TWI736578B - Certain protein kinase inhibitors - Google Patents

Abstract

The present invention relates to a compound or a pharmaceutically acceptable salt thereof that can inhibit the activity of CDK4/6 kinase, and as a medicine to treat proliferative diseases, such as cancer and inflammation.

Description

6-5 member fused azole ring derivative and pharmaceutical composition thereof, and application as medicine

This application claims the priority of U.S. Provisional Application 62/292,259, the entire content of which is incorporated into this application by reference in its entirety.

The present invention relates to a compound or a pharmaceutically acceptable salt thereof that can inhibit the activity of CDK4/6 kinase, and as a medicine to treat proliferative diseases, such as cancer and inflammation.

Hyper-proliferative diseases such as cancer and inflammation attract the academic community to provide effective treatments for them, and efforts are made to identify and target specific mechanisms that play an important role in proliferative diseases.

The development of tumors is closely related to the gene mutation and abnormal regulation of cyclin-dependent kinase (CDK) and its regulatory proteins, indicating that CDK inhibitors may be effective anti-cancer therapies.

CDK is a serine/threonine protein kinase, which is the driving force behind the cell cycle and cell proliferation. CDK regulates the initiation, progression and completion of the mammalian cell cycle and is critical for cell growth. Most of the known CDKs, including CDK1 to CDK9, are directly or indirectly involved in the progression of the cell cycle. CDKs directly involved in cell cycle progression, such as CDK1-4 and CDK6, can be classified as G1, S or G2M phase enzymes. Abnormal proliferation is a characteristic of cancer cells, and abnormal CDK function occurs frequently in many solid tumors.

CDK and its related proteins play a key role in coordinating and driving the cell cycle in proliferating cells. Therefore, targeting multiple CDKs or specific CDKs to treat proliferative disorders, such as cancer, has great potential. CDK inhibitors can also be used to treat other diseases such as viral infections, autoimmune diseases and neurodegenerative diseases. CDK targeted therapy can also be used in combination with other therapeutic drugs for the treatment of the above-mentioned diseases.

Therefore, compounds with CDK inhibitory activity are of great significance for the prevention and treatment of cancer. Although CDK4/6 inhibitors have been reported in the literature, such as WO 2010075074, many have short half-lives or are toxic. Therefore, the demand for new CDK4/6 inhibitors will become more and more urgent, which has advantages in at least one aspect of efficacy, stability, selectivity, safety, pharmacodynamic characteristics and pharmacokinetic characteristics. The present invention relates to a new type of CDK4/6 inhibitor.

The invention relates to a new type of 6-5 membered fused azole ring derivatives and pharmaceutical compositions thereof, and their application as medicines.

(I)或

(II) 其中， Q選自芳基和雜芳基； 每個R¹ 獨立選自氫、鹵素、羥基、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C_1-10 烷基氨基、C_3-10 環烷基氨基、二（C_1-10 烷基）氨基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷基氨基、環烷基氨基、二（烷基）氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^x 的取代基取代； 每個R² 獨立選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、 -NR^A1 R^B1 、-OR^A1 、-S(O)_r R^A1 、-S(O)₂ OR^A1 、-OS(O)₂ R^A1 、-P(O)R^A1 R^B1 、-P(O)(OR^A1 )(OR^B1 )、-C(O)R^A1 、-C(O)OR^A1 、-OC(O)R^A1 、-C(O)NR^A1 R^B1 、-NR^A1 C(O)R^B1 、-OC(O)NR^A1 R^B1 、-NR^A1 C(O)OR^B1 、-NR^A1 C(O)NR^A1 R^B1 、-NR^A1 C(S)NR^A1 R^B1 、-S(O)_r NR^A1 R^B1 、-NR^A1 S(O)_r R^B1 、-NR^A1 S(O)2NR^A1 R^B1 、-S(O)(=NR^E1 )R^B1 、-N=S(O)R^A1 R^B1 、-NR^A1 S(O)(=NR^E1 )R^B1 、-S(O)(=NR^E1 )NR^A1 R^B1 、-NR^A1 S(O)(=NR^E1 )NR^A1 R^B1 、-C(=NR^E1 )R^A1 、-C(=N-OR^B1 )R^A1 、-C(=NR^E1 )NR^A1 R^B1 、-NR^A1 C(=NR^E1 )R^B1 和-NR^A1 C(=NR^E1 )NR^A1 R^B1 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^x 的取代基取代； 每個R³ 獨立選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、-NR^A2 R^B2 、-OR^A2 、-S(O)_r R^A2 、-S(O)₂ OR^A2 、-OS(O)₂ R^A2 、-P(O)R^A2 R^B2 、-P(O)(OR^A2 )(OR^B2 ) 、-C(O)R^A2 、-C(O)OR^A2 、-OC(O)R^A2 、-C(O)NR^A2 R^B2 、-NR^A2 C(O)R^B2 、-OC(O)NR^A2 R^B2 、-NR^A2 C(O)OR^B2 、-NR^A2 C(O)NR^A2 R^B2 、-NR^A2 C(S)NR^A2 R^B2 、-S(O)_r NR^A2 R^B2 、-NR^A2 S(O)_r R^B2 、-NR^A2 S(O)₂ NR^A2 R^B2 、-S(O)(=NR^E2 )R^B2 、-N=S(O)R^A2 R^B2 、-NR^A2 S(O)(=NR^E2 )R^B2 、-S(O)(=NR^E2 )NR^A2 R^B2 、-NR^A2 S(O)(=NR^E2 )NR^A2 R^B2 、-C(=NR^E2 )R^A2 、-C(=N-OR^B2 )R^A2 、-C(=NR^E2 )NR^A2 R^B2 、-NR^A2 C(=NR^E2 )R^B2 和-NR^A2 C(=NR^E2 )NR^A2 R^B2 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 每個R⁴ 選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、-NR^A3 R^B3 、-OR^A3 、-S(O)_r R^A3 、-S(O)₂ OR^A3 、-OS(O)₂ R^A3 、-P(O)R^A3 R^B3 、-P(O)(OR^A3 )(OR^B3 )、-C(O)R^A3 、-C(O)OR^A3 、-OC(O)R^A3 、-C(O)NR^A3 R^B3 、-NR^A3 C(O)R^B3 、-OC(O)NR^A3 R^B3 、-NR^A3 C(O)OR^B3 、-NR^A3 C(O)NR^A3 R^B3 、-NR^A3 C(S)NR^A3 R^B3 、-S(O)_r NR^A3 R^B3 、-NR^A3 S(O)_r R^B3 、-NR^A3 S(O)₂ NR^A3 R^B3 、-S(O)(=NR^E3 )R^B3 、-N=S(O)R^A3 R^B3 、-NR^A3 S(O)(=NR^E3 )R^B3 、-S(O)(=NR^E3 )NR^A3 R^B3 、-NR^A3 S(O)(=NR^E3 )NR^A3 R^B3 、-C(=NR^E3 )R^A3 、-C(=N-OR^B3 )R^A3 、-C(=NR^E3 )NR^A3 R^B3 、-NR^A3 C(=NR^E3 )R^B3 和-NR^A3 C(=NR^E3 )NR^A3 R^B3 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 每個R⁵ 獨立地選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、-NR^A4 R^B4 、-(CH₂ )_t NR^A4 R^B4 、-OR^A4 、-S(O)_r R^A4 、-S(O)₂ OR^A4 、-OS(O)₂ R^A4 、-P(O)R^A4 R^B4 、-P(O)(OR^A4 )(OR^B4 )、-C(O)R^A4 、-C(O)OR^A4 、-OC(O)R^A4 、-C(O)NR^A4 R^B4 、-NR^A4 C(O)R^B4 、-OC(O)NR^A4 R^B4 、-NR^A4 C(O)OR^B4 、-NR^A4 C(O)NR^A4 R^B4 、-NR^A4 C(S)NR^A4 R^B4 、-S(O)_r NR^A4 R^B4 、-NR^A4 S(O)_r R^B4 、-NR^A4 S(O)₂ NR^A4 R^B4 、-S(O)(=NR^E4 )R^B4 、-N=S(O)R^A4 R^B4 、-NR^A4 S(O)(=NR^E4 )R^B4 、-S(O)(=NR^E4 )NR^A4 R^B4 、-NR^A4 S(O)(=NR^E4 )NR^A4 R^B4 、-C(=NR^E4 )R^A4 、-C(=N-OR^B4 )R^A4 、-C(=NR^E4 )NR^A4 R^B4 、-NR^A4 C(=NR^E4 )R^B4 和-NR^A4 C(=NR^E4 )NR^A4 R^B4 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 每個R^A1 、R^A2 、R^A3 、R^A4 、R^B1 、R^B2 、R^B3 和R^B4 獨立地選自氫、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 或每個“R^A1 和R^B1 ”、“R^A2 和R^B2 ”、“R^A3 和R^B3 ”或“R^A4 和R^B4 ”一起連同與它們相連的單個或多個原子共同構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可以是未被取代的或被1、2或3個R^X 基團取代； 每個R^E1 、R^E2 、R^E3 和R^E4 獨立地選自氫、C_1-10 烷基、CN、 NO₂ 、-OR^a1 、-SR^a1 、-S(O)_r R^a1 、-C(O)R^a1 、-C(O)OR^a1 、-C(O)NR^a1 R^b1 和-S(O)_r NR^a1 R^b1 ； 每個R^X 獨立地選自C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、鹵素、CN、NO₂ 、-(CR^c1 R^d1 )_t NR^a1 R^b1 、-(CR^c1 R^d1 )_t OR^b1 、-(CR^c1 R^d1 )_t S(O)_r R^b1 、-(CR^c1 R^d1 )_t S(O)₂ OR^b1 、-(CR^c1 R^d1 )_t OS(O)₂ R^b1 、-(CR^c1 R^d1 )_t P(O)R^a1 R^b1 、-(CR^c1 R^d1 )_t P(O)(OR^a1 )(OR^b1 )、-(CR^c1 R^d1 )_t C(O)R^a1 、-(CR^c1 R^d1 )_t C(O)OR^b1 、-(CR^c1 R^d1 )_t OC(O)R^b1 、-(CR^c1 R^d1 )_t C(O)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(O)R^b1 、-(CR^c1 R^d1 )_t OC(O)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(O)OR^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)_r R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)₂ NR^a1 R^b1 、-(CR^c1 R^d1 )_t S(O)(=NR^e1 )R^b1 、-(CR^c1 R^d1 )_t N=S(O)R^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )R^b1 、-(CR^c1 R^d1 )_t S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t C(=NR^e1 )R^a1 、-(CR^c1 R^d1 )_t C(=N-OR^b1 )R^a1 、-(CR^c1 R^d1 )_t C(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )R^b1 和-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )NR^a1 R^b1 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^Y 的取代基取代； 每個R^a1 和R^b1 獨立地選自氫、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^Y 的取代基取代； 或R^a1 和R^b1 一起連同與它們相連的單個或多個原子共同構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可以是未被取代的或被1、2或3個選自R^Y 的取代基取代； 每個R^c1 和R^d1 獨立地選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^Y 的取代基取代； 或R^c1 和R^d1 一起連同與它們相連的單個或多個碳原子共同構成含有0、1或2個額外的獨立選自氧、硫和氮的雜原子的3-12元雜環，該環可以是未被取代的或被1、2或3個R^Y 基團取代； 每個R^e1 獨立地選自氫、C_1-10 烷基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、CN、NO₂ 、-OR^a2 、-SR^a2 、-S(O)_r R^a2 、-C(O)R^a2 、-C(O)OR^a2 、-S(O)_r NR^a2 R^b2 和-C(O)NR^a2 R^b2 ； 每個R^Y 獨立地選自C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、鹵素、CN、NO₂ 、-(CR^c2 R^d2 )_t NR^a2 R^b2 、-(CR^c2 R^d2 )_t OR^b2 、-(CR^c2 R^d2 )_t S(O)_r R^b2 、-(CR^c2 R^d2 )_t S(O)₂ OR^b2 、-(CR^c2 R^d2 )_t OS(O)₂ R^b2 、-(CR^c2 R^d2 )_t P(O)R^a2 R^b2 、-(CR^c2 R^d2 )_t P(O)(OR^a2 )(OR^b2 )、-(CR^c2 R^d2 )_t C(O)R^a2 、-(CR^c2 R^d2 )_t C(O)OR^b2 、-(CR^c2 R^d2 )_t OC(O)R^b2 、-(CR^c2 R^d2 )_t C(O)NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(O)R^b2 、-(CR^c2 R^d2 )_t OC(O)NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(O)OR^b2 、-(CR^c2 R^d2 )_t NR^a2 C(O)NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(S)NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)_r NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)_r R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)₂ NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)(=NR^e2 )R^b2 、-(CR^c2 R^d2 )_t N=S(O)R^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )R^b2 、-(CR^c2 R^d2 )_t S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t C(=NR^e2 )R^a2 、-(CR^c2 R^d2 )_t C(=N-OR^b2 )R^a2 、-(CR^c2 R^d2 )_t C(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(=NR^e2 )R^b2 和-(CR^c2 R^d2 )_t NR^a2 C(=NR^e2 )NR^a2 R^b2 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自OH、CN、氨基、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C1_-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 每個R^a2 和R^b2 獨立地選自氫、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C_1-10 烷基氨基、C_3-10 環烷基氨基、二（C_1-10 烷基）氨基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 或R^a2 和R^b2 一起連同與它們相連的單個或多個原子共同構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可以是未被取代的或被1或2個獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 每個R^c2 和R^d2 獨立地選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C_1-10 烷基氨基、C_3-10 環烷基氨基、二（C_1-10 烷基）氨基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷基氨基、環烷氨基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 或R^c2 和R^d2 一起連同與它們相連的單個或多個碳原子共同構成含有0、1或2個額外的獨立選自氧、硫和氮的雜原子的3-12元雜環，該環可以是未被取代的或被1或2個獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 每個R^e2 獨立地選自氫、CN、NO₂ 、C_1-10 烷基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、-C(O)C_1-4 烷基、-C(O)C_3-10 環烷基、-C(O)OC_1-4 烷基、-C(O)OC_3-10 環烷基、-C(O)N(C_1-4 烷基)₂ 、-C(O)N(C_3-10 環烷基)₂ 、-S(O)₂ C_1-4 烷基、-S(O)₂ C_3-10 環烷基、-S(O)₂ N(_1-4 烷基₎₂ 和-S(O)₂ N(C_3-10 環烷基)₂ ； m選自0、1、2、3和4； n選自0、1和2； p選自0、1和2； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4。In one aspect, the present invention provides a compound represented by formula (I) or (II):

(I) or

(II) wherein Q is selected from aryl and heteroaryl; each R ^{1 is} independently selected from hydrogen, halogen, hydroxyl, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl , Aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, ring Alkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di(alkyl)amino, heterocyclyl, aryl and heteroaryl are unsubstituted or have at least one, such as 1, 2, 3 or 4, independently selected from R ^x substituents; each R ^{2 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkane Group, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -S(O) _r R ^A1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -P(O)R ^A1 R ^B1 , -P(O)(OR ^A1 )(OR ^B1 ), -C(O)R ^A1 , -C(O)OR ^A1 ,- OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -S(O) _r NR ^A1 R ^B1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O) 2NR ^A1 R ^B1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) (=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 ,- C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 and -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , where each Each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are respectively unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from R ^x Each R ^{3 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 ring Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , -S(O) _r R ^A2 , -S(O) ₂ OR ^A2 , -OS(O) ₂ R ^A2 , -P(O) R ^A2 R ^B2 , -P(O)(OR ^A2 )(OR ^B2 ), -C(O)R ^A2 , -C(O)OR ^A2 , -OC(O)R ^A2 , -C(O)NR ^A2 R ^B2 , -NR ^A2 C(O)R ^B2 , -OC(O)NR ^A2 R ^B2 , -NR ^A2 C(O)OR ^B2 , -NR ^A2 C(O)NR ^A2 R ^B2 , -NR ^A2 C( S)NR ^A2 R ^B2 、-S(O) _r NR ^A2 R ^B2 、-NR ^A2 S(O) _r R ^B2 、-NR ^A2 S(O) ₂ NR ^A2 R ^B2 、-S(O)(=NR ^E2 )R ^B2 , -N=S(O)R ^A2 R ^B2 , -NR ^A2 S(O)(=NR ^E2 )R ^B2 , -S(O)(=NR ^E2 )NR ^A2 R ^B2 , -NR ^A2 S(O)(=NR ^E2 )NR ^A2 R ^B2 , -C(=NR ^E2 )R ^A2 , -C(=N-OR ^B2 )R ^A2 , -C(=NR ^E2 )NR ^A2 R ^B2 , -NR ^A2 C(=NR ^E2 )R ^B2 and -NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group Each is unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; each R ^{4 is} selected from hydrogen, halogen, C _1-10 alkyl, C _{2 -10} alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, Aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -S(O) _r R ^A3 , -S(O) ₂ OR ^A3 , -OS(O) ₂ R ^A3 , -P(O) R ^A3 R ^B3 , -P(O)(OR ^A3 )(OR ^B3 ), -C(O)R ^A3 , -C(O)OR ^A3 , -OC(O)R ^A3 , -C(O)NR ^A3 R ^B3 , -NR ^A3 C(O)R ^B3 , -OC(O)NR ^A3 R ^B3 , -NR ^A3 C(O)OR ^B3 , -NR ^A3 C(O)NR ^A3 R ^B3 , -NR ^A3 C( S)NR ^A3 R ^B3 、-S(O) _r NR ^A3 R ^B3 、-NR ^A3 S(O) _r R ^B3 、-NR ^A3 S(O) ₂ NR ^A3 R ^B3 、-S(O)(=NR ^E3 )R ^B3 , -N=S(O)R ^A3 R ^B3 , -NR ^A3 S(O)(=NR ^E3 )R ^B3 , -S(O)(=NR ^E3 )NR ^A3 R ^B3 , -NR ^A3 S(O)(=NR ^E3 )NR ^A3 R ^B3 , -C(=NR ^E3 )R ^A3 , -C(=N-OR ^B3 )R ^A3 , -C(=NR ^E3 )NR ^A3 R ^B3 , -NR ^A3 C(=NR ^E3 )R ^B3 and -NR ^A3 C(=NR ^E3 )NR ^A3 R ^B3 , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group Each is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X ; each R ^{5 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkane Group, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A4 R ^B4 , -(CH ₂ ) _t NR ^A4 R ^B4 , -OR ^A4 , -S(O) _r R ^A4 , -S(O) ₂ OR ^A4 , -OS(O) ₂ R ^A4 , -P(O)R ^A4 R ^B4 , -P(O)(OR ^A4 )(OR ^B4 ), -C(O)R ^A4 , -C(O)OR ^A4 , -OC(O)R ^A4 , -C(O)NR ^A4 R ^B4 , -NR ^A4 C(O)R ^B4 , -OC(O)NR ^A4 R ^B4 , -NR ^A4 C(O)OR ^B4 , -NR ^A4 C(O)NR ^A4 R ^B4 , -NR ^A4 C(S)NR ^A4 R ^B4 , -S(O) _r NR ^A4 R ^B4 , -NR ^A4 S(O) _r R ^B4 , -NR ^A4 S( O) ₂ NR ^A4 R ^B4 , -S(O)(=NR ^E4 )R ^B4 , -N=S(O)R ^A4 R ^B4 , -NR ^A4 S(O)(=NR ^E4 )R ^B4 , -S (O)(=NR ^E4 )NR ^A4 R ^B4 , -NR ^A4 S(O)(=NR ^E4 )NR ^A4 R ^B4 , -C(=NR ^E4 )R ^A4 , -C(=N-OR ^B4 )R ^A4 , -C(=NR ^E4 )NR ^A4 R ^B4 , -NR ^A4 C(=NR ^E4 )R ^B4 and -NR ^A4 C(=NR ^E4 )NR ^A4 R ^B4 , where each alkyl, alkenyl, alkyne Group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; each R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^B1 , R ^B2 , R ^B3 and R ^{B4 are} independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, Heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is respectively unsubstituted or at least One, such as 1, 2, 3 or 4, independently selected from ^{the substituents of R X} ; or each of "R ^A1 and R ^B1 ", "R ^A2 and R ^B2 ", "R ^A3 and R ^B3 "or" R ^A4 and R ^B4 "together with the single or multiple atoms connected to them form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the The ring may be unsubstituted or substituted with 1, 2 or 3 R ^X groups; each R ^E1 , R ^E2 , R ^E3 and R ^{E4 is} independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ; each R ^{X is} independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl -C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl , Halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t C(= NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 and -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , where each alkyl, alkenyl, alkynyl, cycloalkyl, The heterocyclic group, the aryl group and the heteroaryl group are respectively unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^Y ; each of R ^a1 and R ^{b1 is} independently Selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocycle Group, heterocyclic group-C _1-4 alkyl, aryl, aryl -C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl respectively Is unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y substituents; or R ^a1 and R ^b1 together with the single or multiple atoms connected to them constitute the inclusion 0, 1 or 2 additional 4-12 membered heterocycles independently selected from oxygen, sulfur, nitrogen and phosphorus heteroatoms, the ring may be unsubstituted or 1, 2 or 3 selected from R ^Y Substituent substitution; each R ^c1 and R ^{d1 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _{3 -10} Cycloalkyl- _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _{1 -4} alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is respectively unsubstituted or at least one, such as 1, 2, 3 or 4 One, independently selected from the substituents of ^{R Y ; or R c1} and R ^d1 together with the single or more carbon atoms to which they are connected together form a group containing 0, 1 or 2 additional independently selected from oxygen, sulfur and nitrogen Heteroatomic 3-12 membered heterocycle, the ring may be unsubstituted or substituted by 1, 2 or 3 R ^Y groups; each R ^{e1 is} independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ; each R ^{Y is} independently selected from C _1-10 alkyl, C _2-10 Alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl , Aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) ₂ OR ^b2 , -(CR ^c2 R ^d2 ) _t OS(O ) ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t C(O)R ^a2 , -(CR ^c2 R ^d2 ) _t C(O)OR ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C (O)R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)OR ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(S)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t N=S(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t C (=NR ^e2 )R ^a2 , -(CR ^c2 R ^d2 ) _t C(=N-OR ^b2 )R ^a2 , -(CR ^c2 R ^d2 ) _t C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )R ^b2 and -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , where each alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are respectively unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from OH, CN, amino, halogen, C _1-10 alkyl , C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 Substitution of cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C1 _-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino Group substitution; each of R ^a2 and R ^{b2 is} independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkene Group, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclic, heterocyclic Group-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, ring Alkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _{1- 10} alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and Substitution of bis(C _1-10 alkyl)amino; or R ^a2 and R ^b2 together with the single or multiple atoms connected to them together form 0, 1 or 2 additional independently selected from oxygen, sulfur, A 4-12 membered heterocyclic ring of nitrogen and phosphorus heteroatoms, the ring may be unsubstituted or be 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, Amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^c2 and R ^{d2 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy , C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, two (C _1-10 Alkyl) amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each Alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl groups Each is unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkane Base amino, C _3-10 cycloalkylamine And di (C _1-10 alkyl) amino substituents; or R ^c2 and R ^d2 together with the individual they are attached together form one or more carbon atoms containing 1 or 2 additional independently selected from oxygen , Sulfur and nitrogen heteroatoms 3-12 membered heterocyclic ring, the ring may be unsubstituted or 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio , Amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents; each R ^{e2 is} independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C( O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C( O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N( _1-4 alkyl _{) 2} and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; m is selected from 0, 1, 2, 3 and 4; n is selected from 0, 1, and 2; p is selected from 0, 1, and 2; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4.

In another aspect, the present invention provides a pharmaceutical composition, which includes a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method for regulating CDK4/6, the method comprising administering a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof to a system or individual in need The pharmaceutical composition thereby modulates CDK4/6.

On the other hand, the present invention also provides a method for treating, ameliorating or preventing a disease responsive to CDK4/6 inhibition, including administering to a system or individual in need an effective amount of a compound of formula (I) or (II) or its pharmaceutically acceptable The accepted salt or pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, is used to treat the above-mentioned conditions.

Alternatively, the present invention provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease mediated by CDK4/6. In certain embodiments, the compound can be used alone or in combination with a second therapeutic agent to treat CDK4/6-mediated conditions.

Alternatively, the present invention provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in the treatment of CDK4/6 mediated disorders.

Particularly, the conditions include but are not limited to autoimmune diseases, transplant diseases, infectious diseases or cell proliferation disorders.

In addition, the present invention provides a method for treating cell proliferative disorders, the method comprising administering an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a system or individual in need thereof, and Optionally used in combination with a second therapeutic agent to treat the above-mentioned conditions.

Alternatively, the present invention provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cell proliferative disorders. In certain embodiments, the compound can be used alone or in combination with a second therapeutic agent to treat cell proliferative disorders.

Specifically, wherein the cell proliferative disorder includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or breast, kidney, prostate, colorectal, thyroid, ovarian, pancreatic, neuron, lung, uterine, or gastrointestinal tumors .

