GPR35 Modulators and Uses Thereof

Abstract

Disclosed herein are substituted benzofuran, benzothiophene, and indolecarboxamide compounds, conjugates, and pharmaceutical compositions for use as immunotherapeutics in the treatment of cancers, such as solid tumors. The disclosed compounds are useful in the treatment of solid tumors, particularly those originating in the breast, brain, kidney, ovary, cervix, pancreas, thyroid, colon, bladder, prostate, liver, stomach, or lung.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328,415, filed April 7, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] There is a need in the medical field for effective treatment of solid tumors with small molecule therapeutics. Summary of the Invention

[0003] The present disclosure generally relates to substituted benzofuran, benzothiophene and indole carboxamide compounds, conjugates, compounds or salts of formula (I) or (II), and pharmaceutical compositions thereof. In certain aspects, the present disclosure relates to compounds of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein X is CR 6 and N; Y is CR 12 and N; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 2 teeth, 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) 2 R 10 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 teeth, C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); If Q is -W-, then R3 may additionally be 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) 2 R 10 , -NO 2 -CN; R 3 is not a pyrimidine; Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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)2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 5 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; Each R 7 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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)2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 8 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 9 teeth, 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)OR10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =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 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] are independently selected from Each R 10 teeth, Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl; W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 optionally substituted with one or more substituents independently selected from: carbocycle, and 3- to 10-membered heterocycle; R 12 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; When Z is NH, R 4 NH 2 Instead, Z is O or S, and R 4 -OR 3 and R 5 If H, WR 3 Additionally, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0004] In certain embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutical acceptable salt, wherein X 1 , X 2 , X 3 , and X 4 are CQR 3 , C.R. 6 and N are independently selected; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 2 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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)OR10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by ); C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 is not a pyrimidine; Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by Each R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 independently selected from alkyl; Each R 7 teeth, hydrogen; C1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 8 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 9 teeth, 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) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =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 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] are independently selected from; Each R 10 teeth, Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C1-6 Alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl; W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 carbocycle, and 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from

[0005] In certain aspects, the present disclosure provides a pharmaceutical composition comprising any one of the compounds or salts of Formula (I) and (II) or a pharma- ceutically acceptable excipient. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Disclosed herein are substituted benzofuran, benzothiophene and indolecarboxamide compounds, conjugates, and pharmaceutical compositions for use in the treatment of cancer, such as solid tumors. In some embodiments, the compounds disclosed herein are modulators of G protein-coupled receptor 35 (GPR35). In some embodiments, the compounds disclosed inhibit GPR35 expressed in immune cells and promote anti-tumor immunity.

[0007] definition Unless otherwise defined, 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.

[0008] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0009] "C x-y " or "C x -C y The term "alkyl," when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is intended to include groups containing x to y carbons in the chain. For example, "C 1-6 The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain and branched chain alkyl groups, containing 1 to 6 carbons. x-y The term alkylene- refers to a substituted or unsubstituted alkylene chain containing x to y carbons in the alkylene chain. For example, -C 1-6 Alkylene- can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which are optionally substituted.

[0010] "C x-y alkenyl" and "C x-y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively. x-y The term alkenylene- refers to a substituted or unsubstituted alkenylene chain containing x to y carbons in the alkenylene chain. For example, -C 2-6 Alkenylene- can be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any of which are optionally substituted. The alkenylene chain can have one double bond or two or more double bonds in the alkenylene chain. -C x-yThe term alkynylene- refers to a substituted or unsubstituted alkynylene chain containing x to y carbons in the alkenylene chain. For example, -C 2-6 Alkynylene- can be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any of which are optionally substituted. The alkynylene chain can have one triple bond or two or more triple bonds within the alkynylene chain.

[0011] "Alkylene" refers to a linear divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having 1 to 12 carbon atoms, linking the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. In other embodiments, alkylene contains 1 to 5 carbon atoms (i.e., C 1 -C 5 In other embodiments, the alkylene contains 1 to 4 carbon atoms (i.e., C 1 -C 4 In other embodiments, the alkylene contains 1 to 3 carbon atoms (i.e., C 1 -C 3 In other embodiments, the alkylene contains 1 to 2 carbon atoms (i.e., C 1 -C 2 In other embodiments, the alkylene contains one carbon atom (i.e., C 1 In other embodiments, the alkylene contains 5 to 8 carbon atoms (i.e., C 5 -C 8 In other embodiments, the alkylene contains 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, the alkylene contains 3 to 5 carbon atoms (i.e., C 3 -C 5Unless stated otherwise in the specification, an alkylene chain is optionally substituted with one or more substituents such as those described herein.

[0012] "Alkenylene" refers to a linear divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, the alkenylene contains 2 to 4 carbon atoms (i.e., C 2 -C 4 In other embodiments, the alkenylene contains 2 to 3 carbon atoms (i.e., C 2 -C 3 In other embodiments, the alkenylene contains two carbon atoms (i.e., C 2 In other embodiments, the alkenylene contains 5 to 8 carbon atoms (i.e., C 5 -C 8 In other embodiments, the alkenylene contains 3 to 5 carbon atoms (i.e., C 3 -C 5 Alkenylene). Unless stated otherwise in the specification, an alkenylene chain is optionally substituted with one or more substituents such as those described herein.

[0013] "Alkynylene" refers to a linear divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. In another embodiment, the alkynylene contains 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, the alkynylene contains 2 to 4 carbon atoms (i.e., C 2 -C 4 In other embodiments, the alkynylene contains 2 to 3 carbon atoms (i.e., C 2 -C 3 In other embodiments, the alkynylene contains two carbon atoms (i.e., C 2 In other embodiments, the alkynylene contains 5 to 8 carbon atoms (i.e., C 5 -C 8 In other embodiments, the alkynylene contains 3 to 5 carbon atoms (i.e., C 3 -C 5 Alkynylene). Unless stated otherwise in the specification, an alkynylene chain is optionally substituted with one or more substituents such as those described herein.

