US 2022/0024913 A1Published application

Fgfr4 inhibitor and preparation method and use thereof

AssigneesJiangsu Hansoh Pharmaceutical Group Co., Ltd., Shanghai Hansoh Biomedical Co., Ltd.

InventorsPeng GAO, Guangjun SUN, Songliang TAN, Lei LIU, Rudi BAO

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Abstract

Provided are an FGFR4 inhibitor with the structure of formula (I) and a preparation method and use thereof. The series of compounds of formula (I) have a very strong inhibitory effect on the FGFR4 kinase activity, and have a very high selectivity; and the same can be widely used to prepare drugs for treating cancers, in particular, liver cancer, stomach cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer or colon cancer, and it is expected that the same can be developed into a new generation of FGFR4 inhibitor drugs.

Claims21

Dependent claims

A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein:
R1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10, wherein the hydroxy, thiol, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9,—C0-8—O—R10, —C0-8—C(O)OR10,—C0-8—OR11, C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13—N(R12)—C(O)R11 and —N(R12)—C(O)OR10 are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0- 8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10,
wherein the hydroxy, thiol, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10 are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10;
or, R1 and R2 together with the carbon atom to which they are directly attached form a 5 to 7 membered cycloalkyl or 5 to 7 membered heterocyclyl, optionally substituted by one or more groups selected from the group consisting of halogen, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10;
R3 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, thiocyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C1-8 alkoxy, C3-8 cycloalkoxy and 3 to 8 membered heterocyclyloxy,
wherein the hydroxy, thiol, cyano, thiocyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C1-8 alkoxy, C3-8 cycloalkoxy and 3 to 8 membered heterocyclyloxy are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0- 8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R4 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —C0-8—C(O)R11, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl, wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —C0-8—C(O)R11, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R5 is selected from the group consisting of hydrogen, C1-8 alkyl and 3 to 8 membered heterocyclyl, wherein the C1-8 alkyl and 3 to 8 membered heterocyclyl are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10;
or,
R4 and R5 together with the amido group to which they are directly attached form a 5 to 7 membered heterocyclyl containing lactam, optionally substituted by one or more substituents selected from the group consisting of halogen, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0- 8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10, provided that the substituents are not hydroxy, acetyl, C1-3 alkyl or di C1-3 alkylamino;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R9 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl, haloC1-8 alkyl, phenyl, p-methylphenyl, amino, mono C1-8 alkylamino, di C1-8 alkylamino and C1-8 alkanoylamino;
R10 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C3-8 cycloalkyl, C5-10 aryl, haloC1-8 alkyl and hydroxyC1-8 alkyl;
R11 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, haloC1-8 alkyl, haloC1-8 alkoxy, hydroxyC1-8 alkyl and hydroxyC1-8 alkoxy;
R12 and R13 are each independently selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C1-8 alkyl substituted by C1-8 alkoxy, C1-8 alkyl substituted by C3-8 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5 to 10 membered heteroaryl and C1-8 alkanoyl;
Y is selected from the group consisting of O and S;
and
r is 0, 1 or 2.

