本發明涉及一類新型化合物、其藥學可接受的鹽及其藥學組合物，以及作為藥物的應用。The present invention relates to a new type of compound, its pharmaceutically acceptable salt and its pharmaceutical composition, and its application as a medicine.
在一個方面，本發明提供式（I）所示的化合物：(I) 或其藥學上可接受的鹽，其中， Q選自C3-10
環烷基、雜環基、芳基和雜芳基，其中環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； L選自化學鍵-(CRC0
RD0
)u
-、-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(=NRE0
)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)NRB0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
S(O)r
(CRC0
RD0
)t
-和-(CRC0
RD0
)u
NRA0
S(O)r
NRB0
(CRC0
RD0
)t
-； X1
、X2
、X3
和X4
獨立選自CRX’
和N； Y選自CR4
和N； R1
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA1
RB1
、-ORA1
、-C(O)RA1
、-C(=NRE1
)RA1
、-C(=N-ORB1
)RA1
、-C(O)ORA1
、-OC(O)RA1
、-C(O)NRA1
RB1
、-NRA1
C(O)RB1
、-C(=NRE1
)NRA1
RB1
、-NRA1
C(=NRE1
)RB1
、-OC(O)NRA1
RB1
、-NRA1
C(O)ORB1
、-NRA1
C(O)NRA1
RB1
、-NRA1
C(S)NRA1
RB1
、-NRA1
C(=NRE1
)NRA1
RB1
、-S(O)r
RA1
、-S(O)(=NRE1
)RB1
、-N=S(O)RA1
RB1
、-S(O)2
ORA1
、-OS(O)2
RA1
、-NRA1
S(O)r
RB1
、-NRA1
S(O)(=NRE1
)RB1
、-S(O)r
NRA1
RB1
、-S(O)(=NRE1
)NRA1
RB1
、-NRA1
S(O)2
NRA1
RB1
、-NRA1
S(O)(=NRE1
)NRA1
RB1
、-P(O)RA1
RB1
和-P(O)(ORA1
)(ORB1
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX1
的取代基取代； R2
選自氫、鹵素、CN、NO2
、-NRA2
RB2
、-ORA2
、-C(O)NRA2
RB2
和C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX2
的取代基取代； R3
選自氫、鹵素、CN、NO2
、-NRA3
RB3
、-ORA3
、-C(O)NRA2
RB2
和C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX3
的取代基取代； R4
選自氫、鹵素、CN、NO2
、-NRA4
RB4
、-ORA4
和C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX4
的取代基取代； R5
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA5
RB5
、-ORA5
、-C(O)RA5
、-C(=NRE5
)RA5
、-C(=N-ORB5
)RA5
、-C(O)ORA5
、-OC(O)RA5
、-C(O)NRA5
RB5
、-NRA5
C(O)RB5
、-C(=NRE5
)NRA5
RB5
、-NRA5
C(=NRE5
)RB5
、-OC(O)NRA5
RB5
、-NRA5
C(O)ORB5
、-NRA5
C(O)NRA5
RB5
、-NRA5
C(S)NRA5
RB5
、-NRA5
C(=NRE5
)NRA5
RB5
、-S(O)r
RA5
、-S(O)(=NRE5
)RB5
、-N=S(O)RA5
RB5
、-S(O)2
ORA5
、-OS(O)2
RA5
、-NRA5
S(O)r
RB5
、-NRA5
S(O)(=NRE5
)RB5
、-S(O)r
NRA5
RB5
、-S(O)(=NRE5
)NRA5
RB5
、-NRA5
S(O)2
NRA5
RB5
、-NRA5
S(O)(=NRE5
)NRA5
RB5
、-P(O)RA5
RB5
和-P(O)(ORA5
)(ORB5
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX5
的取代基取代； 每個RA0
和RB0
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX0
的取代基取代； 或每個「RA0
和RB0
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX0
基團取代； 每個RA1
和RB1
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX1
的取代基取代； 或每個「RA1
和RB1
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX1
基團取代； 每個RA2
和RB2
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX2
的取代基取代； 或每個「RA2
和RB2
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX2
基團取代； 每個RA3
和RB3
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX3
的取代基取代； 或每個「RA3
和RB3
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX3
基團取代； 每個RA4
和RB4
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX4
的取代基取代； 或每個「RA4
和RB4
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX4
基團取代； 每個RA5
和RB5
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX5
的取代基取代； 或每個「RA5
和RB5
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX5
基團取代； 每個RC0
和RD0
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX0
的取代基取代； 或RC0
和RD0
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧、硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RX0
基團取代； 每個RE0
、RE1
和RE5
獨立選自氫、C1-10
烷基、CN、NO2
、-ORa1
、-SRa1
、-S(O)r
Ra1
、-C(O)Ra1
、-C(O)ORa1
、-C(O)NRa1
Rb1
和-S(O)r
NRa1
Rb1
； 每個RX
、RX’
、RX0
、RX1
、RX2
、RX3
、RX4
和RX5
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-(CRc1
Rd1
)t
NRa1
Rb1
、-(CRc1
Rd1
)t
ORb1
、-(CRc1
Rd1
)t
C(O)Ra1
、-(CRc1
Rd1
)t
C(=NRe1
)Ra1
、-(CRc1
Rd1
)t
C(=N-ORb1
)Ra1
、-(CRc1
Rd1
)t
C(O)ORb1
、-(CRc1
Rd1
)t
OC(O)Rb1
、-(CRc1
Rd1
)t
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)Rb1
、-(CRc1
Rd1
)t
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)Rb1
、-(CRc1
Rd1
)t
OC(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)ORb1
、-(CRc1
Rd1
)t
NRa1
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(S)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)r
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
N=S(O)Ra1
Rb1
、-(CRc1
Rd1
)t
S(O)2
ORb1
、-(CRc1
Rd1
)t
OS(O)2
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)r
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
S(O)r
NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)2
NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
P(O)Ra1
Rb1
和-(CRc1
Rd1
)t
P(O)(ORa1
)(ORb1
)，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獨立選自RY
的取代基取代； 每個Ra1
和Rb1
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Ra1
和Rb1
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RY
基團取代； 每個Rc1
和Rd1
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Rc1
和Rd1
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RY
基團取代； 每個Re1
獨立選自氫、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、CN、NO2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-C(O)Ra2
、-C(O)ORa2
、-S(O)r
NRa2
Rb2
和-C(O)NRa2
Rb2
； 每個RY
獨立地選自C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-NRa2
Rb2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-S(O)2
ORa2
、-OS(O)2
Rb2
、-S(O)r
NRa2
Rb2
、-P(O)Ra2
Rb2
、-P(O)(ORa2
)(ORb2
)、-(CRc2
Rd2
)t
NRa2
Rb2
、-(CRc2
Rd2
)t
ORb2
、-(CRc2
Rd2
)t
SRb2
、-(CRc2
Rd2
)t
S(O)r
Rb2
、-(CRc2
Rd2
)t
P(O)Ra2
Rb2
、-(CRc2
Rd2
)t
P(O)(ORa2
)(ORb2
)、 -(CRc2
Rd2
)t
CO2
Rb2
、-(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)Rb2
、-(CRc2
Rd2
)t
NRa2
CO2
Rb2
、-(CRc2
Rd2
)t
OC(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
SO2
NRa2
Rb2
、-NRa2
(CRc2
Rd2
)t
NRa2
Rb2
、-O(CRc2
Rd2
)t
NRa2
Rb2
、-S(CRc2
Rd2
)t
NRa2
Rb2
、-S(O)r
(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)Ra2
、-C(O)(CRc2
Rd2
)t
ORb2
、-C(O)(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)(CRc2
Rd2
)t
SRb2
、-C(O)(CRc2
Rd2
)t
S(O)r
Rb2
、-CO2
Rb2
、-CO2
(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-OC(O)Ra2
、-CN、-C(O)NRa2
Rb2
、-NRa2
C(O)Rb2
、-OC(O)NRa2
Rb2
、-NRa2
C(O)ORb2
、-NRa2
C(O)NRa2
Rb2
、-NRa2
S(O)r
Rb2
、-CRa2
(=N-ORb2
)、-C(=NRe2
)Ra2
、-C(=NRe2
)NRa2
Rb2
、-NRa2
C(=NRe2
)NRa2
Rb2
、-CHF2
、-CF3
、-OCHF2
和-OCF3
，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獨立選自羥基、CN、氨基、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Ra2
和Rb2
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基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、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Ra2
和Rb2
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Rc2
和Rd2
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Rc2
和Rd2
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Re2
獨立選自氫、CN、NO2
、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、-C(O)C1-4
烷基、-C(O)C3-10
環烷基、-C(O)OC1-4
烷基、-C(O)OC3-10
環烷基、-C(O)N(C1-4
烷基)2
、-C(O)N(C3-10
環烷基)2
、-S(O)2
C1-4
烷基、-S(O)2
C3-10
環烷基、-S(O)2
N(C1-4
烷基)2
和-S(O)2
N(C3-10
環烷基)2
； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4； 每個u獨立選自0、1、2、3和4。In one aspect, the present invention provides a compound represented by formula (I): 
[11] 在式（1）的一個實施例，本發明提供一個化合物或其藥學可接受的鹽，其中Y是CR4
，化合物如式（II）所示：(II) 其中Q、L、R1
、R2
、R3
、R4
、R5
、X1
、X2
、X3
和X4
的定義與式（I）相同。[11] In an embodiment of formula (1), the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein Y is CR 4 , and the compound is represented by formula (II): (II) The definitions of Q, L, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 and X 4 are the same as those of formula (I).
另一方面，本發明提供藥物組合物，其包含式（I）化合物或至少一個其藥學上可接受的鹽，以及藥學上可接受的賦形劑。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
另一方面，本發明提供用於調節BTK的方法，該方法包括對有需要的系統或個體給予治療有效量的式（I）化合物或其藥學上可接受的鹽或其藥物組合物，從而調節BTK。In another aspect, the present invention provides a method for regulating BTK, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a system or individual in need, thereby regulating BTK.
另一方面，本發明還提供了一種治療、改善或預防對抑制BTK回應的病症的方法，包括給予有需要的系統或個體有效量的式（I）化合物或其藥學上可接受的鹽或其藥物組合物，或任選地與另一治療藥物聯合使用，治療上述病症。On the other hand, the present invention also provides a method for treating, ameliorating or preventing a disease responsive to BTK inhibition, comprising administering to a system or individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof The pharmaceutical composition, or optionally in combination with another therapeutic agent, treats the above-mentioned conditions.
或者，本發明提供了式（I）化合物或其藥學上可接受的鹽在製備用於治療由BTK介導的病症的藥物中的用途。在特定實施例中，所述化合物可單獨或與另一治療藥物聯合使用治療BTK介導的病症。Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases mediated by BTK. In certain embodiments, the compound can be used alone or in combination with another therapeutic agent to treat BTK-mediated conditions.
或者，本發明提供了式（I）化合物或其藥學上可接受的鹽，用於治療BTK介導的病症。Alternatively, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BTK-mediated conditions.
特定地，其中所述病症包括但不僅限於自身免疫性疾病、異種免疫疾病、過敏性疾病、炎症性疾病或細胞增殖異常。Specifically, the conditions include, but are not limited to, autoimmune diseases, xenoimmune diseases, allergic diseases, inflammatory diseases, or abnormal cell proliferation.
此外，本發明提供了治療BTK介導病症的方法，該方法包括給予有需要的系統或個體有效量的式（I）化合物或其藥學上可接受的鹽或藥物組合物，或任選地與另一治療藥物聯合使用，治療上述病症。In addition, the present invention provides a method for treating BTK-mediated 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 optionally with Another therapeutic drug is used in combination to treat the above-mentioned diseases.
或者，本發明提供了式（I）化合物或藥學上可接受的鹽在製備用於治療由BTK介導疾病的藥物的用途。在特定實施例中，所述化合物可單獨或與化療劑聯合使用治療上述細胞增殖異常。Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt in the preparation of a medicament for the treatment of diseases mediated by BTK. In a specific embodiment, the compound can be used alone or in combination with a chemotherapeutic agent to treat the aforementioned abnormal cell proliferation.
特定地，其中所述病症包括但不限於自身免疫性疾病、異種免疫疾病、過敏性疾病、炎症性疾病或細胞增殖異常。Specifically, the conditions include, but are not limited to, autoimmune diseases, xenoimmune diseases, allergic diseases, inflammatory diseases, or abnormal cell proliferation.
在某些實施例中，病症為細胞增殖異常。在某個實施例中，細胞增殖異常為B細胞增殖異常，包括但不僅限於，B細胞惡性腫瘤，B細胞慢性淋巴細胞性淋巴瘤，慢性淋巴細胞白血病，B細胞幼淋巴細胞白血病，淋巴漿細胞性淋巴瘤，多發性硬化症，小淋巴細胞性淋巴瘤，套細胞淋巴瘤，B細胞非霍奇金淋巴瘤，活化B細胞樣彌漫性大B細胞淋巴瘤，多發性骨髓瘤，彌漫性大B細胞淋巴瘤，濾泡性淋巴瘤，原發性滲出性淋巴瘤，伯基特淋巴瘤/白血病，淋巴瘤樣肉芽腫病和漿細胞瘤。In certain embodiments, the disorder is abnormal cell proliferation. In an embodiment, the abnormal cell proliferation is abnormal B cell proliferation, including but not limited to, B-cell malignant tumor, B-cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell young lymphocytic leukemia, lymphoplasmic cells Lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin’s lymphoma, activated B-cell-like diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia, lymphomatoid granulomatosis and plasmacytoma.
在某些實施例中，病症為自身免疫疾病，包括但不僅限於，類風濕性關節炎，銀屑病關節炎，銀屑病，骨關節炎，幼年型關節炎，炎症性腸病，克羅恩病，潰瘍性結腸炎，重症肌無力，橋本氏甲狀腺炎，多發性硬化症，急性播散性腦脊髓炎，愛迪生氏病，強直性脊柱炎，抗磷脂抗體綜合征，再生障礙性貧血，自身免疫性肝炎，乳糜泄，古德帕斯徹氏綜合征，特發性血小板減少性紫癜，硬皮病，原發性膽汁性肝硬化，賴特爾綜合症，銀屑病，自主神經功能障礙，神經性肌強直，間質性膀胱炎，紅斑狼瘡，系統性紅斑狼瘡和狼瘡性腎炎。In certain embodiments, the condition is an autoimmune disease, including but not limited to rheumatoid arthritis, psoriatic arthritis, psoriasis, osteoarthritis, juvenile arthritis, inflammatory bowel disease, Crohn En’s disease, ulcerative colitis, myasthenia gravis, Hashimoto’s thyroiditis, multiple sclerosis, acute disseminated encephalomyelitis, Edison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, Autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, autonomic nervous function Disorders, neuromuscular rigidity, interstitial cystitis, lupus erythematosus, systemic lupus erythematosus and lupus nephritis.
在某些實施例中，病症為異種免疫疾病，包括但不僅限於，移植物抗宿主病，移植，輸血，過敏性反應(anaphylaxis)，過敏(allergy)，I型超敏反應，過敏性結膜炎，過敏性鼻炎和過敏性皮炎。In certain embodiments, the disorder is a xenoimmune disease, including but not limited to, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, Allergic rhinitis and allergic dermatitis.
在某些實施例中，病症為炎症性疾病，包括但不僅限於，哮喘，闌尾炎，瞼緣炎，細支氣管炎，支氣管炎，滑液囊炎，宮頸炎，膽管炎，膽囊炎，大腸炎，結膜炎，膀胱炎，淚腺炎，皮炎，皮肌炎，腦炎，心內膜炎，子宮內膜炎，小腸炎，小腸結腸炎，上髁炎，附睾炎，筋膜炎，纖維組織炎，胃炎，腸胃炎，肝炎，化膿性汗腺炎，喉炎，乳腺炎，腦膜炎，脊髓炎，心肌炎，肌炎，腎炎，卵巢炎，睾丸炎，骨炎，耳炎，胰腺炎，腮腺炎，心包炎，腹膜炎，咽炎，胸膜炎，靜脈炎，局限性肺炎，肺炎，直腸炎，前列腺炎，腎盂腎炎，鼻炎，輸卵管炎，鼻竇炎，口腔炎，滑膜炎，肌腱炎，扁桃腺炎，葡萄膜炎，陰道炎，脈管炎和外陰炎。In certain embodiments, the condition is an inflammatory disease, including but not limited to asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, synovial cystitis, cervicitis, cholangitis, cholecystitis, colitis, Conjunctivitis, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis , Gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis , Peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis , Vaginitis, vasculitis and vulvitis.
在使用本發明所述化合物的上述方法中，式（I）化合物或其藥學上可接受的鹽可被給予包含細胞或組織的系統，或包括哺乳動物個體，如人或動物個體在內的個體。 術語In the above method of using the compound of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system containing cells or tissues, or individuals including mammalian individuals, such as human or animal individuals. . the term
除非另有定義，本專利使用的所有技術和科學術語與該領域專業人員通常理解的含義相同。除非另有說明，本專利參考的所有專利、專利申請、公開披露的資料等全文納入參考文獻。如本專利中同一術語有多個定義，以本節中的定義為准。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.
需要理解的是，前文的一般描述和後文的詳細描述僅僅是解釋性的，對任何請求項都無限制性。在本專利申請中，使用的單數包含複數，除非另有說明。需要注意的是，說明書和所附請求項書中，單數形式指代如「一」、「一個」、「這個」，包含複數指代，除非文中另有說明。還需注意的是，「或」代表「和/或」，除非另有說明。此外，「包含」、「包括」等類似術語不是限制性的。It should be understood that the general description above and the detailed description below are only explanatory and not restrictive to any request items. 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 attached request, the singular form refers to such as "one", "one", "this", including plural designations, unless otherwise specified in the text. It should also be noted that "or" means "and/or" unless otherwise stated. In addition, similar terms such as "including" and "including" are not restrictive.
除非另有說明，本專利使用的質譜、核磁共振、高效液相色譜、紅外和紫外/可見光譜和藥理學常規技術是現有技術。除非有特別定義，本專利中的分析化學、有機合成化學、藥物和製藥化學中所涉及的命名、實驗方法和技術均是已知的。標準技術可用于化學合成、化學分析、藥物製備、製劑和給藥，以及治療患者。反應和純化技術可參考製造商說明書，或參考已知常用技術，或參照本專利中描述方法實施。上述的技術和操作可運用已知常規的和本說明書中所引用文獻的方法實施。在說明書中，基團和取代基可由該領域專業人員選擇，以形成穩定結構和化合物。Unless otherwise specified, the mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy and pharmacological conventional 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.
當用化學式指代取代基時，化學式中的取代基從左至右書寫與從右至左書寫相同。例如，CH2
O與OCH2
相同。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.
「取代」是指氫原子被取代基取代。需要注意的是，特定原子上的取代基是被其價態限制的。"Substitution" means that the hydrogen atom is replaced by a substituent. It should be noted that the substituents on specific atoms are restricted by their valence.
本文使用的術語「Ci-j
」或「i-j 元」是指該部分具有i-j個碳原子或i-j個原子。例如，「C1-6
烷基」是指所述烷基具有1-6個碳原子。同樣，C3-10
環烷基是指所述環烷基具有3-10個碳原子。The term "C ij "or "ij element" 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, a C 3-10 cycloalkyl group means that the cycloalkyl group has 3-10 carbon atoms.
當任何變數（如R）出現在化合物的結構上超過一次時，其在每種情況下獨立定義。因此，例如，如果基團被0-2個R取代，則該基團可以任選地被至多兩個R取代，並且R在每種情況下具有獨立的選擇。另外，僅當這樣的組合將產生穩定的化合物時，才允許取代基和/或其變體的組合。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 may 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.
「一個或多個」或「至少一個」是指一個，兩個，三個，四個，五個，六個，七個，八個，九個或更多個。"One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.
除非另有說明，否則術語「雜」是指雜原子或雜原子基團（即含有雜原子的基團），即碳和氫原子以外的原子或含有這些原子的基團。優選地，雜原子獨立地選自O，N，S，P等。在涉及兩個或更多個雜原子的實施方案中，兩個或更多個雜原子可以是相同的，或者兩個或更多個雜原子可以部分不同或全部不同。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.
「烷基」不論單獨使用或與其他術語合用，是指具有特定碳原子數的分支或直鏈飽和脂肪族烴基團。除另有注明外，「烷基」是指C1
-10
烷基。例如，「C1
-6
烷基」中的「C1
-6
」指的是有1、2、3、4、5或6個碳原子的直鏈或分枝排列的基團。例如，「C1
-8
烷基」包括但不限於甲基、乙基、正丙基、異丙基、正丁基、叔丁基、異丁基、戊基、己基、庚基和辛基。"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" in "C 1 - 6" refers to a straight-chain 5 or 6 carbon atoms or a group branched arrangement. For example, "C 1 - 8 alkyl" includes but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl .
「環烷基」不論單獨或與其他術語組合使用，是指飽和的單環或多環（例如雙環或三環）烴環系統，通常具有3至16個環原子。環烷基的環原子都是碳，並且環烷基包含零個雜原子和零個雙鍵。在多環環烷基中，兩個或多個環可以稠合或橋連或螺合在一起。單環系統的實例包括但不僅限於環丙基、環丁基、環戊基、環己基、環庚基和環辛基。橋環烷基是含有3-10個碳原子的多環體系，其含有一個或兩個亞烷基橋，每個亞烷基橋由1、2或3個碳原子組成，它們連接環系上兩個不相鄰的碳原子。環烷基可以與芳基或雜芳基稠合。在一些實施方案中，環烷基是苯並稠合的。橋環烷體系的代表性例子包含，但不僅限於，雙環[3.1.1]庚烷，雙環[2.2.1]庚烷，雙環[2.2.2]辛烷，雙環[3.2.2]壬烷，雙環[3.3.1]壬烷，雙環[4.2.1]壬烷，三環[3.3.1.03,7]壬烷，和三環[3.3.1.13,7]癸烷（金剛烷）。單環和橋烴環可通過環系中任意可取代的原子與母體分子部分相連。"Cycloalkyl", whether used alone or in combination with other terms, refers to a saturated monocyclic or polycyclic (for example, bicyclic or tricyclic) hydrocarbon ring system, usually having 3 to 16 ring atoms. The ring atoms of a cycloalkyl group are all carbon, and the cycloalkyl group contains zero heteroatoms and zero double bonds. In a polycyclic cycloalkyl group, two or more rings may be fused or bridged or spiro fused together. 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.
「烯基」不論單獨使用或與其他術語合用，是指含有2-10個碳原子且至少有一個碳碳雙鍵的非芳香直鏈、分支或環狀烴基。在一些實施例中，存在1個碳碳雙鍵，多達4個非芳香性的碳碳雙鍵可能存在。因此，「C2 － 6
烯基」是指含有2-6個碳原子的烯基。烯基基團包括但不限於乙烯基、丙烯基、丁烯基、2-甲基丁烯基和環己烯基。烯基中的直鏈、分枝或環狀部分可能含有雙鍵，且若標明取代烯基表示其可能被取代。"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.
「炔基」不論單獨使用或與其他術語合用，是指含有2-10個碳原子且至少一個碳碳三鍵的直鏈、分枝或環狀烴基。在一些實施例中，可存在多達3個碳碳三鍵。因此，「C2
-6
炔基」指含有2-6個碳原子的炔基。炔基基團包括但不限於乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基中的直鏈、分枝或環狀部分可能含有三鍵，若標明取代炔基表示其可能被取代。"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 linear, branched or cyclic part of the alkynyl group may contain a triple bond. If a substituted alkynyl group is indicated, it may be substituted.
「鹵素」是指氟、氯、溴、碘。"Halogen" refers to fluorine, chlorine, bromine, and iodine.
「烷氧基」，其單獨使用或與其他術語合用，是指與氧原子以單鍵相連的如上定義的烷基。烷氧基與分子通過氧原子相連。烷氧基可以表示為-O-烷基。「C1-10
烷氧基」是指含有1-10個碳原子的烷氧基，可為直鏈或分支結構。烷氧基包括但不僅限於，甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、戊氧基、己氧基等。"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. "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.
「環烷氧基」，其單獨使用或與其他術語合用，是指與氧原子以單鍵相連的如上定義的環烷基。環烷氧基與分子通過氧原子相連。環烷氧基可以表示為-O-環烷基。「C3-10
環烷氧基」是指含有3-10個碳原子的環烷氧基。環烷氧基可以與芳基或雜芳基稠合。 在一些實施方案中，環烷氧基是苯並稠合的。環烷氧基包括但不僅限於，環丙氧基、環丁氧基、環戊氧基、環己氧基等。"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.
「烷硫基」，其單獨使用或與其他術語合用，是指與硫原子以單鍵相連的如上定義的烷基。烷硫基與分子通過硫原子相連。烷硫基可以表示為-S-烷基。「C1-10
烷硫基」是指含有1-10個碳原子的烷硫基，可為直鏈或分支結構。烷硫基包括但不僅限於，甲硫基、乙硫基、丙硫基、異丙硫基、丁硫基和己硫基等。"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.
「環烷硫基」，其單獨使用或與其他術語合用，是指與硫原子以單鍵相連的如上定義的環烷基。環烷硫基與分子通過硫原子相連。環烷硫基可以表示為-S-環烷基。「C3-10
環烷硫基」是指含有3-10個碳原子的環烷硫基。環烷硫基可以與芳基或雜芳基稠合。 在一些實施方案中，環烷硫基是苯並稠合的。環烷硫基包括但不僅限於，環丙硫基、環丁硫基和環己硫基等。"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 condensed 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.
「烷氨基」，其單獨使用或與其他術語合用，是指與氮原子以單鍵相連的如上定義的烷基。烷氨基與另一分子通過氮原子相連。烷氨基可以表示為-NH(烷基)。「C1-10
烷氨基」是指含有1-10個碳原子的烷氨基，可為直鏈或分支結構。烷氨基包括但不僅限於，甲氨基、乙氨基、丙氨基、異丙氨基、丁氨基和己氨基等。"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. Alkylamino can be represented as -NH (alkyl). "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 includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, and the like.
「環烷氨基」，其單獨使用或與其他術語合用，是指與氮原子以單鍵相連的如上定義的環烷基。環烷氨基與另一分子通過氮原子相連。環烷氨基可以表示為-NH(環烷基)。「C3-10
環烷氨基」是指含有3-10個碳原子的環烷氨基。環烷基氨基可以與芳基或雜芳基稠合。在一些實施方案中，環烷基氨基是苯並稠合的。環烷氨基包括但不僅限於，環丙氨基、環丁氨基和環己氨基等。"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. Cycloalkylamino 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 includes, but is not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino and the like.
「二(烷基)氨基」，其單獨使用或與其他術語合用，是指與氮原子以單鍵相連的兩個如上定義的烷基。二(烷基)氨基與分子通過氮原子相連。二(烷基)氨基可以表示為-N(烷基)2
。「二(C1-10
烷基)氨基」是指兩個烷基部分分別含有1-10個碳原子的二(C1-10
烷基)氨基，可為直鏈或分支結構。"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 two alkyl moieties containing di (C 1-10 alkyl) of 1 to 10 carbon atoms are amino group, may be linear or branched structure.
「芳基」，其單獨使用或與其他術語合用，是指具有6、7、8、9、10、11、12、13或14個碳原子（「C6-14
芳基」基團）的單價、單環、雙環或三環的芳烴環系統，特別是具有6個碳原子的環（「C6
芳基」基團），例如苯基；或具有10個碳原子的環（「C10
芳基」基團），例如萘基；或具有14個碳原子的環（「C14
芳基」基團），例如蒽基。芳基可以與環烷基或雜環基稠合。"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 "Aryl" group), such as naphthyl; or a ring with 14 carbon atoms ("C 14 aryl" group), such as anthryl. The aryl group may be condensed with a cycloalkyl group or a heterocyclic group.
由取代的苯類衍生物形成的且在環原子上存在自由價電子的二價基團，被命名為取代的亞苯基基團。衍生自名字以「-基」結尾的一價多環烴基團的二價基團，其是在含有自由價電子上的碳原子上再去掉一個氫原子而得到的，其名稱為在單價基團名字加上「-亞（-idene）」，例如，有兩個連接位點的萘基就被稱為亞萘基。A divalent group formed by a substituted benzene derivative and having free valence electrons on a 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.
「雜芳基」，其單獨使用或與其他術語合用，是指具有5、6、7、8、9、10、11、12、13或14個環原子（「5至14元雜芳基」基團）的單價，單環，雙環或三環的芳環系統，特別是5或6或9或10個原子，並且含有至少一個可以相同或不同的雜原子，所述雜原子選自N，O和S，環上其餘的原子為碳原子。雜芳基可以與環烷基或雜環基稠合。在一些實施例中，「雜芳基」是指 5元到8元的芳香單環，該環含有選自N，O和S的，數目為1到4個，在某些實施例中為1到3個的雜原子，其餘均為碳原子；或 8元到-12元雙環芳香環，該環含有選自N，O和S的，數目為1到6個，在某些實施例中為1到4個的雜原子，或在某些實施例中為1到3個的雜原子，其餘均為碳原子；或 11元到14元三環芳香環，該環含有選自N，O和S的，數目為1到8個，在某些實施例中為數目為1到6個，或在某些實施例中為數目為1到4個，或在某些實施例中為1到3個的雜原子，其餘均為碳原子。"Heteroaryl", used alone or in combination with other terms, refers to 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, the remaining atoms in the ring are carbon atoms. The heteroaryl group may be fused with a cycloalkyl group or a heterocyclic group. In some embodiments, "heteroaryl" refers to a 5-membered to 8-membered aromatic monocyclic ring, which contains a ring selected from N, O, and S, the number is 1 to 4, and in some embodiments, it is 1. Up to 3 heteroatoms, the rest are carbon atoms; or 8-membered to -12-membered bicyclic aromatic ring, the ring contains one selected from N, O and S, the number is 1 to 6, in some embodiments 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, and the rest are carbon atoms; or 11- to 14-membered tricyclic aromatic ring containing selected from N, O and S, the number is 1 to 8, in some embodiments, the number is 1 to 6, or in some embodiments, the number is 1 to 4, or in some embodiments, the number is 1 to 3 One of the heteroatoms, the rest are carbon atoms.
