0 mg, 0.45 mmol) in water (3 mL). The mixture was stirred at 40 °C for 12 h, and the reaction was complete as determined by LCMS. The reaction mixture was concentrated directly, and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18-08, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% ammonium bicarbonate), flow rate: 70 mL / min, column temperature: 25°C) to give 7-cyano-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (white solid, 30 mg, 55% yield). LCMS: MS m / z (ESI): 602.2 [M+H] + ,t R =0.86min.

[0348] Step 8: To a solution of 7-cyano-3-(2-{[(1S,3S)-3-[(2,2-dimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (20 mg, 0.033 mmol) in dichloromethane (0.9 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 15° C. for 45 minutes. After completion of the reaction was confirmed by LCMS, N,N-diisopropylethylamine was added to the reaction mixture to adjust the pH to 8. Concentration gave 7-cyano-3-(2-{[(1S,3S)-3-[(4-aminobutyl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (yellow oil, 12 mg, 72% yield). The crude product was used directly in the next step of the reaction. LCMS: MS m / z (ESI): 502.0 [M+H] + ,t R =1.20min.

[0349] Step 9: To a solution of 7-cyano-3-(2-{[(1S,3S)-3-[(4-aminobutyl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (12 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15 mg, 0.04 mmol) and N,N-diisopropylethylamine (21 mg, 0.16 mmol) were added sequentially. The mixture was stirred at 80 °C for 14 h, and the completion of the reaction was confirmed by LCMS. After concentration, the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18-08, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% ammonium bicarbonate), flow rate: 70mL / min, column temperature: 25℃), (4 1 S,4 3 S)-11-oxa-2 5 -(trifluoromethyl)-1 1H-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-1 7 -carbonitrile (4 1 S,4 3 S)-11-oxo-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphane-1 7 -carbonitrile (Z23, 0.8 mg, 7% yield). LCMS: MS m / z (ESI): 484.2 [M+H] + ,t R =0.84min. 1 H NMR (400 MHz, CD3OD): δ 8.73 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 7.96 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 4.18-4.13 (m, 1H), 3.28-3.23 (m, 1H), 3.11-3.00 (m, 1H), 2.91-2.80 (m, 1H), 2.52-2.48 (m, 1H), 2.34-2.08 (m, 4H), 1.84-1.73 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.39 (m, 5H).

[0350] [ka]

[0351] Step 1: Under a nitrogen atmosphere, 2-methylpropan-2-yl [(4-hydroxybutyl)(methyl)amino]methanoate (100 mg, 0.49 mmol), iodine (125 mg, 0.49 mmol), and imidazole (50 mg, 0.74 mmol) were added sequentially to a solution of triphenylphosphine (129 mg, 0.49 mmol) in dichloromethane (3 mL) at 0 °C. After stirring at 0 °C for 5 minutes, the mixture was warmed to room temperature and stirred at room temperature for 4 hours. After completion of the reaction by LCMS, the mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-methylpropan-2-yl [(4-iodobutyl)(methyl)amino]methanoate (120 mg, 78% yield) as a colorless oil. LCMS: m / z (ESI): 258.0 [M+H-56] + ,t R =1.63 min.

[0352] Step 2: 7-[Dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (27 mg, 0.054 mmol) was dissolved in N,N-dimethylformamide (2 mL). [(4-iodobutyl)(methyl)amino]methanoate-2-methylpropan-2-yl (20 mg, 0.065 mmol) and N,N-diisopropylethylamine (28 mg, 0.218 mmol) were added sequentially. The mixture was stirred at 80 °C for 16 hours, and the reaction was complete as determined by LCMS. The reaction mixture was filtered to remove solid impurities, and the organic phase was concentrated to give the crude product, which was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (yellow solid, 28 mg, 75% yield). LCMS: m / z (ESI): 681.3 [M+H] + ,t R =1.17min.

[0353] Step 3: 7-[Dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (110 mg, 0.162 mmol) was dissolved in a mixture of water (2 mL), methanol (2 mL), and tetrahydrofuran (2 mL). Lithium hydroxide (1 water of crystallization, 34 mg, 0.808 mmol) was added. The mixture was stirred at 40 °C for 6 hours. After the completion of the reaction was detected by LCMS, the solvent was removed by rotary evaporation to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (yellow solid, 110 mg, 94% yield) as a crude product, which was used directly in the next step. LCMS: m / z (ESI): 667.4 [M+H] + ,t R =1.04min.

[0354] Step 4: 7-[Dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(2,2,5-trimethyl-4-oxo-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (110 mg, 0.164 mmol) was added to a hydrogen chloride / methanol solution (5 mL, 4 M), and the mixture was stirred at 40° C. for 4 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was spun dry and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to give 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-{[4-(methylamino)butyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (white solid, 80mg, 94% yield). LCMS: m / z (ESI): 567.3 [M+H] + ,t R =0.83 min.

[0355] Step 5: To a solution of 7-[dimethyl(oxo)-λ5-methylphosphoryl]-3-(2-{[(1S,3S)-3-{[4-(methylamino)butyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (60 mg, 0.106 mmol) in N,N-dimethylformamide (5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (40 mg, 0.106 mmol) and N,N-diisopropylethylamine (68 mg, 0.530 mmol) were added sequentially. The mixture was stirred at 80 °C for 4 h, and the completion of the reaction was confirmed by LCMS. After concentration, the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25℃), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z62, 16 mg, 28% yield, trifluoroacetate salt) was obtained. LCMS: m / z (ESI): 549.2 [M+H] + ,t R =0.84min. 1H NMR (400 MHz, CD3OD): δ 8.72-8.36 (m, 2H), 8.05-7.89 (m, 1H), 7.36-7.19 (m, 1H), 3.86-3.73 (m, 1H), 3.23-3.13 (m, 1H), 3.11 (s, 3H), 3.08-2.98 (m, 1H), 2.83-2.63 (m, 3H), 2.41-2.06 (m, 4H), 2.00-1.55 (m, 12H).

[0356] [ka]

[0357] Step 1: At 5°C, a solution of methyl 4-((benzyloxy)carbonyl)amino)-3-oxobutanoate (5.0 g, 18.9 mmol) in tetrahydrofuran (100 mL) was added with a solution of lithium aluminum hydride in tetrahydrofuran (28.3 mL, 1 M, 28.3 mmol). The reaction mixture was stirred at 5°C for 2 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, saturated aqueous ammonium chloride (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give benzyl 2,4-dihydroxybutylcarbamate (1.2 g, 27% yield) as a colorless oil. LCMS: m / z (ESI): 239.8 [M+H] + ,t R =0.99min.

[0358] Step 2: At 5 °C, imidazole (0.68 g, 10.04 mmol) and tert-butyldiphenylchlorosilane (1.38 g, 5.02 mmol) were added to a solution of benzyl (2,4-dihydroxybutyl)carbamate (1.2 g, 5.02 mmol) in dichloromethane (50 mL). The mixture was stirred at 5 °C for 3 h under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give benzyl (4-((tert-butyldiphenylsilyl)oxy)-2-hydroxybutyl)carbamate (2.2 g, 92% yield) as a colorless oil. LCMS: m / z(ESI): 400.2 [M+H] + ,t R =1.69 min.