[0014] The term "carbocycle" as used herein refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3-10 membered monocyclic rings, 5-12 membered bicyclic rings, spiro bicyclic rings, and 5-12 membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as long as valences permit. Bicyclic carbocycles further include spiro bicyclic rings, such as spiro pentane. 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.

[0015] 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, has 5 to 18 carbon atoms, and at least one of the rings of the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Hückel 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 stated in this specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is intended to include aryl radicals that are optionally substituted with one or more substituents, such as those described herein.

[0016] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 5-12 membered bicyclic rings, spiro bicyclic rings, and 5-12 membered bridged rings. In certain embodiments, cycloalkyls contain 3-10 carbon atoms. In other embodiments, cycloalkyls contain 5-7 carbon atoms. Cycloalkyls may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethylbicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like. Unless stated otherwise in the specification, the term "cycloalkyl" is intended to include cycloalkyl radicals optionally substituted with one or more substituents, such as those described herein.

[0017] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 5-12 membered bridged rings. In other embodiments, cycloalkenyls contain 5-7 carbon atoms. Cycloalkenyls may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise stated herein, the term "cycloalkenyl" is intended to include cycloalkenyl radicals that are optionally substituted with one or more substituents, such as those described herein.

[0018] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0019] The term "haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, such as, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl radical is optionally further substituted as described herein.

[0020] The term "heterocycle" as used herein 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 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 5-12 membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as long as valences permit. In exemplary embodiments, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 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. Bicyclic heterocycles further include spiro bicyclic rings, such as 2-oxa-6-azaspiro[3.3]heptane. The term "heterocycle" is intended to encompass "heteroaryl", "heterocycloalkyl" and "heterocycloalkenyl".

[0021] The term "heteroaryl" refers to a radical derived from a 5-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one of the rings of the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) pi-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl is attached to the remainder of the molecule through any atom of the ring(s). Examples of heteroaryl are azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, 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]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]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, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxazolyl Soazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl , pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 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).

[0022] The term "heterocycloalkyl" refers to a saturated ring containing carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyls can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, spiro bicyclic rings, and 5-12 membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. A heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl, such as any carbon or nitrogen atom of the heterocycloalkyl, as long as valence allows. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, the term "heterocycloalkyl" is intended to include heterocycloalkyl radicals as defined above, optionally substituted by one or more substituents, such as those described herein.

[0023] The term "heterocycloalkenyl" refers to an unsaturated ring containing carbon atoms and at least one heteroatom and at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 5-12 membered bridged rings. In other embodiments, heterocycloalkenyl contains 5-7 ring atoms. Heterocycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazolin (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine. Unless stated otherwise in the specification, the term "heterocycloalkenyl" is intended to include heterocycloalkenyl radicals optionally substituted with one or more substituents, such as those described herein.

[0024] The term "substituted" refers to a moiety having a substituent replacing a hydrogen at one or more carbon or substitutable heteroatoms, e.g., NH or NH of a compound. 2"Substituted" or "substituted by" includes the implicit proviso that such substitution results in a stable compound (i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.), subject to the permissible valencies of the substituted atom and substituent. In certain embodiments, substituted refers to a moiety having substituents replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all of the permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0025] In some embodiments, the substituents may include any of the substituents described herein, such as halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazino (=N-NH 2 ), -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 , -Rb -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 selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazine (=N-NH 2 ), -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 , -Rb -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 (wherein t is 1 or 2) and -R b -S(O) t N(R a ) 2 (wherein t is 1 or 2); a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl; each R a is, as far as valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazine (=N-NH 2 ), -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)Ra , -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 (wherein t is 1 or 2) and -R b -S(O) t N(R a ) 2 where t is 1 or 2, and each R b is independently selected from a direct bond, or a straight or branched alkylene, alkenylene, or alkynylene chain; each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0026] A double bond to an oxygen atom, such as an oxo group, is represented herein as both "=O" and "(O)". A double bond to a nitrogen atom is represented herein as both "=NR" and "(NR)". A double bond to a sulfur atom is represented herein as both "=S" and "(S)".

[0027] The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration, usually by injection, excluding enteral and topical administration, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0028] The phrase "pharmaceutical acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0029] The phrase "pharmaceutical acceptable excipient" or "pharmaceutical acceptable carrier" as used herein means a pharmaceutical 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 harmful to the patient. Some examples of materials that can function as pharmaceutical 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) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil. These include oils, (10) glycols such as propylene glycol, (11) polyols such as glycerin, 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) ethyl alcohol, (20) phosphate buffer solutions, and (21) other nontoxic, compatible substances used in pharmaceutical formulations.

[0030] The term "salt" or "pharmaceutical 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 may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, etc. In some embodiments, the pharma- ceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0031] compound The following is a description of compounds and salts thereof that may be used in the methods of the present disclosure. In certain embodiments, the compounds and salts are represented by formula (I):

[0032] In one aspect, disclosed herein is a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein X is CR 6 and N; Y is CR 12and N; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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 )0-, -OC(O)N(R 10 )-, -N(R 10 )C(O)O-, -S(O)-, -S(O) 2 - and -P(O) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; R 2 teeth, 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) 2 R10 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 selected from carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted; R 3 is C 3-6 selected from carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted; Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 independently selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; R 5 and R 6 Each of the groups is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 , -CN, and optionally substituted C 1-6independently selected from alkyl; Each R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 independently selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; R 8 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; Each R 10 are independently selected hydrogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; W is for C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is optionally substituted; R 12 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 , -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; When Z is NH, R 4 NH 2 Instead, Z is O or S, and R 4 -OR 3 and R 5 If H, WR 3Additionally, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0033] In one aspect, disclosed herein is a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein X is CR 6 and N; Y is CR 12 and N; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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 )0-, -OC(O)N(R 10 )-, -N(R 10 )C(O)O-, -S(O)-, -S(O) 2 - and -P(O) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 2 teeth, 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) 2 R 10 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 teeth, C 3-6Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); If Q is -W-, then R 3 may additionally be 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) 2 R 10 , -NO 2 -CN; Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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)R10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 5 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; Each R 7 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 8 teeth, hydrogen; C 1-6 Alkyl, C2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 9 teeth, 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) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-3 Alkyl, C 2-3 Alkenyl, and C 2-3 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] are independently selected from Each R 10 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl; W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C3-10 optionally substituted with one or more substituents independently selected from: carbocycle, and 3- to 10-membered heterocycle; R 12 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; When Z is NH, R 4 NH 2 Instead, Z is O or S, and R 4 -OR 3 and R 5 If H, WR 3 Additionally, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0034] In some embodiments, with respect to the compound or salt of formula (I), X is 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 selected from CR 6 It is.