當雜芳基中S和O的總數大於1時，這些雜原子彼此不相鄰。在一些實施例中，雜芳基中S和O的總數不大於2。在一些實施例中，雜芳基中S和O的總數不大於1。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.
雜芳基的例子包括但不限於2-吡啶基，3-吡啶基，4-吡啶基，2-吡嗪基，3-吡嗪基，2-嘧啶基，4-嘧啶基，5-嘧啶基，6-嘧啶基，1-吡唑基，3-吡唑基，4-吡唑基，5-吡唑基，1-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，噠嗪基，三嗪基，吡咯基，噁唑基，異噁唑基，噻唑基，異噻唑基，噻二唑基，三唑基，四唑基，噻吩基，呋喃基。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.
進一步地，雜芳基包括但不限於吲哚基，苯並噻吩基，苯並呋喃基，苯並咪唑基，苯並三唑基，喹喔啉基，喹啉基和異喹啉基。「雜芳基」包括任何含氮雜芳基的N氧化衍生物。Further, heteroaryl groups include but are not limited to indolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl and isoquinolinyl. "Heteroaryl" includes any N-oxide derivative of nitrogen-containing heteroaryl.
一價雜芳基基團的命名以「-基」結尾，其衍生的二價基團的就是在含有自由價電子上的碳原子上再去掉一個氫原子而得到的，該二價基團的命名系在一價基團的名稱加上 「-亞（-idene）」，例如：有兩個連接位點的吡啶基被稱為吡啶亞基。The name of a 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 pyridinyl group with two attachment points is called a pyridinide group.
「雜環」（和由此衍變的如「雜環的」或「雜環基」）泛指飽和或不包含、單環或多環（如：雙環）的環狀脂肪烴系統，通常有3至12個環原子，至少含有1個（如：2，3或4個）獨立地選自氧、硫、氮和磷的雜原子（優選氧、硫，氮），環上其餘的原子為碳原子。在多環系統中兩個或更多個環可以通過稠合、橋接或螺環連結，雜環可以與芳基或雜芳基稠合。在一些實施例中，雜環是苯並稠合的。雜環還包括被一個或多個氧代或亞氨基部分取代的環系。在一些實施例中，雜環中的C，N，S和P原子任選被氧代取代。在一些實施例中，雜環中的C，S和P原子任選地被亞氨基取代，且亞氨基可以是未取代的或取代的。雜環上的碳原子或雜原子均可是聯接位點，前提是形成一個穩定的結構。當雜環上有取代基時，該取代基可以和雜環上的任何雜原子或碳原子連接，前提是形成一個穩定的化學結構。"Heterocycle" (and derived from it such as "heterocyclic" or "heterocyclic group") generally refers to a saturated or non-containing, monocyclic or polycyclic (such as bicyclic) cyclic aliphatic hydrocarbon system, usually 3 Up to 12 ring atoms, containing at least 1 (such as 2, 3 or 4) heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus (preferably oxygen, sulfur, nitrogen), and the remaining atoms in the ring are carbon atom. In a polycyclic system, two or more rings may be connected by fusion, bridging, or spiro ring, and the heterocyclic ring may be fused with an aryl or heteroaryl group. 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 carbon atom or heteroatom on the heterocyclic ring can be the attachment site, provided that a stable structure is formed. When there is a substituent on the heterocyclic ring, the substituent can be connected to any heteroatom or carbon atom on the heterocyclic ring, provided that a stable chemical structure is formed.
適宜的雜環包括，例如1-吡咯烷基，2-吡咯烷基，3-吡咯烷基，1-咪唑烷基，2-咪唑烷基，3-咪唑烷基，4-咪唑烷基，5-咪唑烷基，1-吡唑烷基，2-吡唑烷基，3-吡唑烷基，4-吡唑烷基，5-吡唑烷基，1-呱啶基，2-呱啶基，3-呱啶基，4-呱啶基，1-呱嗪基，2-呱嗪基，3-呱嗪基，1-六氫噠嗪基，3-六氫噠嗪基和4-六氫噠嗪基。具有一個或多個氧代部分的雜環的實例包括但不限於呱啶基-N-氧化物，嗎啉基-N-氧化物，1-氧代-硫代嗎啉基和1,1-二氧代-硫代嗎啉基。雙環雜環包括但不僅限於： 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-piridinyl, 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, pyridinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl and 1,1- Dioxo-thiomorpholinyl. Bicyclic heterocycles include but are not limited to: and .
此處所用的「芳基-烷基」是指如上定義的芳基取代的如上定義的烷基。示例的芳烷基包括但不僅限於苄基，苯乙基和萘甲基等。在一些實施中，芳烷基含7-20或7-11個碳原子。當使用「芳基C1-4
烷基」時，其中「C1-4
」是指烷基部分而不是芳基部分的碳原子數。As used herein, "aryl-alkyl" 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.
此處所用的「雜環基-烷基」是指如上定義的雜環基取代如上定義的的烷基。當使用「雜環基C1-4
烷基」時，其中「C1-4
」是指烷基部分而不是雜環基部分的碳原子數。As used herein, "heterocyclyl-alkyl" means that a heterocyclic group as defined above is substituted for an alkyl group as defined above. When "heterocyclyl C 1-4 alkyl" is used, "C 1-4 " refers to the number of carbon atoms in the alkyl moiety rather than the heterocyclic moiety.
此處所用的「環烷基-烷基」是指如上定義的環烷基取代的如上定義的烷基。當使用「C3-10
環烷基-C1-4
烷基」時，其中「C3-10
」是指環烷基部分而不是烷基部分的碳原子數。其中「C1-4
」是指烷基部分而不是環烷基部分的碳原子數。"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 in the alkyl moiety rather than the cycloalkyl moiety.
此處所用的「雜芳基-烷基」是指如上定義的雜芳基取代的如上定義的烷基。當使用「雜芳基-C1-4
烷基」時，其中「C1-4
」是指烷基部分而不是雜芳基部分的碳原子數。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.
為避免歧義，例如：當提到烷基，環烷基，雜環基烷基，芳基，和/或其雜芳基取代時，其意是指每個這些基團單獨地取代，或是指這些基團混合取代。亦即：如果R是芳基-C1-4
烷基，並且可以是未取代的或被至少一個取代基取代，如1、2、3或4個獨立地選自RX
的取代基取代，應該理解，芳基部分可以是未取代的或被至少一個，如1、2、3或4個獨自選自RX
的取代基取代，烷基部分也可為未被取代的或被至少一個，如1、2、3或4個獨自選自RX
的取代基取代。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 It means that these groups are mixed and substituted. 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, For example, 1, 2, 3 or 4 substituents independently selected from R X are substituted.
「藥學上可接受的鹽」，是指與藥學上可接受的無毒的堿或酸，包括無機或有機堿和無機或有機酸製成的鹽。無機堿的鹽可以選自，例如：鋁、銨、鈣、銅、鐵、亞鐵、鋰、鎂、錳、二價錳、鉀、鈉、鋅鹽。進一步，藥學上可接受的無機堿的鹽可選自銨，鈣，鎂，鉀，鈉鹽。在固體鹽中可能存在一個或多個晶體形態，或多晶型物，也有可能存在溶劑合物，如水合物的形式。藥學上可接受的有機無毒堿的鹽可選自，例如：伯胺，仲胺和叔胺鹽，取代胺包括自然存在的取代胺，環胺，鹼性離子交換樹脂，如精氨酸，甜菜堿，咖啡鹼，膽鹼，N,N'
-二苄基乙二胺，二乙胺，2-二乙氨基乙醇，2-二甲氨基乙醇,乙醇胺，乙二胺，N
-乙基嗎啉，N
-乙基呱啶，葡萄糖胺，氨基葡萄糖，組氨酸，海巴明胺，異丙胺，賴氨酸，甲葡糖胺，嗎啉，呱嗪，呱啶，多胺樹脂，普魯卡因，嘌呤，可哥堿，三乙胺，三甲胺，三丙胺，氨丁三醇。"Pharmaceutically acceptable salt" refers to a salt made with a pharmaceutically acceptable non-toxic salt or acid, including inorganic or organic salt and inorganic or organic acid. Inorganic salts can be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Further, the pharmaceutically acceptable inorganic salt can 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 pharmaceutically acceptable organic non-toxic salt can be selected from, for example, primary amine, secondary amine and tertiary amine salt. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine and sugar beet. Caffeine, Caffeine, Choline, N,N' -Dibenzylethylenediamine, Diethylamine, 2-Diethylaminoethanol, 2-Dimethylaminoethanol, Ethanolamine, Ethylenediamine, N -Ethylmorpholine, N -ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procal Because, purine, cocotin, triethylamine, trimethylamine, tripropylamine, tromethamine.
當本專利所指化合物是堿時，需要與至少一種藥學上可接受的無毒酸製備其鹽，這些酸選自無機酸和有機酸。例如，選自醋酸，苯磺酸，苯甲酸，樟腦磺酸，檸檬酸，乙烷磺酸，富馬酸，葡萄糖酸，谷氨酸，氫溴酸，鹽酸，羥乙磺酸，乳酸，馬來酸，蘋果酸，扁桃酸，甲烷磺酸，粘酸，硝酸，撲酸，泛酸，磷酸，琥珀酸，硫酸，酒石酸，對甲苯磺酸。在一些實施例中，可選擇這些酸，例如：檸檬酸，氫溴酸，鹽酸，馬來酸，磷酸，硫酸，富馬酸，酒石酸。When the compound referred to in this patent is a salt, it is necessary to prepare its salt 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, benzene sulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, horse Lyric acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, 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.
化合物或其藥學上可接受的鹽的「給予」或「給藥」是指為需要治療的個體提供本發明中的化合物或其藥學可接受的鹽。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.
「有效量」是指化合物或其藥學上可接受的鹽能夠引起組織、系統、動物或人類出現可被研究人員、獸醫、臨床醫生或其他臨床人員觀察到的生物學或醫學反應的劑量。"Effective dose" refers to the dose of the compound or its pharmaceutically acceptable salt 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.
「組合物」，包括：包含特定量的特定成分的產品，以及任何直接或間接這些特定量的特定成分的組合而成的產品。藥物組合物，包含：包含有效成分和作為載體的惰性成分的產品，以及任何兩個或兩個以上的成分直接或間接，通過組合、 複合或聚集而製成的產品，或通過一個或更多的成分分解產生的產品，或通過一個或更多的成分發生其他類型反應或相互作用產生的產品。"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, including: a product containing an active ingredient and an inert ingredient as a carrier, and a product made by combining, compounding, or agglomerating any two or more ingredients directly or indirectly, or through one or more Products produced by the decomposition of the ingredients, or products produced by other types of reactions or interactions of one or more ingredients.
「藥學可接受」是指與製劑中的其它組分相容，並且對使用者無不可接受的毒害。"Pharmaceutically acceptable" means that it is compatible with other ingredients in the formulation and has no unacceptable toxicity to the user.
「個體」是指患有疾病、病症之類的個體，包括哺乳動物和非哺乳動物。哺乳動物包括，但不僅限於，哺乳類的任何成員：人類，非人類的靈長類動物如黑猩猩，和其他猿類和猴子；農場動物如牛、馬、綿陽、山羊、豬；家畜如兔、狗和貓；實驗動物包括齧齒類如大鼠、小鼠和豚鼠等。非哺乳類動物包括，但不僅限於，鳥類、魚類等。本發明的一個實施例中，哺乳動物為人類。"Individual" refers to individuals suffering from diseases, disorders, and the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cows, horses, Mianyang, goats, and pigs; domestic animals such as rabbits and dogs And cats; experimental animals include rodents such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.
「治療」包括緩解、減輕或改善疾病或症狀，預防其他症狀，改善或預防症狀的潛在代謝因素，抑制疾病或症狀，例如，阻止疾病或症狀發展，減輕疾病或症狀，促進疾病或症狀緩解，或使疾病或症狀的病徵停止，和延伸至包括預防。「治療」還包括實現治療性獲益和/或預防性獲益。治療性獲益是指根除或改善所治療的病症。此外，治療性獲益通過根除或改善一個或多個與潛在疾病相關的生理病徵達到，儘管患者可能仍患有潛在疾病，但可觀察到患者疾病的改善。預防性獲益是指，患者為預防某種疾病風險而使用組合物，或患者出現一個或多個疾病生理病症時使用，儘管尚未診斷此疾病。"Treatment" includes alleviating, alleviating or improving diseases or symptoms, preventing other symptoms, improving or preventing underlying metabolic factors of symptoms, inhibiting diseases or symptoms, for example, preventing the development of diseases or symptoms, reducing diseases or symptoms, promoting alleviation of diseases or symptoms, Or stop the symptoms of the disease or symptom, and extend to include prevention. "Treatment" also includes realizing therapeutic benefits and/or preventive benefits. Therapeutic benefit refers to eradicating or improving the condition being treated. In addition, the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease. Although the patient may still have the underlying disease, the improvement of the patient's disease can be observed. Preventive benefit refers to the patient using 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 yet been diagnosed.
「保護基」（Pg）是指一類用於與化合物上其它官能團反應而阻隔或保護特定官能團的取代基。例如，「氨基保護基」是指聯接在氨基上阻隔或保護化合物上氨基官能團的取代基。適合的氨基保護基團包括乙醯基、三氟乙醯基，叔丁氧羰基（BOC），苄氧羰基（CBZ）和9-芴基甲氧基羰基保護基（Fmoc）。同樣，「羥基保護基」是指一類羥基取代基可有效阻擋或保護羥基功能。適當的保護基包括但不限於乙醯基和矽烷基。「羧基保護基」是指一類羧基取代基能有效阻擋或保護羧基的功能。常用羧基保護基包括 -CH2
CH2
SO2
Ph，氰乙基，2-(三甲矽基)乙基，2 -(三甲矽基)乙氧基甲基，2 - (對甲苯磺醯基)乙基，2 -(對硝基苯亞磺醯基)乙基，2-(二苯基膦)-乙基，硝基乙基等。對於保護基的一般描述和使用說明，見參考文獻：T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991
。"Protecting group" (Pg) refers to a type of substituent that is used to react with other functional groups on a compound to block or protect specific functional groups. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the amino functional group on a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl protecting group (Fmoc). Similarly, "hydroxyl protecting group" refers to a type of hydroxyl substituent that can effectively block or protect the hydroxyl function. Suitable protecting groups include, 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 carboxyl 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 and the like. 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保護基」包含，但不僅限於，三氯乙氧羰基、三溴乙氧羰基、苄氧羰基、對硝基苄甲醯基、鄰溴苄氧羰基、氯乙醯基、二氯乙醯基、三氯乙醯基、三氟乙醯基、苯乙醯基、甲醯基、乙醯基、苯甲醯基、叔戊氧羰基、叔丁氧羰基、對甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、4-(苯偶氮基)苄氧羰基、2-糠基氧羰基、二苯基甲氧羰基、1,1-二甲基丙氧基羰基、異丙氧羰基、鄰苯二甲醯基、琥珀醯基、丙氨醯基、亮氨醯基、1-金剛烷氧羰基、8-喹啉基氧羰基、苄基、二苯甲基、三苯甲基、2-硝基苯硫基、甲磺醯基、對甲苯磺醯基、N,N
-二甲基氨基亞甲基、苯亞甲基、2-羥基苯亞甲基、2-羥基-5-氯苯亞甲基、2-羥基-l-萘基亞甲基、3-羥基-4-吡啶基亞甲基、亞環己基、2-乙氧基羰基亞環己基、2-乙氧基羰基亞環戊基、2-乙醯基亞環己基、3,3-二甲基-5-氧亞環己基、二苯基磷醯基、二苄基磷醯基、5-甲基-2-氧基-2H
-l,3-二氧環戊烯-4-基-甲基、三甲基矽烷基、三乙基矽烷基和三苯基矽烷基。"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, phthalate, succinyl, alaninyl, leucinyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, tri Benzyl, 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-ethoxycarbonylcyclohexylene, 2- Ethoxycarbonylcyclopentylene, 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」保護基包含，但不僅限於，甲基、乙基、正丙基、異丙基、1,1-二甲基丙基、正丁基、叔丁基、苯基、萘基、苄基、二苯甲基、三苯甲基、對硝基苄基、對甲氧基苄基、雙(對甲氧苯基)甲基、乙醯甲基、苯甲醯甲基、對硝基苯甲醯甲基、對溴苯甲醯甲基、對甲磺醯苯甲醯甲基、2-四氫吡喃基、2-四氫呋喃基、2,2,2-三氯乙基、2-(三甲基矽烷基)乙基、乙醯氧基甲基、丙醯氧基甲基、新戊醯氧基甲基、鄰苯二甲醯亞胺甲基、琥珀醯亞胺甲基、環丙基、環丁基、環戊基、環己基、甲氧基甲基、甲氧基乙氧基甲基、2-(三甲基矽烷基)乙氧基甲基、苄基氧基甲基、甲基硫基甲基、2-甲基硫基乙基、苯基硫基甲基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、二乙基異丙基矽烷基、叔丁基二甲基矽烷基、叔丁基二苯基矽烷基、二苯基甲基矽烷基和叔丁基甲氧基苯基矽烷基。"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, propionyloxymethyl, 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或SH」保護基包含，但不僅限於，苄氧羰基、4-硝基苄氧羰基、4-溴苄氧羰基、4-甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、甲氧基羰基、乙氧基羰基、叔丁氧羰基、1,1-二甲基丙氧基羰基、異丙氧羰基、異丁氧羰基、二苯基甲氧基羰基、2,2,2-三氯乙氧基羰基、2,2,2-三溴乙氧基羰基、2-(三甲基矽烷)乙氧基羰基、2-(苯磺醯基)乙氧基羰基、2-(三苯基磷鎓基)乙氧基羰基、2-糠基氧基羰基、1-金剛烷氧基羰基、乙烯基氧基羰基、烯丙基氧基羰基、4-乙氧基-1-萘基氧基羰基、8-喹啉基氧基羰基、乙醯基、甲酸基、氯乙醯基、二氯乙醯基、三氯乙醯基、三氟乙醯基、甲氧基乙醯基、苯氧基乙醯基、特戊醯基、苯甲醯基、甲基、叔丁基、2,2,2-三氯乙基、2-三甲基矽烷基乙基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、苄基(苯基甲基)、對甲氧基苄基、3,4-二甲氧基苄基、二苯基甲基、三苯基甲基、四氫呋喃基、四氫吡喃基、四氫噻喃基、甲氧基甲基、甲基硫基甲基、苄基氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯-乙氧基甲基、2-(三甲基矽烷基)乙氧基甲基、1-乙氧基乙基、甲磺醯基、對甲苯磺醯基、三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、二乙基異丙基矽烷基、叔丁基二甲基矽烷基、叔丁基二苯基矽烷基、二苯基甲基矽烷基和叔丁基甲氧基苯基矽烷基。"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, formate, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, 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 Diphenyl silyl group, diphenyl methyl silyl group and tert-butyl methoxyphenyl silyl group.
本發明化合物中可能存在幾何異構體。本發明化合物可能存在E或Z構型的碳-碳雙鍵或碳-氮雙鍵，其中「E」代表按Cahn-Ingold-Prelog優先規則，較優的取代基在碳-碳雙鍵或碳-氮雙鍵的異側，而「Z」代表較優的取代基在碳-碳雙鍵或碳-氮雙鍵的同側。本發明化合物也可能以「E」和「Z」異構體的混合物形式存在。環烷基或雜環基周圍的取代基可以定為順式或反式構型。此外，本發明包括由金剛烷環系周圍取代基排列不同形成的不同異構體及其混合物。金剛烷環系中的一個單環周圍的兩個取代基被定為Z或E相對構型。例如，見C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760。Geometric isomers may exist in the compounds of the present invention. The compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where "E" means that according to the Cahn-Ingold-Prelog priority rule, the preferred substituent is on the carbon-carbon double bond or carbon -The opposite side of the nitrogen double bond, and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers. The substituents surrounding the cycloalkyl or heterocyclic group can be set in a cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. The two substituents around a single ring in the adamantane ring system are defined as the relative configuration of Z or E. For example, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.
本發明化合物可能含有R或S構型的不對稱取代的碳原子，「R」和「S」的定義見IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10。含有不對稱取代碳原子的化合物，若R和S構型的量相同，則為外消旋體。若其中一種構型比另一構型的量更多，則手性碳原子的構型以量多的構型表示，優選對映體過量約85-90%，更優選約95-99%，進一步約99%以上。因此，本發明包含外消旋混合物、相對和絕對立體異構體、和相對和絕對立體異構體的混合物。 同位素富集或標記化合物The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration. For the definitions of "R" and "S", see IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13- 10. Compounds containing asymmetrically substituted carbon atoms, if the amount of R and S configurations are the same, it is a racemate. If one of the configurations has a larger amount than the other configuration, the configuration of the chiral carbon atom is represented by the larger configuration, and the enantiomeric excess is preferably about 85-90%, more preferably about 95-99%, Further more than 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
本發明化合物可以同位素標記或富集的形式存在，包含一個或多個與自然界最普遍原子品質和質量數不同的原子。同位素可以為放射性或非放射性同位素。原子如氫、碳、氮、氧、磷、硫、氟、氯和碘的同位素包括，但不僅限於，2
H、3
H、13
C、14
C、15
N、18
O、32
P、35
S、18
F、36
Cl和125
I。含有這些原子的其他同位素和/或其他原子也在本發明範圍內。The compounds of the present invention can exist in an isotope-labeled or enriched form, and contain one or more atoms with different qualities and mass numbers from the most common atoms in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, 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.
在另一實施例中，同位素標記化合物含有氘（2
H）、氚（3
H）或14
C同位素。本發明的同位素標記化合物可使用該領域專業人員熟知的方法獲得。這些同位素標記化合物可通過參照本發明實施例和反應圖示，將非標記試劑替換為同位素標記試劑而得到。在某些例子中，可用同位素標記試劑處理化合物，將原子替換為同位素原子，例如，將氫替換為氘可通過氘代酸如D2
SO4
/D2
O的作用交換。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 replacing non-labeled reagents with isotope-labeled reagents by referring to the examples and reaction diagrams of the present invention. 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.
本發明同位素標記化合物可作為BTK抑制劑藥效結合試驗的標準。含同位素的化合物可用於藥學研究，評價非同位素標記母體化合物的作用機制和代謝途徑，研究化合物的體內代謝歸轉（Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)）。這類代謝研究對於設計安全有效的治療藥物十分重要，可判斷是患者使用的體內活性化合物或是母體化合物的代謝產物具有毒性或致癌性（Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al, J. Labelled Compounds. Radiopharmaceuticals, 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999)）。The isotope-labeled compound of the present invention can be used as a standard for the pharmacodynamic combination test of the BTK inhibitor. Isotopes-containing compounds can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the in vivo metabolism of compounds (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975) ). This type of metabolic research is very important for the design of safe and effective therapeutic drugs. It can be judged that the active compound in the body or the metabolite of the parent compound used by the patient is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp . 2-36, Academic press, London, 1985; Kato et al, J. Labelled Compounds. Radiopharmaceuticals, 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999)).
此外，含非反射性活性同位素的藥物，例如氘代藥物，稱為「重藥（heavy drugs）」，可用於治療與BTK活性相關的疾病和病症。化合物中某種同位素比例超過其自然豐度被稱為富集。富集的量包括但不僅限於，例如，從約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至約100 mol %。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 BTK 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 %.
藥物穩定的同位素標記可以改變其物理化學性質，例如pKa和液體溶解性。如果同位素取代影響了配體-受體相互作用相關的區域，那麼這些作用和改變可能影響藥物分子的藥效反應。穩定同位素標記分子的某些物理性質與未標記分子不同，而化學和生物學性質相同，但有一個重要區別：由於重同位素的品質增加，任何包含重同位素和另一原子的化學鍵比輕同位素更強。相應的，代謝或酶轉化位點存在同位素會減緩該反應，從而與非同位素標記的化合物相比，可能改變其藥代動力學特徵或藥效。Stable isotope labeling of drugs can change their physicochemical properties, such as pKa and liquid solubility. If the isotope substitution affects the region related to the ligand-receptor interaction, then these effects and changes may affect the pharmacodynamic response of the drug molecule. Certain 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 quality of heavy isotopes, any chemical bond containing a heavy isotope and another atom is more important than a light isotope. powerful. Correspondingly, the presence of isotopes at metabolic or enzymatic conversion sites will slow down the reaction, which may change its pharmacokinetic characteristics or efficacy compared with non-isotopically labeled compounds.
在實施方案（1）中，本發明提供式（I）所示的化合物：(I) 或其藥學上可接受的鹽，其中， Q選自C3-10
環烷基、雜環基、芳基和雜芳基，其中環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； L選自化學鍵、-(CRC0
RD0
)u
-、-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(=NRE0
)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)NRB0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
S(O)r
(CRC0
RD0
)t
-和-(CRC0
RD0
)u
NRA0
S(O)r
NRB0
(CRC0
RD0
)t
-； X1
、X2
、X3
和X4
獨立選自CRX’
和N； Y選自CR4
和N； R1
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA1
RB1
、-ORA1
、-C(O)RA1
、-C(=NRE1
)RA1
、-C(=N-ORB1
)RA1
、-C(O)ORA1
、-OC(O)RA1
、-C(O)NRA1
RB1
、-NRA1
C(O)RB1
、-C(=NRE1
)NRA1
RB1
、-NRA1
C(=NRE1
)RB1
、-OC(O)NRA1
RB1
、-NRA1
C(O)ORB1
、-NRA1
C(O)NRA1
RB1
、-NRA1
C(S)NRA1
RB1
、-NRA1
C(=NRE1
)NRA1
RB1
、-S(O)r
RA1
、-S(O)(=NRE1
)RB1
、-N=S(O)RA1
RB1
、-S(O)2
ORA1
、-OS(O)2
RA1
、-NRA1
S(O)r
RB1
、-NRA1
S(O)(=NRE1
)RB1
、-S(O)r
NRA1
RB1
、-S(O)(=NRE1
)NRA1
RB1
、-NRA1
S(O)2
NRA1
RB1
、-NRA1
S(O)(=NRE1
)NRA1
RB1
、-P(O)RA1
RB1
和-P(O)(ORA1
)(ORB1
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX1
的取代基取代； R2
選自氫、鹵素、CN、NO2
、-NRA2
RB2
、-ORA2
、-C(O)NRA2
RB2
和C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX2
的取代基取代； R3
選自氫、鹵素、CN、NO2
、-NRA3
RB3
、-ORA3
、-C(O)NRA2
RB2
和C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX3
的取代基取代； R4
選自氫、鹵素、CN、NO2
、-NRA4
RB4
、-ORA4
和C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX4
的取代基取代； R5
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA5
RB5
、-ORA5
、-C(O)RA5
、-C(=NRE5
)RA5
、-C(=N-ORB5
)RA5
、-C(O)ORA5
、-OC(O)RA5
、-C(O)NRA5
RB5
、-NRA5
C(O)RB5
、-C(=NRE5
)NRA5
RB5
、-NRA5
C(=NRE5
)RB5
、-OC(O)NRA5
RB5
、-NRA5
C(O)ORB5
、-NRA5
C(O)NRA5
RB5
、-NRA5
C(S)NRA5
RB5
、-NRA5
C(=NRE5
)NRA5
RB5
、-S(O)r
RA5
、-S(O)(=NRE5
)RB5
、-N=S(O)RA5
RB5
、-S(O)2
ORA5
、-OS(O)2
RA5
、-NRA5
S(O)r
RB5
、-NRA5
S(O)(=NRE5
)RB5
、-S(O)r
NRA5
RB5
、-S(O)(=NRE5
)NRA5
RB5
、-NRA5
S(O)2
NRA5
RB5
、-NRA5
S(O)(=NRE5
)NRA5
RB5
、-P(O)RA5
RB5
和-P(O)(ORA5
)(ORB5
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX5
的取代基取代； 每個RA0
和RB0
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX0
的取代基取代； 或每個「RA0
和RB0
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX0
基團取代； 每個RA1
和RB1
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX1
的取代基取代； 或每個「RA1
和RB1
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX1
基團取代； 每個RA2
和RB2
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX2
的取代基取代； 或每個「RA2
和RB2
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX2
基團取代； 每個RA3
和RB3
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX3
的取代基取代； 或每個「RA3
和RB3
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX3
基團取代； 每個RA4
和RB4
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX4
的取代基取代； 或每個「RA4
和RB4
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX4
基團取代； 每個RA5
和RB5
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX5
的取代基取代； 或每個「RA5
和 RB5
」 一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX5
基團取代； 每個RC0
和RD0
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX0
的取代基取代； 或RC0
和RD0
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧、硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RX0
基團取代； 每個RE0
、RE1
和RE5
獨立選自氫、C1-10
烷基、CN、NO2
、-ORa1
、-SRa1
、-S(O)r
Ra1
、-C(O)Ra1
、-C(O)ORa1
、-C(O)NRa1
Rb1
和-S(O)r
NRa1
Rb1
； 每個RX
、RX’
、RX0
、RX1
、RX2
、RX3
、RX4
和RX5
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-(CRc1
Rd1
)t
NRa1
Rb1
、-(CRc1
Rd1
)t
ORb1
、-(CRc1
Rd1
)t
C(O)Ra1
、-(CRc1
Rd1
)t
C(=NRe1
)Ra1
、-(CRc1
Rd1
)t
C(=N-ORb1
)Ra1
、-(CRc1
Rd1
)t
C(O)ORb1
、-(CRc1
Rd1
)t
OC(O)Rb1
、-(CRc1
Rd1
)t
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)Rb1
、-(CRc1
Rd1
)t
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)Rb1
、-(CRc1
Rd1
)t
OC(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)ORb1
、-(CRc1
Rd1
)t
NRa1
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(S)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)r
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
N=S(O)Ra1
Rb1
、-(CRc1
Rd1
)t
S(O)2
ORb1
、-(CRc1
Rd1
)t
OS(O)2
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)r
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
S(O)r
NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)2
NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
P(O)Ra1
Rb1
和-(CRc1
Rd1
)t
P(O)(ORa1
)(ORb1
)，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獨立選自RY
的取代基取代； 每個Ra1
和Rb1
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Ra1
和Rb1
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RY
基團取代； 每個Rc1
和Rd1
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Rc1
和Rd1
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RY
基團取代； 每個Re1
獨立選自氫、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、CN、NO2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-C(O)Ra2
、-C(O)ORa2
、-S(O)r
NRa2
Rb2
和-C(O)NRa2
Rb2
； 每個RY
獨立地選自C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-NRa2
Rb2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-S(O)2
ORa2
、-OS(O)2
Rb2
、-S(O)r
NRa2
Rb2
、-P(O)Ra2
Rb2
、-P(O)(ORa2
)(ORb2
)、-(CRc2
Rd2
)t
NRa2
Rb2
、-(CRc2
Rd2
)t
ORb2
、-(CRc2
Rd2
)t
SRb2
、-(CRc2
Rd2
)t
S(O)r
Rb2
、-(CRc2
Rd2
)t
P(O)Ra2
Rb2
、-(CRc2
Rd2
)t
P(O)(ORa2
)(ORb2
)、 -(CRc2
Rd2
)t
CO2
Rb2
、-(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)Rb2
、-(CRc2
Rd2
)t
NRa2
CO2
Rb2
、-(CRc2
Rd2
)t
OC(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
SO2
NRa2
Rb2
、-NRa2
(CRc2
Rd2
)t
NRa2
Rb2
、-O(CRc2
Rd2
)t
NRa2
Rb2
、-S(CRc2
Rd2
)t
NRa2
Rb2
、-S(O)r
(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)Ra2
、-C(O)(CRc2
Rd2
)t
ORb2
、-C(O)(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)(CRc2
Rd2
)t
SRb2
、-C(O)(CRc2
Rd2
)t
S(O)r
Rb2
、-CO2
Rb2
、-CO2
(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-OC(O)Ra2
、-CN、-C(O)NRa2
Rb2
、-NRa2
C(O)Rb2
、-OC(O)NRa2
Rb2
、-NRa2
C(O)ORb2
、-NRa2
C(O)NRa2
Rb2
、-NRa2
S(O)r
Rb2
、-CRa2
(=N-ORb2
)、-C(=NRe2
)Ra2
、-C(=NRe2
)NRa2
Rb2
、-NRa2
C(=NRe2
)NRa2
Rb2
、-CHF2
、-CF3
、-OCHF2
和-OCF3
，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獨立選自羥基、CN、氨基、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Ra2
和Rb2
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基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、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Ra2
和Rb2
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Rc2
和Rd2
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Rc2
和Rd2
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Re2
獨立選自氫、CN、NO2
、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、-C(O)C1-4
烷基、-C(O)C3-10
環烷基、-C(O)OC1-4
烷基、-C(O)OC3-10
環烷基、-C(O)N(C1-4
烷基)2
、-C(O)N(C3-10
環烷基)2
、-S(O)2
C1-4
烷基、-S(O)2
C3-10
環烷基、-S(O)2
N(C1-4
烷基)2
和-S(O)2
N(C3-10
環烷基)2
； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4； 每個u獨立選自0、1、2、3和4。In embodiment (1), the present invention provides a compound represented by formula (I):
在另一個實施方案(2)中，本發明提供實施方案(1)的化合物或其藥學上可接受的鹽，其中Y是CR4
，化合物如式（II）所示：(II) 其中Q、L、R1
、R2
、R3
、R4
、R5
、X1
、X2
、X3
和X4
的定義與式（I）相同。In another embodiment (2), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is CR 4 , and the compound is represented by formula (II): (II) The definitions of Q, L, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 and X 4 are the same as those of formula (I).