[0359] Step 3: Benzyl (4-((tert-butyldiphenylsilyl)oxy)-2-hydroxybutyl)carbamate (2.2 g, 4.61 mmol) was dissolved in dichloromethane (30 mL). Diethylaminosulfur trifluoride (1.1 g, 6.92 mmol) was then added slowly at 0 °C, and the reaction mixture was stirred at 5 °C for 3 h. After the completion of the reaction was detected by TLC, it was quenched by adding water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 1 / 1) to give benzyl (4-((tert-butyldiphenylsilyl)oxy)-2-fluorobutyl)carbamate (0.7 g, 29% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.80 - 7.18 (m, 16H), 5.04 (s, 2H), 4.77 (d, J = 50.4 Hz, 1H), 3.74 (d, J = 5.6 H, 2H), 3.32 - 3.22 (m, 2H), 1.85 - 1.70 (m, 2H), 0.99 (s, 9H).

[0360] Step 4: Benzyl (4-((tert-butyldiphenylsilyl)oxy)-2-fluorobutyl)carbamate (700 mg, 1.46 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium fluoride (888 mg, 5.84 mmol) was added. The reaction was stirred at 5° C. for 18 hours. After the completion of the reaction was detected by LCMS, water (20 mL) was added and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=15 / 1 to 0 / 1) to give benzyl (2-fluoro-4-hydroxybutyl)carbamate (300 mg, 85% yield) as a colorless oil. LCMS: m / z (ESI): 242.0 [M+H] + ,t R =1.13 min.

[0361] Step 5: In a 50 mL single-neck flask, benzyl (2-fluoro-4-hydroxybutyl)carbamate (300 mg, 1.24 mmol) was dissolved in dichloromethane (10 mL), and imidazole (126 mg, 1.86 mmol), triphenylphosphine (390 mg, 1.50 mmol), and elemental iodine (381 mg, 1.50 mmol) were added. The reaction mixture was stirred at 10 °C for 1 h. After detecting the completion of the reaction by TLC spot, silica gel was directly added, and the mixture was dried by rotary evaporation on an oil pump. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to obtain benzyl (2-fluoro-4-iodobutyl)carbamate (330 mg, 76% yield) as a colorless oil.

[0362] Step 6: 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (220 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (5 mL), and benzyl (2-fluoro-4-iodobutyl)carbamate (156 mg, 0.44 mmol) and N,N-diisopropylethylamine (286 mg, 2.20 mmol) were added. The mixture was stirred at 100° C. for 18 hours. After detecting the completion of the reaction by LCMS, silica gel was directly added, and the sample was mixed by rotary drying with an oil pump. The mixture was then purified by column chromatography (dichloromethane / methanol = 40 / 1 to 5 / 1) to obtain methyl 3-(2-((1S,3S)-3-((benzyloxy)carbonyl)amino)-3-fluorobutylamino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (290 mg, 92% yield) as a white solid. LCMS: m / z (ESI): 719.2 [M+H] + ,t R =1.12 min.

[0363] Step 7: Methyl 3-(2-((1S,3S)-3-((benzyloxy)carbonyl)amino)-3-fluorobutylamino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (290 mg, 0.40 mmol) was dissolved in a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL), and lithium hydroxide monohydrate (84 mg, 2.00 mmol) was added. The reaction was stirred at 40° C. for 18 hours, and after completion of the reaction was detected by LCMS, the reaction was concentrated to give 3-(2-((1S,3S)-3-((benzyloxy)carbonyl)amino)-3-fluorobutylamino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg) as a crude white solid. LCMS: m / z(ESI): 705.2 [M+H] + ,t R =0.94 min.

[0364] Step 8: To a reaction flask of 3-(2-((1S,3S)-3-((benzyloxy)carbonyl)amino)-3-fluorobutylamino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 0.43 mmol) was added trifluoroacetic acid (5 mL) and stirred at 60 °C for 3 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to obtain 3-(2-((1S,3S)-3-((4-amino-3-fluorobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (140mg, 57% yield, trifluoroacetate salt) as a white solid. LCMS: m / z (ESI): 571.2 [M+H]+ ,t R =0.97min.

[0365] Step 9: At room temperature, 3-(2-((1S,3S)-3-((4-amino-3-fluorobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (70 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added in this order with 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55 mg, 0.15 mmol) and N,N-diisopropylethylamine (78 mg, 0.61 mmol). The reaction was carried out at 60°C for 18 hours under a nitrogen atmosphere. After the completion of the reaction was confirmed by LCMS, the mixture was concentrated and the resulting solution (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecan-11-one was obtained as a crude product.

[0366] Step 10: The crude product obtained in the previous step was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to give two isomeric compounds. One of the isomeric compounds was (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S,8R)-17 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 Arbitrarily designated as H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z68-1, 4 mg, 6% yield, trifluoroacetate salt) as a white solid. LCMS: MS m / z (ESI): 553.2 [M+H] + ,t R =1.07min. 1 H NMR (400 MHz, CD3OD): δ 8.57 (s, 1H), 8.45 - 8.42 (m, 1H), 7.96 (s, 1H), 7.32 (dd, J = 8.0, 3.2 Hz, 1H), 4.80-4.61 (m, 1H), 4.22-4.08 (m, 1H), 3.88-3.78 (m, 1H), 3.28-3.17 (m, 2H), 2.96-2.86 (m, 1H), 2.85 - 2.64 (m, 2H), 2.40-2.26 (m, 2H), 2.11 - 1.94 (m, 8H), 1.92 - 1.69 (m, 3H). The other isomer is (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1Arbitrarily designated as H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z68-2, 3 mg, 5% yield, trifluoroacetate salt). LCMS: MS m / z (ESI): 553.3 [M+H] + ,t R =1.08min. 1 H NMR (400 MHz, CD3OD): δ 8.57 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.28 (dd, J = 8.0, 3.2 Hz, 1H), 4.83-4.73 (m, 1H), 4.27 - 4.09 (m, 1H), 3.88-3.78 (m, 1H), 3.27 - 3.08 (m, 2H), 2.92-2.72 (m, 2H), 2.67 - 2.51 (m, 1H), 2.40 - 2.17 (m, 2H), 2.08 - 1.71 (m, 11H).

