TW202028199A - Naphthyridinone and pyridopyrimidinone compounds useful as kinases inhibitors - Google Patents

Abstract

Provided are certain PDGFR inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Description

Naphthyridone and pyridylpyrimidinone compounds as protein kinase inhibitors

This application claims priority from U.S. Provisional Application 62/738,497, the entire content of which is incorporated into this application by reference in its entirety.

The present invention relates to a new class of compounds that can inhibit protein kinases or pharmaceutically acceptable salts thereof, which can be used as drugs to treat hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases.

Hyperproliferative diseases such as cancer and inflammation attract the academic community to provide effective treatments for them. And in this regard, efforts have been made to identify and target specific mechanisms that play a role in proliferative diseases.

Many members of the protein kinase family play important roles in the coordination of various cellular processes and functions. Abnormal activation of kinases has been reported to cause or promote a variety of proliferative diseases, such as cancer, rheumatoid arthritis, atherosclerosis and retinopathy. Therefore, kinase has become a key therapeutic target. Important examples of kinases involved in or contributing to the pathogenesis of proliferative diseases include, but are not limited to: PDGFR, c-KIT, c-MET, RET, AXL, MERTK, TYRO3, TRKA/B/C, EGFR, FGFR and FLT-3. The activation of these kinases is mainly carried out through the downstream Ras/Raf/MEK/ERK signaling pathway. In the present invention, a new compound with inhibitory activity of one or more protein kinases will be a successful treatment plan for patients with abnormally activated kinases.

Therefore, compounds with protein kinase inhibitory activity are of great significance for the prevention and treatment of cancer. Although PDGFR inhibitors have been reported in the literature, such as WO1999028304 and WO2001083450, many of them have short half-lives or are toxic. Therefore, there is still an urgent need for novel PDGFR inhibitors, which have advantages in at least one aspect of efficacy, stability, selectivity, safety and pharmacodynamic characteristics in the treatment of abnormal proliferative diseases. Based on this, the present invention proposes a new class of PDGFR inhibitors.

Summary of the invention

The present invention designs a class of novel compounds, their pharmaceutically acceptable salts and their pharmaceutical compositions, and their applications as medicines.

(I) 或其藥學上可接受的鹽，其中： Z選自CR^X 和N； L選自-NR^A C(O)、-C(O)NR^A 、-NR^A C(O)NR^B 和-NR^A SO₂ ； R¹ 是-NR^A1 R^B1 ； R² 選自氫、鹵素、CN、C_1-10 烷基、C_3-10 環烷基和C_3-10 環烷基-C_1-4 烷基、C_2-10 烯基、C_2-10 炔基，其中每個烷基、環烷基、烯基和炔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 獨立選自鹵素、CN和C_1-10 烷基，其中烷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； R⁴ 選自芳基和雜芳基，其中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； R⁵ 選自氫、鹵素、CN、C_1-10 烷基、C_3-10 環烷基和C_3-10 環烷基-C_1-4 烷基、C_2-10 烯基、C_2-10 炔基，其中每個烷基、環烷基、烯基和炔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； R^A 和R^B 分別獨立選自氫和C_1-10 烷基，其中烷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； R^A1 和R^B1 分別獨立選自氫、C_1-10 烷基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、-C(O)R^A2 、-C(O)OR^A2 、-C(O)NR^A2 R^B2 、-S(O)_r R^A2 和-S(O)_r NR^A2 R^B2 ，其中每個烷基和環烷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； 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一個含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12員雜環，該環可以是未被取代的或被1、2或3個選自R^X 的取代基取代； 每個R^A2 和R^B2 獨立選自氫、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^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一個含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12員雜環，該環可以是未被取代的或被1、2或3個選自R^X 的取代基取代； 每個R^X 獨立選自氫、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、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 C(O)R^a1 、-(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(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 C(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )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 C(O)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(S)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t S(O)_r 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 S(O)₂ OR^b1 、-(CR^c1 R^d1 )_t OS(O)₂ R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)_r R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )R^b1 、-(CR^c1 R^d1 )_t S(O)_r NR^a1 R^b1 、-(CR^c1 R^d1 )_t S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)₂ NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t P(O)R^a1 R^b1 和-(CR^c1 R^d1 )_t P(O)(OR^a1 )(OR^b1 )，其中每個烷基、烯基、炔基、環烷基、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^Y 的取代基取代； 每個R^a1 和R^b1 獨立選自氫、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； 或每個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一個含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12員雜環，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； 或每個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一個含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12員環，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^e1 獨立選自氫，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 C(O)R^a2 、-(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(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 C(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(=NR^e2 )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 NR^a2 C(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)_r 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 S(O)₂ OR^b2 、-(CR^c2 R^d2 )_t OS(O)₂ R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)_r R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )R^b2 、-(CR^c2 R^d2 )_t S(O)_r NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)₂ NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t P(O)R^a2 R^b2 和-(CR^c2 R^d2 )_t P(O)(OR^a2 )(OR^b2 )，其中每個烷基，烯基，炔基，環烷基，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，獨立選自羥基，CN，胺基，鹵素，C_1-10 烷基，C_2-10 烯基，C_2-10 炔基，C_3-10 環烷基，C_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 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 每個R^a2 和每個R^b2 獨立選自氫，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 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基，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，烷胺基，環烷胺基，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 或每個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一個含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12員雜環，該環可以是未被取代的或被1或2個選自鹵素，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 每個R^c2 和R^d2 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，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 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基，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，烷胺基，環烷胺基，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 或每個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一個含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12員環，該環可以是未被取代的或被1或2個選自鹵素，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 每個R^e2 獨立選自氫，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； 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):

(I) or a pharmaceutically acceptable salt thereof, wherein: Z is selected from CR ^X and N; L is selected from -NR ^A C(O), -C(O)NR ^A , -NR ^A C(O)NR ^B And -NR ^A SO ₂ ; R ¹ is -NR ^A1 R ^B1 ; R ^{2 is} selected from hydrogen, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and C _3-10 cycloalkyl-C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein each of the alkyl, cycloalkyl, alkenyl and alkynyl groups is unsubstituted or has at least one, such as 1, 2 , 3 or 4, independently selected from R ^X substituents; each R ^{3 is} independently selected from halogen, CN and C _1-10 alkyl, wherein the alkyl is unsubstituted or is substituted by at least one, such as 1, 2, 3 or 4, independently substituted by substituents selected from R ^X ; R ^{4 is} selected from aryl and heteroaryl, wherein aryl and heteroaryl are respectively unsubstituted or at least one, such as 1, 2 , 3 or 4 substituents independently selected from R ^X ; R ^{5 is} selected from hydrogen, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and C _3-10 cycloalkyl-C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein each of alkyl, cycloalkyl, alkenyl and alkynyl is unsubstituted or has at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; R ^A and R ^B are independently selected from hydrogen and C _1-10 alkyl, wherein the alkyl is unsubstituted or is substituted by at least one, such as 1, 2 , 3 or 4 substituents independently selected from R ^X ; R ^A1 and R ^B1 are independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, -C(O)R ^A2 , -C(O)OR ^A2 , -C(O)NR ^A2 R ^B2 , -S(O) _r R ^A2 and -S(O) _r NR ^A2 R ^B2 , wherein each alkyl group and cycloalkyl group are unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents; or R ^A1 and R ^B1 together together The single or multiple atoms connected to them together form a 4-12 member heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be unsubstituted Or substituted by 1, 2 or 3 substituents selected from R ^X ; each R ^A2 and R ^{B2 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, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or is at least One, such as 1, 2, 3 or 4, independently selected from the substituents of R ^X ; or each R ^A2 and R ^B2 together with the single or multiple atoms connected to them form a 4-12 member heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. May be unsubstituted or substituted by 1, 2 or 3 substituents selected from R ^X ; each R ^{X 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, _{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 C(O)R ^a1 , -(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(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 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 ) 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 C(O )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r 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 S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 And -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is not Substituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y ; each R ^a1 and R ^{b1 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 Group, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y ; or each of R ^a1 and R ^b1 together with one or more of their connected Atoms 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 or be 1, 2, or 3 One substituent 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 ring Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and Heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is unsubstituted or is substituted by at least one, such as 1, 2, 3 or 4 substituents independently selected from R ^Y ; or each of R ^c1 and R ^d1 together with the single or multiple carbon atoms connected to them form a group containing 0, 1 or 2 independently selected from A 3-12 membered ring of heteroatoms of oxygen, sulfur and nitrogen, the ring may be unsubstituted or substituted with 1, 2 or 3 substituents selected from R ^Y ; 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 ring Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, halogen, CN, NO ₂ , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t C(O)R ^a2 ,- (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(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 C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )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 NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r 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 S(O) ₂ OR ^b2 , -(CR ^c2 R ^d2 ) _t OS(O) ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)( =NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P (O) R ^a2 R ^b2 and -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are unsubstituted or have at least one, such as 1, 2, 3 or 4, independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino group, C _3-10 cycloalkylamino group, substitution of di(C _1-10 alkyl)amino group; each R ^a2 and each R ^{b2 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, C _1-10 alkoxy, C _3-10 cycloalkyloxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl ) Amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which Alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl Is unsubstituted or by at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkane Amino group, C _3-10 cycloalkylamino group, substitution of di(C _1-10 alkyl)amino group; or each of R ^a2 and R ^b2 together with the single or multiple atoms connected to them form one 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 or 1 or 2 selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1 -10} Alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino, substituent substitution of di(C _1-10 alkyl)amino group ; Each of 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} cycloalkyloxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl) Amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl Group, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are Unsubstituted or by at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamine Group, C _3-10 cycloalkylamino group, bis(C _1-10 alkyl)amino group substitution; or each of R ^c2 and R ^d2 together with the single or multiple carbon atoms connected to them form one A 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be unsubstituted or 1 or 2 selected from halogen, CN, C _1-10 alkane Group, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio , C _3-10 cycloalkylthio group, amino group, C _1-10 cycloalkylamino group, C _3-10 cycloalkylamino group, substituent substitution of di(C _1-10 alkyl)amino group; each R ^e2 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; 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 a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

On the other hand, the present invention provides a method for regulating protein kinase, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition to a system or individual in need, thereby regulating protein kinase.

The present invention also provides a method for treating, ameliorating or preventing a disease that responds to inhibition of protein kinase, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a system or individual in need thereof, Or use it in combination with another therapeutic drug to treat the above symptoms.

Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating protein kinase-mediated disorders. In certain embodiments, the compound can be used alone or in combination with another therapeutic agent to treat protein kinase-mediated disorders.

Alternatively, the present invention provides compounds of formula (I) for use in the treatment of protein kinase-mediated disorders.

Particularly, the disorder includes, but is not limited to, autoimmune diseases, transplantation diseases, infectious diseases, or cell proliferation disorders.

In addition, the present invention provides a method for treating cell proliferative disorders, the method comprising administering to a system or individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, or with another Combined use of therapeutic drugs to treat the above-mentioned diseases.

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

Particularly, the condition includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or breast, kidney, prostate, colorectal, thyroid, ovarian, pancreas, neuron, lung, uterine or gastrointestinal tumors.

In the above method of using the compound of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt can be administered to a system composed of cells or tissues, or to individuals including mammalian individuals, such as humans or animals. the term

Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by professionals in the field. Unless otherwise specified, all patents, patent applications, and publicly disclosed materials referred to in this patent are incorporated in the reference in their entirety. If there are multiple definitions of the same term in this patent, the definition in this section shall prevail.

It should be understood that the general description above and the detailed description below are only explanatory and have no limitation on the scope of any patent application. In this patent application, the use of the singular includes the plural unless otherwise specified. It should be noted that in the specification and the scope of the attached patent application, the singular form refers to such as "a", "an", "this", including plural designations, unless otherwise specified in the context. It should also be noted that "or" means "and/or" unless otherwise stated. In addition, "including", "including" and similar terms are not restrictive.

Unless otherwise specified, the mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy and conventional pharmacological techniques used in this patent are prior art. Unless specifically defined, the naming, experimental methods and techniques involved in analytical chemistry, synthetic organic chemistry, medicine and pharmaceutical chemistry in this patent are all known. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and administration, and treatment of patients. The reaction and purification techniques can be implemented by referring to the manufacturer's instructions, or referring to known common techniques, or referring to the methods described in this patent. The above-mentioned techniques and operations can be implemented using known conventional methods and the methods cited in this specification. In the specification, the groups and substituents can be selected by professionals in the field to form stable structures and compounds.

When a chemical formula is used to refer to a substituent, writing the substituent in the chemical formula from left to right is the same as writing from right to left. For example, CH ₂ O is the same as OCH ₂ .

"Substitution" means that the hydrogen atom is replaced by a substituent. It should be noted that the substituents on specific atoms are limited by their valence.

The term "C _ij "or "ij member" as used herein means that the moiety has ij carbon atoms or ij atoms. For example, "C _1-6 alkyl" means that the alkyl group has 1 to 6 carbon atoms. Likewise, C _3-10 cycloalkyl means that the cycloalkyl has 3-10 carbon atoms.

When any variable (such as R) appears in the structure of a compound more than once, it is defined independently in each case. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has an independent choice in each case. In addition, combinations of substituents and/or variants thereof are only allowed if such combinations will result in stable compounds.

"One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

Unless otherwise specified, the term "hetero" refers to heteroatoms or heteroatom groups (ie, groups containing heteroatoms), that is, atoms other than carbon and hydrogen atoms or groups containing these atoms. Preferably, the heteroatoms are independently selected from O, N, S, P and the like. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially or completely different.

"Alkyl", whether used alone or in combination with other terms, refers to a branched or straight chain saturated aliphatic hydrocarbon group with a specific number of carbon atoms. Unless otherwise specified, "alkyl" refers to C ₁ - ₁₀ alkyl. For example, "C ₁ - ₆ alkyl""C ₁ - _6" means having 5 or 6 carbon atoms, or a linear group branched arrangement. For example, "C ₁ - ₈ alkyl" includes but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl .

"Cycloalkyl", whether used alone or in combination with other terms, refers to a monocyclic or bridged saturated hydrocarbon ring system. Monocyclic cycloalkyl is a monocyclic hydrocarbon system containing 3-10 carbon atoms, no heteroatoms, and no double bonds. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged cycloalkyl is a polycyclic ring system containing 3-10 carbon atoms, which contains one or two alkylene bridges, and each alkylene bridge consists of 1, 2 or 3 carbon atoms, which are connected to the ring system Two non-adjacent carbon atoms. Cycloalkyl groups may be fused with aryl or heteroaryl groups. In some embodiments, the cycloalkyl group is benzo-fused. Representative examples of bridged cycloalkane systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, Bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic and bridged hydrocarbon rings can be connected to the parent molecular moiety through any substitutable atom in the ring system.

"Alkenyl", whether used alone or in combination with other terms, refers to a non-aromatic linear, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, there is 1 carbon-carbon double bond, and up to 4 non-aromatic carbon-carbon double bonds may exist. Thus, "C _{2 - 6} alkenyl" means an alkenyl group containing 2-6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The linear, branched or cyclic part of the alkenyl group may contain a double bond, and if a substituted alkenyl group is indicated, it may be substituted.

"Alkynyl", whether used alone or in combination with other terms, refers to a linear, branched or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there may be up to 3 carbon-carbon triple bonds. Thus, "C ₂ - ₆ alkynyl" means 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 a substituted alkynyl group is indicated, it means 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 as defined above connected to an oxygen atom by a single bond. The alkoxy group is connected to the molecule through an oxygen atom. Alkoxy can be represented as -O-alkyl. The "C _1-10 alkoxy group" refers to an alkoxy group containing 1-10 carbon atoms, which may be a straight chain or branched structure. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, and the like.

"Cycloalkoxy", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to an oxygen atom by a single bond. The cycloalkoxy group is connected to the molecule through an oxygen atom. Cycloalkoxy can be represented as -O-cycloalkyl. The "C _3-10 cycloalkoxy group" refers to a cycloalkoxy group containing 3-10 carbon atoms. The cycloalkoxy group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkoxy group is benzo-fused. 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 as defined above connected to a sulfur atom by a single bond. The alkylthio group is connected to the molecule through a sulfur atom. Alkylthio can be represented as -S-alkyl. The "C _1-10 alkylthio group" refers to an alkylthio group containing 1-10 carbon atoms, which may be a straight chain or branched structure. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio and the like.

"Cycloalkylthio", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a sulfur atom by a single bond. The cycloalkylthio group is connected to the molecule through a sulfur atom. Cycloalkylthio can be represented as -S-cycloalkyl. The "C _3-10 cycloalkylthio group" refers to a cycloalkylthio group containing 3-10 carbon atoms. The cycloalkylthio group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. Cycloalkylthio includes, but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio and the like.

"Alkylamino", used alone or in combination with other terms, refers to an alkyl group as defined above connected to a nitrogen atom by a single bond. The alkylamino group is connected to another molecule through a nitrogen atom. The alkylamino group can be represented as -NH (alkyl). The "C _1-10 alkylamino group" refers to an alkylamino group containing 1-10 carbon atoms, which may be a straight chain or branched structure. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino groups.

"Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a nitrogen atom by a single bond. The cycloalkylamino group is connected to another molecule through a nitrogen atom. The cycloalkylamino group can be represented as -NH (cycloalkyl). The "C _3-10 cycloalkylamino group" refers to a cycloalkylamino group containing 3-10 carbon atoms. The cycloalkylamino group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylamino group is benzo-fused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, and cyclohexylamino groups.

"Di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl groups as defined above connected by a single bond to a nitrogen atom. The di(alkyl)amino group is connected to the molecule through a nitrogen atom. The di(alkyl)amino group can be represented as -N(alkyl) ₂ . "Two (C _1-10 alkyl) amino" refers to a group, it may be straight-chain or branched alkyl moiety contains two two structures (C _1-10 alkyl) of 1 to 10 carbon atoms, respectively.

"Aryl", used alone or in combination with other terms, refers to those having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C _6-14 aryl" group) A monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system, especially a ring with 6 carbon atoms ("C ₆ aryl" group), such as phenyl; or a ring with 10 carbon atoms ("C ₁₀ An aryl group), such as naphthyl; or a ring having 14 carbon atoms (a “C ₁₄ aryl” group), such as anthryl. The aryl group may be fused with a cycloalkyl group or a heterocyclic group.

A divalent group formed by a substituted benzene derivative with free valence electrons on the ring atom is named a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with "- group", which is obtained by removing a hydrogen atom from a carbon atom containing free valence electrons, and its name is in the monovalent group Add "-idene" to the name. For example, a naphthyl group with two attachment sites is called a naphthylene group.

"Heteroaryl", used alone or in combination with other terms, means having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms ("5 to 14 membered heteroaryl" Group) is a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system, especially 5 or 6 or 9 or 10 atoms, and contains at least one heteroatom which may be the same or different, and the heteroatom is selected from N, O and S. Heteroaryl groups may be fused with cycloalkyl or heterocyclic groups. In some embodiments, "heteroaryl" refers to A 5-membered to 8-membered aromatic monocyclic ring, which 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; with 8-membered to -12-membered bicyclic ring containing heteroatoms selected from the group consisting of N, O and S, the number is 1 to 6, in some embodiments 1 to 4, or in some embodiments 1 to 3 heteroatoms, the rest are carbon atoms, and at least one of them is present in the aromatic ring; and An 11-member to 14-member tricyclic ring, the ring contains one selected from N, O, and S, and the number is 1 to 8, in some embodiments, the number is 1 to 6, or in some embodiments, the number There are 1 to 4, or in some embodiments, 1 to 3 heteroatoms, and the rest are carbon atoms.

When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl group is not more than two. In some embodiments, the total number of S and O in the heteroaryl group is not greater than one.

Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl , 6-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, Pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, furyl.

Further, heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolyl and isoquinolyl. "Heteroaryl" includes any N-oxide derivative of nitrogen-containing heteroaryl.

The name of the monovalent heteroaryl group ends with "- group". The derived divalent group is obtained by removing a hydrogen atom from the carbon atom containing free valence electrons. The nomenclature is based on the name of the monovalent group plus "-idene". For example, a pyridyl group with two attachment points is called a pyridyl group.

"Heterocycle" (and such as "heterocyclic" or "heterocyclic group" derived therefrom) generally refers to a saturated or non-containing, monocyclic or polycyclic (e.g., bicyclic) cyclic aliphatic hydrocarbon system, usually 3 Up to 12 ring atoms, including at least one (eg, 2, 3 or 4) heteroatoms (preferably oxygen, sulfur, nitrogen) independently selected from oxygen, sulfur, nitrogen and phosphorus. In a polycyclic system, two or more rings can be connected by fusion, bridge or spiro ring, and heterocycle can be fused with aryl or heteroaryl. In some embodiments, the heterocyclic ring is benzo-fused. Heterocycles also include ring systems substituted with one or more oxo or imino moieties. In some embodiments, the C, N, S, and P atoms in the heterocyclic ring are optionally substituted by oxo. In some embodiments, the C, S, and P atoms in the heterocyclic ring are optionally substituted with imino groups, and the imino groups may be unsubstituted or substituted. Either a carbon atom or a heteroatom on the heterocyclic ring can be the attachment site, provided that a stable structure is formed. When there is a substituent on the heterocyclic ring, the substituent can be connected to any heteroatom or carbon atom on the heterocyclic ring, provided that a stable chemical structure is formed.

和

。Suitable heterocycles include, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, 4-imidazolidinyl, 5 -Imidazolidinyl, 1-pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 1-piperidinyl, 2-piperidine Group, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 1-hexahydropyridazinyl, 3-hexahydropyridazinyl and 4- Hexahydropyridazinyl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl and 1,1- Dioxo-thiomorpholinyl. Bicyclic heterocycles include but are not limited to:

with

.

"Aryl-alkyl" as used herein refers to an alkyl group as defined above substituted with an aryl group as defined above. Exemplary aralkyl groups include but are not limited to benzyl, phenethyl, naphthylmethyl and the like. In some implementations, the aralkyl group contains 7-20 or 7-11 carbon atoms. When "aryl C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms of the alkyl moiety rather than the aryl moiety.

As used herein, "heterocyclyl-alkyl" refers to a heterocyclic group as defined above substituted with an alkyl group as defined above. When "heterocyclyl C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms of the alkyl moiety rather than the heterocyclic moiety.

"Cycloalkyl-alkyl" as used herein refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. When "C _3-10 cycloalkyl-C _1-4 alkyl" is used, "C _3-10 " refers to the number of carbon atoms of the cycloalkyl moiety rather than the alkyl moiety. Wherein "C _1-4 "refers to the number of carbon atoms of the alkyl moiety rather than the cycloalkyl moiety.

As used herein, "heteroaryl-alkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. When "heteroaryl-C _1-4 alkyl" is used, "C _1-4 " refers to the number of carbon atoms of the alkyl moiety rather than the heteroaryl moiety.

To avoid ambiguity, for example: when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl, and/or heteroaryl substitutions, it means that each of these groups is substituted individually, or Refers to the mixed substitution of these groups. That is: if R is an aryl-C _1-4 alkyl group, and may be unsubstituted or substituted by at least one substituent, such as 1, 2, 3, or 4 substituents independently selected from R ^X , It should be understood that the aryl moiety may be unsubstituted or substituted by at least one, such as 1, 2, 3 or 4 substituents independently selected from R ^X , and the alkyl moiety may also be unsubstituted or substituted by at least one, Such as 1, 2, 3 or 4 substituents independently selected from R ^X.

"Pharmaceutically acceptable salt" refers to a salt made with a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Further, the salt of a pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. There may be one or more crystal forms or polymorphs in the solid salt, and there may also be solvates, such as hydrates. The salt of the pharmaceutically acceptable organic non-toxic base can be selected from, for example: primary amine, secondary amine and tertiary amine salt. Substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as arginine, beet Alkali, caffeine, choline, N,N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -ethyl Morpholine, N -ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin , Procaine, Purine, Theobromine, Triethylamine, Trimethylamine, Tripropylamine, Tromethamine.

When the compound referred to in this patent is a base, its salt needs to be prepared with at least one pharmaceutically acceptable non-toxic acid, and these acids are selected from inorganic acids and organic acids. For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamine acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, horse Lyric acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid. In some embodiments, these acids can be selected, for example: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, tartaric acid.

The "administration" or "administration" of a compound or a pharmaceutically acceptable salt thereof refers to providing the compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

"Effective amount" refers to the dose of a compound or a pharmaceutically acceptable salt thereof that can cause a biological or medical response in tissues, systems, animals or humans that can be observed by researchers, veterinarians, clinicians or other clinical personnel.

"Composition" includes: products containing specific amounts of specific ingredients, and any product that directly or indirectly combines these specific amounts of specific ingredients. A pharmaceutical composition includes: a product containing an active ingredient and an inert ingredient as a carrier, and any two or more ingredients directly or indirectly, a product made through combination, compounding or aggregation, or through one or more Products produced by the decomposition of the components, or products produced by other types of reactions or interactions of one or more components.

"Pharmaceutically acceptable" means that it is compatible with other components in the formulation and does not have unacceptable toxicity to the user.

"Individual" refers to individuals suffering from diseases, disorders, and the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits and dogs And cats; experimental animals include rodents such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.

"Treatment" includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, improvement or prevention of underlying metabolic factors of symptoms, inhibition of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, promoting alleviation of diseases or symptoms, Or stop the symptoms of diseases or symptoms and extend to include prevention. "Treatment" also includes achieving therapeutic benefits and/or preventive benefits. Therapeutic benefit refers to eradicating or improving the condition being treated. In addition, the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease. Although the patient may still have the underlying disease, the improvement of the patient's disease can be observed. Preventive benefit refers to the use of the composition to prevent the risk of a certain disease, or when the patient has one or more physiological conditions of the disease, even though the disease has not been diagnosed.

"Protective group" (Pg) refers to a type of substituent used to react with other functional groups on a compound to block or protect specific functional groups. For example, "amino protecting group" refers to a substituent attached to an amine group to block or protect the amine functional group on a compound. Suitable amine protecting groups include acetyl, trifluoroacetin, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl protecting groups (Fmoc). Similarly, "hydroxyl protecting group" refers to a type of hydroxyl substituent that can effectively block or protect the function of hydroxyl. Suitable protecting groups include, but are not limited to, acetyl and silyl. "Carboxy protecting group" refers to a type of carboxyl substituent that can effectively block or protect the carboxyl group. Commonly used carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl) Ethyl, 2-(p-nitrobenzenesulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and usage instructions of protecting groups, see references: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 .

"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, chloroacetoxy, and dichloroacetoxycarbonyl Group, trichloroacetoxy, trifluoroacetoxy, phenacetoxy, methanoyl, acetoxy, benzyl, tert-pentyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-Dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, Isopropoxycarbonyl, phthalyloxy, succinyl, propylamino, leucyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, triphenyl Methyl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N,N -dimethylaminomethylene, benzylene, 2-hydroxybenzylidene, 2- Hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonyl cyclohexylene, 2- Ethoxycarbonyl cyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxocyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl Group-2-oxy- 2H -l,3-dioxocyclopenten-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

"C(O)OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, Naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzylmethyl , P-nitrobenzyl methyl, p-bromobenzyl methyl, p-toluene benzoyl methyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethane Group, 2-(trimethylsilyl) ethyl, acetoxymethyl, propionoxymethyl, neopentyloxymethyl, phthaliminomethyl, succinimidyl Methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl Oxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butene Group, allyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group Group, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-Trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2-(Triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy- 1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl, formic acid, chloroacetoxy, dichloroacetoxy, trichloroacetoxy, trifluoroacetoxy, methoxy Acetyl, phenoxyacetyl, p-pentyl, benzyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1 ,1-Dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxy Benzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl , 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, Methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

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

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

The compound of the present invention can exist in an isotope-labeled or enriched form, and contains one or more atoms with different atomic masses and mass numbers from the most common atomic masses in nature. Isotope can be radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S , ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Other isotopes and/or other atoms containing these atoms are also within the scope of the present invention.