在另一個實施方案(3)中，本發明提供實施方案(1)的化合物或其藥學上可接受的鹽，其中Y是N。In another embodiment (3), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is N.
在另一個實施方案(4)中，本發明提供實施方案(1)-(3)中任一項的化合物或其藥學上可接受的鹽，其中Q選自C3-10
環烷基和雜環基，其中環烷基和雜環基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (4), the present invention provides the compound of any one of embodiments (1)-(3) or a pharmaceutically acceptable salt thereof, wherein Q is selected from C 3-10 cycloalkyl and hetero A cyclic group, wherein the cycloalkyl group and the heterocyclic group are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案(5)中，本發明提供實施方案(4)的化合物或其藥學上可接受的鹽，其中Q選自、和，其是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (5), the present invention provides the compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q is selected from , and , Which is unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案(6)中，本發明提供實施方案(5)的化合物或其藥學上可接受的鹽，其中Q選自和，是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (6), the present invention provides the compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein Q is selected from and , Is unsubstituted or substituted by at least one substituent independently selected from R X.
在另一個實施方案(7)中，本發明提供實施方案(1)-6)中任一項的化合物或其藥學上可接受的鹽，其中Q的取代基RX
選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基，其中每個烷基、烯基、炔基和環烷基是未被取代的或被至少一個獨立選自RY
的取代基取代。In another embodiment (7), the present invention provides the compound of any one of embodiments (1)-6) or a pharmaceutically acceptable salt thereof, wherein the substituent R X of Q is selected from hydrogen, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, wherein each of the alkyl, alkenyl, alkynyl and cycloalkyl groups is unsubstituted or has at least one Substituents independently selected from R Y are substituted.
在另一個實施方案(8)中，本發明提供實施方案(7)的化合物或其藥學上可接受的鹽，其中Q的取代基RX
選自氫、C1-10
烷基、C2-10
炔基，其中每個烷基和炔基是未被取代的或被至少一個獨立選自RY
的取代基取代。In another embodiment (8), the present invention provides the compound of embodiment (7) or a pharmaceutically acceptable salt thereof, wherein the substituent R X of Q is selected from hydrogen, C 1-10 alkyl, C 2- 10 Alkynyl, wherein each alkyl and alkynyl are unsubstituted or substituted with at least one substituent independently selected from R Y.
在另一個實施方案(9)中，本發明提供實施方案(8)的化合物或其藥學上可接受的鹽，其中Q的取代基RX
選自甲基和乙炔基，其中甲基的取代基RY
是F或OH。In another embodiment (9), the present invention provides the compound of embodiment (8) or a pharmaceutically acceptable salt thereof, wherein the substituent R X of Q is selected from methyl and ethynyl, wherein the substituent of methyl is R Y is F or OH.
在另一個實施方案(10)中，本發明提供實施方案(1)-(9)中任一項的化合物或其藥學上可接受的鹽，其中R1
選自C1-10
烷基和C3-10
環烷基，其中烷基和環烷基分別是未被取代的或被至少一個，獨立選自RX1
的取代基取代。In another embodiment (10), the present invention provides the compound of any one of embodiments (1) to (9) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-10 alkyl and C 3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R X1 .
在另一個實施方案(11)中，本發明提供實施方案(10)的化合物或其藥學上可接受的鹽，其中R1
是C1-10
烷基，其中烷基是未被取代的或被至少一個，獨立選自RX1
的取代基取代。In another embodiment (11), the present invention provides the compound of embodiment (10) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1-10 alkyl group, wherein the alkyl group is unsubstituted or is At least one substituent independently selected from R X1 is substituted.
在另一個實施方案(12)中，本發明提供實施方案(11)的化合物或其藥學上可接受的鹽，其中R1
是甲基，其中甲基的取代基RX1
選自OH、CN、NH2
、、、、、、、,、、、、、、和。In another embodiment (12), the present invention provides the compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, wherein the substituent R X1 of the methyl group is selected from OH, CN, NH 2 , , , , , , , , , , , , , , and .
在另一個實施方案(13)中，本發明提供實施方案(1)-(12)中任一項的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自、、、、、、、、、、、、、、,、、、、、、和。In another embodiment (13), the present invention provides the compound of any one of embodiments (1) to (12) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from , , , , , , , , , , , , , , , , , , , , , and .
在另一個實施方案(14)中，本發明提供實施方案(13)的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自、和。In another embodiment (14), the present invention provides the compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from , and .
在另一個實施方案(15)中，本發明提供實施方案(14)的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自、和。In another embodiment (15), the present invention provides the compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from , and .
在另一個實施方案(16)中，本發明提供實施方案(1)-(15)中任一項的化合物或其藥學上可接受的鹽，其中X1
、X2
、X3
和X4
獨立選自CRX’
和N，其中RX’
獨立選自氫、氘、鹵素、CN、C1-10
烷基、C3-10
環烷基和-(CRc1
Rd1
)t
ORb1
。In another embodiment (16), the present invention provides the compound of any one of embodiments (1) to (15) or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 are independent is selected from CR X 'and N, wherein R X' is independently selected from hydrogen, deuterium, halo, CN, C 1-10 alkyl, C 3-10 cycloalkyl and - (CR c1 R d1) t OR b1.
在另一個實施方案(17)中，本發明提供實施方案(1)-(16)中任一項的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自、、、、、和。In another embodiment (17), the present invention provides the compound of any one of embodiments (1) to (16) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from , , , , , and .
在另一個實施方案(18)中，本發明提供實施方案(17)的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自、、和。In another embodiment (18), the present invention provides the compound of embodiment (17) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from , , and .
在另一個實施方案(19)中，本發明提供實施方案(18)的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自和。In another embodiment (19), the present invention provides the compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from and .
在另一個實施方案(20)中，本發明提供實施方案(16)-(19)中任一項的化合物或其藥學上可接受的鹽，其中RX’
選自氫、F、Cl、Br、CN、甲基、甲氧基和環丙基。In another embodiment (20), the present invention provides the compound of any one of embodiments (16) to (19) or a pharmaceutically acceptable salt thereof, wherein R X'is selected from hydrogen, F, Cl, Br , CN, methyl, methoxy and cyclopropyl.
在另一個實施方案(21)中，本發明提供實施方案(20)的化合物或其藥學上可接受的鹽，其中RX’
選自氫、F、Cl和甲基。In another embodiment (21), the present invention provides the compound of embodiment (20) or a pharmaceutically acceptable salt thereof, wherein R X'is selected from hydrogen, F, Cl and methyl.
在另一個實施方案(22)中，本發明提供實施方案(21)的化合物或其藥學上可接受的鹽，其中RX’
選自氫、F、Cl和甲基，優選F或Cl，進一步優選F。In another embodiment (22), the present invention provides the compound of embodiment (21) or a pharmaceutically acceptable salt thereof, wherein R X'is selected from hydrogen, F, Cl and methyl, preferably F or Cl, further Preferably F.
在另一個實施方案(23)中，本發明提供實施方案(18)的化合物或其藥學上可接受的鹽，其中式(I)或式(II)的部分的結構選自、、、和；優選部分的結構選自、和；進一步優選，部分的結構選自和；更進一步優選，部分的結構選自。In another embodiment (23), the present invention provides the compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or formula (II) Part of the structure is selected from , , , and ; Preferred Part of the structure is selected from , and ; Further preferred, Part of the structure is selected from and ; More preferably, Part of the structure is selected from .
在另一個實施方案(24)中，本發明提供實施方案(1)-(23)中任一項的化合物或其藥學上可接受的鹽，其中L選自化學鍵、-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-和-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-。In another embodiment (24), the present invention provides the compound of any one of embodiments (1) to (23) or a pharmaceutically acceptable salt thereof, wherein L is selected from chemical bond, -(CR CO R D0 ) u O(CR C0 R D0 ) t -, -(CR C0 R D0 ) u S(CR C0 R D0 ) t -and-(CR C0 R D0 ) u C(O)NR A0 (CR C0 R D0 ) t -.
在另一個實施方案(25)中，本發明提供實施方案(24)的化合物或其藥學上可接受的鹽，其中L選自化學鍵、-O-、-S-和-C(O)N(RA0
)-。In another embodiment (25), the present invention provides the compound of embodiment (24) or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of chemical bond, -O-, -S- and -C(O)N( R A0 )-.
在另一個實施方案(26)中，本發明提供實施方案(25)的化合物或其藥學上可接受的鹽，其中L選自化學鍵和-O-。In another embodiment (26), the present invention provides the compound of embodiment (25) or a pharmaceutically acceptable salt thereof, wherein L is selected from a chemical bond and -O-.
另一個實施方案(27)中，本發明提供實施方案(26)的化合物或其藥學上可接受的鹽，其中L是-O-。In another embodiment (27), the present invention provides the compound of embodiment (26) or a pharmaceutically acceptable salt thereof, wherein L is -O-.
在另一個實施方案(28)中，本發明提供實施方案(1)-(27)中任一項的化合物或其藥學上可接受的鹽，其中R5
選自鹵素、C1-10
烷基、C3-10
環烷基、芳基和雜芳基，其中烷基、環烷基、芳基和雜芳基分別是未被取代的或被至少一個，獨立選自RX5
的取代基取代。In another embodiment (28), the present invention provides the compound of any one of embodiments (1) to (27) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from halogen, C 1-10 alkyl , C 3-10 cycloalkyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent independently selected from R X5 .
在另一個實施方案(29)中，本發明提供實施方案(28)的化合物或其藥學上可接受的鹽，其中R5
選自F、苯基和吡啶基，其中苯基和吡啶基分別是未被取代的或被至少一個，獨立選自RX5
的取代基取代。In another embodiment (29), the present invention provides the compound of embodiment (28) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from F, phenyl and pyridyl, wherein phenyl and pyridyl are each Unsubstituted or substituted with at least one substituent independently selected from R X5 .
在另一個實施方案(30)中，本發明提供實施方案(29)的化合物或其藥學上可接受的鹽，其中R5
是苯基，其中苯基是未被取代的或被至少一個，獨立選自RX5
的取代基取代。In another embodiment (30), the present invention provides the compound of embodiment (29) or a pharmaceutically acceptable salt thereof, wherein R 5 is a phenyl group, wherein the phenyl group is unsubstituted or is substituted by at least one, independently Substituents selected from R X5 are substituted.
另一個實施方案(31)中，本發明提供實施方案(28)-(30)中任一項的化合物或其藥學上可接受的鹽，其中RX5
選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基、鹵素、CN、NO2
、-(CRc1
Rd1
)t
NRa1
Rb1
、-(CRc1
Rd1
)t
ORb1
和-(CRc1
Rd1
)t
C(O)Ra1
，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獨立選自RY
的取代基取代。In another embodiment (31), the present invention provides the compound of any one of embodiments (28) to (30) or a pharmaceutically acceptable salt thereof, wherein R X5 is 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 alkane Group, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , -(CR c1 R d1 ) t NR a1 R b1 , -(CR c1 R d1 ) t OR b1 and -(CR c1 R d1 ) t C(O)R a1 , where each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero The aryl group is unsubstituted or substituted with at least one substituent independently selected from R Y.
在另一個實施方案(32)中，本發明提供實施方案(31)的化合物或其藥學上可接受的鹽，其中RX5
選自鹵素和甲氧基。In another embodiment (32), the present invention provides the compound of embodiment (31) or a pharmaceutically acceptable salt thereof, wherein R X5 is selected from halogen and methoxy.
在另一個實施方案(33)中，本發明提供實施方案(32)的化合物或其藥學上可接受的鹽，其中RX5
選自鹵素，優選RX5
是F。In another embodiment (33), the present invention provides the compound of embodiment (32) or a pharmaceutically acceptable salt thereof, wherein R X5 is selected from halogen, preferably R X5 is F.
在另一個實施方案(34)中，本發明提供實施方案(29)的化合物或其藥學上可接受的鹽，其中R5
是苯基，其中苯基是未被取代的或被至少一個，獨立選自F和甲氧基的取代基取代；優選苯基是未被取代的或被至少一個獨立選自F的取代基取代；或R5
是吡啶基，其中吡啶基是未被取代的或被至少一個獨立選自F的取代基取代。In another embodiment (34), the present invention provides the compound of embodiment (29) or a pharmaceutically acceptable salt thereof, wherein R 5 is a phenyl group, wherein the phenyl group is unsubstituted or is substituted by at least one, independently Substituents selected from F and methoxy; preferably phenyl is unsubstituted or substituted with at least one substituent independently selected from F; or R 5 is pyridyl, wherein pyridyl is unsubstituted or is At least one substituent independently selected from F is substituted.
在另一個實施方案(35)中，本發明提供實施方案(34)的化合物或其藥學上可接受的鹽，其中R5
是吡啶基，其中吡啶基是未被取代的。In another embodiment (35), the embodiment of the present invention provides (34) a compound or a pharmaceutically acceptable salt thereof, wherein R 5 is pyridyl, wherein pyridyl is unsubstituted.
在另一個實施方案(36)中，本發明提供實施方案(1)-(35)中任一項的化合物或其藥學上可接受的鹽，其中R5
選自F、苯基、、、、、、、、和。In another embodiment (36), the present invention provides the compound of any one of embodiments (1)-(35) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from F, phenyl, , , , , , , , and .
在另一個實施方案(37)中，本發明提供實施方案(36)的化合物或其藥學上可接受的鹽，其中R5
選自苯基、和。In another embodiment (37), the present invention provides the compound of embodiment (36) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from phenyl, and .
在另一個實施方案(38)中，本發明提供實施方案(37)的化合物或其藥學上可接受的鹽，其中R5
選自和。In another embodiment (38), the present invention provides the compound of embodiment (37) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from and .
在另一個實施方案(39)中，本發明提供實施方案(23)的化合物或其藥學上可接受的鹽，其中部分的結構選自、和；優選部分的結構選自和；進一步優選，部分的結構選自是。In another embodiment (39), the present invention provides the compound of embodiment (23) or a pharmaceutically acceptable salt thereof, wherein Part of the structure is selected from , and ; Preferred Part of the structure is selected from and ; Further preferred, Part of the structure is selected from .
在另一個實施方案(40)中，本發明提供實施方案(1)-(39)中任一項的化合物或其藥學上可接受的鹽，其中R2
選自氫、鹵素、C1-10
烷基、-ORA2
、-C(O)NRA2
RB2
和CN。In another embodiment (40), the present invention provides the compound of any one of embodiments (1)-(39) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, halogen, C 1-10 Alkyl, -OR A2 , -C(O)NR A2 R B2 and CN.
在另一個實施方案(41)中，本發明提供實施方案(40)的化合物或其藥學上可接受的鹽，其中-ORA2
中的RA2
獨立選自氫、C1-10
烷基、C2-10
烯基和C3-10
環烷基，其中烷基、烯基和環烷基分別是未被取代的或被至少一個，獨立選自RX2
的取代基取代。In another embodiment (41), the present invention provides the compound of embodiment (40) or a pharmaceutically acceptable salt thereof, wherein R A2 in -OR A2 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl and C 3-10 cycloalkyl, wherein the alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R X2 .
在另一個實施方案(42)中，本發明提供實施方案(40)-(41)中任一項的化合物或其藥學上可接受的鹽，其中RX2
選自氘和鹵素。In another embodiment (42), the present invention provides the compound of any one of embodiments (40) to (41) or a pharmaceutically acceptable salt thereof, wherein R X2 is selected from deuterium and halogen.
在另一個實施方案(43)中，本發明提供實施方案(1)-(42)中任一項的化合物或其藥學上可接受的鹽，其中R2
選自氫、F、Cl、甲基、乙基、甲氧基、乙氧基、-C(O)NH2
、CN、OH、、、、、、、和。In another embodiment (43), the present invention provides the compound of any one of embodiments (1)-(42) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, F, Cl, methyl , Ethyl, methoxy, ethoxy, -C(O)NH 2 , CN, OH, , , , , , , and .
在另一個實施方案(44)中，本發明提供實施方案(43)的化合物或其藥學上可接受的鹽，其中R2
選自氫、F、Cl、CN、甲氧基和乙氧基。In another embodiment (44), the present invention provides the compound of embodiment (43) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, F, Cl, CN, methoxy and ethoxy.
在另一個實施方案(45)中，本發明提供實施方案(44)的化合物或其藥學上可接受的鹽，其中R2
選自氫、CN、甲氧基和乙氧基。In another embodiment (45), the present invention provides the compound of embodiment (44) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, CN, methoxy and ethoxy.
在另一個實施方案(46)中，本發明提供實施方案(45)的化合物或其藥學上可接受的鹽，其中R2
選自氫、甲氧基和乙氧基。In another embodiment (46), the present invention provides the compound of embodiment (45) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, methoxy and ethoxy.
在另一個實施方案(47)中，本發明提供實施方案(46)的化合物或其藥學上可接受的鹽，其中R2
選自甲氧基和乙氧基。In another embodiment (47), the present invention provides the compound of embodiment (46) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from methoxy and ethoxy.
在另一個實施方案(48)中，本發明提供實施方案(1)-(47)中任一項的化合物或其藥學上可接受的鹽，其中R3
和R4
獨立選自氫、C1-10
烷基和鹵素。In another embodiment (48), the present invention provides the compound of any one of embodiments (1)-(47) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, C 1 -10 alkyl and halogen.
在另一個實施方案(49)中，本發明提供實施方案(48)的化合物或其藥學上可接受的鹽，其中R3
是氫。In another embodiment (49), the present invention provides the compound of embodiment (48) or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
在另一個實施方案(50)中，本發明提供實施方案(48)的化合物或其藥學上可接受的鹽，其中R4
是氫。In another embodiment (50), the present invention provides the compound of embodiment (48) or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
在另一個實施方案(51)中，本發明提供的化合物選自：、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、,、、、、、、、、、、、、、、、、， 和其藥學上可接受的鹽。In another embodiment (51), the compound provided by the present invention is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And its pharmaceutically acceptable salts.
在另一個實施方案(52)中，本發明提供藥物組合物，其包含實施方案(1)-(51)中任一項的化合物或其藥學上可接受的鹽和至少一種藥學上可接受的載體。In another embodiment (52), the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments (1)-(51) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable Carrier.
在另一個實施方案(53)中，本發明提供了治療、改善或預防對抑制BTK回應的病況的方法，包括給予有此需要的個體有效量的實施方案(1)-(51)中任一項的化合物或其藥學上可接受的鹽，或至少一種其藥物組合物，任選地與第二治療劑聯合使用。In another embodiment (53), the present invention provides a method for treating, ameliorating or preventing a condition that responds to BTK inhibition, comprising administering an effective amount of any one of the embodiments (1) to (51) 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.
在另一個實施方案(54)中，本發明提供了實施方案(1)-(51)中任一項的化合物或其藥學上可接受的鹽在製備用於治療細胞增殖異常疾病的藥物中的用途。In another embodiment (54), the present invention provides the use of the compound of any one of embodiments (1)-(51) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of abnormal cell proliferation diseases use.
一些實施例也可以描述如下：Some embodiments can also be described as follows:
在實施方案＜1＞中，本發明提供式＜I’＞所示的化合物：＜I’＞ 或其藥學上可接受的鹽，其中， Q選自C3-10
環烷基、雜環基、芳基和雜芳基，其中環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； L選自化學鍵、-(CRC0
RD0
)u
-、-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(=NRE0
)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)NRB0
(CRC0
RD0
)t
-、 -(CRC0
RD0
)u
S(O)r
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
S(O)r
(CRC0
RD0
)t
-和 -(CRC0
RD0
)u
NRA0
S(O)r
NRB0
(CRC0
RD0
)t
-； X1
、X2
、X3
和X4
獨立選自CRX
和 N； R1
選自氫、氘、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA1
RB1
、-ORA1
、-C(O)RA1
、-C(=NRE1
)RA1
、-C(=N-ORB1
)RA1
、-C(O)ORA1
、-OC(O)RA1
、-C(O)NRA1
RB1
、-NRA1
C(O)RB1
、-C(=NRE1
)NRA1
RB1
、-NRA1
C(=NRE1
)RB1
、-OC(O)NRA1
RB1
、-NRA1
C(O)ORB1
、-NRA1
C(O)NRA1
RB1
、-NRA1
C(S)NRA1
RB1
、-NRA1
C(=NRE1
)NRA1
RB1
、-S(O)r
RA1
、-S(O)(=NRE1
)RB1
、-N=S(O)RA1
RB1
、-S(O)2
ORA1
、-OS(O)2
RA1
、-NRA1
S(O)r
RB1
、-NRA1
S(O)(=NRE1
)RB1
、-S(O)r
NRA1
RB1
、-S(O)(=NRE1
)NRA1
RB1
、-NRA1
S(O)2
NRA1
RB1
、-NRA1
S(O)(=NRE1
)NRA1
RB1
、-P(O)RA1
RB1
和-P(O)(ORA1
)(ORB1
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； R2
選自氫、氘、鹵素、CN、NO2
、-NRA2
RB2
、-ORA2
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R3
選自氫、氘、鹵素、CN、NO2
、-NRA3
RB3
、-ORA3
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R4
選自氫、氘、鹵素、CN、NO2
、-NRA4
RB4
、-ORA4
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R5
選自氫、氘、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA5
RB5
、-ORA5
、-C(O)RA5
、-C(=NRE5
)RA5
、-C(=N-ORB5
)RA5
、-C(O)ORA5
、-OC(O)RA5
、-C(O)NRA5
RB5
、-NRA5
C(O)RB5
、-C(=NRE5
)NRA5
RB5
、-NRA5
C(=NRE5
)RB5
、-OC(O)NRA5
RB5
、-NRA5
C(O)ORB5
、-NRA5
C(O)NRA5
RB5
、-NRA5
C(S)NRA5
RB5
、-NRA5
C(=NRE5
)NRA5
RB5
、-S(O)r
RA5
、-S(O)(=NRE5
)RB5
、-N=S(O)RA5
RB5
、-S(O)2
ORA5
、-OS(O)2
RA5
、-NRA5
S(O)r
RB5
、-NRA5
S(O)(=NRE5
)RB5
、-S(O)r
NRA5
RB5
、-S(O)(=NRE5
)NRA5
RB5
、-NRA5
S(O)2
NRA5
RB5
、-NRA5
S(O)(=NRE5
)NRA5
RB5
、-P(O)RA5
RB5
和-P(O)(ORA5
)(ORB5
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； 每個RA0
、RA1
、RA2
、RA3
、RA4
、RA5
、RB0
、RB1
、RB2
、RB3
、RB4
和RB5
獨立選自氫、氘、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX
的取代基取代； 或每個「RA0
和RB0
、「RA1
和RB1
、「RA2
和RB2
」、「RA3
和RB3
」、「RA4
和RB4
」或「RA5
和RB5
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX
基團取代； 每個RC0
和RD0
獨立選自氫、氘、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX
的取代基取代； 或RC0
和RD0
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RX
基團取代； 每個RE0
、RE1
和RE5
獨立選自氫、氘、C1-10
烷基、CN、NO2
、-ORa1
、-SRa1
、-S(O)r
Ra1
、-C(O)Ra1
、-C(O)ORa1
、-C(O)NRa1
Rb1
和-S(O)r
NRa1
Rb1
； 每個RX
獨立選自氫、氘、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-(CRc1
Rd1
)t
NRa1
Rb1
、-(CRc1
Rd1
)t
ORb1
、-(CRc1
Rd1
)t
C(O)Ra1
、-(CRc1
Rd1
)t
C(=NRe1
)Ra1
、-(CRc1
Rd1
)t
C(=N-ORb1
)Ra1
、-(CRc1
Rd1
)t
C(O)ORb1
、-(CRc1
Rd1
)t
OC(O)Rb1
、-(CRc1
Rd1
)t
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)Rb1
、-(CRc1
Rd1
)t
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)Rb1
、-(CRc1
Rd1
)t
OC(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)ORb1
、-(CRc1
Rd1
)t
NRa1
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(S)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)r
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
N=S(O)Ra1
Rb1
、-(CRc1
Rd1
)t
S(O)2
ORb1
、-(CRc1
Rd1
)t
OS(O)2
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)r
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
S(O)r
NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)2
NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
P(O)Ra1
Rb1
和-(CRc1
Rd1
)t
P(O)(ORa1
)(ORb1
)，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獨立選自RY
的取代基取代； 每個Ra1
和Rb1
獨立選自氫、氘、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Ra1
和Rb1
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RY
基團取代； 每個Rc1
和Rd1
獨立選自氫、氘、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Rc1
和Rd1
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RY
基團取代； 每個Re1
獨立選自氫、氘、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、CN、NO2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-C(O)Ra2
、-C(O)ORa2
、-S(O)r
NRa2
Rb2
和-C(O)NRa2
Rb2
； 每個RY
獨立地選自C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-NRa2
Rb2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-S(O)2
ORa2
、-OS(O)2
Rb2
、-S(O)r
NRa2
Rb2
、-P(O)Ra2
Rb2
、-P(O)(ORa2
)(ORb2
)、-(CRc2
Rd2
)t
NRa2
Rb2
、-(CRc2
Rd2
)t
ORb2
、-(CRc2
Rd2
)t
SRb2
、-(CRc2
Rd2
)t
S(O)r
Rb2
、-(CRc2
Rd2
)t
P(O)Ra2
Rb2
、-(CRc2
Rd2
)t
P(O)(ORa2
)(ORb2
)、 -(CRc2
Rd2
)t
CO2
Rb2
、-(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)Rb2
、-(CRc2
Rd2
)t
NRa2
CO2
Rb2
、-(CRc2
Rd2
)t
OC(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
SO2
NRa2
Rb2
、-NRa2
(CRc2
Rd2
)t
NRa2
Rb2
、-O(CRc2
Rd2
)t
NRa2
Rb2
、-S(CRc2
Rd2
)t
NRa2
Rb2
、-S(O)r
(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)Ra2
、-C(O)(CRc2
Rd2
)t
ORb2
、-C(O)(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)(CRc2
Rd2
)t
SRb2
、-C(O)(CRc2
Rd2
)t
S(O)r
Rb2
、-CO2
Rb2
、-CO2
(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-OC(O)Ra2
、-CN、-C(O)NRa2
Rb2
、-NRa2
C(O)Rb2
、-OC(O)NRa2
Rb2
、-NRa2
C(O)ORb2
、-NRa2
C(O)NRa2
Rb2
、-NRa2
S(O)r
Rb2
、-CRa2
(=N-ORb2
)、-C(=NRe2
)Ra2
、-C(=NRe2
)NRa2
Rb2
、-NRa2
C(=NRe2
)NRa2
Rb2
、-CHF2
、-CF3
、-OCHF2
和-OCF3
，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獨立選自羥基、CN、氨基、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Ra2
和Rb2
獨立選自氫、氘、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基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、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Ra2
和Rb2
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Rc2
和Rd2
獨立選自氫、氘、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Rc2
和Rd2
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個額外的獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Re2
獨立選自氫、氘、CN、NO2
、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、-C(O)C1-4
烷基、-C(O)C3-10
環烷基、-C(O)OC1-4
烷基、-C(O)OC3-10
環烷基、-C(O)N(C1-4
烷基)2
、-C(O)N(C3-10
環烷基)2
、-S(O)2
C1-4
烷基、-S(O)2
C3-10
環烷基、-S(O)2
N(C1-4
烷基)2
和-S(O)2
N(C3-10
環烷基)2
； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4； 每個u獨立選自0、1、2、3和4。In embodiment <1>, the present invention provides a compound represented by formula <I'>: 
在另一個實施方案＜2＞中，本發明提供實施方案＜1＞的化合物或其藥學上可接受的鹽，其中Q選自C3-10
環烷基和雜環基，其中環烷基和雜環基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment <2>, the present invention provides the compound of embodiment <1> or a pharmaceutically acceptable salt thereof, wherein Q is selected from C 3-10 cycloalkyl and heterocyclyl, wherein cycloalkyl and The heterocyclic groups are respectively unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案＜3＞中，本發明提供實施方案＜2＞的化合物或其藥學上可接受的鹽，其中Q選自環己基和四氫吡喃，其中環己基和四氫吡喃分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment <3>, the present invention provides the compound of embodiment <2> or a pharmaceutically acceptable salt thereof, wherein Q is selected from cyclohexyl and tetrahydropyran, wherein cyclohexyl and tetrahydropyran are respectively Is unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案＜4＞中，本發明提供實施方案＜1＞-＜3＞中任一項的化合物或其藥學上可接受的鹽，其中R1
選自C1-10
烷基和C3-10
環烷基，其中烷基和環烷基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment <4>, the present invention provides the compound of any one of embodiments <1>-<3> or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-10 alkyl and C 3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案＜5＞中，本發明提供實施方案＜4＞的化合物或其藥學上可接受的鹽，其中R1
是C1-10
烷基，其中烷基是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment <5>, the present invention provides the compound of embodiment <4> or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1-10 alkyl group, wherein the alkyl group is unsubstituted or is At least one substituent independently selected from R X is substituted.