In the above method of using the compound of the present invention, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may be administered to a system containing cells or tissues, or include mammalian individuals, such as human or animal individuals Within the individual.

the term

和

。 此處所用的“芳基-烷基”是指芳基取代的烷基。示例的芳烷基包括苄基，苯乙基和萘甲基等。在一些實施中，芳烷基含7-20或7-11個碳原子。當使用“芳基C_1-4 烷基”時，其中“C_1-4 ”是指烷基部分而不是芳基部分的碳原子數。 此處所用的“雜環基-烷基”是指雜環基取代的烷基。當使用“雜環基-C_1-4 烷基”時，其中“C_1-4 ”是指烷基部分而不是雜環基部分的碳原子數。 此處所用的“環烷基-烷基”是指環烷基取代的烷基。當使用“C_3-10 環烷基-C_1-4 烷基”時，其中“C_3-10 ”是指環烷基部分而不是烷基部分的碳原子數。其中“C_1-4 ”是指烷基部分而不是環烷基部分的碳原子數。 此處所用的“雜芳基-烷基”是指雜芳基取代的烷基。當使用“雜芳基-C_1-4 烷基”時，其中“C_1-4 ”是指環烷基部分而不是雜芳基部分的碳原子數。 為避免歧義，例如：當提到烷基、環烷基、雜環基烷基、芳基和/或其雜芳基取代時，其意是指每個這些基團單獨地取代，或是指這些基團混合取代。亦即：如果R¹ 是芳烷基，芳基部分可為未被取代的或被至少一個，如1、2、3或4個獨自選自R^x 的取代基取代，烷基部分也可為未被取代的或被至少一個，如1、2、3或4個獨自選自R^x 的取代基。 “藥學上可接受的鹽”是指與藥學上可接受的無毒的鹼或酸，包括無機或有機鹼和無機或有機酸製成的鹽。無機鹼的鹽可以選自，例如：鋁、銨、鈣、銅、鐵、亞鐵、鋰、鎂、錳、二價錳、鉀、鈉、鋅鹽。進一步，藥學上可接受的無機鹼的鹽可選自銨、鈣、鎂、鉀和鈉鹽。在固體鹽中可能存在一個或多個晶體結構，也有可能存在水合物的形式。藥學上可接受的有機無毒鹼的鹽可選自，例如：伯胺、仲胺和叔胺鹽，取代胺包括自然存在的取代胺、環胺和鹼性離子交換樹脂如精氨酸、甜菜鹼、咖啡鹼、膽鹼、N,N-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基呱啶、葡萄糖胺、氨基葡萄糖、組氨酸，海巴明胺、異丙胺、賴氨酸、甲葡糖胺、嗎啉、呱嗪、呱啶、多胺樹脂、普魯卡因、嘌呤、可哥鹼、三乙胺、三甲胺和三丙胺、氨丁三醇。 當本專利所指化合物是鹼時，需要與至少一種藥學上可接受的無毒酸製備其鹽，這些酸選自無機和有機酸。例如，選自醋酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙烷磺酸、富馬酸、葡萄糖酸、谷氨酸、氫溴酸、鹽酸、羥乙磺酸、乳酸、馬來酸、蘋果酸、扁桃酸、甲烷磺酸、黏液酸、硝酸、撲酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸和對甲苯磺酸。在一些實施例中，可選擇這些酸，例如：檸檬酸、氫溴酸、鹽酸、馬來酸、磷酸、硫酸、富馬酸和酒石酸。 化合物或其藥學上可接受的鹽的“給與”或“給藥”是指為需要治療的個體提供本發明中的化合物或其藥學可接受的鹽。 “有效量”是指化合物或其藥學上可接受的鹽能夠引起組織、系統、動物或人類出現可被研究人員、獸醫、臨床醫生或其他臨床人員觀察到的生物學或醫學反應的劑量。 “組合物”包括：包含特定量的特定成分的產品，以及任何直接或間接這些特定量的特定成分的組合而成的產品。藥物組合物包含：包含有效成分和作為載體的惰性成分的產品，以及任何兩個或兩個以上的成分直接或間接，通過組合、複合或聚集而製成的產品，或通過一個或更多的成分分解產生的產品，或通過一個或更多的成分發生其他類型反應或相互作用產生的產品。 “藥學可接受”是指與製劑中的其它組分相容，並且對服用者無不可接受的毒害。 “個體”是指患有疾病、病症之類的個體，包括哺乳動物和非哺乳動物。哺乳動物包括，但不僅限於，哺乳類的任何成員：人類，非人類的靈長類動物如黑猩猩，和其他猿類和猴子；農場動物如牛、馬、綿陽、山羊、豬；家畜如兔、狗和貓；實驗動物包括齧齒類如大鼠、小鼠和豚鼠等。非哺乳類動物包括，但不僅限於，鳥類、魚類等。本發明的一個實施例中，哺乳動物為人類。 “治療”包括緩解、減輕或改善疾病或症狀，預防其他症狀，改善或預防症狀的潛在代謝因素，抑制疾病或症狀，例如，阻止疾病或症狀發展，減輕疾病或症狀，促進疾病或症狀緩解，或使疾病或症狀的病徵停止，和延生至包括預防。“治療”還包括實現治療性獲益和/或預防性獲益。治療性獲益是指根除或改善所治療的病症。此外，治療性獲益通過根除或改善一個或多個與潛在疾病相關的生理病徵達到，儘管患者可能仍患有潛在疾病，但可觀察到患者疾病的改善。預防性獲益是指，患者為預防某種疾病風險而服用組合物，或患者出現一個或多個疾病生理病症時服用，儘管尚未診斷此疾病。 “保護基”（Pg）是指一類用於與化合物上其它官能團反應而阻隔或保護特定官能團的取代基。例如，“氨基保護基”是指聯接在氨基上阻隔或保護化合物上氨基官能團的取代基。適合的氨基保護基團包括乙醯基、三氟基，叔丁酯基(BOC)，叔丁酯基(CBZ)和氯甲酸-9-芴基甲酯(Fmoc)。同樣，“羥基保護基”是指一類羥基取代基可有效阻擋或保護羥基功能。適當的保護基包括乙醯基和甲矽烷基。“羧基保護基”是指一類羧基取代基能有效阻擋或保護羧基的功能。常用羧基保護基包括-CH₂ CH₂ SO₂ Ph，氰乙基，2-(三甲矽基)乙基，2 -(三甲矽基)乙氧基甲基，2 - (對甲苯磺醯胺)乙基，2 -(對硝基苯硫基)乙基，2-(二苯基膦)-乙基，硝基乙基等。對於保護基的一般描述和使用說明，見參考文獻：T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons , New York, 1991。 “NH保護基”包含，但不僅限於，三氯乙氧基甲醯基、三溴乙氧基甲醯基、苄氧羰基、對硝基苄甲醯基、鄰溴苄氧羰基、氯乙醯基、二氯乙醯基、三氯乙醯基、三氟乙醯基、苯乙醯基、甲醯基、乙醯基、苯甲醯基、叔戊氧羰基、叔丁氧羰基、對甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、4-(苯偶氮基)苄氧羰基、2-糠基氧羰基、二苯基甲氧羰基、1,1-二甲基丙氧基羰基、異丙氧羰基、鄰苯二甲醯、琥珀醯、丙氨醯、亮氨醯、1-金剛烷氧羰基、8-喹啉基氧羰基、苄基、二苯甲基、三苯甲基、2-硝基苯基硫醇、甲磺醯基、對甲苯磺醯基、N,N-二甲基氨基亞甲基、苯亞甲基、2-羥基苯亞甲基、2-羥基-5-氯苯亞甲基、2-羥基-l-萘基亞甲基、3-羥基-4-吡啶基亞甲基、亞環己基、2-乙氧基羰基亞環己基、2-乙氧基羰基亞環戊基、2-乙醯基亞環己基、3,3-二甲基-5-氧亞環己基、二苯基磷醯基、5-甲基-2-氧基-2H-l,3-二氧基-4-基-甲基、三甲基矽烷基、三乙基矽烷基和三苯基矽烷基。 “C(O)OH”保護基包含，但不僅限於，甲基、乙基、正丙基、異丙基、1,1-二甲基丙基、正丁基、苯基、萘基、苄基、二苯甲基、三苯甲基、對硝基苄基、對甲氧基苄基、雙(對甲氧苯基)甲基、乙醯甲基、苯甲醯甲基、對硝基苯甲醯甲基、對溴苯甲醯甲基、對甲磺醯苯甲醯甲基、2-四氫吡喃基、2-四氫呋喃基、2,2,2-三氯乙基、2-(三甲基矽烷基)乙基、乙醯氧基甲基、丙醯氧基甲基、特戊醯氧基甲基、苯二甲醯亞胺甲基、琥珀醯亞胺甲基、環丙基、環丁基、環戊基、環己基、甲氧基甲基、甲氧基乙氧基甲基、2-(三甲基矽烷基)乙氧基甲基、苄基氧基甲基、甲基硫基甲基、2-甲基硫基乙基、苯基硫基甲基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、二乙基異丙基矽烷基、叔丁基二甲基矽烷基、叔丁基二苯基矽烷基、叔丁基二苯基矽烷基、二苯基甲基矽烷基和叔丁基甲氧基苯基矽烷基。 “OH或SH”保護基包含，但不僅限於，苄氧羰基、4-硝基苄氧羰基、4-溴苄氧羰基、4-甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、甲氧基羰基、乙氧基羰基、叔丁氧羰基、1,1-二甲基丙氧基羰基、異丙氧羰基、二苯基甲氧基羰基、2,2,2-三氯乙氧基羰基、2,2,2-三溴乙氧基羰基、2-(三甲基矽烷)乙氧基羰基、2-(苯磺醯基)乙氧基羰基、2-(三苯基磷鎓基)乙氧基羰基、2-糠基氧基羰基、1-金剛烷氧基羰基、乙烯基氧基羰基、烯丙基氧基羰基、4-乙氧基-1-萘基氧基羰基、8-喹啉基氧基羰基、乙醯基、甲酸基、氯乙醯基、二氯乙醯基、三氯乙醯基、三氟乙醯基、甲氧基乙醯基、苯氧基乙醯基、特戊醯基、苯甲醯基、甲基、叔丁基、2,2,2-三氯乙基、2-三甲基矽烷基乙基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、苄基(苯基甲基)、對甲氧基苄基、3,4-二甲氧基苄基、二苯基甲基、三苯基甲基、四氫呋喃基、四氫吡喃基、四氫噻喃基、甲氧基甲基、甲基硫基甲基、苄基氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯-乙氧基甲基、2-(三甲基矽烷基)乙氧基甲基、1-乙氧基乙基、甲磺醯基、對甲苯磺醯基、三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、二乙基異丙基矽烷基、叔丁基二甲基矽烷基、叔丁基二苯基矽烷基、二苯基甲基矽烷基和叔丁基甲氧基苯基矽烷基。Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by professionals in the field. Unless otherwise specified, all patents, patent applications, and publicly disclosed materials referred to in this patent are incorporated in the reference in their entirety. If there are multiple definitions of the same term in this patent, the definition in this section shall prevail. It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory, and are not restrictive to any claims. In this patent application, unless otherwise specified, the use of the singular includes the plural. It should be noted that, in the specification and appended claims, unless otherwise specified in the context, the singular form refers to such as "a", "an", "this", including plural designations. It should also be noted that, unless otherwise specified, "or" means "and/or". In addition, "including", "including" and similar terms are not restrictive. Standard definitions of chemical terms can refer to reference books, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4th Edition." Volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise specified, the mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet spectroscopy and conventional pharmacological techniques used in this patent are prior art. Unless specifically defined, the naming, experimental methods and techniques involved in analytical chemistry, synthetic organic chemistry, medicine and pharmaceutical chemistry in this patent are all known. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and administration, and treatment of patients. The reaction and purification techniques can be implemented by referring to the manufacturer's instructions, or referring to known common techniques, or referring to the methods described in this patent. The above-mentioned techniques and operations can be implemented using known conventional methods and the methods cited in this specification. In the specification, the groups and substituents can be selected by professionals in the field to form stable structures and compounds. When a chemical formula is used to refer to a substituent, writing the substituent in the chemical formula from left to right is the same as writing from right to left. For example, CH ₂ O is the same as _{OCH 2.} As used herein, "optionally substituted" includes unsubstituted or substituted. "Substitution" means that the hydrogen atom is replaced by a substituent. It should be noted that the substituents on specific atoms are restricted by their valence. In the definition part, "C _ij "refers to the range including the starting point and the ending point, where i and j are both integers, representing the number of carbon atoms. For example, C _1-4 , C _1-10 , C _3-10 and so on. "Alkyl", whether used alone or in combination with other terms, refers to a branched and straight chain saturated aliphatic hydrocarbon group with a specific number of carbon atoms. Unless otherwise noted, "alkyl" refers to C ₁ -C ₆ alkyl. For example, "C ₁ -C ₆ "in _{"C 1-6} alkyl" refers to a group having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement. For example, "C _1-8 alkyl" includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl and octyl . "Cycloalkyl", whether used alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon ring system. Monocyclic cycloalkyl groups contain 3-10 carbon atoms, no heteroatoms, and no double bonds. Examples of monocyclic ring systems include propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The monocyclic cycloalkyl group contains one or two alkylene bridges, and each alkylene bridge contains 1, 2 or 3 carbon atoms, which connect two non-adjacent carbon atoms on the ring system. Representative examples of bridged hydrocarbon ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, Bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic and bridged hydrocarbon rings can be connected to the parent ring through any suitable atom in the ring system. "Alkenyl", whether used alone or in combination with other terms, refers to a non-aromatic linear, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, there is 1 carbon-carbon double bond, and up to 4 non-aromatic carbon-carbon double bonds may exist. Therefore, "C _2-6 alkenyl" refers to an alkenyl group containing 2-6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The linear, branched or cyclic part of the alkenyl group may contain a double bond, and if a substituted alkenyl group is indicated, it may be substituted. "Alkynyl", whether used alone or in combination with other terms, refers to a linear, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there may be 3 carbon-carbon triple bonds. Therefore, "C _2-6 alkynyl" refers to an alkynyl group containing 2-6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The linear, branched or cyclic part of the alkynyl group may contain a triple bond. If a substituted alkynyl group is indicated, it may be substituted. "Halogen" refers to fluorine, chlorine, bromine, and iodine. "Alkoxy", used alone or in combination with other terms, refers to an alkyl group connected to an oxygen atom by a single bond. The alkoxy group is connected to another molecule through an oxygen atom. Alkoxy can be represented as -O-alkyl. The "C _1-10 alkoxy group" refers to an alkoxy group containing 1-10 carbon atoms, which may be a straight chain or a branched structure. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, and the like. "Cycloalkoxy", used alone or in combination with other terms, refers to a cycloalkyl group connected to an oxygen atom by a single bond. The cycloalkoxy group is connected to another molecule through an oxygen atom. Cycloalkoxy can be represented as -O-cycloalkyl. The "C _3-10 cycloalkoxy group" refers to a cycloalkoxy group containing 3-10 carbon atoms. Cycloalkoxy includes, but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. "Alkylthio", used alone or in combination with other terms, refers to an alkyl group connected to a sulfur atom by a single bond. The alkylthio group is connected to another molecule through a sulfur atom. Alkylthio can be represented as -S-alkyl. The "C _1-10 alkylthio group" refers to an alkylthio group containing 1-10 carbon atoms, which may be a straight chain or branched structure. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like. "Cycloalkylthio", used alone or in combination with other terms, refers to a cycloalkyl group connected to a sulfur atom by a single bond. The cycloalkylthio group is connected to another molecule through a sulfur atom. Cycloalkylthio can be represented as -S-cycloalkyl. The "C _3-10 cycloalkylthio group" refers to a cycloalkylthio group containing 3-10 carbon atoms. Cycloalkylthio includes, but is not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. "Alkylamino", used alone or in combination with other terms, refers to an alkyl group connected to a nitrogen atom by a single bond. The alkylamino group is connected to another molecule through a nitrogen atom. Alkylamino can be represented as -NH (alkyl). The "C _1-10 alkylamino group" refers to an alkylamino group containing 1-10 carbon atoms, which may be a linear or branched structure. Alkylamino includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino, hexylamino and the like. "Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group connected to a nitrogen atom by a single bond. The cycloalkylamino group is connected to another molecule through a nitrogen atom. Cycloalkylamino can be represented as -NH (cycloalkyl). The "C _3-10 cycloalkylamino group" refers to a cycloalkylamino group containing 3-10 carbon atoms. Cycloalkylamino includes, but is not limited to, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like. "Di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl groups connected by a single bond to a nitrogen atom. The di(alkyl)amino group is connected to another molecule through a nitrogen atom. The di(alkyl)amino group can be represented as -N(alkyl) ₂ . "Two (C _1-10 alkyl) amino" refers to two alkyl moieties containing di (C _1-10 alkyl) of 1 to 10 carbon atoms are amino group, may be linear or branched structure. "Aryl" includes: 5- and 6-membered aromatic carbocyclic rings, such as phenyl; bicyclic rings with at least one aromatic carbocyclic ring, such as naphthyl, indan and 1,2,3,4-tetrahydroquinoline and at least An aromatic carbocyclic tricyclic ring, such as fluorene. If the aryl substituent is bicyclic or tricyclic and at least one of the rings is non-aromatic, then it shall be considered to be connected through an aromatic ring. For example, aryl groups include 5- and 6-membered aromatic carbocyclic rings, which are fused with a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is Aromatic carbon ring. A divalent radical formed by a substituted benzene derivative with free valence electrons on a ring atom is named a substituted phenylene radical. A divalent radical derived from a monovalent polycyclic hydrocarbon radical whose name ends with "- radical" is obtained by removing a hydrogen atom from a carbon atom containing free valence electrons, and its name is Add "-idene" to the name of the free radical. For example, a naphthyl group with two attachment sites is called a naphthylene group. However, the definition of aryl does not include or overlap with heteroaryl, and is defined separately as follows. Therefore, if one or more aromatic carbocyclic rings are fused with a heterocyclic aromatic ring, the ring system formed should be considered a heteroaryl group, not an aryl group as defined herein. "Heteroaryl" refers to a 5-membered to 8-membered aromatic monocyclic ring, which contains 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and in certain embodiments 1 to 3 heteroatoms. , The rest are carbon atoms; 8-membered to 12-membered bicyclic ring, the ring contains selected from N, O and S, the number is 1 to 4, in some embodiments, 1 to 3 heteroatoms, the rest are all It is a carbon atom, and at least one of the heteroatoms is present in the aromatic ring; and an 11- to 14-membered tricyclic ring. The ring contains heteroatoms selected from N, O and S, the number is 1 to 4, in some embodiments 1 to 3, the rest are carbon atoms, and at least one of the heteroatoms appears in the aromatic In the ring. When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl group is not more than two. In some embodiments, the total number of S and O in the heteroaryl group is not greater than one. Examples of heteroaryl groups include, but are not limited to (the numbering of the attachment site takes precedence and is designated as position 1) 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyridinyl Azinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazoline, isoxazolyl, oxazolyl, thiazole Group, thiadiazyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolinyl, indoline, pyridizinyl, triazolyl, quine Linyl, pyrazolyl and 5,6,7,8-tetrahydroisoquinolinyl. Further, heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinolyl and isoquinolyl. As defined below for heterocyclic groups, "heteroaryl groups" include N-oxide derivatives of nitrogen-containing heteroaryl groups. The name of the monovalent heteroaryl radical ends with "group", and the derived divalent radical is obtained by removing a hydrogen atom from the carbon atom containing free valence electrons. The name of the divalent radical Add "-idene" to the name of the monovalent radical. For example, a pyridyl group with two attachment sites is called a pyridinyl group. The definition of heteroaryl does not include or overlap with aryl as defined above. If the heteroaryl substituents are bicyclic or tricyclic, and at least one of the rings is non-aromatic or does not contain heteroatoms, it is generally considered to be connected through an aromatic ring or a heteroatom-containing ring, respectively. "Heterocycle" (and its derivatives such as "heterocyclic" or "heterocyclic group") generally refers to a single cyclic aliphatic hydrocarbon, usually having 3 to 12 ring atoms, containing at least 2 carbon atoms, and Containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen also refers to a combination containing at least one of the above heteroatoms. Alternatively, the above-defined heterocyclic ring may be a polycyclic ring system (for example, bicyclic ring), in which two or more rings exist in the form of a fused ring, a bridged ring, or a spiro ring, and at least one ring contains one or more independently selected rings. Heteroatoms from oxygen, sulfur and nitrogen. "Heterocyclic ring" also refers to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur fused with a 5- and 6-membered aromatic carbocyclic ring, provided that the point of attachment is in the heterocyclic ring superior. Heterocycles can be saturated or contain one or more double bonds (ie, partially unsaturated). The heterocyclic ring can be substituted by oxo. Either carbon atom or heteroatom on the heterocyclic ring can be the attachment site, provided that a stable structure is formed. When there is a substituent on the heterocyclic ring, the substituent can be connected to any heteroatom or carbon atom on the heterocyclic ring, provided that a stable chemical structure is formed. The definitions of heterocycle and heteroaryl described herein do not overlap. Suitable heterocycles include, for example (with attachment sites in priority order 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazoalkyl, 2,3-pyrazolidinonyl, 1-pyrrolidinyl Ridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and 2,5-pyridinyl. It also includes 2-morpholinyl and 3-morpholinyl (the oxygen atom position number is preferably 1). Substituent heterocycles also include ring systems substituted by one or more oxo groups, such as pyridinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholine And 1,1-dioxo-1-thiomorpholinyl. Biheterocyclic compounds include but are not limited to:

with

. As used herein, "aryl-alkyl" refers to an aryl substituted alkyl group. Exemplary aralkyl groups include benzyl, phenethyl, naphthylmethyl and the like. In some implementations, the aralkyl group contains 7-20 or 7-11 carbon atoms. When "aryl C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms of the alkyl moiety rather than the aryl moiety. As used herein, "heterocyclyl-alkyl" refers to an alkyl group substituted with a heterocyclic group. When "heterocyclyl-C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms of the alkyl moiety rather than the heterocyclyl moiety. As used herein, "cycloalkyl-alkyl" refers to an alkyl group substituted with a cycloalkyl group. When "C _3-10 cycloalkyl-C _1-4 alkyl" is used, "C _3-10 " refers to the number of carbon atoms of the cycloalkyl moiety rather than the alkyl moiety. Wherein "C _1-4 "refers to the number of carbon atoms of the alkyl moiety rather than the cycloalkyl moiety. As used herein, "heteroaryl-alkyl" refers to an alkyl group substituted with a heteroaryl group. When "heteroaryl-C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms of the cycloalkyl moiety rather than the heteroaryl moiety. To avoid ambiguity, for example, when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substitutions, it means that each of these groups is substituted individually, or that These groups are mixed and substituted. That is: if R ¹ is an aralkyl group, the aryl moiety can be unsubstituted or substituted with at least one, such as 1, 2, 3, or 4 ^{substituents independently selected from R x} , and the alkyl moiety can also be unsubstituted or substituted with at least one, such as 2, 3 or 4 independently selected R ^x substituents. "Pharmaceutically acceptable salt" refers to a salt made with a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Further, the salt of a pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. There may be one or more crystal structures in the solid salt, and may also exist in the form of hydrates. The salt of the pharmaceutically acceptable organic non-toxic base can be selected from, for example: primary amine, secondary amine and tertiary amine salt. Substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine and betaine. , Caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- Ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, Purine, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine. When the compound referred to in this patent is a base, its salt needs to be prepared with at least one pharmaceutically acceptable non-toxic acid, and these acids are selected from inorganic and organic acids. For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, horse Lyric acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. In some embodiments, these acids can be selected, for example: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid. The "administration" or "administration" of a compound or a pharmaceutically acceptable salt thereof refers to providing the compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment. "Effective amount" refers to the dose of a compound or a pharmaceutically acceptable salt thereof that can cause a biological or medical response in tissues, systems, animals, or humans that can be observed by researchers, veterinarians, clinicians, or other clinical personnel. "Composition" includes: a product containing a specific amount of specific ingredients, and any product that directly or indirectly combines these specific amounts of specific ingredients. The pharmaceutical composition includes: a product containing an active ingredient and an inert ingredient as a carrier, and a product made by combining, compounding or agglomerating any two or more ingredients directly or indirectly, or through one or more Products produced by the decomposition of components, or products produced by other types of reactions or interactions of one or more components. "Pharmaceutically acceptable" means that it is compatible with the other ingredients in the formulation and has no unacceptable toxicity to the user. "Individual" refers to individuals suffering from diseases, disorders, and the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cows, horses, Mianyang, goats, and pigs; domestic animals such as rabbits and dogs And cats; experimental animals include rodents such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human. "Treatment" includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, improvement or prevention of underlying metabolic factors of symptoms, suppression of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, promoting alleviation of diseases or symptoms, Or stop the symptoms of the disease or symptom, and prolong the growth to include prevention. "Treatment" also includes realizing therapeutic benefits and/or preventive benefits. Therapeutic benefit refers to eradicating or improving the condition being treated. In addition, the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease. Although the patient may still have the underlying disease, the improvement of the patient's disease can be observed. Preventive benefit refers to the patient taking the composition to prevent the risk of a certain disease, or taking it when the patient has one or more physiological conditions of the disease, although the disease has not yet been diagnosed. "Protecting group" (Pg) refers to a type of substituent used to react with other functional groups on a compound to block or protect specific functional groups. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the amino functional group on a compound. Suitable amino protecting groups include acetyl, trifluoro, tert-butyl ester (BOC), tert-butyl ester (CBZ) and 9-fluorenyl methyl chloroformate (Fmoc). Similarly, "hydroxyl protecting group" refers to a type of hydroxyl substituent that can effectively block or protect the function of the hydroxyl group. Suitable protecting groups include acetyl and silyl. "Carboxy protecting group" refers to a type of carboxyl substituent that can effectively block or protect the carboxyl group. Commonly used carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonamide) Ethyl, 2-(p-nitrophenylthio)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and usage instructions of protecting groups, see References: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons , New York, 1991. "NH protecting group" includes, but is not limited to, trichloroethoxycarbamyl, tribromoethoxycarbamyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, chloroacetoxy Acetyl, dichloroacetoxy, trichloroacetoxy, trifluoroacetoxy, phenethylacetoxy, methanoyl, acetoxy, benzyl, tert-pentoxycarbonyl, tert-butoxycarbonyl, p-methyl Oxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethyl Propoxycarbonyl, isopropoxycarbonyl, phthalate, succinate, alaninyl, leucine, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, benzhydryl , Trityl, 2-nitrophenyl mercaptan, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene , 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonyl cyclohexylidene , 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxocyclohexylene, diphenylphosphoryl, 5-methyl-2- Oxy-2H-l,3-dioxy-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl. "C(O)OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, phenyl, naphthyl, benzyl Benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzylmethyl, p-nitro Benzyl methyl, p-bromobenzyl methyl, p-toluene benzoyl methyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2- (Trimethylsilyl) Ethyl, Acetyloxymethyl, Propyloxymethyl, Pentyloxymethyl, Xylylenedimethylimine Methyl, Succinimidylmethyl, Cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, Methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl , Trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butyl Diphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl. "OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-tri Chloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2-(triphenyl) Phosphonium) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxy Carbonyl, 8-quinolinyloxycarbonyl, acetyl, formate, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, benzene Oxyacetoxy, p-pentanyl, benzyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl 2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, two Phenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxy Ethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methylsulfonyl, P-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl Group, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

Geometric isomers may exist in the compounds of the present invention. The compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where "E" means that according to the Cahn-Ingold-Prelog priority rule, the preferred substituents are on the carbon-carbon double bond or carbon -The opposite side of the nitrogen double bond, and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers. The substituents surrounding the cycloalkyl or heterocyclic group can be set in a cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. The two substituents around a single ring in the adamantane ring system are defined as the relative configuration of Z or E. For example, see C. D. Jones, M. Kaselj, R. N. Salvatore, W.J. le Noble, J. Org. Chem. 1998, 63, 2758-2760.