In another embodiment, the isotope-labeled compound contains deuterium ( ² H), tritium ( ³ H), or ¹⁴ C isotopes. The isotope-labeled compound of the present invention can be obtained using methods well known to those skilled in the art. These isotope-labeled compounds can be obtained by referring to the examples and reaction diagrams of the present invention, and replacing non-labeled reagents with isotope-labeled reagents. In some cases, the compound can be treated with isotope-labeled reagents to replace atoms with isotopic atoms. For example, replacing hydrogen with deuterium can be exchanged through the action of deuterated acids such as D ₂ SO ₄ /D ₂ O.

The isotope-labeled compound of the present invention can be used as a standard for PDGFR inhibitor drug effect binding test. Isotopes-containing compounds can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the results of in vivo metabolism of compounds (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)) . This type of metabolic research is very important for the design of safe and effective therapeutic drugs. It can be judged that the active compound used by the patient or the metabolite of the parent compound is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp . 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol. , 77, 79-88 (1999)).

In addition, drugs containing non-reflective active isotopes, such as deuterated drugs, called "heavy drugs", can be used to treat diseases and disorders related to PDGFR activity. The proportion of a certain isotope in a compound that exceeds its natural abundance is called enrichment. The amount of enrichment includes, but is not limited to, 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 about 100 mol%.

Stable isotope labeling of drugs can change their physical and chemical properties, such as pKa and liquid solubility. If the isotope substitution affects the area related to the ligand-receptor interaction, then these effects and changes may affect the pharmacodynamic response of the drug molecule. Some of the physical properties of stable isotope-labeled molecules are different from those of unlabeled molecules, and the chemical and biological properties are the same, but there is an important difference: due to the increased mass of the heavy isotope, any chemical bond containing a heavy isotope and another atom is more important than a light isotope. Strong. Correspondingly, the presence of isotopes at metabolic or enzymatic conversion sites will slow down the reaction, which may change the pharmacokinetic characteristics or efficacy of non-isotopically labeled compounds.

(I) 或其藥學上可接受的鹽，其中： Z選自CR^X 和N； L選自-NR^A C(O)、-C(O)NR^A 、-NR^A C(O)NR^B 和-NR^A SO₂ ； R¹ 是-NR^A1 R^B1 ； R² 選自氫、鹵素、CN、C_1-10 烷基、C_3-10 環烷基和C_3-10 環烷基-C_1-4 烷基、C_2-10 烯基、C_2-10 炔基，其中每個烷基、環烷基、烯基和炔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 獨立選自鹵素、CN和C_1-10 烷基，其中烷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； R⁴ 選自芳基和雜芳基，其中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； R⁵ 選自氫、鹵素、CN、C_1-10 烷基、C_3-10 環烷基和C_3-10 環烷基-C_1-4 烷基、C_2-10 烯基、C_2-10 炔基，其中每個烷基、環烷基、烯基和炔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； R^A 和R^B 分別獨立選自氫和C_1-10 烷基，其中烷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； R^A1 和R^B1 分別獨立選自氫、C_1-10 烷基、C_3-10 環烷基、C_3-10 環烷基-C_1-4 烷基、-C(O)R^A2 、-C(O)OR^A2 、-C(O)NR^A2 R^B2 、-S(O)_r R^A2 和-S(O)_r NR^A2 R^B2 ，其中每個烷基和環烷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； 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一個含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12員雜環，該環可以是未被取代的或被1、2或3個選自R^X 的取代基取代； 每個R^A2 和R^B2 獨立選自氫、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^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一個含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12員雜環，該環可以是未被取代的或被1、2或3個選自R^X 的取代基取代； 每個R^X 獨立選自氫、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、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 C(O)R^a1 、-(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(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 C(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )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 C(O)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(S)NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 C(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t S(O)_r 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 S(O)₂ OR^b1 、-(CR^c1 R^d1 )_t OS(O)₂ R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)_r R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )R^b1 、-(CR^c1 R^d1 )_t S(O)_r NR^a1 R^b1 、-(CR^c1 R^d1 )_t S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)₂ NR^a1 R^b1 、-(CR^c1 R^d1 )_t NR^a1 S(O)(=NR^e1 )NR^a1 R^b1 、-(CR^c1 R^d1 )_t P(O)R^a1 R^b1 和-(CR^c1 R^d1 )_t P(O)(OR^a1 )(OR^b1 )，其中每個烷基、烯基、炔基、環烷基、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^Y 的取代基取代； 每個R^a1 和R^b1 獨立選自氫、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； 或每個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一個含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12員雜環，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； 或每個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一個含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12員環，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^e1 獨立選自氫，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 C(O)R^a2 、-(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(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 C(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 C(=NR^e2 )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 NR^a2 C(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)_r 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 S(O)₂ OR^b2 、-(CR^c2 R^d2 )_t OS(O)₂ R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)_r R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )R^b2 、-(CR^c2 R^d2 )_t S(O)_r NR^a2 R^b2 、-(CR^c2 R^d2 )_t S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)₂ NR^a2 R^b2 、-(CR^c2 R^d2 )_t NR^a2 S(O)(=NR^e2 )NR^a2 R^b2 、-(CR^c2 R^d2 )_t P(O)R^a2 R^b2 和-(CR^c2 R^d2 )_t P(O)(OR^a2 )(OR^b2 )，其中每個烷基，烯基，炔基，環烷基，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，獨立選自羥基，CN，胺基，鹵素，C_1-10 烷基，C_2-10 烯基，C_2-10 炔基，C_3-10 環烷基，C_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 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 每個R^a2 和每個R^b2 獨立選自氫，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 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基，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，烷胺基，環烷胺基，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 或每個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一個含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12員雜環，該環可以是未被取代的或被1或2個選自鹵素，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 每個R^c2 和R^d2 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，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 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基，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，烷胺基，環烷胺基，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 或每個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一個含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12員環，該環可以是未被取代的或被1或2個選自鹵素，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，胺基，C_1-10 烷胺基，C_3-10 環烷胺基，二(C_1-10 烷基)胺基的取代基取代； 每個R^e2 獨立選自氫，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； 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):

(I) or a pharmaceutically acceptable salt thereof, wherein: Z is selected from CR ^X and N; L is selected from -NR ^A C(O), -C(O)NR ^A , -NR ^A C(O)NR ^B And -NR ^A SO ₂ ; R ¹ is -NR ^A1 R ^B1 ; R ^{2 is} selected from hydrogen, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and C _3-10 cycloalkyl-C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein each of the alkyl, cycloalkyl, alkenyl and alkynyl groups is unsubstituted or has at least one, such as 1, 2 , 3 or 4, independently selected from R ^X substituents; each R ^{3 is} independently selected from halogen, CN and C _1-10 alkyl, wherein the alkyl is unsubstituted or is substituted by at least one, such as 1, 2, 3 or 4, independently substituted by substituents selected from R ^X ; R ^{4 is} selected from aryl and heteroaryl, wherein aryl and heteroaryl are respectively unsubstituted or at least one, such as 1, 2 , 3 or 4 substituents independently selected from R ^X ; R ^{5 is} selected from hydrogen, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and C _3-10 cycloalkyl-C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein each of alkyl, cycloalkyl, alkenyl and alkynyl is unsubstituted or has at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; R ^A and R ^B are independently selected from hydrogen and C _1-10 alkyl, wherein the alkyl is unsubstituted or is substituted by at least one, such as 1, 2 , 3 or 4 substituents independently selected from R ^X ; R ^A1 and R ^B1 are independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, -C(O)R ^A2 , -C(O)OR ^A2 , -C(O)NR ^A2 R ^B2 , -S(O) _r R ^A2 and -S(O) _r NR ^A2 R ^B2 , wherein each alkyl group and cycloalkyl group are unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents; or R ^A1 and R ^B1 together together The single or multiple atoms connected to them together form a 4-12 member heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be unsubstituted Or substituted by 1, 2 or 3 substituents selected from R ^X ; each R ^A2 and R ^{B2 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, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or is at least One, such as 1, 2, 3 or 4, independently selected from the substituents of R ^X ; or each R ^A2 and R ^B2 together with the single or multiple atoms connected to them form a 4-12 member heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. May be unsubstituted or substituted by 1, 2 or 3 substituents selected from R ^X ; each R ^{X 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, _{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 C(O)R ^a1 , -(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(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 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 ) 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 C(O )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r 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 S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 And -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is not Substituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y ; each R ^a1 and R ^{b1 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 Group, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y ; or each of R ^a1 and R ^b1 together with one or more of their connected Atoms 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 or be 1, 2, or 3 One substituent 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 ring Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and Heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is unsubstituted or is substituted by at least one, such as 1, 2, 3 or 4 substituents independently selected from R ^Y ; or each of R ^c1 and R ^d1 together with the single or multiple carbon atoms connected to them form a group containing 0, 1 or 2 independently selected from A 3-12 membered ring of heteroatoms of oxygen, sulfur and nitrogen, the ring may be unsubstituted or substituted with 1, 2 or 3 substituents selected from R ^Y ; 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 ring Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, halogen, CN, NO ₂ , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t C(O)R ^a2 ,- (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(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 C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )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 NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r 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 S(O) ₂ OR ^b2 , -(CR ^c2 R ^d2 ) _t OS(O) ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)( =NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P (O) R ^a2 R ^b2 and -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are unsubstituted or have at least one, such as 1, 2, 3 or 4, independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino group, C _3-10 cycloalkylamino group, substitution of di(C _1-10 alkyl)amino group; each R ^a2 and each R ^{b2 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, C _1-10 alkoxy, C _3-10 cycloalkyloxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl ) Amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which Alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl Is unsubstituted or by at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkane Amino group, C _3-10 cycloalkylamino group, substitution of di(C _1-10 alkyl)amino group; or each of R ^a2 and R ^b2 together with the single or multiple atoms connected to them form one 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 or 1 or 2 selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1 -10} Alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino, substituent substitution of di(C _1-10 alkyl)amino group ; Each of 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} cycloalkyloxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl) Amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl Group, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are Unsubstituted or by at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamine Group, C _3-10 cycloalkylamino group, bis(C _1-10 alkyl)amino group substitution; or each of R ^c2 and R ^d2 together with the single or multiple carbon atoms connected to them form one A 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be unsubstituted or 1 or 2 selected from halogen, CN, C _1-10 alkane Group, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio , C _3-10 cycloalkylthio group, amino group, C _1-10 cycloalkylamino group, C _3-10 cycloalkylamino group, substituent substitution of di(C _1-10 alkyl)amino group; each R ^e2 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; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4.

In another embodiment (2), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Z is CH.

In another embodiment (3), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Z is N.

In another embodiment (4), the present invention provides the compound of any one of embodiments (1)-(3), or a pharmaceutically acceptable salt thereof, wherein L is selected from -NR ^A C(O)- , -C(O)NR ^A -and -NR ^A C(O)NR ^B -.

In another embodiment (5), the present invention provides the compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein L is -NR ^A C(O)NR ^B -.

In another embodiment (6), the present invention provides the compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein L is -NHC(O)NH-.

In another embodiment (7), the present invention provides a compound of any one of embodiments (1) to (6), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is an aryl group, wherein aryl is a Substituted or substituted with at least one substituent independently selected from R ^X.

In another embodiment (8), the present invention provides the compound of embodiment (7) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is phenyl, wherein phenyl is unsubstituted or independently selected by at least one Substitution from halogen, CN, and C _1-10 alkyl substituents, where the alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (9), the present invention provides the compound of any one of embodiments (1) to (6), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is heteroaryl, wherein heteroaryl Is unsubstituted or substituted with at least one substituent independently selected from R ^X.

In another embodiment (10), the present invention provides the compound of embodiment (9) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is pyridyl, wherein pyridyl is unsubstituted or independently selected by at least one Substitution from halogen, CN, and C _1-10 alkyl substituents, where the alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (11), the present invention provides the compound of any one of embodiments (1) to (10), or a pharmaceutically acceptable salt thereof, wherein R ¹ is -NR ^A1 R ^B1 , wherein R ^A1 and R ^B1 are each independently selected from hydrogen and C _1-10 alkyl, wherein the alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X.

、

和

。In another embodiment (12), the present invention provides the compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from -NHCH ₃ , -NH ₂ ,

,

with

.

In another embodiment (13), the present invention provides a compound of any one of embodiments (1) to (12), or a pharmaceutically acceptable salt thereof, wherein R ² 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 each R ^{3 is} independently selected from halogen and C _{1 -10} alkyl.

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 m is 2.

選自

、

、

和

。In another embodiment (16), the present invention provides the compound of embodiment (15) or a pharmaceutically acceptable salt thereof, wherein the substructure of formula (I)

Selected from

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with

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In another embodiment (17), the present invention provides the compound of any one of embodiments (1)-(16), or a pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from hydrogen, C _1-10 alkane Group and C _3-10 cycloalkyl group, wherein each alkyl group and cycloalkyl group are unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (18), the present invention provides the compound of embodiment (17) or a pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from hydrogen, methyl, ethyl, isopropyl and cycloalkyl, Wherein methyl, ethyl, isopropyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from halogen.

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，和其藥學上可接受的鹽。In another embodiment (19), the compound provided by the present invention is selected from

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, And its pharmaceutically acceptable salts.

In another embodiment (20), the present invention provides the compound of any one of embodiments (1) to (19) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

In another embodiment (21), the present invention provides a method for treating, ameliorating or preventing a condition that is responsive to inhibition of PDGFR, comprising administering an effective amount of any one of embodiments (1) to (19) to an individual in need The compound of item or a pharmaceutically acceptable salt thereof, or at least one of its pharmaceutical compositions, optionally in combination with a second therapeutic agent.

In another embodiment (22), the present invention provides that the compound of any one of embodiments (1)-(19) or a pharmaceutically acceptable salt thereof is prepared for use in the treatment of hyperproliferative diseases such as cancer and inflammation. , Or use in drugs for immune and autoimmune diseases.

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

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

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

In another aspect, the present invention provides a method for inhibiting protein kinase through the action of the compound disclosed herein or a pharmaceutically acceptable salt thereof with protein kinase.

