GPR35 modulators and uses thereof

Abstract

Disclosed herein are substituted benzofuran, benzothiophene and indole carboxamide compounds, conjugates and pharmaceutical compositions for use as immunotherapeutic agents in the treatment of cancer, such as solid tumors. The disclosed compounds are particularly useful in the treatment of solid tumors derived from mammary gland, brain, kidney, ovary, cervix, pancreas, thyroid, colon, bladder, prostate, liver, stomach or lung.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 328,415, filed April 7, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] There is a need in medicine for the effective treatment of solid tumors with small molecule therapeutics. Summary of the Invention

[0004] The present disclosure generally relates to substituted benzofuran, benzothiophene and indolecarboxamide compounds, conjugates, compounds or salts and pharmaceutical compositions thereof of formula (I) or (II). In certain aspects, the present disclosure provides compounds represented by formula (I):

[0005] (I);

[0006] or a pharmaceutically acceptable salt thereof, wherein:

[0007] X is selected from CR 6 and N;

[0008] Y is selected from CR 12 and N;

[0009] Z is selected from -O-, -S- and -NR 8 -;

[0010] Q does not exist or is selected from:

[0011] -W-, -O-, -OW-, -WO-, -S-, -SW-, -WS-, -NR 10 -W-, -W-NR 10 -、-C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0012] m is selected from 1, 2, 3, 4 and 5;

[0013] R 1 Selected from:

[0014] hydrogen;

[0015] C 1-6 Alkyl, C2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0016] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0017] R 2 Selected from:

[0018] hydrogen;

[0019] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN;

[0020] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0021] C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0022] R 3 Selected from:

[0023] C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0024] If Q is -W-, then R 3 Additionally selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN; and

[0025] where R 3 Not pyrimidine;

[0026] Each R 4 Independently selected from:

[0027] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0028] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0029] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0030] R 5 Selected from:

[0031] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0032] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0033] R 6 Selected from:

[0034] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0035] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0036] Each R 7 Independently selected from:

[0037] hydrogen;

[0038] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0039] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0040] R 8 Selected from:

[0041] hydrogen;

[0042] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0043] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0044] Each R 9 Independently selected from:

[0045] Halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0046] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0047] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0048] .

[0049] Each R 10 Independently selected from:

[0050] hydrogen; and

[0051] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0052] C 3-10Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 alkyl halide;

[0053] W is selected from:

[0054] C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings;

[0055] R 12 Selected from:

[0056] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0057] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0058] If Z is NH, then R 4 Not NH2, and

[0059] If Z is O or S, R 4 Yes-OR 3 , and R 5 If it is H, then WR 3 Also selected from C 1-6 Alkyl, C 2-6Alkenyl and C 2-6 Alkynyl.

[0060] In certain aspects, the present disclosure provides compounds represented by formula (II):

[0061] (II)

[0062] or a pharmaceutically acceptable salt, wherein:

[0063] X1, X2, X3 and X4 are each independently selected from CQR 3 , CR 6 and N;

[0064] Z is selected from -O-, -S- and -NR 8 -;

[0065] Q does not exist or is selected from:

[0066] -W-, -O-, -OW-, -WO-, -S-, -SW-, -WS-, -NR 10 -W-、-W-NR 10 -、-C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0067] m is selected from 1, 2, 3, 4 and 5;

[0068] R 1 Selected from:

[0069] hydrogen;

[0070] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0071] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0072] R 2 Selected from:

[0073] hydrogen;

[0074] Halogen, -OR 10 、-SR 10 、-N(R 10)2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0075] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0076] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0077] R 3 Selected from:

[0078] hydrogen;

[0079] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0080] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 replace;

[0081] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9Replacement; and

[0082] where R 3 Not pyrimidine;

[0083] Each R 4 Independently selected from:

[0084] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0085] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R9 Replacement; and

[0086] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0087] Each R 6 Independently selected from:

[0088] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0089] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0090] Each R 7 Independently selected from:

[0091] hydrogen;

[0092] C 1-6 Alkyl, C 2-6 Alkenyl and C2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0093] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0094] R 8 Selected from:

[0095] hydrogen;

[0096] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0097] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0098] Each R 9 Independently selected from:

[0099] Halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0100] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10)2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0101] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0102] ;

[0103] Each R 10 Independently selected from:

[0104] hydrogen; and

[0105] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0106] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 alkyl halide;

[0107] W is selected from:

[0108] C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0109] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formula (I) and (II), or a pharmaceutically acceptable excipient. DETAILED DESCRIPTION

[0110] Disclosed herein are substituted benzofuran, benzothiophene, and indolecarboxamide compounds, conjugates, and pharmaceutical compositions for use in treating cancers such as solid tumors. In some embodiments, the compounds disclosed herein are modulators of G protein-coupled receptor 35 (GPR35). In some embodiments, the disclosed compounds inhibit GPR35 expressed in immune cells and promote anti-tumor immunity.

[0111] definition

[0112] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0113] As used in the specification and in the claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0114] When used in conjunction with a chemical moiety such as an alkyl, alkenyl, or alkynyl group, the term "C x-y ” or “C x -C y " is meant to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups containing 1 to 6 carbon atoms. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having from x to y carbons in the alkylene chain. For example, –C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which is optionally substituted.

[0115] The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having from x to y carbons in the alkenylene chain. For example, –C 2-6 Alkenylene - may be selected from ethenylene, propenylene, butenylene, pentenylene and hexenylene, any of which is optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. Term - C x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain having from x to y carbons in the alkenylene chain. For example, –C 2-6 Alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which is optionally substituted. The alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0116] "Alkylene" refers to a straight divalent hydrocarbon chain connecting the rest of the molecule to a free radical, such as methylene, ethylene, propylene, butylene, etc., which is composed only of carbon and hydrogen, does not contain unsaturation, and preferably has one to twelve carbon atoms. The alkylene chain is attached to the rest of the molecule by a single bond and is attached to the free radical by a single bond. The alkylene chain is attached to the rest of the molecule and to the free radical through a terminal carbon. In other embodiments, the alkylene group comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless specifically stated otherwise in the specification, the alkylene chain is optionally substituted with one or more substituents, such as those described herein.

[0117] "Alkenylene" refers to a straight divalent hydrocarbon chain connecting the rest of the molecule to a free radical, the straight divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule by a single bond and to the free radical by a single bond. The alkenylene chain is attached to the rest of the molecule and to the free radical by a terminal carbon. In other embodiments, the alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, the alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, the alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, the alkenylene comprises two carbon atoms (i.e., C2 alkenylene). In other embodiments, the alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, the alkenylene group contains three to five carbon atoms (ie, C3-C5 alkenylene). Unless stated otherwise specifically in the specification, the alkenylene chain is optionally substituted with one or more substituents, such as those described herein.

[0118] "Alkynylidene" refers to a straight divalent hydrocarbon chain connecting the rest of the molecule to a free radical, the straight divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule by a single bond and to the free radical by a single bond. The attachment point of the alkynylene to the rest of the molecule and to the free radical is respectively through a terminal carbon. In other embodiments, the alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted with one or more substituents such as those described herein.

[0119] As used herein, the term "carbocycle" refers to a saturated, unsaturated, and or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3- to 10-membered monocycles, 5- to 12-membered bicyclic rings, spirobicyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). When valence permits, the bicyclic carbocycle includes any combination of saturated, unsaturated, and aromatic bicyclic rings. Bicyclic carbocycles also include spirobicyclic rings, such as spiropentanes. Bicyclic carbocycles include any combination of ring sizes, such as 3-3 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl.

[0120] The term "aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to Huckel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (e.g., in "aralkyl") is intended to include aryl groups that are optionally substituted with one or more substituents, such as those described herein.

[0121] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl can include monocycles and polycycles, such as 3- to 10-membered monocycles, 5- to 12-membered bicycles, spirobicycles, and 5- to 12-membered bridged rings. In certain embodiments, cycloalkyl comprises three to ten carbon atoms. In other embodiments, cycloalkyl comprises five to seven carbon atoms. Cycloalkyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, spiropentanes, norbornyl (i.e., bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, etc. Unless otherwise specifically stated in the specification, the term "cycloalkyl" means a cycloalkyl group optionally substituted with one or more substituents, such as those described herein.

[0122] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and at least one double bond is present between the two ring carbons. The cycloalkenyl group may include monocycles and polycycles, such as 3 to 10-membered monocycles, 6 to 12-membered bicycles, and 5 to 12-membered bridged rings. In other embodiments, the cycloalkenyl group comprises five to seven carbon atoms. The cycloalkenyl group may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, the term "cycloalkenyl" is intended to include cycloalkenyl groups optionally substituted by one or more substituents, such as those described herein.

[0123] The term "halo" or alternatively "halogen" or "halide" refers to fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluorine, chlorine, or bromine.

[0124] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

[0125] As used herein, the term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocycles, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. When valence permits, bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings. In an exemplary embodiment, an aromatic ring, such as a pyridyl group, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. Bicyclic heterocycles also include spiro bicyclic rings, such as 2-oxa-6-azaspiro[3.3]heptane. The term "heterocycle" is meant to encompass "heteroaryl," "heterocycloalkyl," and "heterocycloalkenyl."

[0126] The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to Huckel's theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom of the ring. Examples of heteroaryls include, but are not limited to, aza-, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzo oxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, benzo[b][1,4] Oxazine, 1,4-benzodioxane, benzonaphthofuranyl, benzo Azolyl, benzodioxolyl, benzodioxolyl indole, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5-d]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptyl pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isothiazinyl, imidazolyl, indole, indolyl, isoindolyl, isoquinolinyl, indolizinyl, isothiazinyl, imidazolyl, indolyl ... oxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoline linyl, quinolyl, isoquinolyl, tetrahydroquinolyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).

[0127] The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl groups may include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, spirobicyclic rings, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. Where valence permits, the heterocycloalkyl group is attached to the rest of the molecule through any atom of the heterocycloalkyl group, such as any carbon or nitrogen atom of the heterocycloalkyl group. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazoli ... Oxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl groups as defined above that are optionally substituted with one or more substituents, such as those described herein.

[0128] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom and at least one double bond between two ring carbons. Heterocycloalkenyl groups do not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl groups can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, the heterocycloalkenyl group contains five to seven ring atoms. The heterocycloalkenyl group can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, Oxazoline (dihydro azole), iso Oxazoline (dihydroisoxazolidine azole), thiazoline (dihydrothiazole), isothiazolinone (dihydroisothiazole), Diazoline (dihydro Thiadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydro ... dioxine, dihydrodioxine ene, Oxazine, dihydro Unless stated otherwise specifically in the specification, the term "heterocyclenyl" is meant to include heterocyclenyl groups optionally substituted with one or more substituents, such as those described herein.

[0129] The term "substituted" refers to a portion having a substituent that replaces the hydrogen on one or more carbons or replaceable heteroatoms, such as the NH or NH2 of a compound. It should be understood that "substituted" or "substituted by ... " include implicit conditions, i.e., such substitutions conform to the allowed valences of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformation (such as by rearrangement, cyclization, elimination, etc.). In certain embodiments, substitution refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thio group. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, permissible substituents can be one or more and the same or different.

[0130] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b-N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b-S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a It may be optionally substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a(where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0131] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both "=0" and "(0)". Double bonds to nitrogen atoms are represented as both "=NR" and "(NR)". Double bonds to sulfur atoms are represented as both "=S" and "(S)".

[0132] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to routes of administration other than enteral and topical administration (usually by injection), and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0133] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0134] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltose. Oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0135] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0136] Compound

[0137] The following is a discussion of compounds and salts thereof that can be used in the methods of the present disclosure. In certain embodiments, the compounds and salts are as described in formula (I)

[0138] In one aspect, disclosed herein are compounds represented by formula (I):

[0139] (I);

[0140] or a pharmaceutically acceptable salt thereof, wherein:

[0141] X is selected from CR 6 and N;

[0142] Y is selected from CR 12 and N;

[0143] Z is selected from -O-, -S- and -NR 8 -;

[0144] Q does not exist or is selected from:

[0145] - W-, -O-, -O W-, - WO-, -S-, -S W-, - WS-, -NR 10 -W-、-W-NR 10 -、C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0146] m is selected from 1, 2, 3, 4 and 5;

[0147] R 1 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0148] R 2 Selected from:

[0149] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10)2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN;

[0150] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted;

[0151] R 3 Selected from C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted;

[0152] Each R 4 Independently selected from:

[0153] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0154] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0155] R 5 and R 6 are each independently selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and optionally substituted C 1-6alkyl;

[0156] Each R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0157] R 8 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0158] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0159] W is selected from C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 an alkynylene group, each of which is optionally substituted;

[0160] R 12 Selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0161] If Z is NH, then R 4 Not NH2, and

[0162] If Z is O or S, R 4 Yes-OR 3 , and R 5 If it is H, then WR 3 Also selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0163] In one aspect, disclosed herein are compounds represented by formula (I):

[0164] (I);

[0165] or a pharmaceutically acceptable salt thereof, wherein:

[0166] X is selected from CR 6 and N;

[0167] Y is selected from CR 12 and N;

[0168] Z is selected from -O-, -S- and -NR 8 -;

[0169] Q does not exist or is selected from:

[0170] - W-, -O-, -O W-, - WO-, -S-, -S W-, - WS-, -NR 10 -W-、-W-NR 10 -、C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0171] m is selected from 1, 2, 3, 4 and 5;

[0172] R 1 Selected from:

[0173] hydrogen;

[0174] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0175] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0176] R 2 Selected from:

[0177] hydrogen;

[0178] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10)C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN;

[0179] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0180] C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0181] R 3 Selected from:

[0182] C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 Replacement; and

[0183] If Q is -W-, then R 3Additionally selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN;

[0184] Each R 4 Independently selected from:

[0185] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0186] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0187] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0188] R 5 Selected from:

[0189] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10)2, -NO2 and -CN; and

[0190] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0191] R 6 Selected from:

[0192] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0193] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0194] Each R 7 Independently selected from:

[0195] hydrogen;

[0196] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0197] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0198] R 8 Selected from:

[0199] hydrogen;

[0200] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10)2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0201] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0202] Each R 9 Independently selected from:

[0203] Halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0204] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0205] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0206] .

[0207] Each R 10 Independently selected from:

[0208] hydrogen;

[0209] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0210] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 alkyl halide;

[0211] W is selected from:

[0212] C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings;

[0213] R 12 Selected from:

[0214] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0215] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0216] If Z is NH, then R 4 Not NH2, and

[0217] If Z is O or S, R 4 Yes-OR 3 , and R 5 If it is H, then WR 3 Also selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0218] In some embodiments, for the compound or salt of Formula (I), X is selected from CR 6 and N. In some embodiments, X is selected from CR 6 In some embodiments, X is selected from N. In some embodiments, X is CR 6 .

[0219] In some embodiments, for the compound or salt of Formula (I), Y is selected from CR 12 and N. In some embodiments, Y is selected from CR 12 In some embodiments, Y is selected from N. In some embodiments, Y is CR 12 .

[0220] In some embodiments, for compounds or salts of Formula (I), Z is selected from -O-, -S-, and -NR8 -. In some embodiments, Z is selected from -O- and -S-. In some embodiments, Z is -O-.

[0221] In some embodiments, for compounds or salts of Formula (I), Q is absent or selected from -W-, -O-, -OW-, -WO-, -S-, -SW-, -WS-, -NR 10 W-、-WNR 10 -、C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2-, and -P(O)2O-; In some embodiments, Q is absent or selected from -W-, -O-, -OW-, and -WO-. In some embodiments, Q is absent or is -O-. In some embodiments, Q is absent.

[0222] In some embodiments, for the compound or salt of Formula (I), m is selected from 1, 2, 3, 4, and 5. In some embodiments, m is selected from 1 and 2. In some embodiments, m is 1.

[0223] In some embodiments, for the compound or salt of Formula (I), R 1 Selected from hydrogen, C 1-6 Alkyl C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 1 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 1 Selected from hydrogen and C 1-3 alkyl.

[0224] In some embodiments, for the compound or salt of Formula (I), R 2 Selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 2 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 2 Selected from: hydrogen; halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 and C6 carbocyclic rings and 5- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen. 2 Selected from: hydrogen; halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, R 2 Selected from hydrogen, halogen and C 1-3 alkyl.

[0225] In some embodiments, for the compound or salt of Formula (I), R 3 It is C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 substituted; and wherein if Q is -W-, then R 3 Additionally selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN. In some embodiments, R 3 is C optionally substituted by one or more substituents independently selected from the following 3-6 Carbocyclic ring: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a C6 carbocycle optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3is a phenyl group optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0226] In some embodiments, for the compound or salt of Formula (I), R 3 is a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 5- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10)C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, for the compound or salt of formula (I), R3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, =O, =S, =NH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) and C 1-6 In some embodiments, R 3 Is selected from different Azoles, Azoles, thiadiazoles, 5-membered heterocyclic rings of diazole, pyrazole, tetrazole and thiazole, any of which is optionally replaced by one or more R 9 In some embodiments, R 3 is selected from tetrazole and In some embodiments, R 3 is a 5-membered heterocyclic ring selected from the group consisting of isothiazol-3-ol, isothiazol-3-ol, Oxazole-3-ol, squaric acid, thiazolidinedione, Oxazolidinedione, tetrazole, 1,2,4- 1,2,4-thiadiazole-5(4H)-one, 1,2,4- oxadiazole-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5- Thiadiazole 2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one and tetramic acid, any of which is optionally replaced by one or more R 9 In some embodiments, R 3 is selected from optionally one or more R 9 Replaced and In some embodiments, R 3 Is selected from In some embodiments, R 3 Selected from 、 、 、 、 、 、 、 、 and In some embodiments, Q is -O- and R 3 It is tetrazole.

[0227] In some embodiments, for compounds or salts of Formula (I), Q is -W-; R 3 Additionally selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2, -CN; and -W- is C optionally substituted by one or more substituents independently selected from the following 1-6Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, Q is -W-; and R 3 Additionally selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl), and -W- is C optionally substituted with one or more substituents independently selected from 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, Q is -W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 and -W- is C1 alkylene optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, Q is -W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and -W- is -C(=O)-.

[0228] In some embodiments, R 3 In some embodiments, R3 In some embodiments, R 3 In some embodiments, R 3 no.

[0229] In some embodiments, for the compound or salt of Formula (I), R 4 Selected from halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 4 Selected from: halogen, -OR 7 、-SR 7 、-N(R 7 )2, -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6Alkyl)2 and -NH(C 1-6 In some embodiments, each R 4 Independently selected from -OR 7 、-SR 7 and -N(R 7 )2. In some embodiments, m is 1 and R 4 Yes-OR 7 .