The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration. For the definitions of "R" and "S", see IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13- 10. Compounds containing asymmetrically substituted carbon atoms, if the amount of R and S configurations are the same, it is a racemate. If one of the configurations has a larger amount than the other configuration, the configuration of the chiral carbon atom is represented by the larger configuration, and the enantiomeric excess is preferably about 85-90%, more preferably about 95-99%, Further more than 99%. Therefore, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope-enriched or labeled compounds The compounds of the present invention can exist in an isotope-labeled or enriched form, and contain one or more atoms with different qualities and mass numbers from the most common atoms in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Other isotopes and/or other atoms containing these atoms are also within the scope of the present invention. In another embodiment, the isotope-labeled compound contains deuterium ( ² H), tritium ( ³ H), or ¹⁴ C isotopes. The isotope-labeled compound of the present invention can be obtained using methods well known to those skilled in the art. These isotope-labeled compounds can be obtained by referring to the examples and reaction diagrams of the present invention, and replacing non-labeled reagents with isotope-labeled reagents. In some cases, the actual treatment compound can be labeled with isotope, and atoms are replaced with isotopic atoms. For example, replacement of hydrogen with deuterium can be exchanged through the action of _{deuterated acids such as D 2} SO ₄ /D _{2 O.} In addition, related synthesis steps and intermediates can be found in, for example, Lizondo, J et al, Drugs Fut , 21(11), 1116 (1996); Brickner, SJ et al., J Med Chem , 39(3), 673 (1996); Mallesham, B et al, Org Lett , 5(7), 963 (2003); PCT Publication Nos. WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Patent Nos. 7538189, 7534814, 7531685, 7528131, 7521421, 7514068, 7511013; and US Patent Application Publication Nos. 20090137457, 20090131485, 20090131363, 20090118238, 20090111840, 20090105338, 20090105307, 20090105147, 20090093422, 20090088416 and 20090082471, see references for specific methods. The isotope-labeled compound of the present invention can be used as a standard for CDK4/6 inhibitor drug efficacy binding test. Isotopes-containing compounds can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the in vivo metabolism of compounds (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975) ). This type of metabolic research is very important for the design of safe and effective therapeutic drugs. It can be judged that the active compound in the body or the metabolite of the parent compound taken by the patient is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp . 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut. , 36(10):927-932 (1995); Kushner et al, Can. J. Physiol. Pharmacol , 77, 79-88 (1999)). In addition, drugs containing non-reflective active isotopes, such as deuterated drugs, called "heavy drugs", can be used to treat diseases and disorders related to CDK4/6 activity. The proportion of a certain isotope in a compound that exceeds its natural abundance is called enrichment. The amount of enrichment is, for example, from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to 100 mol%. In mammals, the replacement of 15% of general atoms with heavy isotopes is effective and can last for several days to several weeks, including rodents and dogs, and has fewer adverse reactions (zajka DM and Finkel AJ, Ann. NY Acad. Sci . 1960 84: 770; Thomson JF, Ann. New York Acad Sci 1960 84: 736; Czakja DM et al., Am. J. Physiol. 1961 201: 357). Replacing up to 15-23% of body fluids in the human body with deuterium does not cause toxicity (Blagojevic N et al in "Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing , Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)) Appropriate isotope labeling of drugs can change their physical and chemical properties, such as pKa and liquid solubility. If isotope substitution affects the ligand-receptor interaction area, then these effects and changes may affect the pharmacodynamic response of the drug molecule. Some of the physical properties of stable isotope-labeled molecules are different from those of unlabeled molecules, but the chemical and biological properties are the same. There is only one important difference: due to the increased quality of heavy isotopes, any chemical bond containing a heavy isotope and another atom is better than a light isotope. Stronger. Correspondingly, the presence of isotopes at metabolic or enzymatic conversion sites will slow down the reaction, thereby changing its pharmacokinetic characteristics or efficacy.

(I)或

(II) 其中， Q選自芳基和雜芳基； 每個R¹ 獨立選自氫、鹵素、羥基、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C_1-10 烷基氨基、C_3-10 環烷基氨基、二（C_1-10 烷基）氨基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷基氨基、環烷基氨基、二（烷基）氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^x 的取代基取代； 每個R² 獨立選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、 -NR^A1 R^B1 、-OR^A1 、-S(O)_r R^A1 、-S(O)₂ OR^A1 、-OS(O)₂ R^A1 、-P(O)R^A1 R^B1 、-P(O)(OR^A1 )(OR^B1 )、-C(O)R^A1 、-C(O)OR^A1 、-OC(O)R^A1 、-C(O)NR^A1 R^B1 、-NR^A1 C(O)R^B1 、-OC(O)NR^A1 R^B1 、-NR^A1 C(O)OR^B1 、-NR^A1 C(O)NR^A1 R^B1 、-NR^A1 C(S)NR^A1 R^B1 、-S(O)_r NR^A1 R^B1 、-NR^A1 S(O)_r R^B1 、-NR^A1 S(O)2NR^A1 R^B1 、-S(O)(=NR^E1 )R^B1 、-N=S(O)R^A1 R^B1 、-NR^A1 S(O)(=NR^E1 )R^B1 、-S(O)(=NR^E1 )NR^A1 R^B1 、-NR^A1 S(O)(=NR^E1 )NR^A1 R^B1 、-C(=NR^E1 )R^A1 、-C(=N-OR^B1 )R^A1 、-C(=NR^E1 )NR^A1 R^B1 、-NR^A1 C(=NR^E1 )R^B1 和-NR^A1 C(=NR^E1 )NR^A1 R^B1 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^x 的取代基取代； 每個R³ 獨立選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、-NR^A2 R^B2 、-OR^A2 、-S(O)_r R^A2 、-S(O)₂ OR^A2 、-OS(O)₂ R^A2 、-P(O)R^A2 R^B2 、-P(O)(OR^A2 )(OR^B2 ) 、-C(O)R^A2 、-C(O)OR^A2 、-OC(O)R^A2 、-C(O)NR^A2 R^B2 、-NR^A2 C(O)R^B2 、-OC(O)NR^A2 R^B2 、-NR^A2 C(O)OR^B2 、-NR^A2 C(O)NR^A2 R^B2 、-NR^A2 C(S)NR^A2 R^B2 、-S(O)_r NR^A2 R^B2 、-NR^A2 S(O)_r R^B2 、-NR^A2 S(O)₂ NR^A2 R^B2 、-S(O)(=NR^E2 )R^B2 、-N=S(O)R^A2 R^B2 、-NR^A2 S(O)(=NR^E2 )R^B2 、-S(O)(=NR^E2 )NR^A2 R^B2 、-NR^A2 S(O)(=NR^E2 )NR^A2 R^B2 、-C(=NR^E2 )R^A2 、-C(=N-OR^B2 )R^A2 、-C(=NR^E2 )NR^A2 R^B2 、-NR^A2 C(=NR^E2 )R^B2 和-NR^A2 C(=NR^E2 )NR^A2 R^B2 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 每個R⁴ 選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、-NR^A3 R^B3 、-OR^A3 、-S(O)_r R^A3 、-S(O)₂ OR^A3 、-OS(O)₂ R^A3 、-P(O)R^A3 R^B3 、-P(O)(OR^A3 )(OR^B3 )、-C(O)R^A3 、-C(O)OR^A3 、-OC(O)R^A3 、-C(O)NR^A3 R^B3 、-NR^A3 C(O)R^B3 、-OC(O)NR^A3 R^B3 、-NR^A3 C(O)OR^B3 、-NR^A3 C(O)NR^A3 R^B3 、-NR^A3 C(S)NR^A3 R^B3 、-S(O)_r NR^A3 R^B3 、-NR^A3 S(O)_r R^B3 、-NR^A3 S(O)₂ NR^A3 R^B3 、-S(O)(=NR^E3 )R^B3 、-N=S(O)R^A3 R^B3 、-NR^A3 S(O)(=NR^E3 )R^B3 、-S(O)(=NR^E3 )NR^A3 R^B3 、-NR^A3 S(O)(=NR^E3 )NR^A3 R^B3 、-C(=NR^E3 )R^A3 、-C(=N-OR^B3 )R^A3 、-C(=NR^E3 )NR^A3 R^B3 、-NR^A3 C(=NR^E3 )R^B3 和-NR^A3 C(=NR^E3 )NR^A3 R^B3 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 每個R⁵ 獨立地選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、CN、NO₂ 、-NR^A4 R^B4 、-(CH₂ )_t NR^A4 R^B4 、-OR^A4 、-S(O)_r R^A4 、-S(O)₂ OR^A4 、-OS(O)₂ R^A4 、-P(O)R^A4 R^B4 、-P(O)(OR^A4 )(OR^B4 )、-C(O)R^A4 、-C(O)OR^A4 、-OC(O)R^A4 、-C(O)NR^A4 R^B4 、-NR^A4 C(O)R^B4 、-OC(O)NR^A4 R^B4 、-NR^A4 C(O)OR^B4 、-NR^A4 C(O)NR^A4 R^B4 、-NR^A4 C(S)NR^A4 R^B4 、-S(O)_r NR^A4 R^B4 、-NR^A4 S(O)_r R^B4 、-NR^A4 S(O)₂ NR^A4 R^B4 、-S(O)(=NR^E4 )R^B4 、-N=S(O)R^A4 R^B4 、-NR^A4 S(O)(=NR^E4 )R^B4 、-S(O)(=NR^E4 )NR^A4 R^B4 、-NR^A4 S(O)(=NR^E4 )NR^A4 R^B4 、-C(=NR^E4 )R^A4 、-C(=N-OR^B4 )R^A4 、-C(=NR^E4 )NR^A4 R^B4 、-NR^A4 C(=NR^E4 )R^B4 和-NR^A4 C(=NR^E4 )NR^A4 R^B4 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 每個R^A1 、R^A2 、R^A3 、R^A4 、R^B1 、R^B2 、R^B3 和R^B4 獨立地選自氫、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代； 或每個“R^A1 和R^B1 ”、“R^A2 和R^B2 ”、“R^A3 和R^B3 ”或“R^A4 和R^B4 ”一起連同與它們相連的單個或多個原子共同構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可以是未被取代的或被1、2或3個R^X 基團取代； 每個R^E1 、R^E2 、R^E3 和R^E4 獨立地選自氫、C_1-10 烷基、CN、 NO₂ 、-OR^a1 、-SR^a1 、-S(O)_r R^a1 、-C(O)R^a1 、-C(O)OR^a1 、-C(O)NR^a1 R^b1 和-S(O)_r NR^a1 R^b1 ； 每個R^X 獨立地選自C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、鹵素、CN、NO₂ 、-(CR^c1 R^d1 )_t NR^a1 R^b1 、-(CR^c1 R^d1 )_t OR^b1 、-(CR^c1 R^d1 )_t S(O)_r R^b1 、-(CR^c1 R^d1 )_t S(O)₂ OR^b1 、-(CR^c1 R^d1 )_t OS(O)₂ R^b1 、-(CR^c1 R^d1 )_t P(O)R^a1 R^b1 、-(CR^c1 R^d1 )_t P(O)(OR^a1 )(OR^b1 )、-(CR^c1 R^d1 )_t C(O)R^a1 、-(CR^c1 R^d1 )_t C(O)OR^b1 、-(CR^c1 R^d1 )_t OC(O)R^b1 、-(CR^c1 R^d1 )_t C(O)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(O)R^b1 、-(CR^c1 R^d1 )_t OC(O)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(O)OR^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)_r R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)₂ NR^a1 R^b1 、-(CR^c1 R^d1 )_t S(O)(=NR^e1 )R^b1 、-(CR^c1 R^d1 )_t N=S(O)R^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )R^b1 、-(CR^c1 R^d1 )_t S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t C(=NR^e1 )R^a1 、-(CR^c1 R^d1 )_t C(=N-OR^b1 )R^a1 、-(CR^c1 R^d1 )_t C(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )R^b1 和-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )NR^a1 R^b1 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^Y 的取代基取代； 每個R^a1 和R^b1 獨立地選自氫、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^Y 的取代基取代； 或R^a1 和R^b1 一起連同與它們相連的單個或多個原子共同構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可以是未被取代的或被1、2或3個選自R^Y 的取代基取代； 每個R^c1 和R^d1 獨立地選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^Y 的取代基取代； 或R^c1 和R^d1 一起連同與它們相連的單個或多個碳原子共同構成含有0、1或2個額外的獨立選自氧、硫和氮的雜原子的3-12元雜環，該環可以是未被取代的或被1、2或3個R^Y 基團取代； 每個R^e1 獨立地選自氫、C_1-10 烷基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、CN、NO₂ 、-OR^a2 、-SR^a2 、-S(O)_r R^a2 、-C(O)R^a2 、-C(O)OR^a2 、-S(O)_r NR^a2 R^b2 和-C(O)NR^a2 R^b2 ； 每個R^Y 獨立地選自C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基、雜芳基-C_1-4 烷基、鹵素、CN、NO₂ 、-(CR^c2 R^d2 )_t NR^a2 R^b2 、-(CR^c2 R^d2 )_t OR^b2 、-(CR^c2 R^d2 )_t S(O)_r R^b2 、-(CR^c2 R^d2 )_t S(O)₂ OR^b2 、-(CR^c2 R^d2 )_t OS(O)₂ R^b2 、-(CR^c2 R^d2 )_t P(O)R^a2 R^b2 、-(CR^c2 R^d2 )_t P(O)(OR^a2 )(OR^b2 )、-(CR^c2 R^d2 )_t C(O)R^a2 、-(CR^c2 R^d2 )_t C(O)OR^b2 、-(CR^c2 R^d2 )_t OC(O)R^b2 、-(CR^c2 R^d2 )_t C(O)NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(O)R^b2 、-(CR^c2 R^d2 )_t OC(O)NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(O)OR^b2 、-(CR^c2 R^d2 )_t NR^a2 C(O)NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(S)NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)_r NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)_r R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)₂ NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)(=NR^e2 )R^b2 、-(CR^c2 R^d2 )_t N=S(O)R^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )R^b2 、-(CR^c2 R^d2 )_t S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t C(=NR^e2 )R^a2 、-(CR^c2 R^d2 )_t C(=N-OR^b2 )R^a2 、-(CR^c2 R^d2 )_t C(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(=NR^e2 )R^b2 和-(CR^c2 R^d2 )_t NR^a2 C(=NR^e2 )NR^a2 R^b2 ，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自OH、CN、氨基、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C1_-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 每個R^a2 和R^b2 獨立地選自氫、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C_1-10 烷基氨基、C_3-10 環烷基氨基、二（C_1-10 烷基）氨基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 或R^a2 和R^b2 一起連同與它們相連的單個或多個原子共同構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可以是未被取代的或被1或2個獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 每個R^c2 和R^d2 獨立地選自氫、鹵素、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、C_1-10 烷基氨基、C_3-10 環烷基氨基、二（C_1-10 烷基）氨基、雜環基、雜環基-C_1-4 烷基、芳基、芳基-C_1-4 烷基、雜芳基和雜芳基-C_1-4 烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷基氨基、環烷氨基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個，如1、2、3或4個，獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 或R^c2 和R^d2 一起連同與它們相連的單個或多個碳原子共同構成含有0、1或2個額外的獨立選自氧、硫和氮的雜原子的3-12元雜環，該環可以是未被取代的或被1或2個獨立選自鹵素、CN、C_1-10 烷基、C_2-10 烯基、C_2-10 炔基、C_3-10 環烷基、羥基、C_1-10 烷氧基、C_3-10 環烷氧基、C_1-10 烷硫基、C_3-10 環烷硫基、氨基、C_1-10 烷基氨基、C_3-10 環烷基氨基和二（C_1-10 烷基）氨基的取代基取代； 每個R^e2 獨立地選自氫、CN、NO₂ 、C_1-10 烷基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、C_1-10 烷氧基、C_3-10 環烷氧基、-C(O)C_1-4 烷基、-C(O)C_3-10 環烷基、-C(O)OC_1-4 烷基、-C(O)OC_3-10 環烷基、-C(O)N(C_1-4 烷基)₂ 、-C(O)N(C_3-10 環烷基)₂ 、-S(O)₂ C_1-4 烷基、-S(O)₂ C_3-10 環烷基、-S(O)₂ N(C_1-4 烷基₎₂ 和-S(O)₂ N(C_3-10 環烷基)₂ ； m選自0、1、2、3和4； n選自0、1和2； p選自0、1和2； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4。In embodiment (1), the present invention provides a compound represented by formula (I) or (II):

(I) or

(II) wherein Q is selected from aryl and heteroaryl; each R ^{1 is} independently selected from hydrogen, halogen, hydroxyl, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl , Aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, ring Alkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di(alkyl)amino, heterocyclyl, aryl and heteroaryl are unsubstituted or have at least one, such as 1, 2, 3 or 4, independently selected from R ^x substituents; each R ^{2 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkane Group, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -S(O) _r R ^A1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -P(O)R ^A1 R ^B1 , -P(O)(OR ^A1 )(OR ^B1 ), -C(O)R ^A1 , -C(O)OR ^A1 ,- OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -S(O) _r NR ^A1 R ^B1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O) 2NR ^A1 R ^B1 , -S(O)(=NR ^E1 )R ^B1 , -N=S(O)R ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) (=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 ,- C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 and -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , where each Each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are respectively unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from R ^x Each R ^{3 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 ring Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , -S(O) _r R ^A2 , -S(O) ₂ OR ^A2 , -OS(O) ₂ R ^A2 , -P(O) R ^A2 R ^B2 , -P(O)(OR ^A2 )(OR ^B2 ), -C(O)R ^A2 , -C(O)OR ^A2 , -OC(O)R ^A2 , -C(O)NR ^A2 R ^B2 , -NR ^A2 C(O)R ^B2 , -OC(O)NR ^A2 R ^B2 , -NR ^A2 C(O)OR ^B2 , -NR ^A2 C(O)NR ^A2 R ^B2 , -NR ^A2 C( S)NR ^A2 R ^B2 、-S(O) _r NR ^A2 R ^B2 、-NR ^A2 S(O) _r R ^B2 、-NR ^A2 S(O) ₂ NR ^A2 R ^B2 、-S(O)(=NR ^E2 )R ^B2 , -N=S(O)R ^A2 R ^B2 , -NR ^A2 S(O)(=NR ^E2 )R ^B2 , -S(O)(=NR ^E2 )NR ^A2 R ^B2 , -NR ^A2 S(O)(=NR ^E2 )NR ^A2 R ^B2 , -C(=NR ^E2 )R ^A2 , -C(=N-OR ^B2 )R ^A2 , -C(=NR ^E2 )NR ^A2 R ^B2 , -NR ^A2 C(=NR ^E2 )R ^B2 and -NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group Each is unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; each R ^{4 is} selected from hydrogen, halogen, C _1-10 alkyl, C _{2 -10} alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, Aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -S(O) _r R ^A3 , -S(O) ₂ OR ^A3 , -OS(O) ₂ R ^A3 , -P(O) R ^A3 R ^B3 , -P(O)(OR ^A3 )(OR ^B3 ), -C(O)R ^A3 , -C(O)OR ^A3 , -OC(O)R ^A3 , -C(O)NR ^A3 R ^B3 , -NR ^A3 C(O)R ^B3 , -OC(O)NR ^A3 R ^B3 , -NR ^A3 C(O)OR ^B3 , -NR ^A3 C(O)NR ^A3 R ^B3 , -NR ^A3 C( S)NR ^A3 R ^B3 、-S(O) _r NR ^A3 R ^B3 、-NR ^A3 S(O) _r R ^B3 、-NR ^A3 S(O) ₂ NR ^A3 R ^B3 、-S(O)(=NR ^E3 )R ^B3 , -N=S(O)R ^A3 R ^B3 , -NR ^A3 S(O)(=NR ^E3 )R ^B3 , -S(O)(=NR ^E3 )NR ^A3 R ^B3 , -NR ^A3 S(O)(=NR ^E3 )NR ^A3 R ^B3 , -C(=NR ^E3 )R ^A3 , -C(=N-OR ^B3 )R ^A3 , -C(=NR ^E3 )NR ^A3 R ^B3 , -NR ^A3 C(=NR ^E3 )R ^B3 and -NR ^A3 C(=NR ^E3 )NR ^A3 R ^B3 , where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group Each is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X ; each R ^{5 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkane Group, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A4 R ^B4 , -(CH ₂ ) _t NR ^A4 R ^B4 , -OR ^A4 , -S(O) _r R ^A4 , -S(O) ₂ OR ^A4 , -OS(O) ₂ R ^A4 , -P(O)R ^A4 R ^B4 , -P(O)(OR ^A4 )(OR ^B4 ), -C(O)R ^A4 , -C(O)OR ^A4 , -OC(O)R ^A4 , -C(O)NR ^A4 R ^B4 , -NR ^A4 C(O)R ^B4 , -OC(O)NR ^A4 R ^B4 , -NR ^A4 C(O)OR ^B4 , -NR ^A4 C(O)NR ^A4 R ^B4 , -NR ^A4 C(S)NR ^A4 R ^B4 , -S(O) _r NR ^A4 R ^B4 , -NR ^A4 S(O) _r R ^B4 , -NR ^A4 S( O) ₂ NR ^A4 R ^B4 , -S(O)(=NR ^E4 )R ^B4 , -N=S(O)R ^A4 R ^B4 , -NR ^A4 S(O)(=NR ^E4 )R ^B4 , -S (O)(=NR ^E4 )NR ^A4 R ^B4 , -NR ^A4 S(O)(=NR ^E4 )NR ^A4 R ^B4 , -C(=NR ^E4 )R ^A4 , -C(=N-OR ^B4 )R ^A4 , -C(=NR ^E4 )NR ^A4 R ^B4 , -NR ^A4 C(=NR ^E4 )R ^B4 and -NR ^A4 C(=NR ^E4 )NR ^A4 R ^B4 , where each alkyl, alkenyl, alkyne Group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; each R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^B1 , R ^B2 , R ^B3 and R ^{B4 are} independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, Heteroaryl and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is respectively unsubstituted or at least One, such as 1, 2, 3 or 4, independently selected from ^{the substituents of R X} ; or each of "R ^A1 and R ^B1 ", "R ^A2 and R ^B2 ", "R ^A3 and R ^B3 "or" R ^A4 and R ^B4 "together with the single or multiple atoms connected to them form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the The ring may be unsubstituted or substituted with 1, 2 or 3 R ^X groups; each R ^E1 , R ^E2 , R ^E3 and R ^{E4 is} independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ; each R ^{X is} independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl -C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl , Halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t C(= NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 and -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , where each alkyl, alkenyl, alkynyl, cycloalkyl, The heterocyclic group, the aryl group and the heteroaryl group are respectively unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^Y ; each of R ^a1 and R ^{b1 is} independently Selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocycle Group, heterocyclic group-C _1-4 alkyl, aryl, aryl -C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl respectively Is unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y substituents; or R ^a1 and R ^b1 together with the single or multiple atoms connected to them constitute the inclusion 0, 1 or 2 additional 4-12 membered heterocycles independently selected from oxygen, sulfur, nitrogen and phosphorus heteroatoms, the ring may be unsubstituted or 1, 2 or 3 selected from R ^Y Substituent substitution; each R ^c1 and R ^{d1 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _{3 -10} Cycloalkyl- _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _{1 -4} alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is respectively unsubstituted or at least one, such as 1, 2, 3 or 4 One, independently selected from the substituents of ^{R Y ; or R c1} and R ^d1 together with the single or more carbon atoms to which they are connected together form a group containing 0, 1 or 2 additional independently selected from oxygen, sulfur and nitrogen Heteroatomic 3-12 membered heterocycle, the ring may be unsubstituted or substituted by 1, 2 or 3 R ^Y groups; each R ^{e1 is} independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ; each R ^{Y is} independently selected from C _1-10 alkyl, C _2-10 Alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl , Aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) ₂ OR ^b2 , -(CR ^c2 R ^d2 ) _t OS(O ) ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t C(O)R ^a2 , -(CR ^c2 R ^d2 ) _t C(O)OR ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C (O)R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)OR ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(S)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t N=S(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t C (=NR ^e2 )R ^a2 , -(CR ^c2 R ^d2 ) _t C(=N-OR ^b2 )R ^a2 , -(CR ^c2 R ^d2 ) _t C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )R ^b2 and -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , where each alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are respectively unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from OH, CN, amino, halogen, C _1-10 alkyl , C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 Substitution of cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C1 _-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino Group substitution; each of R ^a2 and R ^{b2 is} independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkene Group, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclic, heterocyclic Group-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, ring Alkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxyl, C _{1- 10} alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and Substitution of bis(C _1-10 alkyl)amino; or R ^a2 and R ^b2 together with the single or multiple atoms connected to them together form 0, 1 or 2 additional independently selected from oxygen, sulfur, A 4-12 membered heterocyclic ring of nitrogen and phosphorus heteroatoms, the ring may be unsubstituted or be 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, Amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents are substituted; each R ^c2 and R ^{d2 is} independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy , C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, two (C _1-10 Alkyl) amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein each Alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl groups Each is unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkane Base amino, C _3-10 cycloalkylamine And di (C _1-10 alkyl) amino substituents; or R ^c2 and R ^d2 together with the individual they are attached together form one or more carbon atoms containing 1 or 2 additional independently selected from oxygen , Sulfur and nitrogen heteroatoms 3-12 membered heterocyclic ring, the ring may be unsubstituted or 1 or 2 independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio , Amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino substituents; each R ^{e2 is} independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C( O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C( O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl _{) 2} and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ; m is selected from 0,1,2 , 3, and 4; n is selected from 0, 1, and 2; p is selected from 0, 1, and 2; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4 .

(I)。In another embodiment (2), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, the chemical formula of which is

(I).

(II)。In another embodiment (3), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, the chemical formula of which is

(II).

In another embodiment (4), the present invention provides the compound of any one of embodiments (1) to (3), or a pharmaceutically acceptable salt thereof, wherein Q is heteroaryl.

和

。In another embodiment (5), the present invention provides the compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from

with

.

In another embodiment (6), the present invention provides the compound of any one of embodiments (1)-(5) or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from C1-10 alkyl, Heterocyclyl, heterocyclyl -C _1-4 alkyl, -S (O) _r R ^A4 , -C (O) R ^A4 and -CH ₂ NR ^A4 R ^B4 , where alkyl and heterocyclyl are not Substituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents.

和

，其是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代。In another embodiment (7), the present invention provides the compound of embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R ^{5 is} independently selected from methyl, ethyl,

with

, Which is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents.