In another aspect, the present invention provides a method for inhibiting protein kinase, which comprises allowing the compound disclosed herein or a pharmaceutically acceptable salt thereof to appear in the body of an individual to inhibit protein kinase activity in the body.

In another aspect, the present invention provides a method of inhibiting protein kinase, comprising administering to an individual a first compound, which is converted into a second compound in vivo, wherein the second compound inhibits protein kinase activity in vivo, and the second compound is Compounds and variants of any of the above embodiments.

In another aspect, the present invention provides a method for treating a disease state in which protein kinase activity causes the pathology and/or symptoms of the disease, the method comprising making a therapeutically effective amount of the compound disclosed herein or a pharmaceutically effective amount of the compound disclosed herein Acceptable salts appear in the individual's body.

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

In the variation of each of the above methods, the disease state is selected from: cancerous proliferative diseases (such as brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, renal, kidney, ovary, Prostate, colorectal, epidermis, esophagus, testicles, gynecology or thyroid cancer); non-cancerous proliferative diseases (such as benign skin hyperplasia (such as psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney Diseases; pain; prevention of blastocyst implantation; treatment of angiogenesis or angiogenesis-related diseases (eg tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases Such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast Cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid carcinoma); asthma; neutrophil chemotaxis (for example, reperfusion injury and inflammatory arthritis due to myocardial infarction and stroke); septic shock; T cell-mediated diseases, in which immunosuppression is of great value (such as prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis and rheumatoid arthritis); atherosclerosis; inhibition of response to growth factor mixtures Keratinocytes; chronic obstructive pulmonary disease (COPD) and other diseases.

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

In another aspect, the present invention relates to the use of the compounds and variants of any of the above embodiments as medicaments. In another aspect, the present invention relates to the use of the compounds and variants of any one of the above embodiments for the preparation of a protein kinase inhibitor drug.

In another aspect, the present invention relates to the use of the compounds and variants of any one of the above embodiments for the preparation of a medicament for the treatment of pathological and/or symptomatic disease states caused by protein kinase activity. Administration and pharmaceutical composition

Generally, the compound of the present invention will be administered in a therapeutically effective amount via any common and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount can vary widely, depending on the severity of the disease, age, and relative health of the subject, the efficacy of the compound used, and other factors known in the art. For example, for the treatment of tumorous diseases and immune system diseases, the required dose will vary according to the mode of administration, the specific condition to be treated and the desired effect.

Generally, satisfactory results can be achieved at a daily dose of 0.001 to 100 mg/kg body weight, specifically, from about 0.03 to 2.5 mg/kg body weight. The daily dose for larger mammals, such as humans, can be from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, in a convenient form, for example, in divided doses up to four times a day. Time or in sustained release form. A suitable unit dosage form for oral administration contains about 1 to 50 mg of active ingredient.

The compound of the present invention can be administered in the form of a pharmaceutical composition through any conventional route; for example, enteral, for example, orally, for example, in the form of tablets or capsules, parenterally, for example, in the form of injectable solutions or suspensions; or Topical administration, for example in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories.

The pharmaceutical composition containing the free base or pharmaceutically acceptable salt compound of the present invention and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or freeze-dried in a conventional manner To make. For example, the pharmaceutical composition comprises a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent, and can be prepared by mixing with a pharmaceutically acceptable carrier or diluent in a conventional manner. A unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.

In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. In the case of a lyophilized composition containing only the active ingredient or mixed with a carrier such as mannitol, the dispersion or suspension can be prepared before use. The pharmaceutical composition may be sterilized and/or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution enhancers, salts to adjust osmotic pressure, and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, and microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain thickeners, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers, such as Tween 80 (polyoxyethylene (20) Sorbitan monooleate).

The suspension in oil may contain vegetable oils as oily ingredients, synthetic or semi-synthetic oils, commonly used for injection purposes. Examples include liquid fatty acid esters containing long-chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms as the acid component. Suitable liquid fatty acid esters include but are not limited to lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated Acids such as oleic acid, elaidic acid, erucic acid, basilic acid and linoleic acid, if necessary, may contain antioxidants such as vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene . The alcohol component of these fatty acid esters may have six carbon atoms, and may be monovalent or multivalent, such as mono-, di- or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or its isomers, ethylene glycol and glycerol.

Other suitable fatty acid esters include but are not limited to ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL ^® M2375, (polyoxyethylene glycerol), LABRAFIL ^® M1944 CS (prepared by alcoholysis of almond oil) Unsaturated PEGylated glycerides, containing glycerides and polyethylene glycol esters), LABRASOL ^TM (saturated PEGylated glycerides prepared by alcoholysis TCM, including glycerides and polyethylene glycol esters; both Obtained from GaKefosse, France), and/or MIGLYOL ^® 812 (saturated fatty acid triglycerides with chain lengths of C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, and sesame oil, Soybean oil or peanut oil.

The pharmaceutical composition for oral administration can be permeable, for example, by mixing the active ingredient with one or more solid carriers, if necessary, granulating the resulting mixture, and processing the mixture or granules by adding additional excipients, To form tablets or tablet cores.

Suitable carriers include, but are not limited to, fillers, such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate, and binders, such as starch, for example Corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if necessary, a disintegrant such as the above-mentioned starch , Carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or its salt, such as sodium alginate. Additional excipients include flow regulators and lubricants, such as silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof .

The tablet core may be provided with a suitable, optionally enteric-coated, by using, in particular, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or dissolved in Coating solutions of suitable organic solvents or solvent mixtures, or, for enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate Ester solution. Dyestuffs or pigments can be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredients.

The pharmaceutical composition for oral administration may also include hard capsules, including gelatin or soft sealed capsules containing gelatin and a plasticizer, such as glycerin or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example mixed with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredients can be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oils or liquid polyethylene glycol or fatty acid esters of ethylene glycol or propylene glycol, and stabilizers and Detergents, such as fatty acid ester type of polyoxyethylene sorbitol, can also be added.

Pharmaceutical compositions suitable for rectal administration, such as suppositories, which contain a combination of active ingredients and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration may contain active ingredients in water-soluble form, such as water-soluble salts or aqueous injection suspensions containing viscosity-increasing substances, such as sodium carboxymethyl cellulose, aqueous solutions of sorbitol and/ Or dextran, and, if necessary, stabilizers. The active ingredient, optionally with excipients, can also be in a freeze-dried form, and can be a solution prepared by adding a suitable solvent before parenteral administration. The solution used, for example, for parenteral administration, can also be used as an infusion solution. The preparation of injection preparations is usually filled into, for example, ampoules or vials, and sealed containers under sterile conditions.

The present invention also provides a pharmaceutical combination, such as a kit, which comprises a) the compound disclosed in the present invention, which may be in a free form or a pharmaceutically acceptable salt form, and b) at least one adjuvant. The kit may include instructions for its use. Combination therapy

The compounds or pharmaceutically acceptable salts described in this patent can be used alone or in combination with other therapeutic agents.

For example, the use of an adjuvant can enhance the therapeutic effect of the compound of the present invention (for example, the therapeutic benefit of using an adjuvant drug alone is very small, but when combined with another drug, it can enhance the therapeutic benefit of the individual), Or, for example, the combination of a compound of the present invention and another therapeutic agent that also has a therapeutic effect can enhance the therapeutic benefit of the individual. For example, in the treatment of gout, when the compound of the present invention is used, the combined use of another drug for the treatment of gout may enhance the clinical benefit. Or, for example, if the adverse reaction of using the compound of the present invention is nausea, an anti-nausea drug can be used in combination. Alternatively, the treatments that can be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of diseased areas, rest, diet improvement, etc. Regardless of the disease, disorder or condition, the two therapies should have an additive effect or a synergistic effect to benefit the individual's treatment.

When the compound of the patent is used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition of the compound of the patent may be the same as that of other drugs, or due to different physical and chemical properties, the route of administration may be different. For example, oral administration of the compound of this patent can produce and maintain a good blood level, while another therapeutic agent may require intravenous administration. Therefore, the compound of this patent and another therapeutic agent can be administered simultaneously, sequentially or separately.

Example

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

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

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

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

The N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known in the art. For example, N-oxide can be obtained by combining the non-oxidized form of the compound of formula (I) with an oxidizing agent (such as trifluoroperoxyacetic acid, permaleic acid, peroxybenzene) at 0~80°C. Formic acid, peroxyacetic acid and m-chloroperoxybenzoic acid, etc.) are obtained by reaction in an inert organic solvent (such as dichloromethane and other halogenated hydrocarbons). Alternatively, the N-oxide of the compound of formula (I) can also be prepared from the N-oxide of the starting material.

The non-oxidized form of the compound of formula (I) can be obtained by combining its N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and phosphorus tribromide, etc.) It is prepared by reaction in the corresponding inert organic solvent (such as acetonitrile, ethanol and dioxane aqueous solution, etc.) under the condition of 0~80°C.

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

These methods, routes, and signs and common sense used in the examples are consistent with current scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise specified, standard one-letter or three-letter abbreviations generally refer to L-form amino acid residues. Unless otherwise stated, all starting materials used were purchased from market suppliers and were used without further purification. For example, the following abbreviations are used in the examples and throughout the description: g (gram), mg (mg), L (liter), mL (milliliters), μL (microliter), psi (pounds per square inch), M ( Mol), mM (millimoles), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (mole), mmol (millimolar), RT (ambient temperature), min (minutes ), h (hours), mp (melting point), TLC (thin layer chromatography), Rt (retention time), RP (reverse phase), MeOH (methanol), i-PrOH (isopropanol), TEA (three Ethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfide), EtOAc (ethyl acetate), DME (1,2-dimethyl ethyl Alkane), DCM (dichloromethane), DCE (dichloroethane), DMF ( N , N -dimethylformamide), DMPU ( N , N' -dimethylpropenylurea), CDI (1 ,1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et ₂ O (ether ), EDCI (1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (Dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMS (2-(trimethylsilyl)ethyl), TMS (trimethylsilyl), TIPS (Triisopropylsilyl), TBS (tert-butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl) , TBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolidinyl) hypophosphite chloride), TBAF (tetra-n-butylammonium fluoride) , MCPBA (m-chloroperoxybenzoic acid).

Ether or Et ₂ O refers to ether; brine refers to saturated aqueous NaCl. Unless otherwise specified, 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 using Varian Mercury Plus 400 Nuclear Magnetic Resonance Spectrometer. Chemical shifts are expressed in ppm. Coupling constants are in Hertz (Hz). Describe the apparent diversity in a segmentation mode, and define it as s (single peak), d (double peak), t (triplet), q (quartet), m (multiple peak), and br (broad peak).

Low-resolution mass spectrometry (MS) and compound purity data come from Shimadzu LC/MS single quadrupole system, which is equipped with electrospray ionization detector (ESI), ultraviolet detector (220 and 254nm) and evaporative light scattering detector (ELSD) . The thin-layer chromatography method uses 0.25 mm Asahi Chemical Silicone Plate (60F-254), 5% phosphomolybdic acid ethanol solution, ninhydrin or p-methoxybenzaldehyde solution and observes under ultraviolet light. The fast column chromatography uses silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.). synthetic route

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

In the following reactions, it may be necessary to protect the active groups to prevent these active groups from participating in other undesired reactions: these groups such as hydroxyl, amine, imino, sulfhydryl or carboxyl groups, in the final product Contain these groups. Commonly used protecting groups can refer to T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

The intermediates listed in the following scheme are known in the literature or prepared by those skilled in the art according to similar methods.

合成方案1The synthesis method of the compound of formula I disclosed in the present invention is illustrated by the synthesis of Ia and Ib shown in Scheme 1. The reaction of II with ethyl cyanoacetate yields Ia-A, and Ia-A can be further decarboxylated to form ester Ia-B. The conversion of ester Ia-B to aldehyde Ia-C can be achieved through reduction and oxidation reactions in sequence. Aldehydes Ia-C and amines Ia-D in organic acids such as HOAc finally give Ia. Alternatively, the reaction of the aldehyde Ib-A derived from the ester II with the amide Ib-B through reduction and oxidation reactions yields the compound of formula Ib.

Synthesis scheme 1

合成方案2Taking the synthesis of the compound of formula Ia as an illustration, Scheme 2 discloses a synthesis method of the compound of formula Iaa disclosed in the present invention. Using commercially provided or reported tricarbonyl IIa-A as the starting material, through condensation with acetal IIa-B, substitution of dimethylamino with aniline IIa-D, and intramolecular in the presence of organic bases such as DBU A series of conversion reactions such as cyclization to obtain pyridone IIa-F. The hydroxyl group of IIa-F is converted into a leaving group such as OTf, and then IIa is reacted with ethyl cyanoacetate IIa-G to form Iaa-A, which is further decarboxylated to obtain ester Iaa-B. The ester group in Iaa-B is converted to aldehyde, and then intramolecular cyclization is carried out through the condensation of aldehyde and methylamine Iaa-F to obtain Iaa-G. The halide Iaa-G and the imine Iaa-H undergo a buchwald coupling reaction, and then the benzhydryl group is deprotected to form the amine Iaa-J. The reaction of Iaa-J with isocyanate Iaa-K produces a compound of formula Iaa.

Synthesis scheme 2

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

2- Bromo- 4- fluoro -5 -iodoaniline ( A )

1- bromine -5- fluorine -4- iodine -2- Nitrobenzene (A-1)

To a suspension of 1-bromo-3-fluoro-4-iodobenzene (20.00 g, 66.50 mmol) in concentrated sulfuric acid (100 mL) at 0ºC, fuming nitric acid (15 mL) was added dropwise. After stirring at 0ºC for 20 min, return to room temperature and stir for another 3 h. The reaction mixture was poured into ice water (300 mL) and extracted with DCM (3×100 mL). The extract was washed with water, saturated Na ₂ S ₂ O ₃ solution and saturated brine successively, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography, eluted with 1-5% EtOAc in n-hexane to obtain 1-bromo-5-fluoro-4-iodo-2-nitrobenzene ( A-1 ).