[0230] In some embodiments, for compounds or salts of Formula (I), each R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, each R 7 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, each R 7 Selected from: C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, each R 7 Selected from: C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -CN and optionally one or more R 9 Substituted C 1-6 In some embodiments, R 7 are independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6Alkyl)2 and -NH(C 1-6 In some embodiments, R 7 are independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 6-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 7 Selected from C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0231] In some embodiments, for the compound or salt of Formula (I), R 5 Selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN. In some embodiments, R 5 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 5 It's hydrogen.

[0232] In some embodiments, for the compound or salt of Formula (I), R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 6 Selected from hydrogen and halogen.

[0233] In some embodiments, for compounds or salts of Formula (I), Z is -NR 8 -. In some embodiments, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 8 In some embodiments, R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 In some embodiments, R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10In some embodiments, R 8 is selected from C optionally substituted by one or more substituents independently selected from 1-6 Alkyl: halogen, -CN, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 8 Selected from C 1-6 In some embodiments, R 8 is selected from C optionally substituted by one or more substituents independently selected from 3-10 :Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 8 is selected from C optionally substituted by one or more substituents independently selected from 3-10 Carbocyclic ring: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 8is selected from a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 8 It's hydrogen.

[0234] In some embodiments, for compounds or salts of Formula (I), each R 9 Selected from halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10)2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R10 、-NO2、=O、=S、=N(R 10 ) and -CN; and In some embodiments, each R 9 Selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and C optionally substituted by one or more substituents independently selected from the following 1-3 Alkyl: -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0235] In some embodiments, for compounds or salts of Formula (I), each R 10 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 In some embodiments, each R 10 hydrogen.

[0236] In some embodiments, for compounds or salts of Formula (I), W is C optionally substituted with one or more substituents independently selected from the group consisting of 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, W is optionally independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 In some embodiments, W is independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 5-membered heterocyclic rings substituted with C 1-6 In some embodiments, W is independently selected from C 3-6 One or more substituents of the carbon ring substituted C 1-6 In some embodiments, for the compound or salt of formula (I), wherein W is selected from 、 、 、 、 and In some embodiments, W is C 1-6 Alkylene.

[0237] In some embodiments, for the compound or salt of Formula (I), R 12 Selected from: hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN. In some embodiments, R 12 Selected from hydrogen and halogen.

[0238] In some embodiments, the compound or salt of formula (I) is selected from:

[0239] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0240] and their combinations.

[0241] In some embodiments, the compound or salt of formula (I) is selected from:

[0242] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

[0243] In some embodiments, the compound or salt of formula (I) is selected from:

[0244] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

[0245] The compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0246] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficiently acidic, sufficiently basic, or both functional groups can react with any of a variety of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those having quaternary nitrogen, can form salts with appropriate counterions, for example, halides, such as bromides, chlorides, or fluorides, particularly bromides.

[0247] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms in some cases. The compounds provided herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. Stereoisomers may be separated by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc. 1981, incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[0248] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated form or in solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0249] In certain embodiments, the salt of compound or compound can be a prodrug, for example, wherein the hydroxyl group in the parent compound exists as an ester or carbonate, or the carboxylic acid present in the parent compound exists as an ester. The term "prodrug" is intended to encompass compounds that are converted into the disclosed medicament under physiological conditions. A method for preparing a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to display the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as a specific target cell in a host animal. For example, esters or carbonates (for example, esters of alcohol or carboxylic acid or esters of carbonate and phosphonic acid) are preferred prodrugs of the present disclosure.

[0250] Prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce a compound as described herein) are included within the scope of the claims. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0251] Prodrugs are generally useful because, in some cases, they may be easier to administer than the parent drug. For example, they may become bioavailable by oral administration, whereas the parent drug is not. Relative to the parent drug, prodrugs can help enhance the cell permeability of the compound. Compared to the parent drug, prodrugs can also have improved solubility in pharmaceutical compositions. Prodrugs can be designed as reversible drug derivatives, used as modulators to enhance drug transport to site-specific tissues or increase drug retention inside cells.

[0252] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Seminar Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which disclosures are incorporated herein. According to another embodiment, the present disclosure provides methods for producing the above-mentioned compounds. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0253] Synthetic chemistry transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larnock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0254] Sexual therapy applications

[0255] The methods of administration of the compounds or salts of Formula (I) or (II) discussed herein can be used to treat cancer.

[0256] In one aspect, disclosed herein is a compound represented by formula (II):

[0257] (II);

[0258] or a pharmaceutically acceptable salt thereof, wherein:

[0259] X1, X2, X3 and X4 are each independently selected from CQR 3 , CR 6 and N;

[0260] Z is selected from -O-, -S- and -NR 8 -;

[0261] Q does not exist or is selected from:

[0262] - W-, -O-, -O W-, - WO-, -S-, -S W-, - WS-, -NR 10 -W-、-W-NR 10 -、C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0263] m is selected from 1, 2, 3, 4 and 5;

[0264] R 1 Selected from:

[0265] Hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0266] R 2 Selected from:

[0267] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0268] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0269] R 3 Selected from C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0270] Each R 4 Independently selected from:

[0271] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0272] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, C 3-10carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0273] Each R 6 Independently selected from:

[0274] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and optionally substituted C 1-6 alkyl;

[0275] Each R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0276] R 8 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0277] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted;

[0278] W is selected from C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 alkynylene, each of which is optionally substituted.

[0279] In one aspect, disclosed herein is a compound represented by formula (II):

[0280] (II);

[0281] or a pharmaceutically acceptable salt thereof, wherein:

[0282] X1, X2, X3 and X4 are each independently selected from CQR 3 , CR 6 and N;

[0283] Z is selected from -O-, -S- and -NR 8 -;

[0284] Q does not exist or is selected from:

[0285] - W-, -O-, -O W-, - WO-, -S-, -S W-, - WS-, -NR 10 -W-、-W-NR 10 -、C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0286] m is selected from 1, 2, 3, 4 and 5;

[0287] R 1 Selected from:

[0288] hydrogen;

[0289] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0290] C 3-10carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0291] R 2 Selected from:

[0292] hydrogen;

[0293] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0294] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0295] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0296] R 3 Selected from:

[0297] hydrogen;

[0298] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0299] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0300] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0301] Each R 4 Independently selected from:

[0302] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0303] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0304] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0305] Each R 6 Independently selected from:

[0306] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0307] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0308] Each R 7 Independently selected from:

[0309] hydrogen;

[0310] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0311] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0312] R 8 Selected from:

[0313] hydrogen;

[0314] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0315] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0316] Each R 9 Independently selected from:

[0317] Halogen, -R 10 、-OR 10 、-SR10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0318] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0319] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0320] ;

[0321] Each R 10 Independently selected from:

[0322] hydrogen; and

[0323] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0324] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 alkyl halide;

[0325] W is selected from:

[0326] C1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0327] In some embodiments, for the compound or salt of formula (II), X1, X2, X3 and X4 are each independently selected from CQR 3 , CR 6 and N. In some embodiments, X1, X2 and X3 are each independently CR 6 , and X4 is CQR 3 In some embodiments, X1, X2 and X4 are each independently CR 6 , and X3 is CQR 3 In some embodiments, X1, X2, X3 or X4 is N. In some embodiments, none of X1, X2, X3 or X4 is N.

[0328] In some embodiments, for the compound or salt of Formula (II), Z is selected from -O-, -S-, and -NR 8 -. In some embodiments, if Z is NH, then R 4 In some embodiments, Z is selected from -O- and -S-. In some embodiments, Z is -O-. In some embodiments, if Z is O or S, R 4 Yes-OR 3 , and R 5 If it is H, then WR 3 Also selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0329] In some embodiments, for compounds or salts of formula (II), Q is absent or selected from -W-, -O-, -OW-, -WO-, -S-, -SW-, -WS-, -NR 10 W-、-WNR 10 -、C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2-, and -P(O)2O-. In some embodiments, Q is absent or selected from -W-, -O-, -OW-, and -WO-. In some embodiments, Q is absent or is -O-. In some embodiments, Q is absent.

[0330] In some embodiments, for the compound or salt of Formula (II), m is selected from 1, 2, 3, 4, and 5. In some embodiments, m is selected from 1 and 2. In some embodiments, m is 1.

[0331] In certain embodiments, for the compound or salt of Formula (II), each R 1 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 1 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 1 Selected from hydrogen and C 1-3 alkyl.

[0332] In certain embodiments, for compounds or salts of formula (II), R 2 Selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 2 Selected from: hydrogen; halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 2 Selected from: hydrogen; halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 and C6 carbocyclic rings and 5- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen. 2 Selected from hydrogen; halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, R 2 Selected from hydrogen, halogen and C 1-3 alkyl.

[0333] In certain embodiments, for the compound or salt of Formula (II), hydrogen; halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10) and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0334] In certain embodiments, for compounds or salts of formula (II), R 3 is C optionally substituted by one or more substituents independently selected from the following 3-6 Carbocyclic ring: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a C6 carbocycle optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0335] In certain embodiments, for compounds or salts of formula (II), R 3 is a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3is a 5- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0336] In certain embodiments, for compounds or salts of formula (II), R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, =O, =S, =NH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) and C 1-6In some embodiments, R 3 Is selected from different Azoles, Azoles, thiadiazoles, 5-membered heterocyclic rings of diazole, pyrazole, tetrazole and thiazole, any of which is optionally replaced by one or more R 9 In some embodiments, R3 is selected from tetrazole and In some embodiments, R 3 is a 5-membered heterocyclic ring selected from the group consisting of isothiazol-3-ol, isothiazol-3-ol, Oxazole-3-ol, squaric acid, thiazolidinedione, Oxazolidinedione, tetrazole, 1,2,4- 1,2,4-thiadiazole-5(4H)-one, 1,2,4- oxadiazole-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5- Thiadiazole 2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one and tetramic acid, any of which is optionally replaced by one or more R 9 In some embodiments, R 3 Is selected from and In some embodiments, R 3 Selected from 、 、 、 、 、 、 、 、 and In some embodiments, Q is -O- and R 3 It is tetrazole.

[0337] In certain embodiments, for compounds or salts of Formula (II), Q is -W-; R 3 Additionally selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10)2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2, -CN; and -W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, Q is -W-; and R 3 Additionally selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl), and -W- is C optionally substituted with one or more substituents independently selected from 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, Q is -W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 and -W- is C1 alkylene optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10In some embodiments, Q is -W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and -W- is -C(=O)-.

[0338] In certain embodiments, for compounds or salts of formula (II), halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, each R 4 Independently selected from: halogen, -OR 7 、-SR 7 、-N(R 7 )2, -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 4 Independently selected from -OR 7 、-SR 7 and -N(R 7 )2. In some embodiments, m is 1 and R 4 Yes-OR 7 .

[0339] In certain embodiments, for the compound or salt of Formula (II), each R 7 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, each R 7 Selected from: C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, each R 7 Selected from: C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 7 Selected from: optionally independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -CN and optionally one or more R 9 Substituted C 1-6 In some embodiments, R 7 are independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 7 are independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 6-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl). R 7 Selected from C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0340] In certain embodiments, for compounds or salts of formula (II), R 6 Selected from: hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN. In some embodiments, R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 6 Selected from hydrogen and halogen.

[0341] In certain embodiments, for compounds or salts of Formula (II), Z is -NR 8 -. In some embodiments, R 8 Selected from hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 8 In some embodiments, R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 In some embodiments, R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, R 8 is selected from C optionally substituted by one or more substituents independently selected from 1-6Alkyl: halogen, -CN, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 8 Selected from C 1-6 In some embodiments, R 8 is selected from C optionally substituted by one or more substituents independently selected from 3-10 Carbocyclic ring: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 8 is selected from C optionally substituted by one or more substituents independently selected from 3-10 Carbocyclic ring: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 In some embodiments, R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, R 8 It's hydrogen.

[0342] In certain embodiments, for the compound or salt of Formula (II), each R 9 Selected from: halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and In some embodiments, each R 9Selected from: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and C optionally substituted by one or more substituents independently selected from the following 1-3 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0343] In certain embodiments, for the compound or salt of Formula (II), each R 10 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 In some embodiments, each R 10 It's hydrogen.

[0344] In certain embodiments, for compounds or salts of Formula (II), W is C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 Alkyl), C 3-10 In some embodiments, W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 In some embodiments, W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 In some embodiments, W is optionally independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 In some embodiments, W is independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 5-membered heterocyclic rings substituted with C 1-6 In some embodiments, W is independently selected from C 3-6 One or more substituents of the carbon ring substituted C 1-6 In some embodiments, W is selected from 、 、 、 、 and In some embodiments, W is C 1-6 Alkylene.

[0345] The methods of administering the compounds or salts of Formula (I) or (II) discussed herein can be used to treat cancer. In some embodiments, the treatment is an immunotherapy treatment. In certain embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a sarcoma, carcinoma, or lymphoma. In some embodiments, the solid tumor is in the breast, brain, kidney, ovary, cervix, pancreas, thyroid, colon, bladder, prostate, liver, stomach, or lung.

[0346] In some embodiments, the compounds or salts of formula (I) or (II) discussed herein can be used to modulate G protein coupled receptor 35 (GPR35). In some embodiments, the compounds disclosed herein inhibit GPR35 expressed in immune cells and promote anti-tumor immunity. In some embodiments, the compounds disclosed herein inhibit GPR35 expressed in tumor cells and tumor cell growth. Such compounds are effective alone or in combination with other therapeutic agents in the treatment of solid tumors.

[0347] pharmaceutical preparations

[0348] The compositions and methods described herein can be considered useful as pharmaceutical compositions for administration to subjects in need thereof. The pharmaceutical compositions can comprise at least a compound or salt of formula (I) or (II) as described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents and / or thickening agents.

[0349] The pharmaceutical composition comprising the compound or salt of formula (I) or (II) can be formulated using one or more physiologically acceptable carriers (comprising excipients and adjuvants). The formulation can be changed according to the selected route of administration. The pharmaceutical composition comprising the compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or embedding the conjugate. The pharmaceutical composition can also include a compound, salt or conjugate in the form of a free base or a pharmaceutically acceptable salt.

[0350] The method for preparing the compound or salt of formula (I) or (II) can include preparing any compound, salt or conjugate together with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semisolid or liquid compositions.Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, solid compositions also contain nontoxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, compound, salt or conjugate can be lyophilized or in powder form, for reconstructing with a suitable vehicle (for example, sterile pyrogen-free water) before use.

[0351] The pharmaceutical composition comprising a compound or salt of formula (I) or (II) may comprise at least one active ingredient (e.g., a compound, salt, or conjugate and another pharmaceutical agent). The active ingredient may be embedded in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, embedded in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or embedded in a coarse emulsion.

[0352] The compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0353] The compositions described herein are administered to a subject via a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. The compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0354] Compositions comprising a compound or salt of formula (I) or (II) can be formulated for use as an injection. Non-limiting examples of preparations for injection may include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. The suspension may also contain suitable stabilizers. The injection may be formulated for push injection or continuous infusion. Alternatively, the composition may be lyophilized or in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0355] For parenteral administration, the compound or salt of formula (I) or (II) can be formulated into a unit dose injectable form (e.g., solution, suspension, emulsion) in combination with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic and non-therapeutic. Vehicles can be water, saline, Ringer's solution, glucose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. Vehicles can contain a small amount of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0356] In one embodiment, the present invention relates to a method and formula (I) or composition (II) for preparing a pharmaceutical composition suitable for intramuscular, subcutaneous or intravenous injection. In one aspect, the preparation suitable for intramuscular, subcutaneous or intravenous injection includes physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and the sterile powder for reconstitution into sterile injectable solution or dispersion. The example of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles includes water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, Cremophor (cremophor) etc.), vegetable oils and organic esters (such as ethyl oleate). In some aspects of the present disclosure, the preparation suitable for subcutaneous injection contains additives, such as preservatives, wetting agents, emulsifiers and dispersants. The extended absorption of injectable drug forms can be achieved by using the medicament (such as aluminum monostearate and gelatin) that delays absorption.

[0357] For intravenous injection, the compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0358] Parenteral injection can include push injection or continuous infusion. Injection preparations can be presented in unit doses, for example, in ampoules or in multidose containers, and are added with preservatives. Pharmaceutical compositions as described herein can be in the form of sterile suspensions, solutions or emulsions suitable for parenteral injection in oily or aqueous vehicles, and can contain preparatons, such as suspending agents, stabilizers and / or dispersants. In one aspect, the active ingredient is in powder form for construction with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0359] In certain aspects of the present disclosure, delivery systems for pharmaceutical compounds such as, for example, liposomes and emulsions can be employed. In certain aspects of the present disclosure, the compositions provided herein can further comprise a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0360] In one embodiment, the present invention relates to methods and compositions of formula (I) or (II) for oral delivery to a subject in need thereof. In one embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the oral cavity or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the stomach and / or intestine.

[0361] In one embodiment, the composition of formula (I) or (II) is provided in a modified release dosage form. Suitable vehicles for modified release dosages include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multi-particulate devices, and combinations thereof. The composition may also include non-controlled release excipients.

[0362] In another embodiment, the composition of formula (I) or (II) is provided in an enteric-coated dosage form. These enteric-coated dosage forms can also include non-controlled release excipients. In one embodiment, the composition is in the form of enteric-coated granules, as a controlled-release capsule for oral administration. The composition can further include cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric-coated pills, as a controlled-release capsule for oral administration. The composition can further include glyceryl monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, C-type methacrylic acid copolymer, polysorbate 80, sugar spheres, talcum or triethyl citrate.

[0363] In another embodiment, the composition of formula (I) or (II) is an enteric-coated controlled-release tablet for oral administration. The composition may further comprise carnauba wax, crospovidone, diacetylated monoglycerides, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide or yellow iron oxide.

[0364] The sustained-release preparation of the compound or salt comprising formula (I) or (II) can also be prepared. The example of sustained-release preparation can include the semipermeable matrix of the solid hydrophobic polymer that can contain compound, salt or conjugate, and these matrices can be in the form of shaped articles (such as film or microcapsule). The example of sustained-release matrix can include polyester, hydrogel (for example, poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactide, L-glutamic acid and γ-ethyl-L-glutamate copolymer, nondegradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer, such as LUPRON DEPO TM (ie, injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0365] Pharmaceutical formulations comprising a compound or salt of formula (I) or (II) can be prepared for storage by mixing the compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient and / or stabilizer. The formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients and / or stabilizers can be non-toxic to the recipient at the dosage and concentration used. Acceptable carriers, excipients and / or stabilizers can include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycol.

[0366] In another embodiment, the composition of formula (I) or (II) may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0367] In another embodiment, the composition of formula (I) or (II) is provided in an effervescent dosage form. These effervescent dosage forms may also contain non-controlling release excipients.