在另一個實施方案＜6＞中，本發明提供實施方案＜5＞的化合物或其藥學上可接受的鹽，其中R1
是甲基，其中甲基被RX
取代。In another embodiment <6>, the present invention provides the compound of embodiment <5> or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, wherein the methyl group is substituted by R X.
在另一個實施方案＜7＞中，本發明提供實施方案＜6＞的化合物或其藥學上可接受的鹽，其中R1
是甲基，其中甲基被OH取代。In another embodiment <7>, the present invention provides the compound of embodiment <6> or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, wherein the methyl group is substituted by OH.
在另一個實施方案＜8＞中，本發明提供實施方案＜1＞-＜7＞中任一項的化合物或其藥學上可接受的鹽，其中X1
、X2
、X3
和X4
選自CRX
，其中RX
獨立選自氫、氘、鹵素、CN和C1-10
烷基。In another embodiment <8>, the present invention provides the compound of any one of embodiments <1>-<7> or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 are selected From CR X , where R X is independently selected from hydrogen, deuterium, halogen, CN, and C 1-10 alkyl.
在另一個實施方案＜9＞中，本發明提供實施方案＜8＞的化合物或其藥學上可接受的鹽，其中式＜I’＞的子結構式＜II’＞是。In another embodiment <9>, the present invention provides the compound of embodiment <8> or a pharmaceutically acceptable salt thereof, wherein the sub-structure of formula <I'> is <II'> Yes .
在另一個實施方案＜10＞中，本發明提供實施方案＜9＞的化合物或其藥學上可接受的鹽，其中RX
選自氫、F、Cl、CN和甲基。In another embodiment <10>, the present invention provides the compound of embodiment <9> or a pharmaceutically acceptable salt thereof, wherein R X is selected from hydrogen, F, Cl, CN and methyl.
在另一個實施方案＜11＞中，本發明提供實施方案＜1＞-＜10＞中任一項的化合物或其藥學上可接受的鹽，其中L選自-(CRC1
RD1
)u
O(CRC1
RD1
)t
-、-(CRC1
RD1
)u
S(CRC1
RD1
)t
-和-(CRC1
RD1
)u
C(O)NRA1
(CRC1
RD1
)t
-。In another embodiment <11>, the present invention provides the compound of any one of the embodiments <1>-<10> or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR C1 R D1 ) u O (CR C1 R D1 ) t -, -(CR C1 R D1 ) u S(CR C1 R D1 ) t -and -(CR C1 R D1 ) u C(O)NR A1 (CR C1 R D1 ) t -.
在另一個實施方案＜12＞中，本發明提供實施方案＜11＞的化合物或其藥學上可接受的鹽，其中L選自-O-、-S-和-C(O)N(RA1
)-。In another embodiment <12>, the present invention provides the compound of embodiment <11> or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R A1 )-.
在另一個實施方案＜13＞中，本發明提供實施方案＜12＞的化合物或其藥學上可接受的鹽，其中L是-O-。In another embodiment <13>, the present invention provides the compound of embodiment <12> or a pharmaceutically acceptable salt thereof, wherein L is -O-.
在另一個實施方案＜14＞中，本發明提供實施方案＜1＞-＜13＞中任一項的化合物或其藥學上可接受的鹽，其中R5
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，獨立選自RX
的取代基取代。In another embodiment <14>, the present invention provides the compound of any one of embodiments <1>-<13> or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from aryl and heteroaryl, wherein The aryl group and the heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案＜15＞中，本發明提供實施方案＜14＞的化合物或其藥學上可接受的鹽，其中R5
選自芳基，其中芳基是未被取代的或被RX
取代。In another embodiment <15>, the present invention provides the compound of embodiment <14> or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from an aryl group, wherein the aryl group is unsubstituted or substituted by R X .
在另一個實施方案＜16＞中，本發明提供實施方案＜15＞的化合物或其藥學上可接受的鹽，其中苯基是未被取代的或被鹵素取代。In another embodiment <16>, the present invention provides the compound of embodiment <15> or a pharmaceutically acceptable salt thereof, wherein the phenyl group is unsubstituted or substituted with halogen.
在另一個實施方案＜17＞中，本發明提供實施方案＜1＞-＜16＞中任一項的化合物或其藥學上可接受的鹽，其中R2
選自氫、氘、鹵素、C1-10
烷基和CN。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 2 is selected from hydrogen, deuterium, halogen, C 1 -10 alkyl and CN.
在另一個實施方案＜18＞中，本發明提供實施方案＜17＞的化合物或其藥學上可接受的鹽，其中R2
選自氫、F和CN。In another embodiment <18>, the present invention provides the compound of embodiment <17> or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, F and CN.
在另一個實施方案＜19＞中，本發明提供實施方案＜1＞-＜18＞中任一項的化合物或其藥學上可接受的鹽，其中R3
和R4
獨立選自氫、氘、C1-10
烷基和鹵素。In another embodiment <19>, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments <1> to <18>, wherein R 3 and R 4 are independently selected from hydrogen, deuterium, C 1-10 alkyl and halogen.
在另一個實施方案＜20＞中，本發明提供實施方案＜19＞的化合物或其藥學上可接受的鹽，其中R3
是氫。In another embodiment <20>, the present invention provides the compound of embodiment <19> or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
在另一個實施方案＜21＞中，本發明提供實施方案＜20＞的化合物或其藥學上可接受的鹽，其中R4
是氫。In another embodiment <21>, the present invention provides the compound of embodiment <20> or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
在另一個實施方案＜22＞中，本發明提供藥物組合物，其包含實施方案＜1＞-＜21＞中任一項的化合物或其藥學上可接受的鹽和至少一種藥學上可接受的載體。In another embodiment <22>, the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments <1>-<21> or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable Carrier.
在另一個實施方案＜23＞中，本發明提供了治療、改善或預防對抑制BTK回應的病況的方法，包括給予有此需要的個體有效量的實施方案＜1＞-＜21＞中任一項的化合物或其藥學上可接受的鹽，或至少一種其藥物組合物，任選地與第二治療劑聯合使用。In another embodiment <23>, the present invention provides a method for treating, ameliorating or preventing a condition that responds to BTK inhibition, comprising administering an effective amount of any one of embodiments <1> to <21> 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.
在另一個實施方案＜24＞中，本發明提供了實施方案＜1＞-＜21＞中任一項的化合物或其藥學上可接受的鹽在製備用於治療細胞增殖異常疾病的藥物中的用途。In another embodiment <24>, the present invention provides the compound of any one of the embodiments <1>-<21> or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of abnormal cell proliferation diseases use.
一些實施例也可以描述如下：Some embodiments can also be described as follows:
在實施方案[1]中，本發明提供式[I’’]所示的化合物：[I’’] 或其藥學上可接受的鹽，其中， Q選自C3-10
環烷基、雜環基、芳基和雜芳基，其中環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； L選自化學鍵、-(CRC0
RD0
)u
-、-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(=NRE0
)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)NRB0
(CRC0
RD0
)t
-、 -(CRC0
RD0
)u
S(O)r
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
S(O)r
(CRC0
RD0
)t
-和 -(CRC0
RD0
)u
NRA0
S(O)r
NRB0
(CRC0
RD0
)t
-； X1
、X2
、X3
和X4
獨立選自CRX
和 N； Y選自CR4
和 N； R1
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA1
RB1
、-ORA1
、-C(O)RA1
、-C(=NRE1
)RA1
、-C(=N-ORB1
)RA1
、-C(O)ORA1
、-OC(O)RA1
、-C(O)NRA1
RB1
、-NRA1
C(O)RB1
、-C(=NRE1
)NRA1
RB1
、-NRA1
C(=NRE1
)RB1
、-OC(O)NRA1
RB1
、-NRA1
C(O)ORB1
、-NRA1
C(O)NRA1
RB1
、-NRA1
C(S)NRA1
RB1
、-NRA1
C(=NRE1
)NRA1
RB1
、-S(O)r
RA1
、-S(O)(=NRE1
)RB1
、-N=S(O)RA1
RB1
、-S(O)2
ORA1
、-OS(O)2
RA1
、-NRA1
S(O)r
RB1
、-NRA1
S(O)(=NRE1
)RB1
、-S(O)r
NRA1
RB1
、-S(O)(=NRE1
)NRA1
RB1
、-NRA1
S(O)2
NRA1
RB1
、-NRA1
S(O)(=NRE1
)NRA1
RB1
、-P(O)RA1
RB1
和-P(O)(ORA1
)(ORB1
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； R2
選自氫、鹵素、CN、NO2
、-NRA2
RB2
、-ORA2
、-C(O)NRA2
RB2
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R3
選自氫、鹵素、CN、NO2
、-NRA3
RB3
、-ORA3
、-C(O)NRA2
RB2
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R4
選自氫、鹵素、CN、NO2
、-NRA4
RB4
、-ORA4
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R5
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA5
RB5
、-ORA5
、-C(O)RA5
、-C(=NRE5
)RA5
、-C(=N-ORB5
)RA5
、-C(O)ORA5
、-OC(O)RA5
、-C(O)NRA5
RB5
、-NRA5
C(O)RB5
、-C(=NRE5
)NRA5
RB5
、-NRA5
C(=NRE5
)RB5
、-OC(O)NRA5
RB5
、-NRA5
C(O)ORB5
、-NRA5
C(O)NRA5
RB5
、-NRA5
C(S)NRA5
RB5
、-NRA5
C(=NRE5
)NRA5
RB5
、-S(O)r
RA5
、-S(O)(=NRE5
)RB5
、-N=S(O)RA5
RB5
、-S(O)2
ORA5
、-OS(O)2
RA5
、-NRA5
S(O)r
RB5
、-NRA5
S(O)(=NRE5
)RB5
、-S(O)r
NRA5
RB5
、-S(O)(=NRE5
)NRA5
RB5
、-NRA5
S(O)2
NRA5
RB5
、-NRA5
S(O)(=NRE5
)NRA5
RB5
、-P(O)RA5
RB5
和-P(O)(ORA5
)(ORB5
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； 每個RA0
、RA1
、RA2
、RA3
、RA4
、RA5
、RB0
、RB1
、RB2
、RB3
、RB4
和RB5
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX
的取代基取代； 或每個「RA0
和RB0
、「RA1
和RB1
、「RA2
和RB2
」、「RA3
和RB3
」、「RA4
和RB4
」或「RA5
和RB5
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX
基團取代； 每個RC0
和RD0
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX
的取代基取代； 或RC0
和RD0
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RX
基團取代； 每個RE0
、RE1
和RE5
獨立選自氫、C1-10
烷基、CN、NO2
、-ORa1
、-SRa1
、-S(O)r
Ra1
、-C(O)Ra1
、-C(O)ORa1
、-C(O)NRa1
Rb1
和-S(O)r
NRa1
Rb1
； 每個RX
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-(CRc1
Rd1
)t
NRa1
Rb1
、-(CRc1
Rd1
)t
ORb1
、-(CRc1
Rd1
)t
C(O)Ra1
、-(CRc1
Rd1
)t
C(=NRe1
)Ra1
、-(CRc1
Rd1
)t
C(=N-ORb1
)Ra1
、-(CRc1
Rd1
)t
C(O)ORb1
、-(CRc1
Rd1
)t
OC(O)Rb1
、-(CRc1
Rd1
)t
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)Rb1
、-(CRc1
Rd1
)t
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)Rb1
、-(CRc1
Rd1
)t
OC(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)ORb1
、-(CRc1
Rd1
)t
NRa1
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(S)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)r
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
N=S(O)Ra1
Rb1
、-(CRc1
Rd1
)t
S(O)2
ORb1
、-(CRc1
Rd1
)t
OS(O)2
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)r
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
S(O)r
NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)2
NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
P(O)Ra1
Rb1
和-(CRc1
Rd1
)t
P(O)(ORa1
)(ORb1
)，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獨立選自RY
的取代基取代； 每個Ra1
和Rb1
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Ra1
和Rb1
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RY
基團取代； 每個Rc1
和Rd1
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Rc1
和Rd1
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RY
基團取代； 每個Re1
獨立選自氫、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、CN、NO2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-C(O)Ra2
、-C(O)ORa2
、-S(O)r
NRa2
Rb2
和-C(O)NRa2
Rb2
； 每個RY
獨立地選自C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-NRa2
Rb2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-S(O)2
ORa2
、-OS(O)2
Rb2
、-S(O)r
NRa2
Rb2
、-P(O)Ra2
Rb2
、-P(O)(ORa2
)(ORb2
)、-(CRc2
Rd2
)t
NRa2
Rb2
、-(CRc2
Rd2
)t
ORb2
、-(CRc2
Rd2
)t
SRb2
、-(CRc2
Rd2
)t
S(O)r
Rb2
、-(CRc2
Rd2
)t
P(O)Ra2
Rb2
、-(CRc2
Rd2
)t
P(O)(ORa2
)(ORb2
)、 -(CRc2
Rd2
)t
CO2
Rb2
、-(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)Rb2
、-(CRc2
Rd2
)t
NRa2
CO2
Rb2
、-(CRc2
Rd2
)t
OC(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
SO2
NRa2
Rb2
、-NRa2
(CRc2
Rd2
)t
NRa2
Rb2
、-O(CRc2
Rd2
)t
NRa2
Rb2
、-S(CRc2
Rd2
)t
NRa2
Rb2
、-S(O)r
(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)Ra2
、-C(O)(CRc2
Rd2
)t
ORb2
、-C(O)(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)(CRc2
Rd2
)t
SRb2
、-C(O)(CRc2
Rd2
)t
S(O)r
Rb2
、-CO2
Rb2
、-CO2
(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-OC(O)Ra2
、-CN、-C(O)NRa2
Rb2
、-NRa2
C(O)Rb2
、-OC(O)NRa2
Rb2
、-NRa2
C(O)ORb2
、-NRa2
C(O)NRa2
Rb2
、-NRa2
S(O)r
Rb2
、-CRa2
(=N-ORb2
)、-C(=NRe2
)Ra2
、-C(=NRe2
)NRa2
Rb2
、-NRa2
C(=NRe2
)NRa2
Rb2
、-CHF2
、-CF3
、-OCHF2
和-OCF3
，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獨立選自羥基、CN、氨基、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Ra2
和Rb2
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基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、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Ra2
和Rb2
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Rc2
和Rd2
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Rc2
和Rd2
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個額外的獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Re2
獨立選自氫、CN、NO2
、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、-C(O)C1-4
烷基、-C(O)C3-10
環烷基、-C(O)OC1-4
烷基、-C(O)OC3-10
環烷基、-C(O)N(C1-4
烷基)2
、-C(O)N(C3-10
環烷基)2
、-S(O)2
C1-4
烷基、-S(O)2
C3-10
環烷基、-S(O)2
N(C1-4
烷基)2
和-S(O)2
N(C3-10
環烷基)2
； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4； 每個u獨立選自0、1、2、3和4。In embodiment [1], the present invention provides a compound represented by formula [I'']:
在另一個實施方案[2]中，本發明提供實施方案[1]的化合物或其藥學上可接受的鹽，其中Y是CR4
，化合物如式[II’’]所示：[II’’] 其中Q、L、R1
、R2
、R3
、R4
、R5
、X1
、X2
、X3
和X4
的定義與式[I’’]相同。In another embodiment [2], the present invention provides the compound of embodiment [1] or a pharmaceutically acceptable salt thereof, wherein Y is CR 4 , and the compound is represented by formula [II'']: [II''] The definitions of Q, L, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 and X 4 are the same as those of formula [I''].
在另一個實施方案[3]中，本發明提供實施方案[1]-[2]中任一項的化合物或其藥學上可接受的鹽，其中Q選自C3-10
環烷基和雜環基，其中環烷基和雜環基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment [3], the present invention provides the compound of any one of embodiments [1]-[2] or a pharmaceutically acceptable salt thereof, wherein Q is selected from C 3-10 cycloalkyl and hetero Cyclic groups, wherein the cycloalkyl group and the heterocyclic group are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案[4]中，本發明提供實施方案[3]的化合物或其藥學上可接受的鹽，其中Q選自、和，是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment [4], the present invention provides the compound of embodiment [3] or a pharmaceutically acceptable salt thereof, wherein Q is selected from , and , Is unsubstituted or substituted by at least one substituent independently selected from R X.
在另一個實施方案[5]中，本發明提供實施方案[1]-[4]中任一項的化合物或其藥學上可接受的鹽，其中R1
選自C1-10
烷基和C3-10
環烷基，其中烷基和環烷基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment [5], the present invention provides the compound of any one of embodiments [1]-[4] or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-10 alkyl and C 3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案[6]中，本發明提供實施方案[5]的化合物或其藥學上可接受的鹽，其中R1
是C1-10
烷基，其中烷基是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment [6], the present invention provides the compound of embodiment [5] or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1-10 alkyl group, wherein the alkyl group is unsubstituted or is At least one substituent independently selected from R X is substituted.
在另一個實施方案[7]中，本發明提供實施方案[6]的化合物或其藥學上可接受的鹽，其中R1
是甲基，其中甲基被OH、CN和。In another embodiment [7], the present invention provides the compound of embodiment [6] or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, wherein the methyl group is replaced by OH, CN and .
在另一個實施方案[8]中，本發明提供實施方案[1]-[7]中任一項的化合物或其藥學上可接受的鹽，其中X1
、X2
、X3
和X4
獨立選自CRX
和N，其中RX
獨立選自氫、氘、鹵素、CN和C1-10
烷基。In another embodiment [8], the present invention provides the compound of any one of embodiments [1]-[7] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 are independently It is selected from CR X and N, wherein R X is independently selected from hydrogen, deuterium, halogen, CN and C 1-10 alkyl.
在另一個實施方案[9]中，本發明提供實施方案[1]-[8]中任一項的化合物或其藥學上可接受的鹽，其中式[I’’]或式[II’’]的子結構[Ⅲ’’]選自、、、和。In another embodiment [9], the present invention provides the compound of any one of embodiments [1]-[8] or a pharmaceutically acceptable salt thereof, wherein formula [I''] or formula [II'' ] Substructure [Ⅲ''] is selected from , , , and .
在另一個實施方案[10]中，本發明提供實施方案[9]的化合物或其藥學上可接受的鹽，其中RX
選自、F、Cl、CN和甲基。In another embodiment [10], the present invention provides the compound of embodiment [9] or a pharmaceutically acceptable salt thereof, wherein R X is selected from, F, Cl, CN and methyl.
在另一個實施方案[11]中，本發明提供實施方案[1]-[10]中任一項的化合物或其藥學上可接受的鹽，其中L選自-(CRC1
RD1
)u
O(CRC1
RD1
)t
-、-(CRC1
RD1
)u
S(CRC1
RD1
)t
-和-(CRC1
RD1
)u
C(O)NRA1
(CRC1
RD1
)t
-。In another embodiment [11], the present invention provides the compound of any one of embodiments [1]-[10] or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR C1 R D1 ) u O (CR C1 R D1 ) t -, -(CR C1 R D1 ) u S(CR C1 R D1 ) t -and -(CR C1 R D1 ) u C(O)NR A1 (CR C1 R D1 ) t -.
在另一個實施方案[12]中，本發明提供實施方案[11]的化合物或其藥學上可接受的鹽，其中L選自-O-、-S-和-C(O)N(RA1
)-。In another embodiment [12], the present invention provides the compound of embodiment [11] or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R A1 )-.
在另一個實施方案[13]中，本發明提供實施方案[12]的化合物或其藥學上可接受的鹽，其中L是-O-。In another embodiment [13], the present invention provides the compound of embodiment [12] or a pharmaceutically acceptable salt thereof, wherein L is -O-.
在另一個實施方案[14]中，本發明提供實施方案[1]-[13]中任一項的化合物或其藥學上可接受的鹽，其中R5
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，獨立選自RX
的取代基取代。In another embodiment [14], the present invention provides the compound of any one of embodiments [1] to [13] or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from aryl and heteroaryl, wherein The aryl group and the heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案[15]中，本發明提供實施方案[14]的化合物或其藥學上可接受的鹽，其中R5
選自苯基和吡啶基，其中苯基和吡啶基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment [15], the present invention provides the compound of embodiment [14] or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from phenyl and pyridyl, wherein phenyl and pyridyl are independently Substituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案[16]中，本發明提供實施方案[15]的化合物或其藥學上可接受的鹽，其中RX
是鹵素。In another embodiment [16], the present invention provides the compound of embodiment [15] or a pharmaceutically acceptable salt thereof, wherein R X is halogen.
在另一個實施方案[17]中，本發明提供實施方案[1]-[16]中任一項的化合物或其藥學上可接受的鹽，其中R2
選自氫、鹵素、C1-10
烷基、-ORA2
、-C(O)NRA2
RB2
和CN。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 2 is selected from hydrogen, halogen, C 1-10 Alkyl, -OR A2 , -C(O)NR A2 R B2 and CN.
在另一個實施方案[18]中，本發明提供實施方案[17]的化合物或其藥學上可接受的鹽，其中R2
選自氫、F、Cl、甲基、-ORA2
、-C(O)NRA2
RB2
和CN。hydrogen, F, Cl, methyl, methoxy, -C(O)NH2
和 CN。In another embodiment [18], the present invention provides the compound of embodiment [17] or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, F, Cl, methyl, -OR A2 , -C( O) NR A2 R B2 and CN. hydrogen, F, Cl, methyl, methoxy, -C(O)NH 2 and CN.
在另一個實施方案[19]中，本發明提供實施方案[1]-[18]中任一項的化合物或其藥學上可接受的鹽，其中R3
和R4
獨立選自氫、C1-10
烷基和鹵素。In another embodiment [19], the present invention provides the compound of any one of embodiments [1] to [18] or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, C 1 -10 alkyl and halogen.
在另一個實施方案[20]中，本發明提供實施方案[19]的化合物或其藥學上可接受的鹽，其中R3
是氫。In another embodiment [20], the present invention provides the compound of embodiment [19] or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
在另一個實施方案[21]中，本發明提供實施方案[19]的化合物或其藥學上可接受的鹽，其中R4
是氫。In another embodiment [21], the present invention provides the compound of embodiment [19] or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
在另一個實施方案[22]中，本發明提供藥物組合物，其包含實施方案[1]-[21]中任一項的化合物或其藥學上可接受的鹽和至少一種藥學上可接受的載體。In another embodiment [22], the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments [1] to [21] or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable Carrier.
在另一個實施方案[23]中，本發明提供了治療、改善或預防對抑制BTK回應的病況的方法，包括給予有此需要的個體有效量的實施方案[1]-[21]中任一項的化合物或其藥學上可接受的鹽，或至少一種其藥物組合物，任選地與第二治療劑聯合使用。In another embodiment [23], the present invention provides a method for treating, ameliorating or preventing a condition that responds to BTK inhibition, comprising administering an effective amount of any one of embodiments [1] to [21] 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.
在另一個實施方案[24]中，本發明提供了實施方案[1]-[21]中任一項的化合物或其藥學上可接受的鹽在製備用於治療細胞增殖異常疾病的藥物中的用途。In another embodiment [24], the present invention provides the use of the compound of any one of embodiments [1]-[21] or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of abnormal cell proliferation diseases use.
