TW201801729A - Certain protein kinase inhibitors - Google Patents

Abstract

Provided are certain CDK4/6 inhibitors, pharmaceutical compositions thereof, and methods of use therefor.

Description

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

This application claims priority from US Provisional Application 62 / 292,259, the entire contents of which are incorporated herein by reference.

The present invention relates to a compound capable of inhibiting the activity of CDK4 / 6 kinase or a pharmaceutically acceptable salt thereof, and as a medicine for treating proliferative diseases such as cancer and inflammation.

Hyper-proliferative diseases such as cancer and inflammation have attracted academia to provide them with effective treatments, and work to identify and target specific mechanisms that play an important role in proliferative diseases.

The development of tumors is closely related to the genetic variation and abnormal regulation of cyclin-dependent kinase (CDK) and its regulatory proteins, suggesting that CDK inhibitors may be effective anticancer therapies.

CDK is a serine / threonine protein kinase, which is the driving force behind cell cycle and cell proliferation. CDK regulates the initiation, progression, and completion of mammalian cell cycles and is critical for cell growth. Most known CDKs, including CDK1 to CDK9, are directly or indirectly involved in cell cycle progression. CDKs that are 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 CDK dysfunction occurs frequently in many solid tumors.

The role of CDK and its related proteins in coordinating and driving the cell cycle in proliferating cells is critical. Therefore, therapies that target multiple CDKs or specific CDKs to treat proliferative disorders such as cancer have 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 diseases.

Therefore, compounds having 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 class of CDK4 / 6 inhibitors.

The invention relates to a new type of 6-5 membered fused azole ring derivative and a pharmaceutical composition thereof, and application as a medicine.

(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, bis (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, ring Alkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one, as 1, 2, 3 or 4, independently selected from the substituents of R ^x ; 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 groups, 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or at least one, such as 1, 2, 3, or 4 Each independently selected from the group consisting of 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 cycloalkane Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, hetero aryl group -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 is unsubstituted Substituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^X ; each R ^{4 is} selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 ene Radical, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl group -C _1-4 alkyl, Aryl, 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 are unsubstituted or substituted with 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, heterocyclic And heterocyclyl-C _{1 -4} alkyl, 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, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or at least One, such as 1, 2, 3, or 4, independently selected from a substituent selected from R ^X ; 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 are unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^X ; or each "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 together constitute 0, 1 or 2 additional independently selected A 4- to 12-membered heterocyclic ring of a heteroatom of oxygen, sulfur, nitrogen and phosphorus, 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 are} 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 N R ^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, heterocyclic ring Group, aryl group and heteroaryl group are unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, each independently selected from R ^Y ; each 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, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^Y ; or R ^a1 and R ^b1 together with the single or multiple atoms attached to them together form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be unsubstituted Substituted or substituted with 1, 2 or 3 substituents selected from R ^Y ; 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, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted Or is substituted by at least one, such as 1, 2, 3, or 4, substituents independently selected from R ^Y ; or R ^c1 and R ^d1 together with the single or multiple carbon atoms attached to them constitute 0, 1 Or 2 additional 3-12 membered heterocycles independently selected from heteroatoms of oxygen, sulfur and nitrogen, the ring may be unsubstituted or substituted with 1, 2 or 3 R ^Y groups; each R ^e1 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} independent Is 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 , _{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 alkane Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are 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 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C1 _-10 alkylamino, C _3-10 cycloalkylamino, and di ( C _1-10 alkyl) amino substituent substitution; each R ^a2 and R ^{b2 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, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 ring Alkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di (C _1-10 alkyl) amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl group -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 are 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 di (C _1-10 Alkyl) amino substituent substitution; or R ^a2 and R ^b2 together with the single or multiple atoms attached to them together form 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus 4-12 membered heterocyclic ring, which 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, 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 di (C _1-10 alkyl) amino substituent substitutions; 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, 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, where each alkyl, alkene Alkynyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl are unsubstituted, respectively Or be 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 cycloalkane Group, 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; or R ^c2 and R ^d2 together with the single or multiple carbon atoms attached to them constitute 0, 1 or 2 additional 3-12 of heteroatoms independently selected from oxygen, sulfur and nitrogen Heterocyclic ring, which 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, 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 di (C _1-10 alkyl) amino substituent substitutions; 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 comprising 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 modulating CDK4 / 6, which method comprises administering to a system or individual in need thereof a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof or Pharmaceutical composition, thereby regulating CDK4 / 6.

In another aspect, the present invention also provides a method for treating, ameliorating, or preventing a disorder that inhibits CDK4 / 6 response, comprising administering to a system or an individual in need thereof an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable compound thereof. The accepted salt or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, treats the aforementioned conditions.

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

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

Specifically, wherein the disorder includes, but is not limited to, an autoimmune disease, a transplant disease, an infectious disease, or a cell proliferation disorder.

Furthermore, the present invention provides a method of treating a cell proliferative disorder, 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 The above conditions are optionally treated in combination with a second therapeutic agent.

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

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

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 comprising cells or tissues, or including a mammalian individual, such as a human or animal individual Within individuals.

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 defined otherwise, all technical and scientific terms used in this patent have the same meaning as commonly understood by those skilled in the art. Unless otherwise stated, all patents, patent applications, publicly disclosed materials, etc. referred to in this patent are incorporated in their entirety by reference. If there are multiple definitions of the same term in this patent, the definitions in this section shall prevail. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory, and are not restrictive to any claims. In this patent application, the use of the singular includes the plural unless stated otherwise. It should be noted that in the description and the appended claims, unless otherwise stated in the text, the singular forms refer to “a”, “an”, “the” and include plural referents. It should also be noted that "or" means "and / or" unless stated otherwise. In addition, "comprising", "including" and the like are not restrictive. Standard definitions of chemical terms can be found in reference books including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4th Edition." Volumes A (2000) and B (2001), Plenum Press, New York. Unless stated otherwise, the conventional techniques of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet spectroscopy, and pharmacology used in this patent are prior art. Unless specifically defined, the nomenclature, experimental methods, and techniques involved in analytical chemistry, organic synthetic chemistry, medicinal, and pharmaceutical chemistry in this patent are known. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and administration, and treating patients. The reaction and purification techniques can be performed with reference to the manufacturer's specifications, or with known and commonly used techniques, or with the methods described in this patent. The techniques and operations described above can be implemented using methods known in the art and cited in this specification. In the description, the groups and substituents may be selected by those skilled in the art to form stable structures and compounds. When a chemical formula is used to refer to a substituent, the substituents written in the chemical formula from left to right are the same as those written from right to left. For example, CH ₂ O is the same as OCH ₂ . As used herein, "optionally substituted" includes unsubstituted or substituted. "Substituted" means that a hydrogen atom is replaced with a substituent. It should be noted that substituents on specific atoms are limited by their valence. In the definition section, "C _ij " refers to a range including a start point and an end point, where i and j are both integers, indicating 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 having a specific number of carbon atoms. Unless otherwise specified, "alkyl" refers to C ₁ -C ₆ alkyl. For example, "C ₁ -C ₆ " in "C _1-6 alkyl" refers to a group having a linear or branched arrangement of 1, 2, 3, 4, 5, or 6 carbon atoms. 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 contains 3-10 carbon atoms, no heteroatoms, and no double bonds. Examples of monocyclic systems include propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A monocyclic cycloalkyl group contains one or two alkylene bridges, each of which contains 1, 2 or 3 carbon atoms, which connects 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 may 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 straight-chain, branched or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, there are 1 carbon-carbon double bond, and up to 4 non-aromatic carbon-carbon double bonds may be present. Therefore, "C _2-6 alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight chain, branched or cyclic portion of an 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 straight-chain, branched, or cyclic hydrocarbon radical containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, three carbon-carbon triple bonds may be present. Thus, "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 straight chain, branched or cyclic part of the alkynyl group may contain a triple bond. If the alkynyl group is designated to indicate that it may be substituted. "Halogen" means fluorine, chlorine, bromine, and iodine. "Alkoxy", used alone or in combination with other terms, refers to an alkyl group connected to an oxygen atom with a single bond. An alkoxy group is connected to another molecule via an oxygen atom. An alkoxy group can be represented as -O-alkyl. "C _1-10 alkoxy" refers to an alkoxy group containing 1 to 10 carbon atoms, and may be a linear or branched structure. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy and the like. "Cycloalkoxy", used alone or in combination with other terms, refers to a cycloalkyl group connected to an oxygen atom with a single bond. A cycloalkoxy group is connected to another molecule via an oxygen atom. A cycloalkoxy group can be represented as -O-cycloalkyl. "C _3-10 cycloalkoxy" refers to a cycloalkoxy group containing 3 to 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 attached to a sulfur atom with a single bond. An alkylthio group is connected to another molecule via a sulfur atom. Alkylthio can be represented as -S-alkyl. The "C _1-10 alkylthio group" refers to an alkylthio group containing 1 to 10 carbon atoms, and may be a linear 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 attached to a sulfur atom by a single bond. A cycloalkylthio group is connected to another molecule via a sulfur atom. A cycloalkylthio group can be represented as -S-cycloalkyl. "C _3-10 cycloalkylthio" refers to a cycloalkylthio group containing 3 to 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 attached to a nitrogen atom with a single bond. An alkylamino group is connected to another molecule via a nitrogen atom. Alkylamino can be represented as -NH (alkyl). "C _1-10 alkylamino" refers to an alkylamino group containing 1 to 10 carbon atoms and may be a linear or branched structure. Alkylamino includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentamino, hexylamino, and the like. "Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group connected to a nitrogen atom with a single bond. A cycloalkylamino group is connected to another molecule via a nitrogen atom. A cycloalkylamino group can be represented as -NH (cycloalkyl). "C _3-10 cycloalkylamino" refers to a cycloalkylamino group containing 3 to 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 to a nitrogen atom with a single bond. A di (alkyl) amino group is connected to another molecule via a nitrogen atom. Di (alkyl) amino 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 having at least one aromatic carbocyclic ring, such as naphthyl, indan, and 1,2,3,4-tetrahydroquinoline; and at least A tricyclic ring of an aromatic carbocyclic ring, such as fluorene. If the aryl substituent is bicyclic or tricyclic and at least one of the rings is a non-aromatic ring, it is considered to be connected through an aromatic ring. For example, aryl includes 5- and 6-membered aromatic carbocyclic rings which are fused with a 5-7 membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the attachment site is Aromatic carbocyclic. A divalent radical formed from a substituted benzene derivative and having a free valence electron 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", which is obtained by removing a hydrogen atom from a carbon atom containing a free valence electron, and its name is The radical name is added with "-idene". For example, a naphthyl group with two attachment sites is called a naphthylene group. However, the definition of aryl does not include and does not overlap with heteroaryl, which is defined separately below. Therefore, if one or more aromatic carbocyclic rings are fused with the heterocyclic aromatic ring, the resulting ring system should be considered a heteroaryl group, not an aryl group as defined herein. "Heteroaryl" means a 5- to 8-membered aromatic monocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, and in some embodiments 1 to 3 heteroatoms , The rest are carbon atoms; 8- to 12-membered bicyclic rings containing 1 to 4 heterocyclic atoms selected from N, O, and S, and in some embodiments 1 to 3 heteroatoms, the rest are Is a carbon atom with at least one heteroatom present in the aromatic ring; and an 11- to 14-membered tricyclic ring. The ring contains 1 to 4 heteroatoms selected from N, O, and S, and in some embodiments 1 to 3 heteroatoms, and 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 greater than two. In some embodiments, the total number of S and O in the heteroaryl group is not greater than one. Examples of heteroaryl include, but are not limited to (the number of attachment sites is preferred, designated as position 1) 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyridine Azinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl Group, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furanyl, benzofuranyl, benzimidazoline, dihydroindolyl, pyridazinyl, triazolyl, quinyl Phenyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. Further, heteroaryl includes, but is not limited to, pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinolyl, and isoquinolyl. As defined below for heterocyclyl, "heteroaryl" includes N-oxygenated derivatives of nitrogen-containing heteroaryl. The monovalent heteroaryl radical ends with a "radical". The derived divalent radical is obtained by removing a hydrogen atom from a carbon atom containing a free valence electron. The name of the divalent radical is The name of a monovalent radical is added with "-idene". For example, a pyridyl group with two attachment sites is called a pyridyl group. The definition of heteroaryl does not include aryl as defined above and does not overlap with it. If the heteroaryl substituent is a bicyclic or tricyclic ring, 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 "heterocyclyl") generally refers to a single cyclic aliphatic hydrocarbon, usually having 3 to 12 ring atoms and containing at least 2 carbon atoms. Containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, also means a combination containing at least one of the above heteroatoms. Alternatively, the heterocycle as defined above may be a polycyclic ring system (such as a bicyclic ring) in which two or more rings exist in the form of a parallel ring, a bridge ring, or a spiro ring, and at least one ring contains one or more independently selected A heteroatom from oxygen, sulfur, and nitrogen. "Heterocycle" also refers to a 5- to 7-membered heterocyclic ring fused to a 5- and 6-membered aromatic carbocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, provided that the attachment site is in the heterocyclic ring on. Heterocyclic rings can be saturated or contain one or more double bonds (ie, partially unsaturated). The heterocyclic ring may be substituted by oxo. The carbon atom or heteroatom on the heterocyclic ring can be a linking site, provided that it forms a stable structure. When a heterocyclic ring has a substituent, the substituent may be connected to any heteroatom or carbon atom on the heterocyclic ring, provided that it forms a stable chemical structure. The heterocyclic and heteroaryl definitions described herein do not overlap. Suitable heterocycles include, for example, (the attachment sites are prioritized as 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinone, 1-fluorene Pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and 2,5-pyrazinyl. Also included are 2-morpholinyl and 3-morpholinyl (the oxygen atom position number is preferably 1). Substituent-containing heterocycles also include ring systems substituted with one or more oxo groups, such as pyridinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholine And 1,1-dioxo-1-thiomorpholinyl. Bicyclic compounds include, but are not limited to:

with

. As used herein, "aryl-alkyl" refers to an aryl-substituted alkyl group. Exemplary aralkyls include benzyl, phenethyl, and naphthylmethyl, among others. In some implementations, the aralkyl group contains 7-20 or 7-11 carbon atoms. When "aryl C _1-4 alkyl" is used, where "C _1-4 " refers to the number of carbon atoms in the alkyl portion rather than the aryl portion. As used herein, "heterocyclyl-alkyl" refers to a heterocyclyl-substituted alkyl group. When "heterocyclyl-C _1-4 alkyl" is used, where "C _1-4 " refers to the number of carbon atoms in the alkyl portion rather than the heterocyclyl portion. As used herein, "cycloalkyl-alkyl" refers to a cycloalkyl-substituted alkyl group. When "C _3-10 cycloalkyl-C _1-4 alkyl" is used, where "C _3-10 " refers to the number of carbon atoms in the cycloalkyl portion instead of the alkyl portion. Where "C _1-4 " refers to the number of carbon atoms in the alkyl moiety rather than the cycloalkyl moiety. As used herein, "heteroaryl-alkyl" refers to a heteroaryl-substituted alkyl group. When "heteroaryl-C _1-4 alkyl" is used, where "C _1-4 " refers to the number of carbon atoms in the cycloalkyl portion rather than the heteroaryl portion. 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 portion may be unsubstituted or substituted with at least one, such as 1, 2, 3, or 4 substituents independently selected from R ^x , and the alkyl portion may 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. The salt of the inorganic base may be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc salts. Further, the salt of the pharmaceutically acceptable inorganic base may be selected from the group consisting of ammonium, calcium, magnesium, potassium, and sodium salts. One or more crystal structures may exist in the solid salt, as well as hydrated forms. The pharmaceutically acceptable organic non-toxic base salts may be selected from, for example, primary, secondary and tertiary amine salts. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine. , Caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- Ethylpyrimidine, glucosamine, glucosamine, histidine, hypamine, isopropylamine, lysine, meglumamine, morpholine, pyrazine, pyridine, polyamine resin, procaine, Purines, coco bases, 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 selected from the group consisting of inorganic and organic acids. For example, selected from the group consisting of 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 Maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, acetic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. In some embodiments, these acids can be selected, such as: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid. By "administering" or "administering" a compound or a pharmaceutically acceptable salt thereof, it is meant to provide a compound in the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment. An "effective amount" refers to the amount of a compound or pharmaceutically acceptable salt thereof that is capable of causing a biological or medical response in a tissue, system, animal, or human that can be observed by a researcher, veterinarian, clinician, or other clinical person. A "composition" includes a product containing specific amounts of specific ingredients, and any product that is a combination of these specific amounts, directly or indirectly. A pharmaceutical composition comprises a product containing an active ingredient and an inert ingredient as a carrier, and any two or more ingredients made directly or indirectly, by combination, compounding or aggregation, or by one or more A product resulting from the decomposition of an ingredient, or a product produced by one or more other types of reactions or interactions. "Pharmaceutically acceptable" means compatible with other components in the formulation and without 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 the mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, Mianyang, goats, pigs; domestic animals such as rabbits, 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, and the like. In one embodiment of the invention, the mammal is a human. "Treatment" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, improving or preventing underlying metabolic factors of the symptom, inhibiting the disease or symptom, for example, preventing the development of the disease or symptom, reducing the disease or symptom, promoting the disease or symptom relief, Or stop the signs of the disease or symptoms, and extend to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit is the eradication or amelioration of the condition being treated. In addition, therapeutic benefits are achieved by eradicating or improving one or more of the physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, improvement in the patient's disease can be observed. Prophylactic benefit is when a patient takes a composition to prevent the risk of a disease, or when a patient has one or more physical symptoms of the disease, although the disease has not been diagnosed. "Protective group" (Pg) refers to a type of substituent that is used to block or protect specific functional groups by reacting with other functional groups on a compound. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the amino functional group on the compound. Suitable amino protecting groups include ethenyl, 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 hydroxyl function. Suitable protecting groups include ethenyl and silyl. "Carboxy protecting group" refers to a type of carboxy substituent which can effectively block or protect the function of carboxy. Common carboxy 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 and the like. For general descriptions and instructions for 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, trichloroethoxymethane, tribromoethoxymethane, benzyloxycarbonyl, p-nitrobenzylformyl, o-bromobenzyloxycarbonyl, chloroacetamidine Base, dichloroethenyl, trichloroethenyl, trifluoroethenyl, phenethenyl, formamidine, ethenyl, benzamidine, tert-pentyloxycarbonyl, tert-butoxycarbonyl, p-methyl Oxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethyl Propylpropoxycarbonyl, isopropyloxycarbonyl, phthalimidine, succinimidine, alanine, leucine, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, diphenylmethyl , Trityl, 2-nitrophenyl mercaptan, methanesulfonyl, p-toluenesulfonyl, N, N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene , 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene , 2-ethoxycarbonylcyclopentylene, 2-ethenylcyclohexylene, 3,3-dimethyl-5-oxocyclohexylene, di Phosphorus acyl group, 5-methyl-2-yloxy -2H-l, 3- dioxy-4-yl - methyl, trimethyl silicon alkyl, silicon triethyl and triphenyl silicon alkyl group. "C (O) OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, phenyl, naphthyl, benzyl Methyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl, acetomethyl, benzamidinemethyl, p-nitro Benzamidinemethyl, p-bromobenzylmethyl, p-toluenesulfonylbenzylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2- (Trimethylsilyl) ethyl, ethoxymethyl, propyloxymethyl, pivaloyloxymethyl, xylylenedimethymethyl, 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-butyldiphenyl Alkyl, tert-butyldiphenylsilyl group silicon, silicon diphenylmethyl group and t-butyl group methoxyphenyl silicon. "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-tris Chloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (benzenesulfonyl) ethoxycarbonyl, 2- (triphenyl Phosphono) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxy Carbonyl, 8-quinolinyloxycarbonyl, ethenyl, formate, chloroethenyl, dichloroethenyl, trichloroethenyl, trifluoroethenyl, methoxyethenyl, benzene Oxyethenyl, pentamyl, benzyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl 2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, di Phenyl Methyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethyl Oxymethyl, 2,2,2-trichloro-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluene Sulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, Diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

Geometric isomers may exist in the compounds of the invention. The compound of the present invention may have a carbon-carbon double bond or a carbon-nitrogen double bond in the E or Z configuration, in which "E" represents a preferred substituent based on the Cahn-Ingold-Prelog rule. -The opposite side of the nitrogen double bond, and "Z" represents a preferred substituent on the same side as the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the invention may also exist as a mixture of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclyl can be in the cis or trans configuration. In addition, the present invention includes different isomers formed from different arrangement of substituents around the adamantane ring system and mixtures thereof. The two substituents around a single ring in the adamantane ring system are assigned the Z or E relative configuration. See, for example, 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 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 are racemic if the amounts of R and S configurations are the same. If the amount of one configuration is greater than the other configuration, the configuration of the chiral carbon atom is expressed as a configuration with a larger amount, preferably an enantiomeric excess of about 85-90%, more preferably about 95-99% More than 99%. Accordingly, the invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labeled compounds The compounds of the present invention can exist in isotopically labeled or enriched forms and contain one or more atoms that differ from the most common atomic mass and mass number in nature. Isotopes can be radioactive or non-radioactive. 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 invention. In another embodiment, the isotope-labeled compounds contain deuterium ⁽² H), tritium ⁽³ H) or ¹⁴ C isotopes. The isotope-labeled compounds 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 schemes of the present invention and replacing unlabeled reagents with isotope-labeled reagents. In some examples, the actual processing compound can be labeled with an isotope, replacing the atom with an isotope atom, for example, replacing hydrogen with deuterium can be exchanged by the action of a deuterated acid such as D ₂ SO ₄ / D ₂ O. In addition, relevant synthetic 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; US Patent Nos. 7538189, 7534814, 7531685, 7528111, 751421, 7514068, 7511013; and U.S. Patent Application Publication Nos. 20090137457, 20090131485, 20090131363, 20090118238, 20090111840, 20090105338, 20090105307, 20090105147, 20090093422, 20090088416, and 20090082471. For specific methods, see references. The isotope-labeled compound of the present invention can be used as a standard for a pharmacodynamic binding test of a CDK4 / 6 inhibitor. Compounds containing isotopes 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 metabolism of compounds in vivo (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, and it can be judged that the active compounds of the patient or the metabolites of the parent compound are 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, are called "heavy drugs" and can be used to treat diseases and conditions associated with CDK4 / 6 activity. A compound whose isotopic ratio 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 days to weeks, including rodents and dogs, with 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).... Replacement of up to 15-23% of human body fluids with deuteration has not caused 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)) Proper isotope labeling of drugs can alter their physicochemical properties, such as pKa and liquid solubility. If isotopic substitution affects the region of the ligand-receptor interaction, these effects and changes may affect the pharmacodynamic response of the drug molecule. Some stable isotopically labeled molecules have different physical properties from unlabeled molecules, but have the same chemical and biological properties. 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 lighter than a light isotope. Stronger. Correspondingly, the presence of an isotope at a metabolic or enzymatic conversion site will slow down the response, thereby altering its pharmacokinetic characteristics or pharmacodynamics.