[0368] In another embodiment, the composition of formula (I) or (II) can be provided in a dosage form having at least one component that promotes immediate release of the active agent and at least one component that promotes controlled release of the active agent. In another embodiment, the dosage form can provide discontinuous release of the compound in the form of at least two consecutive pulses, the pulses being separated in time by 0.1 to 24 hours. The composition can include one or more controlled-release and non-controlled-release excipients, such as those excipients suitable for rupturable semipermeable membranes and as swellable substances.

[0369] In another embodiment, the composition of formula (I) or (II) is provided in a dosage form for oral administration to a subject, comprising one or more pharmaceutically acceptable excipients or carriers encapsulated in an intermediate reaction layer comprising a gastro-resistant polymer layered material partially neutralized with a base and having cation exchange capacity and a gastro-resistant outer layer.

[0370] In some embodiments, the compositions of formula (I) or (II) provided herein can be unit dosage form or multiple dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable for administration to a human or non-human animal subject and individually packaged. Each unit dose may contain a predetermined amount of active ingredient combined with a desired pharmaceutical carrier or excipient sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, unit dosage forms can be administered in part or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, which can be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, tablet or capsule bottles, or pint or gallon bottles. In another embodiment, multiple dosage forms comprise different pharmaceutically active agents.

[0371] In some embodiments, the composition of formula (I) or (II) can also be formulated into a modified release dosage form, including immediate release dosage form, delayed release dosage form, long-term release dosage form, extended release dosage form, sustained release dosage form, pulsed release dosage form, controlled release dosage form, extended release dosage form, accelerated release dosage form and rapid release dosage form, targeted release dosage form, programmed release dosage form and gastric retention dosage form. These dosage forms can be prepared according to known methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126, the entire contents of which are incorporated herein by reference).

[0372] Combination therapy

[0373] Combination therapy is also contemplated herein, such as co-administration of the disclosed compounds and additional active agents as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions produced by the combination of therapeutic agents. The combined administration of these therapeutic agents is typically carried out over a limited time period (typically hours, days, weeks, months, or years, depending on the selected combination). Combination therapy is intended to include administering multiple therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, as well as administering these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0374] Substantially simultaneous administration is achieved, for example, by administering to the subject a single formulation or composition (e.g., a tablet or capsule of each therapeutic agent at a fixed ratio) or multiple single formulations (e.g., capsules) for each therapeutic agent. The sequential or substantially simultaneous administration of each therapeutic agent is achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption by mucosal tissue. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0375] The components of the combination are administered to the patient simultaneously or sequentially. It will be understood that the components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially.

[0376] Example

[0377] Having now generally described the invention, the invention will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0378] In some embodiments, compound 5 described herein is prepared as described in Scheme A.

[0379] Plan A

[0380]

[0381] Compound 5 can be prepared via the synthetic route described in Scheme A. A convenient and selective one-pot reaction with commercially available 2-hydroxybenzaldehyde (1) and ethyl diazoacetate efficiently provides 3-ethoxycarbonylbenzofuran (2), which is converted to compound 3 by palladium-catalyzed cyanation with cyanate salts such as NaCN and Zn(CN). The synthesis of 5-substituted 1H-tetrazoles from organic nitriles (3) can be accomplished by one of a variety of catalysts and methods, and hydrolysis of (1H-tetrazol-5-yl)benzofuran-3-carboxylate in alkaline medium provides the key intermediate 4. Finally, compound 5 is obtained by amide coupling reaction of carboxylic acid (4) with the corresponding substituted aromatic amine in the presence of a coupling agent such as HATU, EDCl or CDI.

[0382] In some embodiments, the compounds described herein are prepared as described in Scheme B.

[0383] Plan B

[0384]

[0385] Alternatively, compound 5 can be prepared via the synthetic route described in Scheme B. Compound 7 is obtained by a two-step sequence starting from benzofuranic acid (6), amide coupling and transition metal catalyzed cyanation. The tetrazole of 5 can then be introduced using a similar approach as described in Scheme A, step c. The cyano group is also converted to other 5-membered heterocycles such as 1,2,4- Oxazolyl-5(4H)-one (eg, 8).

[0386] In some embodiments, the compounds described herein are prepared as described in Scheme C.

[0387] Plan C

[0388]

[0389] Compound 15 can be prepared by the synthetic route described in Scheme C. Commercially available 9 is converted to hydroxybenzaldehyde (10), which is then converted to 3-ethoxycarbonylbenzofuran (11) under similar conditions as described in Scheme A, step a. BBr3-promoted demethylation and subsequent reaction with Br-(CH2) n Realkylation of CN yields compound 13. Starting from 13, the final compound (15) was synthesized in a manner similar to that described in Scheme A, steps ce.

[0390] In some embodiments, the compounds described herein are prepared as described in Scheme D.

[0391] Plan D

[0392]

[0393] Substituted anilines (18, 20, 22) can be prepared by the synthetic route described in Scheme D. Nitrobenzene (16, Y = F) is reacted with the corresponding alcohol in the presence of a base to form a nucleophilic aromatic substitution (S N Ar) to give compound 17, which is subsequently reduced to oxyaniline (18). Compound 19 is obtained from aryl bromide (16, Y = Br) via a palladium-catalyzed coupling reaction of the corresponding amine (known as Buchwald-Hartwig amination) and then reduced to diaminobenzene (20). Finally, the (cyclo)alkylation of aryl bromide (16, Y = Br) to compound 22 is completed in a two-step reaction, Suzuki-Miyaura cross-coupling with the corresponding alkenyl boronic acid / ester and alkenyl reduction.

[0394] In some embodiments, the compounds described herein are prepared as described in Scheme E.

[0395] Plan E

[0396]

[0397] Compound 27 can be prepared in a similar manner as described in Scheme E. Compound 27 is obtained in a similar manner as described in steps b to e of Example A. Alternatively, it can be directly obtained from compound 25 via AlMe3-promoted amide formation with the corresponding aniline.

[0398] The compounds of formula (I) or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during, or after the onset of the disease or condition, and the timing of administration of the composition containing the compound can vary.

[0399] Table 1 below describes the compounds disclosed herein.

[0400] Table 1

[0401] Compound number Structure / Name 1-1 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-2 #timg#N-(4-cyclobutyloxy-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-3 #timg#3-((4-cyclobutyloxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid 1-4 #timg#6-((1H-tetrazol-5-yl)methoxy)-N-(4-cyclobutyloxy-3-fluorophenyl)benzofuran-3-carboxamide 1-5 #timg#6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)benzofuran-3-carboxamide 1-6 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-7 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-8 #timg#6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide 1-9 #timg#N-(4-(Cyclopentyloxy)-2,3-difluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-10 #timg#N-(4-(Cyclopentyloxy)-2,5-difluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-11 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-12 #timg#N-(2-(Cyclopentyloxy)-3,4-difluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-13 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-14 #timg#N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-15 #timg#N-(3-Fluoro-4-(1-methylcyclopropyloxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-16 #timg#5-Fluoro-N-(3-fluoro-4-(1-methylcyclopropyloxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-17 #timg#N-(4-cyclopentyl-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-18 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-19 #timg#N-(4-((2,4-dichlorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-20 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-21 #timg#(S)-5-Fluoro-N-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-22 #timg#(R)-5-Fluoro-N-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-23 #timg#N3-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3,6-dicarboxamide 1-24 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-#timg#oxadiazol-3-yl)benzofuran-3-carboxamide 1-25 #timg#(S)-N-(4-(1-(2-chloro-4-fluorophenyl)ethoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-26 #timg#(R)-N-(4-(1-(2-chloro-4-fluorophenyl)ethoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-27 #timg#N-(4-(3,3-difluorocyclobutyloxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-28 #timg#5-Fluoro-N-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-29 #timg#6-((1H-tetrazol-5-yl)oxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide 1-30 #timg#(S)-5-Fluoro-N-(3-fluoro-4-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-31 #timg#(R)-5-Fluoro-N-(3-fluoro-4-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-32 #timg#(S)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-33 #timg#(R)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-34 #timg#N-(4-(3,3-difluoropyrrolidin-1-yl)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-35 #timg#N-(4-((1,3-difluoropropan-2-yl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-36 #timg#(S)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-37 #timg#(R)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-38 #timg#6-((1H-tetrazol-5-yl)oxy)-N-(4-(3,3-difluorocyclobutyloxy)-3-fluorophenyl)-5-fluorobenzofuran-3-carboxamide 1-39 #timg#6-((1H-tetrazol-5-yl)oxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3-carboxamide 1-40 #timg#N-(4-(2-chloro-4-fluorophenoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-41 #timg#N-(4-((4-chloro-2-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-42 #timg#N-(4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-43 #timg#N-(4-((3-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-44 #timg#N-(4-((2-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-45 #timg#N-(4-((3-chloro-5-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-46 #timg#N-(4-((2-chloro-4-cyanobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-47 #timg#5-Fluoro-N-(4-((5-fluoropyridin-2-yl)methoxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-48 #timg#N-(4-((2-cyano-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-49 #timg#N-(4-((4-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-50 #timg#N-(4-((2-chloro-4,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-51 #timg#N-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-52 #timg#N-(4-((4-chloro-2-cyanobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-53 #timg#N-(4-((4-chloro-3,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-54 #timg#N-(4-((4-chloro-2,6-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-55 #timg#N-(4-((4-chloro-2,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-56 #timg#N-(4-((4-chlorothien-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-57 #timg#N-(4-((4,5-dichlorothien-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 1-58 #timg#N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide 1-59 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide 1-60 #timg#N-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-6-(1H-tetrazol-5-yl)furo[3,2-c]pyridine-3-carboxamide 1-61 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)-1H-indole-3-carboxamide 1-62 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-1-methyl-6-(1H-tetrazol-5-yl)-1H-indole-3-carboxamide 1-63 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-1-(difluoromethyl)-6-(1H-tetrazol-5-yl)-1H-indole-3-carboxamide 1-64 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-1-(difluoromethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indole-3-carboxamide 1-65 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-1-(difluoromethyl)-6-(1H-tetrazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide

[0402] Note that for the compounds disclosed in Table 1 above, the depicted stereochemistry for compounds 1-25, 1-26, 1-30, 1-31, 1-36, and 1-37 is arbitrarily designated as R or S.

[0403] Example 1: N-(4-cyclobutoxy-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0404] (1-2)

[0405] Step 1: Preparation of 1-cyclobutoxy-2-fluoro-4-nitrobenzene

[0406] To a solution of cyclobutanol (3.399 g, 47.14 mmol) in THF (100 mL) was added KO t Bu (5.290 g, 47.14 mmol, 1.5 eq). The resulting mixture was stirred at 0 ° C for 1 hour and then treated with 1,2-difluoro-4-nitrobenzene (5 g, 31.43 mmol, 1 eq). The mixture was stirred at 0 ° C and slowly warmed to room temperature over a period of 4 hours. It was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography to give the title compound (4.5 g, 50% yield). LCMS (M+H) + : 212.1.

[0407] Step 2: Preparation of 4-cyclobutoxy-3-fluoroaniline

[0408] To a solution of 1-cyclobutoxy-2-fluoro-4-nitrobenzene (4.5 g, 21 mmol) in MeOH (100 mL) was added Pd / C (4.5 g, 1.0 equiv) at room temperature under an inert atmosphere. The reaction was stirred at room temperature under an H2 atmosphere for 2 hours. It was then filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (3.4 g, 85% yield) as a yellow solid. LCMS (M+H) + : 182.0.

[0409] Step 3: Preparation of 6-bromo-N-(4-cyclobutoxy-3-fluorophenyl)benzofuran-3-carboxamide

[0410] To a solution of 6-bromobenzofuran-3-carboxylic acid (300 mg, 1.24 mmol) and 4-cyclobutoxy-3-fluoroaniline (226 mg, 1.24 mmol, 1 equivalent) and HATU (568 mg, 1.49 mmol, 1.2 equivalents) in DMF (10 mL) was added DIEA (483 mg, 3.73 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours and quenched with water. The resulting mixture was then extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (15%-50% ethyl acetate / petroleum ether) to give the title compound (440 mg, 68.9%) as a brown solid. LCMS (M+H) + : 404.1.

[0411] Step 4: Preparation of 6-cyano-N-(4-cyclobutyloxy-3-fluorophenyl)benzofuran-3-carboxamide

[0412] A solution of 6-bromo-N-(4-cyclobutyloxy-3-fluorophenyl)benzofuran-3-carboxamide (440 mg, 1.09 mmol) and Zn(CN)2 (153 mg, 1.31 mmol) and Zn (14.2 mg, 218 µmol) and Pd2(dba)3 (99.6 mg, 109 µmol) and dppf (121 mg, 218 µmol) in DMA (10 mL) was stirred at 100 ° C under N2 for 2 hours. The reaction was cooled to room temperature and quenched with water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (15%-50% ethyl acetate / petroleum ether) to give the title compound (220 mg, 41.9%) as a yellow solid. LCMS (M+H) + : 351.3.

[0413] Step 5: Preparation of N-(4-cyclobutoxy-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0414] To a solution of 6-cyano-N-(4-cyclobutyloxy-3-fluorophenyl)benzofuran-3-carboxamide (90 mg, 0.26 mmol) and Bu2SnO (32 mg, 0.13 mmol) in toluene (5 mL) was added TMSN3 (88.8 mg, 0.77 mmol) dropwise. The mixture was stirred at 100 ° C under N2 for 2 hours. The reaction was cooled to room temperature and concentrated. The residue was purified by XBridge Prep OBD C18 column, 30×150mm 5µm column (eluent: 18% to 48% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) to give the title compound (37.6 mg, 37% yield) as a white solid. LCMS (M+H) + :394.0. 1 H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.77 (s, 1H), 8.20 (d, J =1.2 Hz, 1H), 8.16 – 8.03 (m, 2H), 7.73 (dd, J = 13.6, 2.5 Hz, 1H), 7.46 –7.36 (m, 1H), 7.04 (t, J = 9.2 Hz, 2H), 4.80 – 4.65 (m, 1H), 2.48 – 2.37 (m,2H), 2.18 – 2.00 (m, 2H), 1.88 – 1.73 (m, 1H), 1.73 – 1.56 (m, 1H).

[0415] The following compounds were synthesized according to Example 1:

[0416] Compound number Structure / Name <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR <!-- 61 -->]]> 1-1 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 408.1 <![CDATA[(300 MHz, DMSO-d6) δ10.29 (s, 1H), 8.88(s, 1H), 8.36 – 8.23(m, 2H), 8.07 (dd, J= 8.2, 1.4 Hz, 1H),7.70 (dd, J = 13.6,2.5 Hz, 1H), 7.40 (d,J = 9.0, 1H), 7.15(t, J = 9.4 Hz, 1H),4.88 – 4.77 (m, 1H),1.93 – 1.80 (m, 2H),1.80 – 1.67 (m, 4H),1.72 – 1.53 (m, 2H). No NH was observed.]]> 1-6 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 482.0 <![CDATA[(400 MHz, DMSO-d6) δ10.25 (s, 1H), 8.73(s, 1H), 8.16 (d, J =1.1 Hz, 1H), 8.13 -8.00 (m, 2H), 7.75(dd, J = 13.6, 2.5Hz, 1H), 7.71 - 7.63(m, 1H), 7.53 (dd, J= 8.9, 2.6 Hz, 1H),7.48 - 7.40 (m, 1H),7.34 - 7.24 (m, 2H),7.09 (s, 1H), 5.18(s, 2H)。]]> 1-9 #timg#N-(4-(Cyclopentyloxy)-2,3-difluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 426.1 <![CDATA[(400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.87 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.18 - 8.20 (m, 1H), 8.06 - 8.08 (m, 1H), 7.30 - 7.34 (m, 1H), 7.03 - 7.08 (m, 1H), 4.93 - 4.96 (m, 1H), 1.93 - 1.99 (m, 2H), 1.60 - 1.79 (m, 6H), NH not observed. <!-- 62 -->]]> 1-10 #timg#N-(4-(Cyclopentyloxy)-2,5-difluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 426.1 <![CDATA[(400 MHz, DMSO-d6) δ10.01 (s, 1H), 8.78(s, 1H), 8.18 (d, J =8.0 Hz, 1H), 8.03 –8.09 (m, 2H), 7.55 -7.59 (m, 1H), 7.22 -7.27 (m, 1H), 7.09(s, 1H), 4.90 - 4.94(m, 1H), 1.89 - 1.98(m, 2H), 1.70 - 1.80(m, 4H), 1.50 - 1.61(s, 2H)。]]> 1-12 #timg#N-(2-(Cyclopentyloxy)-3,4-difluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 426.1 <![CDATA[(400 MHz, DMSO-d6) δ9.89 (s, 1H), 8.94(d, J = 8.0 Hz, 1H),8.32 (s, 1H), 8.23 -8.25 (m, 1H), 8.06 -8.09 (m, 1H), 7.43 -7.48 (m, 1H), 7.18 –7.25 (m, 1H), 4.81(s, 1H), 1.82 (s,2H), 1.68 (s, 4H),1.49 (s, 2H), NH not observed.]]> 1-14 #timg#N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 392.0 (300 MHz, DMSO-d6) δ10.37 (s, 1H), 8.82(s, 1H), 8.22 (s,1H), 8.15 (d, J = 8.2Hz, 1H), 8.08 (d, J =8.2 Hz, 1H), 7.69(dd, J = 13.0, 2.1Hz, 1H), 7.45 (dd, J= 8.4, 2.1 Hz, 1H),7.33 (t, J = 8.6 Hz,1H), 3.25 – 3.07 (m,1H), 2.08 – 1.91 (m,2H), 1.87 – 1.43 (m,6H), no NH was observed. 1-15 #timg#N-(3-Fluoro-4-(1-methylcyclopropyloxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 394.0 <![CDATA[(300 MHz, DMSO-d6) δ10.27 (s, 1H), 8.79(s, 1H), 8.22 (s,1H), 8.15 (d, J = 8.2Hz, 1H), 8.07 (d, J =8.3 Hz, 1H), 7.75(dd, J = 13.5, 2.5Hz, 1H), 7.50 – 7.40(m, 1H), 7.34 (t, J =9.1 Hz, 1H), 7.14(brs, 1H), 1.52 (s,3H), 1.02 – 0.87 (m,2H), 0.87 – 0.72 (m,2H)。]]>

[0417] Example 2: 3-((4-cyclobutyloxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid

[0418] (1-3)

[0419] Step 1: Preparation of ethyl 3-((4-cyclobutyloxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylate

[0420] To a solution of 6-cyano-N-(4-cyclobutyloxy-3-fluorophenyl)benzofuran-3-carboxamide (100 mg, 285 μmol) in EtOH (5 mL) was added SOCl2 (1.02 g, 8.56 mmol, 30 equivalents) at 0 ° C. The mixture was stirred at 80 ° C for 16 hours. The reaction was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (52 mg, 46% yield) as a white solid. LCMS (M+H) + : 398.0.