一些實施例也可以描述如下：Some embodiments can also be described as follows:
在實施方案(i)中，本發明提供式(I’’’)所示的化合物：(I’’’) 或其藥學上可接受的鹽，其中， Q選自C3-10
環烷基、雜環基、芳基和雜芳基，其中環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； L選自化學鍵、-(CRC0
RD0
)u
-、-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(=NRE0
)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
C(O)NRB0
(CRC0
RD0
)t
-、 -(CRC0
RD0
)u
S(O)r
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(O)r
NRA0
(CRC0
RD0
)t
-、-(CRC0
RD0
)u
NRA0
S(O)r
(CRC0
RD0
)t
-和 -(CRC0
RD0
)u
NRA0
S(O)r
NRB0
(CRC0
RD0
)t
-； X1
、X2
、X3
和X4
獨立選自CRX
和 N； Y選自CR4
和 N； R1
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA1
RB1
、-ORA1
、-C(O)RA1
、-C(=NRE1
)RA1
、-C(=N-ORB1
)RA1
、-C(O)ORA1
、-OC(O)RA1
、-C(O)NRA1
RB1
、-NRA1
C(O)RB1
、-C(=NRE1
)NRA1
RB1
、-NRA1
C(=NRE1
)RB1
、-OC(O)NRA1
RB1
、-NRA1
C(O)ORB1
、-NRA1
C(O)NRA1
RB1
、-NRA1
C(S)NRA1
RB1
、-NRA1
C(=NRE1
)NRA1
RB1
、-S(O)r
RA1
、-S(O)(=NRE1
)RB1
、-N=S(O)RA1
RB1
、-S(O)2
ORA1
、-OS(O)2
RA1
、-NRA1
S(O)r
RB1
、-NRA1
S(O)(=NRE1
)RB1
、-S(O)r
NRA1
RB1
、-S(O)(=NRE1
)NRA1
RB1
、-NRA1
S(O)2
NRA1
RB1
、-NRA1
S(O)(=NRE1
)NRA1
RB1
、-P(O)RA1
RB1
和-P(O)(ORA1
)(ORB1
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； R2
選自氫、鹵素、CN、NO2
、-NRA2
RB2
、-ORA2
、-C(O)NRA2
RB2
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R3
選自氫、鹵素、CN、NO2
、-NRA3
RB3
、-ORA3
、-C(O)NRA2
RB2
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R4
選自氫、鹵素、CN、NO2
、-NRA4
RB4
、-ORA4
、C1-10
烷基，其中烷基是未被取代的或被至少一個獨立選自RX
的取代基取代； R5
選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、CN、NO2
、-NRA5
RB5
、-ORA5
、-C(O)RA5
、-C(=NRE5
)RA5
、-C(=N-ORB5
)RA5
、-C(O)ORA5
、-OC(O)RA5
、-C(O)NRA5
RB5
、-NRA5
C(O)RB5
、-C(=NRE5
)NRA5
RB5
、-NRA5
C(=NRE5
)RB5
、-OC(O)NRA5
RB5
、-NRA5
C(O)ORB5
、-NRA5
C(O)NRA5
RB5
、-NRA5
C(S)NRA5
RB5
、-NRA5
C(=NRE5
)NRA5
RB5
、-S(O)r
RA5
、-S(O)(=NRE5
)RB5
、-N=S(O)RA5
RB5
、-S(O)2
ORA5
、-OS(O)2
RA5
、-NRA5
S(O)r
RB5
、-NRA5
S(O)(=NRE5
)RB5
、-S(O)r
NRA5
RB5
、-S(O)(=NRE5
)NRA5
RB5
、-NRA5
S(O)2
NRA5
RB5
、-NRA5
S(O)(=NRE5
)NRA5
RB5
、-P(O)RA5
RB5
和-P(O)(ORA5
)(ORB5
)，其中每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX
的取代基取代； 每個RA0
、RA1
、RA2
、RA3
、RA4
、RA5
、RB0
、RB1
、RB2
、RB3
、RB4
和RB5
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX
的取代基取代； 或每個「RA0
和RB0
、「RA1
和RB1
、「RA2
和RB2
」、「RA3
和RB3
」、「RA4
和RB4
」或「RA5
和RB5
」一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫，氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RX
基團取代； 每個RC0
和RD0
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RX
的取代基取代； 或RC0
和RD0
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RX
基團取代； 每個RE0
、RE1
和RE5
獨立選自氫、C1-10
烷基、CN、NO2
、-ORa1
、-SRa1
、-S(O)r
Ra1
、-C(O)Ra1
、-C(O)ORa1
、-C(O)NRa1
Rb1
和-S(O)r
NRa1
Rb1
； 每個RX
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-(CRc1
Rd1
)t
NRa1
Rb1
、-(CRc1
Rd1
)t
ORb1
、-(CRc1
Rd1
)t
C(O)Ra1
、-(CRc1
Rd1
)t
C(=NRe1
)Ra1
、-(CRc1
Rd1
)t
C(=N-ORb1
)Ra1
、-(CRc1
Rd1
)t
C(O)ORb1
、-(CRc1
Rd1
)t
OC(O)Rb1
、-(CRc1
Rd1
)t
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)Rb1
、-(CRc1
Rd1
)t
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)Rb1
、-(CRc1
Rd1
)t
OC(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(O)ORb1
、-(CRc1
Rd1
)t
NRa1
C(O)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(S)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
C(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)r
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
N=S(O)Ra1
Rb1
、-(CRc1
Rd1
)t
S(O)2
ORb1
、-(CRc1
Rd1
)t
OS(O)2
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)r
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)Rb1
、-(CRc1
Rd1
)t
S(O)r
NRa1
Rb1
、-(CRc1
Rd1
)t
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)2
NRa1
Rb1
、-(CRc1
Rd1
)t
NRa1
S(O)(=NRe1
)NRa1
Rb1
、-(CRc1
Rd1
)t
P(O)Ra1
Rb1
和-(CRc1
Rd1
)t
P(O)(ORa1
)(ORb1
)，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獨立選自RY
的取代基取代； 每個Ra1
和Rb1
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Ra1
和Rb1
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧、硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1、2或3個RY
基團取代； 每個Rc1
和Rd1
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
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獨立選自RY
的取代基取代； 或Rc1
和Rd1
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1、2或3個RY
基團取代； 每個Re1
獨立選自氫、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、CN、NO2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-C(O)Ra2
、-C(O)ORa2
、-S(O)r
NRa2
Rb2
和-C(O)NRa2
Rb2
； 每個RY
獨立地選自C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基、雜芳基-C1-4
烷基、鹵素、CN、-NO2
、-NRa2
Rb2
、-ORa2
、-SRa2
、-S(O)r
Ra2
、-S(O)2
ORa2
、-OS(O)2
Rb2
、-S(O)r
NRa2
Rb2
、-P(O)Ra2
Rb2
、-P(O)(ORa2
)(ORb2
)、-(CRc2
Rd2
)t
NRa2
Rb2
、-(CRc2
Rd2
)t
ORb2
、-(CRc2
Rd2
)t
SRb2
、-(CRc2
Rd2
)t
S(O)r
Rb2
、-(CRc2
Rd2
)t
P(O)Ra2
Rb2
、-(CRc2
Rd2
)t
P(O)(ORa2
)(ORb2
)、 -(CRc2
Rd2
)t
CO2
Rb2
、-(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)Rb2
、-(CRc2
Rd2
)t
NRa2
CO2
Rb2
、-(CRc2
Rd2
)t
OC(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
C(O)NRa2
Rb2
、-(CRc2
Rd2
)t
NRa2
SO2
NRa2
Rb2
、-NRa2
(CRc2
Rd2
)t
NRa2
Rb2
、-O(CRc2
Rd2
)t
NRa2
Rb2
、-S(CRc2
Rd2
)t
NRa2
Rb2
、-S(O)r
(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)Ra2
、-C(O)(CRc2
Rd2
)t
ORb2
、-C(O)(CRc2
Rd2
)t
NRa2
Rb2
、-C(O)(CRc2
Rd2
)t
SRb2
、-C(O)(CRc2
Rd2
)t
S(O)r
Rb2
、-CO2
Rb2
、-CO2
(CRc2
Rd2
)t
C(O)NRa2
Rb2
、-OC(O)Ra2
、-CN、-C(O)NRa2
Rb2
、-NRa2
C(O)Rb2
、-OC(O)NRa2
Rb2
、-NRa2
C(O)ORb2
、-NRa2
C(O)NRa2
Rb2
、-NRa2
S(O)r
Rb2
、-CRa2
(=N-ORb2
)、-C(=NRe2
)Ra2
、-C(=NRe2
)NRa2
Rb2
、-NRa2
C(=NRe2
)NRa2
Rb2
、-CHF2
、-CF3
、-OCHF2
和-OCF3
，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獨立選自羥基、CN、氨基、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Ra2
和Rb2
獨立選自氫、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基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、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Ra2
和Rb2
一起連同與它們相連的單個或多個原子構成含有0、1或2個額外的獨立選自氧，硫、氮和磷的雜原子的4-12元雜環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Rc2
和Rd2
獨立選自氫、鹵素、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、C1-10
烷氨基、C3-10
環烷氨基、二(C1-10
烷基)氨基、雜環基、雜環基-C1-4
烷基、芳基、芳基-C1-4
烷基、雜芳基和雜芳基-C1-4
烷基，其中每個烷基、烯基、炔基、環烷基、烷氧基、環烷氧基、烷硫基、環烷硫基、烷氨基、環烷氨基、雜環基、芳基和雜芳基是未被取代的或被至少一個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 或Rc2
和Rd2
一起連同與它們相連的單個或多個碳原子構成含有0、1或2個額外的獨立選自氧，硫和氮的雜原子的3-12元環，該環可任選地被1或2個獨立選自鹵素、CN、C1-10
烷基、C2-10
烯基、C2-10
炔基、C3-10
環烷基、羥基、C1-10
烷氧基、C3-10
環烷氧基、C1-10
烷硫基、C3-10
環烷硫基、氨基、C1-10
烷氨基、C3-10
環烷氨基和二(C1-10
烷基)氨基的取代基取代； 每個Re2
獨立選自氫、CN、NO2
、C1-10
烷基、C3-10
環烷基、C3-10
環烷基-C1-4
烷基、C1-10
烷氧基、C3-10
環烷氧基、-C(O)C1-4
烷基、-C(O)C3-10
環烷基、-C(O)OC1-4
烷基、-C(O)OC3-10
環烷基、-C(O)N(C1-4
烷基)2
、-C(O)N(C3-10
環烷基)2
、-S(O)2
C1-4
烷基、-S(O)2
C3-10
環烷基、-S(O)2
N(C1-4
烷基)2
和-S(O)2
N(C3-10
環烷基)2
； 每個r獨立選自0、1和2； 每個t獨立選自0、1、2、3和4； 每個u獨立選自0、1、2、3和4。In embodiment (i), the present invention provides a compound represented by formula (I'''):
在另一個實施方案(ii)中，本發明提供實施方案(1)的化合物或其藥學上可接受的鹽，其中Y是CR4
，化合物如式(II’’’)所示：(II’’’) 其中Q、L、R1
、R2
、R3
、R4
、R5
、X1
、X2
、X3
和X4
的定義與式(I’’’)相同。In another embodiment (ii), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is CR 4 , and the compound is represented by formula (II'''): (II''') Wherein Q, L, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 and X 4 have the same definitions as the formula (I''').
在另一個實施方案(iii)中，本發明提供實施方案(i)-(ii)中任一項的化合物或其藥學上可接受的鹽，其中Q選自C3-10
環烷基和雜環基，其中環烷基和雜環基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (iii), the present invention provides the compound of any one of embodiments (i)-(ii) or a pharmaceutically acceptable salt thereof, wherein Q is selected from C 3-10 cycloalkyl and hetero Cyclic groups, wherein the cycloalkyl group and the heterocyclic group are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案(iv)中，本發明提供實施方案(iii)的化合物或其藥學上可接受的鹽，其中Q選自、和，其是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (iv), the present invention provides the compound of embodiment (iii) or a pharmaceutically acceptable salt thereof, wherein Q is selected from , and , Which is unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案(v)中，本發明提供實施方案(i)-(iv)中任一項的化合物或其藥學上可接受的鹽，其中R1
選自C1-10
烷基和C3-10
環烷基，其中烷基和環烷基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (v), the present invention provides the compound of any one of embodiments (i)-(iv) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-10 alkyl and C 3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案(vi)中，本發明提供實施方案(v)的化合物或其藥學上可接受的鹽，其中R1
是C1-10
烷基，其中烷基是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (vi), the present invention provides the compound of embodiment (v) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1-10 alkyl group, wherein the alkyl group is unsubstituted or is At least one substituent independently selected from R X is substituted.
在另一個實施方案(vii)中，本發明提供實施方案(vi)的化合物或其藥學上可接受的鹽，其中R1
是甲基，其中甲基被OH、CN和取代。In another embodiment (vii), the present invention provides the compound of embodiment (vi) or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, wherein the methyl group is replaced by OH, CN and replace.
在另一個實施方案(viii)中，本發明提供實施方案(i)-(vii)中任一項的化合物或其藥學上可接受的鹽，其中X1
、X2
、X3
和X4
獨立選自CRX
和N，其中RX
獨立選自氫、氘、鹵素、CN、C1-10
烷基、C3-10
環烷基和-(CRc1
Rd1
)t
ORb1
。In another embodiment (viii), the present invention provides the compound of any one of embodiments (i)-(vii) or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 are independently It is selected from CR X and N, wherein R X is independently selected from hydrogen, deuterium, halogen, CN, C 1-10 alkyl, C 3-10 cycloalkyl, and -(CR c1 R d1 ) t OR b1 .
在另一個實施方案(ix)中，本發明提供實施方案(i)-(viii)中任一項的化合物或其藥學上可接受的鹽，其中其中式(I’’’)或式 (II’’’)的子結構(Ⅲ’’’)選自、、、、、和。In another embodiment (ix), the present invention provides the compound of any one of embodiments (i)-(viii) or a pharmaceutically acceptable salt thereof, wherein formula (I''') or formula (II) ''') substructure (Ⅲ''') Selected from , , , , , and .
在另一個實施方案(x)中，本發明提供實施方案(ix)的化合物或其藥學上可接受的鹽，其中RX
選自氫、F、Cl、Br、CN、甲基、甲氧基和環丙基。In another embodiment (x), the present invention provides the compound of embodiment (ix) or a pharmaceutically acceptable salt thereof, wherein R X is selected from hydrogen, F, Cl, Br, CN, methyl, methoxy And cyclopropyl.
在另一個實施方案(xi)中，本發明提供實施方案(i)-(x)中任一項的化合物或其藥學上可接受的鹽，其中L選自-(CRC0
RD0
)u
O(CRC0
RD0
)t
-、-(CRC0
RD0
)u
S(CRC0
RD0
)t
-和-(CRC0
RD0
)u
C(O)NRA0
(CRC0
RD0
)t
-。In another embodiment (xi), the present invention provides the compound of any one of embodiments (i)-(x) or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR CO R D0 ) u O (CR C0 R D0 ) t -, -(CR C0 R D0 ) u S(CR C0 R D0 ) t -and -(CR C0 R D0 ) u C(O)NR A0 (CR C0 R D0 ) t -.
在另一個實施方案(xii)中，本發明提供實施方案(xi)的化合物或其藥學上可接受的鹽，其中L選自-O-、-S-和-C(O)N(RA1
)-。In another embodiment (xii), the present invention provides the compound of embodiment (xi) or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R A1 )-.
另一個實施方案(xiii)中，本發明提供實施方案(xii)的化合物或其藥學上可接受的鹽，其中L是-O-。In another embodiment (xiii), the present invention provides the compound of embodiment (xii) or a pharmaceutically acceptable salt thereof, wherein L is -O-.
在另一個實施方案(xiv)中，本發明提供實施方案(i)-(xiii)中任一項的化合物或其藥學上可接受的鹽，其中R5
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，獨立選自RX
的取代基取代。In another embodiment (xiv), the present invention provides the compound of any one of embodiments (i) to (xiii) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from aryl and heteroaryl, wherein The aryl group and the heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R X.
另一個實施方案(xv)中，本發明提供實施方案(xiv)的化合物或其藥學上可接受的鹽，其中R5
選自苯基和吡啶基，其中苯基和吡啶基分別是未被取代的或被RX
的取代基取代。In another embodiment (xv), the present invention provides the compound of embodiment (xiv) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from phenyl and pyridyl, wherein phenyl and pyridyl are each unsubstituted , Or substituted by R X substituents.
另一個實施方案(xvi)中，本發明提供實施方案(xv)的化合物或其藥學上可接受的鹽，其中RX
選自鹵素和甲氧基。In another embodiment (xvi), the present invention provides the compound of embodiment (xv) or a pharmaceutically acceptable salt thereof, wherein R X is selected from halogen and methoxy.
在另一個實施方案(xvii)中，本發明提供實施方案(i)-(xvi)中任一項的化合物或其藥學上可接受的鹽，其中R2
選自氫、鹵素、C1-10
烷基、-ORA2
、-C(O)NRA2
RB2
和CN。In another embodiment (xvii), the present invention provides the compound of any one of embodiments (i)-(xvi) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, halogen, C 1-10 Alkyl, -OR A2 , -C(O)NR A2 R B2 and CN.
另一個實施方案(xviii)中，本發明提供實施方案(xvii)的化合物或其藥學上可接受的鹽，其中-ORA2
中的RA2
獨立選自氫、C1-10
烷基、C2-10
烯基和C3-10
環烷基，其中烷基、烯基和環烷基分別是未被取代的或被至少一個，獨立選自RX
的取代基取代。In another embodiment (xviii), the present invention provides the compound of embodiment (xvii) or a pharmaceutically acceptable salt thereof, wherein R A2 in -OR A2 is independently selected from hydrogen, C 1-10 alkyl, C 2 -10 alkenyl and C 3-10 cycloalkyl, wherein the alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R X.
在另一個實施方案(xix)中，本發明提供實施方案(xvii)-(xviii)中任一項的化合物或其藥學上可接受的鹽，其中R2
選自氫、F、Cl、甲基、乙基、甲氧基、乙氧基、-C(O)NH2
、CN、OH、、、、、和。In another embodiment (xix), the present invention provides the compound of any one of embodiments (xvii)-(xviii) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, F, Cl, methyl , Ethyl, methoxy, ethoxy, -C(O)NH 2 , CN, OH, , , , , and .
在另一個實施方案(xx)中，本發明提供實施方案(i)-(xix)中任一項的化合物或其藥學上可接受的鹽，其中R3
和R4
獨立選自氫、C1-10
烷基和鹵素。In another embodiment (xx), the present invention provides the compound of any one of embodiments (i)-(xix) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from hydrogen, C 1 -10 alkyl and halogen.
另一個實施方案(xxi)中，本發明提供實施方案(xx)的化合物或其藥學上可接受的鹽，其中R3
是氫。In another embodiment (xxi), the present invention provides the compound of embodiment (xx) or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
另一個實施方案(xxii)中，本發明提供實施方案(xxi)的化合物或其藥學上可接受的鹽，其中R4
是氫。In another embodiment (xxii), the present invention provides the compound of embodiment (xxi) or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
在另一個實施方案(xxiii)中，本發明提供藥物組合物，其包含實施方案(i)-(xxii)中任一項的化合物或其藥學上可接受的鹽和至少一種藥學上可接受的載體。In another embodiment (xxiii), the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments (i)-(xxii) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable Carrier.
在另一個實施方案(xxiv)中，本發明提供了治療、改善或預防對抑制BTK回應的病況的方法，包括給予有此需要的個體有效量的實施方案(i)-(xxii))中任一項的化合物或其藥學上可接受的鹽，或至少一種其藥物組合物，任選地與第二治療劑聯合使用。In another embodiment (xxiv), the present invention provides a method of treating, ameliorating or preventing a condition that responds to BTK inhibition, including administering an effective amount of any of the embodiments (i)-(xxii)) to an individual in need One compound or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.
在另一個實施方案(xxv)中，本發明提供了實施方案(i)-(xxii)中任一項的化合物或其藥學上可接受的鹽在製備用於治療細胞增殖異常疾病的藥物中的用途。In another embodiment (xxv), the present invention provides the use of the compound of any one of embodiments (i)-(xxii) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of abnormal cell proliferation diseases use.
在另一方面，本發明提供了包含本文公開的化合物或其藥學上可接受的鹽的試劑盒；以及包括以下一項或多項資訊的說明書：成分應用於何種疾病狀態、成分的儲存資訊、劑量資訊以及如何使用成分的說明。在一個特殊變體中，試劑盒包含多劑量形式的化合物。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.
在另一方面，本發明提供了包含本文公開的化合物或其藥學上可接受的鹽的製品；以及包裝材料。在一種變化中，包裝材料包括容器。在一個特殊變化中，所述容器包括標籤，其標明一項或多項以下內容：化合物應用於何種疾病狀態、儲存資訊、劑量資訊和/或如何使用化合物的說明。在另一種變體中，製品包括多劑量形式的化合物。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.
在另一方面，本發明提供了一種治療方法，包含向個體給予本文公開的化合物或其藥學上可接受的鹽。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.
在另一方面，本發明提供了一種通過使本文公開的化合物或其藥學上可接受的鹽與BTK接觸從而抑制BTK的方法。In another aspect, the present invention provides a method of inhibiting BTK by contacting a compound disclosed herein or a pharmaceutically acceptable salt thereof with BTK.
在另一方面，本發明提供了一種抑制BTK的方法，包括使本文公開的化合物或其藥學上可接受的鹽，出現在個體體內，以抑制體內BTK活性。In another aspect, the present invention provides a method for inhibiting BTK, comprising allowing the compound disclosed herein or a pharmaceutically acceptable salt thereof to appear in the body of an individual to inhibit BTK activity in the body.
在另一方面，本發明提供了一種抑制BTK的方法，包括對個體給藥第一化合物，此化合物在體內轉化為第二化合物，其中第二化合物抑制體內BTK活性，且第二化合物是以上實施方案中任一項的化合物和變體。In another aspect, the present invention provides a method of inhibiting BTK, comprising administering a first compound to an individual, and this compound is converted into a second compound in vivo, wherein the second compound inhibits BTK activity in vivo, and the second compound is implemented as above Compounds and variants of any of the schemes.
在另一方面，本發明提供了一種治療疾病狀態的方法，其中BTK活性造成了該疾病狀態的病理和/或症狀，該方法包括使對該疾病狀態治療有效量的本文公開的化合物或其藥學上可接受的鹽，出現在個體體內。In another aspect, the present invention provides a method for treating a disease state, wherein the BTK activity causes the pathology and/or symptoms of the disease state, the method comprising making a therapeutically effective amount of a compound disclosed herein or a pharmacological agent of the disease state The most acceptable salt appears in the individual's body.
在另一方面，本發明提供了一種治療疾病狀態的方法，BTK活性造成了該疾病狀態的病理和/或症狀，該方法包含對個體給藥第一化合物，此化合物在體內轉化為第二化合物，其中第二化合物抑制體內BTK活性。值得注意的是，本發明所述化合物可以是轉化前或轉化後的化合物。In another aspect, the present invention provides a method of treating a disease state in which BTK 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 the body , Wherein the second compound inhibits BTK activity in vivo. It is worth noting that the compound of the present invention may be a compound before or after conversion.
上述每個方法的變化中，疾病狀態選自：癌性增殖性疾病（例如腦、肺、鱗狀細胞、膀胱、胃、胰腺、乳腺、頭、頸、腎臟區(renal)、腎、卵巢、前列腺、結腸直腸、表皮、食道、睾丸、婦科或甲狀腺癌）；非癌性增殖性疾病（例如良性皮膚增生（如銀屑病）、再狹窄和良性前列腺肥大（BPH））；胰腺炎；腎臟疾病；疼痛；防止胚泡著床；治療與血管發生或血管生成相關疾病（例如腫瘤血管生成、急性和慢性炎症性疾病如類風濕性關節炎、動脈粥樣硬化、炎性腸病、皮膚病如銀屑病、濕疹和硬皮病、糖尿病、糖尿病性視網膜病變、早產兒視網膜病變、老年性黃斑變性、血管瘤、神經膠質瘤、黑色素瘤、卡波濟氏肉瘤和卵巢癌、乳腺癌、肺癌、胰腺癌、前列腺癌、結腸癌和表皮樣癌）；哮喘；中性粒細胞趨化性（例如，心肌梗死和中風的再灌注損傷和炎症性關節炎）；感染性休克；T細胞介導的疾病，其中免疫抑制很有價值（如預防器官移植排斥、移植物抗宿主病、紅斑狼瘡、多發性硬化和類風濕關節炎）；動脈粥樣硬化；抑制對生長因數混合物反應的角質細胞；肺慢性阻塞性疾病（COPD）和其他疾病。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, testis, 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 diseases related to angiogenesis or angiogenesis (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 (eg, reperfusion injury and inflammatory arthritis due to myocardial infarction and stroke); septic shock; T cells Mediated diseases, in which immunosuppression is valuable (eg prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinous response to a mixture of growth factors Cells; chronic obstructive pulmonary disease (COPD) and other diseases.
在另一方面，本發明提供了一種治療疾病狀態的方法，BTK
基因突變造成了該疾病狀態的病理和/或症狀，例如黑色素瘤、肺癌、結腸癌和其他類型腫瘤。In another aspect, the present invention provides a method for treating a disease state in which BTK gene mutations cause pathology and/or symptoms of the disease state, such as melanoma, lung cancer, colon cancer, and other types of tumors.
在另一方面，本發明涉及以上實施方案中任一項的化合物和變體作為藥物的用途。在另一方面，本發明涉及以上實施方案中任一項的化合物和變體用於製備抑制BTK藥物的用途。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 drugs that inhibit BTK.
在另一方面，本發明涉及以上實施方案中任一項的化合物和變體用於製備治療BTK活性造成的病理和/或症狀的疾病狀態的藥物的用途。 給藥和藥物組合物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 BTK activity. Administration and pharmaceutical composition
一般地，本發明所述化合物將以治療有效量經由任何本領域已知的普通及可接受的方式，單獨或與一種或多種治療劑合用給藥。治療有效量可以廣泛變化，取決於受試者的疾病嚴重性、年齡和相對健康狀況，所用化合物的藥效以及其他本領域已知的因素。例如，對於腫瘤性疾病和免疫系統疾病的治療，所需劑量將根據給藥模式，待治療的具體病症和所需效果而異。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.
一般地，每日劑量為0.001至100 mg/kg體重時可達到滿意的結果，具體來說，從約0.03至2.5 mg/kg體重。較大型哺乳動物的日劑量，如人類，可從約0.5 mg至約2000 mg，或更具體來說，從0.5 mg至1000 mg，以方便的形式給藥，例如，以分劑量最多每日四次或以緩釋形式。合適的口服給藥的單位劑量形式包含約1至50 mg活性成分。Generally, satisfactory results can be achieved at a daily dose of 0.001 to 100 mg/kg body weight, specifically, from about 0.03 to 2.5 mg/kg body weight. The daily dose for larger mammals, such as humans, can be from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, in a convenient form, for example, in divided doses up to four times a day. Times or in sustained release form. A suitable unit dosage form for oral administration contains about 1 to 50 mg of active ingredient.
本發明所述化合物可以以藥物組合物形式給藥，通過任何常規途徑給藥；例如經腸，例如口服，例如以片劑或膠囊形式，腸胃外，例如以可注射溶液或混懸液形式；或局部給藥，例如以洗劑，凝膠劑，軟膏劑或乳膏劑，或者以鼻或栓劑形式。The compound of the present invention can be administered in the form of a pharmaceutical composition, by any conventional route; for example, enteral, for example, orally, for example, in the form of tablets or capsules, parenteral, for example, in the form of injectable solutions or suspensions; Or topical administration, for example in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories.
含有本發明所述的以游離堿或藥學可接受鹽型的化合物與至少一種藥學可接受的載體或稀釋劑的藥物組合物，可以常規方式通過混合、制粒、包衣、溶解或冷凍乾燥流程來製造。例如，藥物組合物包含一個本發明所述化合物與至少一個藥學可接受載體或稀釋劑組合，可以以常規方式通過與藥學可接受載體或稀釋劑混合製成。用於口服的單位劑量形式包含，例如，從約0.1 mg至約500 mg活性物質。The pharmaceutical composition containing the compound in free or pharmaceutically acceptable salt form of the present invention and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or freeze-dried in a conventional manner To make. For example, a pharmaceutical composition comprising a compound of the present invention combined with at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing with a pharmaceutically acceptable carrier or diluent in a conventional manner. A unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.
在一個實施例中，藥物組合物為活性成分的溶液，包括懸浮液或分散體，如等張水溶液。在僅包含活性成分或與如甘露醇的載體混合的凍幹組合物的情況下，分散體或懸浮液可在使用前製備。藥物組合物可以被滅菌和/或含有佐劑，如防腐劑、穩定劑、濕潤劑或乳化劑、溶解促進劑、調節滲透壓的鹽和/或緩衝劑。合適的防腐劑包括但不僅限於抗氧化劑如抗壞血酸，殺微生物劑，如山梨酸或苯甲酸。溶液或懸浮液還可以包含增稠劑，包括但不僅限於羧甲基纖維素鈉、羧甲基纖維素、葡聚糖、聚乙烯吡咯烷酮、明膠，或增溶劑，例如吐溫80（聚氧乙烯(20)失水山梨醇單油酸酯）。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 for adjusting osmotic pressure, and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, and microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain thickeners, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers, such as Tween 80 (polyoxyethylene (20) Sorbitan monooleate).
在油中的懸浮液可能包含作為油性成分的植物油，合成或半合成的油，常用於注射目的。實施例包括含有作為酸組分的具有8至22個碳原子，或在一些實施方案中，從12至22個碳原子的長鏈脂肪酸的液態脂肪酸酯。合適的液態脂肪酸酯包括但不限於月桂酸，十三烷酸，肉豆蔻酸，十五烷酸，棕櫚酸，十七烷酸，硬脂酸，花生酸，山萮酸或相應的不飽和酸，例如油酸，反油酸，芥酸，巴西烯酸和亞油酸，如果需要，可以含有抗氧化劑，例如維生素E，3-胡蘿蔔素或3,5-二-叔丁基-羥基甲苯。這些脂肪酸酯的醇組分可以具有六個碳原子，並且可以是單價或多價的，例如單-，二- 或三價的醇。合適的醇組分包括但不限於甲醇，乙醇，丙醇，丁醇或戊醇或者其異構體，乙二醇和甘油。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.
其它合適的脂肪酸酯包括但不限於油酸乙酯，肉豆蔻酸異丙酯，棕櫚酸異丙酯，LABRAFIL®M2375，（聚氧乙烯甘油），LABRAFIL®M1944 CS（通過醇解杏仁油製備的不飽和聚乙二醇化甘油酯，含有甘油酯和聚乙二醇酯），LABRASOLTM
（通過醇解TCM製備的飽和聚乙二醇化甘油酯，包含甘油酯和聚乙二醇酯；均可從法國GaKefosse公司獲得），和/或MIGLYOL®812（德國Hüls AG公司的鏈長為C8至C12的飽和脂肪酸甘油三酯），以及植物油如棉子油，杏仁油，橄欖油，蓖麻油，芝麻油，豆油或花生油。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 of TCM, including glycerides and polyethylene glycol esters; both Obtained from GaKefosse, France), and/or MIGLYOL®812 (saturated fatty acid triglycerides with chain lengths from 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.
用於口服給藥的藥物組合物可以通過，例如，通過將活性成分與一種或多種固體載體混合，如果需要，顆粒化所得的混合物，並通過加入另外的賦形劑加工所述混合物或顆粒，以形式片劑或片芯。Pharmaceutical compositions for oral administration can be prepared, for example, by mixing the active ingredient with one or more solid carriers, if necessary, granulating the resulting mixture, and processing the mixture or granules by adding additional excipients, In the form of tablets or tablet cores.
合適的載體包括但不限於填充劑，例如糖，例如乳糖，蔗糖，甘露醇或山梨醇，纖維素製劑和/或磷酸鈣，例如磷酸三鈣或磷酸氫鈣，和粘合劑，例如澱粉，例如玉米，小麥，大米或馬鈴薯澱粉，甲基纖維素，羥丙基甲基纖維素，羧甲基纖維素鈉和/或聚乙烯吡咯烷酮，和/或，如果需要的話，崩解劑，如上述澱粉，羧甲基澱粉，交聯聚乙烯吡咯烷酮，藻酸或其鹽，如藻酸鈉。另外的賦形劑包括流動調節劑和潤滑劑，例如矽酸，滑石粉，硬脂酸或其鹽，如硬脂酸鎂或硬脂酸鈣，和/或聚乙二醇，或其衍生物。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, as described above Starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow regulators and lubricants, such as silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof .
可以為片劑芯提供合適的，可選腸溶的包衣，通過使用特別是，濃縮的糖溶液，其可包括阿拉伯樹膠，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化鈦，或者溶於合適有機溶劑或溶劑混合物的塗層溶液，或者，對於腸溶衣，合適的纖維素製劑的溶液，如鄰苯二甲酸乙酸纖維素或羥丙基甲基纖維素鄰苯二甲酸酯溶液。染料或顏料可以加入片劑或片劑包衣中，例如用於標識目的或指示不同劑量的活性成分。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 cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate solutions. 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.
用於口服給藥的藥物組合物還可以包括硬膠囊，包括明膠或含有明膠和增塑劑，如甘油或山梨醇的軟密封膠囊。硬膠囊劑可含有活性成分的顆粒的形式，例如與填充劑如玉米澱粉，粘合劑和/或助流劑如滑石粉或硬脂酸鎂，和任選的穩定劑混合。在軟膠囊中，活性成分可以溶解或懸浮於合適的液體賦形劑如脂肪油，石蠟油或液體聚乙二醇或者乙二醇或丙二醇的脂肪酸酯中，也可向其中加入穩定劑和洗滌劑，例如聚氧乙烯山梨糖醇的脂肪酸酯型，也可加入。The pharmaceutical composition for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerin or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example mixed with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active ingredients can be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oils or liquid polyethylene glycol or fatty acid esters of ethylene glycol or propylene glycol, and stabilizers and propylene glycol can also be added to them. Detergents, such as fatty acid ester type of polyoxyethylene sorbitol, can also be added.
適用於直腸給藥的藥物組合物，例如栓劑，其包含活性成分和栓劑基質的組合。合適的栓劑基質是，例如，天然或合成的甘油三酯，石蠟烴，聚乙二醇或高級烷醇。Pharmaceutical compositions suitable for rectal administration, such as suppositories, contain a combination of active ingredients and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
適於胃腸外給藥的藥物組合物可包含水溶性形式的活性成分，例如水溶性鹽或包含增加粘度的物質的含水注射懸浮液，例如羧甲基纖維素鈉，山梨糖醇的水溶液和/或葡聚糖，和，如果需要，穩定劑。將活性成分，任選地與賦形劑，也可以是在一個冷凍乾燥的形式，並且可在非腸道給藥前通過加入合適的溶劑製成的溶液。使用的解決方案，例如，用於胃腸外給藥，也可以用作輸注溶液。注射製劑的製備通常在無菌條件下，填充進，例如，安瓿或小瓶，和密封的容器中。Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient 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 aseptic conditions.