[0035] In some embodiments, with respect to the compound or salt of formula (I), Y is 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 selected from CR 12It is.

[0036] In some embodiments, with respect to the compound or salt of formula (I), Z is -O-, -S-, or -NR 8 In some embodiments, Z is selected from -O- and -S-. In some embodiments, Z is -O-.

[0037] In some embodiments, with respect to a compound or salt of formula (I), Q is absent, -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) 2 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.

[0038] In some embodiments, with respect to a 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.

[0039] In some embodiments, with respect to the compound or salt of formula (I), R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 is hydrogen and C 1-3 is selected from alkyl.

[0040] In some embodiments, with respect to the compound or salt of formula (I), R 2 is hydrogen, 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) 2 R 10 , -NO 2 , and -CN;C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with halogen, -OH, -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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 2 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R 2 is hydrogen; halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle 1-6 Alkyl; and C 6 carbocycle, and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen. 2 is hydrogen; halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 , -NH(C 1-6 alkyl); halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, R 2 is hydrogen, halogen, and C 1-3 is selected from alkyl.

[0041] In some embodiments, with respect to the compound or salt of formula (I), R 3 is C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 when Q is -W-, R 3 may additionally be 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) 2 R 10 , -NO 2 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 and phenyl optionally substituted with one or more substituents independently selected from:

[0042] In some embodiments, with respect to the compound or salt of formula (I), R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6Alkyl, C 2-6 Alkenyl, and C 2-6 is a 6-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, with respect to the compound or salt of formula (I), R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl,1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 are halogens, -CN, -OH, =O, =S, =NH, -SH, -NO 2 , -NH 2 , -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 is a 5-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl. 3 isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, and thiazole (each of which may contain one or more R 9 In some embodiments, R is a 5-membered heterocycle selected from 3 is a 5-membered heterocycle selected from tetrazole and oxadiazole. 3 isothiazol-3-ol, isoxazol-3-ol, squaric acid, thiazolidinedione, oxazolidinedione, tetrazole, 1,2,4-oxadiazol-5(4H)-one, 1,2,4-thiadiazol-5(4H)-one, 1,2,4-oxadiazol-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5-oxathiadiazole-2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole, or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one, and tetramic acid (each of which may contain one or more R 9 In some embodiments, R is a 5-membered heterocycle selected from 3 is one or more R 9 is optionally replaced by [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, Q is -O- and R 3 is tetrazole.

[0043] In some embodiments, with respect to a compound or salt of formula (I), Q is -W-; R 3 may additionally be 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) 2 R 10 , -NO 2 , -CN; -W- is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, Q is -W-; R 3 may additionally include halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl), -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1 In some embodiments, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); -W- is -C(=O)-.

[0044] In some embodiments, R 3 is not phenyl. In some embodiments, R 3 is not a pyrimidine. 3 is not pyridine. 3 does not exist.

[0045] In some embodiments, with respect to the compound or salt of formula (I), R 4 is 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) 2 R 7 , -NO 2 , and -CN;C 1-6 Alkyl, C 2-6 Alkenyl, and C2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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)2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 4 is halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -NO 2 , and -CN;C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, each R 4 -OR 7 , -SR 7 , and -N(R7 ) 2 In some embodiments, m is 1 and R 4 -OR 7 It is.

[0046] In some embodiments, with respect to a compound or salt of formula (I), each R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -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 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, each R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10, -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, each R 7 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl(C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, each R 7 is C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl(C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -CN, and one or more R 9 C optionally replaced by 1-6 In some embodiments, R 7 is C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R 7 is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl, C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R 7 is C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 and optionally substituted with one or more substituents independently selected from alkyl.

[0047] In some embodiments, with respect to the compound or salt of formula (I), R 5 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 and -CN; and halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 In some embodiments, R 5 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6In some embodiments, R 5 is hydrogen.

[0048] In some embodiments, with respect to the compound or salt of formula (I), R 6 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R 6 is selected from hydrogen and halogen.

[0049] In some embodiments, with respect to a compound or salt 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 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 8 is selected from hydrogen. 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is halogen, -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R10 ) 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 In some embodiments, R 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from. In some embodiments, R 8 is halogen, -CN, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6C optionally substituted with one or more substituents independently selected from 1-6 In some embodiments, R 8 is C 1-6 In some embodiments, R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-10 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6C optionally substituted with one or more substituents independently selected from 3-10 In some embodiments, R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R is selected from the group consisting of 3- to 10-membered heterocycles optionally substituted with one or more substituents independently selected from alkyl, aryl, aryls ... 8is hydrogen.

[0050] In some embodiments, with respect to a compound or salt of formula (I), each R 9 is 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) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN;C 1-3 Alkyl, C 2-3 Alkenyl, and C 2-3 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] In some embodiments, each R 9 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); and halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-3 is selected from alkyl.

[0051] In some embodiments, with respect to a compound or salt of formula (I), each R 10 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl). In some embodiments, each R 10 is hydrogen.

[0052] In some embodiments, with respect to the compound or salt of formula (I), W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 In some embodiments, W is C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, W is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 5-membered heterocycles 1-6 In some embodiments, W is C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 In some embodiments, with respect to a compound or salt of formula (I), W is [ka] In some embodiments, W is selected from C 1-6 It is alkylene.

[0053] In some embodiments, with respect to the compound or salt of formula (I), R 12 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 and -CN; and halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 In some embodiments, R 12 is selected from hydrogen and halogen.