[0421] Step 2: Preparation of 3-((4-cyclobutoxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid

[0422] To a solution of ethyl 3-((4-cyclobutyloxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylate (52 mg, 0.13 mmol) in THF / MeOH / H2O (3 / 1 / 1, 5 mL) was added lithium hydroxide (4.8 mg, 0.20 mmol, 2 equivalents) at 0°C. The mixture was stirred at 0°C for 2 hours, and then the pH was adjusted to 5-6 by the addition of 2 M HCl. The reaction was concentrated, and the residue was further purified by preparative HPLC using an XBridge Prep OBD C18 150 mm x 30 mm x 5 μm column (eluent: 15% to 45% (v / v) CH3CN and H2O, containing 10 MMOL / L NH4HCO3) to give the title compound (19.6 mg, 40% yield) as a white solid. LCMS (M+H) + : 370.0. 1 H NMR (400 MHz, DMSO-d6) δ δ10.30 (s, 1H), 8.88 (s, 1H), 8.19 – 8.10 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 13.5 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 9.3 Hz,1H), 4.75 – 4.61 (m, 1H), 2.45 – 2.35 (m, 2H), 2.13 – 1.94 (m, 2H), 1.83 –1.71 (m, 1H), 1.68 – 1.53 (m, 1H).

[0423] Example 3: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0424] (1-13)

[0425] Step 1: Preparation of 2-chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene

[0426] To a solution of 1-fluoro-4-nitrobenzene (2 g, 0.01 mmol) in THF (50 mL) was added (2-chloro-4-fluorophenyl)methanol (2 g, 0.01 mmol, 1 eq). The resulting mixture was cooled to 0 °C and then eluted with KO t To the product of 4-nitro-1-oxo-2-oxo-4-oxo-5-nitro-2-oxo-3 ...

[0427] Step 2: Preparation of 4-((2-chloro-4-fluorobenzyl)oxy)aniline

[0428] To a solution of 2-chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene (2 g, 0.02 mol) in EtOH / H2O (6:1, 70 mL) was added Fe powder (2 g, 5 eq.) and NHCl (4 g, 10 eq.) at room temperature. The mixture was stirred at 85 ° C for 2 hours, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the product (1.5 g, 70% yield) as a brown solid. CMS (M+H) + : 251.9.

[0429] Step 3: Preparation of ethyl 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate

[0430] To a solution of ethyl 6-cyanobenzofuran-3-carboxylate (1.6 g, 7.4 mmol) and Bu2SnO (1.1 g, 4.5 mmol) in toluene (30 mL) was added TMSN3 (2.6 g, 22 mmol) dropwise. The mixture was stirred at 100 ° C under N2 for 2 hours. The reaction was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (17% MeOH / DCM) to give the title compound (1.6 g, 83%) as a yellow solid. LCMS (M + H) + : 259.1.

[0431] Step 4: Preparation of 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid

[0432] To a solution of ethyl 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (250 mg, 968 μmol) in THF / MeOH / H2O (10 mL, v / v / v=3 / 1 / 1) was added LiOH (46.4 mg, 1.94 mmol) at 0°C. The reaction was then slowly warmed to room temperature and stirred for 2 hours. The pH of the reaction was adjusted to approximately 7 by adding 1 M HCl. After removing the volatile solvent, the residue was purified by a C18 column (eluent: 10% to 30% (v / v) CH3CN and H2O, containing 10MMOL / L NH4HCO3) to give the title compound (205 mg, 85%) as a yellow solid. LCMS (M+H) + : 231.0.

[0433] Step 5: Preparation of 3-((4-cyclobutyloxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid

[0434] To a solution of 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (150 mg, 652 μmol), 4-((2-chloro-4-fluorobenzyl)oxy)aniline (164 mg, 652 μmol, 1 equivalent) and HATU (297 mg, 782 μmol, 1.2 equivalents) in DMF (10 mL) was added DIEA (253 mg, 1.95 mmol, 3 equivalents) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Xselect CSH OBD column, 30×150mm 5μm column (eluent: 44% to 74% (v / v) acetonitrile and water, containing 0.1% FA) to give the title compound (40.3 mg, 13.2% yield) as a yellow solid. LCMS (M+H) + : 463.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.90 (s,1H), 8.37 – 8.27 (m, 2H), 8.09 (dd, J = 8.2, 1.4 Hz, 1H), 7.74 – 7.64 (m,3H), 7.53 (dd, J = 8.9, 2.7 Hz, 1H), 7.34 – 7.24 (m, 1H), 7.15 – 7.03 (m,2H), 5.13 (s, 2H), no -NH was observed.

[0435] Example 4: 6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide

[0436] (1-8)

[0437] Step 1: Preparation of methyl 6-(cyanomethoxy)benzofuran-3-carboxylate

[0438] To a solution of 6-hydroxybenzofuran-3-methyl formates (1.5 g, 7.8 mmol) and 2-bromoacetonitrile (1.1 g, 9.4 mmol, 1.2 equivalents) in acetone (15 mL) was added K at room temperature CO (2.2 g, 16 mmol, 2 equivalents). The reaction mixture was stirred at 60 ° C for 6 hours, cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with salt water, dried over anhydrous Na SO dried, filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (1.08 g, 53% yield) as a white solid.

[0439] Step 2: Preparation of methyl 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylate

[0440] To a solution of methyl 6-(cyanomethoxy)benzofuran-3-carboxylate (1 g, 4 mmol) in toluene (20 mL) was added TMSN3 (1 g, 0.01 mmol, 3 equivalents) and Bu2SnO (0.5 g, 2 mmol, 0.5 equivalents). After removing the air from the reaction flask, the flask was backfilled with nitrogen. The reaction was stirred at 100 ° C under N2 for 2 hours, cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1 g, 80% yield) as a white solid. LCMS (M+H) + : 275.0.

[0441] Step 3: Preparation of 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylic acid

[0442] To a solution of methyl 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylate (900 mg, 3.28 mmol) in THF / MeOH / H2O (3 / 1 / 1, 5 mL) was added lithium hydroxide (157 mg, 6.56 mmol, 2 equivalents) at 0°C. The mixture was stirred at room temperature for 2 hours and the pH was adjusted to 5-6 by the addition of 2 M HCl. The reaction was concentrated and the residue was further purified by silica gel column (eluent: 15% to 25% (v / v) DCM and MeOH) to give the title compound (650 mg, 74.1% yield) as a white solid. LCMS (M+H) + : 261.0.

[0443] Step 4: 6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran Preparation of furan-3-carboxamide

[0444] To a solution of 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylic acid (150 mg, 576 μmol), 4-((2-chloro-4-fluorobenzyl)oxy)aniline (145 mg, 576 μmol, 1 equivalent) and HATU (263 mg, 692 μmol, 1.2 equivalents) in DMF (5 mL) was added DIEA (224 mg, 1.73 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (15%-40% methanol / dichloromethane) to obtain a crude product. The crude product was then further purified by XBridge Prep OBD C18 column, 30×150 mm 5µm column (eluent: 25% to 55% (v / v) acetonitrile and water, containing 10 mmol / l NH4HCO3) to afford the title compound (24.0 mg, 8.33% yield) as a white solid. LCMS (M+H) + : 494.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.05(s, 1H), 8.62 (s, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.72 - 7.62 (m, 3H), 7.58 -7.48 (m, 2H), 7.34 - 7.24 (m, 1H), 7.11 (s, 1H), 7.09 - 6.99 (m, 3H), 5.21 (s, 2H), 5.13 (s, 2H).

[0445] The following compounds were synthesized according to Example 4:

[0446] Compound number Structure / Name <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR]]> 1-4 #timg#6-((1H-tetrazol-5-yl)methoxy)-N-(4-cyclobutyloxy-3-fluorophenyl)benzofuran-3-carboxamide 424.1 <![CDATA[(300 MHz, methanol-d4) δ8.40 (s, 1H), 7.96(d, J = 8.7 Hz, 1H),7.62 (dd, J = 13.2,2.5 Hz, 1H), 7.39 –7.27 (m, 2H), 7.09(dd, J = 8.7, 2.3 Hz,1H), 6.95 (t, J = 9.1Hz, 1H), 5.37 (s,2H), 4.79 – 4.64 (m,1H), 2.56 – 2.38 (m,2H), 2.28 – 2.08 (m,2H), 1.99 – 1.61 (m,2H).]]> 1-5 #timg#6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)benzofuran-3-carboxamide 512.0 <![CDATA[(300 MHz, methanol-d4) δ8.39 (s, 1H), 7.97(d, J = 8.7 Hz, 1H),7.73 – 7.59 (m, 2H),7.43 – 7.27 (m, 3H),7.22 – 7.06 (m, 3H),5.37 (s, 2H), 5.22(s, 2H).]]>

[0447] Example 5: 6-((1H-tetrazol-5-yl)oxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide

[0448] (1-29)

[0449] Step 1: Preparation of ethyl 6-cyanatobenzofuran-3-carboxylate

[0450] To 6-hydroxybenzofuran-3-formic acid ethyl ester (1000 mg, 4.803 mmol) and BrCN (610.5 mg, 5.763 mmol, 1.2 equivalents) in Et at 0 ° C was added Et N (972 mg, 9.606 mmol, 2 equivalents) in a solution of O (10 mL). The mixture was stirred at 0 ° C for 3 hours, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na SO dried, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the product (309 mg, 54.7% yield) as a white solid.

[0451] Step 2: Preparation of ethyl 6-((1H-tetrazol-5-yl)oxy)benzofuran-3-carboxylate

[0452] To a solution of ethyl 6-cyanobenzofuran-3-carboxylate (800 mg, 1.30 mmol) in toluene (1 mL) was added TMSN3 (448 mg, 3.89 mmol, 3 equivalents) and Bu2SnO (162 mg, 0.649 mmol, 0.5 equivalents). After removing air from the reaction flask, the flask was backfilled with nitrogen. The reaction was stirred at 100 ° C under N2 for 3 hours, cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to obtain the title compound (261 mg, 73.3% yield) as a white solid.

[0453] Step 3: 6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran Preparation of furan-3-carboxamide

[0454] To a solution of ethyl 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (299 mg, 1.16 mmol) and 4-((2-chloro-4-fluorobenzyl)oxy)aniline (350 mg, 1.39 mmol, 1.2 equiv) in toluene (10 mL) was added AlMe3 (100 mg, 1.39 mmol, 1.2 equiv) at 0 ° C. The resulting mixture was stirred at 80 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water and concentrated. The residue was purified by C18 column (eluent: 35% to 55% (v / v) CH3CN and H2O, containing 10MMOL / L NH4HCO3) to give the title compound (158 mg, 29.4% yield) as a light yellow solid. LCMS (M+H) + : 480.0. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.93 (s, 1H),8.38 – 8.26 (m, 2H), 8.09 (dd, J = 8.2, 1.4 Hz, 1H), 7.74 – 7.61 (m, 3H),7.51 (dd, J = 8.9, 2.6 Hz, 1H), 7.34 – 7.21 (m, 1H), 7.19 – 6.94 (m, 2H),5.12 (s, 2H), no -NH was observed.

[0455] Example 6: 6-((1H-tetrazol-5-yl)oxy)-N-(4-(3,3-difluorocyclobutyloxy)-3-fluorophenyl)-5-fluorobenzofuran-3-carboxamide

[0456] (1-38)

[0457] Step 1: Preparation of 4-(3,3-difluorocyclobutyloxy)-3-fluoroaniline

[0458] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) - : 216.0.

[0459] Step 2: Preparation of 5-fluoro-2-hydroxy-4-methoxybenzaldehyde

[0460] Under N2, anhydrous magnesium chloride (1.90 g, 20.0 mmol) was added portionwise to an ice-cold solution of 4-fluoro-3-methoxyphenol (1.42 g, 10.0 mmol) in MeCN (50 mL). After adding solid paraformaldehyde (2.10 g, 69.9 mmol) to the reaction mixture, triethylamine (5.60 mL, 40.0 mmol) was added dropwise. The reaction flask was sealed, and the mixture was stirred at 75 ° C for 2 hours. The reaction was cooled to room temperature, diluted with EtOAc, and washed with 1 M HCl, water and brine in sequence. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (1.54 g, 91%) as an off-white solid. The substance was used in the next step without further purification. LCMS (M+H) + : 171.2.

[0461] Step 3: Preparation of ethyl 5-fluoro-6-methoxybenzofuran-3-carboxylate

[0462] To a solution of 5-fluoro-2-hydroxy-4-methoxybenzaldehyde (3.5 g, 21 mmol) in DCM (10 mL) was added BF4. OEt2 (0.33 g, 2.1 mmol, 0.1 eq.) and ethyl 2-diazoacetate (4.7 g, 41 mmol, 2 eq.) were added at room temperature. After the reaction was stirred for 30 minutes, it was treated with H2SO4 (2.0 g, 21 mmol, 1 eq.) and stirred for another 2 hours at room temperature. The reaction was quenched with water and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column to give the title compound (3.9 g, 80%).

[0463] Step 4: Preparation of ethyl 5-fluoro-6-hydroxybenzofuran-3-carboxylate

[0464] To a solution of 5-fluoro-6-methoxybenzofuran-3-ethyl carboxylate (3.9 g, 16 mmol) was added 3,3-difluorocyclobutane-1-ol (4.1 g, 16 mmol). The reaction mixture was cooled to 0 ° C and stirred at 0 ° C for 2 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (2.9 g, 79% yield) as a white solid. LCMS (M+H) + : 225.0.

[0465] Step 5: Preparation of ethyl 6-cyanato-5-fluorobenzofuran-3-carboxylate

[0466] To 5-fluoro-6-hydroxybenzofuran-3-ethyl formate (600 mg, 2.66 mmol) and BrCN (338 mg, 3.19 mmol, 1.2 equivalents) in Et at 0 ° C. Et N (537 mg, 5.32 mmol, 2 equivalents) is added to a solution of 5-fluoro-6-hydroxybenzofuran-3-ethyl formate (600 mg, 2.66 mmol) and BrCN (338 mg, 3.19 mmol, 1.2 equivalents) in Et o (10 mL). The mixture is stirred at 0 ° C. for 3 hours, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts are washed with brine, dried over anhydrous Na sO dried, filtered and concentrated. The crude product is purified by silica gel chromatography to obtain the title compound (200 mg, 30% yield) as a white solid.

[0467] Step 6: Preparation of ethyl 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylate

[0468] To a solution of ethyl 6-cyano-5-fluorobenzofuran-3-carboxylate (350 mg, 1.39 mmol) and Bu2SnO (173 mg, 697 μmol) in toluene (10 mL) was added TMSN3 (482 mg, 4.18 mmol) dropwise. The mixture was stirred at 100 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then directly purified by C18 column (eluent: 35% to 55% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) to obtain the title compound (250 mg, 62% yield) as a yellow solid. LCMS (M+H) + : 293.0.

[0469] Step 7: Preparation of 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylic acid

[0470] To a solution of ethyl 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylate (230 mg, 0.787 mmol) in THF / MeOH / H2O (10 mL, v / v / v=3 / 1 / 1) was added LiOH (94 mg, 3.94 mmol, 5 equivalents) at 0°C. The reaction was slowly warmed to room temperature and stirred for 2 hours. After the pH was adjusted to approximately 7, the reaction was concentrated and directly purified by a C18 column (eluent: 10% to 30% (v / v) CH3CN and H2O, containing 10MMOL / L NH4HCO3) to give the title compound (150 mg, 72%). LCMS (M+H) + : 264.9.

[0471] Step 8: 6-((1H-tetrazol-5-yl)oxy)-N-(4-(3,3-difluorocyclobutyloxy)-3-fluorophenyl)-5-fluorobenzene Preparation of 3-nitrofuran-3-carboxamide

[0472] To a solution of 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylic acid (130 mg, 492 μmol) and 4-(3,3-difluorocyclobutyloxy)-3-fluoroaniline (107 mg, 492 μmol, 1 equivalent) in pyridine (10 mL) was added EDCI (113 mg, 591 μmol, 1.2 equivalents). The reaction was stirred at room temperature for 2 hours, quenched with water and extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was directly purified by C18 column (eluent: 35% to 55% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) to give the title compound (15.1 mg, 6.52% yield) as a yellow solid. LCMS (M+H) + : 464.1. 1 H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.86 (s, 1H), 7.93 – 8.07 (m, 2H), 7.76 (dd, J = 13.6,2.5 Hz, 1H), 7.43 – 7.56 (m, 1H), 7.09 – 7.19 (m, 2H), 4.82 (s, 1H), 3.12 –3.32 (m, 2H), 2.81 – 2.93 (m, 2H).

[0473] The following compounds were synthesized according to Example 6:

[0474] Compound number Structure / Name <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR <!-- 69 -->]]> 1-39 #timg#6-((1H-tetrazol-5-yl)oxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3-carboxamide 498.1 <![CDATA[(400 MHz, DMSO-d6) δ 8.74(s, 1H), 7.86 (d, J =10.6 Hz, 1H), 7.61–7.72(m, 4H), 7.51–7.60 (m,1H), 7.18–7.28 (m, 1H),7.07 (d, J = 10.6 Hz,2H), 5.10 (s, 2H). No 2 NH was observed.]]>

[0475] Example 7: 5-Fluoro-N-(3-fluoro-4-(1-methylcyclopropyloxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0476] (1-16)

[0477] Step 1: Preparation of 4-(3,3-difluorocyclobutyloxy)-3-fluoroaniline

[0478] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 182.0.

[0479] Step 2: Preparation of 5-fluoro-2-hydroxy-4-methoxybenzaldehyde

[0480] To a solution of 4-chloro-5-fluoro-2-hydroxybenzaldehyde (5 g, 0.03 mol) in DCM (50 mL) was added 2-chloro-6-methyl-2-ethoxy-2-oxoethane-1-diazonium (0.01 kg, 0.1 mol, 4 equiv). After removing the air from the reaction flask, the flask was backfilled with N2. The reaction mixture was treated with BF4. OEt2 (0.5 g, 3 mmol, 0.1 equiv) was added at 0°C and stirred under N2 for 2 hours. After removing the volatile solvent, the residue was treated with H2SO4. The resulting mixture was stirred at 0°C for 2 hours, carefully quenched with water (50 mL) and extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (3.5 g, 50% yield) as a yellow solid.

[0481] Step 3: Preparation of ethyl 5-fluoro-6-methoxybenzofuran-3-carboxylate

[0482] By 6-chloro-5-fluorobenzofuran-3-ethyl formate (1 g, 4 mmol) and Zn(CN)2 (0.6 g, 5 mmol) and Zn (0.05 g, 0.8 mmol) and Pd2(dba)3 (0.4 g, 0.4 mmol) and dppf (0.5 g, 0.8 mmol) in DMF (30 mL) reaction mixture by using N2 bubbling 5 minutes degassed, and 100 DEG C in N2 under stirring for 2 hours. After the completion of the reaction, it is cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer is washed with salt water, through anhydrous Na2SO4 dried, filtered and concentrated. Then the residue is purified by silica gel column to obtain the title compound (720 mg, 70% yield) as a yellow solid.