本發明還提供了藥物組合，例如一種藥盒，其包含a）本發明所公開的化合物，可以為游離形式或藥學可接受的鹽形式，和b）至少一種助劑。該藥盒可以包含其使用說明書。 聯合療法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
本專利所述化合物或藥學可接受的鹽可單獨使用，或與其他治療劑聯合使用。The compounds or pharmaceutically acceptable salts described in this patent can be used alone or in combination with other therapeutic agents.
例如，使用佐劑(adjuvant)可增強本發明中的化合物的治療效果（例如，單獨使用輔佐藥物的治療性獲益極小，但與另一種藥物合用時，可增強個體的治療性獲益），或者，例如，本發明的化合物與另一個同樣具有療效的治療劑合用可增強個體的治療獲益。例如，治療痛風時，使用本發明的化合物時，合併使用另一種治療痛風的藥物，有可能會增強臨床獲益。或者，例如，如果使用本發明化合物的不良反應是噁心，那麼可合用抗噁心的藥物。或者，還可以聯合的療法包括，但不僅限於物理療法、心理療法、放射療法、疾病區域的壓迫療法、休息、膳食改善等。無論何種疾病、病症或病況，兩種療法使個體的治療受益應具有加成效應或協同效應。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 individual's therapeutic benefit), 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, treatments that can also be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy for diseased areas, rest, diet improvement, and the like. Regardless of the disease, disorder or condition, the two therapies should have an additive effect or a synergistic effect to benefit the individual's treatment.
在本專利化合物與其他治療劑合用情況下，本專利化合物的藥物組合物給藥途徑可與其他藥物相同，或由於物理和化學性質不同，給藥途徑可以不相同。例如，本專利化合物口服給藥可產生並維持良好血藥水平，而另一種治療劑可能需要靜脈給藥。因此本專利化合物與另一治療劑可同時、先後或分別給藥。In the case where the compound of the patent is used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition of the compound of the patent may be the same as that of other drugs, or due to different physical and chemical properties, the route of administration may be different. For example, oral administration of the compound of this patent can produce and maintain good blood drug levels, while another therapeutic agent may require intravenous administration. Therefore, the compound of this patent and another therapeutic agent can be administered simultaneously, sequentially or separately.
式（I）化合物或其藥學可接受的鹽的合成方法有多種，在本實例中列舉出的是具有代表性的方法。然而，需要指出的是，式（I）的化合物或其藥學可接受的鹽也可能通過其它合成方案的合成得到。There are many methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the representative methods are listed in this example. However, it should be pointed out that the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic schemes.
式（I）的某個化合物中，原子與其它原子之間的連接可能導致存在特殊的立體異構體（如手性中心）。合成式（I）的化合物或其藥學可接受的鹽可能產生不同異構體（對映異構體，非對映異構體）的混合物。除非特別說明是某個特定的立體構型，所列舉的化合物均包括了其可能存在的不同立體異構體。In a compound of formula (I), the connection between atoms and other atoms may result in the presence of special stereoisomers (such as chiral centers). 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 the different stereoisomers that may exist.
式（I）的化合物也可以製成藥學可接受的酸加成鹽，例如，通過將本發明化合物的游離堿的形式與藥學可接受的無機或有機酸反應。或者將一個式（I）的化合物以游離酸的形式與藥學可接受的無機或有機堿反應，將其製成藥學可接受的堿加成鹽。適宜於製備式（I）化合物的藥學可接受鹽的無機和有機的酸和堿已在本申請書的定義部分做了說明。此外，式（I）化合物鹽的形式也可以通過使用起始原料或中間體的鹽進行製備。The compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt, for example, by reacting the free 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 compound in the form of a free acid to prepare a pharmaceutically acceptable salt addition salt. The inorganic and organic acids and salts 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.
式（I）化合物的游離酸或游離堿可以通過其相應的堿加成鹽或者酸加成鹽製備得到。式（I）化合物的酸加成鹽形式可轉化成相應的游離堿，例如通過用合適的堿（如氫氧化銨溶液、氫氧化鈉等）處理。式（I）化合物的堿加成鹽形式可轉化為相應的游離酸，例如通過用合適的酸（如鹽酸等）處理。The free acid or free base of the compound of formula (I) can be prepared by 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 (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The 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.).
一個式（I）的化合物或其一個藥學可接受的鹽的N-氧化物可通過本領域已知的方法制得。例如，N-氧化物可以通過將式（I）化合物的非氧化形式在0 ~ 80°C的條件下與氧化劑（如三氟過氧乙酸、過氧馬來酸（permaleic acid）、過氧苯甲酸、過氧乙酸和間氯過氧苯甲酸等）在惰性有機溶劑（如二氯甲烷等鹵化烴）中反應得到。備擇地，式（I）化合物的N-氧化物也可通過起始原料的N-氧化物製備得到。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 reacting 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.
非氧化形式的式（I）化合物可通過將其N-氧化物與還原劑（如硫、二氧化硫、三苯基膦、硼氫化鋰、硼氫化鈉、三氯化磷和三溴化磷等）在0 ~ 80°C的條件下在相應的惰性有機溶劑（如乙腈、乙醇和二氧六環水溶液等）中反應制得。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.
式（I）化合物的保護衍生物可以通過本領域人員熟知的方法製備得到。關於保護基團的加入和去除的詳細技術描述參見：T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999。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 protecting groups, see: T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
這些方法、路線與實施例中所使用的標誌和常識，均與現行的科學文獻相一致，例如，美國化學協會雜誌或生物化學雜誌。除非另有說明，標準的單字母或三字母的縮寫通常指L型氨基酸殘基。除非另有說明，所有使用的起始原料均從市場供應商購買得到，使用時並未進一步純化。例如，在實例及整個說明書中會用到以下縮寫：g（克）、mg（毫克）、L（升）、mL（毫升）、μL（微升）、psi（磅每平方英寸）、M（摩爾）、mM（毫摩爾）、i.v.（靜脈注射）、Hz（赫茲）、MHz（兆赫）、mol（摩爾）、mmol（毫摩爾）、RT（環境溫度）、min（分鐘）、h（小時）、mp（熔點）、TLC（薄層色譜法）、Rt（保留時間）、RP（反相）、MeOH（甲醇）、i-PrOH（異丙醇）、TEA（三乙胺）、TFA（三氟乙酸）、TFAA（三氟乙酸酐）、THF（四氫呋喃）、DMSO（二甲基亞碸）、EtOAc（乙酸乙酯）、DME（1,2-二甲氧基乙烷）、DCM（二氯甲烷）、DCE（二氯乙烷）、DMF（N
,N
-二甲基甲醯胺）、DMPU（N
,N'
-二甲基丙烯基脲）、CDI（1,1-羰基二咪唑）、IBCF（氯甲酸異丁酯）、HOAc（乙酸）、HOSu（N-羥基琥珀醯亞胺）、HOBT（1-羥基苯並三氮唑）、Et2
O（乙醚）、EDCI（1-（3-二甲基氨基丙基）3-乙基碳二亞胺鹽酸鹽）、BOC（叔丁氧羰基）、FMOC（9-芴基甲氧羰基）、DCC（二環己基碳二亞胺）、CBZ（苄氧羰基）、Ac（乙醯基）、atm（大氣壓）、TMSE（2-（三甲矽基）乙基）、TMS（三甲矽基）、TIPS（三異丙基矽基）、TBS（叔丁基二甲矽基）、DMAP（4-二甲基氨基吡啶）、Me（甲基）、OMe（甲氧基）、Et（乙基）、tBu（叔丁基）、HPLC（高效液相色譜法）、BOP（雙(2-氧代-3-噁唑烷基)次磷醯氯）、TBAF（四正丁基氟化銨）、mCPBA（間氯過氧苯甲酸）。These methods, routes, and the signs and common sense used in the examples are consistent with the 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 (grams), mg (milligrams), L (liters), mL (milliliters), μL (microliters), psi (pounds per square inch), M ( Mol), mM (millimolar), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (mole), mmol (millimoles), RT (ambient temperature), min (minutes), h (hours) ), mp (melting point), TLC (thin layer chromatography), Rt (retention time), RP (reverse phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA ( Trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfide), EtOAc (ethyl acetate), DME (1,2-dimethoxyethane), DCM ( Dichloromethane), DCE (dichloroethane), DMF ( N , N -dimethylformamide), DMPU ( N , N' -dimethylpropenylurea), CDI (1,1-carbonyl two Imidazole), 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) Imine), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMS (2-(trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropyl silicon Base), TBS (tert-butyl dimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl) , HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolidinyl) hypophosphinyl chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (m-chloroperoxybenzene Formic acid).
醚或Et2
O均是指乙醚；鹽水則是指飽和NaCl水溶液。除非另有說明，所有的溫度均是指°C溫度（攝氏度），所有的反應都是在室溫下的惰性氛圍中反應。Ether or Et 2 O refers to diethyl ether; brine refers to saturated NaCl aqueous solution. Unless otherwise specified, all temperatures refer to °C (degrees Celsius), and all reactions are performed in an inert atmosphere at room temperature.
1
H NMR譜採用Varian Mercury Plus 400核磁共振光譜儀記錄。化學位移為以ppm表示。耦合常數均以赫茲為單位(Hz)。以分割模式描述表觀多樣性，並定為s（單峰）、d（雙峰）、t（三重峰）、q（四重峰）、m（多重峰）和br（寬峰）。 1 H NMR spectra were recorded using Varian Mercury Plus 400 Nuclear Magnetic Resonance Spectrometer. The chemical shift is expressed in ppm. Coupling constants are in Hertz (Hz). Describe the apparent diversity in a segmentation mode, and define it as s (single peak), d (double peak), t (triplet peak), q (quartet), m (multiple peak), and br (broad peak).
低分辨質譜（MS）和化合物純度資料來自Shimadzu LC/MS單個四極杆系統，該系統配備有電噴霧離子檢測器（ESI），紫外探測器（220和254nm）及蒸發光散射檢測器（ELSD）。薄層層析法使用的是0.25 mm 旭泊化成矽膠板(60F- 254)，5%的磷鉬酸乙醇溶液，茚三酮或p-甲氧基苯甲醛溶液並在紫外燈下觀察。快速柱層析使用的是矽膠（200-300目，青島海洋化工有限公司）。 合成方案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 Silica Sheet (60F-254), 5% phosphomolybdic acid ethanol solution, ninhydrin or p-methoxybenzaldehyde solution and observes under UV light. Fast column chromatography uses silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.). Synthesis scheme
式I化合物或其藥學上可接受的鹽可由不同方法合成，一些示例性方法提供如下和實施例。其他合成方法可由本領域技術人員根據本發明披露的資訊容易地提出。The compound of formula I or a pharmaceutically acceptable salt thereof can be synthesized by different methods, and some exemplary methods are provided below and examples. Other synthetic methods can be easily proposed by those skilled in the art based on the information disclosed in the present invention.
在如下所述諸反應中可能有必要對活潑基團進行保護，以免這些活性基團參與其它不期望的反應：這些基團如羥基、氨基、亞胺基、含巰基或羧基，最終產物中含有這些基團。常用的保護基團可參考T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991。In the following reactions, it may be necessary to protect the active groups to prevent these active groups from participating in other undesired reactions: these groups such as hydroxyl, amino, imino, sulfhydryl or carboxyl, and the final product contains These groups. 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.
本發明的所有化合物的合成方案由以下方案和實施例加以說明。所用起始原料源於市售商品或可根據已有工藝方法或者此處示例的方法製備。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.
以下合成方案所列的中間體或根據文獻得到，或根據已有的類似的合成方法合成。The intermediates listed in the following synthetic schemes are either obtained according to literature or synthesized according to existing similar synthetic methods.
本發明公開的式I化合物的一種合成方法如合成方案1所示。以商業提供的或者文獻已知的中間體II為起始物，由中間體式II與式III偶聯製備中間體式IV。胺V再進一步置換中間體式IV中的離去基得到式I化合物。合成方案 1A synthetic method of the compound of formula I disclosed in the present invention is shown in synthetic scheme 1. Intermediate formula IV is prepared by coupling intermediate formula II and formula III using commercially available or known intermediate II as a starting material. Amine V further replaces the leaving group in the intermediate formula IV to obtain the compound of formula I. Synthesis scheme 1
作為式I化合物製備方法的說明，式Ia化合物的一種合成方法如方案2所示。以由商業提供的5-溴-7-氮吲哚IIa-A為起始物，IIa-C可以依次通過甲醇鈉置換溴，TIPSCl保護NH得到。通過定向鄰位元金屬化（DoM）將氟引入到IIa-C製備IIa-D。IIa-D中TIPS離去基的離去後再與NBS發生溴化反應得到溴化物IIa。再與中間體III結合，在正丁基鋰（n-BuLi）條件下製備IVa。在堿（如N,N
-二異丙基乙胺（DIPEA））作用下，胺V與芳基氟化物IVa的反應得到式Ia的化合物。合成方案 2As an illustration of the preparation method of the compound of formula I, a synthetic method of the compound of formula Ia is shown in Scheme 2. Starting from commercially available 5-bromo-7-azaindole IIa-A, IIa-C can be obtained by replacing bromine with sodium methoxide and protecting NH with TIPSCl. IIa-D is prepared by introducing fluorine into IIa-C through directed ortho metalization (DoM). After leaving the TIPS leaving group in IIa-D, it undergoes bromination reaction with NBS to obtain bromide IIa. Then combined with Intermediate III to prepare IVa under n-BuLi (n-BuLi) conditions. In the alkali (e.g., N, N - diisopropylethylamine (DIPEA)) under the action of the compound of Formula Ia reaction of the amine V with an aryl fluoride IVa obtained. Synthesis scheme 2
作為式I化合物另一個製備方法的示例，式Ib化合物的一條合成路線如合成方案3所示。保護氮吲哚化合物IIb-A（商業提供）中的NH，再用N
-氟代雙苯磺醯胺進行氟化得到氟化合物IIb-C。二氟化合物IIb-D可通過IIb-C發生如合成方案2中所示DoM方法製備。IIb-D中離去基TIPS離去再與NBS發生溴化反應將IIb-D轉化為溴化物IIb-E，IIb-E通過如方案3所述的反應轉化為Ib。合成方案 3As an example of another preparation method of the compound of formula I, a synthetic route of the compound of formula Ib is shown in synthetic scheme 3. The NH in the azaindole compound IIb-A (commercially available) is protected, and then fluorinated with N -fluorobisphenylsulfonamide to obtain the fluorine compound IIb-C. The difluoro compound IIb-D can be prepared by the DoM method shown in Synthesis Scheme 2 by IIb-C. The leaving group TIPS in IIb-D departs and then undergoes bromination reaction with NBS to convert IIb-D into bromide IIb-E, and IIb-E is converted into Ib through the reaction described in Scheme 3. Synthesis scheme 3
在某些情況下，為了促進反應或避免不必要的反應產物產生，上述合成方案可根據情況調整順序。為了使本發明被更充分地理解，提供了以下實施例。這些實施例只是示例，不應將其理解成是對本發明的限制。中間體 A In some cases, in order to promote the reaction or avoid the generation of unnecessary reaction products, the above-mentioned synthesis scheme can be adjusted according to the situation. In order for the present invention to be more fully understood, the following embodiments are provided. These embodiments are only examples, and should not be construed as limiting the present invention. Intermediate A
甲基 2- 氯 -4- 苯氧基苯甲酸酯 (A) Methyl 2- chloro- 4- phenoxy benzoate (A)
甲基 2-氯-4-苯氧基苯甲酸酯 (A
) 根據專利US9630968, 2017, B1
製備。中間體 B Methyl 2-chloro-4-phenoxy benzoate ( A ) was prepared according to patent US9630968, 2017, B1 . Intermediate B
2- 氯 -6- 氟 -4- 苯氧基苯甲醛 (B
) 2- chloro -6- fluoro- 4- phenoxybenzaldehyde ( B )
甲基methyl
2-2-
氯chlorine
-6--6-
氟fluorine
-4--4-
苯氧基苯甲酸酯Phenoxy benzoate
(B-1
)( B-1 )
N2
保護下，商購甲基 4-溴-2-氯-6-氟苯甲酸酯 (1.04 g, 3.89 mmol)，phenol (434 mg, 4.67 mmol)，Pd(OAc)2
(90.0 mg, 0.401 mmol)，2-(二叔丁基膦)聯苯 (1.7 mg, 0.0080 mmol) 和K3
PO4
(1.7 g, 8.0 mmol) 在甲苯 (30 mL) 中的混合物於90°C攪拌過夜。將混合物冷卻至室溫並用水稀釋，乙酸乙酯萃取。有機相用飽和食鹽水洗滌，Na2
SO4
乾燥並濃縮。殘留物經矽膠柱層析純化，PE洗脫得到標題化合物甲基 2-氯-6-氟-4-苯氧基苯甲酸酯 (B-1
). MS-ESI (m/z): 281 [M + 1]+
。Under N 2 protection, commercially available methyl 4-bromo-2-chloro-6-fluorobenzoate (1.04 g, 3.89 mmol), phenol (434 mg, 4.67 mmol), Pd(OAc) 2 (90.0 mg, 0.401 mmol), a mixture of 2-(di-tert-butylphosphine)biphenyl (1.7 mg, 0.0080 mmol) and K 3 PO 4 (1.7 g, 8.0 mmol) in toluene (30 mL) was stirred at 90°C overnight. The mixture was cooled to room temperature and diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography and eluted with PE to obtain the title compound methyl 2-chloro-6-fluoro-4-phenoxybenzoate ( B-1 ). MS-ESI (m/z): 281 [M + 1] + .
(2-(2-
氯chlorine
-6--6-
氟fluorine
-4--4-
苯氧基苯基Phenoxyphenyl
))
甲醇Methanol
(B-2
)( B-2 )
在冰水浴下，向甲基 2-氯-6-氟-4-苯氧基苯甲酸酯 (B-1
) (50 mg, 0.18 mmol)的THF/EtOH (1 mL/ 0.5 mL) 溶液中加入NaBH4
(20 mg, 0.53 mmol) 和LiCl (22 mg, 0.53 mmol)。反應液在室溫下攪拌2 h，將反應液倒入冰水，乙酸乙酯萃取，水和飽和食鹽水洗滌，Na2
SO4
乾燥，濃縮得(2-氯-6-氟-4-苯氧基苯基)甲醇 (B-2
) 粗品，未經進一步純化，直接用於下一步反應。 MS-ESI (m/z): 253 [M + 1]+
。In an ice-water bath, add methyl 2-chloro-6-fluoro-4-phenoxybenzoate ( B-1 ) (50 mg, 0.18 mmol) in THF/EtOH (1 mL/ 0.5 mL) Add NaBH 4 (20 mg, 0.53 mmol) and LiCl (22 mg, 0.53 mmol). The reaction solution was stirred at room temperature for 2 h. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and saturated brine, dried over Na 2 SO 4 , and concentrated to obtain (2-chloro-6-fluoro-4-benzene The crude oxyphenyl)methanol ( B-2 ) was directly used in the next reaction without further purification. MS-ESI (m/z): 253 [M + 1] + .
2-2-
氯chlorine
-6--6-
氟fluorine
-4--4-
苯氧基苯甲醛Phenoxybenzaldehyde
(B
)( B )
在氮氣保護下，(2-氯-6-氟-4-苯氧基苯基)甲醇 (B-2
) (780 mg, 3.08 mmol) 和MnO2
(2.0 g, 23 mmol) 在甲苯 (15 mL) 的懸濁液中於85°C下攪拌過夜。將混合物冷卻至室溫並過濾，濃縮濾液，殘留物經矽膠柱層析純化，PE/ EtOAc (50:1)洗脫得到標題化合物2-氯-6-氟-4-苯氧基苯甲醛 (B
)。MS-ESI (m/z): 251 [M + 1]+
。實施例 1 Under the protection of nitrogen, (2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( B-2 ) (780 mg, 3.08 mmol) and MnO 2 (2.0 g, 23 mmol) in toluene (15 mL ) The suspension was stirred overnight at 85°C. The mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (50:1) to obtain the title compound 2-chloro-6-fluoro-4-phenoxybenzaldehyde ( B ). MS-ESI (m/z): 251 [M + 1] + . Example 1
(2- 氯 -4- 苯氧基苯基 )(4-(((1r,4r)-4-( 羥甲基 ) 環己基 ) 氨基 )-1H- 吡咯並 [2,3-b] 吡啶 -3- 基 ) 甲酮 (1) (2-chloro-4-phenoxyphenyl) (4 - (((1r , 4r) -4- ( hydroxymethyl) cyclohexyl) amino) lH-pyrrolo [2,3-b] pyridin - 3- yl ) ketone (1)
3-3-
溴bromine
-4--4-
氯chlorine
-1H--1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
(1a
)( 1a )
在室溫下，向商購的4-氯-1H
-吡咯並[2,3-b
]吡啶 (1.525 g, 10.00 mmol) 的 DMF (15 mL) 溶液中加入NBS (1.87 g, 10.50 mmol)。混合物於室溫下攪拌1.5 h。將反應液倒入水 (50 mL) 中，通過過濾收集沉澱的固體，用水沖洗，在空氣中乾燥得到3-溴-4-氯-1H
-吡咯並[2,3-b
]吡啶 (1a
)。MS-ESI (m/z): 231/233/235 (1:1.2:0.3) [M + 1]+
。At room temperature, add NBS (1.87 g, 10.50 mmol) to a solution of commercially available 4-chloro-1 H -pyrrolo[2,3- b ]pyridine (1.525 g, 10.00 mmol) in DMF (15 mL) . The mixture was stirred at room temperature for 1.5 h. The reaction solution was poured into water (50 mL), the precipitated solid was collected by filtration, washed with water, and dried in the air to obtain 3-bromo-4-chloro-1 H -pyrrolo[2,3- b ]pyridine ( 1a ). MS-ESI (m/z): 231/233/235 (1:1.2:0.3) [M + 1] + .
(4-(4-
氯chlorine
-1H--1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
-3--3-
基base
)(2-)(2-
氯chlorine
-4--4-
苯氧基苯基Phenoxyphenyl
))
甲酮Ketone
(1b
)( 1b )
在-78°C下，向3-溴-4-氯-1H
-吡咯並[2,3-b
]吡啶 (1a
) (244 mg, 1.06 mmol) 的THF (7 mL) 溶液中滴加正丁基鋰 (2.5 M 己烷溶液, 0.89 mL, 2.2 mmol)。混合物在此溫度下攪拌1 h，然後逐滴添加2-氯-4-苯氧基苯甲酸甲酯 (A
) 的THF (2 mL) 溶液。混合物在-78°C下攪拌一小時。在此溫度下，緩慢添加1 N HCl (3 mL)。然後將混合物升至室溫，用水 (10 mL) 稀釋，乙酸乙酯 (2 ×) 提取。萃取液用鹽水洗滌，Na2
SO4
乾燥。溶劑在減壓下蒸發。殘留物用矽膠柱層析純化（洗脫劑：20 - 70% EtOAc / 正己烷）得到(4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-苯氧基苯基)甲酮 (1b
)。 MS-ESI (m/z): 383 [M + 1]+
。At -78°C, to 3-bromo-4-chloro- 1H -pyrrolo[2,3- b ]pyrrolo[2,3-b]pyridine( 1a ) (244 mg, 1.06 mmol) in THF (7 mL) was added dropwise normal Butyl lithium (2.5 M hexane solution, 0.89 mL, 2.2 mmol). The mixture was stirred at this temperature for 1 h, and then a solution of methyl 2-chloro-4-phenoxybenzoate ( A ) in THF (2 mL) was added dropwise. The mixture was stirred at -78°C for one hour. At this temperature, slowly add 1 N HCl (3 mL). Then the mixture was warmed to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2×). The extract was washed with brine and dried over Na 2 SO 4. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20-70% EtOAc/n-hexane) to obtain (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl) (2-chloro -4-phenoxyphenyl)methanone ( 1b ). MS-ESI (m/z): 383 [M + 1] + .
((1r,4r)-4-((1r,4r)-4-
氨基環己基Aminocyclohexyl
))
甲醇Methanol
三氟乙酸鹽Trifluoroacetate
(1c
)( 1c )
向商購的叔丁基
((1r,4r
)-4-(羥甲基)環己基)氨基甲酸酯 (1.00 g, 4.36 mmol) 的DCE (10 mL) 溶液中加入TFA (5 mL)。混合物在室溫下攪拌1 h。蒸幹溶劑得到 ((1r,4r
)-4-氨基環己基)甲醇 三氟乙酸鹽 (1c
)。 MS-ESI (m/z): 130 [M + 1]+
。To a solution of commercially available tert-butyl (( 1r, 4r )-4-(hydroxymethyl)cyclohexyl) carbamate (1.00 g, 4.36 mmol) in DCE (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 1 h. Evaporate the solvent to obtain (( 1r, 4r )-4-aminocyclohexyl) methanol trifluoroacetate ( 1c ). MS-ESI (m/z): 130 [M + 1] + .
(2-(2-
氯chlorine
-4--4-
苯氧基苯基Phenoxyphenyl
)(4-(((1r,4r)-4-()(4-(((1r,4r)-4-(
羥甲基Hydroxymethyl
))
環己基Cyclohexyl
))
氨基Amino
)-1H-)-1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
-3--3-
基base
))
甲酮Ketone
(1
)( 1 )
向 ((1r
,4r
)-4-氨基環己基)甲醇 三氟乙酸鹽 (1c
) (56.0 mg, 0.23 mmol), 和 (4-氯-1H
-吡咯並[2,3-b]吡啶-3-基)(2-氯-4-苯氧基苯基)甲酮 (1b
) (44.0 mg, 0.115 mmol) 的二氧六環溶液 (1.5 mL) 中加入Pd2
(dba)3
(10.5 mg, 0.0115 mmol)，xantphos (13.3 mg, 0.023 mmol) 和Cs2
CO3
(150 mg, 0.46 mmol)。混合物於110°C氮氣保護下攪拌54 h。冷卻後，混合物用水稀釋，乙酸乙酯萃取 (2 ×)。萃取液Na2
SO4
乾燥濃縮得粗品。用矽膠柱層析純化（洗脫劑：5% 甲醇 / DCM）得到(2-氯-4-苯氧基苯基)(4-(((1r
,4r
)-4-(羥甲基)環己基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 (1
)。 MS-ESI (m/z): 476 [M + 1]+
。實施例 2 To ((1 r , 4 r )-4-aminocyclohexyl) methanol trifluoroacetate ( 1c ) (56.0 mg, 0.23 mmol), and (4-chloro-1 H -pyrrolo[2,3-b] Pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone ( 1b ) (44.0 mg, 0.115 mmol) in dioxane solution (1.5 mL) was added Pd 2 (dba) 3 ( 10.5 mg, 0.0115 mmol), xantphos (13.3 mg, 0.023 mmol) and Cs 2 CO 3 (150 mg, 0.46 mmol). The mixture was stirred at 110°C under nitrogen protection for 54 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate (2×). The extract was dried and concentrated with Na 2 SO 4 to obtain a crude product. Purified by silica gel column chromatography (eluent: 5% methanol/DCM) to obtain (2-chloro-4-phenoxyphenyl)(4-(((1 r ,4 r )-4-(hydroxymethyl) ) cyclohexyl) amino) -1 H - pyrrolo [2,3- b] pyridin-3-yl) methanone (1). MS-ESI (m/z): 476 [M + 1] + . Example 2
(2- 氯 -4- 苯氧基苯基 )(4-(((3R,6S)-6-( 羥甲基 ) 四氫 -2H- 吡喃 -3- 基 ) 氨基 )-1H- 吡咯並 [2,3-b] 吡啶 -3- 基 ) 甲酮 (2
) (2- Chloro- 4- phenoxyphenyl )(4-(((3R,6S)-6-( hydroxymethyl ) tetrahydro -2H- pyran- 3 -yl ) amino )-1H- pyrrolo [2,3-b] pyridin- 3 -yl ) methanone ( 2 )
((2S,5R)-5-((2S,5R)-5-
氨基四氫Aminotetrahydro
-2H--2H-
吡喃Pyran
-2--2-
基base
))
甲醇Methanol
鹽酸鹽Hydrochloride
(2a
)( 2a )
標題化合物 ((2S
,5R
)-5-氨基四氫-2H
-吡喃-2-基)甲醇 鹽酸鹽 (2a
) 根據專利US2018/051235
製備。 The title compound ((2 S, 5 R) -5- amino-tetrahydro -2 H - pyran-2-yl) methanol hydrochloride (2a) prepared according to patent US2018 / 051235.