[0367] [ka]

[0368] Step 1: N-[(benzyloxy)carbonyl]-N-methylglycine (10.8 g, 48.4 mmol), tetrahydrofuran (100 mL), and carbonyldiimidazole (7.8 g, 48.4 mmol) were added to a 250 mL three-neck flask in this order. The reaction mixture was purged with nitrogen and stirred at 10 °C for 12 hours. Magnesium chloride (2.3 g, 24.2 mmol) and monomethyl malonate potassium salt (7.6 g, 48.4 mmol) were added, and the mixture was heated to 60 °C and stirred for 6 hours. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated, diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 50 / 50) to give benzyl (3,5-dioxo-7-aza-2-oxaoct-7-yl)methanoate (5.8 g, yield 43%) as a pale yellow oily liquid. 1 H NMR (400 MHz, CD3OD): δ 7.47 - 7.21 (m, 5H), 5.13 - 5.06 (m, 2H), 4.29 - 4.25 (m, 2H), 3.70 - 3.64 (m, 3H), 2.94 - 2.91 (m, 3H).

[0369] Step 2: Benzyl (3,5-dioxo-7-aza-2-oxaoct-7-yl)methanoate (5.8 g, 20.8 mmol) was dissolved in dichloromethane (50 mL), and diethylamine sulfur trifluoride (5.0 g, 31.2 mmol) was added dropwise at 0° C. The mixture was stirred at 25° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction was quenched by adding water (40 mL), extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, and the concentrated crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50 * 250 mm, 10 um (PARP-02), flow rate: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25 ° C.) to obtain benzyl (5,5-difluoro-3-oxo-7-aza-2-oxaoct-7-yl)methanoate (1.4 g, 22% yield) as an off-white solid. LCMS: m / z (ESI): 301.8 [M + H] +,t R =1.48min.

[0370] Step 3: Benzyl (5,5-difluoro-3-oxo-7-aza-2-oxaoct-7-yl)methanoate (1.4 g, 4.7 mmol) was dissolved in tetrahydrofuran (20 mL). A solution of lithium aluminum tetrahydrofuran (4.7 mL, 1 M) was added dropwise at 0 °C and stirred at 10 °C for 2 hours. After completion of the reaction was confirmed by LCMS, the reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 80 / 20) to obtain benzyl [(2,2-difluoro-4-hydroxybutyl)(methyl)amino]methanoate (1.0 g, 80% yield) as a colorless oil. LCMS: m / z (ESI): 274.2 [M+H] + ,t R =1.14 min.

[0371] Step 4: To a solution of benzyl [(2,2-difluoro-4-hydroxybutyl)(methyl)amino]methanoate (400 mg, 1.46 mmol) in pyridine (5 mL), p-methylsulfonyl chloride (558 mg, 2.93 mmol) was added and stirred at 10 °C for 3 h. After the completion of the reaction was confirmed by LCMS, silica gel was added directly, and the mixture was mixed by rotary drying on an oil pump. The mixture was then purified by column chromatography (100% dichloromethane) to give 6,6-difluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl 4-methylbenzenesulfonate (370 mg, 59% yield) as a yellow oil. LCMS: m / z (ESI): 428.2 [M+H] + ,t R =1.44min.

[0372] Step 5: 7-[dimethyl(oxo)-λ 5[1-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (426 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (7 mL), and 4-methylbenzenesulfonate-6,6-difluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl (350 mg, 0.82 mmol) and N,N-diisopropylethylamine (0.68 mL, 4.09 mmol) were added. The mixture was stirred at 100 °C for 16 h. After the completion of the reaction was confirmed by LCMS, silica gel was added, the mixture was dried on an oil pump, and the mixture was purified by column chromatography (dichloromethane:methanol = 100:6) to give 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (350 mg, 57% yield) was obtained as a yellow solid. LCMS: m / z (ESI): 751.3 [M+H] + ,t R =1.15min.

[0373] Step 6: 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (330 mg, 0.46 mmol) was dissolved in a mixture of water (3 mL), methanol (3 mL) and tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (96.6 mg, 2.30 mmol) was added and stirred at 40 ° C. for 16 hours. After the completion of the reaction was detected by LCMS, it was directly concentrated to give 7-[dimethyl(oxo)-λ 5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid was added and used directly in the next step of the reaction. LCMS: m / z (ESI): 737.4 [M+H] + ,t R =1.43 min.

[0374] Step 7: 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6,6-difluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (350 mg, 0.48 mmol) was added to trifluoroacetic acid (5 mL). After stirring at 60 ° C for 1.5 hours and completion detected by LCMS, the crude product was concentrated and purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50 * 250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25 ° C), 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-{[3,3-difluoro-4-(methylamino)butyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (215 mg, 81% yield over two steps) was obtained as a white solid. LCMS: m / z (ESI): 603.2 [M+H] + ,t R =0.78min.

[0375] Step 8: 7-[dimethyl(oxo)-λ 5To a solution of [2-{[(1S,3S)-3-{[3,3-difluoro-4-(methylamino)butyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (215 mg, 0.36 mmol) in N,N-dimethylformamide (10 mL) were added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (149 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.78 mmol) in sequence. After stirring at 60°C for 16 hours and detecting the completion of the reaction by LCMS, the mixture was concentrated and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C), (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z66, 22 mg, 11% yield, trifluoroacetate salt) was obtained. LCMS: m / z (ESI): 585.2 [M+H] + ,t R =0.87min. 1H NMR (400 MHz, CD3OD): δ 8.45-8.65 (m, 2H), 7.93 (s, 1H), 7.26 (s, 1H), 4.00-4.38 (m, 1H), 3.96-3.47 (m, 3H), 3.25 (s, 3H), 3.01-2.52 (m, 3H), 2.52-2.09 (m, 4H), 2.08-1.51 (m, 9H). .

[0376] [ka]

[0377] Step 1: In a 10 mL single-neck flask, add (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 To a solution of H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (14 mg, 0.02 mmol, trifluoroacetate salt) in tetrahydrofuran (3 mL), paraformaldehyde (9 mg, 0.10 mmol) and tetraisopropyl titanate (28 mg, 0.10 mmol) were added in that order. The mixture was stirred at 70°C for 14 hours, then cooled to 25°C. Sodium cyanoborohydride (4 mg, 0.06 mmol) was added and the mixture was stirred at 25°C for 2 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C). 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-5,10-dimethyl-2 5 -(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-5,10-dimethyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z65, 2 mg, 14% yield, trifluoroacetate salt) was obtained. LCMS: m / z (ESI): 599.2 [M+H] + ,t R =1.31min. 1 H NMR (400 MHz, CD3OD): δ 8.86 - 8.41 (m, 2H), 8.00 (s, 1H), 7.23 (dd, J = 8.0, 3.2 Hz, 1H), 4.28 - 4.06 (m, 1H), 3.92-3.76 (m, 1H), 3.68-3.47 (m, 2H), 3.25 (s, 3H), 2.90-2.77 (m, 1H), 2.46-2.38 (m, 1H), 2.33-2.16 (m, 5H), 2.13 - 1.94 (m, 6H), 1.90 - 1.86 (m, 3H), 1.78 - 1.55 (m, 3H).