[0483] Step 4: Preparation of ethyl 5-fluoro-6-hydroxybenzofuran-3-carboxylate

[0484] To a solution of ethyl 6-cyano-5-fluorobenzofuran-3-carboxylate (900 mg, 3.86 mmol) and Bu2SnO (480 mg, 1.93 mmol) in toluene (20 mL) was added TMSN3 (1.33 g, 11.6 mmol) dropwise. The mixture was stirred at 100 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (5%-20% methanol / DCM) to give the title compound (810 mg, 71% yield) as a yellow solid. LCMS (M+H)+ : 277.1.

[0485] Step 5: Preparation of ethyl 6-cyanato-5-fluorobenzofuran-3-carboxylate

[0486] To a solution of ethyl 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (770 mg, 2.79 mmol) in THF / H2O (10 mL, v / v=3 / 1) was added LiOH (134 mg, 5.58 mmol) at 0°C. The reaction was slowly warmed to room temperature and stirred for 2 hours. After completion of the reaction, the pH was adjusted to approximately 7. The reaction was concentrated to give the title compound (700 mg, 79% yield), which was used directly without further purification. LCMS (M+H) + : 249.0.

[0487] Step 6: Preparation of ethyl 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylate

[0488] To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-formic acid (200 mg, 806 μmol) and 3-fluoro-4-(1-methylcyclopropyloxy)aniline (146 mg, 806 μmol, 1 equivalent) and HATU (367 mg, 967 μmol, 1.2 equivalents) in DMF (10 mL) was added DIEA (312 mg, 2.42 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated. Residue was passed through C18 columns (eluent: 30% to 50% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) purified to obtain a crude product. The crude product was further purified by Xselect CSH OBD C18 column, 30×150 mm 5µm column (eluent: 40% to 66% (v / v) acetonitrile and water with 0.05% TFA) to give the title compound (45.6 mg, 13.7% yield) as a yellow solid. LCMS (M+H) + : 412.0. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.98 (s, 1H), 8.40 (d, J = 5.4 Hz, 1H), 8.06 (d, J =10.3 Hz, 1H), 7.74 (dd, J = 13.6, 2.4 Hz, 1H), 7.50 – 7.23 (m, 2H), 1.52 (s,3H), 1.01 – 0.92 (m, 2H), 0.92 – 0.72 (m, 2H), no -NH was observed.

[0489] The following compounds were synthesized according to Example 7:

[0490] Compound number Structure / Name <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR]]> 1-20 #timg#N-(4-(Cyclopentyloxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 426.1 <![CDATA[(300 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.31 (d, J = 5.4, 1H), 7.97 (d, J = 10.2, 1H), 7.69 (dd, J = 13.5, 2.5 Hz, 1H), 7.46–7.36 (m, 1H), 7.17 (t, J = 9.3, 1H), 4.90 – 4.80 (m, 1H), 2.01 – 1.84 (m, 2H), 1.88 – 1.64 (m, 4H), 1.64 – 1.53 (m, 2H), 2 NH not observed. <!-- 71 -->]]> 1-21 #timg#(S)-5-Fluoro-N-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 428.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.37(s, 1H), 8.96 (s, 1H), 8.36(d, J = 5.4 Hz, 1H), 8.02(d, J = 10.3 Hz, 1H), 7.75(dd, J = 13.6, 2.5 Hz, 1H),7.43 (d, J = 9.0 Hz, 1H),7.20 (t, J = 9.2 Hz, 1H),5.12 – 5.01 (m, 1H), 4.04 –3.68 (m, 4H), 2.31 – 2.13(m, 1H), 2.09 – 1.94 (m,1H), NH not observed.]]> 1-22 #timg#(R)-5-Fluoro-N-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 428.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.36(s, 1H), 8.95 (s, 1H), 8.35(d, J = 5.5 Hz, 1H), 8.01(d, J = 10.3 Hz, 1H), 7.75(dd, J = 13.6, 2.5 Hz, 1H),7.43 (d, J = 9.0 Hz, 1H),7.20 (t, J = 9.2 Hz, 1H),5.12 – 5.01 (m, 1H), 3.94 –3.73 (m, 4H), 2.29 – 2.13(m, 1H), 2.08 – 1.94 (m,1H), NH not observed.]]> 1-27 #timg#N-(4-(3,3-difluorocyclobutyloxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 448.1 <![CDATA[(300 MHz, DMSO-d6) δ 10.47(s, 1H), 9.03 (s, 1H), 8.35(d, J = 5.4 Hz, 1H), 8.01(d, J = 10.2 Hz, 1H), 7.78(d, J = 13.6 Hz, 1H), 7.46(d, J = 8.8 Hz, 1H), 7.12(t, J = 9.2 Hz, 1H), 4.88 –4.73 (m, 1H), 3.32 – 3.07(m, 2H), 2.87 – 2.65 (m,2H), NH not observed. <!-- 72 -->]]> 1-28 #timg#5-Fluoro-N-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 414.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.40(s, 1H), 8.95 (s, 1H), 8.32(d, J = 5.4 Hz, 1H), 7.98(d, J = 10.3 Hz, 1H), 7.77(dd, J = 13.6, 2.5 Hz, 1H),7.45 – 7.34 (m, 1H), 6.88(t, J = 9.2 Hz, 1H), 5.38 –5.24 (m, 1H), 4.99 – 4.88(m, 2H), 4.65 – 4.55 (m,2H), NH not observed.]]> 1-35 #timg#N-(4-((1,3-difluoropropan-2-yl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 436.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.48(s, 1H), 8.98 (s, 1H), 8.25(d, J = 5.5 Hz, 1H), 7.91(d, J = 10.3 Hz, 1H), 7.80(dd, J = 13.5, 2.5 Hz, 1H),7.53 – 7.44 (m, 1H), 7.32(t, J = 9.2 Hz, 1H), 4.97 –4.73 (m, 3H), 4.73 – 4.58(m, 2H), NH not observed.]]>

[0491] Example 8: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0492] (1-18)

[0493] Step 1: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran- Preparation of 3-formamide

[0494] To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (200 mg, 806 μmol) and 4-((2-chloro-4-fluorobenzyl)oxy)aniline (203 mg, 806 μmol, 1 equivalent) in pyridine (10 mL) was added EDCI (185 mg, 967 μmol, 1.2 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours, quenched with water and extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then directly purified by C18 column (eluent: 35% to 55% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) to give the title compound (108.3 mg, 27.4% yield) as a yellow solid. LCMS (M+H) + : 482.0. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.01 (s, 1H), 8.38 (d, J = 5.4 Hz, 1H), 8.05 (d, J= 10.3 Hz, 1H), 7.75 – 7.62 (m, 3H), 7.53 (dd, J = 8.9, 2.6 Hz, 1H), 7.35 –7.22 (m, 1H), 7.18 – 7.01 (m, 2H), 5.13 (s, 2H), no -NH was observed.

[0495] Example 9: N-(4-((4-chlorothien-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0496] (1-56)

[0497] Step 1: Preparation of 4-chloro-2-((4-nitrophenoxy)methyl)thiophene

[0498] To a solution of (4-chlorothiophene-2-yl)methanol (500 mg, 3.36 mmol) and 1-fluoro-4-nitrobenzene (712 mg, 5.05 μmol, 1.5 equivalents) in THF (10 mL) was added t-BuOK (566 mg, 5.05 mmol, 1.5 equivalents) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mLx 3). The combined organic extracts were washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (800 mg, 88.2% yield) as a white solid.

[0499] Step 2: Preparation of 4-((4-chlorothiophen-2-yl)methoxy)aniline

[0500] To a solution of 4-chloro-2-((4-nitrophenoxy)methyl)thiophene (750 mg, 2.78 mmol) in EtOH / H2O (4:1, 12.5 mL) was added NH4Cl (1.5 g, 27.8 mmol, 10 equivalents) and Fe (0.78 g, 13.9 mmol, 5 equivalents). After removing the air from the reaction flask, the flask was backfilled with N2. The reaction was stirred at 85 ° C under N2 for 2 hours. It was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (600 mg, 90% yield) as a white solid. LCMS (M+H) + : 240.0.

[0501] Step 3: N-(4-((4-chlorothien-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran Preparation of furan-3-carboxamide

[0502] To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (150 mg, 0.604 mmol) in DMF (5 mL) was added 4-((4-chlorothiophene-2-yl)methoxy)aniline (174 mg, 0.725 mmol, 1.2 equivalents), HATU (275 mg, 0.725 mmol, 1.2 equivalents) and DIEA (234 mg, 1.81 mmol, 3 equivalents). The reaction was stirred at room temperature for 1 hour, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered and concentrated. The crude product was further purified by XBridge Prep C18 OBD column (eluent: 22% to 47% (v / v) CH3CN and H2O containing 10 M MOL / L NH4HCO3) to give the title compound as a white solid (20.1 mg, 6.93% yield). LCMS (M+H) + : 470.1. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s,1H), 8.78 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 10.3 Hz, 1H), 7.68– 7.60 (m, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.18 – 7.08 (brs, 1H), 7.09 – 6.97 (m, 2H), 5.25 (s, 2H).

[0503] Example 10: N-(4-((4-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0504] (1-49)

[0505] Step 1: Preparation of 4-((4-chloro-3-fluorobenzyl)oxy)aniline

[0506] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 251.9.

[0507] Step 2: N-(4-((4-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran- Preparation of 3-formamide

[0508] To a solution of 4-((4-chloro-3-fluorobenzyl)oxy)aniline (50 mg, 0.2 mmol), 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (49 mg, 0.2 mmol, 1 equivalent) and HATU (91 mg, 0.24 mmol, 1.2 equivalents) in DMF (5 mL) was added DIEA (77 mg, 0.6 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with salt water, dried over anhydrous NaSO, filtered and concentrated. The residue was then purified by XBridge Prep C18 OBD column (30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 minutes) to give the title compound (11.9 mg, 12.0% yield) as a white solid. LCMS (M+H) + :482.0. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.81 (s, 1H), 8.12 (d, J =5.6 Hz, 1H), 7.81 (d, J = 10.3 Hz, 1H), 7.72 – 7.57 (m, 3H), 7.52 (dd, J =10.3, 1.9 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.16 (s, 1H), 7.10 – 6.99 (m,2H), 5.13 (s, 2H).

[0509] Example 11: N-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0510] (1-51)

[0511] Step 1: Preparation of 4-((5-chloropyridin-2-yl)methoxy)aniline

[0512] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 235.2.

[0513] Step 2: N-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran Preparation of furan-3-carboxamide

[0514] To a solution of 4-((5-chloropyridin-2-yl)methoxy)aniline (50 mg, 0.21 mmol), 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (53 mg, 0.21 mmol, 1 equivalent) and HATU (97 mg, 0.26 mmol, 1.2 equivalents) in DMF (5 mL) was added DIEA (82 mg, 0.64 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated. The residue was passed through a C18 reverse phase column (eluent: 30% to 50% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) purified to obtain a crude product. The crude product was then further purified by XBridge Prep OBD C18 column (19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 45% B to 65% B in 10 minutes) to give the title compound (13.9 mg, 14% yield) as a white solid. LCMS (M+H) + : 465.0. 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.83 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.99 (dd, J= 8.4, 2.5 Hz, 1H), 7.85 (d, J = 10.3 Hz, 1H), 7.71 – 7.62 (m, 2H), 7.58 (d,J = 8.4 Hz, 1H), 7.18 – 6.96 (m, 3H), 5.19 (s, 2H).

[0515] Example 12: N-(4-((4-chloro-3,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0516] (1-53)

[0517] Step 1: Preparation of 4-((4-chloro-3,5-difluorobenzyl)oxy)aniline

[0518] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 270.1.

[0519] Step 2: N-(4-((4-chloro-3,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran Preparation of furan-3-carboxamide

[0520] To a solution of 4-((4-chloro-3,5-difluorobenzyl)oxy)aniline (50 mg, 0.19 mmol), 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (46 mg, 0.19 mmol, 1 equivalent) and HATU (85 mg, 0.22 mmol, 1.2 equivalents) in DMF (5 mL) was added DIEA (72 mg, 0.56 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was passed through a C18 reverse phase column (eluent: 30% to 50% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) to give a crude product. The crude product was then further purified by XBridge Prep C18 OBD column (30*100 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 53% B in 9 minutes) to give the title compound (14.2 mg, 15% yield) as a white solid. LCMS (M+H) + : 500.0. 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.83 (s, 1H), 8.16 (d,J = 5.6 Hz, 1H), 7.84 (d, J = 10.3 Hz, 1H), 7.73 – 7.61 (m, 2H), 7.50 – 7.39 (m, 2H), 7.19 – 6.94 (m, 3H), 5.15 (s, 2H).

[0521] The following compounds were synthesized according to Example 12:

[0522] Compound number Structure / Name <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR <!-- 76 -->]]> 1-19 #timg#N-(4-((2,4-dichlorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 498.0 <![CDATA[(300 MHz, DMSO-d6)δ 10.21 (s, 1H),8.90 (s, 1H), 8.26(d, J = 5.5 Hz,1H), 7.93 (d, J =10.3 Hz, 1H), 7.75– 7.60 (m, 4H),7.51 (dd, J = 8.3,2.2 Hz, 1H), 7.07(m, 3H), 5.16 (s,2H)。]]> 1-41 #timg#N-(4-((4-chloro-2-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 482.0 <![CDATA[(300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.92 (d, J = 10.3 Hz, 1H), 7.72 – 7.55 (m, 3H), 7.50 (dd, J = 10.0, 2.1 Hz, 1H), 7.35 (dd, J = 8.2, 2.2 Hz, 1H), 7.12 – 7.01 (m, 2H), 5.13 (s, 2H), no 2NH observed.]]> 1-43 #timg#N-(4-((3-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 482.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.98 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 10.2 Hz, 1H), 7.77–7.64 (m, 3H), 7.58–7.41 (m, 2H), 7.13–7.03 (m, 2H), 5.13 (s, 2H), no NH observed. <!-- 77 -->]]> 1-44 #timg#N-(4-((2-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 482.0 <![CDATA[(300 MHz, DMSO-d6)δ 10.15 (s, 1H),8.82 (s, 1H), 8.15(d, J = 5.5 Hz,1H), 7.83 (d, J =10.3 Hz, 1H), 7.72-7.64(m, 2H), 7.53 –7.37 (m, 3H), 7.14– 7.02 (m, 3H),5.21 (s, 2H)。]]> 1-45 #timg#N-(4-((3-chloro-5-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 482.0 <![CDATA[(300 MHz, DMSO-d6)δ 10.14 (s, 1H),8.81 (s, 1H), 8.15(d, J = 5.9 Hz,1H), 7.82 (dd, J =11.0, 4.9 Hz, 1H),7.72 – 7.61 (m,2H), 7.47 – 7.27(m, 3H), 7.22 –6.96 (m, 3H), 5.15(s, 2H)。]]> 1-46 #timg#N-(4-((2-chloro-4-cyanobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 489.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.87 (s, 1H), 8.25–8.12 (m, 2H), 7.94–7.86 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.73–7.64 (m, 2H), 7.13–7.04 (m, 2H), 5.25 (s, 2H), NH not observed. <!-- 78 -->]]> 1-47 #timg#5-Fluoro-N-(4-((5-fluoropyridin-2-yl)methoxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 449.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.88 (s, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.95 – 7.88 (m, 1H), 7.86 – 7.73 (m, 1H), 7.72 – 7.58 (m, 3H), 7.12 – 7.00 (m, 2H), 5.18 (s, 2H), NH not observed.]]> 1-48 #timg#N-(4-((2-cyano-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 473.1 <![CDATA[(300 MHz, DMSO-d6)δ 10.17 (s, 1H),8.82 (s, 1H), 8.13(d, J = 5.6 Hz,1H), 7.95 (dd, J =8.6, 2.7 Hz, 1H),7.87 – 7.76 (m,2H), 7.74 – 7.60(m, 3H), 7.21 –7.00 (m, 3H), 5.23(s, 2H)。]]> 1-50 #timg#N-(4-((2-chloro-4,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 500.0 <![CDATA[(300 MHz, DMSO-d6)δ 10.19 (s, 1H),8.86 (s, 1H), 8.20(d, J = 5.6 Hz,1H), 7.93 – 7.65(m, 5H), 7.16 –7.01 (m, 3H), 5.12(s, 2H)。 <!-- 79 -->]]> 1-52 #timg#N-(4-((4-chloro-2-cyanobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 489.1 <![CDATA[(300 MHz, DMSO-d6)δ 10.15 (s, 1H),8.81 (s, 1H), 8.16– 8.07 (m, 2H),7.90 – 7.73 (m,3H), 7.73 – 7.63(m, 2H), 7.14 –6.95 (m, 3H), 5.25(s, 2H)。]]> 1-54 #timg#N-(4-((4-chloro-2,6-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 500.1 <![CDATA[(300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.91 (s, 1H), 8.29 (d, J = 5.5 Hz, 1H), 7.96 (d, J = 10.3 Hz, 1H), 7.73–7.63 (m, 2H), 7.55–7.42 (m, 2H), 7.12–7.00 (m, 2H), 5.10 (s, 2H), NH not observed.]]> 1-55 #timg#N-(4-((4-chloro-2,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 500.0 <![CDATA[(300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.86 (s, 1H), 8.21 (d, J = 5.5 Hz, 1H), 7.89 (d, J = 10.3 Hz, 1H), 7.79–7.62 (m, 4H), 7.13–7.03 (m, 2H), 5.13 (s, 2H), NH not observed. <!-- 80 -->]]> 1-57 #timg#N-(4-((4,5-dichlorothien-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 503.9 <![CDATA[(300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.84 (s, 1H), 8.18 (d, J = 5.4 Hz, 1H), 7.86 (d, J = 10.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.29 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 5.25 (s, 2H), NH not observed.]]>

[0523] Example 13: N-(4-cyclopentyl-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0524] (1-17)

[0525] Step 1: Preparation of 1-(cyclopent-1-en-1-yl)-2-fluoro-4-nitrobenzene

[0526] 1-Bromo-2-fluoro-4-nitrobenzene (1 g, 5 mmol) was added to 1,4-difluoro- 2-(cyclopent-1-ene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9 g, 5 mmol, 1 equivalent), Pd(dppf)Cl2 (0.3 g, 0.5 mmol, 0.1 equivalent) and K2CO3 (1 g, 9 mmol, 2 equivalents) were added to a solution in alkane / H2O (3:1, 12 mL). After removing the air in the reaction flask, the flask was backfilled with N2. The reaction was stirred at 110 ° C under N2 for 30 minutes. After the reaction was completed, it was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to obtain the product (800 mg, 60% yield) as a white solid.