[0054] In some embodiments, the compound or salt of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] and combinations thereof.

[0055] In some embodiments, the compound or salt of formula (I) is [ka] [ka] [ka] [ka] [ka] is selected from.

[0056] In some embodiments, the compound or salt of formula (I) is [ka] [ka] is selected from.

[0057] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharma- ceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0058] The present disclosure includes the salts of the compounds described herein, particularly pharma- ceutically acceptable salts.Compounds of the present disclosure that have sufficiently acidic, sufficiently basic, or both functional groups can react with some inorganic bases and inorganic and organic acids to form salts.Alternatively, compounds that are inherently charged, such as those that have quaternary nitrogen, can form salts with suitable counterions, such as halides, such as bromide, chloride, or fluoride, particularly bromide.

[0059] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms in some cases. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by formation of diastereomers and recrystallization or separation by chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, which is incorporated herein by reference for the present disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0060] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. However, in some embodiments, the active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. Furthermore, the compounds described herein may exist in unsolvated form as well as 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.

[0061] In certain embodiments, the compound or salt of the compound may be a prodrug, for example, a hydroxyl in the parent compound exists as an ester or carbonate, or a carboxylic acid in the parent compound exists as an ester. The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to become pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzyme activity of the host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0062] Prodrug forms of the compounds described herein that are metabolized in vivo to provide the compounds described herein are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0063] Prodrugs are often useful because in some circumstances they can be administered more easily than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help improve the cell permeability of the compound compared to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed as reversible drug derivatives to improve drug transport to site-specific tissues or to be used as modifiers to enhance drug retention inside cells.

[0064] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective aqueous solubility. For example, 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,Vol.14 of the ACSSymposium Series, and Edward See B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein for such disclosure. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0065] 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. Larock, Comprehensive Organic Transformations (1989), T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d. 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).

[0066] Therapeutic Applications The methods of administration of compounds or salts of formula (I) or (II) described herein can be used in the treatment of cancer.

[0067] In one aspect, disclosed herein is a compound of formula (II): [ka] or a pharma- ceutical acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are CQR 3 , C.R. 6 and N are independently selected; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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 )0-, -OC(O)N(R 10 )-, -N(R 10 )C(O)O-, -S(O)-, -S(O) 2 - and -P(O) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, Hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, C 3-10 selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; R 2 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, C 3-10 selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; R 3 is C3-10 selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, C 3-10 independently selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; Each R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 and -CN; and optionally substituted C 1-6 independently selected from alkyl; Each R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, C 3-10 independently selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; R 8is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, C 3-10 selected from carbocycle and 3-10 membered heterocycle, each of which is optionally substituted; Each R 10 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, C 3-10 independently selected from carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted; W is for C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 alkynylene, each of which is optionally substituted.

[0068] In one aspect, disclosed herein is a compound of formula (II): [ka] or a pharma- ceutical acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are CQR 3 , C.R. 6 and N are independently selected; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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 )0-, -OC(O)N(R 10)-, -N(R 10 )C(O)O-, -S(O)-, -S(O) 2 - and -P(O) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -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 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 2 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by Each R6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 independently selected from alkyl; Each R 7 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 8 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Each alkynyl may be one or more R 9 (optionally replaced by); Each R 9 teeth, 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) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =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 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] are independently selected from; Each R 10 teeth, Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl; W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 carbocycle, and 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from

[0069] In some embodiments, with respect to the compound or salt of formula (II), X 1 , X 2 , X 3 , and X 4 are CQR 3, C.R. 6 and N. In some embodiments, X 1 , X 2 , and X 3 are each independently CR 6 and X 4 is CQR 3 In some embodiments, X 1 , X 2 , and X 4 are each independently CR 6 and X 3 is CQR 3 In some embodiments, X 1 , X 2 , X 3 , or X 4 In some embodiments, one of X is N. 1 , X 2 , X 3 , or X 4 Neither of these is N.

[0070] In some embodiments, with respect to the compound or salt of formula (II), Z is -O-, -S-, or -NR 8 In some embodiments, when Z is NH, R 4 NH 2 In some embodiments, Z is selected from -O- and -S-. In some embodiments, Z is -O-. In some embodiments, Z is O or S and R 4 -OR 3 and R 5 If H, WR 3 Additionally, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0071] In some embodiments, with respect to the compound or salt of formula (II), Q is absent, -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) 2 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.

[0072] In some embodiments, with respect to a 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.

[0073] In certain embodiments, with respect to the compound or salt of formula (II), R 1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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)R10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 1 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 is hydrogen and C 1-3 is selected from alkyl.

[0074] In certain embodiments, with respect to the compound or salt of formula (II), R 2 is 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) 2 R10 , -NO 2 , and -CN;C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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)OR10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 2 is hydrogen; halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6In some embodiments, R 2 is hydrogen; halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle 1-6 Alkyl; and C 6 carbocycle, and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen. 2 is hydrogen; halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6In some embodiments, R 2 is hydrogen, halogen, and C 1-3 is selected from alkyl.

[0075] In certain embodiments, with respect to 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN;C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by ).

[0076] In certain embodiments, with respect to the compound or salt of formula (II), R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 and phenyl optionally substituted with one or more substituents independently selected from:

[0077] In certain embodiments, with respect to the compound or salt of formula (II), R 3 is 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) 2 R 10, -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 6-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 and m is 0, 1 or 2. A 6-membered heterocycle optionally substituted with one or more substituents independently selected from:

[0078] In certain embodiments, with respect to the compound or salt of formula (II), R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 3 are halogens, -CN, -OH, =O, =S, =NH, -SH, -NO 2 , -NH 2 , -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 is a 5-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl. 3 isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, and thiazole (each of which may contain one or more R 9 In some embodiments, R is a 5-membered heterocycle selected from tetrazole and oxadiazole. In some embodiments, R 3isothiazol-3-ol, isoxazol-3-ol, squaric acid, thiazolidinedione, oxazolidinedione, tetrazole, 1,2,4-oxadiazol-5(4H)-one, 1,2,4-thiadiazol-5(4H)-one, 1,2,4-oxadiazol-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5-oxathiadiazole-2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole, or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one, and tetramic acid (each of which may contain one or more R 9 In some embodiments, R is a 5-membered heterocycle selected from 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, Q is -O- and R 3 is tetrazole.