In another embodiment (8), the present invention provides the compound of embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R ^{5 is} independently selected from -S(O) ₂ R ^A4 and -C(O ) R ^A4 , wherein each R ^{A4 is} independently selected from heterocyclyl and heterocyclyl-C _1-4 alkyl, wherein each alkyl and heterocyclyl is unsubstituted or is replaced by at least one, such as 1, 2 , 3 or 4 ^{substituents independently selected from R X} , and each R ^{B4 is} independently selected from C _1-10 alkyl.

和

，其是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代，且每個R^B4 為甲基。。In another embodiment (9), the present invention provides the compound of embodiment (8) or a pharmaceutically acceptable salt thereof, wherein each R ^{5 is} independently selected from S(O) ₂ R ^A4 and -C(O) R ^A4 , where each R ^{4 is} independently selected from

with

, Which is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents, and each R ^B4 is a methyl group. .

，是未被取代的或被至少一個，如1、2、3或4個，獨立選自R^X 的取代基取代，且每個R^B4 為甲基。In another embodiment (10), the present invention provides the compound of embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R ^{5 is} independently selected from -CH ₂ NR ^A4 R ^B4 , wherein each R ^A4 for

, Is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents, and each R ^B4 is a methyl group.

In another embodiment (11), the present invention provides the compound of any one of embodiments (6) to (10) or a pharmaceutically acceptable salt thereof, wherein each R ^{X is} independently selected from methyl, ethyl , Methoxymethyl, cyanoethyl and oxetan-3-yl.

In another embodiment (12), the present invention provides the compound of any one of embodiments (1) to (11) or a pharmaceutically acceptable salt thereof, wherein m is 1.

In another embodiment (13), the present invention provides the compound of any one of embodiments (1) to (12) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen.

In another embodiment (14), the present invention provides the compound of any one of embodiments (1) to (13) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen.

In another embodiment (15), the present invention provides the compound of any one of embodiments (1) to (14) or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} independently selected from C _1-10 alkyl.

In another embodiment (16), the present invention provides the compound of embodiment (15) or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} independently selected from methyl, isopropyl and tert-butyl.

In another embodiment (17), the present invention provides the compound of any one of embodiments (15) to (16) or a pharmaceutically acceptable salt thereof, wherein p is 2.

In another embodiment (18), the present invention provides the compound of any one of embodiments (1) to (17) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is halogen.

In another embodiment (19), the present invention provides the compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein each R ^{4 is} independently selected from fluorine and chlorine.

In another embodiment (20), the compound provided by the invention is selected from 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine-6- Yl)-N-(5-(pyrazine-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H- Imidazo[4,5-b]pyridin-6-yl)-N-(5-((4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N -(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[ 4,5-b]pyridin-6-yl)pyrimidin-2-amine, (S)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H )-Yl)methyl)pyridin-2-yl)-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine , (R)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)methyl)pyridin-2-yl)-4-( 1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N-(5-(((1S,4S)-2,5 -Diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo [4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine- 6-yl)-N-(5-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridine-2 -Yl)pyrimidin-2-amine, N-(5-(((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl )Pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N -(5-((3,8-Diazabicyclo[3.2.1]octane-8-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl- 2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo [4,5-b]pyridin-6-yl)-N-(5-((3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl) Pyridin-2-yl)pyrimidin-2-amine, N-(5-((3-ethyl-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)pyridine- 2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N-(5 -(( 3,8-Diazabicyclo[3.2.1]octane-3-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H -Imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b ]Pyridin-6-yl)-N-(5-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl) Pyrimidine-2-amine, N-(5-((8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-5 -Fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-N-(5-( (Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)-4-(1-isopropyl-2-methyl-1H-imidazo[ 4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine-6 -Yl)-N-(5-((5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((5-Ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1- Isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N-(5-((2,7-azaspiro[3.5]non Alk-2-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl )Pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-(( 7-Methyl-2,7-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((7-ethyl-2 ,7-Azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4 ,5-b)pyridin-6-yl)pyrimidin-2-amine, N-(5-((2,6-azaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl) -5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1 -Isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((6-methyl-2,6-azaspiro[3.3] Heptan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((6-ethyl-2,6-azaspiro[3.3]heptan-2-yl )Methyl)pyridine- 2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N-(5 -((3,9-azaspiro[5.5]undecan-3-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H -Imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b ]Pyridin-6-yl)-N-(5-((9-methyl-3,9-azaspiro[5.5]undec-3-yl)methyl)pyridin-2-yl)pyrimidine-2 -Amine, N-(5-((9-ethyl-3,9-azaspiro[5.5]undec-3-yl)methyl)pyridin-2-yl)-5-fluoro-4-( 1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N-(5-fluoro-4-(1-isopropyl- 2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine , N-(5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)-6-methyl -5,6,7,8-Tetrahydro-1,6-naphthyridin-2-amine, 6-ethyl-N-(5-fluoro-4-(1-isopropyl-2-methyl-1H -Imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, (6-(( 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)( Pirazin-1-yl)methanone, (6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl) Pyrimidine-2-yl)amino)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone, (4-ethylpiperazin-1-yl)(6-((5-fluoro- 4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, (3 ,8-Diazabicyclo[3.2.1]octan-3-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4, 5-b)pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, (6-((5-fluoro-4-(1-isopropyl-2-methyl- 1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(8-methyl-3,8-diazabicyclo[3.2.1 ]Octan-3-yl)methanone, (8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)(6-((5-fluoro-4-( 1-isopropyl-2-methyl-1H-imid Azolo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, (6-((5-fluoro-4-(1-isopropyl- 2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(2,7-azaspiro[3.5]nonane- 2-yl) ketone, (6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidine-2 -Amino)pyridin-3-yl)(7-methyl-2,7-azaspiro[3.5]nonan-2-yl)methanone, (7-ethyl-2,7-azaspiro [3.5]Nonane-2-yl)(6-((5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl) Pyrimidine-2-yl)amino)pyridin-3-yl)methanone, (6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b ]Pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone, (6-(( 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)( 5-Methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone, (5-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- Group) (6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino) Pyridin-3-yl)methanone, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5- (Pizazine-1-ylsulfonyl)pyridin-2-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5- b)pyridin-6-yl)-N-(5-((4-methylpiperazine-1-yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-(( 4-ethylpiperazine-1-yl)sulfonyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b ]Pyridin-6-yl)pyrimidin-2-amine, N-(5-((3,8-diazabicyclo[3.2.1]octane-3-yl)sulfonyl)pyridin-2-yl )-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-( 1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((8-methyl-3,8-diazabicyclo [3.2.1]octane-3-yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((8-ethyl-3,8-diazabicyclo[ 3.2. 1]octane-3-yl)sulfonyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine -6-yl)pyrimidin-2-amine, 5-fluoro-N-(5-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)pyridine-2- Yl)-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-iso Propyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((5-methylhexahydropyrrolo[3,4-c]pyrrole- 2(1H)-yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((5-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H )-Yl)sulfonyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl) Pyrimidine-2-amine, N-(5-((2,7-azaspiro[3.5]nonane-2-yl)sulfonyl)pyridin-2-yl)-5-fluoro-4-(1- Isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4-(1-isopropyl-2-methyl- 1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((7-methyl-2,7-azaspiro[3.5]nonane-2-yl)sulfonyl )Pyridin-2-yl)pyrimidin-2-amine, N-(5-((7-ethyl-2,7-azaspiro[3.5]nonane-2-yl)sulfonyl)pyridine-2- Yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((4-(oxetan-3-yl) (Pazizin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (S)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4 ,5-b)pyridin-6-yl)-N-(5-((2-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridine-2 -Yl)pyrimidin-2-amine, (R)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N -(5-((2-Methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (R)- 5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((3-methyl-4- (Oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (S)-5-fluoro-4-(1-isopropyl- 2-Methyl-1H-imidazo[4,5-b]pyridine (Pyridin-6-yl)-N-(5-((3-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidine- 2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-((4 -(Oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (S)-4-(1-(tert-butyl)-2 -Methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-((2-methyl-4-(oxetan-3-yl )Pazizin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (R)-4-(1-(tert-butyl)-2-methyl-1H-imidazo[4, 5-b)pyridin-6-yl)-5-fluoro-N-(5-((2-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl) Pyridin-2-yl)pyrimidin-2-amine, (R)-4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)- 5-Fluoro-N-(5-((3-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine , (S)-4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-(( 3-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-(tert-butyl) -2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-(pyrazine-1-ylmethyl)pyridin-2-yl)pyrimidine -2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-(( 4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5 -b)pyridin-6-yl)-N-(5-((4-ethylpiperazine-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, N-( 5-((3,8-Diazabicyclo[3.2.1]octane-8-yl)methyl)pyridin-2-yl)-4-(1-(tert-butyl)-2-methyl -1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoropyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4 ,5-b]pyridin-6-yl)-5-fluoro-N-(5-((3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl)methan Yl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N- (5-((3-Ethyl-3,8-diazabicyclo[3.2.1]octane-8 -Yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, (S)-4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5 -b)pyridin-6-yl)-5-fluoro-N-(5-((3-(methoxymethyl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidine-2- Amine, (S)-4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-( (3-(Methoxymethyl)-4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (S)-4-(1-(tert-butyl )-2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((4-ethyl-3-(methoxymethyl)piperazine-1 -Yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, N-(5-((3,8-diazabicyclo[3.2.1]octane-3-yl) (Methyl)pyridin-2-yl)-4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoropyrimidine-2 -Amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-((8- Methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-(tert-butyl)- 2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((8-ethyl-3,8-diazabicyclo[3.2.1]octane Alkyl-3-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5- b)pyridin-6-yl)-5-fluoro-N-(5-(1-(piperazine-1-yl)ethyl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-( Tert-Butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-fluoro-N-(5-(1-(4-methylpiperazine-1- (Yl)ethyl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl) -N-(5-(1-(4-ethylpiperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, 4-(1-(tert-butyl) -2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-chloro-N-(5-(pyrazine-1-ylmethyl)pyridin-2-yl)pyrimidine -2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5-chloro-N-(5-(( 4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4,5 -b)pyridin-6-yl)-5-chloro-N-(5-((4 -Ethylpyrazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3 ,4-b)pyridin-5-yl)-N-(5-(piperazine-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl 2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((4-methylpiperazine-1-yl)methyl)pyridine-2 -Yl)pyrimidin-2-amine, N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl- 2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-1-methyl-1H-pyridine Azolo[3,4-b]pyridin-5-yl)-N-(5-((4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N -(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]pyridin-5-yl)pyrimidin-2-amine, N-(5-((3,8-diazabicyclo[3.2.1]octane-8-yl)methyl) Pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5 -Fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((3-methyl-3, 8-Diazabicyclo[3.2.1]octane-8-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((3-ethyl-3,8- Diazabicyclo[3.2.1]octane-8-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo [3,4-b]pyridin-5-yl)pyrimidin-2-amine, N-(5-((3,8-diazabicyclo[3.2.1]octan-3-yl)methyl) Pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5 -Fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((8-methyl-3, 8-Diazabicyclo[3.2.1]octane-3-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((8-ethyl-3,8- Diazabicyclo[3.2.1]octane-3-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo [3,4-b]pyridin-5-yl)pyrimidin-2-amine, (R)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2( 1H)-yl)methyl)pyridin-2-yl)-4-(3-isopropyl-2-methyl Yl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, N-(5-((2,7-azaspiro[3.5]nonane-2-yl) (Methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-2- Amine, 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((7-methyl -2,7-azaspiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((7-ethyl-2,7-nitrogen Heterospiro[3.5]nonan-2-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-N-(5-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)pyridine- 2-yl)-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-( 3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((5-methylhexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((5-ethylhexahydropyrrolo[3,4-c]pyrrole- 2(1H)-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5 -Yl)pyrimidin-2-amine, N-(5-((2,7-azaspiro[3.5]nonane-7-yl)methyl)pyridin-2-yl)-5-fluoro-4-( 3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-2- Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((2-methyl-2,7-azaspiro[3.5]nonane-7-yl )Methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((2-ethyl-2,7-azaspiro[3.5]nonane-7-yl)methyl)pyridine- 2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, N-( 5-((3,9-Azaspiro[5.5]undecan-3-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3, 4-b]pyridin-5-yl)-N-(5-((9-methyl-3,9-azaspiro[5.5]undec-3-yl)methyl)pyridin-2-yl) Pyrimidine-2-amine, N-(5-((9-B Yl-3,9-azaspiro[5.5]undecane-3-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H- Pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4- b)Pyridin-5-yl)-N-(5-((4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine , (S)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((2 -Methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (R)-5-fluoro-4-( 3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((2-methyl-4-(oxetane -3-yl)piperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (R)-5-fluoro-4-(3-isopropyl-2-methyl-2H -Pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((3-methyl-4-(oxetan-3-yl)piperazin-1-yl) (Methyl)pyridin-2-yl)pyrimidin-2-amine, (S)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridine -5-yl)-N-(5-((3-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidine-2 -Amine, (6-((5-Fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)(piazine-1-yl)methanone, (6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3, 4-b)pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone, (4-ethylpiperazin-1-yl) )(6-((5-Fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino) Pyridin-3-yl)methanone, (3,8-diazabicyclo[3.2.1]octane-8-yl)(6-((5-fluoro-4-(3-isopropyl-2 -Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, (6-((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(3-methyl- 3,8-diazabicyclo[3.2.1]octane-8-yl)methanone, (3-ethyl-3,8-diazabicyclo[3.2.1]octane-8-yl )(6-((5-Fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3 ,4-b)pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, (3,8-diazabicyclo[3.2.1]octane-3-yl) (6-((5-Fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)pyridine -3-yl) ketone, (6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine -2-yl)amino)pyridin-3-yl)(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone, (8-ethyl-3 ,8-Diazabicyclo[3.2.1]octan-3-yl)(6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3 ,4-b)pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, (6-((5-fluoro-4-(3-isopropyl-2-methyl) -2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(2,7-azaspiro[3.5]nonane-2-yl ) Ketone, (6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl )Amino)pyridin-3-yl)(7-methyl-2,7-azaspiro[3.5]nonan-2-yl)methanone, (7-ethyl-2,7-azaspiro[3.5 ]Nonane-2-yl)(6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine -2-yl)amino)pyridin-3-yl)methanone, (6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b ]Pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone, (6-(( 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl) (5-Methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone, (5-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H) -Yl)(6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)methanone, N-(5-((3,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)pyridin-2-yl)- 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3 -Isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((8-methyl-3,8-diazabicyclo [3.2.1] Octane-3 -Yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((8-ethyl-3,8-diazabicyclo[3.2.1]octane-3- (Yl)sulfonyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine -2-amine, N-(5-((2,7-azaspiro[3.5]nonan-2-yl)sulfonyl)pyridin-2-yl)-5-fluoro-4-(3-iso Propyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((7-methyl-2,7-azaspiro[3.5]nonane-2-yl)sulfonyl Yl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((7-ethyl-2,7-azaspiro[3.5]nonane-2-yl)sulfonyl)pyridine-2 -Yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro- N-(5-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)pyridin-2-yl)-4-(3-isopropyl-2-methyl 2-H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[ 3,4-b]pyridin-5-yl)-N-(5-((5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)pyridine- 2-yl)pyrimidin-2-amine, N-(5-((5-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)pyridin-2-yl )-5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, 4-(3-( Tert-Butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5-((4-(oxetane-3 -Yl)pirazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4 -b)pyridin-5-yl)-5-fluoro-N-(5-((4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-( 3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((4-ethylpiperazine-1-yl) (Methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, (R)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b ]Pyridin-5-yl)-5-fluoro-N-(5-((methyl((1-methylpyrrol-2-yl)methyl)amino)methyl)pyridin-2-yl)pyrimidine-2 -Amine, (R)-4-(3-(tert-butyl)-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl )Methyl)pyridin-2-yl)pyrimidin-2-amine, N-(5-((3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)pyridine-2 -Yl)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-amine, 4- (3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5-((3-methyl-3 ,8-Diazabicyclo[3.2.1]octane-8-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(3-(tert-butyl)-2-methyl -2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((3-ethyl-3,8-diazabicyclo[3.2.1]octane-8 -Yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, (S)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3, 4-b)pyridin-5-yl)-5-fluoro-N-(5-((3-(methoxymethyl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidine-2 -Amine, (S)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5 -((3-(Methoxymethyl)-4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, (S)-4-(3-(tert Butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((4-ethyl-3-(methoxymethyl)gua (Azin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, N-(5-(((1R,5S)-3,8-diazabicyclo[3.2. 1]octane-3-yl)methyl)pyridin-2-yl)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5 -Yl)-5-fluoropyrimidin-2-amine, 4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- Fluoro-N-(5-(((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)methyl)pyridin-2-yl) Pyrimidine-2-amine, 4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-(((1R ,5S)-8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, 4 -(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5-(1-(pazine- 1-yl)ethyl)pyridin-2-yl)pyrimidin-2-amine, 4-(3-( Tert-Butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5-(1-(4-methylpiperazine-1 -Yl)ethyl)pyridin-2-yl)pyrimidin-2-amine, 4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5- Yl)-N-(5-(1-(4-ethylpiperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, N-(4-(3- (Tert-Butyl)-2-methyl-2H-pyrazolo(3,4-b)pyridin-5-yl)-5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydro -1,6-naphthyridin-2-amine, N-(4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)- 5-fluoropyrimidin-2-yl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, N-(4-(3-(tert-butyl) -2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)-6-ethyl-5,6,7,8-tetrahydro -1,6-naphthyridin-2-amine, 4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro -N-(5-(morpholinomethyl)pyridin-2-yl)pyrimidin-2-amine, 3-(4-((6-((4-(3-(tert-butyl)-2-methyl -2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-1-yl)propionitrile, N-(4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)-6- (Pepridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, N-(4-(3-(tert-butyl)-2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)-6-(1-methylpiridin-4-yl)-5,6,7, 8-Tetrahydro-1,6-naphthyridin-2-amine, N-(4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5 -Yl)-5-fluoropyrimidin-2-yl)-6-(1-ethylpiridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine , Or a pharmaceutically acceptable salt thereof.

In another embodiment (21), the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments (1) to (20) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier .

In another embodiment (22), the present invention provides a method for treating, ameliorating or preventing a disorder that responds to the inhibition of cyclin-dependent kinase 4/6, which comprises administering an effective amount to an individual in need of the embodiment (1)- (20) The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof according to any one of (20), optionally used in combination with a second therapeutic agent.

In another embodiment (23), the present invention provides that the compound of any one of embodiments (1) to (20) or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the treatment of cell proliferative diseases the use of.

In another aspect, the present invention provides a kit containing the compound disclosed herein or a pharmaceutically acceptable salt thereof; and an instruction including one or more of the following information: what kind of disease the ingredient is used for, the storage information of the ingredient, and the dosage Information and instructions on how to use the ingredients. In a particular variant, the kit contains the compound in multiple doses.

In another aspect, the present invention provides an article comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof; and packaging materials. In a variation, the packaging material includes a container. In a particular variation, the container includes a label indicating one or more of the following: what disease the compound is used for, storage information, dosage information, and/or instructions on how to use the compound. In another variation, the preparation includes the compound in multiple dose form.

In another aspect, the present invention provides a method of treatment, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof to an individual.

In another aspect, the present invention provides a method of inhibiting CDK4/6 kinase by contacting a compound disclosed herein or a pharmaceutically acceptable salt thereof with CDK4/6.

In another aspect, the present invention provides a method for inhibiting CDK4/6, comprising allowing the compound disclosed herein or a pharmaceutically acceptable salt thereof to appear in the body of an individual to inhibit CDK4/6 activity in vivo.

In another aspect, the present invention provides a method for inhibiting CDK4/6, comprising administering to an individual a first compound, which is converted into a second compound in vivo, wherein the second compound inhibits CDK4/6 activity in vivo, and the second The compound is any one of the compounds and modifications in the above embodiments.

In another aspect, the present invention provides a method of treating a disease state, wherein CDK4/6 activity causes the pathology and/or symptoms of the disease state, the method comprising making a therapeutically effective amount of the compound disclosed herein or Its pharmaceutically acceptable salt appears in the individual's body.

In another aspect, the present invention provides a method for treating a disease state in which CDK4/6 activity causes the pathology and/or symptoms of the disease state, the method comprising administering a first compound to an individual, and the compound is converted into a first compound in the body. Two compounds, wherein the second compound inhibits CDK4/6 activity in vivo. It is worth noting that the compound of the present invention may be a compound before or after conversion.

In the variation of each of the above methods, the disease state is selected from: cancerous proliferative diseases (such as brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colon, epidermis, Esophageal, testicular, gynecological or thyroid cancer); non-cancerous proliferative diseases (such as benign skin hyperplasia (such as psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain; prevention of blast cells Implantation; treatment of diseases related to angiogenesis or angiogenesis (eg tumor angiogenesis, acute and chronic infectious diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema And scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate Cancer, colon cancer, and epidermoid carcinoma); asthma; neutrophil chemotaxis (for example, reperfusion injury and inflammatory arthritis due to myocardial infarction and stroke); septic shock; T cell-received diseases, among which immunity Inhibition is valuable (such as prevention of organ transplant rejection, graft-versus-host disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinocytes that respond to a mixture of growth factors; chronic pulmonary obstruction Sexual diseases (COPD) and other diseases.

In another aspect, the present invention provides a method for treating disease states in which CDK4/6 gene mutations cause pathology and/or symptoms of the disease, such as melanoma, lung cancer, colon cancer, and other types of tumors.

In another aspect, the present invention relates to the use of any of the compounds and modifications of any of the above embodiments as medicaments. In another aspect, the present invention relates to the use of any of the compounds and modifications of the above embodiments as drugs for inhibiting the production of CDK4/6.

In another aspect, the present invention relates to the production of a compound of any one of the above embodiments and a medicament modified as a treatment for pathological and/or symptomatic disease states caused by CDK4/6 activity.

Administration and Pharmaceutical Compositions Generally, the compounds of the present invention will be administered in a therapeutically effective amount via any common and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount can vary widely, depending on the severity of the disease, age, and relative health of the subject, the efficacy of the compound used, and other general skills known in the art. For example, for the treatment of tumorous diseases and immune system diseases, the required dose will vary according to the mode of administration, the specific condition to be treated and the desired effect. Generally, satisfactory results can be achieved at a daily dose of 0.001 to 100 mg/kg body weight, specifically, from about 0.03 to 2.5 mg/kg body weight. The daily dose for larger mammals, such as humans, can be from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, in a convenient form, for example, in divided doses up to four times a day. Times or in sustained release form. A suitable unit dosage form for oral administration contains about 1 to 50 mg of active ingredient. The compound of the present invention can be administered in the form of a pharmaceutical composition, by any conventional route; for example, enteral, for example, orally, for example, in the form of tablets or capsules, parenteral, for example, in the form of injectable solutions or suspensions; Or topical administration, for example in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories. The pharmaceutical composition containing the free base or pharmaceutically acceptable salt compound of the present invention and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or freeze-dried in a conventional manner. To make. For example, a pharmaceutical composition comprising a compound of the present invention combined with at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing with a pharmaceutically acceptable carrier or diluent in a conventional manner. A unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance. In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. In the case of a lyophilized composition containing only the active ingredient or mixed with a carrier such as mannitol, the dispersion or suspension can be replenished before use. The pharmaceutical composition may be sterilized and/or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution enhancers, salts for adjusting osmotic pressure, and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, and microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain a viscosity increasing agent, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizing agents, such as Tween 80 (polyoxyethylene (20) Sorbitan monooleate). The suspension may contain vegetable oils as oily ingredients in the oil, synthetic or semi-synthetic oils, and are often used for injection purposes. Examples include liquid fatty acid esters containing long-chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms as the acid component. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated Acids, such as oleic acid, elaidic acid, erucic acid, basilic acid, and linoleic acid, may contain antioxidants, such as vitamin E, 3-carotene, or 3,5-di-tert-butylhydroxytoluene, if necessary. The alcohol component of these fatty acid esters may have six carbon atoms, and may be monovalent or multivalent, such as mono-, di- or trivalent alcohols. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or its isomers, ethylene glycol and glycerol. Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL ^® M2375 (polyoxyethylene glycerol), LABRAFIL ® M1944 CS (non-alcoholic almond oil) Saturated PEGylated glycerides and containing glycerides and polyethylene glycol esters), LABRASOLTM (saturated PEGylated glycerides prepared by alcoholysis TCM and containing glycerides and polyethylene glycol esters; all available from GaKefosse, France Obtained by the company), and/or MIGLYOL ^® 812 (saturated fatty acid triglycerides with chain lengths of C ₈ to C ₁₂ from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, Soybean oil or peanut oil. Pharmaceutical compositions for oral administration can be prepared, for example, by mixing the active ingredient with one or more solid carriers, if necessary, granulating the resulting mixture, and processing the mixture or granules by adding additional excipients, In the form of tablets or tablet cores. Suitable carriers include, but are not limited to, fillers, such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate, and also binders, such as Starches, such as corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if necessary, disintegrants, Such as the above-mentioned starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow regulators and lubricants, such as silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof . The tablet core can be provided with a suitable, optionally enteric coating, by using, in particular, a concentrated sugar solution, which can include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or as appropriate Coating solutions of organic solvents or solvent mixtures, or, for enteric coatings, suitable cellulosic products, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate solutions preparation. Dyestuffs or pigments can be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredients. The pharmaceutical composition for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerin or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example mixed with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active ingredients can be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oils or liquid polyethylene glycol or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents, For example, the fatty acid ester type of polyoxyethylene sorbitol can also be added. Pharmaceutical compositions suitable for rectal administration, such as suppositories, contain a combination of active ingredients and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Pharmaceutical compositions suitable for parenteral administration may contain the active ingredients in water-soluble form, such as water-soluble salts or aqueous injection suspensions containing viscosity-increasing substances, such as sodium carboxymethyl cellulose, aqueous solutions of sorbitol and/ Or dextran, if necessary, and stabilizers. The active ingredient, optionally with excipients, can also be in a freeze-dried form, and can be a solution prepared by adding a suitable solvent before parenteral administration. The solution used, for example, for parenteral administration, can also be used as an infusion solution. The preparation of injection preparations is usually filled into, for example, ampoules or vials, and sealed containers under aseptic conditions. The present invention also provides a pharmaceutical combination, such as a kit, which comprises a) a compound disclosed in the present invention, which may be in a free form or a pharmaceutically acceptable salt form, and b) at least one common drug. The kit may include instructions for its use.