2- Bromo- 4- fluoro -5 -iodoaniline ( A )

To the stirring 1-bromo-5-fluoro-4-iodo-2-nitrobenzene ( A-1 ) (7.47 g, 21.6 mmol) and NH ₄ Cl (9.26 g, 173 mmol) in EtOH-H ₂ O (3:1, 120 mL), add iron powder (9.67 g, 173 mmol). The mixture was heated to reflux for 2 h. After cooling, the reaction mixture was filtered through Celite and washed with EtOAc (3×20 mL). The filtrate was concentrated and redissolved in EtOAc (200 mL). The solution was washed with water and saturated brine, dried over Na ₂ SO ₄ , and concentrated to obtain 2-bromo-4-fluoro-5-iodoaniline ( A ). MS-ESI (m/z): 316/318 (1:1) [M + 1] ⁺ . It was used directly in the next reaction without further purification. Intermediate B

2- chloro- 4- fluoro -5 -iodoaniline ( B )

The synthesis of 2-chloro-4-fluoro-5-iodoaniline (Intermediate B ) is based on the synthesis method of Intermediate A , with 1-chloro-3-fluoro-4-iodobenzene as the starting material. MS-ESI (m/z): 272 [M + 1] ⁺ . Intermediate C

2-(1-(2- Bromo- 4- fluoro -5- iodophenyl )-3 -ethyl -5 -methanyl- 2- oxo- 1,2- dihydropyridin- 4 -yl ) acetonitrile ( C )

Ethyl 1-(2- bromo- 4- fluoro -5- iodophenyl )-5- ethyl- 4 -hydroxy -6- oxo- 1,6- dihydropyridine- 3- carboxylate ( C- 1 )

Starting material ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-5-ethyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate ( C-1 ) Synthesis reference J. Baskovc, et al, ACS Combinatorial Science, 2012, 14, 513-519 . It was prepared with commercially available diethyl 1,3-acetone dicarboxylate and intermediate A as starting materials.

Ethyl 1-(2- bromo- 4- fluoro -5- iodophenyl )-5- ethyl -6- oxo- 4-((( trifluoromethyl ) -sulfonyl ) oxy )-1, 6 -Dihydropyridine- 3- carboxylate ( C-2 )

To 1-(2-bromo-4-fluoro-5-iodophenyl)-5-ethyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid at 0°C Et ₃ N (1.46 g, 14.4 mmol) was added to a solution of ester ( C-1 ) (4.91 g, 9.63 mmol) in DCM (90 mL) followed by Tf ₂ O (3.26 g, 11.6 mmol) dropwise. The mixture was returned to room temperature and stirred for 2 h. The reaction mixture was diluted with water, the layers were separated, and the aqueous phase was extracted with DCM. The organic solution was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 5% EtOAc in n-hexane to obtain ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-5-ethyl-6-oxo-4-( ((Trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine e-3-carboxylate ( C-2 ). MS-ESI (m/z): 642/644 (1:1) [M + 1] ⁺ .

Ethyl 1-(2- bromo- 4- fluoro -5- iodophenyl )-4-(1- cyano -2- ethoxy -2 -oxoethyl )-5- ethyl -6- oxy Generation -1,6- dihydropyridine- 3- carboxylate ( C-3 )

Under N ₂ protection, to a solution of ethyl cyanoacetate (1.700 g, 15.05 mmol) in THF (20 mL) was added LiHMDS (1.0 M in THF, 15.05 mL, 15.05 mmol) at 0°C. The mixture was stirred at this temperature for 30 min. Ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-5-ethyl-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)- 1,6-Dihydropyridine-3-carboxylate ( C-2 ) (3.22 g, 5.02 mmol) in THF (30 mL) solution, the mixture was heated to 45°C for 2 h. After cooling, the reaction mixture was diluted with saturated aqueous NH ₄ Cl, extracted with EtOAc (2×), the extract was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 10-20% EtOAc in n-hexane to obtain ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-4-(1-cyano-2-ethyl) (Oxy-2-oxoethyl)-5-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate ( C-3 ). MS-ESI (m/z): 605/607 (1:1) [M + 1] ⁺ .

Ethyl 1-(2- bromo- 4- fluoro -5- iodophenyl )-4-( cyanomethyl )-5- ethyl -6- oxo- 1,6- dihydropyridine- 3- carboxy Ester ( C-4 )

To ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)-5-ethyl-6- Oxo-1,6-dihydropyridine-3-carboxylate ( C-3 ) (2.20 g, 3.64 mmol) in DMSO (40 mL) solution was added LiCl (308 mg, 7.27 mmol) and water (131 mg, 7.27 mmol). The mixture was heated to 125°C for 2 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (3×). The extract was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 20-30% EtOAc in n-hexane to obtain ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-4-(cyanomethyl)-5- Ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate ( C-4 ). MS-ESI (m/z): 533/535 (1:1) [M + 1] ⁺ .

1-(2- Bromo- 4- fluoro -5- iodophenyl )-4-( cyanomethyl )-5- ethyl -6- oxo- 1,6- dihydropyridine- 3- carboxylic acid ( C-5 )

To ethyl 1-(2-bromo-4-fluoro-5-iodophenyl)-4-(cyanomethyl)-5-ethyl-6-oxo-1,6-dihydropyridine-3- THF-carboxylate (C-4) (1.82 g , 3.41 mmol) in _{/ H 2 O (3: 1} , 60 mL) was added _{LiOH H 2 O (574 mg,} 13.7 mmol).. The mixture was stirred at room temperature for 14 h. Most of the THF was evaporated, the residue was acidified with 1 N HCl to pH=2~3, and extracted with EtOAc (3×). The extract was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 2-4% MeOH and DCM to obtain 1-(2-bromo-4-fluoro-5-iodophenyl)-4-(cyanomethyl)-5-ethyl- 6-oxo-1,6-dihydropyridine-3-carboxylic acid ( C-5 ). MS-ESI (m/z): 505/507 (1:1) [M + 1] ⁺ .

2-(1-(2- Bromo- 4- fluoro -5- iodophenyl )-3 -ethyl -5-( hydroxymethyl )-2- oxo- 1,2- dihydropyridin- 4 -yl ) Acetonitrile ( C-6 )

At 0°C, to 1-(2-bromo-4-fluoro-5-iodophenyl)-4-(cyanomethyl)-5-ethyl-6-oxo-1,6-dihydro To a solution of pyridine-3-carboxylic acid ( C-5 ) (1.52 g, 3.01 mmol) in THF (45 mL) was added human BH ₃ -SMe ₂ (458 mg, 6.02 mmol) dropwise. The mixture was stirred at room temperature for 21 h. Dilute with water and extract with EtOAc (2×). The extract was washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain the crude product, which was purified by silica gel column chromatography and eluted with 30-50% EtOAc in n-hexane to obtain 2-(1-(2-bromo-4- Fluoro-5-iodophenyl)-3-ethyl-5-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-4-yl)acetonitrile ( C-6 ). MS-ESI (m/z): 491/493 (1:1) [M + 1] ⁺ .

2-(1-(2- Bromo- 4- fluoro -5- iodophenyl )-3 -ethyl -5 -methanyl- 2- oxo- 1,2- dihydropyridin- 4 -yl ) acetonitrile ( C )

To 2-(1-(2-bromo-4-fluoro-5-iodophenyl)-3-ethyl-5-(hydroxymethyl)-2-oxo-1,2-di A solution of hydropyridin-4-yl)acetonitrile ( C-6 ) (701 mg, 1.43 mmol) in DCM (18 mL) was added with Dess-Martin oxidant (1.21 g, 2.86 mmol). The mixture was stirred at room temperature for 2 h. The mixture was directly purified by silica gel column chromatography and eluted with 30-40% EtOAc in n-hexane to obtain 2-(1-(2-bromo-4-fluoro-5-iodophenyl)-3-ethyl-5-methyl Acetyl-2-oxo-1,2-dihydropyridin-4-yl)acetonitrile ( C ). MS-ESI (m/z): 489/491 (1:1) [M + 1] ⁺ . Intermediate D

2-(1-(2- chloro- 4- fluoro -5- iodophenyl )-3 -ethyl -5 -methanyl- 2- oxo- 1,2- dihydropyridin- 4 -yl ) acetonitrile ( D )

2-(1-(2-chloro-4-fluoro-5-iodophenyl)-3-ethyl-5-methanyl-2-oxo-1,2-dihydropyridin-4-yl)acetonitrile The synthesis of (Intermediate D ) refers to the synthesis method of Intermediate C , using commercially available diethyl 1,3-acetonedicarboxylate and Intermediate B as starting materials. MS-ESI (m/z): 445 [M + 1] ⁺ . Intermediate E

2,4 -Difluoro -5 -iodoaniline ( E )

1,5 -Difluoro -2- iodo- 4 -nitrobenzene ( E-1 )

At 0 ^o C solution of 2,4-difluoro-1-nitrobenzene (10.0 g, 62.9 mmol) in TfOH (28 mL) was added NIS (14.2 g, 62.9 mmol) . The reaction solution was stirred at room temperature for 3 hours and then poured into ice water for quenching, and DCM was extracted with dichloromethane (2×). The extract was washed with 10% NaHSO ₃ solution and saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain the title compound 1,5-difluoro-2-iodo-4-nitrobenzene ( E-1 ).

2,4 -Difluoro -5 -iodoaniline ( E )

To 1,5-difluoro-2-iodo-4-nitrobenzene ( E-1 ) (13.4 g, 44.3 mmol) and NH ₄ Cl (18.8 g, 355 mmol) in EtOH/H ₂ O at room temperature (210 mL/70 mL) The solution was slowly added Fe powder (19.9 g, 355 mmol), heated to 80 ^o C and stirred for 0.5 hours. The reaction solution was cooled to room temperature, filtered through Celite and evaporated under vacuum to remove EtOH. The residue was extracted with EtOAc (2×), washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain the title compound 2,4-difluoro-5-iodoaniline ( E ) as a crude product. MS-ESI (m/z): 256 [M + 1] ⁺ . Intermediate F

2-(3- Cyclopropyl- 1-(2,4 -difluoro -5- iodophenyl )-5 -methanyl- 2- oxo- 1,2- dihydropyridin- 4 -yl ) acetonitrile ( F )

Ethyl 2 -cyclopropyl acetate ( F-1 )

Slowly add SOCl ₂ (28.6 g, 242 mmol) to a solution of 2-cyclopropylacetic acid (12.1 g, 121 mmol) in anhydrous EtOH (60 mL) at 0 ^o C, and then heat to 70 ^o C to react overnight. The mixture was cooled to room temperature, H ₂ O was added, extracted with hexane/EtOAc (3:1), washed with saturated brine, dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure at 30 ^o C to obtain the title compound ethyl 2 -Cyclopropyl acetate ( F-1 ).

1-( tert-butyl ) 3- ethyl 2 -cyclopropyl malonate ( F-2 )

(150 mL) at -780C in THF diisopropylamine (29.8 g, 295 mmol) at -20 ^o C was added dropwise n -BuLi (2.5 M in hexane, 118 mL, 295 mmol) and stirred for 20 min. Cool the solution to -60 ^o C and add ethyl 2-cyclopropyl acetate ( F-1 ) (15.1 g, 118 mmol), then warm to -10 ^o C and react for 1.5 hours. Cool again to -60 ^o C. After adding di-tert-butyl dicarbonate (27 g, 124 mmol), the reaction was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous NH ₄ Cl, acidified with 1 MH ₃ PO ₄ to pH=6-7, extracted with EtOAc, washed with water and saturated brine successively, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (10:1) to obtain the title compound 1-( tert-butyl ) 3-ethyl 2-cyclopropylmalonate ( F-2 ). MS-ESI (m/z): 229 [M + 1] ⁺ .

2- Cyclopropyl- 3- ethoxy- 3 -oxopropionic acid ( F-3 )

Combine 1-( tert-butyl ) 3-ethyl 2-cyclopropylmalonate ( F-2 ) (12.2 g, 53.5 mmol) and hydrochloric acid (12 M, 45 mL, 535 mmol) in dioxane (22 mL) The solution was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with EtOAc, washed with saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain the title compound 2-cyclopropyl-3-ethoxy-3-oxopropionic acid ( F-3 ). MS-ESI (m/z): 173 [M + 1] ⁺ .

Ethyl 2 -cyclopropyl- 3-(2,2 -dimethyl -4,6- dioxo- 1,3 -dioxan- 5- yl )-3 -oxopropionate ( F- 4 )

Combine 2-cyclopropyl-3-ethoxy-3-oxopropionic acid ( F-3 ) (8.27 g, 48.1 mmol), cyclo(propylene) malonate (6.58 g, 45.7 mmol), DCC (14.9 g, 72.3 mmol) and DMAP (8.80 g, 72.1 mmol) were stirred in DCM (110 mL) at room temperature overnight. After filtration, the filtrate was washed with 1N HCl, H ₂ O, saturated brine, dried over Na ₂ SO ₄ and concentrated to obtain the title compound ethyl 2-cyclopropyl-3-(2,2-dimethyl-4,6- Crude dioxo-1,3-dioxan-5-yl)-3-oxopropionate ( F-4 ). MS-ESI (m/z): 299 [M + 1] ⁺ .

2 -cyclopropyl- 4-(( dimethylamino ) methylene )-3 -oxoglutarate diethyl ester ( F-5 )

Ethyl 2-cyclopropyl-3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropionate ( F -4) (18 g) a crude product (240 mL) was heated with stirring overnight at 80 ^o C in EtOH. It was then added dropwise DMF-DMA (16 g) and stirred at 80 ^o C 2 hours. After the solvent was evaporated under reduced pressure, it was purified by silica gel column chromatography and eluted with PE/EtOAc (10:1-6:1-4:1-3:1) to obtain the title compound 2-cyclopropyl-4-(( Dimethylamino)methylene)-3-oxoglutarate ( F-5 ). MS-ESI (m/z): 298 [M + 1] ⁺ .