[0079] In certain embodiments, with respect to a compound or salt of formula (II), Q is -W-; R 3 may additionally be 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) 2 R 10 , -NO 2 , -CN; -W- is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, Q is -W-; R 3 may additionally include halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl), -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 , and -NH(C 1-6 alkyl); -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1 In some embodiments, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); -W- is -C(=O)-.

[0080] In certain embodiments, with respect to the compound or salt 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) 2 R 7 , -NO 2 , and -CN;C 1-6 Alkyl, C 2-6Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, each R 4 is halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -NO 2 , and -CN;C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 is independently selected from the group consisting of aryl, ... 4 -OR 7 , -SR 7, and -N(R 7 ) 2 In some embodiments, m is 1 and R 4 -OR 7 It is.

[0081] In certain embodiments, with respect to a compound or salt of formula (II), each R 7 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -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 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, each R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10, -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, each R 7 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl(C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 7 is C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl(C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -CN, and one or more R 9 C optionally replaced by 1-6 In some embodiments, R 7 is C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R 7 is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl, C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 R is optionally substituted with one or more substituents independently selected from alkyl, 7 is C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 and optionally substituted with one or more substituents independently selected from alkyl.

[0082] In certain embodiments, with respect to the compound or salt of formula (II), R 6 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 and -CN; and halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 In some embodiments, R 6 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6In some embodiments, R 6 is selected from hydrogen and halogen.

[0083] In certain embodiments, with respect to compounds or salts of formula (II), Z is -NR 8 In some embodiments, R 8 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R10 , -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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 8 is selected from hydrogen. 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10, -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 In some embodiments, R 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from. In some embodiments, R 8 is halogen, -CN, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 In some embodiments, R 8 is C 1-6 In some embodiments, R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-10 Carbocyclic rings, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 3-10 In some embodiments, R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 In some embodiments, R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 In some embodiments, R is selected from the group consisting of 3- to 10-membered heterocycles optionally substituted with one or more substituents independently selected from alkyl, aryl, aryls ... 8 is hydrogen.

[0084] In certain embodiments, with respect to a compound or salt of formula (II), each R 9 is 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 , -OC(O) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN;C 1-3 Alkyl, C 2-3 Alkenyl, and C 2-3 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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)R10 、 -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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] In some embodiments, each R 9 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); and halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-3 is selected from alkyl.

[0085] In certain embodiments, with respect to a compound or salt of formula (II), each R 10 is hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl). In some embodiments, each R 10 is hydrogen.

[0086] In certain embodiments, with respect to the compound or salt of formula (II), W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 Alkyl), C 3-10In some embodiments, W is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 In some embodiments, W is C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 In some embodiments, W is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 5-membered heterocycles 1-6In some embodiments, W is C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 In some embodiments, W is [ka] In some embodiments, W is selected from C 1-6 It is alkylene.

[0087] The administration method of the compound or salt of formula (I) or (II) described herein can be used to treat cancer. In some embodiments, the treatment is an immunotherapy treatment. In some 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.

[0088] In some embodiments, the compounds or salts of formula (I) or (II) described herein may 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 in the treatment of solid tumors, alone or in combination with additional therapeutic agents.

[0089] Pharmaceutical preparations The compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical compositions may include at least a compound or salt of formula (I) or (II) described herein and one or more pharma- ceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and / or thickening agents.

[0090] Pharmaceutical compositions comprising the compound or salt of formula (I) or (II) can be formulated using one or more physiologically acceptable carriers, including excipients and auxiliaries. Formulations can be modified according to the route of administration selected. Pharmaceutical compositions comprising the compound, salt or conjugate can be prepared, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. Pharmaceutical compositions can comprise the compound, salt or conjugate in free base form or in pharma-ceutical acceptable salt form.

[0091] The method of formulating the compound or salt of formula (I) or (II) may include formulating either the compound, salt or conjugate with one or more inert and pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.Solid compositions may include, for example, powders, tablets, dispersible granules, and capsules, and in some embodiments, the solid compositions further contain non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharma-ceutically acceptable additives.Alternatively, the compound, salt, or conjugate may be lyophilized or in powder form to be reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0092] Pharmaceutical compositions containing a compound or salt of formula (I) or (II) may contain at least one active ingredient (e.g., a compound, a salt or a conjugate, and other agents). The active ingredient may be entrapped, for example, in microcapsules prepared by coacervation techniques or interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions.

[0093] The compositions and formulations may be sterilized. Sterilization may be accomplished by filtration by sterile filtration.

[0094] The compositions described herein are administered to a subject by a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. 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 dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0095] The composition containing the compound or salt of formula (I) or (II) can be formulated for administration as an injection. Non-limiting examples of the formulation for injection can include sterile suspension, solution, or emulsion in oily or aqueous vehicle. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. The suspensions can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the composition can be lyophilized or in powder form that is reconstituted with a suitable vehicle such as sterile pyrogen-free water before use.

[0096] For parenteral administration, the compound or salt of formula (I) or (II) can be formulated in a single dose injectable form (e.g., solution, suspension, emulsion) in association with a pharma- ceutically acceptable parenteral vehicle. Such vehicles can be essentially non-toxic and non-therapeutic. The vehicle can be water, saline, Ringer's solution, dextrose 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. The vehicle can contain small amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0097] In one embodiment, the present invention relates to a method and a composition of formula (I) or (II) configured to be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In one aspect, formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders to be reconstituted into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), vegetable oils, and organic esters such as ethyl oleate. In some aspects of the present disclosure, formulations suitable for subcutaneous injection contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin.