Combination Therapy The compound or pharmaceutically acceptable salt described in this patent can be taken alone or in combination with other therapeutic agents. For example, taking the adjuvant drug can have the therapeutic effect of the compound of the present invention (for example, the therapeutic benefit of taking the adjuvant drug alone is very small, but when combined with another drug, it can enhance the individual's therapeutic benefit), or, for example, The combination of the compound of the present invention and another therapeutic agent with the same curative effect can enhance the therapeutic benefit of the individual. For example, in the treatment of gout, when the compound of the present invention is taken, the combined administration of another drug for the treatment of gout may enhance the clinical benefit. Or, for example, if the adverse reaction of taking the compound of the present invention is nausea, an anti-nausea drug can be used in combination. Alternatively, treatments that can also be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy for diseased areas, rest, diet improvement, and the like. Regardless of the disease, discomfort or symptom, the two therapies should have an additive effect or a synergistic effect to benefit the individual's treatment. In the case where the compound of the patent is used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition of the compound of the patent may be the same as that of other drugs, or due to different physical and chemical properties, the route of administration may be different. For example, oral administration of the compound of this patent can produce and maintain good blood drug levels, while another therapeutic agent may require intravenous administration. Therefore, the compound of this patent and another combined drug can be administered simultaneously, sequentially or separately. The compound represented by formula (I) or (II) is expected to be effective when used in combination with one or more of the following drugs: alkylating agent, angiogenesis inhibitor, antibody, anti-metabolite, anti-mitotic, anti-proliferative, anti-viral, aurora kinase inhibitor Inhibitors, other apoptotic promoters (for example, Bcl-xL, Bcl-W and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, BiTE (bispecific T cell adapter Organ) antibodies, antibody-drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homologous genes (ErbB2 ) Receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone acetylase (HDAC) inhibitors, hormone therapy, immune agents, inhibitors of apoptosis protein inhibitors ( IAPs), embedded antibiotics, kinase inhibitors, kinesin inhibitors, JAK2 inhibitors, mammalian rapamycin inhibitors, small RNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding Proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (PLK) inhibitors, phosphoinositide 3-kinase ( PI3K) inhibitors, protein body inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoid plant alkaloids, small ribonucleic acid (siRNAs) inhibitors, topoisomerism Enzyme inhibitors, ubiquitin ligase inhibitors and the like.

There are many methods for synthesizing the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and the representative methods are listed in this example. However, it should be pointed out that the compound of formula (I) or (II) or its pharmaceutically acceptable salt may also be synthesized by other synthetic schemes.

In a compound of formula (I) or (II), the connection between atoms and other atoms may result in the existence of special stereoisomers (such as chiral centers). The synthesis of the compound of formula (I) or (II) or its pharmaceutically acceptable salt may produce a mixture of different isomers (enantiomers, diastereomers). Unless it is specifically stated that it is a specific stereo configuration, the listed compounds all include the different stereoisomers that may exist.

The compound of formula (I) or (II) can also be prepared as a pharmaceutically acceptable acid addition salt, for example, by reacting the free base form of the compound of the present invention with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a compound of formula (I) or (II) is reacted with a pharmaceutically acceptable inorganic or organic base in the form of a free acid to prepare a pharmaceutically acceptable base addition salt. The inorganic and organic acids and bases suitable for preparing the pharmaceutically acceptable salts of the compounds of formula (I) or (II) have been described in the definition section of this application. In addition, the salt form of the compound of formula (I) or (II) can also be prepared by using the salt of the starting material or intermediate.

The free acid or free base of the compound of formula (I) or (II) can be prepared by its corresponding base addition salt or acid addition salt. The acid addition salt form of the compound of formula (I) or (II) can be converted into the corresponding free base, for example, by treatment with a suitable base (such as ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of the compound of formula (I) or (II) can be converted into the corresponding free acid, for example, by treatment with a suitable acid (such as hydrochloric acid, etc.).

The N-oxide of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof can be prepared by methods known in the art. For example, N-oxide can be obtained by combining the non-oxidized form of the compound of formula (I) with an oxidizing agent (such as trifluoroperoxyacetic acid, permaleic acid, peroxybenzoic acid, Peroxyacetic acid and m-chloroperoxybenzoic acid, etc.) are obtained by reacting in an inert organic solvent (such as dichloromethane and other halogenated hydrocarbons). Alternatively, the N-oxide of the compound of formula (I) or (II) can also be prepared from the N-oxide of the starting material.

The non-oxidized form of the compound of formula (I) or (II) can be obtained by combining its N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and tribromo Phosphorus, etc.) at 0 ~ 80 °C in the corresponding inert organic solvents (such as acetonitrile, ethanol and hydrated dioxane, etc.) prepared by reaction.

The protected derivatives of the compounds of formula (I) or (II) can be prepared by methods well known to those skilled in the art. For detailed technical description of the addition and removal of protecting groups, see: TW Greene, Protecting Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, Inc. 1999.

The signs, common sense, diagrams, and examples used in these reactions are consistent with current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise specified, standard one-letter or three-letter abbreviations generally refer to L-form amino acid residues. Unless otherwise stated, all starting materials used were purchased from market suppliers and were used without further purification. For example, the following abbreviations are used in the examples and throughout the description: g (grams), mg (milligrams), L (liters), mL (milliliters), μL (microliters), psi (pounds per square inch), M ( Mol), mM (millimolar), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (mole), mmol (millimoles), RT (ambient temperature), min (minutes), h (hours) ), mp (melting point), TLC (thin layer chromatography), Rr (retention time), RP (reverse phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA ( Trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfide), EtOAc (ethyl acetate), DME (1,2-dimethyl ether), DCM (dichloromethane) ), DCE (dichloroethane), DMF (N,N-dimethylformamide), DMPU (N,N-dimethylpropenylurea), CDI (1,1-carbonyldiimidazo), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et ₂ O (ether), EDCI (1-(3 -Dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (Benoxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMS (2-(trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropyl silane), TBS ( Tert-butyl dimethylsilyl), DMAP (dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl), HPLC (high performance liquid chromatography) Method), BOP (bis(2-oxo-3-oxazolidinyl) hypophosphinyl chloride), TBAF (tetrabutylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

Ether or Et ₂ O refers to diethyl ether; brine refers to saturated NaCl aqueous solution. Unless otherwise specified, all temperatures refer to °C (degrees Celsius), and all reactions are performed in an inert atmosphere at room temperature.

^{The 1} H NMR spectrum was recorded with a Bruker Avance 400 nuclear magnetic resonance spectrometer. The chemical shift is expressed in ppm. Coupling constants are in Hertz (Hz). Describe the apparent diversity in a segmentation mode, and define it as s (single peak), d (double peak), t (triplet peak), q (quartet), m (multiple peak) and br (wide peak)

Low-resolution mass spectrometry (MS) and compound purity data come from the monopole system of Waters ZQ LC/MS, which is equipped with electrospray ionization detector (ESI), ultraviolet detector (220 and 254 nm) and evaporative light scattering Detector (ELSD). The thin layer chromatography method uses 0.25 mm Asahi Chemical Silica Sheet (60F-254), 5% phosphomolybdic acid ethanol solution, ninhydrin or p-oxyphenyl phenyl solution and observes under ultraviolet light. Fast column chromatography uses silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.).

Synthesis scheme

The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof can be synthesized by different methods, and some exemplary methods are provided below and examples. Other synthetic methods can be easily proposed by those skilled in the art based on the information disclosed in the present invention.

In the following reactions, it may be necessary to protect the active groups to prevent these active groups from participating in other undesired reactions: these groups such as hydroxyl, amino, imino, sulfhydryl or carboxyl, and the final product contains These groups. The commonly used protecting groups can refer to TW Greene and PGM Wuts in " Protective Groups in Organic Chemistry " John Wiley and Sons, 1991.

The synthetic schemes of all the compounds of the present invention are illustrated by the following schemes and examples. The starting materials used are derived from commercially available products or can be prepared according to existing processes or methods exemplified here.

The intermediates listed in the following synthetic schemes are either obtained according to literature or synthesized according to existing similar synthetic methods.

合成方案 1 A synthetic route of the compound of formula I or II of the present invention is shown in Synthetic Scheme 1. Compounds of formula I or II can be synthesized from intermediates III to VIII shown in the synthesis scheme, and these intermediates can be synthesized according to literature or methods well-known to those skilled in the art. The pyrimidine intermediate represented by formula VI and the heteroaromatic intermediate represented by formula VII or VIII are prepared by palladium-catalyzed coupling reaction, such as Suzuki reaction or other coupling conditions reported in the literature, to prepare the pyrimidine intermediate represented by formula IV or V . The formula IV or V and the amino aromatic hydrocarbon represented by the formula III are prepared by coupling reaction, such as Buchwald amination reaction or other coupling conditions reported in the literature, to prepare the compound of formula I or II, respectively.

Synthesis scheme 1

R^a 、R^b 、R^c 獨立選自R⁷ 和R⁸ ； M=B 或Sn；L=配體；LG=離去基合成方案 2 As an example of the preparation method of Intermediate IV, a synthetic route of the compound of formula IVa is shown in Synthesis Scheme 2. A commercially available diaminopyridine A was used as the starting material. Intermediate IVa is prepared by successively reductive amination, formation of imidazole and conversion of halogen groups into groups such as B or Sn, and then palladium-catalyzed coupling reaction.

R ^a , R ^b , and R ^{c are} independently selected from R ⁷ and R ⁸ ; M=B or Sn; L=ligand; LG=leaving group synthesis scheme 2

R^a 、R^b 、R^c 獨立選自 R⁷ 和R⁸ ； M=B或Sn； L=配體；LG=離去基合成方案 3 A synthetic route of the intermediate Vb compound is shown in Synthetic Scheme 3. Ketone N reacts with hydrazine to obtain intermediate O, which is alkylated to obtain intermediate P, the halogen group in intermediate P is converted into a group such as B or Sn, and then palladium catalyzes the coupling reaction to obtain intermediate Vb.

R ^a , R ^b , and R ^{c are} independently selected from R ⁷ and R ⁸ ; M=B or Sn; L=ligand; LG=leaving group Synthesis scheme 3

In some cases, in order to promote the reaction or avoid the generation of unnecessary reaction products, the above-mentioned synthesis scheme can be adjusted according to the situation. In order for the present invention to be more fully understood, the following embodiments are provided. These embodiments are only examples, and should not be construed as limiting the present invention.

中間體 A 5- 溴 -N³ - 異丙基吡啶 -2,3- 二胺 (A-1) 向商購的2,3-二氨基-5-溴吡啶 (1.88 g, 10 mmol) 和丙酮 (0.7 g, 12 mmol) 的醋酸異丙酯溶液 (15 mL) 中加入TFA (2.51 g, 22 mmol)，然後在0°C下加入NaBH(OAc)₃ (3.18g, 15 mmol)。混合物在室溫下攪拌2小時。用EtOAc (50 mL) 淬滅反應。用飽和NaHCO₃ 水溶液 (30 mL) 和飽和食鹽水 (30 mL) 洗滌，Na₂ SO₄ 乾燥。過濾並旋蒸，殘留物用矽膠柱層析純化 (洗脫劑：石油醚/乙酸乙酯=9:1 ~ 2:1)，得到黃色固體5-溴-N3-異丙基吡啶-2,3-二胺 (A-1)。MS-ESI (m/z): 230, 232 [M + 1]⁺ 。 6- 溴 -1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 (A-2) 5-溴-N3-異丙基吡啶-2,3-二胺 (A-1) (1.2 g, 5.2 mmol) 和Ac₂ O (2.6 g, 26 mmol) 在HOAc (10 mL) 中的混合物於90°C攪拌過夜。將溶劑真空旋幹，殘留物用DCM (50 mL) 稀釋。用NaOH (1 N) 調節pH至8 ~ 9。分離有機層。萃取物用飽和食鹽水 (50 mL) 洗滌，Na₂ SO₄ 乾燥。過濾並濃縮，殘留物用矽膠柱層析純化，(洗脫劑：石油醚/乙酸乙酯=5:1 ~ 1:2)，得到黃色固體6-溴-1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶 (A-2)。MS-ESI (m/z): 254, 256 [M + 1]⁺ 。 6-( 三 - 正丁基甲錫烷基 )-1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 (A-3) 向 -溴-1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶 (A-2) (0.5 g, 2 mmol) 的THF溶液 (10 mL) 中加入 (Bu₃ Sn)₂ (2.32 g, 4 mmol)，Pd(PPh₃ )(OAc)₂ (0.08 g, 0.1 mmol) 和TBAF (1.044 g, 8 mmol)。在氮氣保護下於70°C攪拌4 h。混合物濃縮，殘留物用乙酸乙酯 (50 mL) 稀釋。萃取物用水 (50 mL) 洗滌，MgSO₄ 乾燥。過濾並濃縮，殘留物用矽膠柱層析純化 (洗脫劑：石油醚/乙酸乙酯=9:1 ~ 1:1)，得到黃色油狀物6-(三-正丁基甲錫烷基)-1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶 (A-3)。MS-ESI (m/z): 466 [M + 1]⁺ 。 6-(2- 氯 -5- 氟嘧啶 -4- 基 )-1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 ( 中間體 A) 向6-(三-正丁基甲錫烷基)-1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶 (A-3) (0.455 g, 0.97 mmol) 和2, 4-二氯-5-氟嘧啶 (0.25 g, 1.49 mmol) 的甲苯溶液 (8 mL) 中加入Pd(PPh₃ )₄ (0.06 g, 0.05 mmol)。在氮氣保護下於110°C攪拌4 h。混合物濃縮。殘留物用快速矽膠柱層析純化 (洗脫劑：乙酸乙酯)，得到黃色固體6-(2-氯-5-氟嘧啶-4-基)-1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶 (中間體A)。MS-ESI (m/z): 306 [M + 1]⁺ 。中間體 B 5-(2- 氯 -5- 氟嘧啶 -4- 基 )-7- 氟 -3- 異丙基 -1- 甲基 -3a,7a- 二氫 -1H- 吲唑 ( 中間體 B) 中間體 B 5- 溴 -2- 氯煙酸 ( 異丁基 碳酸 ) 酐 (B-1) 在0°C下，向5-溴-2-氯煙酸 (10.0 g, 42.3 mmol) 的無水THF溶液 (440 mL) 中加入TEA (7.06 mL, 50.8 mmol)，然後加入氯甲酸異丁酯 (6.64 mL, 50.76 mmol)，有白色沉澱迅速生成。混合物在0°C下攪拌反應75分鐘。過濾後固體用THF (30 mL) 洗滌。濃縮得含有5-溴-2-氯煙酸 (異丁基碳酸)酐(B-1) 的溶液200 mL，直接用於下一步反應。 (5- 溴 -2- 氯吡啶 -3- 基 ) 甲醇 (B-2) 向上述溶液中加水(10 mL)。混合物冷卻至0°C後加入NaBH₄ (3.38 g, 89 mmol)，將混合物在0°C下攪拌1小時，然後升至室溫超過2小時。加入乙酸乙酯，混合物用水及飽和食鹽水洗滌，無水碳酸鉀和硫酸鈉乾燥，濃縮得 (5-溴-2-氯吡啶-3-基)甲醇 (B-2) 粗品，直接用於下一步反應。 5- 溴 -2- 氯 -3- 吡啶甲醛 (B-3) 在-78 °C下，向(COCl)₂ (2.95 mL, 34.84 mmol) 的無水DCM溶液 (26 mL) 中滴加DMSO (4.94 mL, 69.7mmol) 的DCM溶液 (45 mL)，並在-78°C下攪拌10分鐘。逐滴加入(5-溴-2-氯吡啶-3-基)甲醇 (B-2) 的DCM溶液 (45 mL)。將混合物在-78°C下攪拌10分鐘。再逐滴加入TEA (18.2 mL, 131 mmol)，繼續在-78°C下攪拌1小時。混合物升高至室溫攪拌1小時。用水 (100 mL) 稀釋，分液後有機層用水及飽和食鹽水洗滌，無水硫酸鎂乾燥，濃縮。殘留物用矽膠柱層析純化，3-5%的乙酸乙酯己烷溶液洗脫，得到白色固體5-溴-2-氯-3-吡啶甲醛 (B-3)。MS-ESI (m/z): 220 [M + 1]⁺ 。 1-(5- 溴 -2- 氯吡啶 -3- 基 )-2- 甲基丙烷 -1- 醇 (B-4) 在N₂ 環境下，於-78°C向5-溴-2-氯-3-吡啶甲醛 (B-3) (5.63 g, 25.53 mmol) 的無水THF溶液 (70 mL) 中逐滴加入異丙基氯化鎂 (2.0 M 的THF溶液 15.3 mL)。混合物升到到室溫攪拌過夜。加水後分液，水層用乙酸乙酯萃取，有機層用水及飽和食鹽水洗滌，無水硫酸鎂乾燥，濃縮。殘留物用矽膠柱層析純化得到1-(5-溴-2-氯吡啶-3-基)-2-甲基丙烷-1-醇 (B-4)。MS-ESI (m/z): 264 [M + 1]⁺ 。 1-(5- 溴 -2- 氯吡啶 -3- 基 )-2- 甲基丙烷 -1- 酮 (B-5) B-4 (265 mg, 1 mmol)，PCC (431 mg, 2 mmol) 和SiO₂ (0.5 g) 在DCM (8 mL) 中的混合物於室溫下攪拌5小時。混合物用矽藻土過濾，DCM洗滌殘留固體。濃縮濾液，殘留物用矽膠柱層析純化得到1-(5-溴-2-氯吡啶-3-基)-2-甲基丙烷-1-酮 (B-5)。MS-ESI (m/z): 262 [M + 1]⁺ 。 5- 溴 -3- 異丙基 -1H- 吡唑並 [3,4-b] 吡啶 (B-6) 在室溫下，向1-(5-溴-2-氯吡啶-3-基)-2-甲基丙烷-1-酮 (B-5) (177 mg, 0.674 mmol) 的異丙醇 (2 mL) 溶液中加入水合肼 (0.5 mL)。混合物升溫至80°C攪拌過夜。混合物冷卻至室溫，用水稀釋，用乙酸乙酯萃取。萃取物用飽和食鹽水洗滌，Na₂ SO₄ 乾燥並濃縮。殘留物用矽膠柱層析純化 (洗脫劑：正己烷/乙酸乙酯=1:1)，得到5-溴-3-異丙基-1H-吡唑並[3,4-b]吡啶 (B-6)。MS-ESI (m/z): 240 [M + 1]⁺ 。 5- 溴 -3- 異丙基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 (B-7) 在0°C下，向5-溴-3-異丙基-1H-吡唑並[3,4-b]吡啶(B-6) (48 mg, 0.2 mmol) 的THF溶液中加入NaH (10 mg, 含量60%在油中)，攪拌5分鐘後滴加MeI (25 μL, 0.4 mmol)。混合物在0°C下攪拌20分鐘。用水淬滅反應。混合物用乙酸乙酯萃取，用飽和食鹽水洗滌，Na₂ SO₄ 乾燥，濃縮。殘留物用矽膠柱層析純化，10% ~ 100%的乙酸乙酯己烷溶液洗脫，得到5-溴-3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶 (B-7)，MS-ESI (m/z):254 [M + 1]⁺ ，和5-溴-3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶(B-7b)。MS-ESI (m/z): 254 [M + 1]⁺ 。 (3- 異丙基 -1- 甲基 -1H- 吡唑並 [3,4-b] 吡啶 -5- 基 ) 硼酸 (B-8) 5-溴-3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶 (B-7) (724 mg, 2.85 mmol)，聯硼酸頻哪醇酯 (1.09 g, 4.27 mmol)，Pd(OAc)₂ (64 mg,0.28 mmol)，Cy₃ P (160 mg, 0.57 mmol) 和KOAc (838 mg, 8.55 mmol) 在DMSO (10 mL) 中的混合物在氮氣保護下於封管中100°C下攪拌2小時。用水淬滅反應。混合物用DCM萃取，萃取物Na₂ SO₄ 乾燥，濃縮得到標題化合物 (3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶-5-基)硼酸 (B-8)。MS-ESI (m/z): 220 [M + 1]⁺ 。 5-(2- 氯 -5- 氟嘧啶 -4- 基 )-7- 氟 -3- 異丙基 -1- 甲基 -3a,7a- 二氫 -1H- 吲唑 ( 中間體 B) (3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶-5-基)硼酸 (B-8) (624 mg, 2.85 mmol)，2, 4-二氯-5-氟嘧啶 (952 mg, 5.7 mmol)，Pd(PPh₃ )₂ Cl₂ (200 mg,0.28 mmol) 和Na₂ CO₃ (906 mg, 8.55 mmol) 在DME/H₂ O (24 ml/ 10 ml) 溶液的混合物在氮氣保護下於封管中80°C下攪拌2小時。用水淬滅反應。混合物用DCM萃取，合併有機層用Na₂ SO₄ 乾燥，濃縮。殘留物用矽膠柱層析純化 (洗脫劑：正己烷/乙酸乙酯=2:1)，得到標題化合物5-(2-氯-5-氟嘧啶-4-基)-7-氟-3-異丙基-1-甲基-3a,7a-二氫-1H-吲唑 (中間體 B)。 MS-ESI (m/z): 306 [M + 1]⁺ 。中間體 C 5-(2- 氯 -5- 氟嘧啶 -4- 基 )-3- 異丙基 -1- 甲基 -1H- 吡唑並 [3,4-b] 吡啶 ( 中間體 C)

中間體 C 5- 溴 -3- 異丙基 -1- 甲基 -1H- 吡唑並 [3,4-b] 吡啶 (C-1) 向1-(5-溴-2-氯吡啶-3-基)-2-甲基丙烷-1-酮 (B-5) (38 mg, 0.15 mmol) 和甲基肼硫酸鹽 (25 mg, 0.2 mmol) 的EtOH (2 mL)溶液中加入TEA (50 mg, 5 mmol)。混合物在室溫下攪拌0.5小時後回流過夜。混合物冷卻至室溫並濃縮。殘留物用DCM (20 mL) 稀釋，依次用水和飽和食鹽水 (20 mL) 洗滌，Na₂ SO₄ 乾燥並旋蒸。殘留物用矽膠柱層析純化 (洗脫劑：石油醚/乙酸乙酯=100:1 ~ 50:1)，得到5-溴-3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶 (C-1)。MS-ESI (m/z):254 [M + 1]⁺ 。 (3- 異丙基 -1H- 吡唑並 [3,4-b] 吡啶 -5- 基 ) 硼酸 (C-2) 依照B-8的合成方法，將5-溴-3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶 (B-7) 替換為5-溴-3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶 (C-1)，製備了標題化合物 (3-異丙基-1H-吡唑並[3,4-b]吡啶-5-基)硼酸 (C-2)。MS-ESI (m/z): 220 [M + 1]⁺ 。 5-(2- 氯 -5- 氟嘧啶 -4- 基 )-3- 異丙基 -1- 甲基 -1H- 吡唑並 [3,4-b] 吡啶 ( 中間體 C) 依照中間體 B的合成方法，將(3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶-5-基)硼酸 (B-8) 替換為(3-異丙基-1H-吡唑並[3,4-b]吡啶-5-基)硼酸 (C-2)，製備了標題化合物 5-(2-氯-5-氟嘧啶-4-基)-3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶 (中間體 C) 。MS-ESI (m/z): 306 [M + 1]⁺ 。中間體 D 6- 溴 -1- 叔丁基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 ( 中間體 D)

中間體 D 5- 溴 -3- 氟吡啶 -2- 胺 (D-1) 在0°C下，向3-氟吡啶-2-胺 (11.0 g, 98.0 mmol) 的ACN (300 mL) 溶液中加入NBS (8.72 g, 49.0 mmol)，常溫下攪拌1小時。再逐滴加入NBS (8.72 g, 49.0 mmol)。反應混合物濃縮後用水(100 mL) 稀釋。用矽藻土過濾。濾餅用水洗滌，濾液濃縮得到標題化合物5-溴-3-氟吡啶-2-胺 (D-1) 粗品。MS-ESI (m/z): 191 [M + 1]⁺ 。 5- 溴 -3- 氟 -2- 硝基吡啶 (D-2) 在0°C下，向5-溴-3-氟吡啶-2-胺 (D-1) (4.0 g, 21.0 mmol) 的濃硫酸 (20 mL) 混合物中加入H₂ O₂ (33 mL, 29.1 mmol) 的濃硫酸 (66 mL) 溶液。混合物升高到室溫攪拌過夜。在0°C下用碳酸鈉稀溶液鹼化至pH為7，乙酸乙酯萃取。有機層依次用Na₂ S₂ O₃ 水溶液和飽和食鹽水洗滌，Na₂ SO₄ 乾燥。過濾並濃縮，殘留物用矽膠柱層析純化 (洗脫劑：石油醚/乙酸乙酯 = 40:1)，得到標題化合物5-溴-3-氟-2-硝基吡啶 (D-2)。MS-ESI (m/z): 220 [M + 1]⁺ 。 5- 溴 -N- 叔丁基 -2- 硝基吡啶 -3- 胺 (D-3) 5-溴-3-氟-2-硝基吡啶 (D-2) (1.63 g, 7.38 mmol)，叔丁基胺 (1.08 g, 14.8 mmol) 和TEA (1.49 g, 14.8 mmol) 在THF (30 mL) 中的混合物於45°C下攪拌過夜。加入水和乙酸乙酯。水層用EtOAc (3 × 30 mL) 萃取。有機層用飽和食鹽水洗滌，Na₂ SO₄ 乾燥，濃縮，殘留物用矽膠柱層析純化 (洗脫劑：石油醚/乙酸乙酯=30:1)，得到標題化合物5-溴-N-叔丁基-2-硝基吡啶-3-胺 (D-3)。MS-ESI (m/z): 274 [M+ 1]⁺ 。 5- 溴 -N3- 叔丁基吡啶 -2,3- 二胺 (D-4) 5-溴-N-叔丁基-2-硝基吡啶-3-胺 (D-3) (1.3 g, 4.7 mmol)，NH₄ Cl水溶液 (16 mL) 和Fe (2.6 g, 46 mmol) 在EtOH (16 mL) 中的混合物於75°C下攪拌40分鐘。混合物過濾，濾液用DCM (3 × 30 mL) 萃取。有機層用飽和食鹽水洗滌，Na₂ SO₄ 乾燥，濃縮，得到標題化合物5-溴-N3-叔丁基吡啶-2,3-二胺 (D-4)。MS-ESI (m/z): 244 [M+ 1]⁺ 。 6- 溴 -1- 叔丁基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 ( 中間體 D) 5-溴-N3-叔丁基吡啶-2,3-二胺 (D-4) (50 mg, 0.205 mmol) 和Ac₂ O (21μl, 0.225 mmol) 在AcOH (1 mL) 中的混合物於90°C下攪拌過夜。濃縮混合物，殘留物用碳酸氫鈉溶液 (50 ml) 洗滌，然後EtOAc (3 × 30 mL) 萃取。萃取物依次用水(2 × 30 mL) 和飽和食鹽水 (30 mL)洗滌，乾燥濃縮得到標題化合物6-溴-1-叔丁基-2-甲基-1H-咪唑並[4,5-b]吡啶 (中間體 D)。MS-ESI (m/z): 268 [M + 1]⁺ 。中間體 E 3- 叔丁基 -2- 甲基 -5-( 三丁基錫基 )-2H- 吡唑並 [3,4-b] 吡啶 ( 中間體 E)