(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, bis (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, ring Alkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one, as 1, 2, 3 or 4, independently selected from the substituents of R ^x ; 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 groups, 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or at least one, such as 1, 2, 3, or 4 Each independently selected from the group consisting of 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 cycloalkane Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, hetero aryl group -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 is unsubstituted Substituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^X ; each R ^{4 is} selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 ene Radical, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl group -C _1-4 alkyl, Aryl, 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 are unsubstituted or substituted with 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, heterocyclic And heterocyclyl-C _{1 -4} alkyl, 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, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or at least One, such as 1, 2, 3, or 4, independently selected from a substituent selected from R ^X ; 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 are unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^X ; or each "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 together constitute 0, 1 or 2 additional independently selected A 4- to 12-membered heterocyclic ring of a heteroatom of oxygen, sulfur, nitrogen and phosphorus, 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 are} 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 N R ^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, heterocyclic ring Group, aryl group and heteroaryl group are unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, each independently selected from R ^Y ; each 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, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^Y ; or R ^a1 and R ^b1 together with the single or multiple atoms attached to them together form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be unsubstituted Substituted or substituted with 1, 2 or 3 substituents selected from R ^Y ; 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, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted Or is substituted by at least one, such as 1, 2, 3, or 4, substituents independently selected from R ^Y ; or R ^c1 and R ^d1 together with the single or multiple carbon atoms attached to them constitute 0, 1 Or 2 additional 3-12 membered heterocycles independently selected from heteroatoms of oxygen, sulfur and nitrogen, the ring may be unsubstituted or substituted with 1, 2 or 3 R ^Y groups; each R ^e1 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} independent Is 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 , _{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 alkane Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are 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 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C1 _-10 alkylamino, C _3-10 cycloalkylamino, and di ( C _1-10 alkyl) amino substituent substitution; each R ^a2 and R ^{b2 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, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 ring Alkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di (C _1-10 alkyl) amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl group -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 are 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 di (C _1-10 Alkyl) amino substituent substitution; or R ^a2 and R ^b2 together with the single or multiple atoms attached to them together form 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus 4-12 membered heterocyclic ring, which 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, 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 di (C _1-10 alkyl) amino substituent substitutions; 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, 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, where each alkyl, alkene Alkynyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl are unsubstituted, respectively Or be 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 cycloalkane Group, 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; or R ^c2 and R ^d2 together with the single or multiple carbon atoms attached to them constitute 0, 1 or 2 additional 3-12 of heteroatoms independently selected from oxygen, sulfur and nitrogen Heterocyclic ring, which 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, 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 di (C _1-10 alkyl) amino substituent substitution; 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 the embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the chemical formula is

(I).

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

(II).

In another embodiment (4), the present invention provides a compound according to 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) to (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 substituents independently selected from R ^X.

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 with at least one, such as 1, 2, 3, or 4 substituents independently selected from R ^X.

In another embodiment (8), the present invention provides a 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 at least one, such as 1, 2 , 3 or 4, substituted independently with a substituent 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

with

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

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 present invention is selected from 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6- ) -N- (5- (fluorazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine, 5-fluoro-4- (1-isopropyl-2-methyl-1H- Imidazolo [4,5-b] pyridin-6-yl) -N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N -(5-((4-ethylpyrazin-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] heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-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 ] Heptane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((((1S, 4S) -5-ethyl-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 ] Pyridine-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) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine- 6-yl) pyrimidin-2-amine, N- (5-((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-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) 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- (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) methyl) pyridine-2- ) -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) 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) pyrimidine- 2-amine, N- (5-((2,7-azaspiro [3.5] nonane-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-imidazole Benzo [4,5-b] pyridine-6-yl) -N- (5-((7-methyl-2,7-azaspiro [3.5] nonane-2-yl) methyl) pyridine-2 -Yl) pyrimidin-2-amine, N- (5-((7-ethyl-2,7-azaspiro [3.5] nonane-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] heptane-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-((6-methyl-2,6-azaspiro [3.3] heptane-2-yl) methyl) pyridin-2-yl) pyrimidine-2 -Amine, N- (5-((6-ethyl-2,6-azaspiro [3.3] heptane-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-((3,9-azaspiro [5.5] Undecane-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-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) pyrimidin-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- Imidazolo [4,5-b] pyridin-6-yl) pyrimidin-2-amine, N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5 -b) pyridine-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) (fluorazin-1-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) (4 -Methylpyrazine-1-yl) methanone, (4-ethylpyrazine-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] octane- 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] octane-3-yl) (6-((5-fluoro-4- (1-isopropyl-2- 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) (2,7-azaspiro [3.5 ] Nonane-2-yl) methanone, (6-((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6-yl ) Pyrimidin-2-yl) amino) pyridin-3-yl) (7-methyl-2,7-azaspiro [3.5] nonane-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] pyridine- 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) (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) pyridine-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- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidin-2- ) Amino) pyridin-3-yl) methanone, 5-fluoro-4- ( 1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) -N- (5- (fluorazin-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-methylfluorazin-1-yl) sulfofluorenyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((4-ethylfluorinazin-1-yl) sulfonamido) 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) 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] pyridine-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) pyridine) 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) sulfonyl) 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] pyridin-6-yl) -N- (5-((5-methylhexahydropyrrolo [3,4-c] pyrrole-2 ( 1H) -yl) sulfofluorenyl) pyridin-2-yl) pyrimidine-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) sulfonamido) 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- Imidazolo [4,5-b] pyridin-6-yl) -N- (5-((7-methyl-2,7-azaspiro [3.5] nonane-2-yl) sulfonyl) pyridine -2-yl) pyrimidin-2-amine, N- (5-((7-ethyl-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-((4- (oxetan-3-yl) pyrazine -1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5 -b] pyridine-6-yl) -N- (5-((2-methyl-4- (oxetan-3-yl) pyrazin-1-yl) methyl ) Pyridin-2-yl) pyrimidin-2-amine, (R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6- ) -N- (5-((2-methyl-4- (oxetan-3-yl) pyrazin-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) pyrazin-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-((3-methyl-4- (oxetan-3- Yl) pyrazine-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] Pyridine-6-yl) -5-fluoro-N- (5-((4- (oxetan-3-yl) pyrazin-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 -((2-methyl-4- (oxetan-3-yl) pyrazin-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- ( Oxetane-3-yl) pyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (R) -4- (1- (tert-butyl) -2-methyl Radical-1H- Imidazolo [4,5-b] pyridin-6-yl) -5-fluoro-N- (5-((3-methyl-4- (oxetan-3-yl) pyrazine-1- (Methyl) pyridin-2-yl) pyrimidin-2-amine, (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridine- 6-yl) -5-fluoro-N- (5-((3-methyl-4- (oxetan-3-yl) fluorazin-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- ( Perazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridine- 6-yl) -5-fluoro-N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1- (tert-butyl Yl) -2-methyl-1H-imidazo [4,5-b] pyridine-6-yl) -N- (5-((4-ethylpyrazin-1-yl) methyl) pyridine-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-diaza Heterobicyclo [3.2.1] octane-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazole Benzo [4,5-b] pyridine-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] pyridine- 6-yl) -5-fluoro-N- (5-((3- (methoxymethyl) pyrazin-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 (Oxymethyl) -4-methylpyrazin-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) pyrazin-1-yl) methyl ) Pyridin-2-yl) -5-fluoropyrimidin-2-amine, N- (5-((3,8-diazabicyclo [3.2.1] octane-3-yl) methyl) pyridine- 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-((8-methyl-3, 8-diazabicyclo [3.2.1] octane-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-3-yl ) Methyl) pyridine 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- (fluorazin-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-methylpyrazin-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-ethylpyrazin-1-yl) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridine-6-yl) -5-chloro-N- (5- (pyrazin-1-ylmethyl) 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-methylpyrazin-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-ethylfluorazin-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- (fluorazin-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-methylfluorene (Azin-1-yl) (Methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((4-ethylpyrazin-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-pyrazolo [3,4-b] pyridin-5-yl) -N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidine -2-amine, N- (5-((4-ethylfluorazin-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) pyrimidine -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] octane-3 -Yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) Pyridin-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-2H-pyrazolo [3,4-b] pyridine- 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) 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) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((7-ethyl-2,7-azaspiro [3.5] nonane-2-yl) methyl) 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) methyl) pyridin-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] pyridin-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) pyridin-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] undecane-3- 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-((9- methyl- 3,9-azaspiro [5.5] undec-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((9-ethyl-3,9-nitrogen Heterospiro [5.5] undec-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) pyrazin-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- ( Oxetane-3-yl) pyrazin-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- (oxetan-3-yl) pyrazine -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) fluorazin-1-yl) methyl) pyridine-2- ) Pyrimidin-2-amine, (S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N -(5-((3-methyl-4- (oxetan-3-yl) pyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (6- ( (5- 4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (pyrazine 1-yl) methanone, (6-((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidine -2-yl) amino) pyridin-3-yl) (4-methylpyrazin-1-yl) methanone, (4-ethylpyrazin-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) pyridin-3-yl) methanone, (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridine-3- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) methanone, (8-ethyl-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) 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) methanone, (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] nonane-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) pyrimidin-2-yl) amino) pyridine-3- Methyl) methanone, (6-((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2- ) 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) pyridine -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) pyrimidine -2-yl) amino) pyridin-3-yl) methanone, N- (5-((3,8-diazabicyclo [3.2.1] octane-3-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 -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) sulfofluorenyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((8-ethyl-3,8-di Azabicyclo [3.2.1] octane-3-yl) sulfofluorenyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-amine, N- (5-((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- 4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5-((7-methyl-2,7-nitrogen Heterospiro [3.5] nonane-2-yl) sulfofluorenyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((7-ethyl-2,7-nitrogen Spiro [3.5] nonane-2-yl) sulfofluorenyl) 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) sulfonyl) 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) sulfofluorenyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((5-ethylhexahydropyrrolo [3,4-c] Pyrrole-2 (1H) -yl) sulfofluorenyl) 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- (oxetan-3-yl) pyrazin-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-methylpyrazin-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-ethylpyrazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine, (R) -4- (3- ( Butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -5-fluoro-N- (5-((methyl ((1-methylpyrrole-2 -Yl) methyl) amino) methyl) pyridin-2-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) pyridine-2 -Yl) pyrimidin-2-amine, N- (5-((3,8-diazabicyclo [3.2.1] octane-8-yl) methyl) pyridin-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-diazabis Cyclo [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) pyridine 2-yl) -5-fluoropyrimidin-2-amine, (S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridine-5 -Yl) -5-fluoro-N- (5-((3- (methoxymethyl) pyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (S)- 4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -5-fluoro-N- (5-((3- (methyl (Oxymethyl) -4-methyl Perazin-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) pyrazin-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] 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-(((1R, 5S) -8- Methyl-3,8-diazabicyclo [3.2.1] octane-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, 4- (3- (tert-butyl)- 2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5-(((1R, 5S) -8-ethyl-3,8-diazabis Cyclo [3.2.1] octane-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- (fluorazin-1-yl) ethyl) pyridin-2-yl) pyrimidine-2- Amine, 4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -5-fluoro-N- (5- (1- ( 4-methylpyrazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine, 4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b) pyridin-5-yl)- N- (5- (1- (4-ethylpyrazin-1-yl) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine, N- (4- (3- (tert-butyl Yl) -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-fluoro Pyrimidin-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- (morpholinemethyl) 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) pyrazin-1-yl) propionitrile, N- ( 4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (piperidine -4-yl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, N- (4- (3- (tert-butyl) -2-methyl-2H-pyridine Zolo [3,4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-methylpyridin-4-yl) -5,6,7,8-tetra Hydrogen-1,6-naphthyridin-2-amine, N- (4- (3- (tert-butyl) -2-methyl-2H-pyridine Benzo [3,4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-ethylpyridin-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, comprising administering to an individual in need thereof an effective amount of embodiments (1)- The compound of any one of (20) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

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

In another aspect, the present invention provides a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and a description including one or more of the following information: to which disease the ingredient is applied, storage information of the ingredient, dosage Information and instructions on how to use the ingredients. In a special variant, the kit contains the compound in multiple dosage forms.

In another aspect, the invention provides an article of manufacture comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and a packaging material. In one variation, the packaging material includes a container. In a special variation, the container includes a label indicating one or more of the following: information about the disease to which the compound is applied, storage information, dosage information, and / or instructions on how to use the compound. In another variation, the article of manufacture includes the compound in multiple dosage forms.

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

In another aspect, the 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 causing a compound disclosed herein or a pharmaceutically acceptable salt thereof to occur in 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 a subject 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 above embodiments and variations.

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

In another aspect, the present invention provides a method for treating a disease state in which CDK4 / 6 activity causes pathology and / or symptoms of the disease state, the method comprising administering to a subject a first compound, which is converted into the first 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 transformation.

In a variation of each of the above methods, the disease state is selected from: cancerous proliferative diseases (such as brain, lung, squamous cells, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colon, epidermis, Esophagus, testis, 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 germ cells Implantation; treatment of diseases related to angiogenesis or angiogenesis (such as 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, premature infant retinopathy, age-related macular degeneration, hemangiomas, gliomas, 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, myocardial infarction and stroke reperfusion injury and inflammatory arthritis) Septic shock; T cell-received diseases in which immunosuppression is valuable (such as prevention of organ transplant rejection, graft versus host disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; Inhibits keratinocytes responding to growth factor mixtures; chronic obstructive pulmonary disease (COPD) and other diseases.

