	US 12,410,192 B2
	Compound for inhibiting and inducing degradation of EGFR kinase
Yanping Zhao, Beijing (CN); Hongjun Wang, Beijing (CN); Yeming Wang, Beijing (CN); Yuanyuan Jiang, Beijing (CN); Futian Fan, Beijing (CN); Huining Liang, Beijing (CN); Xiaoqian Wang, Beijing (CN); Yong Xie, Beijing (CN); Yanhao Zhang, Beijing (CN); and Xuelian Liu, Beijing (CN)
Assigned to BEIJING TIDE PHARMACEUTICAL CO., LTD., Beijing (CN)
Appl. No. 17/785,608
Filed by BEIJING TIDE PHARMACEUTICAL CO., LTD., Beijing (CN)
PCT Filed Dec. 16, 2020, PCT No. PCT/CN2020/136773 § 371(c)(1), (2) Date Jun. 15, 2022, PCT Pub. No. WO2021/121261, PCT Pub. Date Jun. 24, 2021.
Claims priority of application No. 201911291237.9 (CN), filed on Dec. 16, 2019.
Prior Publication US 2023/0159559 A1, May 25, 2023
Int. Cl. C07D 498/22 (2006.01); A61P 35/00 (2006.01)

CPC C07D 498/22 (2013.01) [A61P 35/00 (2018.01)]

20 Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof:

wherein

represents single bond or double bond;

----- represents that the point of attachment to the rest of the molecule can be located at an available point of a ring;

Z₁is O, S, N or C atom, which is optionally substituted with one or two R_Z1;

Z₂is O, S, N or C atom, which is optionally substituted with one or two R_Z2;

Z₃is O, S, N or C atom, which is optionally substituted with one or two R_Z3; with the proviso that when custom character

represents double bond, Z₂is N or C atom, and Z₃is N or C atom;

Z₄is N or CR_Z4;

Z₅is N or CR_Z5;

R_a, R_band R_care independently H, halogen, C_1-6alkyl or C_1-6haloalkyl;

R_N1is H, C_1-6alkyl or C_1-6haloalkyl;

R_Z1is absent, H, CN, halogen, C_1-6alkyl, or C_1-6haloalkyl; or two R_Z1are taken together with Z₁to form C═O;

R_Z2is absent, H, CN, halogen, C_1-6alkyl, or C_1-6haloalkyl;

R_Z3is absent, H, CN, halogen, C_1-6alkyl, or C_1-6haloalkyl; or two R_Z3are taken together with Z₃to form C═O;

R_Z4is H, CN, halogen, C_1-6alkyl, or C_1-6haloalkyl;

R_Z5is H, CN, halogen, C_1-6alkyl, or C_1-6haloalkyl;

L₁is selected from bond, —O—, —S(O)_p—, —NR^#—, —CR^#R^#′— or —C_aR^#R^#′—C_bR^#R^#′—;

L₂is selected from bond, —O—, —S(O)_p—, —NR^#—, —CR^#R^{190 ′}— or —C_aR^#R^#′—C_bR^#R^#′—;

wherein any one of C_aR^#R^#′ or C_bR^#R^#′ can be replaced by O, S(O)_por NR^#, and when any one of C_aR^#R^#′ or C_bR^#R^#′ is replaced by O, S or NR^#, the other of C_aR^#R^#′ or C_bR^#R^#′ can further be replaced by S(O)_q;

E is independently selected from: —C_cR^#R^#′—C_dR^#R^#′—C_cR^#R^#′ or

wherein any one of C_cR^#R^#′, C_dR^#R^#′ or C_eR^#R^#′, or both of C_cR^#R^#′ and C_eR^#R^#′ can be replaced by O, S(O)_por NR^#, and when any one of C_cR^#R^#′, C_dR^#R^#′ or C_eR^#R^# is replaced by O, S or NR^#, the other one or two of C_cR^#R^#′, C_dR^#R^#′ or C_eR^#R^#′ adjacent to it can further be replaced by S(O)_q;

H₄and H₅are N or C atom;

p is 0, 1 or 2;

q is 1 or 2;

R^# is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl or C_2-6alkynyl;

R^#′ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl or C_2-6alkynyl;

or, R^# and R^# on adjacent atoms can be taken together to form bond, and R^#′ and R^#′ on adjacent atoms can be taken together to form bond;

or, R^# and R^#′ on the same or different atoms can be taken together to form —O;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

X₁is C or N atom;

X₂is C or N atom;

X₃is C or N atom;

X₄is O, S, C or N atom, which is optionally substituted with one or two R₂;

X₅is O, S, C or N atom;

X₆is C or N atom;

X₇is O, S, C or N atom;

R₁is H, CN, halogen, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl or C_2-6alkynyl;

R₂is H, CN, halogen, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl or C_2-6alkynyl;

R_N2is H, C_1-6alkyl or C_1-6haloalkyl;

the definition of L₁′ is the same as that of L₁;

the definition of L₂′ is the same as that of L₂;

the definition of E′ is the same as that of E;

the definition of m′ is the same as that of m;

R_s1is selected from H, CN, halogen, C_1-6alkyl or C_1-6haloalkyl;

R_s2is selected from H, CN, halogen, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl or C_2-6alkynyl;

R_s3is selected from H, CN, halogen, C_1-6alkyl or C_1-6haloalkyl;

R_s4is selected from H, CN, halogen, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl or C_2-6alkynyl;

s1 is 0, 1, 2 or 3;

s2 is 0, 1, 2 or 3;

s3 is 0, 1 or 2;

s4 is 0, 1, 2, 3, 4 or 5.