中間體 E 5- 溴 -2- 氯 -N- 甲氧基 -N- 甲基煙酸胺 (E-1) 依照B-1的合成方法，將氯甲酸異丁酯替換為二甲羥胺鹽酸鹽，製備了標題化合物5-溴-2-氯-N-甲氧基-N-甲基煙酸胺 (E-1)。MS-ESI (m/z): 279 [M + 1]⁺ 。 5- 溴 -2- 氯 -3- 吡啶甲醛 (E-2) 在-78°C下，向5-溴-2-氯-N-甲氧基-N-甲基煙酸胺 (E-1) (11.8 g, 42 mmol) 的CDM (250 mL) 溶液中加入DIBAl-H (70 mL, 105 mmol)，混合物在0°C下攪拌0.5小時。濃縮混合物，殘留物用矽膠柱層析純化 (洗脫劑：石油醚/乙酸乙酯=10:1)，得到標題化合物5-溴-2-氯-3-吡啶甲醛 (E-2)。MS-ESI (m/z): 220 [M + 1]⁺ 。 1-(5- 溴 -2- 氯吡啶 -3- 基 )-2,2- 二甲基丙烷 -1- 醇 (E-3) 在0°C下，向5-溴-2-氯-3-吡啶甲醛 (E-2) (2.1 g, 10 mmol) 的THF (60 ml) 溶液中加入叔丁基氯化鎂 (50 mL, 50 mmol)。混合物在0 - 10°C下攪拌2小時，用MeOH (10 mL) 淬滅反應。混合物濃縮得到標題化合物1-(5-溴-2-氯吡啶-3-基)-2,2-二甲基丙烷-1-醇 (E-3)。MS-ESI (m/z): 278 [M + 1]⁺ 。 1-(5- 溴 -2- 氯吡啶 -3- 基 )-2,2- 二甲基丙烷 -1- 酮 (E-4) 依照B-5的合成方法，將1-(5-溴-2-氯吡啶-3-基)-2-甲基丙烷-1-醇 (B-4) 替換為1-(5-溴-2-氯吡啶-3-基)-2,2-二甲基丙烷-1-醇 (E-3)，製備了標題化合物1-(5-溴-2-氯吡啶-3-基)-2,2-二甲基丙烷-1-酮 (E-4)。MS-ESI (m/z): 276 [M + 1]⁺ 。 5- 溴 -3- 叔丁基 -1H- 吡唑並 [3,4-b] 吡啶 (E-5) 依照B-6的合成方法，將1-(5-溴-2-氯吡啶-3-基)-2-甲基丙烷-1-酮 (B-5) 替換為1-(5-溴-2-氯吡啶-3-基)-2,2-二甲基丙烷-1-酮 (E-4)，製備了標題化合物5-溴-3-叔丁基-1H-吡唑並[3,4-b]吡啶 (E-5)。MS-ESI (m/z): 254 [M + 1]⁺ 。 5- 溴 -3- 叔丁基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 (E-6) 在0°C下，向5-溴-3-叔丁基-1H-吡唑並[3,4-b]吡啶 (E-5) (320 mg, 1.3 mmol) 的THF (10 ml) 溶液中加入NaH (80 mg, 在油中含量60%)，攪拌5分鐘後滴加MeI (370 mg, 2.6 mmol)。混合物在0°C下攪拌20分鐘。用水淬滅反應。混合物用乙酸乙酯萃取，用飽和食鹽水洗滌，Na₂ SO₄ 乾燥，濃縮。殘留物用矽膠柱層析純化，10-100%的乙酸乙酯己烷溶液洗脫，得到5-溴-3-叔丁基-2-甲基-2H-吡唑並[3,4-b]吡啶 (E-6)，MS-ESI (m/z):268 [M + 1]⁺ ，和5-溴-3-叔丁基-1-甲基-1H-吡唑並[3,4-b]吡啶 (E-6b)。MS-ESI (m/z): 268 [M + 1]⁺ 。 3- 叔丁基 -2- 甲基 -5-( 三丁基錫基 )-2H- 吡唑並 [3,4-b] 吡啶 ( 中間體 E) 5-溴-3-叔丁基-2-甲基-2H-吡唑並[3,4-b]吡啶 (E-6) (134 mg, 0.5 mmol)，(Bu₃ Sn)₂ (870 mg, 1.5 mmol)，Pd(PPh₃ )₄ (22 mg, 0.02 mmol) 和TEA (150 mg, 1.5 mmol) 在1,4-二氧六環 (5 mL) 的混合物在80°C下攪拌過夜。混合物濃縮，殘留物用矽膠柱層析純化 (洗脫劑：乙酸乙酯)，得到標題化合物3-叔丁基-2-甲基-5-(三丁基錫基)-2H-吡唑並[3,4-b]吡啶 (中間體 E)。MS-ESI (m/z): 480 [M + 1]⁺ 。實施例 1 5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 )-N-(5-( 呱嗪 -1- 基甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (1)

叔丁基 4-((6- 溴吡啶 -3- 基 ) 甲基 ) 呱嗪 -1- 羧酸酯 (1a) 在0°C下，向2-溴-5-醛基吡啶 (11.0 g, 59.1 mmol) 和1-Boc-呱嗪 (10.0 g, 53.7 mmol) 的DCM (100 mL) 溶液中分批加入NaBH(OAc)₃ (13.6 g, 64.1 mmol)。混合物升高到室溫攪拌過夜。加入DCM (100 mL)，然後在0°C下加入NaOH水溶液 (2 N, 100 mL)。分離有機層，水層用DCM (100 mL) 萃取。萃取物用飽和食鹽水 (100 mL) 洗滌，Na₂ SO₄ 乾燥濃縮得到叔丁基 4-((6-溴吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1a) 粗品，直接用於下一步反應。MS-ESI (m/z): 356，358 [M + 1]⁺ 。 叔丁基 4-((6- 氨基吡啶 -3- 基 ) 甲基 ) 呱嗪 -1- 羧酸酯 (1b) 在氮氣保護下，叔丁基 4-((6-溴吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1a) (3.56 g, 10 mmol)，Cu₂ O (0.50 g, 0.3 mmol) 在NH₃ .H₂ O (20 mL) 和MeOH (20 mL) 中的混合物于封管中70°C下攪拌過夜。混合物冷卻至室溫，過濾後將濾液濃縮。用NaOH水溶液 (2 N, 50 mL) 稀釋，用DCM (2 × 100 mL) 萃取。萃取物用飽和食鹽水 (100 mL) 洗滌，Na₂ SO₄ 乾燥，過濾並濃縮得到黃色油狀粗品，MTBE重結晶提純得到叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b)。 MS-ESI (m/z): 293 [M + 1]⁺ 。 叔丁基 4-((6-((5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 基 ) 氨基 ) 吡啶 -3- 基 ) 甲基 ) 呱嗪 -1- 羧酸酯 (1c) 6-(2-氯-5-氟嘧啶-4-基)-1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶 (中間體 A) (0.045 g, 0.15 mmol)，叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b) (0.055 g, 0.18 mmol)，Pd₂ (dba)₃ (0.008 g, 0.015 mmol)，Xantphos (0.01 g, 0.015 mmol) 和Cs₂ CO₃ (0.103 g, 0.3 mmol) 在1,4-二氧六環 (3 mL) 中的混合物氮氣保護下於90°C攪拌1小時。混合物冷卻至室溫，用DCM (10 mL) 稀釋。用矽藻土過濾。濃縮濾液，殘留物用製備薄層層析純化 (洗脫劑：DCM /MeOH = 20:1)，得到叔丁基 4-((6-((5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1c)。MS-ESI (m/z): 562 [M + 1]⁺ 。 5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 )-N-(5-( 呱嗪 -1- 基甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (1) 叔丁基 4-((6-((5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1c) (0.03 g, 0.05 mmol) 在TFA (2 mL) 和DCM (4 mL) 中的混合物室溫下攪拌2小時。真空下旋蒸溶劑，殘留物用水 (10 mL) 稀釋，DCM (10 mL) 洗滌。水層用NaOH (2 N) 調節pH至11 ~ 12。用IPA / DCM (25%, 4 × 20 mL) 萃取。萃取物用飽和食鹽水 (40 mL) 洗滌，Na₂ SO₄ 乾燥並濃縮。殘留物用製備薄層層析純化 (洗脫劑：DCM /MeOH = 10:1)，得到5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-N-(5-(呱嗪-1-基甲基)吡啶-2-基)嘧啶-2-胺 (1)。MS-ESI (m/z): 462 [M + 1]⁺ 。實施例 2 5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 )-N-(5-((4- 甲基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (2)

5-((4- 甲基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 胺 (2a) 依照1b的合成方法，將1-Boc-呱嗪替換為1-甲基呱嗪，製備了標題化合物5-((4-甲基呱嗪-1-基)甲基)吡啶-2-胺 (2a)。MS-ESI (m/z): 207 [M + 1]⁺ 。 5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 )-N-(5-((4- 甲基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (2) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b) 替換為5-((4-甲基呱嗪-1-基)甲基)吡啶-2-胺 (2a)，製備了標題化合物5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-N-(5-((4-甲基呱嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺 (2)。MS-ESI (m/z): 476 [M + 1]⁺ 。實施例 3 N-(5-((4- 乙基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (3)

5-((4- 乙基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 胺 (3a) 依照1b的合成方法，將1-Boc-呱嗪替換為1-乙基呱嗪，製備了標題化合物5-((4-乙基呱嗪-1-基)甲基)吡啶-2-胺 (3a)。MS-ESI (m/z): 221 [M + 1]⁺ 。 N-(5-((4- 乙基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (3) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b) 替換為5-((4-乙基呱嗪-1-基)甲基)吡啶-2-胺 (3a)，製備了標題化合物N-(5-((4-乙基呱嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-胺 (3)。MS-ESI (m/z): 490 [M + 1]⁺ 。實施例 4 (S)-5- 氟 -N-(5-(( 六氫吡咯 [1,2-a] 吡嗪 -2(1H)- 基 ) 甲基 ) 吡啶 -2- 基 )-4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (4)

( 叔丁氧羰基 )-L- 脯氨酸 (4a) (叔丁氧羰基)-L-脯氨酸 (4a) 按文獻Tetrahedron. 2013, 10, 156.所述方法製備。 叔丁基 (S)-2-((2- 乙氧基 -2- 氧乙基 ) 氨甲醯基 ) 吡咯烷 -1- 羧酸酯 (4b) 在0°C下，向 (叔丁氧羰基)-L-脯氨酸 (4a) (21.5 g, 100 mmol) 的THF (200 mL) 溶液中分批加入CDI (17.8 g, 110 mmol)。混合物在室溫下攪拌0.5小時。在0°C下加入甘氨酸乙酯鹽酸鹽 (15.3 g, 110 mmol)，然後加入TEA (15.0g, 150 mmol)，混合物在室溫下攪拌過夜。真空旋幹溶劑，殘留物用乙酸乙酯 (250 mL) 稀釋，依次用飽和NaHCO₃ 溶液 (200 mL)、10% 檸檬酸 (2 × 200 mL)和飽和食鹽水 (200 mL) 洗滌，Na₂ SO₄ 乾燥並濃縮得到標題化合物 叔丁基 (S)-2-((2-乙氧基-2-氧乙基)氨甲醯基)吡咯烷-1-羧酸酯 (4b)。 (S)- 脯氨醯甘氨酸乙酯 三氟乙酸鹽 (4c) 叔丁基 (S)-2-((2-乙氧基-2-氧乙基)氨甲醯基)吡咯烷-1-羧酸酯 (4b) (24.8 g, 82.6 mmol) 和TFA (100mL) 在DCM (125 mL) 中的混合物室溫下攪拌2小時，濃縮得到(S)-脯氨醯甘氨酸乙酯 三氟乙酸鹽 (4c) 粗品，直接用於下一步反應。MS-ESI (m/z): 201 [M + 1]⁺ 。 (S)- 六氫吡咯並 [1,2-a] 吡嗪 -1,4- 二酮 (4d) (S)-脯氨醯甘氨酸乙酯 三氟乙酸鹽 (4c) (40 g, 127 mmol) 在TEA (150 mL) 和MeOH (800 mL) 中的混合物回流過夜。真空旋幹溶劑，殘留物用IPA (100 mL) 稀釋。過濾，濾餅用正己烷洗滌。固體真空乾燥得到 (S)-六氫吡咯並[1,2-a]吡嗪-1,4-二酮 (4d)。MS-ESI (m/z): 154 [M + 1]⁺ 。 苄基 (S)- 六氫吡咯並 [1,2-a] 吡嗪 -2(1H)- 羧酸酯 (4e) 向LAH (5.9 g, 156 mmol) 的THF (60 mL) 懸濁液中逐滴加入 (S)-六氫吡咯並[1,2-a]吡嗪-1,4-二酮 (4d) (4.0 g, 26 mmol) 的THF (40 mL) 溶液，混合物回流16小時。反應混合物冷卻至0°C後滴加飽和NaHCO₃ (100 mL) 溶液，然後再加入氯甲酸苄酯 (6.67 g, 39 mmol)。混合物在0°C下攪拌1小時，室溫下再攪拌2小時。反應溶液用三氯甲烷 (3 × 200 mL) 萃取，萃取物用飽和食鹽水 (400 mL) 洗滌，Mg₂ SO₄ 乾燥。濃縮，殘留物用矽膠柱層析純化，(洗脫劑：DCM /MeOH =25:1)，得到苄基 (S)-六氫吡咯並[1,2-a]吡嗪-2(1H)-羧酸酯 (4e)。MS-ESI (m/z): 261 [M + 1]⁺ 。 (S)- 八氫吡咯並 [1,2-a] 吡嗪 (4f) 苄基 (S)-六氫吡咯並[1,2-a]吡嗪-2(1H)-羧酸酯 (4e) (5.0 g, 19 mmol) 和Pd/C (10%, 1.0 g) 在MeOH (50 mL) 中的混合物在氫氣環境下室溫攪拌2小時。混合物用矽藻土過濾，濃縮濾液得到 (S)-八氫吡咯並[1,2-a]吡嗪 (4f) 粗品。MS-ESI (m/z): 127 [M + 1]⁺ 。 (S)-2-((6- 溴吡啶 -3- 基 ) 甲基 ) 八氫吡咯並 [1,2-a] 吡嗪 (4g) 依照1a的合成方法，將1-Boc-呱嗪替換為(S)-八氫吡咯並[1,2-a]吡嗪 (4f)，製備了標題化合物 (S)-2-((6-溴吡啶-3-基)甲基)八氫吡咯並[1,2-a]吡嗪 (4g)。MS-ESI (m/z): 296, 298 [M + 1]⁺ 。 (S)-5-(( 六氫吡咯並 [1,2-a] 吡嗪 -2(1H)- 基 ) 甲基 ) 吡啶 -2- 胺 (4h) 依照1b的合成方法，將叔丁基 4-((6-溴吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1a)替換為(S)-2-((6-溴吡啶-3-基)甲基)八氫吡咯並[1,2-a]吡嗪 (4g)，製備了標題化合物 (S)-5-((六氫吡咯並[1,2-a]吡嗪-2(1H)-基)甲基)吡啶-2-胺 (4h)。MS-ESI (m/z): 233 [M + 1]⁺ 。 (S)-5- 氟 -N-(5-(( 六氫吡咯 [1,2-a] 吡嗪 -2(1H)- 基 ) 甲基 ) 吡啶 -2- 基 )-4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (4) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b)替換為 (S)-5-((六氫吡咯並[1,2-a]吡嗪-2(1H)-基)甲基)吡啶-2-胺 (4h)，製備了標題化合物(S)-5-氟-N-(5-((六氫吡咯[1,2-a]吡嗪-2(1H)-基)甲基)吡啶-2-基)-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-胺 (4)。MS-ESI (m/z): 502 [M + 1]⁺ 。實施例 5 (R)-5- 氟 -N-(5-(( 六氫吡咯並 [1,2-a] 吡嗪 -2(1H)- 基 ) 甲基 ) 吡啶 -2- 基 )-4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (5)

(R)-5-(( 六氫吡咯並 [1,2-a] 吡嗪 -2(1H)- 基 ) 甲基 ) 吡啶 -2- 胺 (5a) 依照4h的合成方法，將起始物L-脯氨酸替換為D-脯氨酸，製備了標題化合物 (R)-5-((六氫吡咯並[1,2-a]吡嗪-2(1H)-基)甲基)吡啶-2-胺 (5a)。MS-ESI (m/z): 233 [M + 1]⁺ 。 (R)-5- 氟 -N-(5-(( 六氫吡咯並 [1,2-a] 吡嗪 -2(1H)- 基 ) 甲基 ) 吡啶 -2- 基 )-4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (5) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b)替換為(R)-5-((六氫吡咯並[1,2-a]吡嗪-2(1H)-基)甲基)吡啶-2-胺 (5a)，製備了標題化合物(R)-5-氟-N-(5-((六氫吡咯並[1,2-a]吡嗪-2(1H)-基)甲基)吡啶-2-基)-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-胺 (5)。MS-ESI (m/z): 502 [M + 1]⁺ 。實施例 6 N-(5-(((1S,4S)-2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (6)

叔丁基 (1S,4S)-5-((6- 溴吡啶 -3- 基 ) 甲基 )-2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 羧酸酯 (6a) 向叔丁基 (1S,4S)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (0.099 g, 0.5 mmol)，5-溴-2-吡啶甲醛 (0.093 g, 0.5 mmol) 和AcOH (0.03 g, 0.5 mmol) 的THF (1 mL) 溶液中加入三乙醯氧基硼氫化鈉 (0.159 g, 0.75 mmol)。反應混合物在室溫下攪拌過夜。混合物用飽和NaHCO₃ 溶液淬滅，EtOAc萃取，有機層用飽和食鹽水 (20 mL) 洗滌，Na₂ SO₄ 乾燥。濃縮得到叔丁基 (1S,4S)-5-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6a)。MS-ESI (m/z): 368, 390 [M + 1]⁺ 。 叔丁基 (1S,4S)-5-((6- 氨基吡啶 -3- 基 ) 甲基 )-2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 羧酸酯 (6b) 叔丁基 (1S,4S)-5-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6a) (180 mg, 0.49 mmol)，NH3•H₂ O (4.5 mL)，Cu₂ O (80.0 mg, 0.56 mmol) 在MeOH (1.5 mL) 中的混合物于封管中65°C下攪拌過夜。冷卻至室溫後過濾，濾液減壓濃縮。殘留物在DCM 和NaOH (2 N) 之間區分。分離有機層用飽和食鹽水洗滌，Na₂ SO₄ 乾燥並濃縮，殘留物用矽膠柱層析純化，(洗脫劑：DCM:MeOH =10:1)，得到叔丁基 (1S,4S)-5-((6-氨基吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6b) 粗品。MS-ESI (m/z): 305 [M + 1]⁺ 。 叔丁基 (1S,4S)-5-((6-((5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 基 ) 氨基 ) 吡啶 -3- 基 ) 甲基 )-2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 羧酸酯 (6c) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b)替換為叔丁基 (1S,4S)-5-((6-氨基吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6b)，製備了標題化合物叔丁基 (1S,4S)-5-((6-((5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6c)。MS-ESI (m/z): 574 [M + 1]⁺ 。 N-(5-(((1S,4S)-2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (6) 依照1的合成方法，將叔丁基 4-((6-((5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1c) 替換為叔丁基 (1S,4S)-5-((6-((5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6c)，製備了標題化合物N-(5-(((1S,4S)-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-基)-5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-胺 (6)。MS-ESI (m/z): 474 [M + 1]⁺ 。實施例 7 5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 )-N-(5-(((1S,4S)-5- 甲基 -2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (7)

(1S,4S)-2-((6- 溴吡啶 -3- 基 ) 甲基 )-2,5- 二氮雜二環 [2.2.1] 庚烷 (7a) 在室溫下向叔丁基 (1S,4S)-5-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6a) (0.81 g, 2.2 mmol) 的DCM (6 mL) 溶液中加入TFA (4 mL)。混合物攪拌2小時。用Na₂ CO₃ 溶液調節pH至8。混合物用DCM (3 × 6 mL) 萃取。萃取物依次用水和飽和食鹽水 (5 mL) 洗滌，Na₂ SO₄ 乾燥並濃縮得到 (1S,4S)-2-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷 (7a) (0.534 g)。 MS-ESI (m/z): 268 [M + 1]⁺ 。 (1S,4S)-2-((6- 溴吡啶 -3- 基 ) 甲基 )-5- 甲基 -2,5- 二氮雜二環 [2.2.1] 庚烷 (7b) 在室溫下，向 (1S,4S)-2-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷 (7a) (0.15 g, 0.56 mmol) 的DCM (2 mL) 溶液中加入甲醛 (37%, 63 μL)，然後加入NaBH(OAc)₃ (0.273 g, 1.12 mmol)。混合物用力攪拌30分鐘。混合物用飽和Na2CO3溶液淬滅，DCM (2 × 5 mL) 萃取，萃取物依次用水和飽和食鹽水 (5 mL) 洗滌，Na₂ SO₄ 乾燥。過濾並濃縮。殘留物用矽膠柱層析純化，(洗脫劑：DCM:MeOH =10:1)，得到(1S,4S)-2-((6-溴吡啶-3-基)甲基)-5-甲基-2,5-二氮雜二環[2.2.1]庚烷 (7b)。MS-ESI (m/z): 282, 284 [M + 1]⁺ 。 5-(((1S,4S)-5- 甲基 -2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 胺 (7c) 依照6b的合成方法，將叔丁基 (1S,4S)-5-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6a) 替換為(1S,4S)-2-((6-溴吡啶-3-基)甲基)-5-甲基-2,5-二氮雜二環[2.2.1]庚烷 (7b)，製備了標題化合物5-(((1S,4S)-5-甲基-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-胺 (7c)。MS-ESI (m/z): 219 [M + 1]⁺ 。 5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 )-N-(5-(((1S,4S)-5- 甲基 -2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (7) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b)替換為5-(((1S,4S)-5-甲基-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-胺 (7c)，製備了標題化合物5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-N-(5-(((1S,4S)-5-甲基-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-基)嘧啶-2-胺 (7)。MS-ESI (m/z): 488 [M + 1]⁺ 。實施例 8 N-(5-(((1S,4S)-5- 乙基 -2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (8)

(1S,4S)-2-((6- 溴吡啶 -3- 基 ) 甲基 )-5- 乙基 -2,5- 二氮雜二環 [2.2.1] 庚烷 (8a) 在室溫下，向 (1S,4S)-2-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷 (7a) (0.10 g, 0.37 mmol) 和TEA (60 μL, 0.41 mmol) 的DMF (1 mL) 溶液中逐滴加入溴乙烷。混合物攪拌3.5小時。用水 (5 mL) 和DCM (5 mL) 萃取。萃取物依次用水 (2 mL) 和飽和食鹽水 (2 mL) 洗滌，Na₂ SO₄ 乾燥並濃縮。殘留物用矽膠柱層析純化，(洗脫劑：DCM:MeOH =10:1)，得到 (1S,4S)-2-((6-溴吡啶-3-基)甲基)-5-乙基-2,5-二氮雜二環[2.2.1]庚烷 (8a)。MS-ESI (m/z): 296, 298 [M + 1]⁺ 。 5-(((1S,4S)-5- 乙基 -2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 胺 (8b) 依照6b的合成方法，將叔丁基 (1S,4S)-5-((6-溴吡啶-3-基)甲基)-2,5-二氮雜二環[2.2.1]庚烷-2-羧酸酯 (6a) 替換為 (1S,4S)-2-((6-溴吡啶-3-基)甲基)-5-乙基-2,5-二氮雜二環[2.2.1]庚烷 (8a)，製備了標題化合物5-(((1S,4S)-5-乙基-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-胺 (8b)。MS-ESI (m/z): 233 [M + 1]⁺ 。 N-(5-(((1S,4S)-5- 乙基 -2,5- 二氮雜二環 [2.2.1] 庚烷 -2- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(1- 異丙基 -2- 甲基 -1H- 咪唑並 [4,5-b] 吡啶 -6- 基 ) 嘧啶 -2- 胺 (8) 依照1c的合成方法，將叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b)替換為5-(((1S,4S)-5-乙基-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-胺 (8b)，製備了標題化合物N-(5-(((1S,4S)-5-乙基-2,5-二氮雜二環[2.2.1]庚烷-2-基)甲基)吡啶-2-基)-5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-胺 (8)。MS-ESI (m/z): 488 [M + 1]⁺ 。 Intermediate preparation Intermediate A 6-(2- chloro -5- fluoropyrimidin- 4 -yl )-1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridine ( Intermediate A )