[0378] [ka]

[0379] Step 1: To a solution of 7-bromo-1H-indole-6-carboxylic acid methyl ester (2.0 g, 7.9 mmol) in dimethyl sulfoxide (15 mL) was added L-proline (0.18 g, 1.6 mmol), copper iodide (0.95 g, 0.8 mmol), and sodium methyl sulfite (1.1 g, 9.5 mmol) at room temperature. The mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, the reaction mixture was quenched by the slow addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to give 7-(methanesulfonyl)-1H-indole-6-carboxylic acid methyl ester (1.4 g, 70% yield) as a white solid. LCMS: m / z(ESI): 254.0 [M+H] + ,t R =1.10 min.

[0380] Step 2: N-iodosuccinimide (1.5 g, 6.6 mmol) was added to a solution of 7-(methanesulfonyl)-1H-indole-6-carboxylic acid methyl ester (1.4 g, 5.5 mmol) in N,N-dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by LCMS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1:1) to give 3-iodo-7-(methanesulfonyl)-1H-indole-6-carboxylic acid methyl ester (1.8 g, 86% yield). LCMS: m / z (ESI): 380.0 [M+H] + ,t R =1.25min.

[0381] Step 3: To a sealed tube, 3-iodo-7-(methanesulfonyl)-1H-indole-6-carboxylic acid methyl ester (1.8 g, 4.7 mmol), tris(dibenzylideneacetone)dipalladium (0.44 g, 0.47 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.45 g, 0.94 mmol), pinacolborane (0.91 g, 7.1 mmol), triethylamine (1.4 g, 14.1 mmol), and tetrahydrofuran (15 mL) were added in this order at room temperature. The mixture was stirred at 90° C. under a nitrogen atmosphere for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was directly concentrated by rotary evaporation to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain methyl 7-(methanesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (1.1 g, 61% yield) as a white solid. LCMS: m / z (ESI): 380.2 [M+H] + ,t R =1.35min.

[0382] Step 4: At room temperature, a dry 50 mL single-neck flask was charged with a mixture of methyl 7-(methanesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (1.1 g, 2.9 mmol), chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (0.19 g, 0.29 mmol), potassium phosphate (1.8 g, 8.7 mmol), tert-butyl ((1S,3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)carbamate (1.1 g, 2.9 mmol), tetrahydrofuran (25 mL), and water (5 mL). The mixture was stirred at 60° C. under a nitrogen atmosphere for 16 hours. After detecting the completion of the reaction by LCMS, the reaction solution was directly concentrated by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain methyl 3-(2-((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methanesulfonyl)-1H-indole-6-carboxylate (0.57 g, 33% yield) as a white solid. LCMS: m / z (ESI): 598.2 [M+H] + ,t R =1.38min.

[0383] Step 5: At room temperature, methyl 3-(2-((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methanesulfonyl)-1H-indole-6-carboxylate (570 mg, 0.95 mmol) was dissolved in a mixture of hydrogen chloride / ethyl acetate (5 mL, 4 M) and ethyl acetate (3 mL), and the mixture was reacted at 30° C. for 16 hours. After detecting the completion of the reaction by LCMS, saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (dichloromethane / methanol = 20:1) to give 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methanesulfonyl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 64% yield) as a white solid. LCMS: m / z (ESI): 498.3 [M+H] + ,t R =1.12 min.

[0384] Step 6: To a solution of 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methanesulfonyl)-1H-indole-6-carboxylic acid methyl ester (300 mg, 0.60 mmol) in N,N-dimethylformamide (10 mL) at room temperature, tert-butyl (2-(2-iodoethoxy)ethyl)(methyl)carbamate (197 mg, 0.60 mmol) and N,N-diisopropylethylamine (310 mg, 2.40 mmol) were added in this order, and the mixture was stirred at 80° C. for 16 hours. After detecting the completion of the reaction by LCMS, saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (dichloromethane / methanol = 30:1) to give methyl 3-(2-((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylate (180 mg, 43% yield) as a white solid. LCMS: m / z (ESI): 699.4 [M+H] + ,t R =1.29 min.

[0385] Step 7: Methyl 3-(2-((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylate (180 mg, 0.26 mmol) was dissolved in a mixture of water (3 mL), methanol (3 mL), and tetrahydrofuran (3 mL). Lithium hydroxide monohydrate (55 mg, 1.3 mmol) was then added and the mixture was stirred at 40° C. for 16 hours. After completion of the reaction was detected by LCMS, the reaction solution was directly rotovapped to dryness by rotary evaporation to give 3-(2-((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylic acid (176 mg, 100% yield) as a crude product, which was used directly in the next step without purification. LCMS: m / z (ESI): 685.3 [M+H] + ,t R =1.21 min.

[0386] Step 8: 3-(2-((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylic acid (176 mg, 0.26 mmol) was dissolved in methanol (5 mL), followed by the addition of hydrochloric acid / methanol (5 mL, 4 M) and stirring at 40° C. for 16 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to obtain 3-(2-((1S,3S)-3-((2-(methylamino)ethoxy)ethyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methanesulfonyl)-1H-indole-6-carboxylic acid (110mg, 72% yield, trifluoroacetate salt) as a white solid. LCMS: m / z (ESI): 585.2 [M+H] + ,t R =0.78min.

[0387] Step 9: To a solution of 3-(2-((1S,3S)-3-((2-(methylamino)ethoxy)ethyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methanesulfonyl)-1H-indole-6-carboxylic acid (110 mg, 0.16 mmol, trifluoroacetate salt) in N,N-dimethylformamide (10 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) and N,N-diisopropylethylamine (83 mg, 0.64 mmol) were added in that order and stirred at 60 °C for 16 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-11-methyl-1 7 -(methylsulfonyl)-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one (4 1 S,4 3 S)-11-methyl-1 7 -(methylsulfonyl)-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z72, 55 mg, 51% yield, trifluoroacetate salt) was obtained as a white solid. LCMS: m / z (ESI): 567.2 [M+H] + ,t R =1.12 min. 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.39 (d, J = 8.0, 1H), 4.48 - 4.10 (m, 1H), 4.05 - 3.89 (m, 1H), 3.86-3.70 (m, 2H), 3.68-3.60 (m, 1H), 3.57 - 3.39 (m, 3H), 3.33 (s, 3H), 3.25-3.16 (m, 2H), 3.16 - 3.09 (m, 3H), 2.80 - 2.52 (m, 1H), 2.44 - 2.25 (m, 1H), 2.24 - 1.90 (m, 2H), 1.86 - 1.53 (m, 2H).