16 more elements

A compound of formula (I-a), a stereoisomer or a pharmaceutically acceptable salt thereof, or a compound of formula (I-b), a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein:
Y is selected from the group consisting of O and S;
A is 5 to 6 membered heterocyclyl or heteroaryl;
B is 5 to 6 membered heterocyclyl, aryl or heteroaryl;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —NR12)—C(O)OR10, wherein the hydroxy, thiol, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10 are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—C(O)OR10, —C0-8—C(O)R10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, N(R12)—C(O)R11 and —NR12)—C(O)OR10;
R4 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —C0-8—C(O)R11, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl, wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —C0-8—C(O)R11, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
Ra is a substituent selected from the group consisting of hydrogen, deuterium, halogen, thiol, cyano, nitro, azido, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10, provided that the substituent is not hydroxy, acetyl, or di C1-3 alkylamino;
Rb is a substituent selected from the group consisting of hydrogen, deuterium, halogen, thiol, cyano, nitro, azido, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10, provided that the substituent is not hydroxy, acetyl, or di C1-3 alkylamino;
R9 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl, haloC1-8 alkyl, phenyl, p-methylphenyl, amino, mono C1-8 alkylamino, di C1-8 alkylamino and C1 alkanoylamino;
R10 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C3-8 cycloalkyl, C5-10 aryl, haloC1-8 alkyl and hydroxyC1-8 alkyl;
R11 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, haloC1-8 alkyl, haloC1-8 alkoxy, hydroxyC1-8 alkyl and hydroxyC1-8 alkoxy;
R12 and R13 are each independently selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C1-8 alkyl substituted by C1-8 alkoxy C1-8 alkyl substituted by C3-8 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5 to 10 membered heteroaryl and C1-8 alkanoyl;
r is 0, 1, or 2;
x is 0, 1, 2, or 3;
and
y is 0, 1, 2, or 3.

13 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein:
R1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10, wherein the hydroxy, thiol, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9,—C0-8—O—R10, —C0-8—C(O)OR10,—C0-8—OR11, C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13—N(R12)—C(O)R11 and —N(R12)—C(O)OR10 are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0- 8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10,
wherein the hydroxy, thiol, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10 are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10;
or, R1 and R2 together with the carbon atom to which they are directly attached form a 5 to 7 membered cycloalkyl or 5 to 7 membered heterocyclyl, optionally substituted by one or more groups selected from the group consisting of halogen, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10;
R3 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, thiocyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C1-8 alkoxy, C3-8 cycloalkoxy and 3 to 8 membered heterocyclyloxy,
wherein the hydroxy, thiol, cyano, thiocyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C1-8 alkoxy, C3-8 cycloalkoxy and 3 to 8 membered heterocyclyloxy are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0- 8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R4 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —C0-8—C(O)R11, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl, wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —C0-8—C(O)R11, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R5 is selected from the group consisting of hydrogen, C1-8 alkyl and 3 to 8 membered heterocyclyl, wherein the C1-8 alkyl and 3 to 8 membered heterocyclyl are each optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11, and —N(R12)—C(O)OR10;
or,
R4 and R5 together with the amido group to which they are directly attached form a 5 to 7 membered heterocyclyl containing lactam, optionally substituted by one or more substituents selected from the group consisting of halogen, thiol, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryloxy, 5 to 10 membered heteroarylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0- 8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10, provided that the substituents are not hydroxy, acetyl, C1-3 alkyl or di C1-3 alkylamino;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, thiol, cyano, nitro, azido, C1-8 alkyl, haloC1-8 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyloxy, 3 to 8 membered heterocyclylthio, —C0-8—S(O)rR9, —C0-8—O—R10, —C0-8—C(O)OR10, —C0-8—C(O)R11, —C0-8—O—C(O)R11, —C0-8—NR12R13, —C0-8—C(O)NR12R13, —N(R12)—C(O)R11 and —N(R12)—C(O)OR10;
R9 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl, haloC1-8 alkyl, phenyl, p-methylphenyl, amino, mono C1-8 alkylamino, di C1-8 alkylamino and C1-8 alkanoylamino;
R10 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C3-8 cycloalkyl, C5-10 aryl, haloC1-8 alkyl and hydroxyC1-8 alkyl;
R11 is selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, haloC1-8 alkyl, haloC1-8 alkoxy, hydroxyC1-8 alkyl and hydroxyC1-8 alkoxy;
R12 and R13 are each independently selected from the group consisting of hydrogen, deuterium, C1-8 alkyl, C1-8 alkoxy substituted by C1-8 alkyl, C1-8 alkyl substituted by C1-8 alkoxy, C1-8 alkyl substituted by C3-8 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5 to 10 membered heteroaryl and C1-8 alkanoyl;
Y is selected from the group consisting of O and S;
and
r is 0, 1 or 2.

16 more elements