Intermediate A 5- bromo- N ³ -isopropylpyridine- 2,3- diamine (A-1) commercially available 2,3-diamino-5-bromopyridine (1.88 g, 10 mmol) and acetone Add TFA (2.51 g, 22 mmol) to a solution of isopropyl acetate (0.7 g, 12 mmol) (15 mL), and then add NaBH(OAc) ₃ (3.18 g, 15 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with EtOAc (50 mL). It was washed with saturated aqueous NaHCO ₃ (30 mL) and saturated brine (30 mL), and dried over _{Na 2} SO _4. After filtration and rotary evaporation, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=9:1 ~ 2:1) to obtain 5-bromo-N3-isopropylpyridine-2 as a yellow solid. 3-Diamine (A-1). MS-ESI (m/z): 230, 232 [M + 1] ⁺ . 6- Bromo- 1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridine (A-2) 5-bromo-N3-isopropylpyridine-2,3-diamine( A-1) A mixture of (1.2 g, 5.2 mmol) and Ac ₂ O (2.6 g, 26 mmol) in HOAc (10 mL) was stirred at 90°C overnight. The solvent was spin-dried in vacuo, and the residue was diluted with DCM (50 mL). Adjust the pH to 8-9 with NaOH (1 N). Separate the organic layer. The extract was washed with saturated brine (50 mL) and dried over _{Na 2} SO _4. Filtered and concentrated, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1 ~ 1:2) to obtain 6-bromo-1-isopropyl-2-methyl as a yellow solid Group-1H-imidazo[4,5-b]pyridine (A-2). MS-ESI (m/z): 254, 256 [M + 1] ⁺ . 6-( Tri - n-butylstannyl )-1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridine (A-3) to -bromo-1-isopropyl- 2-Methyl-1H-imidazo[4,5-b]pyridine (A-2) (0.5 g, 2 mmol) in THF (10 mL) was added (Bu ₃ Sn) ₂ (2.32 g, 4 mmol) ), Pd(PPh ₃ )(OAc) ₂ (0.08 g, 0.1 mmol) and TBAF (1.044 g, 8 mmol). Stir at 70°C for 4 h under nitrogen protection. The mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL). The extract was washed with water (50 mL) and dried over MgSO ₄ . After filtration and concentration, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=9:1 ~ 1:1) to obtain the yellow oil 6-(tri-n-butylstannyl)- 1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (A-3). MS-ESI (m/z): 466 [M + 1] ⁺ . 6-(2- Chloro -5- fluoropyrimidin- 4 -yl )-1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridine ( Intermediate A) to 6-(Triple -N-butylstannyl)-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (A-3) (0.455 g, 0.97 mmol) and 2,4-dichloro _{Pd(PPh 3} ) ₄ (0.06 g, 0.05 mmol) was added to a toluene solution (8 mL) of -5-fluoropyrimidine (0.25 g, 1.49 mmol). Stir at 110°C for 4 h under nitrogen protection. The mixture was concentrated. The residue was purified by flash silica gel column chromatography (eluent: ethyl acetate) to obtain 6-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-2-methyl- as a yellow solid 1H-imidazo[4,5-b]pyridine (Intermediate A). MS-ESI (m/z): 306 [M + 1] ⁺ . Intermediate B 5-(2- chloro -5- fluoropyrimidin- 4 -yl )-7- fluoro- 3- isopropyl- 1 -methyl- 3a,7a -dihydro- 1H -indazole ( Intermediate B ) Intermediate B 5- bromo -2- chloronicotinic acid ( isobutyl carbonic acid ) anhydride (B-1) at 0 °C, to 5-bromo-2-chloronicotinic acid (10.0 g, 42.3 mmol) anhydrous TEA (7.06 mL, 50.8 mmol) was added to the THF solution (440 mL), and then isobutyl chloroformate (6.64 mL, 50.76 mmol) was added. A white precipitate formed quickly. The mixture was stirred at 0°C for 75 minutes. After filtration, the solid was washed with THF (30 mL). Concentrate to obtain 200 mL of a solution containing 5-bromo-2-chloronicotinic acid (isobutyl carbonic acid) anhydride (B-1), which is directly used in the next reaction. (5- Bromo -2 -chloropyridin- 3 -yl ) methanol (B-2) Water (10 mL) was added to the above solution. After the mixture was cooled to 0°C, NaBH ₄ (3.38 g, 89 mmol) was added, the mixture was stirred at 0°C for 1 hour, and then warmed to room temperature for more than 2 hours. Add ethyl acetate, wash the mixture with water and saturated brine, dry with anhydrous potassium carbonate and sodium sulfate, and concentrate to obtain crude (5-bromo-2-chloropyridin-3-yl)methanol (B-2), which is used directly in the next step reaction. 5- Bromo -2- chloro- 3- pyridinecarbaldehyde (B-3) at -78 °C, to (COCl) ₂ (2.95 mL, 34.84 mmol) in anhydrous DCM solution (26 mL) was added dropwise DMSO (4.94 mL, 69.7 mmol) in DCM (45 mL) and stirred at -78°C for 10 minutes. A solution of (5-bromo-2-chloropyridin-3-yl)methanol (B-2) in DCM (45 mL) was added dropwise. The mixture was stirred at -78°C for 10 minutes. Then TEA (18.2 mL, 131 mmol) was added dropwise, and stirring was continued for 1 hour at -78°C. The mixture was raised to room temperature and stirred for 1 hour. Dilute with water (100 mL). After separation, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and eluted with 3-5% ethyl acetate and hexane solution to obtain 5-bromo-2-chloro-3-pyridinecarboxaldehyde (B-3) as a white solid. MS-ESI (m/z): 220 [M + 1] ⁺ . 1-(5- Bromo -2 -chloropyridin- 3 -yl )-2 -methylpropane- 1- ol (B-4) under N ₂ environment, at -78°C to 5-bromo-2-chloro To a solution of -3-pyridinecarboxaldehyde (B-3) (5.63 g, 25.53 mmol) in anhydrous THF (70 mL) was added isopropyl magnesium chloride (2.0 M in THF 15.3 mL) dropwise. The mixture was warmed to room temperature and stirred overnight. After adding water, the layers were separated, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 1-(5-bromo-2-chloropyridin-3-yl)-2-methylpropane-1-ol (B-4). MS-ESI (m/z): 264 [M + 1] ⁺ . 1-(5- Bromo -2 -chloropyridin- 3 -yl )-2 -methylpropane- 1 -one (B-5) B-4 (265 mg, 1 mmol), PCC (431 mg, 2 mmol) A mixture of SiO ₂ (0.5 g) in DCM (8 mL) was stirred at room temperature for 5 hours. The mixture was filtered through Celite, and the residual solid was washed with DCM. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain 1-(5-bromo-2-chloropyridin-3-yl)-2-methylpropan-1-one (B-5). MS-ESI (m/z): 262 [M + 1] ⁺ . 5- Bromo- 3- isopropyl- 1H- pyrazolo [3,4-b] pyridine (B-6) at room temperature, to 1-(5-bromo-2-chloropyridin-3-yl) Add hydrazine hydrate (0.5 mL) to a solution of -2-methylpropan-1-one (B-5) (177 mg, 0.674 mmol) in isopropanol (2 mL). The mixture was heated to 80°C and stirred overnight. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1:1) to obtain 5-bromo-3-isopropyl-1H-pyrazolo[3,4-b]pyridine ( B-6). MS-ESI (m/z): 240 [M + 1] ⁺ . 5- Bromo- 3- isopropyl- 2- methyl -2H- pyrazolo [3,4-b] pyridine (B-7) at 0°C, to 5-bromo-3-isopropyl- 1H-pyrazolo[3,4-b]pyridine (B-6) (48 mg, 0.2 mmol) in THF was added with NaH (10 mg, content 60% in oil), stirred for 5 minutes and then added MeI dropwise (25 μL, 0.4 mmol). The mixture was stirred at 0°C for 20 minutes. The reaction was quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine, _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography and eluted with 10% ~ 100% ethyl acetate and hexane solution to obtain 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo[3,4- b] Pyridine (B-7), MS-ESI (m/z): 254 [M + 1] ⁺ , and 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo[3, 4-b] Pyridine (B-7b). MS-ESI (m/z): 254 [M + 1] ⁺ . (3- isopropyl- 1 -methyl -1H- pyrazolo [3,4-b] pyridin -5- yl ) boronic acid (B-8) 5-bromo-3-isopropyl-2-methyl -2H-pyrazolo[3,4-b]pyridine(B-7) (724 mg, 2.85 mmol), pinacol diborate (1.09 g, 4.27 mmol), Pd(OAc) ₂ (64 mg, A mixture of 0.28 mmol), Cy ₃ P (160 mg, 0.57 mmol) and KOAc (838 mg, 8.55 mmol) in DMSO (10 mL) was stirred in a sealed tube at 100°C for 2 hours under nitrogen protection. The reaction was quenched with water. The mixture was extracted with DCM, the extract was _{dried over Na 2} SO ₄ and concentrated to give the title compound (3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (B -8). MS-ESI (m/z): 220 [M + 1] ⁺ . 5-(2- Chloro -5- fluoropyrimidin- 4 -yl )-7- fluoro- 3- isopropyl- 1 -methyl- 3a,7a -dihydro- 1H -indazole ( Intermediate B) (3 -Isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (B-8) (624 mg, 2.85 mmol), 2,4-dichloro-5 -Fluoropyrimidine (952 mg, 5.7 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (200 mg, 0.28 mmol) and Na ₂ CO ₃ (906 mg, 8.55 mmol) in DME/H ₂ O (24 ml/ 10 ml ) The mixture of the solution was stirred for 2 hours at 80°C in a sealed tube under the protection of nitrogen. The reaction was quenched with water. The mixture was extracted with DCM, and the combined organic layers were _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2:1) to obtain the title compound 5-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-3 -Isopropyl-1-methyl-3a,7a-dihydro-1H-indazole (Intermediate B). MS-ESI (m/z): 306 [M + 1] ⁺ . Intermediate C 5-(2- chloro -5- fluoropyrimidin- 4 -yl )-3- isopropyl- 1 -methyl -1H- pyrazolo [3,4-b] pyridine ( Intermediate C)

Intermediate C 5- bromo- 3- isopropyl- 1 -methyl -1H- pyrazolo [3,4-b] pyridine (C-1) to 1-(5-bromo-2-chloropyridine-3 -Yl)-2-methylpropan-1-one (B-5) (38 mg, 0.15 mmol) and methylhydrazine sulfate (25 mg, 0.2 mmol) in EtOH (2 mL) was added TEA (50 mg, 5 mmol). The mixture was stirred at room temperature for 0.5 hours and then refluxed overnight. The mixture was cooled to room temperature and concentrated. The residue was diluted with DCM (20 mL), washed successively with water and saturated brine (20 mL), _{dried over Na 2} SO ₄ and rotary evaporated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100:1 ~ 50:1) to obtain 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3,4-b] Pyridine (C-1). MS-ESI (m/z): 254 [M + 1] ⁺ . (3- isopropyl- 1H- pyrazolo [3,4-b] pyridin -5- yl ) boronic acid (C-2) According to the synthesis method of B-8, the 5-bromo-3-isopropyl- 2-Methyl-2H-pyrazolo[3,4-b]pyridine (B-7) is replaced with 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4- b] Pyridine (C-1), the title compound (3-isopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (C-2) was prepared. MS-ESI (m/z): 220 [M + 1] ⁺ . 5-(2- Chloro -5- fluoropyrimidin- 4 -yl )-3- isopropyl- 1 -methyl -1H- pyrazolo [3,4-b] pyridine ( Intermediate C) According to Intermediate B Synthesis method, replace (3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (B-8) with (3-isopropyl- 1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (C-2), the title compound 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl was prepared Yl-1-methyl-1H-pyrazolo[3,4-b]pyridine (Intermediate C). MS-ESI (m/z): 306 [M + 1] ⁺ . Intermediate D 6- bromo- 1 -tert-butyl -2- methyl -1H- imidazo [4,5-b] pyridine ( Intermediate D)

Intermediate D 5- bromo- 3- fluoropyridin -2- amine (D-1) into a solution of 3-fluoropyridin-2-amine (11.0 g, 98.0 mmol) in ACN (300 mL) at 0°C Add NBS (8.72 g, 49.0 mmol) and stir at room temperature for 1 hour. Then NBS (8.72 g, 49.0 mmol) was added dropwise. The reaction mixture was concentrated and diluted with water (100 mL). Filter with diatomaceous earth. The filter cake was washed with water, and the filtrate was concentrated to obtain the title compound 5-bromo-3-fluoropyridin-2-amine (D-1) as a crude product. MS-ESI (m/z): 191 [M + 1] ⁺ . 5- Bromo- 3- fluoro -2- nitropyridine (D-2) at 0°C, to 5-bromo-3-fluoropyridin-2-amine (D-1) (4.0 g, 21.0 mmol) Concentrated sulfuric acid (20 mL) was added to the mixture of H ₂ O ₂ (33 mL, 29.1 mmol) in concentrated sulfuric acid (66 mL). The mixture was raised to room temperature and stirred overnight. At 0°C, it was alkalized with a dilute sodium carbonate solution to a pH of 7, and extracted with ethyl acetate. The organic layer was washed successively with _{an aqueous Na 2} S ₂ O ₃ solution and saturated brine, and dried over _{Na 2} SO _4. After filtration and concentration, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 40:1) to obtain the title compound 5-bromo-3-fluoro-2-nitropyridine (D-2) . MS-ESI (m/z): 220 [M + 1] ⁺ . 5- bromo -N- tert-butyl -2- nitropyridine- 3- amine (D-3) 5-bromo-3-fluoro-2-nitropyridine (D-2) (1.63 g, 7.38 mmol), A mixture of tert-butylamine (1.08 g, 14.8 mmol) and TEA (1.49 g, 14.8 mmol) in THF (30 mL) was stirred at 45°C overnight. Add water and ethyl acetate. The aqueous layer was extracted with EtOAc (3 × 30 mL). The organic layer was washed with saturated brine, _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 30:1) to obtain the title compound 5-bromo-N- Tert-Butyl-2-nitropyridin-3-amine (D-3). MS-ESI (m/z): 274 [M+1] ⁺ . 5- bromo- N3 -tert-butylpyridine -2,3- diamine (D-4) 5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3) (1.3 g, 4.7 mmol), _{a mixture of NH 4} Cl aqueous solution (16 mL) and Fe (2.6 g, 46 mmol) in EtOH (16 mL) was stirred at 75°C for 40 minutes. The mixture was filtered, and the filtrate was extracted with DCM (3 × 30 mL). The organic layer was washed with saturated brine, _{dried over Na 2} SO ₄ and concentrated to obtain the title compound 5-bromo-N3-tert-butylpyridine-2,3-diamine (D-4). MS-ESI (m/z): 244 [M+1] ⁺ . 6- Bromo- 1 -tert-butyl -2- methyl -1H- imidazo [4,5-b] pyridine ( Intermediate D) 5-bromo-N3-tert-butylpyridine-2,3-diamine ( D-4) A mixture of (50 mg, 0.205 mmol) and Ac ₂ O (21 μl, 0.225 mmol) in AcOH (1 mL) was stirred at 90°C overnight. The mixture was concentrated, and the residue was washed with sodium bicarbonate solution (50 ml), and then extracted with EtOAc (3 × 30 mL). The extract was washed successively with water (2 × 30 mL) and saturated brine (30 mL), dried and concentrated to obtain the title compound 6-bromo-1-tert-butyl-2-methyl-1H-imidazo[4,5-b ] Pyridine (Intermediate D). MS-ESI (m/z): 268 [M + 1] ⁺ . Intermediate E 3- tert-butyl -2- methyl -5-( tributylstannyl )-2H- pyrazolo [3,4-b] pyridine ( Intermediate E)

Intermediate E 5- bromo -2- chloro -N- methoxy- N- methylnicotinic acid amine (E-1) According to the synthesis method of B-1, replace isobutyl chloroformate with dimethylhydroxylamine hydrochloride Salt, the title compound 5-bromo-2-chloro-N-methoxy-N-methylnicotinic acid amine (E-1) was prepared. MS-ESI (m/z): 279 [M + 1] ⁺ . 5- Bromo -2- chloro- 3- pyridinecarbaldehyde (E-2) at -78°C, to 5-bromo-2-chloro-N-methoxy-N-methylnicotinic acid amine (E-1 ) (11.8 g, 42 mmol) in CDM (250 mL) was added DIBAl-H (70 mL, 105 mmol), and the mixture was stirred at 0°C for 0.5 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to obtain the title compound 5-bromo-2-chloro-3-pyridinecarbaldehyde (E-2). MS-ESI (m/z): 220 [M + 1] ⁺ . 1-(5- Bromo -2 -chloropyridin- 3 -yl )-2,2 -dimethylpropane- 1- ol (E-3) at 0°C, to 5-bromo-2-chloro-3 -Pyridinecarboxaldehyde (E-2) (2.1 g, 10 mmol) in THF (60 ml) was added tert-butylmagnesium chloride (50 mL, 50 mmol). The mixture was stirred at 0-10°C for 2 hours, and the reaction was quenched with MeOH (10 mL). The mixture was concentrated to obtain the title compound 1-(5-bromo-2-chloropyridin-3-yl)-2,2-dimethylpropane-1-ol (E-3). MS-ESI (m/z): 278 [M + 1] ⁺ . 1-(5- Bromo -2 -chloropyridin- 3 -yl )-2,2 -dimethylpropane- 1 -one (E-4) According to the synthesis method of B-5, 1-(5-bromo- 2-Chloropyridin-3-yl)-2-methylpropane-1-ol (B-4) replaced with 1-(5-bromo-2-chloropyridin-3-yl)-2,2-dimethyl Propan-1-ol (E-3), the title compound 1-(5-bromo-2-chloropyridin-3-yl)-2,2-dimethylpropan-1-one (E-4) was prepared. MS-ESI (m/z): 276 [M + 1] ⁺ . 5- Bromo- 3 -tert-butyl -1H- pyrazolo [3,4-b] pyridine (E-5) According to the synthesis method of B-6, 1-(5-bromo-2-chloropyridine-3 -Yl)-2-methylpropane-1-one (B-5) replaced with 1-(5-bromo-2-chloropyridin-3-yl)-2,2-dimethylpropane-1-one ( E-4), the title compound 5-bromo-3-tert-butyl-1H-pyrazolo[3,4-b]pyridine (E-5) was prepared. MS-ESI (m/z): 254 [M + 1] ⁺ . 5- Bromo- 3 -tert-butyl -2- methyl -2H- pyrazolo [3,4-b] pyridine (E-6) at 0°C, to 5-bromo-3-tert-butyl- 1H-pyrazolo[3,4-b]pyridine (E-5) (320 mg, 1.3 mmol) in THF (10 ml) was added with NaH (80 mg, 60% in oil) and stirred for 5 minutes Then MeI (370 mg, 2.6 mmol) was added dropwise. The mixture was stirred at 0°C for 20 minutes. The reaction was quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine, _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography and eluted with 10-100% ethyl acetate and hexane solution to obtain 5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo[3,4-b ] Pyridine (E-6), MS-ESI (m/z): 268 [M + 1] ⁺ , and 5-bromo-3-tert-butyl-1-methyl-1H-pyrazolo[3,4 -b] Pyridine (E-6b). MS-ESI (m/z): 268 [M + 1] ⁺ . 3- tert-butyl -2- methyl -5-( tributylstannyl )-2H- pyrazolo [3,4-b] pyridine ( intermediate E) 5-bromo-3-tert-butyl-2-methyl Pyrazolo[3,4-b]pyridine (E-6) (134 mg, 0.5 mmol), (Bu ₃ Sn) ₂ (870 mg, 1.5 mmol), Pd(PPh ₃ ) ₄ (22 A mixture of mg, 0.02 mmol) and TEA (150 mg, 1.5 mmol) in 1,4-dioxane (5 mL) was stirred overnight at 80°C. The mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound 3-tert-butyl-2-methyl-5-(tributylstannyl)-2H-pyrazolo[3 ,4-b] Pyridine (Intermediate E). MS-ESI (m/z): 480 [M + 1] ⁺ . Example 1 5- Fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl )-N-(5-( piazine- 1- (Methyl ) pyridin -2- yl ) pyrimidin -2- amine (1)

Tert-Butyl 4-((6- bromopyridin- 3 -yl ) methyl ) piperazine- 1- carboxylate (1a) to 2-bromo-5-aldehyde pyridine (11.0 g, 59.1 mmol) and 1-Boc-piperazine (10.0 g, 53.7 mmol) in DCM (100 mL) were added NaBH(OAc) ₃ (13.6 g, 64.1 mmol) in batches. The mixture was raised to room temperature and stirred overnight. DCM (100 mL) was added, and then NaOH aqueous solution (2 N, 100 mL) was added at 0°C. The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The extract was washed with saturated brine (100 mL), _{dried over Na 2} SO ₄ and concentrated to obtain crude tert-butyl 4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylate (1a) , Directly used in the next reaction. MS-ESI (m/z): 356,358 [M + 1] ⁺ . Tert-butyl 4-((6 -aminopyridin- 3 -yl ) methyl ) piperazine- 1- carboxylate (1b) under nitrogen protection, tert-butyl 4-((6-bromopyridin-3-yl )Methyl)piperazine-1-carboxylate (1a) (3.56 g, 10 mmol), Cu ₂ O (0.50 g, 0.3 mmol) in NH ₃ .H ₂ O (20 mL) and MeOH (20 mL) The mixture in the tube was stirred overnight at 70°C in a sealed tube. The mixture was cooled to room temperature, and after filtration, the filtrate was concentrated. Dilute with aqueous NaOH (2 N, 50 mL) and extract with DCM (2 × 100 mL). The extract was washed with saturated brine (100 mL), _{dried over Na 2} SO ₄ , filtered and concentrated to obtain a crude yellow oil, which was recrystallized and purified by MTBE to obtain tert-butyl 4-((6-aminopyridin-3-yl)methyl ) Piperazine-1-carboxylate (1b). MS-ESI (m/z): 293 [M + 1] ⁺ . Tert-butyl 4-((6-((5- fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidine -2- ( Yl) amino ) pyridin- 3 -yl ) methyl ) piperazine- 1- carboxylate (1c) 6-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-2-methyl Yl-1H-imidazo[4,5-b]pyridine (Intermediate A) (0.045 g, 0.15 mmol), tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1 -Carboxylate (1b) (0.055 g, 0.18 mmol), Pd ₂ (dba) ₃ (0.008 g, 0.015 mmol), Xantphos (0.01 g, 0.015 mmol) and Cs ₂ CO ₃ (0.103 g, 0.3 mmol) in The mixture in 1,4-dioxane (3 mL) was stirred at 90°C for 1 hour under nitrogen protection. The mixture was cooled to room temperature and diluted with DCM (10 mL). Filter with diatomaceous earth. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (eluent: DCM /MeOH = 20:1) to obtain tert-butyl 4-((6-((5-fluoro-4-(1-isopropyl) -2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (1c ). MS-ESI (m/z): 562 [M + 1] ⁺ . 5- fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl )-N-(5-( piazine- 1 -ylmethyl) ) Pyridin -2- yl ) pyrimidin -2- amine (1) tert-butyl 4-((6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4 ,5-b)pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (1c) (0.03 g, 0.05 mmol) in TFA (2 The mixture in DCM (4 mL) and DCM (4 mL) was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum, the residue was diluted with water (10 mL) and washed with DCM (10 mL). Adjust the pH of the water layer to 11 ~ 12 with NaOH (2 N). Extract with IPA / DCM (25%, 4 × 20 mL). The extract was washed with saturated brine (40 mL), _{dried over Na 2} SO ₄ and concentrated. The residue was purified by preparative thin layer chromatography (eluent: DCM /MeOH = 10:1) to obtain 5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5 -b]Pyridin-6-yl)-N-(5-(pyrazine-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine (1). MS-ESI (m/z): 462 [M + 1] ⁺ . Example 2 5- Fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl )-N-(5-((4 -methyl (Pazizin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine (2)

5-((4 -Methylpazine- 1 -yl ) methyl ) pyridin -2- amine (2a) According to the synthesis method of 1b, 1-Boc-pazine was replaced with 1-methylpazine to prepare The title compound 5-((4-methylpiperazin-1-yl)methyl)pyridin-2-amine (2a). MS-ESI (m/z): 207 [M + 1] ⁺ . 5-fluoro-4- (l-isopropyl-2-methyl -1H- imidazo [4,5-b] pyridin-6-yl) -N- (5 - ((4- methyl-piperazine - 1- yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine (2) According to the synthesis method of 1c, tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperazine- The 1-carboxylate (1b) was replaced with 5-((4-methylpiperazine-1-yl)methyl)pyridin-2-amine (2a) to prepare the title compound 5-fluoro-4-(1- Isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((4-methylpiperazine-1-yl)methyl)pyridine- 2-yl)pyrimidin-2-amine (2). MS-ESI (m/z): 476 [M + 1] ⁺ . Example 3 N-(5-((4 -ethylpiperazine- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro- 4-(1- isopropyl- 2- methyl- 1H - imidazo [4,5-b] pyridin-6-yl) pyrimidin-2-amine (3)

5-((4 -Ethylpiperazine- 1 -yl ) methyl ) pyridin -2- amine (3a) was prepared according to the synthetic method of 1b, replacing 1-Boc-piperazine with 1-ethylpiperazine The title compound 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (3a). MS-ESI (m/z): 221 [M + 1] ⁺ . N-(5-((4 -ethylpiperazine- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] Pyridin -6- yl ) pyrimidin -2- amine (3) According to the synthesis method of 1c, tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperazine- The 1-carboxylate (1b) was replaced with 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (3a) to prepare the title compound N-(5-((4- Ethylpiperazine-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine- 6-yl)pyrimidin-2-amine (3). MS-ESI (m/z): 490 [M + 1] ⁺ . Example 4 (S)-5- fluoro -N-(5-(( hexahydropyrrole [1,2-a] pyrazine -2(1H) -yl ) methyl ) pyridin -2- yl )-4- (1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidin -2- amine (4)