(2-(2-
氯chlorine
-4--4-
苯氧基苯基Phenoxyphenyl
)(4-(((3R,6S)-6-()(4-(((3R,6S)-6-(
羥甲基Hydroxymethyl
))
四氫Tetrahydro
-2H--2H-
吡喃Pyran
-3--3-
基base
))
氨基Amino
)-1H-)-1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
-3--3-
基base
))
甲酮Ketone
(2
)( 2 )
向 ((2S
,5R
)-5-氨基四氫-2H
-吡喃-2-基)甲醇 鹽酸鹽(2a
) (122 mg, 0.50 mmol), 和 (4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-苯氧基苯基)甲酮 (1b
) (89.6 mg, 0.234 mmol) 的正丁醇 (2 mL) 溶液中加入DIPEA (130 mg, 1.0 mmol)。混合物在氮氣保護下於125°C 攪拌過夜。冷卻後，混合物用水稀釋，乙酸乙酯萃取 (3 ×)。萃取液用鹽水洗，Na2
SO4
乾燥濃縮得粗品。用矽膠柱層析純化（洗脫劑：DCM/MeOH = 20:1）得到標題化合物(2-氯-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 (2
)。 MS-ESI (m/z): 478 [M + 1]+
。實施例 3 To ((2 S , 5 R )-5-aminotetrahydro-2 H -pyran-2-yl) methanol hydrochloride ( 2a ) (122 mg, 0.50 mmol), and (4-chloro-1 H- Pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone ( 1b ) (89.6 mg, 0.234 mmol) in n-butanol (2 mL) Add DIPEA (130 mg, 1.0 mmol). The mixture was stirred overnight at 125°C under nitrogen protection. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3×). The extract was washed with brine, dried over Na 2 SO 4 and concentrated to obtain a crude product. Purified by silica gel column chromatography (eluent: DCM/MeOH = 20:1) to obtain the title compound (2-chloro-4-phenoxyphenyl) (4-(((3 R ,6 S )-6- (hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin-3-yl) methanone (2). MS-ESI (m/z): 478 [M + 1] + . Example 3
(2- 氯 -6- 氟 -4- 苯氧基苯基 )(4-(((3R,6S)-6-( 羥甲基 ) 四氫 -2H- 吡喃 -3- 基 ) 氨基 )-1H- 吡咯並 [2,3-b] 吡啶 -3- 基 ) 甲酮 (3
) (2- Chloro -6- fluoro- 4- phenoxyphenyl )(4-(((3R,6S)-6-( hydroxymethyl ) tetrahydro -2H- pyran- 3 -yl ) amino )- 1H- pyrrolo [2,3-b] pyridin- 3 -yl ) methanone ( 3 )
(4-(4-
氯chlorine
-1H--1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
-3--3-
基base
)(2-)(2-
氯chlorine
-6--6-
氟fluorine
-4--4-
苯氧基苯基Phenoxyphenyl
))
甲醇Methanol
(3a
)( 3a )
依照實施例1b
中的合成方法，將甲基 2-氯-4-苯氧基苯甲酸酯 (A
) 替換為2-氯-6-氟-4-苯氧基苯甲醛 (B
) 製備得到標題化合物 (4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-6-氟-4- 苯氧基苯基)甲醇 (3a
)。MS-ESI (m/z): 403 [M + 1]+
。According to the synthesis method in Example 1b , the methyl 2-chloro-4-phenoxybenzoate ( A ) was replaced with 2-chloro-6-fluoro-4-phenoxybenzaldehyde ( B ). The title compound (4-chloro- 1H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( 3a ). MS-ESI (m/z): 403 [M + 1] + .
(4-(4-
氯chlorine
-1H--1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
-3--3-
基base
)(2-)(2-
氯chlorine
-6--6-
氟fluorine
-4--4-
苯氧基苯基Phenoxyphenyl
))
甲First
酮ketone
(3b
)( 3b )
室溫條件下，向(4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-6-氟-4-苯氧基苯基)甲醇 (3a
) (30 mg, 0.07 mmol)的DMSO溶液中，加入IBX (40 mg, 0.14 mmol)。反應液在室溫下攪拌1 h, 倒入冰水中，乙酸乙酯萃取（3 x），萃取相分別用水，飽和食鹽水洗，無水硫酸鈉乾燥，濃縮得到粗產品。用矽膠柱層析純化（洗脫劑：PE/EA = 3:1）得到標題化合物(4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-6-氟-4-苯氧基苯基)甲酮 (3b
)。MS-ESI (m/z): 401 [M + 1]+
.At room temperature, to (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol ( 3a ) (30 mg, 0.07 mmol) in DMSO solution, add IBX (40 mg, 0.14 mmol). The reaction solution was stirred at room temperature for 1 h, poured into ice water, and extracted with ethyl acetate (3 x). The extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purified by silica gel column chromatography (eluent: PE/EA = 3:1) to obtain the title compound (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl) (2-chloro- 6-Fluoro-4-phenoxyphenyl)methanone ( 3b ). MS-ESI (m/z): 401 [M + 1] + .
(2-(2-
氯chlorine
-6--6-
氟fluorine
-4--4-
苯氧基苯基Phenoxyphenyl
)(4-(((3R,6S)-6-()(4-(((3R,6S)-6-(
羥甲基Hydroxymethyl
))
四氫Tetrahydro
-2H--2H-
吡喃Pyran
-3--3-
基base
))
氨基Amino
)-1H-)-1H-
吡咯並Pyrrolo
[2,3-b][2,3-b]
吡啶Pyridine
-3--3-
基base
))
甲酮Ketone
(3
)( 3 )
依照實施例2
中的合成方法，將(4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-苯氧基苯基)甲酮 (1b
) 替換為 (4-氯-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-6-氟-4-苯氧基苯基)甲酮 (3b
) 製備得到標題化合物(2-氯-6-氟-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 (3
)。MS-ESI (m/z): 496 [M + 1]+
。According to the synthesis method in Example 2 , (4-chloro- 1H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone ( 1b ) Replaced with (4-chloro-1 H -pyrrolo[2,3- b ]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanone ( 3b ) The title compound (2-chloro-6-fluoro-4-phenoxyphenyl) (4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone ( 3 ). MS-ESI (m/z): 496 [M + 1] + .
表1中列出實施例4-225是基本上按照與實施例1-3相同的方法，使用的起始物料是商購或者根據文獻方法制得。表1給出了實施例4-225的名稱及結構。 表 1 實施例 結構式 名稱 數據
4 (2-氯-4-苯氧基苯基)(5-氟-4-(((1r
,4r
)-4-(羥甲基)環己基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z): 494 [M + 1]+
5 3-(2-氯-4-苯氧基苯甲醯)-4-(((1r
,4r
)-4-(羥甲基)環己基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):501 [M + 1]+
6 (2-氯-4-苯氧基苯基)(5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):496 [M + 1]+
7 3-(2-氯-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):503 [M + 1]+
8 3-(2-氯-4-(4-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):521 [M + 1]+
9 (2-氯-4-(4-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):496 [M + 1]+
10 (2-氟-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):462 [M + 1]+
11 4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-3-(2-甲基-4-苯氧基苯甲醯)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):483 [M + 1]+
12 3-(2-氰基-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):494 [M + 1]+
13 (4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-甲基-4-苯氧基苯基)甲酮 MS-ESI (m/z):458 [M + 1]+
14 2-(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-羰基)-5-苯氧基苯甲腈 MS-ESI (m/z):469 [M + 1]+
15 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-甲基-4-苯氧基苯基)甲酮 MS-ESI (m/z):476 [M + 1]+
16 2-(5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-羰基)-5-苯氧基苯甲腈 MS-ESI (m/z):487 [M + 1]+
17 1st
-洗脫異構體 3-(2-氯-4-苯氧基苯甲醯)-4-(((1R
,5R
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):501 [M + 1]+
18 2nd
-洗脫異構體 3-(2-氯-4-苯氧基苯甲醯)-4-(((1R
,5R
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z): 501 [M + 1]+
19 2nd
-洗脫異構體 4-(((1R
,5R
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-3-(2-甲基-4-苯氧基苯甲醯)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):481 [M + 1]+
20 1st
-洗脫異構體 4-(((1R
,5R
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-3-(2-甲基-4-苯氧基苯甲醯)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):481 [M + 1]+
21 1st
-洗脫異構體 3-(2-氰基-4-苯氧基苯甲醯)-4-(((1R
,5R
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):492 [M + 1]+
22 2nd
-洗脫異構體 3-(2-氰基-4-苯氧基苯甲醯)-4-(((1R
,5R
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):492 [M + 1]+
23 3-(2-氯-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲醯胺 MS-ESI (m/z):521 [M + 1]+
24 4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-3-(2-甲基-4-苯氧基苯甲醯)-1H
-吡咯並[2,3-b
]吡啶-5-甲醯胺 MS-ESI (m/z):501 [M + 1]+
25 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-苯氧基苯基)甲酮 MS-ESI (m/z):512 [M + 1]+
26 (2-氯-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):492 [M + 1]+
27 (2-氯-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):508 [M + 1]+
28 (4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-苯氧基苯基)甲酮 MS-ESI (m/z):444 [M + 1]+
29 4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-3-(4-苯氧基苯甲醯)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):469 [M + 1]+
30 (2-氯-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):496 [M + 1]+
31 (2-氯-4-(3-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):496 [M + 1]+
32 3-(2-氯-4-(2-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):521 [M + 1]+
33 3-(2-氯-4-(3-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):521 [M + 1]+
34 (2,6-二氯-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):512 [M + 1]+
35 3-(2,6-二氯-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):537 [M + 1]+
36 (2,3-二氯-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):512 [M + 1]+
37 3-(2,3-二氯-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):537 [M + 1]+
38 3-(2-氯-4-(2-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(氰甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):530 [M + 1]+
39 3-(2-氯-4-(3-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(氰甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):530 [M + 1]+
40 (2-氯-4-(吡啶-3-基氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):479 [M + 1]+
41 (4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-甲基-6-苯氧基吡啶-3-基)甲酮 MS-ESI (m/z):459 [M + 1]+
42 3-(2-氯-4-(吡啶-3-基氧基)苯醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):504 [M + 1]+
43 4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-3-(2-甲基-6-苯氧基煙醯基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):484 [M + 1]+
44 (2,6-二氟-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):480 [M + 1]+
45 3-(2,6-二氟-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):505 [M + 1]+
46 (4-(2-氟苯氧基)-2-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):476 [M + 1]+
47 (4-(3-氟苯氧基)-2-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):476 [M + 1]+
48 3-(4-(2-氟苯氧基)-2-甲基苯醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):501 [M + 1]+
49 3-(4-(3-氟苯氧基)-2-甲基苯醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):501 [M + 1]+
50 4-(((3R
,6S
)-6-(氰甲基)四氫-2H
-吡喃-3-基)氨基)-3-(4-(2-氟苯氧基)-2-甲基苯醯基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):510 [M + 1]+
51 4-(((3R
,6S
)-6-(氰甲基)四氫-2H
-吡喃-3-基)氨基)-3-(4-(3-氟苯氧基)-2-甲基苯醯基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):510 [M + 1]+
52 (2-氯-5-氟-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):496 [M + 1]+
53 3-(2-氯-5-氟-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):521 [M + 1]+
54 3-(2-氯-4-(2-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(((二甲基(氧代)-λ6
-硫亞基)氨基)甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):596 [M + 1]+
55 3-(2,6-二甲基-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):497 [M + 1]+
56 (2,6-二甲基-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI (m/z):472 [M + 1]+
57 3-(2-氯-6-氟-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z):521 [M + 1]+
58 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-苯氧基苯基)甲酮 MS-ESI (m/z): 480 [M + 1]+
59 3-(2-氟-4-苯氧基苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI (m/z): 487 [M + 1]+
60 (2-氯-4-(4-氯苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b]吡啶-3-基)甲酮 MS-ESI (m/z): 512 [M + 1]+
61 (2-氯-4-(2-氟苯氧基)苯基)(4-(((3R
,6S)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-(2,2,2-三氟乙氧基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):594 [M+1]+
62 (2-氯-4-(2-氟苯氧基)苯基)(5-((2,2-二氟乙烯基)氧基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):574 [M+1]+
63 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):506 [M+1]+
64 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):520 [M+1]+
65 (2-氯-4-(2-氟苯氧基)苯基)(5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):540 [M+1]+
66 (2-氯-4-(2-氟苯氧基)苯基)(5-羥基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):512 [M+1]+
67 (2-氯-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡唑並[3,4-b
]吡啶-3-基)甲酮 MS-ESI(m/z):497 [M+1]+
68 (4-(2-氟苯氧基)-2-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡唑並[3,4-b
]吡啶-3-基)甲酮 MS-ESI(m/z):477 [M+1]+
69 2-((3-(2-氯-4-(2-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-基)氧基)-2,2-二氟乙酸 MS-ESI(m/z):606 [M+1]+
70 (2-氯-4-(2-氟苯氧基)苯基)(5-乙基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):524 [M+1]+
71 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):524 [M+1]+
72 (5-(2-氟苯氧基)-3-甲基吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):507 [M+1]+
73 (4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):492 [M+1]+
74 (5-(2-氟苯氧基)吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):493 [M+1]+
75 (2-氟-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):510 [M+1]+
76 (6-(2-氟苯氧基)-4-甲基吡啶-3-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):507 [M+1]+
77 (2-氯-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):526 [M+1]+
78 (4-(2-氟苯氧基)-2-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):506 [M+1]+
79 (6-(2-氟苯氧基)吡啶-3-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):493 [M+1]+
80 (6-(2-氟苯氧基)-2-甲基吡啶-3-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):507 [M+1]+
81 (4-(2-氟苯氧基)-2-甲氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):522 [M+1]+
82 (3-氯-5-(2-氟苯氧基)吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):527 [M+1]+
83 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(6-(2-氟苯氧基)吡啶-3-基)甲酮 MS-ESI(m/z):497 [M+1]+
84 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(6-(2-氟苯氧基)-2-甲基吡啶-3-基)甲酮 MS-ESI(m/z):511 [M+1]+
85 (2-溴-4-(2-氟苯氧基)苯基)(5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):574/576 [M+1]+
86 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(5-(2-氟苯氧基)吡啶-2-基)甲酮 MS-ESI(m/z):497 [M+1]+
87 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):510 [M+1]+
88 3-(4-(2-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):487 [M+1]+
89 3-(5-(2-氟苯氧基)吡啶甲醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):488 [M+1]+
90 3-(2-氟-4-(2-氟苯氧基)苯甲醯)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):505 [M+1]+
91 3-(6-(2-氟苯氧基)煙醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):488 [M+1]+
92 3-(6-(2-氟苯氧基)-2-甲基煙醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):502 [M+1]+
93 3-(6-(2-氟苯氧基)-4-甲基煙醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):502 [M+1]+
94 3-(5-(2-氟苯氧基)-3-甲基吡啶甲醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):502 [M+1]+
95 3-(3-氯-5-(2-氟苯氧基)吡啶甲醯基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-5-甲腈 MS-ESI(m/z):522 [M+1]+
96 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-環丙基-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):536 [M+1]+
97 (2-溴-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):540/542 [M+1]+
98 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):496 [M+1]+
99 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):514 [M+1]+
100 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):530 [M+1]+
101 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(6-(2-氟苯氧基)-4-甲基吡啶-3-基)甲酮 MS-ESI(m/z):511 [M+1]+
102 (2-氟-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):480 [M+1]+
103 (6-(2-氟苯氧基)-4-甲基吡啶-3-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):477 [M+1]+
104 (4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):462 [M+1]+
105 (6-(2-氟苯氧基)吡啶-3-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):463 [M+1]+
106 (6-(2-氟苯氧基)-2-甲基吡啶-3-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):477 [M+1]+
107 (5-(2-氟苯氧基)吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):463 [M+1]+
108 (3-氯-5-(2-氟苯氧基)吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):497 [M+1]+
109 (5-(2-氟苯氧基)-3-甲基吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):477 [M+1]+
110 (5-(2-氟苯氧基)-3-甲氧基吡啶-2-基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):493 [M+1]+
111 (2-氯-4-(2-氟-3-甲氧基苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):526 [M+1]+
112 (4-(2-氟-3-甲氧基苯氧基)-2-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):506 [M+1]+
113 (2-環丙基-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):502 [M+1]+
114 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):480 [M+1]+
115 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):498 [M+1]+
116 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(5-(2-氟苯氧基)-3-甲基吡啶-2-基)甲酮 MS-ESI(m/z):495 [M+1]+
117 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(6-(2-氟苯氧基)-4-甲基吡啶-3-基)甲酮 MS-ESI(m/z):495 [M+1]+
118 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(5-(2-氟苯氧基)吡啶-2-基)甲酮 MS-ESI(m/z):481 [M+1]+
119 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-(2-氟-3-甲氧基苯氧基)苯基)甲酮 MS-ESI(m/z):560 [M+1]+
120 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟-3-甲氧基苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):540 [M+1]+
121 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(6-(2-氟苯氧基)吡啶-3-基)甲酮 MS-ESI(m/z):481 [M+1]+
122 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(6-(2-氟苯氧基)-2-甲基吡啶-3-基)甲酮 MS-ESI(m/z):495 [M+1]+
123 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(3-氯-5-(2-氟苯氧基)吡啶-2-基)甲酮 MS-ESI(m/z):531 [M+1]+
124 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(5-(2-氟苯氧基)-3-甲基吡啶-2-基)甲酮 MS-ESI(m/z):511 [M+1]+
125 (2-氯-4-(2-氟苯氧基)苯基)(5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):514 [M+1]+
126 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):494 [M+1]+
127 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-甲基-4-苯氧基苯基)甲酮 MS-ESI(m/z):502 [M+1]+
128 (2-氯-4-苯氧基苯基)(5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):522 [M+1]+
129 (2-氯-4-(2-氟苯氧基)苯基)(5-環丙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):552 [M+1]+
130 (2-氟-4-(2-氟苯氧基)-6-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):494 [M+1]+
131 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)-6-甲基苯基)甲酮 MS-ESI(m/z):528 [M+1]+
132 (2-氟-4-(2-氟苯氧基)-6-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):524 [M+1]+
133 (5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)-6-甲基苯基)甲酮 MS-ESI(m/z):512 [M+1]+
134 (4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-甲基-4-苯氧基苯基)甲酮 MS-ESI(m/z):488 [M+1]+
135 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)-6-甲基苯基)甲酮 MS-ESI(m/z):538 [M+1]+
136 (5-(二氟甲氧基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):528 [M+1]+
137 (5-(二氟甲氧基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):546 [M+1]+
138 (2-氯-4-(2-氟苯氧基)苯基)(5-(二氟甲氧基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):562 [M+1]+
139 (5-(二氟甲氧基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):542 [M+1]+
140 (2-氯-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-(三氟甲氧基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):580 [M+1]+
141 (2-氟-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-(三氟甲氧基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):564 [M+1]+
142 (4-(((3R
,6S
)-6-(氨甲基)四氫-2H-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):509 [M+1]+
143 1-(((2S
,5R
)-5-((3-(2-氟-4-(2-氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)脲 MS-ESI(m/z):552 [M+1]+
144 (2-氟-4-(2-氟苯氧基)苯基)(5-甲氧基-4-(((3R
,6S
)-6-((甲基氨基)甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):523 [M+1]+
145 (4-(((3R
,6S
)-6-((二甲基氨基)甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):537 [M+1]+
146 (4-(((3R
,6S
)-6-(氮雜環丁烷-1-基甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):549 [M+1]+
147 (2-氟-4-(2-氟苯氧基)苯基)(5-甲氧基-4-(((3R
,6S
)-6-(吡咯-1-基甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):563 [M+1]+
148 (2-氟-4-(2-氟苯氧基)苯基)(5-甲氧基-4-(((3R
,6S
)-6-(嗎啉甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):579 [M+1]+
149 (2-氟-4-(2-氟苯氧基)苯基)(5-甲氧基-4-(((3R
,6S
)-6-(呱啶-1-基甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):577 [M+1]+
150 (2-氟-4-(2-氟苯氧基)苯基)(5-甲氧基-4-(((3R
,6S
)-6-(呱嗪-1-基甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):578 [M+1]+
151 1-(4-(((2S
,5R
)-5-((3-(2-氟-4-(2-氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)呱嗪-1-基)乙-1-酮 MS-ESI(m/z):620 [M+1]+
152 (2-氟-4-(2-氟苯氧基)苯基)(5-甲氧基-4-(((3R
,6S
)-6-((4-(甲基磺醯基)呱嗪-1-基)甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):656 [M+1]+
153 N
-(((2S
,5R
)-5-((3-(4-(2,6-二氟苯氧基)-2-氟苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)乙醯胺 MS-ESI(m/z):569 [M+1]+
154 (4-(((3R
,6S
)-6-(氨甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2,6-二氟苯氧基)-2-氟苯基)甲酮 MS-ESI(m/z):527 [M+1]+
155 1-(((2S
,5R
)-5-((3-(4-(2,6-二氟苯氧基)-2-氟苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)脲 MS-ESI(m/z):570 [M+1]+
156 N
-(((2S
,5R
)-5-((3-(4-(2,6-二氟苯氧基)-2-甲基苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)乙醯胺 MS-ESI(m/z):565 [M+1]+
157 N
-(((2S
,5R
)-5-((3-(2-氯-4-(2,6-二氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)乙醯胺 MS-ESI(m/z):585 [M+1]+
158 (2-氯-4-苯氧基苯基)(5-(乙氧基-d5
)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):527 [M+1]+
159 (4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-(甲氧基-d3
)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-苯氧基苯基)甲酮 MS-ESI(m/z):477 [M+1]+
160 N
-(((2S
,5R
)-5-((3-(2-氟-4-(2-氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)乙醯胺 MS-ESI(m/z):551 [M+1]+
161 N
-(((2S
,5R
)-5-((3-(2-氟-4-(2-氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)甲磺醯胺 MS-ESI(m/z):587 [M+1]+
162 N
-(((2S
,5R
)-5-((3-(2-氟-4-(2-氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)氨基磺醯胺 MS-ESI (m/z):588 [M+1]+
163 甲基 (((2S
,5R
)-5-((3-(2-氟-4-(2-氟苯氧基)苯甲醯)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-4-基)氨基)四氫-2H
-吡喃-2-基)甲基)氨基甲酸酯 MS-ESI(m/z):567 [M+1]+
164 (R
)-(4-((6,6-二(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):540 [M+1]+
165 (2-氟-4-(2-氟苯氧基)苯基)(4-(((3R
)-6-(氟甲基)-6-(羥甲基) 四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):542 [M+1]+
166 1st
-洗脫異構體 (4-(2-氟苯氧基)-2-甲基苯基)(4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):504 [M+1]+
167 2nd
-洗脫異構體 (4-(2-氟苯氧基)-2-甲基苯基)(4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):504 [M+1]+
168 1st
-洗脫異構體 (2-氟-4-(2-氟苯氧基)苯基)(4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):508 [M+1]+
169 2nd
-洗脫異構體 (2-氟-4-(2-氟苯氧基)苯基)(4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):508 [M+1]+
170 1st
-洗脫異構體 (5-乙氧基-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):518 [M+1]+
171 2nd
-洗脫異構體 (5-乙氧基-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):518 [M+1]+
172 1st
-洗脫異構體 (5-乙氧基-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):522 [M+1]+
173 2nd
-洗脫異構體 (5-乙氧基-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):522 [M+1]+
174 (5-(二氟甲氧基)-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-氟-2-甲基苯基)甲酮 MS-ESI(m/z):450 [M+1]+
175 (4-(((3R
)-6-乙炔基-6-(羥甲基) 四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-(2-氟苯氧基)苯基)甲酮 MS-ESI(m/z):534 [M+1]+
176 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-苯氧基苯基)甲酮 MS-ESI(m/z):506 [M+1]+
177 (4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-苯氧基苯基)甲酮 MS-ESI(m/z):474 [M+1]+
178 (5-乙氧基-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-苯氧基苯基)甲酮 MS-ESI(m/z):488 [M+1]+
179 1st
-洗脫異構體 (5-氟-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):492 [M+1]+
180 2nd
-洗脫異構體 (5-氟-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2-氟苯氧基)-2-甲基苯基)甲酮 MS-ESI(m/z):492 [M+1]+
181 1st
-洗脫異構體 (5-乙氧基-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-苯氧基苯基)甲酮 MS-ESI(m/z):504 [M+1]+
182 2nd
-洗脫異構體 (5-乙氧基-4-(((1R
,4S
)-4-(羥甲基)-3-氧雜二環[3.1.0]己烷-1-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氟-4-苯氧基苯基)甲酮 MS-ESI(m/z):504 [M+1]+
183 (4-(2,6-二氟苯氧基)苯基)(5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):498 [M+1]+
184 (4-(2,6-二氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):510 [M+1]+
185 (4-(2,6-二氟苯氧基)-2-甲基苯基)(5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):512 [M+1]+
186 (2-氯-4-(2,6-二氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):544 [M+1]+
187 (2-氯-4-(2,6-二氟苯氧基)苯基)(5-氟-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):532 [M+1]+
188 (4-(2,6-二氟苯氧基)-2-甲基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):524 [M+1]+
189 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(2-氯-4-(2,6-二氟苯氧基)苯基)甲酮 MS-ESI(m/z):548 [M+1]+
190 (5-氯-4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-1H
-吡咯並[2,3-b
]吡啶-3-基)(4-(2,6-二氟苯氧基)苯基)甲酮 MS-ESI(m/z):514 [M+1]+
191 (2-氟-4-苯氧基苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):492 [M+1]+
192 (4-(2,6-二氟苯氧基)-2-氟苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):528 [M+1]+
193 (4-(2,6-二氟苯氧基)-2,6-二氟苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):546 [M+1]+
194 (2,6-二氟-4-(2-氟苯氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):528 [M+1]+
195 (2-氟-4-((3-氟吡啶-2-基)氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):511 [M+1]+
196 (2-氟-4-(吡啶-2-基氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):493 [M+1]+
197 (2,6-二氟-4-((3-氟吡啶-2-基)氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):529 [M+1]+
198 (2,6-二氟-4-(吡啶-2-基氧基)苯基)(4-(((3R
,6S
)-6-(羥甲基)四氫-2H
-吡喃-3-基)氨基)-5-甲氧基-1H
-吡咯並[2,3-b
]吡啶-3-基)甲酮 MS-ESI(m/z):511 [M+1]+
激酶試驗Example 4-225 listed in Table 1 basically followed the same method as Example 1-3, and the starting materials used were commercially available or prepared according to literature methods. Table 1 shows the name and structure of Example 4-225. Table 1 Example Structural formula name data
4 (2-Chloro-4-phenoxyphenyl)(5-fluoro-4-(((1 r ,4 r )-4-(hydroxymethyl)cyclohexyl)amino)-1 H -pyrrolo[2 ,3- b )pyridin-3-yl)methanone MS-ESI (m/z): 494 [M + 1] +
5 3-(2-Chloro-4-phenoxybenzoyl)-4-(((1 r ,4 r )-4-(hydroxymethyl)cyclohexyl)amino)-1 H -pyrrolo[2, 3- b ]pyridine-5-carbonitrile MS-ESI (m/z):501 [M + 1] +
6 (2-Chloro-4-phenoxyphenyl)(5-fluoro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):496 [M + 1] +
7 3-(2-Chloro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino )-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):503 [M + 1] +
8 3-(2-Chloro-4-(4-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):521 [M + 1] +
9 (2-Chloro-4-(4-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):496 [M + 1] +
10 (2-Fluoro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z): 462 [M + 1] +
11 4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-3-(2-methyl-4-phenoxybenzyl醯)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):483 [M + 1] +
12 3-(2-cyano-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):494 [M + 1] +
13 (4 - (((3 R , 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin - 3-yl)(2-methyl-4-phenoxyphenyl)methanone MS-ESI (m/z):458 [M + 1] +
14 2-(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ] (Pyridine-3-carbonyl)-5-phenoxybenzonitrile MS-ESI (m/z):469 [M + 1] +
15 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-methyl-4-phenoxyphenyl)methanone MS-ESI (m/z):476 [M + 1] +
16 2-(5-Fluoro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrolo[2, 3- b pyridine-3-carbonyl)-5-phenoxybenzonitrile MS-ESI (m/z):487 [M + 1] +
17 1 st -eluting isomer 3-(2-Chloro-4-phenoxybenzyl)-4-(((1 R ,5 R )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane -1-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):501 [M + 1] +
18 2 nd -eluting isomer 3-(2-Chloro-4-phenoxybenzyl)-4-(((1 R ,5 R )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane -1-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 501 [M + 1] +
19 2 nd -eluting isomer 4-(((1 R ,5 R )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-3-(2-methyl-4 -Phenoxybenzoyl)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 481 [M + 1] +
20 1 st -eluting isomer 4-(((1 R ,5 R )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-3-(2-methyl-4 -Phenoxybenzoyl)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 481 [M + 1] +
twenty one 1 st -eluting isomer 3-(2-cyano-4-phenoxybenzoyl)-4-(((1 R ,5 R )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane Alk-1-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):492 [M + 1] +
twenty two 2 nd -eluting isomer 3-(2-cyano-4-phenoxybenzoyl)-4-(((1 R ,5 R )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane Alk-1-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):492 [M + 1] +
twenty three 3-(2-Chloro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino )-1 H -pyrrolo[2,3- b ]pyridine-5-carboxamide MS-ESI (m/z):521 [M + 1] +
twenty four 4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-3-(2-methyl-4-phenoxybenzyl醯)-1 H -pyrrolo[2,3- b ]pyridine-5-carboxamide MS-ESI (m/z):501 [M + 1] +
25 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone MS-ESI (m/z):512 [M + 1] +
26 (2-Chloro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5 -Methyl-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):492 [M + 1] +
27 (2-Chloro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5 -Methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):508 [M + 1] +
28 (4 - (((3 R , 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin - 3-yl)(4-phenoxyphenyl)methanone MS-ESI (m/z):444 [M + 1] +
29 4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-3-(4-phenoxybenzoyl)-1 H -Pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):469 [M + 1] +
30 (2-Chloro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):496 [M + 1] +
31 (2-Chloro-4-(3-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):496 [M + 1] +
32 3-(2-Chloro-4-(2-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):521 [M + 1] +
33 3-(2-Chloro-4-(3-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):521 [M + 1] +
34 (2,6-Dichloro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino )-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):512 [M + 1] +
35 3-(2,6-Dichloro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):537 [M + 1] +
36 (2,3-Dichloro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino )-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):512 [M + 1] +
37 3-(2,3-Dichloro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):537 [M + 1] +
38 3-(2-chloro-4-(2-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(cyanomethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 530 [M + 1] +
39 3-(2-Chloro-4-(3-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(cyanomethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 530 [M + 1] +
40 (2-Chloro-4-(pyridin-3-yloxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):479 [M + 1] +
41 (4 - (((3 R , 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin - 3-yl)(2-methyl-6-phenoxypyridin-3-yl)methanone MS-ESI (m/z):459 [M + 1] +
42 3-(2-Chloro-4-(pyridin-3-yloxy)phenanyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):504 [M + 1] +
43 4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-3-(2-methyl-6-phenoxynicotinol Base)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):484 [M + 1] +
44 (2,6-Difluoro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino )-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):480 [M + 1] +