[0527] Step 2: Preparation of 4-cyclopentyl-3-fluoroaniline

[0528] To a solution of 1-(cyclopent-1-ene-1-yl)-2-fluoro-4-nitrobenzene (800 mg, 3.86 mmol) in MeOH (10 mL) was added wet Pd / C (400 mg, 0.5 eq) at room temperature. After removing the air from the reaction flask, the flask was backfilled with N2. After repeating the above process three times, the reaction flask was backfilled with H2. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was carefully filtered through a celite pad. The filtrate was concentrated to give a crude product (650 mg, 88% yield), which was used directly in the next step. LCMS (M+H) + : 180.1.

[0529] Step 3: Preparation of N-(4-cyclopentyl-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide preparation

[0530] To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-formic acid (200 mg, 806 μmol) and 4-cyclopentyl-3-fluoroaniline (144 mg, 806 μmol, 1 equivalent) and HATU (367 mg, 967 μmol, 1.2 equivalents) in DMF (10 mL) was added DIEA (312 mg, 2.42 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours. After the completion of the reaction, it was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then passed through C18 columns (eluent: 35% to 55% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) directly purified to obtain the title compound (40.1 mg, 11.9% yield) as a yellow solid. LCMS (M+H) + : 410.0. 1 H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.86 (s, 1H), 8.16(d, J = 5.6 Hz, 1H), 7.84 (d, J = 10.2 Hz, 1H), 7.68 (dd, J = 13.0, 2.1 Hz,1H), 7.45 (dd, J = 8.5, 2.1 Hz, 1H), 7.34 (t, J = 8.5 Hz, 1H), 7.17 (brs,1H), 3.25 – 3.08 (m, 1H), 2.07 – 1.92 (m, 2H), 1.84 – 1.49 (m, 6H).

[0531] Example 14: (S)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0532] (1-32)

[0533] Step 1: Preparation of (S)-1-(2-fluoro-4-nitrophenyl)-2-(trifluoromethyl)pyrrolidine

[0534] 1-Bromo-2-fluoro-4-nitrobenzene (1 g, 5 mmol) was added to 1,4-difluoro- To a solution in 2-(trifluoromethyl)pyrrolidine (0.6 g, 5 mmol), XPhos Pd G3 (0.4 g, 0.5 mmol), XPhos (0.2 g, 0.5 mmol) and Cs2CO3 (3 g, 9 mmol) was added. The reactants were stirred at 90 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated and the residue was purified by silica gel chromatography to give the title compound (1 g, 80% yield) as an off-white solid. LCMS (M+H) + : 279.2.

[0535] Step 2: Preparation of (S)-3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)aniline

[0536] The title compound was prepared according to step 2 of Example 1. LCMS (MH) + : 249.1.

[0537] Step 3: (S)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazolyl-5- Preparation of benzofuran-3-carboxamide

[0538] To a solution of ethyl 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (200 mg, 742 µmol) and (S)-3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)aniline (216 mg, 869 µmol, 1.5 eq) in toluene (10 mL) was added AlMe3 (104 mg, 1.45 mmol, 2 eq) at 0°C. The reaction was heated at 80°C under N 2 The product was stirred for 2 hours at 4 ℃ for 10 minutes. After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then directly purified by C18 column (eluent: 35% to 55% (v / v) acetonitrile and water, containing 10MMOL / L NH4HCO3) to obtain the title compound (34.7 mg, 9.85% yield) in a pink solid state. LCMS (M+H) + : 479.0. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.88(s, 1H), 8.26 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 10.5 Hz, 1H), 7.66 (dd, J =15.6, 2.1 Hz, 1H), 7.36 (m, 1H), 7.15 – 7.21 (m, 1H), 4.75 (m, 1 H), 3.62 (m,1H), 3.15 (m, 1H), 2.22 (m, 1H), 1.92 – 2.16 (m, 3H), no -NH was observed.

[0539] The following compounds were synthesized according to Example 14:

[0540] Compound number structure <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR <!-- 82 -->]]> 1-33 #timg#(R)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 479.1 <![CDATA[(300 MHz, DMSO-d6) δ10.29 (s, 1H), 8.90(s, 1H), 8.28 (d, J =5.5 Hz, 1H), 7.95 (d,J = 10.3 Hz, 1H), 7.64(dd, J = 15.6, 2.4 Hz,1H), 7.38 (m, 1H),7.10 – 7.21 (m, 2H),4.74 (m, 1 H), 3.68(m, 1H), 3.15 (m, 1H),2.22 (m, 1H), 1.90 –2.09 (m, 3H)]]> 1-34 #timg#N-(4-(3,3-difluoropyrrolidin-1-yl)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 447.0 <![CDATA[(400 MHz, DMSO-d6) δ10.29 (s, 1H), 8.89(s, 1H), 8.26 (d, J =5.4 Hz, 1H), 7.93 (d,J = 10.2 Hz, 1H), 7.69(dd, J = 15.6, 2.3 Hz,1H), 7.39 (dd, J =8.9, 2.4 Hz, 1H),7.21– 6.95 (m, 1H),6.90 (t, J = 9.5 Hz,1H), 3.72 (t, J = 13.5Hz, 2H), 3.50 (m, 2H),2.42 (m, 2H)]]> 1-42 #timg#N-(4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 459.0 <![CDATA[(300 MHz, DMSO-d6) δ8.78 (s, 1H), 8.14 (d, J = 5.5 Hz, 1H), 7.82 (d, J = 10.2 Hz, 1H), 7.62 (dd, J = 16.2, 2.4 Hz, 1H), 7.35 (dd, J = 9.0, 2.4 Hz, 1H), 6.78 (t, J = 9.6 Hz, 1H), 3.79 – 3.70 (m, 2H), 3.67 – 3.58 (m, 2H), 2.67 – 2.56 (m, 2H), no 2 NH observed]]>

[0541] Example 15: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-yl)benzofuran-3-carboxamide

[0542] (1-24)

[0543] Step 1: Preparation of N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-cyano-5-fluorobenzofuran-3-carboxamide preparation

[0544] To a solution of ethyl 6-cyano-5-fluorobenzofuran-3-carboxylate (150 mg, 640 µmol) and 4-((2-chloro-4-fluorobenzyl)oxy)aniline (165 mg, 640 µmol, 1 eq) in toluene (10 mL) was added AlMe3 (57 mg, 788 µmol, 1.2 eq) at 0°C. The reaction was stirred at 80°C under N2 for 2 hours. After completion of the reaction, it was cooled to room temperature and quenched with water. The resulting mixture was then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then directly purified by C18 column (eluent: 35% to 55% (v / v) acetonitrile and water, containing 10 MMOL / L NH4HCO3) to give the title compound (84 mg, 30%). LCMS (M+H) + : 439.0.

[0545] Step 2: (Z)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(N'-hydroxycarbamimidoyl)benzo Preparation of furan-3-carboxamide

[0546] To a solution of H2NOH-HCl (79 mg, 1.14 mmol, 2.5 equiv) and K2CO3 (94.5 mg, 684 µmol, 1.5 equiv) in MeOH (10 mL) was added N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-cyano-5-fluorobenzofuran-3-carboxamide (200 mg, 456 µmol, 1 equiv) at room temperature. The reactant was stirred at 70 ° C for 4 hours. After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (200 mg, 65% yield) as an off-white solid. LCMS (M+H) + : 472.0.

[0547] Step 3: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4- Preparation of oxadiazole-3-yl)benzofuran-3-carboxamide

[0548] To (Z)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(N'-hydroxycarbamimidoyl)benzofuran-3-carboxamide (200 mg, 424 µmol) and bis(1H-imidazol-1-yl)methanone (82.5 mg, 509 µmol, 1.2 equiv) was added dichloromethane. To a solution of 4-nitropropane (10 mL) was added DBU (71 mg, 466 µmol, 1.1 equiv). The reaction was stirred at 100 ° C for 3 hours and cooled to room temperature under N2. After completion of the reaction, the pH was adjusted to about 2 with 2 M HCl. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by C18 reverse phase column to give the title compound (37.7 mg, 17.5% yield) as an off-white solid. LCMS (MH) - : 495.9. 1 H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.87 (s, 1H), 8.05(d, J = 5.4 Hz, 1H), 7.81 (d, J = 10.5 Hz, 1H), 7.74 – 7.61 (m, 3H), 7.54(dd, J = 8.8, 2.6 Hz, 1H), 7.36 – 7.23 (m, 1H), 7.16 – 7.01 (m, 2H), 5.14 (s,2H), no -NH was observed.

[0549] Example 16: N 3 -(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3,6-dicarboxamide

[0550] (1-23)

[0551] Step 1: N 3 Preparation of -(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3,6-dicarboxamide Preparation

[0552] To a solution of N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-cyano-5-fluorobenzofuran-3-carboxamide (120 mg, 273 µmol) in toluene (10 mL) was added (E)-acetaldehyde oxime (16.2 mg, 273 µmol, 1 eq) and Pd(AcO)2 (6.14 mg, 27.3 µmol, 0.1 eq) and PPh3 (71.7 mg, 273 µmol, 1 eq). The resulting mixture was stirred at 80 ° C under N2 for 2 hours. After completion of the reaction, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column to give the crude product. The crude product was further purified by XBridge Prep OBD C18 column, 30×150 mm 5µm column (eluent: 43% to 68% (v / v) acetonitrile and water, containing 10 mmol / L NH4HCO3) to give the title compound as a light yellow solid (32.4 mg, 25.7% yield). LCMS (M+H) + : 457.0. 1 H NMR (300 MHz, DMSO-d6) δ10.21 (s, 1H), 8.92 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.88 – 7.63 (m, 6H), 7.55 (dd, J = 8.9, 2.6 Hz, 1H), 7.36 – 7.23 (m, 1H), 7.12 – 7.01 (m, 2H), 5.14 (s, 2H).

[0553] Example 17: (S)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide and (R)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0554] (1-36), (1-37)

[0555] Step 1: Preparation of 4-((3,3-difluorocyclopentyl)oxy)-3-fluoroaniline

[0556] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 232.2.

[0557] Step 2: (rac)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazolyl- Preparation of 5-benzofuran-3-carboxamide

[0558] To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-formic acid (280 mg, 1.13 mmol), 4-((3,3-difluorocyclopentyl)oxy)-3-fluoroaniline (287 mg, 1.24 mmol, 1.1 equivalents) and HATU (514 mg, 1.35mmol, 1.2 equivalents) in DMF (10 mL) was added DIEA (437 mg, 3.38 mmol, 3 equivalents) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with salt water, dried over anhydrous NaSO, filtered and concentrated. The residue was directly purified by C18 column (eluent: 25% to 55% (v / v) acetonitrile and water containing 10 M OL / L NH4HCO3) to give the title compound (300 mg, 57.3% yield) as a yellow solid. LCMS (M+H) + : 462.2.

[0559] Step 3: (S)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazolyl-5- 1-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6- Preparation of (1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0560] A sample of (rac)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide (300 mg, 650 μmol) was purified by chiral HPLC using a CHIRALPAK IF, 2*25 cm, 5 μm column (eluent: hexane (0.1% TFA): EtOH = 70:30) to give (S)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide as an off-white solid (31.9 mg, 99.511% purity, 99.7% ee) (peak 2) and the (R)-isomer (peak 1). Stereochemistry is arbitrarily assigned. (S)-isomer: LCMS (M+H) +: 462.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.04 (d, J = 10.0 Hz, 1H), 7.74 (dd, J = 13.5, 2.5 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.20 (t, J = 9.2 Hz, 1H), 4.97 (s, 1H), 2.79 – 2.60 (m, 1H), 2.40 – 2.10 (m, 4H), 2.08 – 1.90 (m, 1H), 2-NH was not observed. (R)-isomer: LCMS (M+H) + : 462.0. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.39 (d, J = 5.4Hz, 1H), 8.04 (d, J = 10.3 Hz, 1H), 7.74 (dd, J = 13.5, 2.5 Hz, 1H), 7.43 (d,J = 8.9 Hz, 1H), 7.20 (t, J = 9.2 Hz, 1H), 4.98 (s, 1H), 2.77 – 2.60 (m, 1H),2.40 – 2.09 (m, 4H), 2.04 – 1.93 (m, 1H), 2-NH was not observed.

[0561] The following compounds were synthesized according to Example 17:

[0562] Compound number Structure / Name <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR]]> 1-25 #timg#(S)-N-(4-(1-(2-chloro-4-fluorophenyl)ethoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 496.0 <![CDATA[(300 MHz, DMSO-d6) δ8.76 (s, 1H), 8.26(d, J = 5.4 Hz,1H), 7.91 (d, J =10.2 Hz, 1H), 7.56– 7.45 (m, 3H),7.38 (dd, J = 8.8,2.6 Hz, 1H), 7.23 –7.10 (m, 1H), 6.82(d, J = 9.1 Hz,2H), 5.71 – 5.58(m, 1H), 1.53 (d, J= 6.3 Hz, 3H), no 2 NH observed]]> 1-26 #timg#(R)-N-(4-(1-(2-chloro-4-fluorophenyl)ethoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 496.0 <![CDATA[(300 MHz, DMSO-d6) δ8.77 (s, 1H), 8.26(d, J = 5.4 Hz,1H), 7.92 (d, J =10.3 Hz, 1H), 7.55– 7.44 (m, 3H),7.37 (dd, J = 8.8,2.6 Hz, 1H), 7.25 –7.09 (m, 1H), 6.82(d, J = 8.9 Hz,2H), 5.69 – 5.57(m, 1H), 1.52 (d, J= 6.2 Hz, 3H), no 2 NH observed <!-- 86 -->]]> 1-30 #timg#(S)-5-Fluoro-N-(3-fluoro-4-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 454.0 <![CDATA[(400 MHz, DMSO-d6) δ9.02 (s, 1H), 8.38(d, J = 5.6 Hz,1H), 8.03 (d, J =10.2 Hz, 1H), 7.76(dd, J = 13.2, 2.5Hz, 1H), 7.42 –7.51 (m, 1H), 7.35– 7.41 (m, 1H),5.01 – 5.12 (m,1H), 1.46 (d, J =6.4 Hz, 3H), no 2 NH observed]]> 1-31 #timg#(R)-5-Fluoro-N-(3-fluoro-4-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 454.0 <![CDATA[(400 MHz, DMSO-d6) δ8.93 (s, 1H), 8.38(d, J = 5.4 Hz,1H), 8.03 (d, J =10.2 Hz, 1H), 7.76(dd, J = 13.2, 2.5Hz, 1H), 7.42 –7.51 (m, 1H), 7.35– 7.41 (m, 1H),5.01 – 5.12 (m,1H), 1.46 (d, J =6.8 Hz, 3H), no 2 NH observed]]>

[0563] Example 18: N-(4-(2-chloro-4-fluorophenoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0564] (1-40)

[0565] Step 1: Preparation of 4-(2-chloro-4-fluorophenoxy)aniline

[0566] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 238.1.

[0567] Step 2: N-(4-(2-chloro-4-fluorophenoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate Preparation of amides

[0568] To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid ethyl ester (232 mg, 842 μmol) and 4-(2-chloro-4-fluorophenoxy)aniline (200 mg, 842 μmol, 1 equivalent) in toluene (10 mL) was added AlMe3 (72.8 mg, 1.01 mmol, 1.2 equivalents) at 0 ° C. The reaction was stirred at 80 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by C18 reverse phase column to give the title compound (42.3 mg, 10.7% yield) as a white solid. LCMS (M+H) + : 468.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H),8.21 (d, J = 5.5 Hz, 1H), 7.88 (d, J = 10.3 Hz, 1H), 7.81 – 7.70 (m, 2H),7.63 (dd, J = 8.4, 3.0 Hz, 1H), 7.32 – 7.15 (m, 2H), 7.05 – 6.94 (m, 2H), 2-NH was not observed.

[0569] Example 19: N-(4-(cyclopentyloxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide

[0570] (1-7)

[0571] Step 1: Preparation of 4-(cyclopentyloxy)-3-fluoroaniline

[0572] The title compound was prepared according to steps 1 and 2 of Example 1. LCMS (MH) + : 195.9.

[0573] Step 2: Preparation of ethyl 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylate

[0574] To a solution of ethyl 7-cyanobenzofuran-3-carboxylate (1 g, 4 mmol) in toluene (20 mL) was added TMSN3 (2 g, 0.01 mmol, 3 equivalents) and Bu2SnO (0.5 g, 2 mmol, 0.5 equivalents). After removing the air in the reaction flask under vacuum, the flask was backfilled with nitrogen. The reactants were stirred at 100 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (1.05 g, 80% yield) as a white solid. LCMS (M+H) + : 259.0.

[0575] Step 3: Preparation of 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid

[0576] To a solution of ethyl 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (980 mg, 3.79 mmol) in THF / MeOH / H2O (10 mL, v / v / v=3 / 1 / 1) was added LiOH (182 mg, 7.59 mmol) at 0°C. The solution was then slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, its pH was adjusted to about 7. A crude product was precipitated during the pH adjustment. The solid product was filtered, collected, and further purified by a C18 column (eluent: 25% to 45% (v / v) CH3CN and H2O, containing 10MMOL / LNH4HCO3) to give the title compound (1.0 g, 90%). LCMS (M+H) + : 231.0.

[0577] Step 4: Preparation of N-(4-(cyclopentyloxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide preparation

[0578] At room temperature to 7-(1H-tetrazol-5-yl)benzofuran-3-formic acid (300 mg, 1.3 mmol), 4-(cyclopentyloxy)-3-fluoroaniline (254 mg, 1.3 mmol, 1 equivalent) and HATU (594 mg, 1.56 mmol, 1.2 equivalents) in DMF (10mL) solution, add DIEA (505 mg, 3.91 mmol, 3 equivalents).Reaction is stirred at room temperature 2 hours.After the completion of the reaction, it is quenched with water and extracted with ethyl acetate (3 x 50 mL).By the organic extract washed with salt water merged, through anhydrous Na sO dry, filter and concentrate.Then residue is passed through silica gel chromatography (15%-40% methanol / DCM) purifying, obtain crude product. The crude product was then further purified by XBridge Prep OBD C18 column, 30×150 mm 5µm column (eluent: 20% to 50% (v / v) acetonitrile and water, containing 10 mmol / l NH4HCO3) to afford the title compound as a white solid (97.7 mg, 18.2% yield). LCMS (M+H) + : 408.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.90 (s, 1H), 8.22 (dd, J = 7.9, 1.3 Hz, 1H), 8.03 (dd, J = 7.6, 1.3 Hz, 1H), 7.74 (dd, J = 13.6, 2.5 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.47 - 7.39 (m,1H), 7.18 (t, J = 9.3 Hz, 1H), 4.90 - 4.81 (m, 1H), 1.97 - 1.83 (m, 2H), 1.81- 1.68 (m, 4H), 1.68 - 1.53 (m, 2H), no NH observed.