2-(3- Cyclopropyl- 1-(2,4 -difluoro -5- iodophenyl )-5 -methanyl- 2- oxo- 1,2- dihydropyridin- 4 -yl ) acetonitrile ( F )

The title compound 2-(3-cyclopropyl-1-(2,4-difluoro-5-iodophenyl)-5-methanyl-2-oxo-1,2-dihydropyridin-4-yl ) Acetonitrile ( F ) is synthesized with reference to the synthesis method described in Intermediate C , with 2-cyclopropyl-4-((dimethylamino)methylene)-3-oxoglutarate diethyl ( F-5 ) and intermediate E are prepared as starting materials. MS-ESI (m/z): 441 [M + 1] ⁺ . Example 1

1-(4- Bromo -5-(4- ethyl -6-( methylamino )-3 -oxo- 2,7 -naphthyridin -2(3H) -yl )-2- fluorophenyl )- 3 -phenylurea ( 1 )

2-(2- Bromo- 4- fluoro -5- iodophenyl )-4 -ethyl -6-( methylamino )-2,7 -naphthyridin -3(2H) -one ( 1a )

To 2-(1-(2-bromo-4-fluoro-5-iodophenyl)-3-ethyl-5-methanyl-2-oxo-1,2-dihydropyridin-4-yl) Add Bu ₄ NBr (49 mg, 0.15 mmol), HOAc (441 mg, 7.36 mmol) and 5 N MeNH ₂ (aq., 1.23 mL) to the DCE (10 mL) solution of acetonitrile (intermediate C , 300 mg, 0.613 mmol) , 6.13 mmol). The mixture was put into a sealed tube and heated at 70°C for 20 h. After cooling, the mixture was diluted with saturated aqueous NaHCO ₃ and extracted with DCM (5×) containing 10% MeOH. The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 5-10% MeOH in DCM to obtain 2-(2-bromo-4-fluoro-5-iodophenyl)-4-ethyl-6-(methylamino)-2 ,7-Naphthyridin-3(2H)-one ( 1a ). MS-ESI (m/z): 502/504 (1:1) [M + 1] ⁺ .

2-(2- Bromo- 5-(( diphenylmethylene ) amino )-4- fluorophenyl )-4 -ethyl -6-( methylamino )-2,7 -naphthyridine -3( 2H) -ketone ( 1b )

To 2-(2-bromo-4-fluoro-5-iodophenyl)-4-ethyl-6-(methylamino)-2,7-naphthyridin-3(2H)-one ( 1a , 249 mg , 0.496 mmol) in dioxane solution (7.5 mL) was added benzophenone imine (108 mg, 0.595 mmol), Pd ₂ (dba) ₃ (22.7 mg, 0.0248 mmol), xantphos (28.7 mg, 0.0496 mmol) ), and Cs ₂ CO ₃ (323 mg, 0.992 mmol). The mixture was heated at 90°C for 8 h under a nitrogen atmosphere. After cooling, the mixture was diluted with water and extracted with EtOAc (3x). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 40-60% EtOAc in n-hexane to obtain 2-(2-bromo-5-((benzylidene)amino)-4-fluorophenyl)-4-ethane Group-6-(methylamino)-2,7-naphthyridin-3(2H)-one ( 1b ). MS-ESI (m/z): 555/557 (1:1) [M + 1] ⁺ .

2-(5- amino -2- bromo- 4- fluorophenyl )-4 -ethyl -6-( methylamino )-2,7 -naphthyridin -3(2H) -one ( 1c )

To 2-(2-bromo-5-((diphenylmethylene)amino)-4-fluorophenyl)-4-ethyl-6-(methylamino)-2,7-naphthyridine-3 Add 2 N HCl (0.15 mL) to a solution of (2 H )-ketone ( 1b , 115 mg, 0.206 mmol) in THF (3 mL). The mixture was stirred at room temperature for 20 min, diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (2×). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 50-80% EtOAc in n-hexane to obtain 2-(5-amino-2-bromo-4-fluorophenyl)-4-ethyl-6-(methylamino) -2,7-naphthyridin-3(2H)-one ( 1c ). MS-ESI (m/z): 391/393 (1:1) [M + 1] ⁺ .

1-(4- Bromo -5-(4- ethyl -6-( methylamino )-3 -oxo- 2,7 -naphthyridin -2(3H) -yl )-2- fluorophenyl )- 3 -phenylurea ( 1 )

To 2-(5-amino-2-bromo-4-fluorophenyl)-4-ethyl-6-(methylamino)-2,7-naphthyridin-3( 2H )-one ( 1c , A solution of 14.4 mg, 0.0368 mmol) in THF (0.5 mL) was added with triethylamine (3.7 mg, 0.037 mmol) and phenyl isocyanate (38.8 mg, 0.326 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (2x). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 10-15% MeOH in DCM to obtain 1-(4-bromo-5-(4-ethyl-6-(methylamino)-3-oxo-2,7- Naphthyridin-2( 3H )-yl)-2-fluorophenyl)-3-phenylurea ( 1 ). MS-ESI (m/z): 510/512 (1:1) [M + 1] ⁺ . Example 2

1-(4- Chloro -5-(4- ethyl -6-( methylamino )-3 -oxo- 2,7 -naphthyridin -2(3H) -yl )-2- fluorophenyl )- 3 -Phenylurea ( 2 )

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) The synthesis of -3-phenylurea ( 2 ) is obtained by referring to the synthesis method described in Example 1, starting from the intermediate D. MS-ESI (m/z): 466 [M + 1] ⁺ . Example 3

1-(5-(6- amino- 4 -ethyl- 3 -oxo- 2,7 -naphthyridin -2(3H) -yl )-4- bromo -2- fluorophenyl )-3 -benzene Base urea ( 3 )

2-(2- Bromo- 4- fluoro -5- iodophenyl )-6-((2,4 -dimethoxybenzyl ) amino )-4 -ethyl- 2,7 -naphthyridine -3 (2H) -ketone ( 3a )

To 2-(1-(2-bromo-4-fluoro-5-iodophenyl)-3-ethyl-5-methanyl-2-oxo-1,2-dihydropyridin-4-yl) Add 2,4-Dimethoxybenzylamine (DMBNH ₂ , 68 mg, 0.41 mmol) and HOAc (25 mg, 0.41 mmol) to a DCE (2 mL) solution of acetonitrile (intermediate C , 100 mg, 0.204 mmol) . After the mixture was stirred at room temperature for 3 h, it was diluted with saturated aqueous NaHCO ₃ solution. Extract with 10% MeOH in DCM (5×). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 5-10% MeOH in DCM to obtain 2-(2-bromo-4-fluoro-5-iodophenyl)-6-((2,4-dimethoxybenzyl) )Amino)-4-ethyl-2,7-naphthyridin-3( 2H )-one ( 3a ). MS-ESI (m/z): 638/640 (1:1) [M + 1] ⁺ .

2-(2- Bromo- 5-(( diphenylmethylene ) amino )-4- fluorophenyl )-6-((2,4 -dimethoxybenzyl ) amino )-4- ethyl Base- 2,7 -naphthyridin -3(2H) -one ( 3b )

To 2-(2-bromo-4-fluoro-5-iodophenyl)-6-((2,4-dimethoxybenzyl)-amino)-4-ethyl-2,7-naphthyridine -3(2 H )-ketone ( 3a ) (107 mg, 0.168 mmol) in dioxane (5 mL) was added to benzophenone imine (40 mg, 0.336 mmol), Pd ₂ (dba) ₃ ( 15.3 mg, 0.017 mmol), xantphos (19.4 mg, 0.034 mmol), and Cs ₂ CO ₃ (109 mg, 0.336 mmol). The mixture was reacted at 90°C for 8 h under a nitrogen atmosphere. After cooling, the mixture was diluted with water and extracted with EtOAc (3x). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 40-60% EtOAc in n-hexane to obtain 2-(2-bromo-5-((benzylidene)amino)-4-fluorophenyl)-6-( (2,4-Dimethoxybenzyl)amino)-4-ethyl-2,7-naphthyridin-3( 2H )-one ( 3b ). MS-ESI (m/z): 691/693 (1:1) [M + 1] ⁺ .

2- (5-amino-2-bromo-4-fluorophenyl) -6 - ((2,4-dimethoxybenzyl) amino) -4-ethyl-2,7-naphthyridine - 3(2H) -ketone ( 3c )

To 2-(2-bromo-5-((diphenylmethylene)amino)-4-fluorophenyl)-6-((2,4-dimethoxybenzyl)amino)-4- A solution of ethyl-2,7-naphthyridin-3( 2H )-one ( 3b ) (58 mg, 0.084 mmol) in THF (2 mL) was added to 2 N HCl (0.1 mL). After the mixture was stirred at room temperature for 20 min, it was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (2×). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 50-80% EtOAc in n-hexane to obtain 2-(5-amino-2-bromo-4-fluorophenyl)-6-((2,4-dimethoxy Benzyl)amino)-4-ethyl-2,7-naphthyridin-3( 2H )-one ( 3c ). MS-ESI (m/z): 527/529 (1:1) [M + 1] ⁺ .

1-(4- Bromo -5-(6-((2,4 -dimethoxybenzyl ) amino )-4 -ethyl- 3 -oxo- 2,7 -naphthyridine -2(3H) - yl) -2-fluorophenyl) -3-phenylurea (3d)

To 2-(5-amino-2-bromo-4-fluorophenyl)-6-((2,4-dimethoxybenzyl)-amino)-4-ethyl-2,7-naphthalene Triethylamine (3.7 mg, 0.037 mmol) and phenyl isocyanate (42.3 mg, 0.356 mmol) are added to a solution of pyridine-3( 2H )-one ( 3c ) (18.7 mg, 0.0356 mmol) in THF (0.5 mL) . After the mixture was stirred at room temperature for 16 h, it was diluted with water and extracted with EtOAc (2×). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 10-15% MeOH in DCM to obtain 1-(4-bromo-5-(6-((2,4-dimethoxybenzyl)amino)-4-ethyl 3-oxo-2,7-naphthyridin-2(3H)-yl)-2-fluorophenyl)-3-phenylurea ( 3d ). MS-ESI (m/z): 646/648 (1:1) [M + 1] ⁺ .

1-(5-(6- amino- 4 -ethyl- 3 -oxo- 2,7 -naphthyridin -2(3H) -yl )-4- bromo -2- fluorophenyl )-3 -benzene Base urea ( 3 )

To 1-(4-bromo-5-(6-((2,4-dimethoxybenzyl)amino)-4-ethyl-3-oxo-2,7-naphthyridine-2(3 (H )-yl)-2-fluorophenyl)-3-phenylurea ( 3d ) (13.1 mg, 0.020 mmol) in DCM (0.8 mL) was added TFA (0.8 mL). After the mixture was stirred at room temperature for 30 min, it was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (2×). The extract was dried with Na ₂ SO ₄ and concentrated to obtain a crude product. Purified by silica gel column chromatography, eluted with 4% MeOH and DCM to obtain 1-(5-(6-amino-4-ethyl-3-oxo-2,7-naphthyridine-2(3 H )- Yl)-4-bromo-2-fluorophenyl)-3-phenylurea ( 3 ). MS-ESI (m/z): 496/498 (1:1) [M + 1] ⁺ . Example 4

1-(5-(4- Cyclopropyl- 6-( methylamino )-3 -oxo- 2,7 -naphthyridin -2(3H) -yl )-2,4 -difluorophenyl )- 3 -phenylurea ( 4 )

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) The synthesis of -3-phenylurea ( 4 ) was prepared by referring to the synthesis method described in Example 1, using intermediate F as the starting material. MS-ESI (m/z): 462 (1:1) [M + 1] ⁺ .

1-(4-溴-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 528/530 [M + 1]⁺ 6

1-(4-溴-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 546/548 [M + 1]⁺ 7

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 484 [M + 1]⁺ 8

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 484 [M + 1]⁺ 9

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 502 [M + 1]⁺ 10

1-(5-(6-胺基-4-乙基-3-氧代-2,7-萘啶-2(3H )-基)-4-溴-2-氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 514/516 [M + 1]⁺ 11

1-(5-(6-胺基-4-乙基-3-氧代-2,7-萘啶-2(3H )-基)-4-溴-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 514/516 [M + 1]⁺ 12

1-(5-(6-胺基-4-乙基-3-氧代-2,7-萘啶-2(3H )-基)-4-溴-2-氟苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 532/534 [M + 1]⁺ 13

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-苯基脲 MS-ESI (m/z): 436 [M + 1]⁺ 14

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 454 [M + 1]⁺ 15

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 454 [M + 1]⁺ 16

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 455 [M + 1]⁺ 17

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 454 [M + 1]⁺ 18

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 472 [M + 1]⁺ 19

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 472 [M + 1]⁺ 20

1-(2,4-二氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 472 [M + 1]⁺ 21

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-苯基脲 MS-ESI (m/z): 450 [M + 1]⁺ 22

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 468 [M + 1]⁺ 23

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 468 [M + 1]⁺ 24

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 469 [M + 1]⁺ 25

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 468 [M + 1]⁺ 26

1-(2,4-二氟苯基)-3-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)脲 MS-ESI (m/z): 486 [M + 1]⁺ 27

1-(3,5-二氟苯基)-3-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)脲 MS-ESI (m/z): 486 [M + 1]⁺ 28

1-(2,3-二氟苯基)-3-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)脲 MS-ESI (m/z): 486 [M + 1]⁺ 29

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-苯基脲 MS-ESI (m/z): 464 [M + 1]⁺ 30

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 482 [M + 1]⁺ 31

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 482 [M + 1]⁺ 32

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 483 [M + 1]⁺ 33

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 482 [M + 1]⁺ 34

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 500 [M + 1]⁺ 35

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 500 [M + 1]⁺ 36

1-(2,4-二氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 500 [M + 1]⁺ 37

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 480 [M + 1]⁺ 38

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 480 [M + 1]⁺ 39

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 480 [M + 1]⁺ 40

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-苯基脲 MS-ESI (m/z): 480 [M + 1]⁺ 41

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 42

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 43

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 499 [M + 1]⁺ 44

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 45

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 516 [M + 1]⁺ 46

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 516 [M + 1]⁺ 47

1-(4-氯-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 516 [M + 1]⁺ 48

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 484 [M + 1]⁺ 49

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 485 [M + 1]⁺ 50

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 502 [M + 1]⁺ 51

1-(4-氯-2-氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-苯基脲 MS-ESI (m/z): 452 [M + 1]⁺ 52