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

In another aspect, the invention relates to the use of a compound and modification of any one of the above embodiments as a medicament. In another aspect, the invention relates to the use of any one of the compounds and modifications of any of the above embodiments as an inhibitor of CDK4 / 6 drug production.

In another aspect, the present invention relates to the production of a compound according to any one of the above embodiments and a medicament for modifying a disease state of pathology and / or symptoms caused by CDK4 / 6 activity.

Administration and Pharmaceutical Compositions Generally, the compounds described herein will be administered in a therapeutically effective amount via any of the ordinary and acceptable means known in the art, either 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 neoplastic diseases and immune system diseases, the required dosage will vary depending on the mode of administration, the specific condition to be treated and the desired effect. Generally, satisfactory results are achieved at daily doses of 0.001 to 100 mg / kg body weight, specifically from about 0.03 to 2.5 mg / kg body weight. Daily doses for larger mammals, such as humans, may be from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, in a convenient form, e.g., in divided doses of up to four daily Times or in slow-release form. A suitable unit dosage form for oral administration contains about 1 to 50 mg of the active ingredient. The compounds of the invention can be administered in the form of a pharmaceutical composition, by any conventional route; for example, enterally, for example orally, for example in the form of tablets or capsules, parenterally, for example in the form of injectable solutions or suspensions; Or topically, for example in the form of a lotion, gel, ointment or cream, or in the form of a nose or suppository. The pharmaceutical composition containing the compound of the present invention in the form of a free base or a pharmaceutically acceptable salt 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 invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. 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 lyophilized compositions containing only the active ingredient or mixed with a carrier such as mannitol, the dispersion or suspension may be supplemented before use. The pharmaceutical composition may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts and / or buffering agents to adjust osmotic pressure. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. Solutions or suspensions may also contain viscosifying agents, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers such as Tween 80 (polyoxyethylene (20) Sorbitol monooleate). Suspensions in oils may contain vegetable oils as oily ingredients, synthetic or semi-synthetic oils, 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, 12 to 22 carbon atoms as an 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, oleic acid, erucic acid, pasenoic acid, and linoleic acid, may contain antioxidants, such as vitamin E, 3-carotene, or 3,5-di-tert-butylhydroxytoluene, if desired. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di- or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, 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 (apricot kernel oil solution of an alcohol is not Saturated PEGylated glycerides and glycerides and polyethylene glycol esters), LABRASOLTM (saturated PEGylated glycerides and glycerides and polyethylene glycol esters prepared by alcoholysis TCM; all available from GaKefosse, France Obtained by the company), and / or MIGLYOL ^® 812 (saturated fatty acid triglycerides with a chain length 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, Soy or peanut oil. Pharmaceutical compositions for oral administration can be obtained, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture, if necessary, and processing the mixture or granules by adding additional excipients, In the form of tablets or tablets. Suitable carriers include, but are not limited to, fillers such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose formulations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen 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 desired, disintegrants, As mentioned above, starch, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, 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 a salt thereof, such as magnesium or calcium stearate, and / or polyethylene glycol, or a derivative thereof . A suitable, optionally enteric coating can be provided for the tablet cores by using, in particular, a concentrated sugar solution, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or honorably suitable Coating solutions of organic solvents or solvent mixtures, or, for enteric coatings, suitable cellulose products such as ethyl acetate cellulose phthalate or hydroxypropyl methylcellulose phthalate solutions preparation. Dyes or pigments can be added to tablets or tablet coatings, for example for identification purposes or to indicate different doses of the active ingredient. Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may be in the form of granules containing the active ingredient, 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 glycols or fatty acid esters of ethylene glycol or propylene glycol, into which stabilizers and detergents, For example, fatty acid esters of polyoxyethylene sorbitol may also be added. Pharmaceutical compositions suitable for rectal administration, such as suppositories, comprise 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 forms, such as water-soluble salts or aqueous injection suspensions containing substances that increase viscosity, such as sodium carboxymethyl cellulose, aqueous solutions of sorbitol, and / Or dextran, if needed, and a stabilizer. The active ingredient, optionally with excipients, can also be a solution in a lyophilized form and can be prepared by adding a suitable solvent before parenteral administration. The solutions used, for example, for parenteral administration, can also be used as infusion solutions. Injectable preparations are usually prepared under sterile conditions, filled into, for example, ampoules or vials, and sealed containers. The present invention also provides a pharmaceutical combination, such as a kit comprising 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 can contain its instructions for use.

Combination therapy The compounds or pharmaceutically acceptable salts described in this patent can be taken alone or in combination with other therapeutic agents. For example, the adjuvant drug may have a therapeutic effect on the compounds of the present invention (eg, the therapeutic benefit of the adjuvant drug alone is minimal, but it may enhance the therapeutic benefit of an individual when used in combination with another drug), or, for example, Combinations of the compounds of the present invention with another therapeutic agent that is also therapeutically effective can enhance the therapeutic benefit of an individual. For example, when treating gout, when taking a compound of the present invention, concomitant administration of another drug for treating gout may increase clinical benefit. Alternatively, for example, if the adverse reaction of taking the compound of the present invention is nausea, an anti-nausea drug may be used in combination. Alternatively, the combination therapy may include, but is not limited to, physical therapy, psychological therapy, radiation therapy, compression therapy in a diseased area, rest, diet improvement, and the like. Regardless of the disease, discomfort, or symptoms, the two therapies should have an additive or synergistic effect on the individual's therapeutic benefit. In the case where the patent compound is used in combination with other therapeutic agents, the pharmaceutical composition of the patent compound may be administered in the same route as other drugs, or due to different physical and chemical properties, the administration route may be different. For example, oral administration of a compound of this patent produces and maintains good blood levels, while another therapeutic agent may require intravenous administration. Therefore, the patent compound and another concomitant drug can be administered simultaneously, sequentially or separately. Compounds of formula (I) or (II) are expected to be effective in combination with one or more of the following drugs: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotic, antiproliferative, antiviral agents, aurora kinase inhibition Agents, other apoptosis promoters (eg, 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, cyclin inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogenes (ErbB2 ) Receptor inhibitors, growth factor inhibitors, heat shock protein (HSP) -90 inhibitors, histone acetate enzymes (HDAC) inhibitors, hormone therapy, immunologics, 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, -Valent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum-based chemotherapeutics, polo-like kinase (PLK) inhibitors, and inositol phosphate 3 Kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid / delta muscle plant alkaloids, small ribonucleic acid (siRNAs) inhibitors, topology Isomerase inhibitors, ubiquitin ligase inhibitors and analogs.

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

In a compound of formula (I) or (II), the connection between an atom and other atoms may lead to the existence of a specific stereoisomer (such as a chiral center). The synthesis of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may result in a mixture of different isomers (enantiomers, diastereomers). Unless specifically stated to be a specific stereo configuration, the listed compounds include different stereoisomers that may exist.

Compounds of formula (I) or (II) can also be made into pharmaceutically acceptable acid addition salts, for example, by reacting the free base form of a compound of the 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 form a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of formula (I) or (II) have been described in the definition section of this application. In addition, the salt form of a compound of formula (I) or (II) can also be prepared by using a salt of a starting material or an 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 to 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 a compound of formula (I) or (II) can be converted to 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-oxides can be obtained by contacting a non-oxidized form of a compound of formula (I) with an oxidant such as trifluoroperacetic acid, permaleic acid, peroxybenzoic acid, Peracetic acid, m-chloroperoxybenzoic acid, etc.) are obtained by reaction in an inert organic solvent (such as halogenated hydrocarbons such as dichloromethane). Alternatively, the N-oxide of the compound of formula (I) or (II) can also be prepared from the N-oxide of the starting material.

Compounds of formula (I) or (II) in non-oxidized form can be obtained by combining their N-oxides with reducing agents such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and tribromo Phosphorus, etc.) It is prepared by reacting in the corresponding inert organic solvents (such as acetonitrile, ethanol and dioxane hydrate, etc.) under the conditions of 0 ~ 80 ° C.

Protected derivatives of compounds of formula (I) or (II) can be prepared by methods well known to those skilled in the art. For a 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 and 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 Biochemistry. Unless otherwise stated, standard one- or three-letter abbreviations generally refer to L-type amino acid residues. Unless otherwise stated, all starting materials used were purchased from market suppliers and used without further purification. For example, the following abbreviations will be used in the examples and throughout the specification: g (grams), mg (millions), L (liters), mL (milliliters), μL (microliters), psi (pounds per square inch), M ( Mole), mM (mmol), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (mol), mmol (mmol), 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 (dimethylsulfinyl), EtOAc (ethyl acetate), DME (1,2-dimethyl ether), DCM (dichloromethane) ), DCE (dichloroethane), DMF (N, N-dimethylformamide), DMPU (N, N-dimethylpropenyl urea), 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-ethylcarbimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (fluorenyloxycarbonyl), Ac (Ethenyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilane), TBS (tert-butyldimethylsilyl) , DMAP (dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis (2 (2 -Oxo-3-oxazolidinyl) phosphinium chloride), TBAF (tetrabutylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

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

¹ H NMR spectra were recorded on a Bruker Avance 400 nuclear magnetic resonance spectrometer. Chemical shifts are expressed in ppm. Coupling constants are in Hertz (Hz). Describe apparent diversity in segmentation mode and define it as s (single peak), d (double peak), t (triple peak), q (quartet), m (multiple peak), and br (broad peak)

Low resolution mass spectrometry (MS) and compound purity data were obtained from a Waters ZQ LC / MS single-pole system equipped with an electrospray ion detector (ESI), UV detector (220 and 254 nm), and evaporative light scattering Detector (ELSD). Thin-layer chromatography was performed using a 0.25 mm Xupo chemical conversion silica gel plate (60F-254), 5% ethanol solution of phosphomolybdic acid, ninhydrin or p-oxidized phenyl solution and observed under UV light. Silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.) was used for flash column chromatography.

Synthesis scheme

The compounds of formula (I) or (II) or their pharmaceutically acceptable salts can be synthesized by different methods, 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 by the present invention.

It may be necessary to protect reactive groups in the reactions described below to prevent these reactive groups from participating in other undesired reactions: these groups such as hydroxyl, amino, imine, thiol or carboxyl groups, the final product contains These groups. Common protective groups can refer to TW Greene and PGM Wuts in " Protective Groups in Organic Chemistry " John Wiley and Sons, 1991.

The synthetic schemes for all compounds of the 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 herein.

The intermediates listed in the following synthesis schemes are either obtained from the 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 Synthesis Scheme 1. Compounds of formula I or II can be synthesized from intermediates III to VIII shown in the synthetic scheme, and these intermediates can be synthesized according to the literature or methods well known to those skilled in the art. A pyrimidine intermediate represented by Formula VI and a heteroaromatic intermediate represented by Formula VII or VIII are prepared by a palladium-catalyzed coupling reaction, such as the Suzuki reaction or other coupling conditions reported in the literature, to prepare a pyrimidine intermediate represented by Formula IV or V . Compounds of formula IV or V and aminoaromatic hydrocarbons of formula III are prepared by coupling reactions, such as Buchwald amination reactions or other coupling conditions reported in the literature, to prepare compounds 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, one synthetic route of the compound of formula IVa is shown in Synthesis Scheme 2. A commercially available diaminopyridine A was used as a starting material. Intermediate IVa is prepared by reductive amination, formation of imidazole and halogen groups, and then conversion to groups such as B or Sn, followed by palladium-catalyzed coupling reaction.

R ^a , R ^b , 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 Synthesis Scheme 3. Ketone N is reacted 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 the palladium-catalyzed coupling reaction is used to obtain intermediate Vb.