[0579] The following compounds were synthesized according to Example 19:

[0580] Compound number structure <![CDATA[MS (M+H) + ]]> <![CDATA[ 1 H NMR]]> 1-11 #timg#N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 482.0 <![CDATA[(400 MHz, DMSO-d6) δ10.31 (s, 1H), 8.87(s, 1H), 8.11 (dd, J= 7.9, 1.3 Hz, 1H),8.00 (dd, J = 7.6,1.3 Hz, 1H), 7.79(dd, J = 13.6, 2.5Hz, 1H), 7.69 (dd, J= 8.6, 6.2 Hz, 1H),7.55 (dd, J = 8.9,2.6 Hz, 1H),7.51 –7.42 (m, 2H), 7.36 –7.26 (m, 2H), 7.17(s, 1H), 5.21 (s,2H)]]>

[0581] Example 20: N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide

[0582] (1-58)

[0583] Step 1: Preparation of ethyl 6-cyanobenzo[b]thiophene-3-carboxylate

[0584] Under an inert atmosphere, Zn(CN)2 (394 mg, 3.37 mmol), Zn (36 mg, 561 μmol), Pd2(dba)3 (257 mg, 281 μmol) and dppf (311 mg, 561 μmol) were added to a solution of ethyl 6-bromobenzo[b]thiophene-3-carboxylate (800 mg, 2.81 mmol) in DMA (10 mL). The resulting mixture was stirred at 100 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (10%-55% ethyl acetate / petroleum ether) to give the title compound (500 mg, 73.2% yield) as a yellow solid.

[0585] Step 2: Preparation of ethyl 6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxylate

[0586] To a solution of ethyl 6-cyanobenzo[b]thiophene-3-carboxylate (490 mg, 2.12 mmol) and Bu2SnO (264 mg, 1.06 mmol) in toluene (10 mL) was added TMSN3 (732 mg, 6.36 mmol) dropwise. The resulting mixture was stirred at 100 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature and concentrated. The residue was directly purified by silica gel chromatography (5%-20% methanol / DCM) to give the title compound (490 mg, 83.5% yield) as a white solid. LCMS (M+H) + : 275.9.

[0587] Step 3: Preparation of N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide Preparation

[0588] To a solution of ethyl 6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxylate (220 mg, 802 μmol) and 4-cyclopentyl-3-fluoroaniline (144 mg, 802 μmol, 1 equivalent) in toluene (10 mL) was added AlMe3 (69.4 mg, 962 μmol, 1.2 equivalents) at 0 ° C. The resulting mixture was stirred at 80 ° C under N2 for 2 hours. The reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 column (eluent: 35% to 55% (v / v) CH3CN and H2O, containing 10M MOL / L NH4HCO3) to give a crude product. The crude product was further purified by XBridge Prep OBD C18 column, 30×150 mm 5µm column (eluent: 38% to 58% (v / v) acetonitrile and water, containing 10 mmol / L NH4HCO3) to give the title compound as a white solid (35.4 mg, 10.8% yield). LCMS (M+H) + : 408.1. 1 H NMR (300 MHz, DMSO-d6) δ 10.54 (s,1H), 8.79 (d, J = 1.5 Hz, 1H), 8.75 (s, 1H), 8.60 (d, J = 8.6 Hz, 1H), 8.14(dd, J = 8.5, 1.6 Hz, 1H), 7.71 (dd, J = 13.0, 2.1 Hz, 1H), 7.50 (dd, J =8.5, 2.1 Hz, 1H), 7.34 (t, J = 8.6 Hz, 1H), 3.26 – 3.11 (m, 1H), 2.06 – 1.92(m, 2H), 1.89 – 1.47 (m, 6H), no -NH was observed.

[0589] Example 21: N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide

[0590] (1-59)

[0591] Step 1: N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiazole Preparation of phenanthracene-3-carboxamide

[0592] To a solution of ethyl 6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxylate (200 mg, 729 μmol) and 4-((2-chloro-4-fluorobenzyl)oxy)-3-fluoroaniline (197 mg, 729 μmol, 1 equivalent) in toluene (10 mL) was added AlMe3 (63.1 mg, 875 μmol, 1.2 equivalents) at 0 ° C. The reaction was then stirred at 80 ° C under N2 for 2 hours. After the reaction was completed, it was cooled to room temperature and quenched with water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20%-50% methanol / DCM) to give a crude product. The crude product was further purified by C18 column (eluent: 25% to 60% (v / v) acetonitrile and water containing 10 M OL / L NH4HCO3) to give the title compound (49.9 mg, 13.6% yield) as a white solid. LCMS (M+H) + : 497.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.70 (s, 1H), 8.62 (s,1H), 8.50 (dd, J = 8.6, 0.6 Hz, 1H), 8.13 (dd, J = 8.5, 1.5 Hz, 1H), 7.80(dd, J = 13.6, 2.5 Hz, 1H), 7.69 (dd, J = 8.6, 6.3 Hz, 1H), 7.62 – 7.47 (m,2H), 7.38 – 7.27 (m, 2H), 7.11 (brs, 1H), 5.21 (s, 2H).

[0593] Example 22: Luciferase reporter gene assay

[0594] HEK293 cells stably transfected with human GPR35 were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS, 300 µg / mL zeocin, and 200 µg / mL hygromycin at 37°C in 10% CO2. On day 1, cells were plated in regular growth medium (DMEM / 10% FBS / 300 µg / mL zeocin / 200 µg / mL hygromycin) in poly-D-lysine-coated 96-well tissue culture plates. On day 2, luciferase reporter plasmid DNA harboring a YAP-responsive element was transfected into the cells using lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. Six hours after transfection, cells were treated with test compounds in a three-fold serial dilution format in fasting DMEM (without phenol red and FBS) at various compound concentrations ranging from 10 µM to 169 pM. After overnight incubation, luciferase activity was measured using the SteadyLite Plus kit (PerkinElmer) according to the manufacturer's protocol. IC50s were determined by fitting dose-response data to a four-parameter logistic curve using GraphPad Prism.

[0595] Luciferase IC 50 The data are provided in Table 2. The symbol “+” indicates IC 50 Greater than 1 mM. “++” indicates IC 50 >100nM but ≤ 1 mM. “+++” indicates IC 50 ≤100 nM.

[0596] Table 2

[0597]

[0598] Although preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only, which will be apparent to those skilled in the art. Various modifications, variations, and substitutions will now be made by those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed in practicing the present invention. The following claims are intended to define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are thereby encompassed.

[0599] Additional numbered implementation plans

[0600] 1. A compound represented by formula (I):

[0601] (I);

[0602] or a pharmaceutically acceptable salt thereof, wherein:

[0603] X is selected from CR 6 and N;

[0604] Y is selected from CR 12 and N;

[0605] Z is selected from -O-, -S- and -NR 8 -;

[0606] Q does not exist or is selected from:

[0607] - W-, -O-, -OW-, -WO-, -S-, -SW-, -WS-, -NR 10 -W-、-W-NR 10 -、-C(O)-、-C(O)N(R 10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 ) -、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0608] m is selected from 1, 2, 3, 4 and 5;

[0609] R 1 Selected from:

[0610] hydrogen;

[0611] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10)C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0612] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0613] R 2 Selected from:

[0614] hydrogen;

[0615] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN;

[0616] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0617] C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0618] R 3 Selected from:

[0619] C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 Replacement; and

[0620] If Q is -W-, then R 3 Additionally selected from halogen, -OR 10 、-SR10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN; and

[0621] Each R 4 Independently selected from:

[0622] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0623] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0624] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0625] R 5 Selected from:

[0626] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0627] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0628] R 6 Selected from:

[0629] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0630] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0631] Each R 7 Independently selected from:

[0632] hydrogen;

[0633] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R9 Replacement; and

[0634] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0635] R 8 Selected from:

[0636] hydrogen;

[0637] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0638] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0639] Each R 9 Independently selected from:

[0640] Halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0641] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、 -OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0642] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、 -OC(O)N(R10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0643] .

[0644] Each R 10 Independently selected from:

[0645] hydrogen; and

[0646] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0647] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 alkyl halide;

[0648] W is selected from:

[0649] C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings;

[0650] R 12 Selected from:

[0651] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0652] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0653] If Z is NH, then R 4 Not NH2, and

[0654] If Z is O or S, R 4 Yes-OR 3 , and R 5 If it is H, then WR 3 Also selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0655] 2. The compound or salt of embodiment 1, wherein Z is selected from -O- and -S-.

[0656] 3. The compound or salt of embodiment 1 or 2, wherein Z is -O-.

[0657] 4. A compound or salt as described in any one of embodiments 1 to 3, wherein X is CR 6 .

[0658] 5. A compound or salt as described in any one of embodiments 1 to 4, wherein Y is CR 12 .

[0659] 6. The compound or salt of any one of embodiments 1 to 5, wherein Q is absent or selected from -W-, -O-, -OW-, and -WO-.

[0660] 7. A compound or salt as described in any one of embodiments 1 to 6, wherein Q is absent or is -O-.

[0661] 8. The compound or salt of any one of embodiments 1 to 7, wherein Q is absent.

[0662] 9. The compound or salt of any one of embodiments 1 to 8, wherein m is selected from 1 and 2.

[0663] 10. The compound or salt of any one of embodiments 1 to 9, wherein m is 1.

[0664] 11. A compound or salt as described in any one of embodiments 1 to 10, wherein R 1 Selected from:

[0665] hydrogen;

[0666] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0667] C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0668] 12. A compound or salt as described in any one of embodiments 1 to 11, wherein R 1 Selected from hydrogen and C 1-3 alkyl.

[0669] 13. A compound or salt as described in any one of embodiments 1 to 12, wherein R 2 Selected from:

[0670] hydrogen;

[0671] Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl);

[0672] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0673] C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0674] 14. A compound or salt as described in any one of embodiments 1 to 13, wherein R 2 Selected from:

[0675] hydrogen;

[0676] Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl);

[0677] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0678] C6 carbocycle and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen.

[0679] 15. A compound or salt as described in any one of embodiments 1 to 14, wherein R 2 Selected from:

[0680] hydrogen;

[0681] Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl);

[0682] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0683] 16. A compound or salt as described in any one of embodiments 1 to 15, wherein R 2 Selected from hydrogen, halogen and C 1-3 alkyl.

[0684] 17. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is C optionally substituted by one or more substituents independently selected from the following 3-6 Carbocyclic ring: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0685] 18. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a C6 carbocycle optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0686] 19. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0687] 20. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0688] 21. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 5- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0689] 22. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0690] 23. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0691] 24. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0692] 25. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, =O, =S, =NH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) and C 1-6 alkyl.

[0693] 26. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 Is selected from different Azoles, Azoles, thiadiazoles, 5-membered heterocyclic rings of diazole, pyrazole, tetrazole and thiazole, any of which is optionally replaced by one or more R 9 replace.

[0694] 27. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is selected from tetrazole and A 5-membered heterocyclic ring of oxadiazole.

[0695] 28. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is a 5-membered heterocyclic ring selected from the group consisting of isothiazol-3-ol, isothiazol-3-ol, Oxazole-3-ol, squaric acid, thiazolidinedione, Oxazolidinedione, tetrazole, 1,2,4- 1,2,4-thiadiazole-5(4H)-one, 1,2,4- oxadiazole-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5- Thiadiazole 2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one and tetramic acid, any of which is optionally replaced by one or more R 9 replace.

[0696] 29. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 is selected from optionally one or more R 9 Replaced and 5-membered heterocyclic ring.

[0697] 30. A compound or salt as described in any one of embodiments 1 to 16, wherein R 3 Selected from 、 、 、 、 、 、 、 、 、 .

[0698] 31. A compound or salt as described in any one of embodiments 1 to 16, wherein

[0699] Q is - W-;

[0700] R 3 Additionally selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2, -CN; and

[0701] - W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0702] 32. A compound or salt as described in any one of embodiments 1 to 16, wherein

[0703] Q is - W-; and

[0704] R 3 Additionally selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl), and

[0705] - W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0706] 33. A compound or salt as described in any one of embodiments 1 to 16, wherein

[0707] Q is - W-; and

[0708] R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and

[0709] - W- is C1 alkylene optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0710] 34. A compound or salt as described in any one of embodiments 1 to 16, wherein

[0711] Q is - W-; and

[0712] R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and

[0713] - W- is -C(=O)-.

[0714] 35. A compound or salt as described in any one of embodiments 1 to 34, wherein each R 4 Independently selected from:

[0715] Halogen, -OR 7 、-SR 7 、-N(R 7 )2, -NO2 and -CN;

[0716] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C1-6 Alkyl), C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings; and

[0717] C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl);

[0718] 36. A compound or salt as described in any one of embodiments 1 to 35, wherein R 4 Independently selected from -OR 7 、-SR 7 and -N(R 7 )2.

[0719] 37. A compound or salt as described in any one of embodiments 1 to 36, wherein m is 1 and R 4 Yes-OR 7 .

[0720] 38. A compound or salt as described in any one of embodiments 1 to 37, wherein each R 7 Selected from:

[0721] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0722] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0723] 39. A compound or salt as described in any one of embodiments 1 to 38, wherein each R 7 Selected from:

[0724] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0725] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0726] 40. A compound or salt as described in any one of embodiments 1 to 39, wherein each R 7 Selected from:

[0727] Optionally independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0728] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -CN and optionally one or more R 9 Substituted C 1-6 alkyl.

[0729] 41. A compound or salt as described in any one of embodiments 1 to 40, wherein R 7 are independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0730] 42. A compound or salt as described in any one of embodiments 1 to 41, wherein R 7 are independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 6-membered heterocyclic rings substituted with C 1-6 Alkyl, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0731] 43. A compound or salt as described in any one of embodiments 1 to 40, wherein R 7 Selected from C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0732] 44. A compound or salt as described in any one of embodiments 1 to 43, wherein R 5 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0733] 45. A compound or salt as described in any one of embodiments 1 to 44, wherein R 5 It's hydrogen.

[0734] 46. ​​A compound or salt as described in any one of embodiments 1 to 45, wherein R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0735] 47. A compound or salt as described in any one of embodiments 1 to 46, wherein R 6 Selected from hydrogen and halogen.

[0736] 48. A compound or salt as described in any one of embodiments 1 to 47, wherein Z is -NR 8 -.

[0737] 49. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 Selected from hydrogen.

[0738] 50. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 replace.

[0739] 51. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring.

[0740] 52. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from 1-6 Alkyl: halogen, -CN, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0741] 53. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 Selected from C 1-6 alkyl.

[0742] 54. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from 3-10 :Halogen, -OR 10 、-SR10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0743] 55. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from 3-10 Carbocyclic ring: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0744] 56. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

[0745] 57. A compound or salt as described in any one of embodiments 1 to 48, wherein R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0746] 58. A compound or salt as described in any one of embodiments 1 to 57, wherein R 8 It's hydrogen.

[0747] 59. A compound or salt as described in any one of embodiments 1 to 58, wherein each R 9 Selected from:

[0748] Halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and

[0749] C optionally substituted with one or more substituents independently selected from the following 1-3 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2-NH(C 1-6 alkyl).

[0750] 60. A compound or salt as described in any one of embodiments 1 to 59, wherein each R 10 It's hydrogen.

[0751] 61. A compound or salt as described in any one of embodiments 1 to 60, wherein W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0752] 62. A compound or salt as described in any one of embodiments 1 to 60, wherein W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0753] 63. A compound or salt as described in any one of embodiments 1 to 60, wherein W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

[0754] 64. A compound or salt as described in any one of embodiments 1 to 60, wherein W is optionally independently selected from C 3-10 One or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings substituted with C 1-6 Alkylene.

[0755] 65. A compound or salt as described in any one of embodiments 1 to 60, wherein W is independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 5-membered heterocyclic rings substituted with C 1-6 Alkylene.

[0756] 66. A compound or salt as described in any one of embodiments 1 to 60, wherein W is independently selected from C 3-6 One or more substituents of the carbon ring substituted C 1-6 Alkylene.

[0757] 67. A compound or salt as described in any one of embodiments 1 to 60, wherein W is selected from 、 、 、 、 and .

[0758] 68. A compound or salt as described in any one of embodiments 1 to 60, wherein W is C 1-6 Alkylene.

[0759] 69. A compound or salt as described in any one of embodiments 1 to 68, wherein R 12 Selected from hydrogen and halogen.

[0760] 70. The compound or salt according to embodiment 1, wherein the compound or salt is selected from:

[0761] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0762] and their combinations.

[0763] 71. A pharmaceutical composition comprising a compound or salt as described in any one of embodiments 1 to 70 and a pharmaceutically acceptable excipient.

[0764] 72. A method of treating cancer, comprising administering to a subject in need thereof a compound or salt of any one of embodiments 1 to 70.

[0765] 73. A method of treating cancer, comprising administering to a subject in need thereof a compound represented by formula (II):

[0766] (II)

[0767] or a pharmaceutically acceptable salt, wherein:

[0768] X1, X2, X3 and X4 are each independently selected from CQR 3 , CR 6 and N;

[0769] Z is selected from -O-, -S- and -NR 8 -;

[0770] Q does not exist or is selected from:

[0771] - W-, -O-, -O W-, - WO-, -S-, -S W-, - WS-, -NR 10 -W-、-W-NR 10 -、C(O)-、-C(O)N(R10 )-、-N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-、-OC(O)N(R 10 )-、-N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-;

[0772] m is selected from 1, 2, 3, 4 and 5;

[0773] R 1 Selected from:

[0774] hydrogen;

[0775] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0776] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0777] R 2 Selected from:

[0778] hydrogen;

[0779] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0780] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0781] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0782] R 3 Selected from:

[0783] hydrogen;

[0784] Halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN;

[0785] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0786] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0787] Each R 4 Independently selected from:

[0788] Halogen, -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 , -NO2 and -CN;

[0789] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0790] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0791] Each R 6 Independently selected from:

[0792] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0793] C optionally substituted with one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0794] Each R 7 Independently selected from:

[0795] hydrogen;

[0796] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0797] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0798] R 8 Selected from:

[0799] hydrogen;

[0800] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and

[0801] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ),-CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace;

[0802] Each R 9 Independently selected from:

[0803] Halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-OC(O)2R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0804] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、 -OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0805] C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、 -OC(O)N(R 10 )2、-N(R10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and

[0806] ;

[0807] Each R 10 Independently selected from:

[0808] hydrogen; and

[0809] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is opti...