1-(4-氯-2-氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 470 [M + 1]⁺ 53

1-(4-氯-2-氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 470 [M + 1]⁺ 54

1-(4-氯-2-氟-5-(4-甲基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 488 [M + 1]⁺ 55

1-(4-氯-5-(4-乙基-6-((2-羥基乙基)胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-苯基脲 MS-ESI (m/z): 496 [M + 1]⁺ 56

(R )-1-(4-氯-5-(4-乙基-6-((2-羥基丙基)胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-苯基脲 MS-ESI (m/z): 450 [M + 1]⁺ 57

(R )-1-(4-氯-5-(4-乙基-6-((2-羥基丙基)胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 528 [M + 1]⁺ 58

1-(4-氯-5-(4-乙基-6-((2-羥基乙基)胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 514 [M + 1]⁺ 59

(S )-1-(4-氯-5-(4-乙基-6-((1-羥基丙烷-2-基)胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-苯基脲 MS-ESI (m/z): 510 [M + 1]⁺ 60

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 502 [M + 1]⁺ 61

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-苯基脲 MS-ESI (m/z): 524/526 [M + 1]⁺ 62

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 542/544 [M + 1]⁺ 63

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 542/544 [M + 1]⁺ 64

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 543/545 [M + 1]⁺ 65

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 542/544 [M + 1]⁺ 66

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 560/562 [M + 1]⁺ 67

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 560/562 [M + 1]⁺ 68

1-(4-溴-2-氟-5-(4-異丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 560/562 [M + 1]⁺ 69

1-(4-溴-2-氟-5-(6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 500/502 [M + 1]⁺ 70

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟-4-甲基苯基)-3-苯基脲 MS-ESI (m/z): 446 [M + 1]⁺ 71

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟-4-甲基苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 464 [M + 1]⁺ 72

1-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟-4-甲基苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 464 [M + 1]⁺ 73

1-(2,4-二氟苯基)-3-(5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟-4-甲基苯基)脲 MS-ESI (m/z): 482 [M + 1]⁺ 74

1-(4-溴-5-(4-乙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 528/530 [M + 1]⁺ 75

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 76

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 77

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(3-(三氟甲基)苯基)脲 MS-ESI (m/z): 530 [M + 1]⁺ 78

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 79

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(5-氟吡啶-3-基)脲 MS-ESI (m/z): 481 [M + 1]⁺ 80

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(3-氟苯基)脲 MS-ESI (m/z): 496 [M + 1]⁺ 81

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 496 [M + 1]⁺ 82

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 496 [M + 1]⁺ 83

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(3-(三氟甲基)苯基)脲 MS-ESI (m/z): 546 [M + 1]⁺ 84

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 514 [M + 1]⁺ 85

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-苯基脲 MS-ESI (m/z): 478 [M + 1]⁺ 86

1-(6-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-3,5-二氟吡啶-2-基)-3-(2-氟苯基)脲 MS-ESI (m/z): 481 [M + 1]⁺ 87

1-(6-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-3,5-二氟吡啶-2-基)-3-(4-氟苯基)脲 MS-ESI (m/z): 481 [M + 1]⁺ 88

1-(6-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-3,5-二氟吡啶-2-基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 499 [M + 1]⁺ 89

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(3,5-二氟苯基)脲 MS-ESI (m/z): 514 [M + 1]⁺ 90

1-(4-氯-5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2-氟苯基)-3-(2,3-二氟苯基)脲 MS-ESI (m/z): 514 [M + 1]⁺ 91

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2,6-二氟苯基)脲 MS-ESI (m/z): 498 [M + 1]⁺ 92

1-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(吡啶-3-基)脲 MS-ESI (m/z): 463 [M + 1]⁺ 93

1-(2-氰基苯基)-3-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)脲 MS-ESI (m/z): 487 [M + 1]⁺ 94

1-(2-氯苯基)-3-(5-(4-環丙基-6-(甲胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)脲 MS-ESI (m/z): 496 [M + 1]⁺ 95

1-(5-(4-環丙基-6-((甲基-d₃ )胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2-氟苯基)脲 MS-ESI (m/z): 483 [M + 1]⁺ 96

1-(5-(4-環丙基-6-((甲基-d₃ )胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 483 [M + 1]⁺ 97

1-(5-(4-環丙基-6-((甲基-d₃ )胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 501 [M + 1]⁺ 98

1-(4-氯-5-(4-乙基-6-(甲胺基)-3-氧代-3,4-二氫-2,7-萘啶-2(1H )-基)-2-氟苯基)-3-(4-氟苯基)脲 MS-ESI (m/z): 486 [M + 1]⁺ 99

1-(2,4-二氟-5-(6-(甲胺基)-3-氧代-4-(2,2,2-三氟乙基)-2,7-萘啶-2(3H )-基)苯基)-3-(2,4-二氟苯基)脲 MS-ESI (m/z): 540 [M + 1]⁺ 100

1-(2,4-二氟-5-(6-(甲胺基)-3-氧代-4-(2,2,2-三氟乙基)-2,7-萘啶-2(3H )-基)苯基)-3-苯基脲 MS-ESI (m/z): 504 [M + 1]⁺ 101

1-(5-(4-環丙基-6-((甲基-d₃ )胺基)-3-氧代-2,7-萘啶-2(3H )-基)-2,4-二氟苯基)-3-苯基脲 MS-ESI (m/z): 465 [M + 1]⁺ 生物活性試驗 Example 5-101 listed in Table 1 basically followed the same method as Example 1-4, and the starting materials used were commercially available or prepared according to literature methods. Table 1 shows the name and structure of Example 5-101. Table 1 Example structure name data 5

1-(4-Bromo-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(4-fluorophenyl)urea MS-ESI (m/z): 528/530 [M + 1] ⁺ 6

1-(4-Bromo-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(2,4-difluorophenyl)urea MS-ESI (m/z): 546/548 [M + 1] ⁺ 7

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(2-fluorophenyl)urea MS-ESI (m/z): 484 [M + 1] ⁺ 8

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(4-fluorophenyl)urea MS-ESI (m/z): 484 [M + 1] ⁺ 9

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(2,4-difluorophenyl)urea MS-ESI (m/z): 502 [M + 1] ⁺ 10

1-(5-(6-amino-4-ethyl-3-oxo-2,7-naphthyridin-2(3 H )-yl)-4-bromo-2-fluorophenyl)-3- (2-Fluorophenyl)urea MS-ESI (m/z): 514/516 [M + 1] ⁺ 11

1-(5-(6-amino-4-ethyl-3-oxo-2,7-naphthyridin-2(3 H )-yl)-4-bromo-2-fluorophenyl)-3- (4-Fluorophenyl)urea MS-ESI (m/z): 514/516 [M + 1] ⁺ 12

1-(5-(6-amino-4-ethyl-3-oxo-2,7-naphthyridin-2(3 H )-yl)-4-bromo-2-fluorophenyl)-3- (2,4-Difluorophenyl)urea MS-ESI (m/z): 532/534 [M + 1] ⁺ 13

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-phenylurea MS-ESI (m/z): 436 [M + 1] ⁺ 14

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(2-fluorophenyl)urea MS-ESI (m/z): 454 [M + 1] ⁺ 15

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(3-fluorophenyl)urea MS-ESI (m/z): 454 [M + 1] ⁺ 16

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 455 [M + 1] ⁺ 17

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(4-fluorophenyl)urea MS-ESI (m/z): 454 [M + 1] ⁺ 18

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(2,4-difluorophenyl)urea MS-ESI (m/z): 472 [M + 1] ⁺ 19

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(3,5-difluorophenyl)urea MS-ESI (m/z): 472 [M + 1] ⁺ 20

1-(2,4-Difluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)- 3-(2,3-difluorophenyl)urea MS-ESI (m/z): 472 [M + 1] ⁺ twenty one

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl)- 3-phenylurea MS-ESI (m/z): 450 [M + 1] ⁺ twenty two

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl)- 3-(2-fluorophenyl)urea MS-ESI (m/z): 468 [M + 1] ⁺ twenty three

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl)- 3-(3-fluorophenyl)urea MS-ESI (m/z): 468 [M + 1] ⁺ twenty four

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl)- 3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 469 [M + 1] ⁺ 25

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl)- 3-(4-fluorophenyl)urea MS-ESI (m/z): 468 [M + 1] ⁺ 26

1-(2,4-Difluorophenyl)-3-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridine-2(3 H )- Yl)-2,4-difluorophenyl)urea MS-ESI (m/z): 486 [M + 1] ⁺ 27

1-(3,5-Difluorophenyl)-3-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridine-2(3 H )- Yl)-2,4-difluorophenyl)urea MS-ESI (m/z): 486 [M + 1] ⁺ 28

1-(2,3-Difluorophenyl)-3-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridine-2(3 H )- Yl)-2,4-difluorophenyl)urea MS-ESI (m/z): 486 [M + 1] ⁺ 29

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-phenylurea MS-ESI (m/z): 464 [M + 1] ⁺ 30

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(2-fluorophenyl)urea MS-ESI (m/z): 482 [M + 1] ⁺ 31

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(3-fluorophenyl)urea MS-ESI (m/z): 482 [M + 1] ⁺ 32

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 483 [M + 1] ⁺ 33

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(4-fluorophenyl)urea MS-ESI (m/z): 482 [M + 1] ⁺ 34

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(2,4-difluorophenyl)urea MS-ESI (m/z): 500 [M + 1] ⁺ 35

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(3,5-difluorophenyl)urea MS-ESI (m/z): 500 [M + 1] ⁺ 36

1-(2,4-Difluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(2,3-difluorophenyl)urea MS-ESI (m/z): 500 [M + 1] ⁺ 37

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(2-fluorophenyl)urea MS-ESI (m/z): 480 [M + 1] ⁺ 38

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(3-fluorophenyl)urea MS-ESI (m/z): 480 [M + 1] ⁺ 39

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(4-fluorophenyl)urea MS-ESI (m/z): 480 [M + 1] ⁺ 40

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-phenylurea MS-ESI (m/z): 480 [M + 1] ⁺ 41

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(2-Fluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 42

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(3-Fluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 43

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 499 [M + 1] ⁺ 44

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(4-Fluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 45

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(2,4-Difluorophenyl)urea MS-ESI (m/z): 516 [M + 1] ⁺ 46

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(3,5-difluorophenyl)urea MS-ESI (m/z): 516 [M + 1] ⁺ 47

1-(4-Chloro-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(2,3-difluorophenyl)urea MS-ESI (m/z): 516 [M + 1] ⁺ 48

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(3-fluorophenyl)urea MS-ESI (m/z): 484 [M + 1] ⁺ 49

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 485 [M + 1] ⁺ 50

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(3,5-difluorophenyl)urea MS-ESI (m/z): 502 [M + 1] ⁺ 51

1-(4-chloro-2-fluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-phenylurea MS-ESI (m/z): 452 [M + 1] ⁺ 52

1-(4-chloro-2-fluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(2-fluorophenyl)urea MS-ESI (m/z): 470 [M + 1] ⁺ 53

1-(4-chloro-2-fluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(4-fluorophenyl)urea MS-ESI (m/z): 470 [M + 1] ⁺ 54

1-(4-chloro-2-fluoro-5-(4-methyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl) -3-(2,4-difluorophenyl)urea MS-ESI (m/z): 488 [M + 1] ⁺ 55

1-(4-Chloro-5-(4-ethyl-6-((2-hydroxyethyl)amino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)- 2-fluorophenyl)-3-phenylurea MS-ESI (m/z): 496 [M + 1] ⁺ 56

( R )-1-(4-Chloro-5-(4-ethyl-6-((2-hydroxypropyl)amino)-3-oxo-2,7-naphthyridine-2(3 H ) -Yl)-2-fluorophenyl)-3-phenylurea MS-ESI (m/z): 450 [M + 1] ⁺ 57

( R )-1-(4-Chloro-5-(4-ethyl-6-((2-hydroxypropyl)amino)-3-oxo-2,7-naphthyridine-2(3 H ) -Yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea MS-ESI (m/z): 528 [M + 1] ⁺ 58

1-(4-Chloro-5-(4-ethyl-6-((2-hydroxyethyl)amino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)- 2-fluorophenyl)-3-(4-fluorophenyl)urea MS-ESI (m/z): 514 [M + 1] ⁺ 59

( S )-1-(4-Chloro-5-(4-ethyl-6-((1-hydroxypropan-2-yl)amino)-3-oxo-2,7-naphthyridine-2( 3 H )-yl)-2-fluorophenyl)-3-phenylurea MS-ESI (m/z): 510 [M + 1] ⁺ 60

1-(4-chloro-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(2,3-difluorophenyl)urea MS-ESI (m/z): 502 [M + 1] ⁺ 61

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-phenylurea MS-ESI (m/z): 524/526 [M + 1] ⁺ 62

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(2-Fluorophenyl)urea MS-ESI (m/z): 542/544 [M + 1] ⁺ 63

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(3-Fluorophenyl)urea MS-ESI (m/z): 542/544 [M + 1] ⁺ 64

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 543/545 [M + 1] ⁺ 65

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(4-Fluorophenyl)urea MS-ESI (m/z): 542/544 [M + 1] ⁺ 66

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(2,4-Difluorophenyl)urea MS-ESI (m/z): 560/562 [M + 1] ⁺ 67

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(3,5-difluorophenyl)urea MS-ESI (m/z): 560/562 [M + 1] ⁺ 68

1-(4-Bromo-2-fluoro-5-(4-isopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl )-3-(2,3-difluorophenyl)urea MS-ESI (m/z): 560/562 [M + 1] ⁺ 69

1-(4-Bromo-2-fluoro-5-(6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)phenyl)-3-(4 -Fluorophenyl)urea MS-ESI (m/z): 500/502 [M + 1] ⁺ 70

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluoro-4-methylphenyl )-3-phenylurea MS-ESI (m/z): 446 [M + 1] ⁺ 71

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluoro-4-methylphenyl )-3-(2-Fluorophenyl)urea MS-ESI (m/z): 464 [M + 1] ⁺ 72