[0388] Step 10: In a 10 mL single-neck flask, add (4 1 S,4 3 S)-11-methyl-1 7 -(methylsulfonyl)-2 5 -(trifluoromethyl)-1 1 To a solution of H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one (30 mg, 0.044 mmol, trifluoroacetate) in tetrahydrofuran (10 mL), paraformaldehyde (20 mg, 0.221 mmol) and tetraisopropyl titanate (63 mg, 0.221 mmol) were added in that order, and the reaction mixture was stirred at 70°C for 14 hours. The reaction mixture was then cooled to 30°C, and sodium cyanoborohydride (41 mg, 0.660 mmol) was added, followed by stirring at 30°C for 2 hours. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70 mL / min, column temperature: 25°C), (4 1 S,4 3 S)-5,11-dimethyl-1 7 -(methylsulfonyl)-2 5-(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecyclododecan-12-one (4 1 S,4 3 S)-5,11-dimethyl-1 7 -(methylsulfonyl)-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one (Z75, 8 mg, 26% yield, trifluoroacetate salt) was obtained. LCMS: m / z (ESI): 581.2 [M+H] + ,t R =1.12 min. 1 H NMR (400 MHz, CD3OD): δ 8.60 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 4.19 - 4.03 (m, 1H), 3.98-3.89 (m, 1H), 3.88 - 3.72 (m, 3H), 3.70-3.52 (m, 2H), 3.49-3.37 (m, 1H), 3.32 (s, 3H), 3.19-3.11 (m, 5H), 2.87 - 2.82 (m, 3H), 2.61 - 2.43 (m, 1H), 2.31 - 2.21 (m, 3H), 1.86-1.73 (m, 2H).

[0389] [ka]

[0390] Step 1: To a solution of N-[(benzyloxy)carbonyl]glycine (100.0 g, 478.49 mmol) in tetrahydrofuran (1000 mL) was added carbonyldiimidazole (85.3 g, 526.34 mmol) at 15° C. The reaction was stirred at 15° C. for 18 hours under a nitrogen atmosphere. Magnesium chloride (22.8 g, 239.25 mmol) and monomethyl malonate potassium salt (82.2 g, 526.34 mmol) were then added to the reaction. The reaction was continued to stir at 45° C. for 6 hours under a nitrogen atmosphere. After detecting the completion of the reaction by LCMS, water (600 mL) was added to the reaction mixture and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 3 / 1) to obtain benzyl [(1-methoxy-1,3-dioxobutyl-4-yl)amino]methanoate (85.3 g, 67% yield) as a colorless oil. LCMS: m / z (ESI): 220.0 [M-44+H] + ,t R =1.58min.

[0391] Step 2: At 15°C, lithium borohydride (14.0 g, 643.78 mmol) was added portionwise to a solution of benzyl [(1-methoxy-1,3-dioxobutyl-4-yl)amino]methanoate (85.3 g, 321.89 mmol) in tetrahydrofuran (900 mL). The reaction mixture was stirred at 15°C for 18 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by TLC, saturated ammonium chloride solution (400 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (600 mL x 3). The combined organic layer was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give benzyl [(2,4-dihydroxybutyl)amino]methanoate (60.0 g, 78% yield) as a colorless oil.

[0392] Step 3: To a solution of benzyl [(2,4-dihydroxybutyl)amino]methanoate (60.0 g, 251.05 mmol) in dichloromethane (600 mL) was added imidazole (22.2 g, 326.37 mmol) at 15° C., followed by the slow dropwise addition of tert-butyldiphenylchlorosilane (69.0 g, 251.05 mmol). The reaction mixture was stirred at 15° C. under a nitrogen atmosphere for 2 hours. After detecting the completion of the reaction by LCMS, saturated ammonium chloride solution (400 mL) was added to the reaction mixture and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain benzyl [(7-hydroxy-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaoct-8-yl)amino]methanoate (88.0 g, 74% yield) as a colorless oil. LCMS: m / z (ESI): 402.2 [M-77+H] + ,t R =1.74 min.

[0393] Step 4: [(7-hydroxy-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaoct-8-yl)amino]benzyl methanate (88.0 g, 184.49 mmol) was dissolved in dichloromethane (900 mL), and then diethylamine sulfur trifluoride (38.7 g, 239.83 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 15° C. for 2 hours. After detecting the completion of the reaction by TLC, saturated ammonium chloride solution (400 mL) was added to the reaction mixture and extracted with ethyl acetate (600 mL × 3). The combined organic layers were washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 5 / 1) to obtain benzyl [(7-fluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaoct-8-yl)amino]methanoate (20.5 g, 23% yield) as a colorless oil. LCMS: m / z (ESI): 502.2 [M+Na] + ,t R =1.74 min.

[0394] Step 5: [(7-fluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaoct-8-yl)amino]benzyl methanate (20.5 g, 42.80 mmol) was dissolved in tetrahydrofuran (150 mL), and sodium hydride (5.1 g, 60% dispersion in mineral oil, 128.40 mmol) was added portionwise at room temperature, followed by the dropwise addition of methyl iodide (12.2 g, 85.60 mmol). The reaction mixture was stirred at 15° C. for 12 hours. After detecting the completion of the reaction by LCMS, saturated ammonium chloride solution (200 mL) was added to the reaction mixture and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 5 / 1) to obtain benzyl (7-fluoro-2,2-dimethyl-3,3-diphenyl-9-aza-4-oxa-3-siladec-9-yl)methanoate (16.5 g, 78% yield) as a colorless oil. LCMS: m / z (ESI): 516.2 [M+Na] + ,t R =1.85min.

[0395] Step 6: Benzyl (7-fluoro-2,2-dimethyl-3,3-diphenyl-9-aza-4-oxa-3-siladec-9-yl)methanoate (10.0 g, 20.24 mmol) was dissolved in N,N-dimethylformamide (60 mL). Cesium fluoride (15.4 g, 101.20 mmol) was added and the mixture was stirred at 50 °C for 8 hours. After the completion of the reaction was confirmed by LCMS, saturated ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give benzyl [(2-fluoro-4-hydroxybutyl)(methyl)amino]methanoate (4.4 g, 85% yield) as a colorless oil. LCMS: m / z(ESI): 256.2 [M+H]+ ,t R =1.08min.

[0396] Step 7: At room temperature, benzyl [(2-fluoro-4-hydroxybutyl)(methyl)amino]methanoate (4.4 g, 17.25 mmol) was dissolved in dichloromethane (40 mL), followed by the addition of imidazole (1.4 g, 20.70 mmol), triphenylphosphine (5.4 g, 20.70 mmol), and elemental iodine (5.3 g, 20.70 mmol). The reaction was allowed to stir at room temperature for 2 hours. After detecting the completion of the reaction by LCMS, saturated ammonium chloride solution (50 mL) was added to the reaction mixture and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to obtain benzyl [(2-fluoro-4-iodobutyl)(methyl)amino]methanoate (5.0 g, 79% yield) as a colorless oil. LCMS: m / z (ESI): 366.0 [M+H] + ,t R =1.44min.

[0397] Step 8: In a 250 mL single-neck flask, add 7-[dimethyl(oxo)-λ 5 [-methylphosphoryl]-3-(2-{[(1S,3S)-3-aminocyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (5.0 g, 10.10 mmol) was dissolved in N,N-dimethylformamide (70 mL), and then [(2-fluoro-4-iodobutyl)(methyl)amino]benzyl methanate (3.7 g, 10.10 mmol) and N,N-diisopropylethylamine (5.2 g, 40.40 mmol) were added and stirred at 100 °C for 16 hours. After the completion of the reaction was confirmed by LCMS, silica gel was added directly, and the sample was mixed and dried on an oil pump. The mixture was purified by column chromatography (dichloromethane:methanol = 100:8) to give 7-[dimethyl(oxo)-λ 5-methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6-fluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (7.0 g, 95% yield) was obtained as a yellow solid. LCMS: m / z (ESI): 733.2 [M+H] + ,t R =1.14 min.