Claims

1. A compound represented by formula (I): (I)； or a pharmaceutically acceptable salt thereof, wherein: X is selected from CR 6 and N; Y is selected from CR 12 and N; Z is selected from -O-, -S- and -NR 8 -; Q is absent or selected from: -W-, -O-, -O-W-, -W-O-, -S-, -S-W-, -W-S-, -NR 10 - W-, -W-NR 10 -, -C(O)-, -C(O)N(R 10 )-, -N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 ) -, -OC(O)N(R 10 )-, -N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-; m is selected from 1, 2, 3, 4 and 5; R 1 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more substituents independently selected from: halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 2 Selected from: hydrogen; halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 3 Selected from: C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 Replacement; and If Q is -W-, then R 3 Also selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2 and -CN; and Where R 3 It is not pyrimidine; Each R 4 Independently selected from: halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , -S(O)2R 7 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 5 Selected from: Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; as well as C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; R 6 Selected from: Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; as well as C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; Each R 7 Independently selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 8 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; Each R 9 Independently selected from: Halogen, -R 10 , -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)2R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; as well as ； Each R 10 Independently selected from: Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 Haloalkyl; W is selected from: C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings; R 12 Selected from: Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; as well as C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; If Z is NH, then R 4 Not NH2, and If Z is O or S, R 4 Yes-OR 3 , and R 5 is H, then WR 3 Also selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

2. The compound or salt of claim 1, wherein Z is selected from -O- and -S-.

3. The compound or salt of claim 1 or 2, wherein Z is -O-.

4. The compound or salt of any one of claims 1 to 3, wherein X is CR 6 .

5. The compound or salt of any one of claims 1 to 4, wherein Y is CR 12 .

6. The compound or salt of any one of claims 1 to 5, wherein Q is absent or selected from -W-, -O-, -OW- and -WO-.

7. The compound or salt of any one of claims 1 to 6, wherein Q is absent or is -O-.

8. The compound or salt of any one of claims 1 to 7, wherein Q is absent.

9. The compound or salt of any one of claims 1 to 8, wherein m is selected from 1 and 2.

10. The compound or salt of any one of claims 1 to 9, wherein m is 1.

11. The compound or salt of any one of claims 1 to 10, wherein R 1 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

12. The compound or salt of any one of claims 1 to 11, wherein R 1 Selected from hydrogen and C 1-3 alkyl.

13. The compound or salt of any one of claims 1 to 12, wherein R 2 Selected from: hydrogen; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

14. The compound or salt of any one of claims 1 to 13, wherein R 2 Selected from: hydrogen; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C6 carbocycle and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen.

15. The compound or salt of any one of claims 1 to 14, wherein R 2 Selected from: hydrogen; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and 16. The compound or salt of any one of claims 1 to 15, wherein R 2 is selected from hydrogen, halogen and C 1-3 alkyl.

17. A compound or salt as claimed in any one of claims 1 to 16, wherein R 3 is C optionally substituted by one or more substituents independently selected from the following 3-6 Carbon ring: halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

18. A compound or salt as claimed in any one of claims 1 to 16, wherein R 3 is a C6 carbocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

19. A compound or salt as claimed in any one of claims 1 to 16, wherein R 3 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

20. The compound or salt of any one of claims 1 to 16, wherein R 3 is a 3- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

21. A compound or salt as claimed in any one of claims 1 to 16, wherein R 3 is a 5- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

22. A compound or salt as claimed in any one of claims 1 to 16, wherein R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

23. A compound or salt as described in any one of claims 1 to 16, wherein R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

24. A compound or salt as described in any one of claims 1 to 16, wherein R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

25. A compound or salt as described in any one of claims 1 to 16, wherein R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, =O, =S, =NH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl) and C 1-6 alkyl.

26. The compound or salt of any one of claims 1 to 16, wherein R 3 Is selected from different Azoles, Azoles, thiadiazoles, A 5-membered heterocyclic ring of diazole, pyrazole, tetrazole and thiazole, any of which is optionally replaced by one or more R 9 replace.

27. A compound or salt as described in any one of claims 1 to 16, wherein R 3 is selected from tetrazole and A 5-membered heterocyclic ring of oxadiazole.

28. A compound or salt as described in any one of claims 1 to 16, wherein R 3 is a 5-membered heterocyclic ring selected from the group consisting of isothiazol-3-ol, isothiazol-3-ol, Oxazole-3-ol, squaric acid, thiazolidinedione, Oxazolidinone, tetrazole, 1,2,4- 1,2,4-thiadiazole-5(4H)-one, 1,2,4- oxadiazole-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5- Thiadiazole 2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole or 1,4-dihydro-5H-tetrazolyl-5-one, 3-hydroxyquinolin-2-one and tetramic acid, any of which is optionally replaced by one or more R 9 replace.

29. A compound or salt as described in any one of claims 1 to 16, wherein R 3 is selected from optionally one or more R 9 Replaced and A 5-membered heterocyclic ring.

30. A compound or salt as described in any one of claims 1 to 16, wherein R 3 Selected from , , , , , , , , , .

31. A compound or salt according to any one of claims 1 to 16, wherein Q is - W-; R 3 Also selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2, -CN; and - W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

32. A compound or salt as described in any one of claims 1 to 16, wherein Q is - W-; and R 3 Also selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl), and - W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

33. A compound or salt according to any one of claims 1 to 16, wherein Q is - W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and - W- is C1 alkylene optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

34. A compound or salt as described in any one of claims 1 to 16, wherein Q is - W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and - W- is -C(=O)-.

35. A compound or salt as described in any one of claims 1 to 34, wherein each R 4 Independently selected from: Halogen, -OR 7 、-SR 7 、-N(R 7 )2, -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

36. A compound or salt as described in any one of claims 1 to 35, wherein R 4 Independently selected from -OR 7 、-SR 7 and -N(R 7 )2.

37. A compound or salt as described in any one of claims 1 to 36, wherein m is 1 and R 4 Yes-OR 7 .

38. A compound or salt as described in any one of claims 1 to 37, wherein each R 7 Selected from: C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

39. A compound or salt as described in any one of claims 1 to 38, wherein each R 7 Selected from: C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

40. A compound or salt as described in any one of claims 1 to 39, wherein each R 7 Selected from: Optionally independently selected from C 3-10 The C substituted with one or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -CN and optionally one or more R 9 Substituted C 1-6 alkyl.

41. A compound or salt as described in any one of claims 1 to 40, wherein R 7 are independently selected from C 3-10 The C substituted with one or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

42. A compound or salt as described in any one of claims 1 to 41, wherein R 7 are independently selected from C 3-6 One or more substituents of a carbocyclic ring or a 3- to 6-membered heterocyclic ring substituted with C 1-6 Alkyl, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

43. A compound or salt as described in any one of claims 1 to 40, wherein R 7 Selected from C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

44. A compound or salt as described in any one of claims 1 to 43, wherein R 5 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

45. A compound or salt as described in any one of claims 1 to 44, wherein R 5 It's hydrogen.

46. ​​A compound or salt as described in any one of claims 1 to 45, wherein R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

47. A compound or salt as described in any one of claims 1 to 46, wherein R 6 is selected from hydrogen and halogen.

48. A compound or salt as described in any one of claims 1 to 47, wherein Z is -NR 8 -.

49. A compound or salt as described in any one of claims 1 to 48, wherein R 8 Selected from hydrogen.

50. A compound or salt as described in any one of claims 1 to 48, wherein R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 replace.

51. A compound or salt as described in any one of claims 1 to 48, wherein R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring.

52. A compound or salt as described in any one of claims 1 to 48, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

53. A compound or salt as described in any one of claims 1 to 48, wherein R 8 Selected from C 1-6 alkyl.

54. A compound or salt as described in any one of claims 1 to 48, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from the following 3-10 :Halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

55. A compound or salt as described in any one of claims 1 to 48, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from the following 3-10 Carbocyclic ring: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

56. A compound or salt as described in any one of claims 1 to 48, wherein R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

57. A compound or salt as described in any one of claims 1 to 48, wherein R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

58. A compound or salt as described in any one of claims 1 to 57, wherein R 8 It's hydrogen.

59. A compound or salt as described in any one of claims 1 to 58, wherein each R 9 Selected from: Halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and C optionally substituted by one or more substituents independently selected from the following 1-3 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2-NH(C 1-6 alkyl).

60. A compound or salt as described in any one of claims 1 to 59, wherein each R 10 It's hydrogen.

61. A compound or salt as described in any one of claims 1 to 60, wherein W is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

62. A compound or salt as described in any one of claims 1 to 60, wherein W is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

63. A compound or salt as described in any one of claims 1 to 60, wherein W is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

64. A compound or salt as described in any one of claims 1 to 60, wherein W is optionally independently selected from C 3-10 The C substituted with one or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings 1-6 Alkylene.

65. A compound or salt as described in any one of claims 1 to 60, wherein W is independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 5-membered heterocyclic rings substituted with C 1-6 Alkylene.

66. A compound or salt as described in any one of claims 1 to 60, wherein W is independently selected from C 3-6 One or more substituents of the carbon ring are substituted with 1-6 Alkylene.

67. A compound or salt as described in any one of claims 1 to 60, wherein W is selected from , , , , and .

68. A compound or salt as described in any one of claims 1 to 60, wherein W is C 1-6 Alkylene.

69. A compound or salt as described in any one of claims 1 to 68, wherein R 12 is selected from hydrogen and halogen.

70. The compound or salt of claim 1, selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and their combinations.

71. A pharmaceutical composition comprising a compound or salt as described in any one of claims 1 to 70 and a pharmaceutically acceptable excipient.

72. A method of treating cancer comprising administering to a subject in need thereof a compound or salt as claimed in any one of claims 1 to 70.

73. A method for treating cancer, the method comprising administering to a subject in need thereof a compound represented by formula (II): (II) or a pharmaceutically acceptable salt, wherein: X1, X2, X3 and X4 are each independently selected from CQR 3 , CR 6 and N; Z is selected from -O-, -S- and -NR 8 -; Q is absent or selected from: - W-, -O-, -O W-, - WO-, -S-, -S W-, - WS-, -NR 10 - W-, - W-NR 10 -, C(O)-, -C(O)N(R 10 )-, -N(R 10 )C(O)-, -C(O)O-, -OC(O)-, -N(R 10 )C(O)N(R 10 )0-, -OC(O)N(R 10 )-, -N(R 10 )C(O)O-, -S(O)-, -S(O)2- and -P(O)2O-; m is selected from 1, 2, 3, 4 and 5; R 1 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 2 Selected from: hydrogen; halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 3 Selected from: hydrogen; halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; Where R 3 It is not pyridine; Each R 4 Independently selected from: halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , -S(O)2R 7 , -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; Each R 6 Independently selected from: Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; as well as C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; Each R 7 Independently selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; R 8 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace; Each R 9 Independently selected from: Halogen, -R 10 , -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)2R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -R 10 、-OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ) and -CN; as well as ； Each R 10 Independently selected from: Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 Haloalkyl; W is selected from: C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

74. The method of claim 73, wherein if Z is NH, then R 4 Not NH2.

75. The method of claim 73, wherein if Z is O or S, R 4 Yes-OR 3 , and R 5 is H, then W-R3 is additionally selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

76. The method of claim 73 or 74, wherein X1, X2 and X3 are each independently CR 6 , and X4 is CQR 3 .

77. The method of claim 73, wherein Z is selected from -O- and -S-.

78. The method of claim 73 or 76, wherein Z is -O-.

79. The method of any one of claims 73 to 78, wherein X is CR 6 .

80. The method of any one of claims 73 to 79, wherein Y is CR 12 .

81. The method of any one of claims 73 to 80, wherein Q is absent or selected from -W-, -O-, -OW- and -WO-.

82. The method of any one of claims 73 to 81, wherein Q is absent or is -O-.

83. The method of any one of claims 73 to 82, wherein Q is absent.

84. The method of any one of claims 73 to 83, wherein m is selected from 1 and 2.

85. The method of any one of claims 73 to 84, wherein m is 1.

86. The method of any one of claims 73 to 85, wherein R 1 Selected from: hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

87. The method of any one of claims 73 to 84, wherein R 1 Selected from hydrogen and C 1-3 alkyl.

88. The method of any one of claims 73 to 86, wherein R 2 Selected from: hydrogen; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

89. The method of any one of claims 73 to 85, wherein R 2 Selected from: hydrogen; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C6 carbocycle and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen.

90. The method of any one of claims 73 to 86, wherein R 2 Selected from: hydrogen; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl); C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

91. The method of any one of claims 73 to 86, wherein R 2 is selected from hydrogen, halogen and C 1-3 alkyl.

92. The method of any one of claims 73 to 91, wherein R 3 is C optionally substituted by one or more substituents independently selected from the following 3-6 Carbon ring: halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

93. The method of any one of claims 73 to 91, wherein R 3 is a C6 carbocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

94. The method of any one of claims 73 to 91, wherein R 3 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

95. The method of any one of claims 73 to 91, wherein R 3 is a 3- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

96. The method of any one of claims 73 to 91, wherein R 3 is a 5- to 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

97. The method of any one of claims 73 to 91, wherein R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

98. The method of any one of claims 73 to 91, wherein R 3 is a 6-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

99. The method of any one of claims 73 to 91, wherein R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

100. The method of any one of claims 73 to 91, wherein R 3 is a 5-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, =O, =S, =NH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl) and C 1-6 alkyl.

101. The method of any one of claims 73 to 91, wherein R 3 Is selected from different Azoles, Azoles, thiadiazoles, A 5-membered heterocyclic ring of diazole, pyrazole, tetrazole and thiazole, any of which is optionally replaced by one or more R 9 replace.

102. The method of any one of claims 73 to 91, wherein R 3 is selected from tetrazole and A 5-membered heterocyclic ring of oxadiazole.

103. The method of any one of claims 73 to 91, wherein R 3 is a 5-membered heterocyclic ring selected from the group consisting of isothiazol-3-ol, isothiazol-3-ol, Oxazole-3-ol, squaric acid, thiazolidinedione, Oxazolidinone, tetrazole, 1,2,4- 1,2,4-thiadiazole-5(4H)-one, 1,2,4- oxadiazole-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5- Thiadiazole 2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole or 1,4-dihydro-5H-tetrazolyl-5-one, 3-hydroxyquinolin-2-one and tetramic acid, any of which is optionally replaced by one or more R 9 replace.

104. The method of any one of claims 73 to 91, wherein R 3 Is selected from and A 5-membered heterocyclic ring.

105. A compound or salt as described in any one of claims 73 to 91, wherein R 3 Selected from , , , , , , , , and .

106. The method of any one of claims 73 to 91, wherein Q is -O- and R 3 It is tetrazole.

107. The method of any one of claims 73 to 91, wherein Q is - W-; R 3 Also selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 , -NO2, -CN; and - W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

108. The method of any one of claims 73 to 91, wherein Q is - W-; and R 3 Also selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl), and - W- is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

109. The method of any one of claims 73 to 91, wherein Q is - W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and - W- is C1 alkylene optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

110. The method of any one of claims 73 to 91, wherein Q is - W-; and R 3 Also selected from -OH, -SH, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and - W- is -C(=O)-.

111. The method of any one of claims 73 to 110, wherein each R 4 Independently selected from: Halogen, -OR 7 、-SR 7 、-N(R 7 )2, -NO2 and -CN; C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring; and C 3-6 carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

112. The method of any one of claims 73 to 110, wherein R 4 Independently selected from -OR 7 、-SR 7 and -N(R 7 )2.

113. The method of any one of claims 73 to 110, wherein m is 1 and R 4 Yes-OR 7 .

114. The method of any one of claims 73 to 113, wherein each R 7 Selected from: C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

115. The method of any one of claims 73 to 113, wherein each R 7 Selected from: C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

116. The method of any one of claims 73 to 113, wherein each R 7 Selected from: Optionally independently selected from C 3-10 The C substituted with one or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 Replacement; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -CN and optionally one or more R 9 Substituted C 1-6 alkyl.

117. The method of any one of claims 73 to 113, wherein R 7 are independently selected from C 3-10 The C substituted with one or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings 1-6 Alkyl, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

118. The method of any one of claims 73 to 113, wherein R 7 are independently selected from C 3-6 One or more substituents of a carbocyclic ring or a 3- to 6-membered heterocyclic ring substituted with C 1-6 Alkyl, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

119. The method of any one of claims 73 to 113, wherein R 7 Selected from C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

120. The method of any one of claims 73 to 119, wherein R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

121. The method of any one of claims 73 to 120, wherein R 6 is selected from hydrogen and halogen.

122. The method of any one of claims 73 to 121, wherein Z is -NR 8 -.

123. The method of any one of claims 73 to 121, wherein R 8 Selected from hydrogen.

124. The method of any one of claims 73 to 121, wherein R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 replace.

125. The method of any one of claims 73 to 121, wherein R 8 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring.

126. The method of any one of claims 73 to 121, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -CN, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

127. The method of any one of claims 73 to 121, wherein R 8 Selected from C 1-6 alkyl.

128. The method of any one of claims 73 to 121, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from the following 3-10 :Halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

129. The method of any one of claims 73 to 121, wherein R 8 is selected from C optionally substituted by one or more substituents independently selected from the following 3-10 Carbocyclic ring: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

130. The method of any one of claims 73 to 121, wherein R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2. -C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replace.

131. The method of any one of claims 73 to 121, wherein R 8 is selected from a 3- to 10-membered heterocyclic ring optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

132. The method of any one of claims 73 to 121, wherein R 8 It's hydrogen.

133. The method of any one of claims 73 to 132, wherein each R 9 Selected from: Halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl); and C optionally substituted by one or more substituents independently selected from the following 1-3 Alkyl: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2-NH(C 1-6 alkyl).

134. The method of any one of claims 73 to 133, wherein each R 10 It's hydrogen.

135. The method of any one of claims 73 to 134, wherein W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

136. The method of any one of claims 73 to 134, wherein W is C optionally substituted with one or more substituents independently selected from the following: 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl), C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

137. The method of any one of claims 73 to 134, wherein W is C optionally substituted with one or more substituents independently selected from the following 1-6 Alkylene: halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl).

138. The method of any one of claims 73 to 134, wherein W is optionally independently selected from C 3-10 The C substituted with one or more substituents of carbocyclic and 3- to 10-membered heterocyclic rings 1-6 Alkylene.

139. The method of any one of claims 73 to 134, wherein W is independently selected from C 3-6 One or more substituents of carbocyclic and 3- to 5-membered heterocyclic rings substituted with C 1-6 Alkylene.

140. The method of any one of claims 73 to 134, wherein W is independently selected from C 3-6 One or more substituents of the carbon ring are substituted with 1-6 Alkylene.

141. The method of any one of claims 73 to 134, wherein W is selected from , , , , and .

142. The method of any one of claims 73 to 141, wherein R 12 is selected from hydrogen and halogen.

143. The method of any one of claims 73 to 141, wherein the method of treating cancer is cancer immunotherapy.

144. The method of any one of claims 73 to 143, wherein the cancer is a solid tumor.

145. The method of claim 143, wherein the solid tumor is a sarcoma, carcinoma, or lymphoma.

146. The method of claim 143, wherein the solid tumor is in the breast, brain, kidney, ovary, cervix, pancreas, thyroid, colon, bladder, prostate, liver, stomach, or lung.

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