R ^a , R ^b , 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 to avoid the generation of unnecessary reaction products, the above-mentioned synthetic scheme may be adjusted according to circumstances. In order that the present invention may be more fully understood, the following examples are provided. These examples are merely examples and should not be construed as limiting the 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- chlorine -5- Fluoropyrimidine -4- base )-1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine ( Intermediate A)

Intermediate A 5- bromine -N ^3- Isopropylpyridine -2,3- Diamine (A-1) To a commercially available solution of 2,3-diamino-5-bromopyridine (1.88 g, 10 mmol) and acetone (0.7 g, 12 mmol) in isopropyl acetate (15 mL) was added TFA (2.51 g, 22 mmol) ), Then add NaBH (OAc) at 0 ° C₃ (3.18g, 15 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with EtOAc (50 mL). With saturated NaHCO₃ Wash with aqueous solution (30 mL) and saturated brine (30 mL), Na₂ SO₄ dry. 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- bromine -1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine (A-2) 5-bromo-N3-isopropylpyridine-2,3-diamine (A-1) (1.2 g, 5.2 mmol) and Ac₂ A mixture of 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). The organic layer was separated. The extract was washed with saturated brine (50 mL), Na₂ SO₄ dry. Filtration and concentration, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5: 1 ~ 1: 2) to give 6-bromo-1-isopropyl-2-methyl as a yellow solid. 1H-imidazo [4,5-b] pyridine (A-2). MS-ESI (m / z): 254, 256 [M + 1]⁺ . 6- ( three - N-butylstannyl )-1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine (A-3) To a solution of -bromo-1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine (A-2) (0.5 g, 2 mmol) in THF (10 mL) was added (Bu₃ Sn)₂ (2.32 g, 4 mmol), Pd (PPh₃ ) (OAc)₂ (0.08 g, 0.1 mmol) and TBAF (1.044 g, 8 mmol). Stir at 70 ° C for 4 h under nitrogen. The mixture was concentrated and the residue was diluted with ethyl acetate (50 mL). The extract was washed with water (50 mL) and MgSO₄ dry. It was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 9: 1 ~ 1: 1) to obtain 6- (tri-n-butyltinyl)-as a yellow oil. 1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine (A-3). MS-ESI (m / z): 466 [M + 1]⁺ . 6- (2- chlorine -5- Fluoropyrimidine -4- base )-1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine ( Intermediate A) 6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine (A-3) (0.455 g, 0.97 mmol) and 2 , 4-Dichloro-5-fluoropyrimidine (0.25 g, 1.49 mmol) in toluene solution (8 mL) was added with Pd (PPh₃ )₄ (0.06 g, 0.05 mmol). Stir at 110 ° C for 4 h under the protection of nitrogen. The mixture was concentrated. The residue was purified by flash silica gel column chromatography (eluent: ethyl acetate) to give 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- chlorine -5- Fluoropyrimidine -4- base ) -7- fluorine -3- Isopropyl -1- methyl -3a, 7a- Dihydro -1H- Indazole ( Intermediate B) Intermediate B 5- bromine -2- Chloronicotinic acid ( Isobutyl Carbonic acid ) anhydride (B-1) To a solution of 5-bromo-2-chloronicotinic acid (10.0 g, 42.3 mmol) in anhydrous THF (440 mL) at 0 ° C was added TEA (7.06 mL, 50.8 mmol), and then isobutyl chloroformate ( 6.64 mL, 50.76 mmol), a white precipitate formed rapidly. The mixture was stirred at 0 ° C for 75 minutes. After filtration, the solid was washed with THF (30 mL). Concentrated to obtain 200 mL of a solution containing 5-bromo-2-chloronicotinic acid (isobutyl carbonate) anhydride (B-1), which was directly used in the next reaction. (5- bromine -2- Clopyridine -3- base ) Methanol (B-2) To the above solution was added water (10 mL). The mixture was cooled to 0 ° C and NaBH was added.₄ (3.38 g, 89 mmol), the mixture was stirred at 0 ° C for 1 hour, and then warmed to room temperature for more than 2 hours. Ethyl acetate was added, the mixture was washed with water and saturated brine, dried over anhydrous potassium carbonate and sodium sulfate, and concentrated to obtain a crude (5-bromo-2-chloropyridin-3-yl) methanol (B-2), which was directly used in the next step reaction. 5- bromine -2- chlorine -3- Pyridinaldehyde (B-3) To (COCl) at -78 ° C₂ (2.95 mL, 34.84 mmol) in anhydrous DCM solution (26 mL) was added dropwise a solution of 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. TEA (18.2 mL, 131 mmol) was added dropwise, and stirring was continued at -78 ° C for 1 hour. The mixture was raised to room temperature and stirred for 1 hour. It was diluted 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, eluting with 3-5% ethyl acetate in hexane, to give 5-bromo-2-chloro-3-pyridinaldehyde (B-3) as a white solid. MS-ESI (m / z): 220 [M + 1]⁺ . 1- (5- bromine -2- Clopyridine -3- base )-2- Methylpropane -1- alcohol (B-4) In N₂ To a solution of 5-bromo-2-chloro-3-pyridinaldehyde (B-3) (5.63 g, 25.53 mmol) in anhydrous THF (70 mL) at -78 ° C under ambient conditions, isopropyl magnesium chloride ( 2.0 M in THF 15.3 mL). 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- bromine -2- Clopyridine -3- base )-2- Methylpropane -1- ketone (B-5) B-4 (265 mg, 1 mmol), PCC (431 mg, 2 mmol) and SiO₂ (0.5 g) of the mixture 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-methylpropane-1-one (B-5). MS-ESI (m / z): 262 [M + 1]⁺ . 5- bromine -3- Isopropyl -1H- Pyrazolo [3,4-b] Pyridine (B-6) To 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropane-1-one (B-5) (177 mg, 0.674 mmol) in isopropanol (2 mL) solution was added to hydrazine hydrate (0.5 mL). The mixture was warmed 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, Na₂ SO₄ Dry and concentrate. 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- bromine -3- Isopropyl -2- methyl -2H- Pyrazolo [3,4-b] Pyridine (B-7) To a solution of 5-bromo-3-isopropyl-1H-pyrazolo [3,4-b] pyridine (B-6) (48 mg, 0.2 mmol) in THF at 0 ° C was added NaH (10 mg, 60% in oil), and after stirring for 5 minutes, MeI (25 μL, 0.4 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, and Na₂ SO₄ Dry and concentrate. The residue was purified by silica gel column chromatography and eluted with 10% to 100% ethyl acetate in hexane 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] Pyridine -5- base ) Boric acid (B-8) 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridine (B-7) (724 mg, 2.85 mmol), diboronic acid pinacol ester (1.09 g , 4.27 mmol), Pd (OAc)₂ (64 mg, 0.28 mmol), Cy₃ A mixture of 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 a nitrogen blanket. The reaction was quenched with water. The mixture was extracted with DCM, extract Na₂ SO₄ Dry and concentrate 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- chlorine -5- Fluoropyrimidine -4- base ) -7- fluorine -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 (PPh₃ )₂ Cl₂ (200 mg, 0.28 mmol) and Na₂ CO₃ (906 mg, 8.55 mmol) in DME / H₂ The mixture of O (24 ml / 10 ml) solution was stirred at 80 ° C in a sealed tube under nitrogen for 2 hours. The reaction was quenched with water. The mixture was extracted with DCM and the organic layers were combined with Na₂ SO₄ Dry and concentrate. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2: 1) to give 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- chlorine -5- Fluoropyrimidine -4- base ) -3- Isopropyl -1- methyl -1H- Pyrazolo [3,4-b] Pyridine ( Intermediate C)

Intermediate C 5- bromine -3- Isopropyl -1- methyl -1H- Pyrazolo [3,4-b] Pyridine (C-1) To 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropane-1-one (B-5) (38 mg, 0.15 mmol) and methylhydrazine sulfate (25 mg, 0.2 To a solution of mmol) of 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 sequentially with water and saturated brine (20 mL), and Na₂ SO₄ Dry and spin. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100: 1 to 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] Pyridine -5- base ) Boric acid (C-2) 5-Bromo-3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridine (B-7) was 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). MS-ESI (m / z): 220 [M + 1]⁺ . 5- (2- chlorine -5- Fluoropyrimidine -4- base ) -3- Isopropyl -1- methyl -1H- Pyrazolo [3,4-b] Pyridine ( Intermediate C) According to the synthesis method of intermediate B, (3-isopropyl-1-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) boronic acid (B-8) was replaced 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-1-methyl-1H-pyrazolo [3,4-b] pyridine (Intermediate C). MS-ESI (m / z): 306 [M + 1]⁺ .Intermediate D 6- bromine -1- Tert-butyl -2- methyl -1H- Imidazo [4,5-b] Pyridine ( Intermediate D)

Intermediate D 5- bromine -3- Flupyridine -2- amine (D-1) To a solution of 3-fluoropyridine-2-amine (11.0 g, 98.0 mmol) in ACN (300 mL) at 0 ° C, NBS (8.72 g, 49.0 mmol) was added, followed by stirring at room temperature for 1 hour. NBS (8.72 g, 49.0 mmol) was added dropwise. The reaction mixture was concentrated and diluted with water (100 mL). Filter through diatomaceous earth. The filter cake was washed with water and the filtrate was concentrated to give the crude 5-bromo-3-fluoropyridine-2-amine (D-1) as the title compound. MS-ESI (m / z): 191 [M + 1]⁺ . 5- bromine -3- fluorine -2- Nitropyridine (D-2) To a mixture of 5-bromo-3-fluoropyridine-2-amine (D-1) (4.0 g, 21.0 mmol) in concentrated sulfuric acid (20 mL) at 0 ° C was added H₂ O₂ (33 mL, 29.1 mmol) of concentrated sulfuric acid (66 mL). The mixture was warmed to room temperature and stirred overnight. It was basified with dilute sodium carbonate solution to pH 7 at 0 ° C, and extracted with ethyl acetate. Organic layer with Na₂ S₂ O₃ Washed with aqueous solution and saturated brine, Na₂ SO₄ dry. Filtration and concentration, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40: 1) to give the title compound 5-bromo-3-fluoro-2-nitropyridine (D-2) . MS-ESI (m / z): 220 [M + 1]⁺ . 5- bromine -N- Tert-butyl -2- Nitropyridine -3- amine (D-3) 5-bromo-3-fluoro-2-nitropyridine (D-2) (1.63 g, 7.38 mmol), tert-butylamine (1.08 g, 14.8 mmol) and TEA (1.49 g, 14.8 mmol) in THF (30 The mixture in mL) was stirred at 45 ° C overnight. Water and ethyl acetate were added. The aqueous layer was extracted with EtOAc (3 x 30 mL). The organic layer was washed with saturated brine, Na₂ SO₄ Dry, concentrate, and purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30: 1) to obtain the title compound 5-bromo-N-tert-butyl-2-nitropyridine-3- Amine (D-3). MS-ESI (m / z): 274 [M + 1]⁺ . 5- bromine -N3- Tert-butylpyridine -2,3- Diamine (D-4) 5-bromo-N-tert-butyl-2-nitropyridine-3-amine (D-3) (1.3 g, 4.7 mmol), NH₄ A mixture of aqueous Cl (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, Na₂ SO₄ Dry and concentrate to give the title compound 5-bromo-N3-tert-butylpyridine-2,3-diamine (D-4). MS-ESI (m / z): 244 [M + 1]⁺ . 6- bromine -1- Tert-butyl -2- methyl -1H- Imidazo [4,5-b] Pyridine ( Intermediate D) 5-bromo-N3-tert-butylpyridine-2,3-diamine (D-4) (50 mg, 0.205 mmol) and Ac₂ A mixture of 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 x 30 mL). The extract was washed with water (2 × 30 mL) and saturated brine (30 mL), dried and concentrated to give the title compound 6-bromo-1-t-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- ( Tributyltin ) -2H- Pyrazolo [3,4-b] Pyridine ( Intermediate E)