[0098] For intravenous injection, the compounds described herein will be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0099] Parenteral injection may include bolus injection or continuous infusion. Preparations for injection may be provided in unit dosage form, such as ampoules, or in multi-dose containers, with added preservatives. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. In one embodiment, the active ingredient is in powder form, which is constituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0100] In certain aspects of the disclosure, delivery systems for pharmaceutical compounds may be used, such as liposomes and emulsions. In certain aspects of the disclosure, the compositions provided herein may also include 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.

[0101] In one embodiment, the present invention relates to a method and a composition of formula (I) or (II) configured for oral delivery to a subject in need thereof. In one embodiment, the composition is formulated to deliver one or more pharmacologic active agents to a subject through the mucosal layer of the oral cavity or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmacologic active agents to a subject through the mucosal layer of the stomach and / or intestine.

[0102] In one embodiment, the composition of formula (I) or (II) is provided in a modified release dosage form.Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof.The composition can also include non-release controlled excipients.

[0103] In another embodiment, the composition of formula (I) or (II) is provided in an enteric coated dosage form. These enteric coated dosage forms may also contain non-release controlled excipients. In one embodiment, the composition is in the form of enteric coated granules as a controlled release capsule for oral administration. The composition may further comprise cellulose, disodium hydrogen phosphate, hydroxypropylcellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric coated pellets as a controlled release capsule for oral administration. The composition may further comprise glycerol monostearate 40-50, hydroxypropylcellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[0104] 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 monoglyceride, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow ferric oxide.

[0105] Sustained release preparations containing the compound or salt of formula (I) or (II) can also be prepared. Examples of sustained release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (for example, films or microcapsules). Examples of sustained release matrices can include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPO (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0106] Pharmaceutical formulations containing the compounds or salts of formula (I) or (II) can be prepared for storage by mixing the compounds, salts or conjugates with pharma- ceutically acceptable carriers, excipients, and / or stabilizers. The formulations can be lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, and / or stabilizers can be non-toxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citric acid, 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes; and / or non-ionic surfactants or polyethylene glycols.

[0107] 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.

[0108] In another embodiment, the compositions of formula (I) or (II) are provided in effervescent dosage forms. These effervescent dosage forms may also contain non-release controlling excipients.

[0109] In another embodiment, the composition of formula (I) or (II) can be provided in a dosage form having at least one component that can facilitate immediate release of the active agent and at least one component that can facilitate controlled release of the active agent.In a further embodiment, the dosage form can provide intermittent release of the compound in the form of at least two successive pulses separated in time by an interval of 0.1 to 24 hours.The composition can include one or more release-controlling excipients and non-release-controlling excipients, for example, excipients suitable for a breakable semipermeable membrane and excipients as a swellable substance.

[0110] In another embodiment, a composition of formula (I) or (II) is provided in a dosage form for oral administration to a subject, the dosage form comprising one or more pharma- ceutically acceptable excipients or carriers comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and surrounded by an intermediate reactive layer having cation exchange capacity and an outer gastric juice-resistant layer.

[0111] In some embodiments, the compositions of formula (I) or (II) provided herein may be in unit dosage form or multiple dosage form. Unit dosage form as used herein refers to physically separate units suitable for administration to human and non-human animal subjects and packaged individually. Each unit dose may contain a predetermined amount of active ingredient(s) sufficient to produce the desired therapeutic effect in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, a unit dosage form may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container and may be administered in divided unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment, a multiple dosage form contains different pharma- ceutical active agents.

[0112] In some embodiments, the composition of formula (I) or (II) can also be formulated as modified release dosage forms, including immediate release, delayed release, sustained release, extended release, sustained release, pulsed release, controlled release, sustained release, accelerated and fast release, targeted release, programmed release, and gastric retention dosage forms. 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, which are incorporated herein by reference in their entirety).

[0113] Combination therapy Combination therapy is also contemplated herein, for example, co-administration of the disclosed compounds and additional active agents as part of a specific treatment plan intended to produce beneficial effects from the co-action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically carried out over a period of time (usually hours, days, weeks, months or years, depending on the combination selected). Combination therapy is intended to encompass not only the administration of multiple therapeutic agents or at least two of the therapeutic agents substantially simultaneously, but also the sequential administration of these therapeutic agents, i.e., administration of each therapeutic agent at a different time.

[0114] Substantially simultaneous administration can be achieved, for example, by administering to the subject separate formulations or compositions (e.g., tablets or capsules with a fixed ratio of each therapeutic agent), or multiple separate formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent of the selected combination is administered by intravenous injection, and the other therapeutic agent of the combination is administered orally. Alternatively, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered by intravenous injection.

[0115] The components of the combination are administered to a patient simultaneously or sequentially. It will be understood that the components are administered simultaneously by being present in the same pharma- ceutically acceptable carrier. Alternatively, the active components are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered either simultaneously or sequentially. EXAMPLES

[0116] The invention, generally described herein, 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.

[0117] In some embodiments, compound 5 described herein is prepared as depicted in Scheme A.

[0118] Scheme A. [ka] Compound 5 can be prepared via the synthetic route described in Scheme A. A simple and selective one-pot reaction using commercially available 2-hydroxybenzaldehyde (1) and ethyl diazoacetate efficiently affords 3-ethoxycarbonylbenzofuran (2), which can be easily converted to 3-ethoxycarbonylbenzofuran by the addition of NaCN and Zn(CN). 2 Palladium catalyzed cyanation with a cyanaide salt such as 3 affords compound 3. The synthesis of 5-substituted 1H-tetrazoles from organic nitriles 3 can be achieved by one of a number of catalysts and methodologies, where hydrolysis of (1H-tetrazol-5-yl)benzofuran-3-carboxylate in basic medium affords key intermediate 4. Finally, compound 5 is obtained from the amide coupling reaction of carboxylic acid 4 with the corresponding substituted aromatic amine in the presence of a coupling reagent such as HATU, EDCl, or CDI.

[0119] In some embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0120] Scheme B. [ka] Compound 5 may alternatively be prepared via the synthetic route described in Scheme B. Starting from benzofuran acid (6), compound 7 is obtained from a two-step sequence of amide coupling and transition metal-catalyzed cyanation. The tetrazole of 5 can then be introduced using a procedure similar to that described in step c of Scheme A. The cyano group can also be converted to other five-membered heterocycles such as 1,2,4-oxadiazol-5(4H)-ones (e.g., 8) via an N-hydroxyimide amide intermediate.