1-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluoro-4-methylphenyl )-3-(4-Fluorophenyl)urea MS-ESI (m/z): 464 [M + 1] ⁺ 73

1-(2,4-Difluorophenyl)-3-(5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridine-2(3 H )- (Yl)-2-fluoro-4-methylphenyl)urea MS-ESI (m/z): 482 [M + 1] ⁺ 74

1-(4-Bromo-5-(4-ethyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl) -3-(2-fluorophenyl)urea MS-ESI (m/z): 528/530 [M + 1] ⁺ 75

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(2,4-difluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 76

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(3,5-difluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 77

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(3-(trifluoromethyl)phenyl)urea MS-ESI (m/z): 530 [M + 1] ⁺ 78

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(2,3-difluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 79

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(5-fluoropyridin-3-yl)urea MS-ESI (m/z): 481 [M + 1] ⁺ 80

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(3-Fluorophenyl)urea MS-ESI (m/z): 496 [M + 1] ⁺ 81

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(2-Fluorophenyl)urea MS-ESI (m/z): 496 [M + 1] ⁺ 82

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(4-Fluorophenyl)urea MS-ESI (m/z): 496 [M + 1] ⁺ 83

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(3-(Trifluoromethyl)phenyl)urea MS-ESI (m/z): 546 [M + 1] ⁺ 84

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(2,4-Difluorophenyl)urea MS-ESI (m/z): 514 [M + 1] ⁺ 85

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-phenylurea MS-ESI (m/z): 478 [M + 1] ⁺ 86

1-(6-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-3,5-difluoropyridine-2 -Yl)-3-(2-fluorophenyl)urea MS-ESI (m/z): 481 [M + 1] ⁺ 87

1-(6-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-3,5-difluoropyridine-2 -Yl)-3-(4-fluorophenyl)urea MS-ESI (m/z): 481 [M + 1] ⁺ 88

1-(6-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-3,5-difluoropyridine-2 -Yl)-3-(2,4-difluorophenyl)urea MS-ESI (m/z): 499 [M + 1] ⁺ 89

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(3,5-difluorophenyl)urea MS-ESI (m/z): 514 [M + 1] ⁺ 90

1-(4-Chloro-5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2-fluorophenyl )-3-(2,3-difluorophenyl)urea MS-ESI (m/z): 514 [M + 1] ⁺ 91

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(2,6-difluorophenyl)urea MS-ESI (m/z): 498 [M + 1] ⁺ 92

1-(5-(4-Cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4-difluorophenyl) -3-(pyridin-3-yl)urea MS-ESI (m/z): 463 [M + 1] ⁺ 93

1-(2-cyanophenyl)-3-(5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl )-2,4-Difluorophenyl)urea MS-ESI (m/z): 487 [M + 1] ⁺ 94

1-(2-chlorophenyl)-3-(5-(4-cyclopropyl-6-(methylamino)-3-oxo-2,7-naphthyridin-2(3 H )-yl) -2,4-Difluorophenyl)urea MS-ESI (m/z): 496 [M + 1] ⁺ 95

1-(5-(4-Cyclopropyl-6-((methyl- d ₃ )amino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4 -Difluorophenyl)-3-(2-fluorophenyl)urea MS-ESI (m/z): 483 [M + 1] ⁺ 96

1-(5-(4-Cyclopropyl-6-((methyl- d ₃ )amino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4 -Difluorophenyl)-3-(4-fluorophenyl)urea MS-ESI (m/z): 483 [M + 1] ⁺ 97

1-(5-(4-Cyclopropyl-6-((methyl- d ₃ )amino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4 -Difluorophenyl)-3-(2,4-difluorophenyl)urea MS-ESI (m/z): 501 [M + 1] ⁺ 98

1-(4-Chloro-5-(4-ethyl-6-(methylamino)-3-oxo-3,4-dihydro-2,7-naphthyridin-2(1 H )-yl) -2-fluorophenyl)-3-(4-fluorophenyl)urea MS-ESI (m/z): 486 [M + 1] ⁺ 99

1-(2,4-Difluoro-5-(6-(methylamino)-3-oxo-4-(2,2,2-trifluoroethyl)-2,7-naphthyridine-2( 3 H )-yl)phenyl)-3-(2,4-difluorophenyl)urea MS-ESI (m/z): 540 [M + 1] ⁺ 100

1-(2,4-Difluoro-5-(6-(methylamino)-3-oxo-4-(2,2,2-trifluoroethyl)-2,7-naphthyridine-2( 3 H )-yl)phenyl)-3-phenylurea MS-ESI (m/z): 504 [M + 1] ⁺ 101

1-(5-(4-Cyclopropyl-6-((methyl- d ₃ )amino)-3-oxo-2,7-naphthyridin-2(3 H )-yl)-2,4 -Difluorophenyl)-3-phenylurea MS-ESI (m/z): 465 [M + 1] ⁺ Biological activity test

The MTS detection kit was purchased from Promega. DMEM medium, RPMI-1640 medium fetal bovine serum and penicillin-streptomycin were purchased from BI. Glutamine and dimethylsulfoxide (DMSO) were purchased from Sigma. The medium of Kasumi-1 is RPMI-1640+ 25% FBS.

By measuring the inhibitory effect of the compound on the proliferation of Kasumi-1 (KIT exon 17 N822K) cells, the inhibitory effect of the compound on the KIT mutation was detected. The cells were treated with digestive enzymes, and Kasumi-1 cells were seeded on a 96-well culture dish at a cell concentration of 30,000/well, and incubated at 37°C, 5% CO _{2 for} 4 h. Compounds with different concentrations (final concentrations 10000, 3333.3, 1111.1, 370, 123, 41, 14, 4.6 and 1.5 nM) were added to the 96-well cell culture plate in 3 parallel wells, and incubated at 37°C, 5% CO _{2 for} 120 h. Add MTS to each well at a concentration of 20 µL MTS per 100 µL medium. After incubating for 2 h, add 25 µL 10% SDS to each well to stop the reaction. Measure the absorbance at 490 nm and 650 nm with a microplate reader. Calculated using GraphPad Prism 5.0 IC _50.

The selected compounds prepared above were tested according to the biological methods described herein. The results are shown in the table below: Table 2 Example Kasumi-1 Example Kasumi-1 Example Kasumi-1 IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM) 1 13 31 1 61 62 2 5 32 80 62 54 3 39 33 1 63 65 4 1 34 1 65 45 5 13 35 10 66 70 6 12 36 27 67 118 7 8 37 3 70 17 8 8 38 5 71 73 9 12 39 6 72 31 11 34 40 15 73 28 12 42 41 14 74 14 13 7 42 18 75 6 14 2 43 27 76 43 15 13 44 16 77 118 16 14 45 30 78 11 17 1 46 19 79 47 18 2 47 92 80 1 19 42 48 75 81 1 20 7 49 2 82 1 twenty one 9 50 39 84 1 twenty two 26 51 39 85 3 twenty three 7 52 15 89 40 twenty four 10 53 17 90 25 25 34 54 15 91 9 26 11 55 112 94 11 27 13 56 56 95 6 28 3 57 41 96 3 29 1 58 42 97 2 30 2 60 2 / /

Claims (22)

A compound represented by formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein: Z is selected from CR ^X and N; L is selected from -NR ^A C(O), -C(O)NR ^A , -NR ^A C(O)NR ^B And -NR ^A SO ₂ ; R ¹ is -NR ^A1 R ^B1 ; R ^{2 is} selected from hydrogen, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and C _3-10 cycloalkyl-C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein each of the alkyl, cycloalkyl, alkenyl and alkynyl groups is unsubstituted or has at least one, such as 1, 2 , 3 or 4, independently selected from R ^X substituents; each R ^{3 is} independently selected from halogen, CN and C _1-10 alkyl, wherein the alkyl is unsubstituted or is substituted by at least one, such as 1, 2, 3 or 4, independently substituted by substituents selected from R ^X ; R ^{4 is} selected from aryl and heteroaryl, wherein aryl and heteroaryl are respectively unsubstituted or at least one, such as 1, 2 , 3 or 4 substituents independently selected from R ^X ; R ^{5 is} selected from hydrogen, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and C _3-10 cycloalkyl-C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein each of alkyl, cycloalkyl, alkenyl and alkynyl is unsubstituted or has at least one, such as 1, 2, 3 or 4, independently selected from R ^X substituents; R ^A and R ^B are independently selected from hydrogen and C _1-10 alkyl, wherein the alkyl is unsubstituted or is substituted by at least one, such as 1, 2 , 3 or 4 substituents independently selected from R ^X ; R ^A1 and R ^B1 are independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl- C _1-4 alkyl, -C(O)R ^A2 , -C(O)OR ^A2 , -C(O)NR ^A2 R ^B2 , -S(O) _r R ^A2 and -S(O) _r NR ^A2 R ^B2 , wherein each alkyl group and cycloalkyl group are unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R ^X substituents; or R ^A1 and R ^B1 together together The single or multiple atoms connected to them together form a 4-12 member heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. The ring may be unsubstituted Or substituted by 1, 2 or 3 substituents selected from R ^X ; each R ^A2 and R ^{B2 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, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or is at least One, such as 1, 2, 3 or 4, independently selected from the substituents of R ^X ; or each R ^A2 and R ^B2 together with the single or multiple atoms connected to them form a 4-12 member heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. May be unsubstituted or substituted by 1, 2 or 3 substituents selected from R ^X ; each R ^{X 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, _{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 C(O)R ^a1 , -(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(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 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 ) 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 C(O )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r 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 S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 And -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is not Substituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y ; each R ^a1 and R ^{b1 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 Group, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, independently selected from R ^Y ; or each of R ^a1 and R ^b1 together with one or more of their connected Atoms 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 or be 1, 2, or 3 One substituent 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 ring Alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and Heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is unsubstituted or is substituted by at least one, such as 1, 2, 3 or 4 substituents independently selected from R ^Y ; or each of R ^c1 and R ^d1 together with the single or multiple carbon atoms connected to them form a group containing 0, 1 or 2 independently selected from A 3-12 membered ring of heteroatoms of oxygen, sulfur and nitrogen, the ring may be unsubstituted or substituted with 1, 2 or 3 substituents selected from R ^Y ; 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 ring Alkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 Alkyl, halogen, CN, NO ₂ , -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t C(O)R ^a2 ,- (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(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 C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(=NR ^e2 )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 NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r 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 S(O) ₂ OR ^b2 , -(CR ^c2 R ^d2 ) _t OS(O) ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)( =NR ^e2 )R ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O) ₂ NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 S(O)(=NR ^e2 )NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P (O) R ^a2 R ^b2 and -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are unsubstituted or have at least one, such as 1, 2, 3 or 4, independently selected from hydroxyl, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino group, C _3-10 cycloalkylamino group, substitution of di(C _1-10 alkyl)amino group; each R ^a2 and each R ^{b2 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, C _1-10 alkoxy, C _3-10 cycloalkyloxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl ) Amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which Alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl Is unsubstituted or by at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkane Amino group, C _3-10 cycloalkylamino group, substitution of di(C _1-10 alkyl)amino group; or each of R ^a2 and R ^b2 together with the single or multiple atoms connected to them form one 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 or 1 or 2 selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1 -10} Alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino, substituent substitution of di(C _1-10 alkyl)amino group ; Each of 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} cycloalkyloxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl) Amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, each of which is alkyl Group, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are Unsubstituted or by at least one, such as 1, 2, 3 or 4, independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamine Group, C _3-10 cycloalkylamino group, bis(C _1-10 alkyl)amino group substitution; or each of R ^c2 and R ^d2 together with the single or multiple carbon atoms connected to them form one A 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, the ring may be unsubstituted or 1 or 2 selected from halogen, CN, C _1-10 alkane Group, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, hydroxy, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio , C _3-10 cycloalkylthio group, amino group, C _1-10 cycloalkylamino group, C _3-10 cycloalkylamino group, substituent substitution of di(C _1-10 alkyl)amino group; each R ^e2 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; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is CH. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is N. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L is selected from -NR ^AC (O)-, -C(O)NR ^A -and -NR ^AC (O) NR ^B -. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein L is -NR ^A C(O)NR ^B -. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is -NHC(O)NH-. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R ⁴ is an aryl group, wherein the aryl group is unsubstituted or substituted with at least one substituent independently selected from R ^X. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is phenyl, wherein phenyl is unsubstituted or is substituted by at least one substituent independently selected from halogen, CN and C _1-10 alkyl Substitution, where the alkyl group is unsubstituted or substituted with at least one substituent independently selected from halogen. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R ⁴ is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by at least one substituent independently selected from R ^X replace. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is pyridyl, wherein pyridyl is unsubstituted or is substituted by at least one substituent independently selected from halogen, CN and C _1-10 alkyl Substitution, where the alkyl group is unsubstituted or substituted with at least one substituent independently selected from halogen. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein R ¹ is -NR ^A1 R ^B1 , wherein R ^A1 and R ^B1 are each independently selected from hydrogen and C _1-10 alkyl , Wherein the alkyl group is unsubstituted or substituted with at least one substituent independently selected from R ^X. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from -NHCH ₃ , -NH ₂ ,

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with

. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein R ² is hydrogen. The compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein each R ^{3 is} independently selected from halogen and C _1-10 alkyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein m is 2. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the substructure of formula (I)

Selected from

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with

. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R ^{5 is} selected from hydrogen, C _1-10 alkyl and C _3-10 cycloalkyl, wherein each alkyl and ring The alkyl group is unsubstituted or substituted with at least one substituent independently selected from halogen. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from hydrogen, methyl, ethyl, isopropyl and cycloalkyl, wherein methyl, ethyl, isopropyl and cycloalkyl Is unsubstituted or substituted with at least one substituent independently selected from halogen. A compound selected from:

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, And its pharmaceutically acceptable salts. The pharmaceutical composition comprises the compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A method for ameliorating or preventing a condition responsive to inhibition of PDGFR, comprising administering to an individual in need an effective amount of the compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or at least one drug thereof Composition, and optionally combined with a second therapeutic agent. Use of the compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases mediated by PDGFR.