Intermediate E 5- bromine -2- chlorine -N- Methoxy -N- Methyl nicotinamide (E-1) According to the synthesis method of B-1, isobutyl chloroformate was replaced with dimethylhydroxylamine hydrochloride to prepare the title compound 5-bromo-2-chloro-N-methoxy-N-methylnicotinic acid amine (E -1). MS-ESI (m / z): 279 [M + 1]⁺ . 5- bromine -2- chlorine -3- Pyridinaldehyde (E-2) To a solution of 5-bromo-2-chloro-N-methoxy-N-methylnicotinic acid amine (E-1) (11.8 g, 42 mmol) in CDM (250 mL) at -78 ° C 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 give the title compound 5-bromo-2-chloro-3-pyridinaldehyde (E-2). MS-ESI (m / z): 220 [M + 1]⁺ . 1- (5- bromine -2- Clopyridine -3- base ) -2,2- Dimethylpropane -1- alcohol (E-3) To a solution of 5-bromo-2-chloro-3-pyridinaldehyde (E-2) (2.1 g, 10 mmol) in THF (60 ml) at 0 ° C 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 give 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- bromine -2- Clopyridine -3- base ) -2,2- Dimethylpropane -1- ketone (E-4) According to the synthesis method of B-5, 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropane-1-ol (B-4) was replaced with 1- (5-bromo-2 -Chloropyridin-3-yl) -2,2-dimethylpropane-1-ol (E-3) to prepare the title compound 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropane-1-one (E-4). MS-ESI (m / z): 276 [M + 1]⁺ . 5- bromine -3- Tert-butyl -1H- Pyrazolo [3,4-b] Pyridine (E-5) According to the synthesis method of B-6, 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropane-1-one (B-5) was replaced with 1- (5-bromo-2 -Chloropyridin-3-yl) -2,2-dimethylpropane-1-one (E-4) to prepare the title compound 5-bromo-3-tert-butyl-1H-pyrazolo [3,4 -b] pyridine (E-5). MS-ESI (m / z): 254 [M + 1]⁺ . 5- bromine -3- Tert-butyl -2- methyl -2H- Pyrazolo [3,4-b] Pyridine (E-6) To a solution of 5-bromo-3-tert-butyl-1H-pyrazolo [3,4-b] pyridine (E-5) (320 mg, 1.3 mmol) in THF (10 ml) at 0 ° C Add NaH (80 mg, 60% in oil), stir for 5 minutes and add MeI (370 mg, 2.6 mmol) 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, and Na₂ SO₄ Dry and concentrate. The residue was purified by silica gel column chromatography, eluting with 10-100% ethyl acetate in hexane, to give 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- ( Tributyltin ) -2H- Pyrazolo [3,4-b] Pyridine ( Intermediate E) 5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3,4-b] pyridine (E-6) (134 mg, 0.5 mmol), (Bu₃ Sn)₂ (870 mg, 1.5 mmol), Pd (PPh₃ )₄ A mixture of (22 mg, 0.02 mmol) and TEA (150 mg, 1.5 mmol) in 1,4-dioxane (5 mL) was stirred at 80 ° C overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound 3-tert-butyl-2-methyl-5- (tributyltinyl) -2H-pyrazolo [3 , 4-b] pyridine (Intermediate E). MS-ESI (m / z): 480 [M + 1]⁺ .Examples 1 5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) -N- (5- ( Verazine -1- Methyl ) Pyridine -2- base ) Pyrimidine -2- amine (1)

Tert-butyl 4-((6- Bromopyridine -3- base ) methyl ) Verazine -1- Carboxylate (1a) To a solution of 2-bromo-5-aldehydepyridine (11.0 g, 59.1 mmol) and 1-Boc-pyrazine (10.0 g, 53.7 mmol) in DCM (100 mL) at 0 ° C was added NaBH ( OAc)₃ (13.6 g, 64.1 mmol). The mixture was warmed to room temperature and stirred overnight. DCM (100 mL) was added, then aqueous NaOH (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), Na₂ SO₄ The crude product was dried and concentrated to give the crude tert-butyl 4-((6-bromopyridin-3-yl) methyl) pyrazine-1-carboxylate (1a), which was directly used in the next reaction. MS-ESI (m / z): 356,358 [M + 1]⁺ . Tert-butyl 4-((6- Aminopyridine -3- base ) methyl ) Verazine -1- Carboxylate (1b) Under nitrogen, tert-butyl 4-((6-bromopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1a) (3.56 g, 10 mmol), Cu₂ O (0.50 g, 0.3 mmol) in NH₃ .H₂ The mixture in O (20 mL) and MeOH (20 mL) was stirred in a sealed tube at 70 ° C overnight. The mixture was cooled to room temperature, and the filtrate was concentrated after filtration. Dilute with aqueous NaOH (2 N, 50 mL) and extract with DCM (2 × 100 mL). The extract was washed with saturated brine (100 mL), Na₂ SO₄ Dry, filter, and concentrate to obtain a crude product as a yellow oil, which was purified by recrystallization of MTBE to obtain tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylate (1b). MS-ESI (m / z): 293 [M + 1]⁺ . Tert-butyl 4-((6-((5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- base ) Amino ) Pyridine -3- base ) methyl ) Verazine -1- Carboxylate (1c) 6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine (Intermediate A) (0.045 g, 0.15 mmol), tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1b) (0.055 g, 0.18 mmol), Pd₂ (dba)₃ (0.008 g, 0.015 mmol), Xantphos (0.01 g, 0.015 mmol) and Cs₂ CO₃ (0.103 g, 0.3 mmol) in a mixture of 1,4-dioxane (3 mL) was stirred at 90 ° C. for 1 hour under the protection of nitrogen. The mixture was cooled to room temperature and diluted with DCM (10 mL). Filter through diatomaceous earth. The filtrate was concentrated and the residue was purified by preparative thin layer chromatography (eluent: DCM / MeOH = 20: 1) to give 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) pyrazine-1-carboxylic acid ester (1c ). MS-ESI (m / z): 562 [M + 1]⁺ . 5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) -N- (5- ( Verazine -1- Methyl ) Pyridine -2- base ) Pyrimidine -2- amine (1) Tert-butyl 4-((6-((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidin-2- (Methyl) amino) pyridin-3-yl) methyl) pyrazine-1-carboxylate (1c) (0.03 g, 0.05 mmol) in TFA (2 mL) and DCM (4 mL) 2 hours. The solvent was spun under vacuum and the residue was diluted with water (10 mL) and washed with DCM (10 mL). The aqueous layer was adjusted to pH 11 to 12 with NaOH (2 N). Extract with IPA / DCM (25%, 4 × 20 mL). The extract was washed with saturated brine (40 mL), Na₂ SO₄ Dry and concentrate. The residue was purified by preparative thin layer chromatography (eluent: DCM / MeOH = 10: 1) to give 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5 -b] pyridine-6-yl) -N- (5- (fluorazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (1). MS-ESI (m / z): 462 [M + 1]⁺ .Examples 2 5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) -N- (5-((4- Methylpyrazine -1- base ) methyl ) Pyridine -2- base ) Pyrimidine -2- amine (2)

5-((4- Methylpyrazine -1- base ) methyl ) Pyridine -2- amine (2a) According to the synthetic method of 1b, 1-Boc-pyrazine was replaced with 1-methylpyrazine to prepare the title compound 5-((4-methylpyrazin-1-yl) methyl) pyridine-2-amine ( 2a). MS-ESI (m / z): 207 [M + 1]⁺ . 5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) -N- (5-((4- Methylpyrazine -1- base ) methyl ) Pyridine -2- base ) Pyrimidine -2- amine (2) According to the synthetic method of 1c, tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylate (1b) was replaced with 5-((4-methylpyrazine- 1-yl) methyl) pyridine-2-amine (2a) to prepare the title compound 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine -6-yl) -N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (2). MS-ESI (m / z): 476 [M + 1]⁺ .Examples 3 N- (5-((4- Ethylpyrazine -1- base ) methyl ) Pyridine -2- base ) -5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (3)

5-((4- Ethylpyrazine -1- base ) methyl ) Pyridine -2- amine (3a) According to the synthetic method of 1b, 1-Boc-pyrazine was replaced with 1-ethylpyrazine to prepare the title compound 5-((4-ethylpyrazine-1-yl) methyl) pyridine-2-amine ( 3a). MS-ESI (m / z): 221 [M + 1]⁺ . N- (5-((4- Ethylpyrazine -1- base ) methyl ) Pyridine -2- base ) -5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (3) According to the synthesis method of 1c, tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylate (1b) was replaced with 5-((4-ethylpyrazine- 1-yl) methyl) pyridin-2-amine (3a) to prepare the title compound N- (5-((4-ethylfluorazin-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). MS-ESI (m / z): 490 [M + 1]⁺ .Examples 4 (S) -5- fluorine -N- (5-(( Hexahydropyrrole [1,2-a] Pyrazine -2 (1H)- base ) methyl ) Pyridine -2- base ) -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (4)

( Tert-butoxycarbonyl ) -L- Proline (4a) (Tert-butoxycarbonyl) -L-proline (4a) was prepared according to the method described in the document Tetrahedron. 2013, 10, 156. Tert-butyl (S) -2-((2- Ethoxy -2- Oxyethyl ) Carbamate ) Pyrrolidine -1- Carboxylate (4b) To a solution of (tert-butoxycarbonyl) -L-proline (4a) (21.5 g, 100 mmol) in THF (200 mL) at 0 ° C was added CDI (17.8 g, 110 mmol) in portions. The mixture was stirred at room temperature for 0.5 hours. 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, and the residue was diluted with ethyl acetate (250 mL) and successively saturated NaHCO₃ Solution (200 mL), 10% citric acid (2 × 200 mL) and saturated brine (200 mL), Na₂ SO₄ Drying and concentration gave the title compound tert-butyl (S) -2-((2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylic acid ester (4b). (S)- Proline glycine ethyl ester Trifluoroacetate (4c) Tert-butyl (S) -2-((2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylate (4b) (24.8 g, 82.6 mmol) and TFA (100mL ) The mixture in DCM (125 mL) was stirred at room temperature for 2 hours, and concentrated to obtain the crude (S) -proline glycine ethyl trifluoroacetate (4c), which was directly used in the next reaction. MS-ESI (m / z): 201 [M + 1]⁺ . (S)- Hexahydropyrrolo [1,2-a] Pyrazine -1,4- Dione (4d) A mixture of (S) -proline glycine ethyl ester trifluoroacetate (4c) (40 g, 127 mmol) in TEA (150 mL) and MeOH (800 mL) was refluxed overnight. The solvent was spun in vacuo and the residue was diluted with IPA (100 mL). It was filtered and the filter cake was washed with n-hexane. The solid was dried under vacuum to give (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) To a suspension of LAH (5.9 g, 156 mmol) in THF (60 mL) was added (S) -hexahydropyrrolo [1,2-a] pyrazine-1,4-dione (4d) ( 4.0 g, 26 mmol) in THF (40 mL), and the mixture was refluxed for 16 hours. After the reaction mixture was cooled to 0 ° C, saturated NaHCO was added dropwise.₃ (100 mL) solution and then benzyl chloroformate (6.67 g, 39 mmol). 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), Mg₂ SO₄ dry. Concentrated and the residue was purified 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) -carboxylic acid ester (4e) (5.0 g, 19 mmol) and Pd / C (10%, 1.0 g) at The mixture in MeOH (50 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude (S) -octahydropyrrolo [1,2-a] pyrazine (4f). MS-ESI (m / z): 127 [M + 1]⁺ . (S) -2-((6- Bromopyridine -3- base ) methyl ) Octahydropyrrolo [1,2-a] Pyrazine (4g) According to the synthetic method of 1a, 1-Boc-pyrazine was replaced with (S) -octahydropyrrolo [1,2-a] pyrazine (4f) to prepare the title compound (S) -2-((6- Bromopyridin-3-yl) methyl) octahydropyrrolo [1,2-a] pyrazine (4 g). MS-ESI (m / z): 296, 298 [M + 1]⁺ . (S) -5-(( Hexahydropyrrolo [1,2-a] Pyrazine -2 (1H)- base ) methyl ) Pyridine -2- amine (4h) According to the synthesis method of 1b, tert-butyl 4-((6-bromopyridin-3-yl) methyl) pyrazine-1-carboxylate (1a) was replaced with (S) -2-((6-bromo Pyridine-3-yl) methyl) octahydropyrrolo [1,2-a] pyrazine (4g), the title compound (S) -5-((hexahydropyrrolo [1,2-a] pyridine Azine-2 (1H) -yl) methyl) pyridin-2-amine (4h). MS-ESI (m / z): 233 [M + 1]⁺ . (S) -5- fluorine -N- (5-(( Hexahydropyrrole [1,2-a] Pyrazine -2 (1H)- base ) methyl ) Pyridine -2- base ) -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (4) According to the synthesis method of 1c, tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1b) was replaced with (S) -5-((hexahydropyrrole [1,2-a] pyrazine-2 (1H) -yl) methyl) pyridine-2-amine (4h) to prepare the title compound (S) -5-fluoro-N- (5-((hexa Hydropyrrole [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]⁺ .Examples 5 (R) -5- fluorine -N- (5-(( Hexahydropyrrolo [1,2-a] Pyrazine -2 (1H)- base ) methyl ) Pyridine -2- base ) -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (5)

