US 12,479,843 B2
Spiro ring-containing quinazoline compounds
Yuli Xie, Shanghai (CN); Houxing Fan, Shanghai (CN); Gang Cao, Shanghai (CN); and Lihui Qian, Shanghai (CN)
Assigned to SOOCHOW UNIVERSITY, Suzhou (CN)
Appl. No. 17/767,034
Filed by WIGEN BIOMEDICINE TECHNOLOGY (SHANGHAI) CO., LTD., Shanghai (CN)
PCT Filed Dec. 25, 2020, PCT No. PCT/CN2020/139530
§ 371(c)(1), (2) Date Apr. 6, 2022,
PCT Pub. No. WO2021/129820, PCT Pub. Date Jul. 1, 2021.
Claims priority of application No. 201911386239.6 (CN), filed on Dec. 27, 2019; and application No. 202010486384.8 (CN), filed on Jun. 1, 2020.
Prior Publication US 2023/0002382 A1, Jan. 5, 2023
Int. Cl. C07D 471/10 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/10 (2013.01) [C07D 519/00 (2013.01)] 18 Claims
 
1. A compound with a structure as shown in general formula (1), optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:

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wherein in formula (1):
R1 is H, halogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl;
R2 is C1-C3 alkoxy, C1-C3 haloalkoxy or -NRaRb, wherein Ra and Rb are independently H, C1-C3 alkyl or C1-C3 haloalkyl, or Ra and Rb, together with a N atom, form a 4-7 membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted with 1-3 halogen atoms;
R3 is

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wherein Rc is H or F; Rd is H, F, Cl or Me; Re is H, F, Cl or Me; Rf is F, NH2, Me or cyclopropyl; Rx1, Rx2, Rx3, Rx4, Rx5, Rx6 and Rx7 are independently H, F, Cl, OH, OMe, NH2, CF3, C1-C3 alkyl or C3-C6 cycloalkyl;
R4 is H, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or heteroaryl; and
when R3 is

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and R4 is H, R5 is:

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wherein n1, n2, n3, m1, m2 and m3 are independently integers of 1 or 2; Rg is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; Rh is

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when R3 is

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and R4 is halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or heteroaryl; or, when R3 is

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wherein n1, n2, n3, m1, m2 and m3 are independently integers of 1 or 2; Rg is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3alkyl; Rh is

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Ri is H, halogen, methyl or cyano.
 
10. A compound with a structure as shown in general formula (2), optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:

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wherein in general formula (2):
R1a is

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R2a is CH3O—, CH3CH2O—, CF3CH2O- or CHF2CH2O—;
R3a is

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wherein Rc is H or F, Rd is H, F, Cl or Me, Re is H, F, Cl or Me, and Rf is F, NH2, Me or cyclopropyl;
R4a is H or F; and
R5a is: H,

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wherein n1, n2, n3, m1, m2 and m3 are independently integers of 1 or 2; v is an integer of 1, 2 or 3; Rg is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; Rj is independently halogen, CN, SO2Me, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6cycloalkyl or

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Rk is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or

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Rn is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl, two Rn groups, together with one carbon atom, form a spiro ring, or two Rn groups, together with different carbon atoms, form a bridged ring; R1 and Rm are independently C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, or R1 and Rm, together with a N atom, form a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3)alkoxy or (halogenated C1-C3)alkoxy.
 
14. A compound with a structure as shown in general formula (3), optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof:

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wherein, R5b is:

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wherein n1, n2, n3, m1, m2 and m3 are independently integers of 1 or 2; Rg is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; Rh is

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Ri is H, halogen, methyl or cyano; or
R5b is: H,

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wherein n1, n2, n3, m1, m2 and m3 are independently integers of 1 or 2; v is an integer of 1, 2 or 3; Rg is C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl or cyano-substituted C1-C3 alkyl; Rj is independently halogen, CN, SO2Me, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6cycloalkyl or

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Rk is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or

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Rn is independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl, two Rn groups, together with one carbon atom, form a spiro ring, or two Rn groups, together with different carbon atoms, form a bridged ring; R1 and Rm are independently C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6) cycloalkyl-(C1-C3)alkyl-, or R1 and Rm, together with a N atom, form a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group may be substituted with 1-3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3)alkoxy or (halogenated C1-C3)alkoxy.