( Tert-butoxycarbonyl )-L- proline (4a) (tert-butoxycarbonyl)-L-proline (4a) was prepared according to the method described in the literature Tetrahedron. 2013, 10, 156. Tert-butyl (S)-2-((2- ethoxy -2 -oxoethyl ) carbamyl ) pyrrolidine- 1- carboxylate (4b) at 0°C, to (tert-butoxy To a solution of carbonyl)-L-proline (4a) (21.5 g, 100 mmol) in THF (200 mL) was added CDI (17.8 g, 110 mmol) in portions. The mixture was stirred at room temperature for 0.5 hour. Glycine ethyl ester hydrochloride (15.3 g, 110 mmol) was added at 0°C, then TEA (15.0 g, 150 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was spin-dried in vacuo, the residue was diluted with ethyl acetate (250 mL), and washed with saturated NaHCO ₃ solution (200 mL), 10% citric acid (2 × 200 mL) and saturated brine (200 mL), and then washed with Na ₂ Dried over SO ₄ and concentrated to obtain the title compound tert-butyl (S)-2-((2-ethoxy-2-oxyethyl)carbamidine)pyrrolidine-1-carboxylate (4b). (S) -Prolinoglycine ethyl ester trifluoroacetate (4c) tert-butyl(S)-2-((2-ethoxy-2-oxoethyl)carbamidine)pyrrolidine-1- A mixture of carboxylate (4b) (24.8 g, 82.6 mmol) and TFA (100 mL) in DCM (125 mL) was stirred at room temperature for 2 hours, and concentrated to obtain (S)-proline glycinate ethyl trifluoroacetate. (4c) Crude product, directly used in the next reaction. MS-ESI (m/z): 201 [M + 1] ⁺ . (S) -Hexahydropyrrolo [1,2-a] pyrazine -1,4- dione (4d) (S)-Prolinac glycine ethyl ester trifluoroacetate (4c) (40 g, 127 mmol ) A mixture of TEA (150 mL) and MeOH (800 mL) was refluxed overnight. The solvent was spin-dried in vacuo, and the residue was diluted with IPA (100 mL). Filter and wash the filter cake with n-hexane. The solid was dried under vacuum to obtain (S)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (4d). MS-ESI (m/z): 154 [M + 1] ⁺ . Benzyl (S) -hexahydropyrrolo [1,2-a] pyrazine -2(1H) -carboxylate (4e ) in a suspension of LAH (5.9 g, 156 mmol) in THF (60 mL) A solution of (S)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (4d) (4.0 g, 26 mmol) in THF (40 mL) was added dropwise, and the mixture was refluxed for 16 hours. After the reaction mixture was cooled to 0°C, saturated NaHCO ₃ (100 mL) solution was added dropwise, and then benzyl chloroformate (6.67 g, 39 mmol) was added. The mixture was stirred at 0°C for 1 hour and at room temperature for another 2 hours. The reaction solution was extracted with chloroform (3 × 200 mL), and the extract was washed with saturated brine (400 mL) and dried _{with Mg 2} SO _4. Concentrate, and purify the residue by silica gel column chromatography (eluent: DCM /MeOH =25:1) to obtain benzyl(S)-hexahydropyrrolo[1,2-a]pyrazine-2(1H) -Carboxylic acid ester (4e). MS-ESI (m/z): 261 [M + 1] ⁺ . (S) -Octahydropyrrolo [1,2-a] pyrazine (4f) benzyl(S)-hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (4e A mixture of) (5.0 g, 19 mmol) and Pd/C (10%, 1.0 g) in MeOH (50 mL) was stirred at room temperature under hydrogen for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain crude (S)-octahydropyrrolo[1,2-a]pyrazine (4f). MS-ESI (m/z): 127 [M + 1] ⁺ . (S)-2-((6- Bromopyridin- 3 -yl ) methyl ) octahydropyrrolo [1,2-a] pyrazine (4g) According to the synthesis method of 1a, replace 1-Boc-pazine For (S)-octahydropyrrolo[1,2-a]pyrazine (4f), the title compound (S)-2-((6-bromopyridin-3-yl)methyl)octahydropyrrolo [1,2-a] Pyrazine (4g). MS-ESI (m/z): 296, 298 [M + 1] ⁺ . (S)-5-(( hexahydropyrrolo [1,2-a] pyrazine -2(1H) -yl ) methyl ) pyridin -2- amine (4h) According to the synthesis method of 1b, the tert-butyl 4-((6-Bromopyridin-3-yl)methyl)piperazine-1-carboxylate (1a) is replaced by (S)-2-((6-bromopyridin-3-yl)methyl) Hydropyrrolo[1,2-a]pyrazine (4g), the title compound (S)-5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)methan was prepared Yl)pyridin-2-amine (4h). MS-ESI (m/z): 233 [M + 1] ⁺ . (S)-5- fluoro -N-(5-(( hexahydropyrrole [1,2-a] pyrazine -2(1H) -yl ) methyl ) pyridin -2- yl )-4-(1- Isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidin -2- amine (4) According to the synthesis method of 1c, the tert-butyl 4-((6- Aminopyridin-3-yl)methyl)piperazine-1-carboxylate (1b) is replaced by (S)-5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)- Yl)methyl)pyridine-2-amine (4h), the title compound (S)-5-fluoro-N-(5-((hexahydropyrrole[1,2-a]pyrazine-2(1H)) -Yl)methyl)pyridin-2-yl)-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine ( 4). MS-ESI (m/z): 502 [M + 1] ⁺ . Example 5 (R)-5- fluoro -N-(5-(( hexahydropyrrolo [1,2-a] pyrazine -2(1H) -yl ) methyl ) pyridin -2- yl )-4 -(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidin -2- amine (5)

(R)-5-(( hexahydropyrrolo [1,2-a] pyrazine -2(1H) -yl ) methyl ) pyridin -2- amine (5a) According to the synthesis method of 4h, the starting material The title compound (R)-5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)methyl)pyridine was prepared by replacing L-proline with D-proline -2-amine (5a). MS-ESI (m/z): 233 [M + 1] ⁺ . (R)-5- Fluoro -N-(5-(( hexahydropyrrolo [1,2-a] pyrazine -2(1H) -yl ) methyl ) pyridin -2- yl )-4-(1 - isopropyl-2-methyl -1H- imidazo [4,5-b] pyridin-6-yl) pyrimidin-2-amine (5) in accordance with the synthesis methods 1c, the tert-butyl 4 - ((6 -Aminopyridin-3-yl)methyl)piperazine-1-carboxylate (1b) is replaced by (R)-5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H) -Yl)methyl)pyridine-2-amine (5a), the title compound (R)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2( 1H)-yl)methyl)pyridin-2-yl)-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidine-2- Amine (5). MS-ESI (m/z): 502 [M + 1] ⁺ . Example 6 N-(5-(((1S,4S)-2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- yl )-5- fluoro -4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidin -2- amine (6)

Tert-Butyl (1S,4S)-5-((6- bromopyridin- 3 -yl ) methyl )-2,5 -diazabicyclo [2.2.1] heptane- 2- carboxylate (6a ) To tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.099 g, 0.5 mmol), 5-bromo-2-pyridinecarbaldehyde ( To a solution of 0.093 g, 0.5 mmol) and AcOH (0.03 g, 0.5 mmol) in THF (1 mL) was added sodium triacetoxyborohydride (0.159 g, 0.75 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was _{quenched with saturated NaHCO 3} solution, extracted with EtOAc, the organic layer was washed with saturated brine (20 mL), and dried over _{Na 2} SO _4. Concentrate to obtain tert-butyl (1S,4S)-5-((6-bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6a). MS-ESI (m/z): 368, 390 [M + 1] ⁺ . Tert-Butyl (1S,4S)-5-((6 -aminopyridin- 3 -yl ) methyl )-2,5 -diazabicyclo [2.2.1] heptane- 2- carboxylate (6b ) Tert-butyl(1S,4S)-5-((6-bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate ( 6a) A mixture of (180 mg, 0.49 mmol), NH3•H ₂ O (4.5 mL), Cu ₂ O (80.0 mg, 0.56 mmol) in MeOH (1.5 mL) was stirred overnight at 65°C in a sealed tube. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue is distinguished between DCM and NaOH (2 N). The organic layer was separated and washed with saturated brine, _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM: MeOH = 10:1) to obtain tert-butyl (1S, 4S)- 5-((6-Aminopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6b) crude product. MS-ESI (m/z): 305 [M + 1] ⁺ . Tert-Butyl (1S,4S)-5-((6-((5- Fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridine -6- ( Yl) pyrimidin -2- yl ) amino ) pyridin- 3 -yl ) methyl )-2,5 -diazabicyclo [2.2.1] heptane- 2- carboxylate (6c) according to the synthetic method of 1c , Replace tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate (1b) with tert-butyl(1S,4S)-5-((6-amino (Pyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6b), the title compound tert-butyl (1S,4S)-5 was prepared -((6-((5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino) (Pyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6c). MS-ESI (m/z): 574 [M + 1] ⁺ . N-(5-(((1S,4S)-2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- yl )-5- fluoro- 4- (1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidin -2- amine (6) According to the synthesis method of 1, the tert-butyl 4-( (6-((5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridine- 3-yl)methyl)piperazine-1-carboxylate (1c) replaced with tert-butyl(1S,4S)-5-((6-((5-fluoro-4-(1-isopropyl- 2-Methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)-2,5-diazabicyclo[ 2.2.1]Heptane-2-carboxylate (6c), the title compound N-(5-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane- 2-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidine -2-amine (6). MS-ESI (m/z): 474 [M + 1] ⁺ . Example 7 5- Fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl )-N-(5-(((1S,4S )-5- methyl -2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine (7)

(1S,4S)-2-((6- Bromopyridin- 3 -yl ) methyl )-2,5 -diazabicyclo [2.2.1] heptane (7a) to tert-butyl at room temperature (1S,4S)-5-((6-Bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6a) (0.81 g, 2.2 mmol) in DCM (6 mL) was added TFA (4 mL). The mixture was stirred for 2 hours. Adjust the pH to 8 with Na ₂ CO _{3 solution.} The mixture was extracted with DCM (3 × 6 mL). The extract was washed successively with water and saturated brine (5 mL), _{dried over Na 2} SO ₄ and concentrated to obtain (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-2,5-di Azabicyclo[2.2.1]heptane (7a) (0.534 g). MS-ESI (m/z): 268 [M + 1] ⁺ . (1S,4S)-2-((6- Bromopyridin- 3 -yl ) methyl )-5- methyl -2,5 -diazabicyclo [2.2.1] heptane (7b) at room temperature Down, to (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane(7a) (0.15 g, 0.56 Add formaldehyde (37%, 63 μL) to a solution of mmol) in DCM (2 mL), and then add NaBH(OAc) ₃ (0.273 g, 1.12 mmol). The mixture was stirred vigorously for 30 minutes. The mixture was quenched with saturated Na2CO3 solution and extracted with DCM (2 × 5 mL). The extract was washed with water and saturated brine (5 mL) successively, and dried over _{Na 2} SO _4. Filter and concentrate. The residue was purified by silica gel column chromatography (eluent: DCM:MeOH =10:1) to obtain (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-5-methyl Group-2,5-diazabicyclo[2.2.1]heptane (7b). MS-ESI (m/z): 282, 284 [M + 1] ⁺ . 5-(((1S,4S)-5- methyl -2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- amine (7c) in accordance with 6b Synthetic method, the tert-butyl (1S,4S)-5-((6-bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxy Ester (6a) replaced with (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (7b), the title compound 5-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridine- 2-amine (7c). MS-ESI (m/z): 219 [M + 1] ⁺ . 5- Fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl )-N-(5-(((1S,4S)-5 - methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7) in accordance with synthetic methods 1c, the tert Butyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate (1b) is replaced with 5-(((1S,4S)-5-methyl-2,5- Diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridin-2-amine (7c), the title compound 5-fluoro-4-(1-isopropyl-2-methyl) was prepared -1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]Heptan-2-yl)methyl)pyridin-2-yl)pyrimidin-2-amine (7). MS-ESI (m/z): 488 [M + 1] ⁺ . Example 8 N-(5-(((1S,4S)-5- ethyl -2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- yl )-5- fluoro- 4-(1- isopropyl- 2- methyl -1H- imidazo [4,5-b] pyridin -6- yl ) pyrimidin -2- amine (8)

(1S,4S)-2-((6- Bromopyridin- 3 -yl ) methyl )-5- ethyl -2,5 -diazabicyclo [2.2.1] heptane (8a) at room temperature Down, to (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane(7a) (0.10 g, 0.37 Add bromoethane dropwise to a solution of TEA (60 μL, 0.41 mmol) and TEA (60 μL, 0.41 mmol) in DMF (1 mL). The mixture was stirred for 3.5 hours. Extract with water (5 mL) and DCM (5 mL). The extract was washed successively with water (2 mL) and saturated brine (2 mL), _{dried over Na 2} SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM:MeOH =10:1) to obtain (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-5-ethyl Group-2,5-diazabicyclo[2.2.1]heptane (8a). MS-ESI (m/z): 296, 298 [M + 1] ⁺ . 5-(((1S,4S)-5- ethyl -2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- amine (8b) in accordance with 6b Synthetic method, the tert-butyl (1S,4S)-5-((6-bromopyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxy Ester (6a) replaced by (1S,4S)-2-((6-bromopyridin-3-yl)methyl)-5-ethyl-2,5-diazabicyclo[2.2.1]heptane Alkane (8a), the title compound 5-(((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridine- 2-amine (8b). MS-ESI (m/z): 233 [M + 1] ⁺ . N-(5-(((1S,4S)-5- ethyl -2,5 -diazabicyclo [2.2.1] heptan- 2- yl ) methyl ) pyridin -2- yl )-5 - fluoro-4- (l-isopropyl-2-methyl -1H- imidazo [4,5-b] pyridin-6-yl) pyrimidin-2-amine (8) in accordance with synthetic methods 1c, the tert Butyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate (1b) is replaced with 5-(((1S,4S)-5-ethyl-2,5- Diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridin-2-amine (8b), the title compound N-(5-(((1S,4S)-5-ethyl -2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-2-methyl- 1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine (8). MS-ESI (m/z): 488 [M + 1] ⁺ .

實施例 83 5- 氟 -4-(3- 異丙基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 -5- 基 )-N-(5-( 呱嗪 -1- 基甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (83)

叔丁基 4-((6-((5- 氟 -4-(3- 異丙基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 -5- 基 ) 嘧啶 -2- 基 ) 氨基 ) 吡啶 -3- 基 ) 甲基 ) 呱嗪 -1- 羧酸酯 (83a) 依照1c的合成方法，反應物為叔丁基 4-((6-氨基吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1b) 和5-(2-氯-5-氟嘧啶-4-基)-7-氟-3-異丙基-1-甲基-3a,7a-二氫-1H-吲唑 (中間體 B)，製備了標題化合物叔丁基 4-((6-((5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基) 嘧啶-2-基)氨基)吡啶-3-基)甲基)呱嗪-1-羧酸酯 (83a)。MS-ESI (m/z): 562 [M + 1]⁺ 。 5- 氟 -4-(3- 異丙基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 -5- 基 )-N-(5-( 呱嗪 -1- 基甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (83) 依照1的合成方法，將叔丁基 4-((6-((5-氟-4-(1-異丙基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)呱嗪-1-羧酸酯 (1c) 替換為叔丁基 4-((6-((5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基) 嘧啶-2-基)氨基)吡啶-3-基)甲基)呱嗪-1-羧酸酯 (83a)，製備了標題化合物5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基)-N-(5-(呱嗪-1-基甲基)吡啶-2-基)嘧啶-2-胺 (83)。MS-ESI (m/z): 462 [M + 1]⁺ 。實施例 84 5- 氟 -4-(3- 異丙基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 -5- 基 )-N-(5-((4- 甲基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (84)

在室溫下向5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基)-N-(5-(呱嗪-1-基甲基)吡啶-2-基)嘧啶-2-胺 (83) (17.8 mg, 0.0386 mmol)，NaBH(OAc)₃ (12.3 mg, 0.0579 mmol) 的DCE (1 mL) 溶液中滴入HCHO (37%水溶液) (2滴)，混合物在室溫下攪拌4小時。混合物用NaHCO₃ 溶液稀釋，DCM萃取。萃取物Na₂ SO₄ 乾燥並濃縮。殘留物用製備薄層層析純化得到5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基)-N-(5-((4-甲基呱嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺 (84)。MS-ESI (m/z): 476 [M + 1]⁺ 。實施例 85 N-(5-((4- 乙基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(3- 異丙基 -2- 甲基 -2H- 吡唑並 [3,4-b] 吡啶 -5- 基 ) 嘧啶 -2- 胺 (85)

在室溫下向5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基)-N-(5-(呱嗪-1-基甲基)吡啶-2-基)嘧啶-2-胺 (83) (17.8 mg, 0.0386 mmol)，NaBH(OAc)₃ (12.3 mg, 0.0579 mmol) 的DCE (1 mL) 溶液中滴入MeCHO (40%水溶液) (2滴)，混合物在室溫下攪拌4小時。混合物用NaHCO₃ 溶液稀釋，DCM萃取。萃取物Na₂ SO₄ 乾燥並濃縮。殘留物用製備薄層層析純化得到N-(5-((4-乙基呱嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(3-異丙基-2-甲基-2H-吡唑並[3,4-b]吡啶-5-基)嘧啶-2-胺 (85)。MS-ESI (m/z): 490 [M + 1]⁺ 。實施例 86 5- 氟 -4-(3- 異丙基 -1- 甲基 -1H- 吡唑並 [3,4-b] 吡啶 -5- 基 )-N-(5-((4- 甲基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 ) 嘧啶 -2- 胺 (86)

依照1c的合成方法，反應物為5-(2-氯-5-氟嘧啶-4-基)-3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶 (中間體 C) 和5-((4-甲基呱嗪-1-基)甲基)吡啶-2-胺 (2a)，製備了標題化合物5-氟-4-(3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶-5-基)-N-(5-((4-甲基呱嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺 (86)。MS-ESI (m/z): 476 [M + 1]⁺ 。實施例 87 N-(5-((4- 乙基呱嗪 -1- 基 ) 甲基 ) 吡啶 -2- 基 )-5- 氟 -4-(3- 異丙基 -1- 甲基 -1H- 吡唑並 [3,4-b] 吡啶 -5- 基 ) 嘧啶 -2- 胺 (87)

依照1c的合成方法，反應物為5-(2-氯-5-氟嘧啶-4-基)-3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶 (中間體 C) 和5-((4-乙基呱嗪-1-基)甲基)吡啶-2-胺 (3a)，製備了標題化合物N-(5-((4-乙基呱嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(3-異丙基-1-甲基-1H-吡唑並[3,4-b]吡啶-5-基)嘧啶-2-胺 (87)。MS-ESI (m/z): 476 [M + 1]⁺ 。Examples 9-81 listed in Table 1 basically follow the same method as in Example 1-8, or use similar synthesis strategies or methods. The starting materials used are commercially available or prepared according to literature methods and carried out as necessary. The modification is prepared. Table 1 shows the names and structures of Examples 9-81. Table 1

Example 83 5- Fluoro- 4-(3- isopropyl- 2- methyl -2H- pyrazolo [3,4-b] pyridin -5- yl )-N-(5-( pazine -1 - ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83)

Tert-Butyl 4-((6-((5- Fluoro- 4-(3- isopropyl- 2- methyl -2H- pyrazolo [3,4-b] pyridin -5- yl ) pyrimidine -2 - yl) amino) pyridin-3-yl) methyl) piperazine-l-carboxylate (83a) in accordance with synthetic methods 1c reactants is tert-butyl 4 - ((6-amino-pyridin-3-yl) (Methyl)piperazine-1-carboxylate (1b) and 5-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-3-isopropyl-1-methyl-3a,7a -Dihydro-1H-indazole (Intermediate B), the title compound tert-butyl 4-((6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyridine) Azolo[3,4-b]pyridin-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (83a). MS-ESI (m/z): 562 [M + 1] ⁺ . 5-fluoro-4- (3-isopropyl-2-methyl -2H- pyrazol pyrazolo [3,4-b] pyridin-5-yl) -N- (5- (piperazine-l-carboxylic yl) pyridin-2-yl) pyrimidin-2-amine (83) in accordance with the synthesis method 1, tert-butyl 4 - ((6 - ((5-fluoro-4- (l-isopropyl-2- -1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (1c) Replaced with tertiary Butyl 4-((6-((5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-2- Yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (83a), the title compound 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyridine) was prepared Azolo[3,4-b]pyridin-5-yl)-N-(5-(pyrazine-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine (83). MS-ESI (m/z): 462 [M + 1] ⁺ . Example 84 5- Fluoro- 4-(3- isopropyl- 2- methyl -2H- pyrazolo [3,4-b] pyridin -5- yl )-N-(5-((4- methyl Pyrazin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine (84)

To 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-(pazine -1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine (83) (17.8 mg, 0.0386 mmol), NaBH(OAc) ₃ (12.3 mg, 0.0579 mmol) in DCE (1 mL) solution HCHO (37% aqueous solution) (2 drops) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was _{diluted with NaHCO 3} solution and extracted with DCM. The extract was _{dried over Na 2} SO ₄ and concentrated. The residue was purified by preparative thin-layer chromatography to obtain 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-( 5-((4-Methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine (84). MS-ESI (m/z): 476 [M + 1] ⁺ . Example 85 N-(5-((4 -ethylpiperazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro- 4-(3- isopropyl- 2- methyl- 2H - pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-amine (85)

To 5-fluoro-4-(3-isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-(pazine -1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine (83) (17.8 mg, 0.0386 mmol), NaBH(OAc) ₃ (12.3 mg, 0.0579 mmol) in DCE (1 mL) solution MeCHO (40% aqueous solution) (2 drops) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was _{diluted with NaHCO 3} solution and extracted with DCM. The extract was _{dried over Na 2} SO ₄ and concentrated. The residue was purified by preparative thin layer chromatography to obtain N-(5-((4-ethylpiperazine-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl -2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (85). MS-ESI (m/z): 490 [M + 1] ⁺ . Example 86 5- Fluoro- 4-(3- isopropyl- 1 -methyl -1H- pyrazolo [3,4-b] pyridin -5- yl )-N-(5-((4- methyl Pyrazin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine (86)

According to the synthesis method of 1c, the reactant is 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine (Intermediate C) and 5-((4-methylpiperazine-1-yl)methyl)pyridin-2-amine (2a) to prepare the title compound 5-fluoro-4-(3-isopropyl- 1-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(5-((4-methylpiperazine-1-yl)methyl)pyridin-2-yl ) Pyrimidine-2-amine (86). MS-ESI (m/z): 476 [M + 1] ⁺ . Example 87 N-(5-((4 -ethylpiperazine- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro- 4-(3- isopropyl- 1 -methyl- 1H - pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-amine (87)

According to the synthetic method of 1c, the reactant is 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine (Intermediate C) and 5-((4-ethylpiperazine-1-yl)methyl)pyridin-2-amine (3a) to prepare the title compound N-(5-((4-ethylpiperazine) -1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ) Pyrimidine-2-amine (87). MS-ESI (m/z): 476 [M + 1] ⁺ .

Examples 88-156 listed in Table 2 were prepared by using the methods described in Examples 83-87 by replacing the corresponding aminopyridines and making necessary modifications, or using similar synthetic strategies or methods. Table 2

Cell proliferation detection In order to detect the inhibitory effect of compounds on CDK4/6 kinase in vitro, a detection method based on BE(2)-C cells was established. In this method, the inhibitory activity of the compound on CDK4/6 is determined by detecting the inhibitory effect on the proliferation of BE(2)-C cells. Inoculate BE(2)-C cells into a 96-well culture plate at 5000/well, and add 150 µl medium to each well. Compound dilution: Use DMSO to dilute each compound to a concentration of 20 mM as a storage solution. On the day of dosing, use the current culture medium to prepare a working solution of 4 times the final concentration. 24 hours after BE(2)-C cell inoculation, 50 µl of compound working solution was added to each well (replicate well for each compound). After 72 hours of incubation, the cell proliferation activity was measured by the MTS method. The prepared compounds were tested according to the above-mentioned biological activity test method. The results are shown in Table 3. table 3

However, the above are only examples of the present invention. When the scope of implementation of the present invention cannot be limited by this, all simple equivalent changes and modifications made in accordance with the scope of the patent application of the present invention and the content of the patent specification still belong to Within the scope covered by the patent of the present invention.

without

Claims (18)

A compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof:

Wherein, Q is selected from heteroaryl; each R ^{1 is} independently selected from hydrogen; each R ^{2 is} independently selected from hydrogen; each R ^{3 is} independently selected from C _1-10 alkyl; each R ^{4 is} selected from halogen; Each R ^{5 is} independently selected from methyl, ethyl,

,

,

,

with

, Which is unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; each R ^{X is} independently selected from C _1-10 alkyl, wherein each Alkyl groups are respectively unsubstituted or substituted with ^{a substituent independently selected from R Y} ; each R ^{Y is} independently selected from -(CR ^c2 R ^d2 ) _t OR ^b2 ; each R ^{b2 is} independently selected from C _1-10 alkyl; M is selected from 1; n is selected from 0, 1, and 2; p is selected from 2; each t is independently selected from 0. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the chemical formula is:

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the chemical formula is:

The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Q is pyridine. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from

. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R ^{5 is} independently selected from

,

with

, Which is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ⁵ is

, Which is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Q is

. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R ^{5 is} independently selected from methyl, ethyl and

, Which is unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R ^{3 is} independently selected from methyl, isopropyl and tert-butyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R ^{4 is} independently selected from fluorine. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ^X is independently selected from a C _1-10 alkyl group and a methoxymethyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ^X is independently selected from C _1-10 alkyl groups. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R ^X is independently selected from methyl, ethyl and methoxymethyl. A compound selected from (S)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)methyl)pyridin-2-yl) -4-(1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, (R)-5-fluoro-N-(5 -((Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)methyl)pyridin-2-yl)-4-(1-isopropyl-2-methyl-1H- Imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-amine, N-(5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazo[4,5 -b)pyridin-6-yl)pyrimidin-2-yl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, (S)-4-( 1-(tert-butyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(5-((4-ethyl-3-(methoxymethyl (Yl)piperazine-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine, 4-(1-(tert-butyl)-2-methyl-1H-imidazo[4 ,5-b]pyridin-6-yl)-N-(5-((8-ethyl-3,8-diazabicyclo[3.2.1]octane-3-yl)methyl)pyridine- 2-yl)-5-fluoropyrimidin-2-amine, N-(5-((4-ethylpiperazine-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3 -Isopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine, (R)-5-fluoro-N-(5-((六Hydropyrrolo[1,2-a]pyrazine-2(1H)-yl)methyl)pyridin-2-yl)-4-(3-isopropyl-2-methyl-2H-pyrazolo[ 3,4-b]pyridin-5-yl)pyrimidin-2-amine, (R)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b] Pyridin-5-yl)-5-fluoro-N-(5-((hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl) (Methyl)pyridin-2-yl)pyrimidin-2-amine, 4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)- N-(5-((3-ethyl-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)pyridin-2-yl)-5-fluoropyrimidine-2- Amine, (S)-4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoro-N-(5- ((3-(Methoxymethyl)-4-methylpiperazine-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine, N-(4-(3-(tert-butyl )-2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)-6-methyl-5,6,7,8-tetra Hydrogen-1,6-naphthyridin-2-amine, N-(4-(3-(tert-butyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl) -5-fluoropyrimidin-2-yl)-6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, N-(4-(3-(tert-butyl )-2-Methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-fluoropyrimidin-2-yl)-6-(1-ethylpiridin-4-yl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 and a pharmaceutical composition of claim 16 or optionally in combination with a second therapeutic agent in preparation for treatment, improvement or prevention Use in drugs for conditions that are responsive to the inhibition of CDK4/6. A use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 16 in the preparation of a medicament for the treatment of abnormal cell proliferation.