(R) -5-(( Hexahydropyrrolo [1,2-a] Pyrazine -2 (1H)- base ) methyl ) Pyridine -2- amine (5a) The title compound (R) -5-((hexahydropyrrolo [1,2-a] pyrazine-2) was prepared according to the 4h synthesis method by replacing the starting material L-proline with D-proline. (1H) -yl) methyl) pyridin-2-amine (5a). MS-ESI (m / z): 233 [M + 1]⁺ . (R) -5- fluorine -N- (5-(( Hexahydropyrrolo [1,2-a] Pyrazine -2 (1H)- base ) methyl ) Pyridine -2- base ) -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (5) According to the synthesis method of 1c, tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1b) was replaced with (R) -5-((hexahydropyrrole) [1,2-a] pyrazine-2 (1H) -yl) methyl) pyridin-2-amine (5a) to prepare the title compound (R) -5-fluoro-N- (5-((hexa Hydropyrrolo [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). MS-ESI (m / z): 502 [M + 1]⁺ .Examples 6 N- (5-(((1S, 4S) -2,5- Diazabicyclo [2.2.1] Heptane -2- base ) methyl ) Pyridine -2- base ) -5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (6)

Tert-butyl (1S, 4S) -5-((6- Bromopyridine -3- base ) methyl ) -2,5- Diazabicyclo [2.2.1] Heptane -2- Carboxylate (6a) To tert-butyl (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (0.099 g, 0.5 mmol), 5-bromo-2-pyridinaldehyde (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 at room temperature overnight. Saturated NaHCO₃ The solution was quenched, extracted with EtOAc, and the organic layer was washed with saturated brine (20 mL), Na₂ SO₄ dry. Concentrated to give tert-butyl (1S, 4S) -5-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (6a). MS-ESI (m / z): 368, 390 [M + 1]⁺ . Tert-butyl (1S, 4S) -5-((6- Aminopyridine -3- base ) 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-carboxylic acid ester (6a ) (180 mg, 0.49 mmol), NH3 • H₂ O (4.5 mL), Cu₂ A mixture of O (80.0 mg, 0.56 mmol) in MeOH (1.5 mL) was stirred in a sealed tube at 65 ° C overnight. After cooling to room temperature and filtering, the filtrate was concentrated under reduced pressure. The residue was distinguished between DCM and NaOH (2 N). The organic layer was separated and washed with saturated brine, Na₂ SO₄ Dried and concentrated, the residue was purified by silica gel column chromatography (eluent: DCM: MeOH = 10: 1) to give tert-butyl (1S, 4S) -5-((6-aminopyridin-3-yl) Methyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (6b) crude. MS-ESI (m / z): 305 [M + 1]⁺ . Tert-butyl (1S, 4S) -5-((6-((5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- base ) Amino ) Pyridine -3- base ) methyl ) -2,5- Diazabicyclo [2.2.1] Heptane -2- Carboxylate (6c) According to the synthesis method of 1c, tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1b) was replaced with tert-butyl (1S, 4S) -5- ((6-aminopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (6b) to prepare the title compound tert-butyl (1S , 4S) -5-((6-((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidine-2 -Yl) amino) pyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (6c). MS-ESI (m / z): 574 [M + 1]⁺ . N- (5-(((1S, 4S) -2,5- Diazabicyclo [2.2.1] Heptane -2- base ) methyl ) Pyridine -2- base ) -5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (6) According to the synthetic method of 1, tert-butyl 4-((6-((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6 -Yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1c) 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) formaldehyde ) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (6c) to prepare 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) pyrimidin-2-amine (6). MS-ESI (m / z): 474 [M + 1]⁺ .Examples 7 5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) -N- (5-(((1S, 4S) -5- methyl -2,5- Diazabicyclo [2.2.1] Heptane -2- base ) methyl ) Pyridine -2- base ) Pyrimidine -2- amine (7)

(1S, 4S) -2-((6- Bromopyridine -3- base ) methyl ) -2,5- Diazabicyclo [2.2.1] Heptane (7a) To tert-butyl (1S, 4S) -5-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane-2- at room temperature To a solution of the carboxylic acid ester (6a) (0.81 g, 2.2 mmol) in DCM (6 mL) was added TFA (4 mL). The mixture was stirred for 2 hours. With Na₂ CO₃ The solution was adjusted to pH 8. The mixture was extracted with DCM (3 × 6 mL). The extract was washed sequentially with water and saturated brine (5 mL), Na₂ SO₄ Dry and concentrate to give (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane (7a) (0.534 g) . MS-ESI (m / z): 268 [M + 1]⁺ . (1S, 4S) -2-((6- Bromopyridine -3- base ) methyl ) -5- methyl -2,5- Diazabicyclo [2.2.1] Heptane (7b) To (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane (7a) (0.15 g, 0.56 mmol) in DCM (2 mL) was added with formaldehyde (37%, 63 μL), and then 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) in that order, and₂ SO₄ dry. Filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM: MeOH = 10: 1) to give (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -5-formaldehyde. -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] Heptane -2- base ) methyl ) Pyridine -2- amine (7c) According to the synthesis method of 6b, tert-butyl (1S, 4S) -5-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane- 2-carboxylic acid ester (6a) was replaced with (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -5-methyl-2,5-diazabicyclo [2.2. 1] heptane (7b) to prepare the title compound 5-((((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) methyl ) Pyridine-2-amine (7c). MS-ESI (m / z): 219 [M + 1]⁺ . 5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) -N- (5-(((1S, 4S) -5- methyl -2,5- Diazabicyclo [2.2.1] Heptane -2- base ) methyl ) Pyridine -2- base ) Pyrimidine -2- amine (7) According to the synthesis method of 1c, replace tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1b) with 5-(((1S, 4S) -5 -Methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) methyl) pyridin-2-amine (7c) to prepare the title compound 5-fluoro-4- (1- Isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) -N- (5-((((1S, 4S) -5-methyl-2,5-di Azabicyclo [2.2.1] heptane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7). MS-ESI (m / z): 488 [M + 1]⁺ .Examples 8 N- (5-(((1S, 4S) -5- Ethyl -2,5- Diazabicyclo [2.2.1] Heptane -2- base ) methyl ) Pyridine -2- base ) -5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (8)

(1S, 4S) -2-((6- Bromopyridine -3- base ) methyl ) -5- Ethyl -2,5- Diazabicyclo [2.2.1] Heptane (8a) At room temperature, (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane (7a) (0.10 g, 0.37 mmol) and TEA (60 μL, 0.41 mmol) in DMF (1 mL) was added dropwise to the solution. The mixture was stirred for 3.5 hours. Extract with water (5 mL) and DCM (5 mL). The extract was washed sequentially with water (2 mL) and saturated brine (2 mL), and Na₂ SO₄ Dry and concentrate. The residue was purified by silica gel column chromatography (eluent: DCM: MeOH = 10: 1) to give (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -5-ethyl -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] Heptane -2- base ) methyl ) Pyridine -2- amine (8b) According to the synthesis method of 6b, tert-butyl (1S, 4S) -5-((6-bromopyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane- 2-carboxylic acid ester (6a) was replaced with (1S, 4S) -2-((6-bromopyridin-3-yl) methyl) -5-ethyl-2,5-diazabicyclo [2.2. 1] heptane (8a) to prepare the title compound 5-((((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptane-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] Heptane -2- base ) methyl ) Pyridine -2- base ) -5- fluorine -4- (1- Isopropyl -2- methyl -1H- Imidazo [4,5-b] Pyridine -6- base ) Pyrimidine -2- amine (8) According to the synthesis method of 1c, replace tert-butyl 4-((6-aminopyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (1b) with 5-(((1S, 4S) -5 -Ethyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) methyl) pyridin-2-amine (8b) to prepare the title compound N- (5-(((1S , 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-iso Propyl-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 are basically according to the same method as in Example 1-8, or using a similar synthesis strategy or method. The starting materials used are commercially available or are prepared according to literature methods and necessary. Modified and 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- ( pyrazine -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 ) pyrimidin -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) pyrazine-1-carboxylic acid esters (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 Zolo [3,4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (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) pyrazine-1-carboxylic acid ester (1c) is replaced with Butyl 4-((6-((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2- ) Amino) pyridin-3-yl) methyl) pyrazine-1-carboxylic acid ester (83a) to prepare the title compound 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyridine Zolo [3,4-b] pyridin-5-yl) -N- (5- (fluorazin-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 piperazine-l-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (84)

5-Fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5- (pyrazine) at room temperature -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 a solution of DCE (1 mL) 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, DCM and extracted. The extract was dried and concentrated Na ₂ SO _4. The residue was purified by preparative thin layer chromatography to give 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- ( 5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (84). MS-ESI (m / z): 476 [M + 1] ⁺ . Example 85 N- (5-((4 -ethylfluorazin- 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)

5-Fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5- (pyrazine) at room temperature -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 a solution of DCE (1 mL) 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, DCM and extracted. The extract was dried and concentrated Na ₂ SO _4. The residue was purified by preparative thin layer chromatography to obtain N- (5-((4-ethylfluorazin-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 piperazine-l-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (86)

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-methylpyrazin-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-methylpyrazin-1-yl) methyl) pyridin-2-yl ) Pyrimidine-2-amine (86). MS-ESI (m / z): 476 [M + 1] ⁺ . Example 87 N- (5-((4 -ethylfluorazin- 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-ethylfluorenazin-1-yl) methyl) pyridin-2-amine (3a) to prepare the title compound N- (5-((4-ethylphosphorazine -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 by using similar synthetic strategies or methods. Table 2

Cell proliferation assay 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 effect of the compound on CDK4 / 6 is determined by detecting the inhibitory effect on the proliferation of BE (2) -C cells. BE (2) -C cells were seeded at 5000 / well into a 96-well culture plate, and 150 µl of medium was added to each well. Compound Dilution: Dilute each compound to a concentration of 20 mM with DMSO as the storage solution. On the day of dosing, use the current medium to prepare a working solution with a final concentration four times. After 24 hours of BE (2) -C cell seeding, add 50 µl of compound working solution to each well (replicate wells for each compound). After 72 hours of incubation, the cell proliferation activity was determined by the MTS method. The prepared compound was 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, any simple equivalent changes and modifications made according to the scope of the patent application and the contents of the patent specification of the present invention are still Within the scope of the invention patent.

no

Claims (23)

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

(I)

(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, bis (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, ring Alkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl are unsubstituted or at least one, as 1, 2, 3 or 4, independently selected from the substituents of R ^x ; 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 groups, 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) ₂ NR ^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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or at least one, such as 1, 2, 3, or 4, independently substituted ^by a substituent 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 ring Alkyl, 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 ^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 are Unsubstituted or substituted with at least one, such as 1, 2, 3, or 4 substituents independently selected from R ^X ; 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 group 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, naphthenic , Heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with 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, hetero Cyclic, heterocyclyl-C _1-4 alkyl, 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, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or substituted respectively At least one, such as 1, 2, 3, or 4, independently selected from a substituent selected from R ^X ; each R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^B1 , R ^B2 , R ^B3, and R ^B4 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, cycloalkane Group, heterocyclyl group, aryl group and heteroaryl group are unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^X ; or each "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 together constitute 0, 1 or 2 additional independent A 4- to 12-membered heterocyclic ring selected from heteroatoms of oxygen, sulfur, nitrogen and phosphorus, 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 are} 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, _{halo, 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, heterocyclic ring Group, aryl group and heteroaryl group are unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, each independently selected from R ^Y ; each 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, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, where each alkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^Y ; or R ^a1 and R ^b1 together with the single or multiple atoms attached to them together form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be unsubstituted Substituted or substituted with 1, 2 or 3 substituents selected from R ^Y ; 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 are each Substituted or substituted with at least one, such as 1, 2, 3, or 4, independently selected from R ^Y ; or R ^c1 and R ^d1 together with the single or multiple carbon atoms attached to them together constitute 0 , 1 or 2 additional 3-12 membered heterocyclic rings independently selected from heteroatoms selected from oxygen, sulfur and nitrogen, the ring may be unsubstituted or substituted with 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, hetero Cyclic, 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 , each of which Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are 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 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, and Di (C _1-10 alkyl) amino substituent substitution; each R ^a2 and R ^{b2 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, 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, aromatic group, aryl group -C _1-4 alkyl, heteroaryl and heteroaryl -C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy Group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group are respectively 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 di (C _{1- 10} alkyl) amino substituent substitution; or R ^a2 and R ^b2 together with the single or multiple atoms attached to them together constitute 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus A 4- to 12-membered heterocyclic ring, which 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, 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 cycloalkyl, amino and di (C _1-10 alkyl) amino substituents; each R ^c2 and R ^d2 are 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, 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, where each alkyl, alkene Group, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl are unsubstituted Or be 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 cycloalkane Group, 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; or R ^c2 and R ^d2 together with the single or multiple carbon atoms attached to them constitute 0, 1 or 2 additional A heteroatom independently selected from the group consisting of oxygen, sulfur, and nitrogen 12-membered heterocyclic ring which 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, 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 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. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the chemical formula is:

(I). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the chemical formula is:

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

with

. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein each R ^{5 is} independently selected from C _1-10 alkyl, heterocyclyl, heterocyclyl-C _{1- 4} alkyl, -S (O) _r R ^A4 , -C (O) R ^A4 and -CH ₂ NR ^A4 R ^B4 , where each alkyl and heterocyclic group is unsubstituted or at least one, such as 1 , 2, 3, or 4, independently selected from substituents selected from R ^X. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein each R ^{5 is} independently selected from methyl, ethyl,

with

, Which is unsubstituted or substituted with at least one, such as 1, 2, 3, or 4 substituents independently selected from R ^X. The compound or pharmaceutically acceptable salt thereof according to claim 6, 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 Self-heterocyclyl and heterocyclyl-C _1-4 alkyl, wherein each alkyl and heterocyclyl is unsubstituted or at least one, such as 1, 2, 3 or 4, independently selected from R ^X And each R ^{B4 is} independently selected from C _1-10 alkyl. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein each R ^{5 is} independently selected from S (O) ₂ R ^A4 and -C (O) R ^A4 , wherein each R ^{4 is} independently selected from

with

, Which is unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, a substituent independently selected from R ^X , and each R ^B4 is a methyl group. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein each R ^{5 is} independently selected from -CH ₂ NR ^A4 R ^B4 , wherein each R ^A4 is

Is unsubstituted or substituted with at least one, such as 1, 2, 3, or 4, substituents independently selected from R ^X , and each R ^B4 is methyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 10, wherein each R ^{X is} independently selected from methyl, ethyl, methoxymethyl, cyanoethyl, and oxa Cyclobutane-3-yl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein m is 1. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ¹ is hydrogen. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R ² is hydrogen. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein each R ^{3 is} independently selected from a C _1-10 alkyl group. The compound or pharmaceutically acceptable salt thereof according to claim 15, 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 16, wherein p is 2. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein each R ⁴ is a halogen. The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein each R ^{4 is} independently selected from fluorine and chlorine. A compound selected from 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, 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6 -Yl) -N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((4-ethylpyrazine -1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) Pyrimidine-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] heptane 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-(( (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) methyl) pyridin-2-yl) pyrimidine- 2-amine, N- (5-(((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) methyl) pyridine-2- ) -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) 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) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazole Benzo [4,5-b] pyridine-6-yl) pyrimidin-2-amine, 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine -6-yl) -N- (5-((8-methyl-3,8-diazabicyclo [3.2.1] octane-3-yl) methyl) pyridin-2-yl) pyrimidine- 2-amine, N- (5-((8-ethyl-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-N- (5- ( (Hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [ 4,5-b] pyridine-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] nonane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((7-ethyl-2 , 7-azaspiro [3.5] nonane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4 , 5-b] pyridine-6-yl) pyrimidin-2-amine, N- (5-((2,6-azaspiro [3.3] heptan-2-yl) formaldehyde ) 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] heptane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((6-ethyl-2,6-azaspiro [3.3 ] Heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6 -Yl) pyrimidin-2-amine, N- (5-((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, 5-fluoro-4- (1-isopropyl-2- Methyl-1H-imidazo [4,5-b] pyridin-6-yl) -N- (5-((9-methyl-3,9-azaspiro [5.5] undecane-3-yl ) Methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((9-ethyl-3,9-azaspiro [5.5] undec-3-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-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] pyridine-6- ) 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) (fluorazin-1-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) (4-methylpyrazin-1-yl) methanone, (4-ethylpyrazine-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] octane-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-imidazo [4,5-b] pyridin-6-yl) pyrimid Pyridin-2-yl) amino) pyridin-3-yl) methanone, (6-((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] Pyridine-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (2,7-azaspiro [3.5] nonane-2-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) (7-form -2,7-azaspiro [3.5] nonane-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) pyrimidin-2-yl) amino) pyridin-3-yl) formaldehyde Ketone, (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) -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, 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] Pyridin-6-yl) -N- (5- (fluorazin-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-methylpyrazin-1-yl) sulfonyl) pyridin-2-yl) pyrimidine -2-amine, N- (5-((4-ethylfluorazin-1-yl) sulfofluorenyl) 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) sulfofluorenyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidine -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) sulfofluorenyl) 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) sulfofluorenyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidine- 2-amine, 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6- ) -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) pyrimidin-2-amine, N- (5-((2,7-azaspiro [3.5] non Alk-2-yl) sulfofluorenyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine-6- ) 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] nonan-2-yl) sulfofluorenyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazole Benzo [4,5-b] pyridine-6-yl) pyrimidin-2-amine, 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridine -6-yl) -N- (5-((4- (oxetan-3-yl) pyrazin-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) pyrazin-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-((2-methyl-4- (oxa Cyclobutane-3-yl) pyrazin-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) pyrazine-1- (Methyl) pyridin-2-yl) pyrimidin-2-amine, (S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] Pyridine-6-yl) -N- (5-((3-methyl-4- (oxetan-3-yl) pyrazin-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 -(Oxetane-3-yl) pyrazin-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) ) Pyrazine-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b) pyridine-6-yl) -5-fluoro-N- (5-((2-methyl-4- (oxetan-3-yl) pyrazin-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) pyrazin-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- (oxy Heterobutane-3-yl) pyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazole Benzo [4,5-b] pyridine-6-yl) -5-fluoro-N- (5- (pyrazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1 -(Tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) -5-fluoro-N- (5-((4-methylpyrazine-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-ethylpyrazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine, N- (5-((3,8-bis Azabicyclo [3.2.1] octane-8-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5 -b] pyridine-6-yl) -5-fluoropyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridine-6- ) -5-fluoro-N- (5-((3-methyl-3,8-diazabicyclo [3.2.1] octane-8-yl) methyl) pyridin-2-yl) pyrimidine -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) pyrazine- 1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] Pyridine-6-yl) -5-fluoro-N- (5-((3- (methoxymethyl) -4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidine- 2-amine, (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) -N- (5-((4 -Ethyl-3- (methoxymethyl) pyrazin-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] pyridine-6-yl) -5-fluoropyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridine-6 -Yl) -5-fluoro-N- (5-((8-methyl-3,8-diazabicyclo [3.2.1] octane-3-yl) methyl) pyridin-2-yl) Pyrimidine-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) pyridin-2-yl) -5-fluoropyrimidin-2-amine, 4- (1- (tertiary ) -2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) -5-fluoro-N- (5- (1- (fluorazin-1-yl) ethyl) pyridine 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-methylpyrazin-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-ethylpyrazin-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- (Xazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine, 4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b] pyridine -6-yl) -5-chloro-N- (5-((4-methylpyrazin-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-ethylpyrazin-1-yl) methyl Yl) pyridin-2-yl) pyrimidin-2-amine, 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5- (fluorazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine, 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazole Benzo [3,4-b] pyridin-5-yl) -N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5- ((4-ethylfluorazin-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-pyrazolo [3,4-b] pyridin-5-yl ) -N- (5-((4-methylpyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5-((4-ethylpyrazine-1 -Yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidine -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) pyrimidine -2-amine, N- (5-((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, 5-fluoro-4- (3-isopropyl-2- A -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) pyrimidine- 2-amine, (R) -5-fluoro-N- (5-((hexahydropyrrolo [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, N- (5-((2,7-nitrogen Heterospiro [3.5] nonane-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-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) methyl) pyridin-2-yl) pyrimidin-2-amine, N- (5- ((7-ethyl-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) pyrimidin-2-amine, 5-fluoro-N- (5-((hexahydropyrrolo [3,4-c] pyrrole- 2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidine -2- , 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5-((5-methylhexa Hydropyrrolo [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] pyridin-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) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidine -2-amine, N- (5-((3,9-azaspiro [5.5] undec-3-yl) methyl) 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-((9-methyl-3,9-azaspiro [5.5] undec-3-yl) methyl base) Pyridin-2-yl) pyrimidin-2-amine, N- (5-((9-ethyl-3,9-azaspiro [5.5] undec-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 ) Pyrazine-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) pyrazin-1-yl) methyl) pyridine 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- (oxetan-3-yl) pyrazin-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 Methyl-4- (oxetan-3-yl) fluorazin-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-((3-methyl-4- (oxetane-3 -Yl) pyrazin-1-yl) methyl) pyridin-2-yl) pyrimidin-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) (pyrazin-1-yl) methanone, (6-((5-fluoro-4- (3-iso Propyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methylpyrazine-1- Methyl) methanone, (4-ethylpyrazin-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) pyridine-3- Methyl) 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- Methyl) methanone, (6-((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazole) Benzo [3,4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (8-methyl-3,8-diazabicyclo [3.2.1] octane -3-yl) methanone, (8-ethyl-3,8-diazabicyclo [3.2.1] octan-3-yl) (6-((5-fluoro-4- (3-iso Propyl-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) methanone, (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] nonane-2-yl) methanone, (7-ethyl-2,7-azaspiro [3.5] nonane-2-yl) (6-((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazole Benzo [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) (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] octane-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) pyridine) -2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) pyrimidin-2-amine, N- (5-((2,7-Azaspiro [3.5] nonane-2-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-((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- (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 -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) 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) pyrazin-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-methylpyrazin-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-ethylpyrazin-1-yl) (Methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine, (R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] Py Pyridin-5-yl) -5-fluoro-N- (5-((methyl ((1-methylpyrrole-2-yl) methyl) amino) methyl) pyridin-2-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, N- (5-((3,8-di Azabicyclo [3.2.1] octane-8-yl) methyl) pyridin-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] pyridine- 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- (methoxy (Methyl) pyrazine-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, (S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -5-fluoro-N- (5-((3- (methoxymethyl) -4-methylpyrazin-1-yl) methyl) pyridine -2-yl) pyrimidine -2-amine, (S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5- ( (4-ethyl-3- (methoxymethyl) pyrazin-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] 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-((((1R, 5S) -8-methyl-3,8-diazabicyclo [3.2.1] Octyl-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine, 4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] Pyridine-5-yl) -N- (5-((((1R, 5S) -8-ethyl-3,8-diazabicyclo [3.2.1] octane-3-yl) methyl) pyridine 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- (fluorazin-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-methylpyrazin-1-yl) ethyl) pyridine-2 -Yl) pyrimidin-2-amine, 4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -N- (5- ( 1- (4-ethylpyrazin-1-yl) ethyl) pyridine 2-yl) -5-fluoropyrimidin-2-amine, N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridine-5- ) -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- (morpholinmethyl) 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- ) Amino) pyridin-3-yl) methyl) pyrazin-1-yl) propionitrile, N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b) pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (pyridin-4-yl) -5,6,7,8-tetrahydro-1,6-naphthyridine- 2-amine, N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl ) -6- (1-methylpyridin-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- ) -6- (1-ethyl-piperidin-4-yl) -5,6,7,8-tetrahydro-2-amine, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A method for ameliorating or preventing a condition responsive to the inhibition of CDK4 / 6, comprising administering to a patient in need thereof an effective amount of a compound described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof Optionally in combination with a second therapeutic agent. A use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell proliferation disorder.