[0398] Step 9: 7-[dimethyl(oxo)-λ 5

[0047]

[0048]

[0049]

[0050]

[0049]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0056]

[0057]

[0058] [0059 ... 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-[(6-fluoro-4-methyl-3-oxo-1-phenyl-4-aza-2-oxaoct-8-yl)amino]cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (crude product containing salt) was obtained, which was used directly in the next step reaction without purification. LCMS: m / z (ESI): 719.2 [M+H] + ,t R =1.09min.

[0399] Step 10: Trifluoroacetic acid (30 mL) was added to the crude product from the previous step and stirred at 60°C for 3 hours. After completion was confirmed by LCMS, the reaction mixture was concentrated and the resulting crude product was purified by reverse phase chromatography (70 mL / min, 25°C, Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), acetonitrile-water (0.1% trifluoroacetic acid)) with 7-[dimethyl(oxo)-λ 5 -methylphosphoryl]-3-(2-{[(1S,3S)-3-{[3-fluoro-4-(methylamino)butyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (4.0 g, 72% yield over two steps, white solid). LCMS: m / z (ESI): 585.2 [M+H] + ,t R =1.13 min.

[0400] Step 11: 7-[dimethyl(oxo)-λ 5 To a solution of [2-(2-methylphosphoryl]-3-{[(1S,3S)-3-{[3-fluoro-4-(methylamino)butyl]amino}cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (4.0 g, 6.85 mmol) in N,N-dimethylformamide (60 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.6 g, 6.85 mmol) and N,N-diisopropylethylamine (3.6 g, 27.4 mmol) were added sequentially, and the reaction mixture was stirred at 60°C for 16 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL / min, column temperature: 25°C) to obtain two isomeric compounds. One of the isomeric compounds was (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-25 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 Arbitrarily designated as H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z76, 0.7 g, 18% yield, trifluoroacetate salt) as an off-white solid. LCMS: m / z (ESI): 567.2 [M+H] + ,t R =0.86min. 1 H NMR (400 MHz, CD3OD): δ 8.55 (s, 1H), 8.30-7.70 (m, 2H), 7.30 (m, 1H), 5.69-4.98 (m, 1H), 4.28-3.95 (m, 1H), 3.87-3.76 (m, 1H), 3.69-3.37 (m, 2H), 3.21 (s, 3H), 2.89-2.78 (m, 1H), 2.74-2.64 (m, 1H), 2.48-2.14 (m, 3H), 2.12-1.54 (m, 11H). The other isomeric compound is (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5-(trifluoromethyl)-1 1 Arbitrarily designated as H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z77, 0.8 g, 21% yield, trifluoroacetate salt) as an off-white solid. LCMS: m / z (ESI): 567.2 [M+H] + ,t R =0.87min.. 1 H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.21 (dd, J = 8.0, 3.2 Hz, 1H), 5.26-4.96 (m, 1H), 4.32-3.97 (m, 1H), 3.86-3.72 (m, 1H), 3.54-3.31 (m, 2H), 3.22 (s, 3H), 2.91-2.79 (m, 1H), 2.73-2.37 (m, 2H), 2.36-2.16 (m, 2H), 2.12-1.65 (m, 11H).

[0401] Step 12: (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1To a solution of H-3,5,10-triaza-1(3,6)-indole-2(4,2)-pyrimidin-4(1,3)-cyclopentanecycloundecan-11-one (Z76, 220 mg, 0.39 mmol) in tetrahydrofuran (20 mL), paraformaldehyde (176 mg, 1.95 mmol) and tetraisopropyl titanate (554 mg, 1.95 mmol) were added sequentially, and the reaction was stirred at 70° C. for 16 h. The reaction was then cooled to 10° C., and sodium cyanoborohydride (74 mg, 1.17 mmol) was added to the reaction, and stirring was continued for 2 h. After detecting the completion of the reaction by LCMS, the reaction mixture was concentrated, and the resulting crude product was purified by reverse phase chromatography (chromatography column: Ultimate XB-C18, 50*250 mm, 10 μm (PARP-02), mobi...