[0121] In some embodiments, the compounds described herein are prepared as depicted in Scheme C.

[0122] Scheme C. [ka] Compound 15 can be prepared via the synthetic route described in Scheme C. Commercially available 9 is converted to hydroxybenzaldehyde (10), which is then converted to 3-ethoxycarbonylbenzofuran (11) under conditions similar to those described in Scheme A, step a. 3 Demethylation facilitated by Br-(CH 2 ) n Realkylation with CN affords compound 13. Final compound (15) is synthesized starting from 13 in a similar manner as described in steps c-e of Scheme A.

[0123] In some embodiments, the compounds described herein are prepared as depicted in Scheme D.

[0124] Scheme D. [ka] Substituted anilines (18, 20, 22) can be prepared via the synthetic route described in Scheme D. Nucleophilic aromatic substitution (S N Ar) reaction gives compound 17, which is then reduced to oxyaniline (18). Compound 19 can be obtained from aryl bromide (16, Y=Br) via a palladium-catalyzed coupling reaction of the corresponding amine, known as the Buchwald-Hartwig amination, which is then reduced to diaminobenzene (20). Finally, the (cyclo)alkylation of aryl bromide (16, Y=Br) to compound 22 is completed by a two-step reaction of Suzuki-Miyaura cross-coupling with the corresponding alkenylboronic acid / ester and alkenyl reduction.

[0125] In some embodiments, the compounds described herein are prepared as depicted in Scheme E.

[0126] Scheme E. [ka] Compound 27 can be prepared by a procedure similar to that described in Scheme E. Compound 27 can be obtained from a procedure similar to that described in steps b-e of Example A. Alternatively, AlMe 3 Compound 25 can also be obtained directly by amide formation with the corresponding aniline promoted by:

[0127] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds may vary.

[0128] Table 1 below lists the compounds disclosed herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0129] Note that with respect to the compounds disclosed in Table 1 above, the stereochemistry depicted for compounds 1-25, 1-26, 1-30, 1-31, 1-36, and 1-37 has been arbitrarily designated as R or S.

[0130] Example 1: N-(4-cyclobutoxy-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 1-cyclobutoxy-2-fluoro-4-nitrobenzene Cyclobutanol (3.399 g, 47.14 mmol) in THF (100 mL) was added to KO t Bu (5.290 g, 47.14 mmol, 1.5 equiv) was added at 0° C. The resulting mixture was stirred at 0° C. for 1 h and then treated with 1,2-difluoro-4-nitrobenzene (5 g, 31.43 mmol, 1 equiv). The mixture was stirred at 0° C. and slowly warmed to room temperature over 4 h. It was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness under reduced pressure to give the crude product which was purified by silica gel chromatography to give the title compound (4.5 g, 50% yield). LCMS (M+H) + :212.1.

[0131] Step 2: Preparation of 4-cyclobutoxy-3-fluoroaniline 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 heated at room temperature with H 2 Stirred under atmosphere for 2 hours. Then it was filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound as a yellow solid (3.4 g, 85% yield). LCMS (M+H) + :182.0.

[0132] Step 3: Preparation of 6-bromo-N-(4-cyclobutoxy-3-fluorophenyl)benzofuran-3-carboxamide To a solution of 6-bromobenzofuran-3-carboxylic acid (300 mg, 1.24 mmol), 4-cyclobutoxy-3-fluoroaniline (226 mg, 1.24 mmol, 1 equiv.) and HATU (568 mg, 1.49 mmol, 1.2 equiv.) in DMF (10 mL) was added DIEA (483 mg, 3.73 mmol, 3 equiv.) at room temperature. The reaction was stirred at room temperature for 2 h and quenched with water. The resulting mixture was then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (15%-50% ethyl acetate / petroleum ether) to give the title compound as a brown solid (440 mg, 68.9%). LCMS (M+H) + :404.1.

[0133] Step 4: Preparation of 6-cyano-N-(4-cyclobutoxy-3-fluorophenyl)benzofuran-3-carboxamide 6-Bromo-N-(4-cyclobutoxy-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 Pd 2 (dba) 3 A DMA solution (10 mL) of dppf (99.6 mg, 109 μmol) and dppf (121 mg, 218 μmol) was heated at 100 °C for 2 h in N 2 The mixture was stirred under reduced pressure. The reaction was cooled to room temperature and quenched with water. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (15%-50% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (220 mg, 41.9%). LCMS (M+H) + :351.3.

[0134] Step 5: Preparation of N-(4-cyclobutoxy-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 6-cyano-N-(4-cyclobutoxy-3-fluorophenyl)benzofuran-3-carboxamide (90 mg, 0.26 mmol) and Bu 2 A solution of SnO (32 mg, 0.13 mmol) in toluene (5 mL) was added to TMSN 3 (88.8 mg, 0.77 mmol) was added dropwise. The mixture was heated at 100 °C for 2 h with N 2 The reaction was stirred under reduced pressure for 10 min. The reaction was cooled to room temperature and concentrated. The residue was purified by XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm column (eluent: 18% to 48% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a white solid (37.6 mg, 37% yield). LCMS (M+H) + :394.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0135] The following compounds were synthesized according to Example 1: [Table 2-1] [Table 2-2] [Table 2-3]

[0136] Example 2: 3-((4-cyclobutoxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid [ka] Step 1: Preparation of ethyl 3-((4-cyclobutoxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylate A solution of 6-cyano-N-(4-cyclobutoxy-3-fluorophenyl)benzofuran-3-carboxamide (100 mg, 285 μmol) in EtOH (5 mL) was diluted with SOCl 2 (1.02 g, 8.56 mmol, 30 equiv) was added at 0° C. The mixture was stirred at 80° C. for 16 h. The reaction was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (52 mg, 46% yield). LCMS (M+H) + :398.0.