45 3-(2,6-Difluoro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):505 [M + 1] +
46 (4-(2-Fluorophenoxy)-2-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):476 [M + 1] +
47 (4-(3-Fluorophenoxy)-2-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):476 [M + 1] +
48 3-(4-(2-Fluorophenoxy)-2-methylphenanyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):501 [M + 1] +
49 3-(4-(3-Fluorophenoxy)-2-methylphenanyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):501 [M + 1] +
50 4-(((3 R ,6 S )-6-(cyanomethyl)tetrahydro-2 H -pyran-3-yl)amino)-3-(4-(2-fluorophenoxy)-2 -Methylphenanyl)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 510 [M + 1] +
51 4-(((3 R ,6 S )-6-(cyanomethyl)tetrahydro-2 H -pyran-3-yl)amino)-3-(4-(3-fluorophenoxy)-2 -Methylphenanyl)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 510 [M + 1] +
52 (2-Chloro-5-fluoro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):496 [M + 1] +
53 3-(2-chloro-5-fluoro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3 -Yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):521 [M + 1] +
54 3-(2-Chloro-4-(2-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(((dimethyl(oxo)-λ 6- sulfur-ylidene) amino) methyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridine-5-carbonitrile MS-ESI (m/z):596 [M + 1] +
55 3-(2,6-Dimethyl-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3 -Yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):497 [M + 1] +
56 (2,6-Dimethyl-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI (m/z):472 [M + 1] +
57 3-(2-Chloro-6-fluoro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2H-pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z):521 [M + 1] +
58 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-fluoro-4-phenoxyphenyl)methanone MS-ESI (m/z): 480 [M + 1] +
59 3-(2-Fluoro-4-phenoxybenzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino )-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI (m/z): 487 [M + 1] +
60 (2-Chloro-4-(4-chlorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3-b]pyridin-3-yl)methanone MS-ESI (m/z): 512 [M + 1] +
61 (2-Chloro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6S)-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl) Amino)-5-(2,2,2-trifluoroethoxy)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):594 [M+1] +
62 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-((2,2-difluorovinyl)oxy)-4-(((3 R ,6 S )-6- (hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin-3-yl) methanone MS-ESI(m/z):574 [M+1] +
63 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):506 [M+1] +
64 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):520 [M+1] +
65 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-ethoxy-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H- Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):540 [M+1] +
66 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-hydroxy-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):512 [M+1] +
67 (2-Chloro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrazolo[3,4- b ]pyridin-3-yl)methanone MS-ESI(m/z):497 [M+1] +
68 (4-(2-Fluorophenoxy)-2-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrazolo[3,4- b ]pyridin-3-yl)methanone MS-ESI(m/z):477 [M+1] +
69 2-((3-(2-Chloro-4-(2-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)-2,2-difluoroacetic acid MS-ESI(m/z):606 [M+1] +
70 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-ethyl-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyridine (Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):524 [M+1] +
71 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):524 [M+1] +
72 (5-(2-Fluorophenoxy)-3-methylpyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):507 [M+1] +
73 (4-(2-Fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)- 5-Methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):492 [M+1] +
74 (5-(2-Fluorophenoxy)pyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):493 [M+1] +
75 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):510 [M+1] +
76 (6-(2-Fluorophenoxy)-4-methylpyridin-3-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):507 [M+1] +
77 (2-Chloro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):526 [M+1] +
78 (4-(2-Fluorophenoxy)-2-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):506 [M+1] +
79 (6-(2-Fluorophenoxy)pyridin-3-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):493 [M+1] +
80 (6-(2-Fluorophenoxy)-2-methylpyridin-3-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):507 [M+1] +
81 (4-(2-Fluorophenoxy)-2-methoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3 -Yl)amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):522 [M+1] +
82 (3-Chloro-5-(2-fluorophenoxy)pyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):527 [M+1] +
83 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(6-(2-fluorophenoxy)pyridin-3-yl)methanone MS-ESI(m/z):497 [M+1] +
84 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(6-(2-fluorophenoxy)-2-methylpyridin-3-yl)methanone MS-ESI(m/z):511 [M+1] +
85 (2-Bromo-4-(2-fluorophenoxy)phenyl)(5-chloro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):574/576 [M+1] +
86 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(5-(2-fluorophenoxy)pyridin-2-yl)methanone MS-ESI(m/z):497 [M+1] +
87 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):510 [M+1] +
88 3-(4-(2-Fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):487 [M+1] +
89 3-(5-(2-fluorophenoxy)picolinyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):488 [M+1] +
90 3-(2-Fluoro-4-(2-fluorophenoxy)benzoyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):505 [M+1] +
91 3-(6-(2-Fluorophenoxy)nicotinyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):488 [M+1] +
92 3-(6-(2-Fluorophenoxy)-2-methylnicotinyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):502 [M+1] +
93 3-(6-(2-Fluorophenoxy)-4-methylnicotinyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):502 [M+1] +
94 3-(5-(2-Fluorophenoxy)-3-methylpicolinyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyridine (Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):502 [M+1] +
95 3-(3-chloro-5-(2-fluorophenoxy)picolinyl)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridine-5-carbonitrile MS-ESI(m/z):522 [M+1] +
96 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-cyclopropyl-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):536 [M+1] +
97 (2-Bromo-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):540/542 [M+1] +
98 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):496 [M+1] +
99 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):514 [M+1] +
100 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-chloro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):530 [M+1] +
101 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(6-(2-fluorophenoxy)-4-methylpyridin-3-yl)methanone MS-ESI(m/z):511 [M+1] +
102 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):480 [M+1] +
103 (6-(2-Fluorophenoxy)-4-methylpyridin-3-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):477 [M+1] +
104 (4-(2-Fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)- 1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):462 [M+1] +
105 (6-(2-Fluorophenoxy)pyridin-3-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):463 [M+1] +
106 (6-(2-Fluorophenoxy)-2-methylpyridin-3-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):477 [M+1] +
107 (5-(2-Fluorophenoxy)pyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):463 [M+1] +
108 (3-Chloro-5-(2-fluorophenoxy)pyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):497 [M+1] +
109 (5-(2-Fluorophenoxy)-3-methylpyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):477 [M+1] +
110 (5-(2-Fluorophenoxy)-3-methoxypyridin-2-yl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyridine (Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):493 [M+1] +
111 (2-Chloro-4-(2-fluoro-3-methoxyphenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H- Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):526 [M+1] +
112 (4-(2-Fluoro-3-methoxyphenoxy)-2-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):506 [M+1] +
113 (2-Cyclopropyl-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3 -Yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):502 [M+1] +
114 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):480 [M+1] +
115 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):498 [M+1] +
116 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(5-(2-fluorophenoxy)-3-methylpyridin-2-yl)methanone MS-ESI(m/z):495 [M+1] +
117 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(6-(2-fluorophenoxy)-4-methylpyridin-3-yl)methanone MS-ESI(m/z):495 [M+1] +
118 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(5-(2-fluorophenoxy)pyridin-2-yl)methanone MS-ESI(m/z):481 [M+1] +
119 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-chloro-4-(2-fluoro-3-methoxyphenoxy)phenyl)methanone MS-ESI(m/z):560 [M+1] +
120 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)-2-methylphenyl)methanone MS-ESI(m/z):540 [M+1] +
121 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(6-(2-fluorophenoxy)pyridin-3-yl)methanone MS-ESI(m/z):481 [M+1] +
122 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(6-(2-fluorophenoxy)-2-methylpyridin-3-yl)methanone MS-ESI(m/z):495 [M+1] +
123 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(3-chloro-5-(2-fluorophenoxy)pyridin-2-yl)methanone MS-ESI(m/z):531 [M+1] +
124 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(5-(2-fluorophenoxy)-3-methylpyridin-2-yl)methanone MS-ESI(m/z):511 [M+1] +
125 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-fluoro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):514 [M+1] +
126 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):494 [M+1] +
127 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(2-methyl-4-phenoxyphenyl)methanone MS-ESI(m/z):502 [M+1] +
128 (2-Chloro-4-phenoxyphenyl)(5-ethoxy-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):522 [M+1] +
129 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-cyclopropoxy-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):552 [M+1] +
130 (2-Fluoro-4-(2-fluorophenoxy)-6-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyridine (Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):494 [M+1] +
131 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)-6-methylphenyl)methanone MS-ESI(m/z):528 [M+1] +
132 (2-Fluoro-4-(2-fluorophenoxy)-6-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyridine (Pyran-3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):524 [M+1] +
133 (5-fluoro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)-6-methylphenyl)methanone MS-ESI(m/z):512 [M+1] +
134 (4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5-methoxy- 1H -pyrrolo[2, 3- b )pyridin-3-yl)(2-methyl-4-phenoxyphenyl)methanone MS-ESI(m/z):488 [M+1] +
135 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)-6-methylphenyl)methanone MS-ESI(m/z):538 [M+1] +
136 (5-(Difluoromethoxy)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrole And [2,3- b ]pyridin-3-yl)(4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):528 [M+1] +
137 (5-(Difluoromethoxy)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrole And [2,3- b ]pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):546 [M+1] +
138 (2-Chloro-4-(2-fluorophenoxy)phenyl)(5-(difluoromethoxy)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro -2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):562 [M+1] +
139 (5-(Difluoromethoxy)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrole And [2,3- b ]pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):542 [M+1] +
140 (2-Chloro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-5-(trifluoromethoxy)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):580 [M+1] +
141 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl )Amino)-5-(trifluoromethoxy)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):564 [M+1] +
142 (4-(((3 R ,6 S )-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3 -b )pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):509 [M+1] +
143 1-(((2 S ,5 R )-5-((3-(2-Fluoro-4-(2-fluorophenoxy)benzoyl)-5-methoxy-1 H -pyrrolo[ 2,3- b )pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)urea MS-ESI(m/z):552 [M+1] +
144 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(5-methoxy-4-(((3 R ,6 S )-6-((methylamino)methyl)tetrahydro -2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):523 [M+1] +
145 (4-(((3 R ,6 S )-6-((dimethylamino)methyl)tetrahydro-2 H -pyran-3-yl)amino)-5-methoxy-1 H- Pyrrolo[2,3- b ]pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):537 [M+1] +
146 (4-(((3 R ,6 S )-6-(azetidin-1-ylmethyl)tetrahydro- 2H -pyran-3-yl)amino)-5-methoxy- 1 H -pyrrolo[2,3- b ]pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):549 [M+1] +
147 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(5-methoxy-4-(((3 R ,6 S )-6-(pyrrol-1-ylmethyl)tetrahydro -2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):563 [M+1] +
148 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(5-methoxy-4-(((3 R ,6 S )-6-(morpholinomethyl)tetrahydro-2 H -Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):579 [M+1] +
149 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(5-methoxy-4-(((3 R ,6 S )-6-(piridin-1-ylmethyl)tetra hydrogen -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin-3-yl) methanone MS-ESI(m/z):577 [M+1] +
150 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(5-methoxy-4-(((3 R ,6 S )-6-(pazine-1-ylmethyl)tetra hydrogen -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin-3-yl) methanone MS-ESI(m/z):578 [M+1] +
151 1-(4-(((2 S ,5 R )-5-((3-(2-fluoro-4-(2-fluorophenoxy)benzyl)-5-methoxy-1 H- Pyrrolo[2,3- b ]pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)piperazin-1-yl)ethan-1-one MS-ESI(m/z):620 [M+1] +
152 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(5-methoxy-4-(((3 R ,6 S )-6-((4-(methylsulfonyl) piperazine-1-yl) methyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b] pyridin-3-yl) methanone MS-ESI(m/z):656 [M+1] +
153 N -(((2 S ,5 R )-5-((3-(4-(2,6-difluorophenoxy)-2-fluorobenzyl)-5-methoxy-1 H- Pyrrolo[2,3- b ]pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)acetamide MS-ESI(m/z):569 [M+1] +
154 (4-(((3 R ,6 S )-6-(aminomethyl)tetrahydro- 2H -pyran-3-yl)amino)-5-methoxy- 1H -pyrrolo[2, 3- b )pyridin-3-yl)(4-(2,6-difluorophenoxy)-2-fluorophenyl)methanone MS-ESI(m/z):527 [M+1] +
155 1-(((2 S ,5 R )-5-((3-(4-(2,6-difluorophenoxy)-2-fluorobenzyl)-5-methoxy-1 H- Pyrrolo[2,3- b ]pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)urea MS-ESI(m/z):570 [M+1] +
156 N -(((2 S ,5 R )-5-((3-(4-(2,6-difluorophenoxy)-2-methylbenzyl)-5-methoxy-1 H -Pyrrolo[2,3- b ]pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)acetamide MS-ESI(m/z):565 [M+1] +
157 N -(((2 S ,5 R )-5-((3-(2-chloro-4-(2,6-difluorophenoxy)benzyl)-5-methoxy-1 H- Pyrrolo[2,3- b ]pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)acetamide MS-ESI(m/z):585 [M+1] +
158 (2-Chloro-4-phenoxyphenyl)(5-(ethoxy- d 5 )-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H- Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):527 [M+1] +
159 (4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-5-(methoxy- d 3 )-1 H- Pyrrolo[2,3- b ]pyridin-3-yl)(4-phenoxyphenyl)methanone MS-ESI(m/z):477 [M+1] +
160 N -(((2 S ,5 R )-5-((3-(2-Fluoro-4-(2-fluorophenoxy)benzoyl)-5-methoxy-1 H -pyrrolo[ 2,3- b )pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)acetamide MS-ESI(m/z):551 [M+1] +
161 N -(((2 S ,5 R )-5-((3-(2-Fluoro-4-(2-fluorophenoxy)benzoyl)-5-methoxy-1 H -pyrrolo[ 2,3- b )pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)methanesulfonamide MS-ESI(m/z):587 [M+1] +
162 N -(((2 S ,5 R )-5-((3-(2-Fluoro-4-(2-fluorophenoxy)benzoyl)-5-methoxy-1 H -pyrrolo[ 2,3- b )pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)aminosulfonamide MS-ESI (m/z):588 [M+1] +
163 Methyl (((2 S ,5 R )-5-((3-(2-fluoro-4-(2-fluorophenoxy)benzoyl)-5-methoxy-1 H -pyrrolo[ 2,3- b )pyridin-4-yl)amino)tetrahydro- 2H -pyran-2-yl)methyl)carbamate MS-ESI(m/z):567 [M+1] +
164 ( R )-(4-((6,6-bis(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5-methoxy- 1H -pyrrolo[2,3 -b )pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):540 [M+1] +
165 (2-Fluoro-4-(2-fluorophenoxy)phenyl)(4-(((3 R )-6-(fluoromethyl)-6-(hydroxymethyl) tetrahydro-2 H -pyridine (Pyran-3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):542 [M+1] +
166 1 st -eluting isomer (4-(2-Fluorophenoxy)-2-methylphenyl)(4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0 ]Hexane-1-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):504 [M+1] +
167 2 nd -eluting isomer (4-(2-Fluorophenoxy)-2-methylphenyl)(4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0 ]Hexane-1-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):504 [M+1] +
168 1 st -eluting isomer (2-Fluoro-4-(2-fluorophenoxy)phenyl)(4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0] Hexane-1-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):508 [M+1] +
169 2 nd -eluting isomer (2-Fluoro-4-(2-fluorophenoxy)phenyl)(4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0] Hexane-1-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):508 [M+1] +
170 1 st -eluting isomer (5-Ethoxy-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -Pyrrolo[2,3- b ]pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):518 [M+1] +
171 2 nd -eluting isomer (5-Ethoxy-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -Pyrrolo[2,3- b ]pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):518 [M+1] +
172 1 st -eluting isomer (5-Ethoxy-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -Pyrrolo[2,3- b ]pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):522 [M+1] +
173 2 nd -eluting isomer (5-Ethoxy-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -Pyrrolo[2,3- b ]pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):522 [M+1] +
174 (5-(Difluoromethoxy)-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrole And [2,3- b ]pyridin-3-yl)(4-fluoro-2-methylphenyl)methanone MS-ESI(m/z):450 [M+1] +
175 (4-(((3 R )-6-ethynyl-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5-methoxy- 1H -pyrrolo[ 2,3- b )pyridin-3-yl)(2-fluoro-4-(2-fluorophenoxy)phenyl)methanone MS-ESI(m/z):534 [M+1] +
176 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(2-fluoro-4-phenoxyphenyl)methanone MS-ESI(m/z):506 [M+1] +
177 (4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5-methoxy- 1H -pyrrolo[2, 3- b )pyridin-3-yl)(4-phenoxyphenyl)methanone MS-ESI(m/z):474 [M+1] +
178 (5-ethoxy -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2, 3- b )pyridin-3-yl)(4-phenoxyphenyl)methanone MS-ESI(m/z):488 [M+1] +
179 1 st -eluting isomer (5-Fluoro-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -pyrrole And [2,3- b ]pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):492 [M+1] +
180 2 nd -eluting isomer (5-Fluoro-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -pyrrole And [2,3- b ]pyridin-3-yl)(4-(2-fluorophenoxy)-2-methylphenyl)methanone MS-ESI(m/z):492 [M+1] +
181 1 st -eluting isomer (5-Ethoxy-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -Pyrrolo[2,3- b ]pyridin-3-yl)(2-fluoro-4-phenoxyphenyl)methanone MS-ESI(m/z):504 [M+1] +
182 2 nd -eluting isomer (5-Ethoxy-4-(((1 R ,4 S )-4-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexane-1-yl)amino)-1 H -Pyrrolo[2,3- b ]pyridin-3-yl)(2-fluoro-4-phenoxyphenyl)methanone MS-ESI(m/z):504 [M+1] +
183 (4-(2,6-Difluorophenoxy)phenyl)(5-fluoro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):498 [M+1] +
184 (4-(2,6-Difluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl) Amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):510 [M+1] +
185 (4-(2,6-Difluorophenoxy)-2-methylphenyl)(5-fluoro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):512 [M+1] +
186 (2-Chloro-4-(2,6-difluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):544 [M+1] +
187 (2-Chloro-4-(2,6-difluorophenoxy)phenyl)(5-fluoro-4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -Pyran-3-yl)amino)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z): 532 [M+1] +
188 (4-(2,6-Difluorophenoxy)-2-methylphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):524 [M+1] +
189 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(2-chloro-4-(2,6-difluorophenoxy)phenyl)methanone MS-ESI(m/z):548 [M+1] +
190 (5-chloro -4 - (((3 R, 6 S) -6- ( hydroxymethyl) tetrahydro -2 H - pyran-3-yl) amino) -1 H - pyrrolo [2,3- b )Pyridin-3-yl)(4-(2,6-difluorophenoxy)phenyl)methanone MS-ESI(m/z):514 [M+1] +
191 (2-Fluoro-4-phenoxyphenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)amino)-5 -Methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):492 [M+1] +
192 (4-(2,6-Difluorophenoxy)-2-fluorophenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):528 [M+1] +
193 (4-(2,6-Difluorophenoxy)-2,6-difluorophenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H- Pyran-3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):546 [M+1] +
194 (2,6-Difluoro-4-(2-fluorophenoxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran- 3-yl)amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):528 [M+1] +
195 (2-Fluoro-4-((3-fluoropyridin-2-yl)oxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H- Pyran-3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):511 [M+1] +
196 (2-Fluoro-4-(pyridin-2-yloxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran-3- (Yl)amino)-5-methoxy- 1H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):493 [M+1] +
197 (2,6-Difluoro-4-((3-fluoropyridin-2-yl)oxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro- 2 H -pyran-3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):529 [M+1] +
198 (2,6-Difluoro-4-(pyridin-2-yloxy)phenyl)(4-(((3 R ,6 S )-6-(hydroxymethyl)tetrahydro-2 H -pyran -3-yl)amino)-5-methoxy-1 H -pyrrolo[2,3- b ]pyridin-3-yl)methanone MS-ESI(m/z):511 [M+1] +
Kinase test
BTK（C481S）的激酶活性反應在Reaction Biology Corporation測定。在新鮮反應緩衝液（20 mM Hepes（pH 7.5），10 mM MgCl2
, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3
VO4
, 2 mM DTT, 1% DMSO）中製備BTK（C481S）反應底物pEY（poly [Glu:Tyr]（4:1））（Sigma，Cat.# P7244-250MG）。將BTK（C481S）（SignalChem，Cat.# B10-12CH）加入底物溶液中並輕輕混合。BTK（C481S）和底物的反應體系終濃度分別為6 nM和0.2 mg/ml。受試化合物將以10個濃度/回應模式，從1μM開始進行3倍梯度稀釋。The kinase activity response of BTK (C481S) was measured at Reaction Biology Corporation. Prepared in fresh reaction buffer (20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO) BTK (C481S) reaction substrate pEY (poly [Glu:Tyr] (4:1)) (Sigma, Cat.# P7244-250MG). Add BTK (C481S) (SignalChem, Cat.# B10-12CH) to the substrate solution and mix gently. The final concentration of the reaction system of BTK (C481S) and substrate is 6 nM and 0.2 mg/ml, respectively. The test compound will be diluted 3 times in 10 concentration/response modes, starting from 1 μM.
溶解於100%DMSO的受試化合物通過超聲波流體處理系統（Echo550；納升範圍）加入激酶反應體系中，並在室溫下孵育20分鐘。將10μM的[33
P] -ATP（ATP：Sigma，Cat.# A7699；[33
P] -ATP：Hartmann Analytic，Cat.# SCF-301-12）加入反應液以引發反應，並在室溫下孵育120分鐘。使用特定的親和力分析方法檢測螢光強度。通過與對照組（DMSO）的螢光強度比值進行比較計算化合物在各濃度下的百分比抑制率，並通過GraphPad Prism軟體得到化合物的IC50
值。The test compound dissolved in 100% DMSO was added to the kinase reaction system through an ultrasonic fluid treatment system (Echo550; nanoliter range) and incubated at room temperature for 20 minutes. Add 10μM [ 33 P] -ATP (ATP: Sigma, Cat.# A7699; [ 33 P] -ATP: Hartmann Analytic, Cat.# SCF-301-12) into the reaction solution to initiate the reaction, and keep it at room temperature Incubate for 120 minutes. Use a specific affinity analysis method to detect the fluorescence intensity. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio of the control group (DMSO), and the IC 50 value of the compound was obtained by GraphPad Prism software.
選擇的化合物根據本文所述的生物學方法進行測定。其結果如表2所示： 表2 實施例 BTK (C481S) IC50 (nM)
2 2.22
27 1.12
63 1.0
71 0.77
127 0.959
128 0.972
176 0.455
細胞增殖試驗The selected compounds are determined according to the biological methods described herein. The results are shown in Table 2: Table 2 Example BTK (C481S) IC50 (nM)
2 2.22
27 1.12
63 1.0
71 0.77
127 0.959
128 0.972
176 0.455
Cell proliferation test
通過測定化合物對DOHH2 (DSMZ catalog#: ACC47)細胞增殖的抑制作用，研究化合物是否能夠抑制細胞中BTK的活性。在試驗中，通過抑制DOHH2細胞增殖來檢測化合物對BTK的抑制活性。消化細胞，將細胞均按5000個/孔的細胞濃度接種于96孔板，37°C，5% CO2
孵育4 h。96孔細胞培養板中加入平行3孔不同濃度（終濃度10000、3333.3、1111.1、270.4、123.5、41.2、13.7、4.6和1.5 nM）的化合物，於37°C，5% CO2
孵育120h。每孔按照每100 µL培養基20 µL MTS的濃度加入MTS。孵育2 h後，每孔加入25 µL 10% SDS終止反應。用酶標儀測量490 nm和650 nm處的吸收。用GraphPad Prism 5.0計算IC50
。By measuring the inhibitory effect of the compound on the proliferation of DOHH2 (DSMZ catalog#: ACC47) cells, it is investigated whether the compound can inhibit the activity of BTK in the cells. In the test, the compound's inhibitory activity on BTK was tested by inhibiting the proliferation of DOHH2 cells. The cells were digested, and the cells were seeded in a 96-well plate at a cell concentration of 5000 cells/well, and incubated at 37°C and 5% CO 2 for 4 h. Compounds of different concentrations (final concentrations 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM) were added to a 96-well cell culture plate in 3 parallel wells, and incubated at 37°C, 5% CO 2 for 120 hours. 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.
選擇的化合物根據本文所述的生物學方法進行測定。其結果如表3所示： 表3 實施例 DoHH2 IC50
(nM) 實施例 DoHH2 IC50
(nM)
2 26 114 12
6 89 115 5
7 83 117 69
10 19 125 1
11 60 126 4
13 19 127 1
15 85 128 1
17 43 130 36
19 88 132 7
20 20 134 1
27 1 135 1
28 32 160 1
29 99 161 14
30 21 163 45
32 15 164 22
36 69 166 21
37 48 167 18
41 53 168 8
44 7 169 65
45 57 170 12
46 1 171 2
47 46 172 1
48 1 173 7
49 100 176 1
58 23 177 9
63 1 178 15
64 1 179 1
65 1 181 1
71 1 182 31
73 1 183 17
75 1 184 1
76 47 185 14
77 1 186 17
78 1 187 52
81 19 188 4
87 17 189 32
88 99 190 11
90 50 191 1
98 41 192 8
99 24 193 12
100 67 194 26
102 7 195 83
103 39 196 44
104 23 198 52
110 95 / /
藥代動力學實驗The selected compounds are determined according to the biological methods described herein. The results are shown in Table 3: Table 3 Example DoHH2 IC 50 (nM) Example DoHH2 IC 50 (nM)
2 26 114 12
6 89 115 5
7 83 117 69
10 19 125 1
11 60 126 4
13 19 127 1
15 85 128 1
17 43 130 36
19 88 132 7
20 20 134 1
27 1 135 1
28 32 160 1
29 99 161 14
30 twenty one 163 45
32 15 164 twenty two
36 69 166 twenty one
37 48 167 18
41 53 168 8
44 7 169 65
45 57 170 12
46 1 171 2
47 46 172 1
48 1 173 7
49 100 176 1
58 twenty three 177 9
63 1 178 15
64 1 179 1
65 1 181 1
71 1 182 31
73 1 183 17
75 1 184 1
76 47 185 14
77 1 186 17
78 1 187 52
81 19 188 4
87 17 189 32
88 99 190 11
90 50 191 1
98 41 192 8
99 twenty four 193 12
100 67 194 26
102 7 195 83
103 39 196 44
104 twenty three 198 52
110 95 / /
Pharmacokinetic experiment
本試驗旨在研究實施例71、實施例75在雄性Sprague-Dawley （SD）大鼠（由北京維通利華實驗動物技術有限公司提供）體內的藥代動力學性質。The purpose of this experiment is to study the pharmacokinetic properties of Example 71 and Example 75 in male Sprague-Dawley (SD) rats (provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.).
第1組動物分別單次靜脈注射給藥1mg/kg，1mg/mL的實施例71，第2組動物分別單次灌胃給藥5mg/kg，1mg/mL的實施例71溶液。這兩組給藥製劑溶媒均為60% Phosal 50 PG (Lipoid，批號：368315-3180028/009)：30%聚乙二醇400 (Sigma，批號：MKCH6281)：10%乙醇(Merck，批號：K48244883634)。應用LC/MS/MS方法測定血漿樣本中實施例71的濃度。(液相：Waters UPLC；質譜：API4000)。其結果如表4所示。The animals in the first group were given a single intravenous injection of 1 mg/kg and 1 mg/mL of Example 71, and the animals in the second group were given a single intragastric administration of 5 mg/kg and 1 mg/mL of the solution of Example 71. The formulations for the two groups are 60% Phosal 50 PG (Lipoid, lot number: 368315-3180028/009): 30% polyethylene glycol 400 (Sigma, lot number: MKCH6281): 10% ethanol (Merck, lot number: K48244883634 ). The LC/MS/MS method was used to determine the concentration of Example 71 in plasma samples. (Liquid phase: Waters UPLC; Mass spectrum: API4000). The results are shown in Table 4.
第3組動物單次靜脈注射給藥2mg/kg，2mg/mL的實施例75溶液，第4組動物單次灌胃給藥10mg/kg，2mg/mL的實施例75溶液。兩組給藥製劑溶媒均為10%二甲基亞碸 (Sigma，批號：LPC0S181)：60%聚乙二醇400(Sigma，批號：MKCH6281)：30%水。應用LC/MS/MS方法測定血漿樣本中實施例75的濃度。(液相：Waters UPLC；質譜：Triple Quad 6500 plus)。其結果如表4所示。 表4 實施例71 實施例75
給藥途徑 灌胃 靜脈注射 灌胃 靜脈注射
劑量(mg/kg) 5 1 10 2
Tmax
(h) 4 / 2.83 /
T1/2
(h) 2.74 3.07 2.8 2.56
MRT0-t
(h) 5.26 1.93 5.58 2.43
Cmax
/C0
(ng/mL) 1676 4364 4136 6347
AUClast
(h.ng/mL) 10098 3761 28888 10145
AUCinf
(h.ng/mL) 10131 3773 29039 10164
CL (mL/kg/min) / 4.7 / 3.33
Vdss
(L/kg) / 0.541 / 0.489
F (%) 53.7 / 57.1 /
Group 3 animals were given a single intravenous injection of 2 mg/kg, 2 mg/mL of Example 75 solution, and group 4 animals were given a single intragastric administration of 10 mg/kg, 2 mg/mL of Example 75 solution. The solvents of the two groups were 10% dimethyl sulfoxide (Sigma, lot number: LPC0S181): 60% polyethylene glycol 400 (Sigma, lot number: MKCH6281): 30% water. The LC/MS/MS method was used to determine the concentration of Example 75 in the plasma sample. (Liquid phase: Waters UPLC; mass spectrum: Triple Quad 6500 plus). The results are shown in Table 4. Table 4 Example 71 Example 75
Route of administration Gavage Intravenous injection Gavage Intravenous injection
Dose (mg/kg) 5 1 10 2
T max (h) 4 / 2.83 /
T 1/2 (h) 2.74 3.07 2.8 2.56
MRT 0-t (h) 5.26 1.93 5.58 2.43
C max /C 0 (ng/mL) 1676 4364 4136 6347
AUC last (h.ng/mL) 10098 3761 28888 10145
AUC inf (h.ng/mL) 10131 3773 29039 10164
CL (mL/kg/min) / 4.7 / 3.33
Vd ss (L/kg) / 0.541 / 0.489
F (%) 53.7 / 57.1 /