Claims

1. A compound represented by formula (A) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (however, 【Chemistry 2】 and Ring A is absent, or ring A is a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, a 5- to 12-membered heteroaryl group, C ５－１２ aryl groups, ring A is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from group S1, said 3-14 membered heterocycle having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said 5-12 membered heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L ３ No, C １－６ Alkylene group, C ２－６ alkenylene group or ring B; １－６ 1, 2, 3, 4, or 5 hydrogen atoms of the alkylene group are each independently R １３ may be substituted with, ２－６ 1, 2, 3, 4 or 5 hydrogen atoms of the alkenylene group are each independently R １３ may be substituted with Ring B is a 3- to 14-membered carbocyclic ring, a 3- to 14-membered heterocyclic ring, a 5- to 12-membered heteroaryl group, C ５－１２ aryl groups, Ring B is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from Group S1, said 3-14 membered heterocycle having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said 5-12 membered heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L １ No, C １－６ Alkylene group, C ２－６ Alkenylene group, —O—, —NR １０ -, -C=N-, C ５－１２ Aryl group, 5- to 12-membered heteroaryl group, —C(O)—, —C(O)—NR １０ -or-NR １０ -C(O)-, １－６ 1, 2, 3, 4, or 5 hydrogen atoms of the alkylene group are each independently R １３ may be substituted with, ２－６ 1, 2, 3, 4 or 5 hydrogen atoms of the alkenylene group are each independently R １３ wherein the 5-12 membered heteroaryl group has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C ５－１２ the aryl group, the 5- to 12-membered heteroaryl group are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from the S1 group; L ２ teeth, -(O) ｍ２ -(CR １３ R １４ ) ｍ１ -(NR １２ ) ｍ３ -、 -(NR) １１ ) ｍ２ -(CR) １３ R １４ ) ｍ１ -(NR) １２ ) ｍ３ -、 - (O) ｍ２ - (CR １３ R １４ ) ｍ５ - (3-7 membered carbon ring) ｍ４ - (CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ - -(NR １１ ) ｍ２ - (CR １３ R １４ ) ｍ５ - (3-7 membered carbon ring) ｍ４ - (CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ - - (O) ｍ２ - (CR １３ R １４ ) ｍ５ -(3- to 7-membered heterocycle) ｍ４ - (CR １３ R １４ ) ｍ６ - (NR １２ ) ｍ３ --, - (NR １１ ) ｍ２ - (CR １３ R １４ ) ｍ５ -(3- to 7-membered heterocycle) ｍ４ - (CR １３ R １４ ) ｍ６ - (NR １２ ) ｍ３ --, -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -NR １０ -(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(NR １１ ) ｍ２ -(CR １３ R １４ ) ｍ５ -NR １０ -(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -NR １０ C(O)-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(NR １１ ) ｍ２ -(CR １３ R １４ ) ｍ５ -NR １０ C(O)-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -C(O)NR １０ -(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(NR １１ ) ｍ２ -(CR １３ R １４ ) ｍ５ -C(O)NR １０ -(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -O-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(NR １１ ) ｍ２ -(CR １３ R １４ ) ｍ５ -O-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -OC(O)-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(NR １１ ) ｍ２ -(CR １３ R １４ ) ｍ５ -OC(O)-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -C(O)O-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(NR １１ ) ｍ２ -(CR １３ R １４ ) ｍ５ -C(O)O-(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 -(O) ｍ２ -(CR １３ R １４ ) ｍ５ -(CH=CH) ｍ７ -(CR １３ R １４ ) ｍ６ -(NR １２ ) ｍ３ -、 - (NR １１ ) ｍ２ - (CR １３ R １４ ) ｍ５ -(CH=CH) ｍ７ - (CR １３ R １４ ) ｍ６ - (NR １２ ) ｍ３ - selected from the group consisting of R １０ are each independently hydrogen, C １－６ Alkyl groups, deuterated C １－６ Alkyl group, -3 to 7 membered carbocyclic group, -C(O)-C １－６ Alkyl group, —C(O)—C １－４ Alkyl-C １－６ Alkoxy group, —C(O)-3 to 7 membered carbocyclic group, —C １－４ Alkyl-hydroxy group, -C １－４ Alkyl-cyano group, -C １－４ Alkyl-C １－６ Alkoxy group, -C １－４ Alkyl-NHC(O)-C １－６ Alkyl group, -C １－４ Alkyl-NHC(O)-C １－４ Alkyl-C １－６ Alkoxy group, -C １－４ Alkyl-NHC(O)-3 to 7-membered carbocyclic group or -C １－４ alkyl-NRR′, each 3- to 7-membered heterocyclic group independently has 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said 3- to 7-membered carbocyclic rings are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from the S1 group; each 3- to 7-membered carbocyclic group is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from the S1 group; R １１ are each independently hydrogen, C １－６ Alkyl group or deuterated C １－６ is an alkyl group, R １２ are each independently hydrogen, C １－６ Alkyl group or deuterated C １－６ is an alkyl group, R １３ are each independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups, halogenated C １－６ Alkoxy group, -3 to 7 membered carbocyclic group, -C ０－６ Alkylene -NRR', -C １－６ Alkylene-hydroxy group or -C ０－６ an alkylene-cyano group, R １４ are each independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl groups, halogenated C １－６ Alkoxy group, -3 to 7 membered carbocyclic group, -C ０－６ Alkylene -NRR', -C １－６ Alkylene-hydroxy group or -C ０－６ an alkylene-cyano group, Each m1 is independently 1, 2, 3, 4, 5 or 6; Each m2 is independently 0 or 1; Each m3 is independently 0 or 1; Each m4 is independently 1 or 2; Each m5 is independently 0, 1, 2, 3, 4, 5 or 6; Each m6 is independently 0, 1, 2, 3, 4, 5 or 6; Each m7 is independently 1 or 2; R １ is hydrogen, halogen, cyano group, C １－６ is an alkyl group or a 3- to 14-membered carbocyclic group, １－６ The alkyl group and the 3- to 14-membered carbocyclic group are independently unsubstituted or substituted with an oxo group, a hydroxy group, a halogen, a C １－６ Alkyl groups, halogenated C １－６ substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of alkyl groups; R ２ is hydrogen, halogen, cyano group, C １－６ is an alkyl group or a 3- to 14-membered carbocyclic group, １－６ The alkyl group and the 3- to 14-membered carbocyclic group are independently unsubstituted or substituted with an oxo group, a hydroxy group, a halogen, a C １－６ Alkyl groups, halogenated C １－６ substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of alkyl groups; X ２ is N or C(R ３ ) and X １ is N or C(R ４ ) and Y is N or C(R ４ ) and Z is N or C(R ３ ) and R ３ are independently hydrogen, halogen, cyano group, C １－６ Alkyl group or halogenated C １－６ is an alkyl group, R ４ are independently hydrogen, halogen, a hydroxyl group, a cyano group, -C ２－４ Alkenylene-phenyl group, -C ２－４ Alkynylene-phenyl group, -S(O)-OH, -S(O) ２ -OH, -S-(C １－６ Alkyl group), C １－６ Alkyl group, —O—C １－６ Alkyl group, -C １－６ Alkylene -O-C １－６ Alkyl group, —O—C １－６ Alkylene -O-C １－６ Alkyl group, -C ０－６ Alkylene -NRR', -C ０－６ Alkylene -C(O)OH, -C ０－６ Alkylene-C(O)-C １－６ Alkyl group, -C ０－６ Alkylene-C(O)-NRR′, —C ０－６ Alkylene -NR-C(O)-C １－６ Alkyl group, -C ０－６ Alkylene-S(O) ２ -C １－６ Alkyl group, -C ０－６ Alkylene-S(O) ２ -NRR', -C ０－６ Alkylene -NR-S(O) ２ -C １－６ Alkyl group, -C ０－６ Alkylene -NR-S(O) ２ -NRR', -C ０－６ Alkylene-P(O)O-(C １－６ Alkyl group) ２ , -C ０－６ Alkylene-P(O)-(C １－６ alkyl group) (O-C １－６ alkyl group), -C ０－６ Alkylene-P(O)-(C １－６ Alkyl group) ２ , -C ０－６ alkylene-3 to 14 membered carbocyclic group, -C ０－６ alkylene-3 to 14 membered heterocyclic group, -C ０－６ alkylene-5 to 12 membered heteroaryl group, -C ０－６ Alkylene-C ５－１２ Aryl group, -C ０－６ alkylene-C(O)-3 to 14 membered heterocyclic group, -C ０－６ alkylene-C(O)-5 to 12 membered heteroaryl group, —O—C ０－６ Alkylene -O-C １－６ Alkyl group, —O—C ０－６ alkylene-3 to 14-membered carbocyclic group, —O—C ０－６ alkylene-3 to 14 membered heterocyclic group, —O—C ０－６ alkylene-5 to 12 membered heteroaryl group, —O—C ０－６ Alkylene-C ５－１２ Aryl group, -S(O)-C １－６ is an alkyl group, １－６ Alkyl group, C ０－６ Alkylene group, C ２－４ alkenylene group, 3- to 14-membered carbocyclic group, 3- to 14-membered heterocyclic group, 5- to 12-membered heteroaryl group, C ５－１２ the aryl groups are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from the S1 group, the 3- to 14-membered heterocycle has 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 12-membered heteroaryl groups have 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The groups in the S1 group include oxo (=O), halogen, hydroxyl, cyano, C １－６ Alkyl group, —O—C １－６ Alkyl group, -C １－６ Alkylene -O-C １－６ Alkyl group, —O—C １－６ Alkylene -O-C １－６ Alkyl group, -C ０－６ Alkylene -NRR', -C ０－６ Alkylene -C(O)OH, -C ０－６ Alkylene-C(O)-C １－６ Alkyl group, -C ０－６ Alkylene-C(O)-NRR′, —C ０－６ Alkylene -NR-C(O)-C １－６ Alkyl group, -C ０－６ Alkylene-S(O) ２ -C １－６ Alkyl group, -C ０－６ Alkylene-S(O) ２ -NRR', -C ０－６ Alkylene -NR-S(O) ２ -C １－６ Alkyl group, -C ０－６ Alkylene -NR-S(O) ２ -NRR', -C ０－６ Alkylene-P(O)O-(C １－６ Alkyl group) ２ , -C ０－６ Alkylene-P(O)-(C １－６ alkyl group) (O-C １－６ alkyl group), -C ０－６ Alkylene-P(O)-(C １－６ Alkyl group) ２ , -C ０－６ alkylene-3 to 14 membered carbocyclic group, -C ０－６ alkylene-3 to 14 membered heterocyclic group, -C ０－６ alkylene-5 to 12 membered heteroaryl group, -C ０－６ Alkylene-C ５－１２ Aryl group, -C ０－６ alkylene-C(O)-3 to 14 membered heterocyclic group, -C ０－６ alkylene-C(O)-5 to 12 membered heteroaryl group, —O—C ０－６ Alkylene -O-C １－６ Alkyl group, —O—C ０－６ alkylene-3 to 14-membered carbocyclic group, —O—C ０－６ alkylene-3 to 14 membered heterocyclic group, —O—C ０－６ alkylene-5 to 12 membered heteroaryl group, —O—C ０－６ Alkylene-C ５－１２ Aryl group, -S(O)-C １－６ Contains an alkyl group, R and R′ are each independently hydrogen, C １－６ Alkyl group or deuterated C １－６ R and R' may be alkyl groups, or R and R' may be combined with the nitrogen atom to form a 3- to 14-membered heterocyclic group or a 5- to 12-membered heteroaryl group, each of which independently contains, in addition to the existing nitrogen atom, 0, 1 or 2 heteroatoms selected from N, O and S; In each of the above groups, ０－６ two hydrogen atoms on any same carbon atom of an alkylene group may be simultaneously replaced by a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic spiro ring; In each of the above groups, １－６ Any two hydrogen atoms on the same carbon atom of the alkylene group may be simultaneously replaced with a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic spiro ring.

2. The compound of formula (A) is a compound of formula (IA), 【Chemistry 3】 However, X １ , Y, Z, X ２ , R １ , R ２ , L １ , L ２ , ring A and ring B are each as defined in claim 1; or The compound of formula (A) is a compound of formula (IB), 【Chemistry 4】 However, X １ , Y, Z, X ２ , R １ , R ２ , L １ , L ２ , ring A, R １３ , R １４ are each as defined in claim 1, and m0 is 1, 2, 3, 4, 5 or 6; or The compound of formula (A) is a compound of formula (A1), 【Chemistry 5】 However, X １ , Y, Z, X ２ , R １ , R ２ , L １ , L ２ , ring A and ring B are each as defined in claim 1; or The compound of formula (A) is a compound of formula (A2), 【Chemistry 6】 However, X １ , Y, Z, X ２ , R １ , R ２ , L １ , L ２ , ring A, R １３ , R １４ and m0 is 1, 2, 3, 4, 5 or 6, or a pharma- ceutically acceptable salt thereof.

3. The compound of formula (A) is a compound of formula (II-A), 【Chemistry 7】 However, R １ , R ２ , L １ , L ２ , ring A, ring B, X １ are each as defined in claim 1, or The compound of formula (A) is a compound of formula (II-B), 【Chemistry 8】 However, X １ , R １ , R ２ , L １ , L ２ , ring A, R １３ , R １４ are each as defined in claim 1, and m0 is 1, 2, 3, 4, 5 or 6; or The compound of formula (A) is a compound of formula (A3), 【Chemistry 9】 However, X １ , R １ , R ２ , L １ , L ２ , ring A and ring B are each as defined in claim 1; or The compound of formula (A) is a compound of formula (A4), 【Chemistry 10】 However, X １ , R １ , R ２ , L １ , L ２ , ring A, R １３ , R １４ and m0 is 1, 2, 3, 4, 5 or 6, or a pharma- ceutically acceptable salt thereof.

4. The compound of formula (A) is a compound of formula (III-A), 【Chemistry 11】 However, L １ , L ２ , ring A, ring B, X １ are each as defined in claim 1, or The compound of formula (A) is a compound of formula (III-B): 【Chemistry 12】 However, X １ , L １ , L ２ , ring A, R １３ , R １４ are each as defined in claim 1, and m0 is 1, 2, 3, 4, 5 or 6; or The compound of formula (A) is a compound of formula (A5), 【Chemistry 13】 However, X １ , L １ , L ２ , ring A and ring B are each as defined in claim 1; or The compound of formula (A) is a compound of formula (A6), 【Chemistry 14】 However, X １ , L １ , L ２ , ring A, R １３ , R １４ are each as defined in claim 1, and m0 is 1, 2, 3, 4, 5 or 6; Or, the compound of formula (A) is a compound of formula (IV-a), 【Chemistry 15】 However, X １ , L １ , L ２ and ring B are each as defined in claim 1; Or, the compound of formula (A) is a compound of formula (IV-b), 【Chemistry 16】 However, X １ , L １ , L ２ and ring B are each as defined in claim 1; 【Chemistry 17】 However, X １ , L １ , L ２ 2. The compound according to claim 1, wherein ring A is as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

5. The compound or its pharma- ceutically acceptable salt according to any one of claims 1 to 4, wherein ring A is absent or selected from the group consisting of a cyclobutane ring, a cyclopentyl ring, a cyclohexane ring, a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a pyrazole ring, an imidazole ring, and a pyridine ring, and ring A is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from Group S1.

6. The compound or its pharma- ceutically acceptable salt according to any one of claims 1 to 4, wherein ring B is selected from the group consisting of a cyclobutane ring, a cyclopentyl ring, a cyclohexane ring, a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a pyrazole ring, and an imidazole ring, and ring B is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups selected from group S1.

7. X １ is N or C(R ４ ) and R ４ is hydrogen, halogen, cyano group, -S(O) ２ CH ３ or -P(O)(CH ３ ) ２ 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein:

8. The compound according to any one of claims 1 to 4, wherein the compound is selected from Table (I), or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for preventing and / or treating a CDK7-associated disease.

11. Use of the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a CDK7 inhibitor.

12. The use according to claim 11, characterized in that the CDK7-related disease is a proliferative disease (such as a tumor or cancer), an infectious disease, an immune disease, an autoimmune disease and an inflammatory disease.

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