[0137] Step 2: Preparation of 3-((4-cyclobutoxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid Ethyl 3-((4-cyclobutoxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylate (52 mg, 0.13 mmol) in THF / MeOH / H 2 To the HO solution (3 / 1 / 1, 5 mL) was added lithium hydroxide (4.8 mg, 0.20 mmol, 2 equiv.) at 0 °C. The mixture was stirred at 0 °C for 2 h, then 2 M HCl was added to adjust the pH to 5-6. The reaction was concentrated and purified using an XBridge Prep OBD C18 150 mm × 30 mm × 5 μm column (eluent: 15%-45% (v / v) CH). 3CN and H 2 O and 10 mmol / L NH 4 HCO 3 The residue was further purified by preparative HPLC using 1,2-dichloro-1,3-dichloro-2,4-dichloro-1,5-dichloro-2,6-dichloro-1,7-dichloro-2,7-dichloro-1,8-dichloro-2,8-dichloro-2,9 ... + :370.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ δ 10.30 (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).

[0138] Example 3: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 2-chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene 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 equiv.). The resulting mixture was cooled to 0° C. and then cooled to 50° C. with KO t The reaction was stirred at room temperature for 4 h, quenched with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4It was dried at 40° C., filtered and concentrated. The crude product was recrystallized with DCM / PE solvent to give the title compound as a white solid (4 g, 60% yield).

[0139] Step 2: Preparation of 4-((2-chloro-4-fluorobenzyl)oxy)aniline 2-Chloro-4-fluoro-1-((4-nitrophenoxy)methyl)benzene (2 g, 0.02 mol) in EtOH / H 2 To a 6:1, 70 mL solution of Fe powder (2 g, 5 equiv.) and NH 4 Cl (4 g, 10 equiv.) was added at room temperature. The mixture was stirred at 85° C. for 2 h, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by silica gel chromatography to give the product as a brown solid (1.5 g, 70% yield). CMS (M+H) + :251.9.

[0140] Step 3: Preparation of ethyl 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate Ethyl 6-cyanobenzofuran-3-carboxylate (1.6 g, 7.4 mmol) and Bu 2 A solution of SnO (1.1 g, 4.5 mmol) in toluene (30 mL) was added to TMSN 3 (2.6 g, 22 mmol) was added dropwise. The mixture was heated at 100 °C for 2 h with N 2 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 and anhydrous Na 2 SO 4 It was dried at 40° C., 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.

[0141] Step 4: Preparation of 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid Ethyl 6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (250 mg, 968 μmol) in THF / MeOH / H 2 To the 2H2O solution (10 mL, v / v / v = 3 / 1 / 1), LiOH (46.4 mg, 1.94 mmol) was added at 0 °C. The reaction was then slowly warmed to room temperature and stirred for 2 h. The pH of the reaction was adjusted to about 7 by adding 1 M HCl. After removal of the volatile solvents, the residue was purified by column chromatography (eluent: 10%-30% (v / v) CH4Cl). 3 CN and H 2 O and 10 mmol / L NH 4 HCO 3 ) to give the title compound as a yellow solid (205 mg, 85%). LCMS (M+H) + :231.0.

[0142] Step 5: Preparation of 3-((4-cyclobutoxy-3-fluorophenyl)carbamoyl)benzofuran-6-carboxylic acid 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 equiv.) and HATU (297 mg, 782 μmol, 1.2 equiv.) in DMF (10 mL) was added DIEA (253 mg, 1.95 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 h, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by Xselect CSH OBD Column, 30×150 mm 5 μm column (eluent: 44%-74% (v / v) acetonitrile and water with 0.1% FA) to give the title compound as a yellow solid (40.3 mg, 13.2% yield). LCMS (M+H) + :463.9. 1 H NMR (400 MHz, DMSO-d 6) 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), -NH was not observed.

[0143] Example 4: 6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide [ka] Step 1: Preparation of methyl 6-(cyanomethoxy)benzofuran-3-carboxylate A solution of methyl 6-hydroxybenzofuran-3-carboxylate (1.5 g, 7.8 mmol) and 2-bromoacetonitrile (1.1 g, 9.4 mmol, 1.2 equiv.) in acetone (15 mL) was added with K 2 CO 3 (2.2 g, 16 mmol, 2 equiv.) was added at room temperature. The reaction mixture was stirred at 60° C. for 6 h, cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (1.08 g, 53% yield).

[0144] Step 2: Preparation of methyl 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylate A solution of methyl 6-(cyanomethoxy)benzofuran-3-carboxylate (1 g, 4 mmol) in toluene (20 mL) was added to TMSN 3 (1 g, 0.01 mmol, 3 equiv.) and Bu 2SnO (0.5 g, 2 mmol, 0.5 equiv.) was added. The reaction flask was evacuated and then refilled with nitrogen. The reaction was stirred at 100 °C for 2 h with N 2 The mixture was stirred under reduced pressure, 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 and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound as a white solid (1 g, 80% yield). LCMS (M+H) + :275.0.

[0145] Step 3: Preparation of 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylic acid Methyl 6-((1H-tetrazol-5-yl)methoxy)benzofuran-3-carboxylate (900 mg, 3.28 mmol) in THF / MeOH / H 2 To the 2H2O solution (3 / 1 / 1, 5 mL) was added lithium hydroxide (157 mg, 6.56 mmol, 2 equiv) at 0 °C. The mixture was stirred at room temperature for 2 h and the pH was adjusted to 5-6 by adding 2 M HCl. The reaction was concentrated and the residue was further purified by silica gel column (eluent: 15%-25% (v / v) DCM and MeOH) to give the title compound as a white solid (650 mg, 74.1% yield). LCMS (M+H) + :261.0.

[0146] Step 4: Preparation of 6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide 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 equiv.) and HATU (263 mg, 692 μmol, 1.2 equiv.) in DMF (5 mL) was added DIEA (224 mg, 1.73 mmol, 3 equiv.) at room temperature. The reaction was stirred at room temperature for 2 h. After the reaction was complete, it was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated. The residue was purified by silica gel chromatography (15%-40% methanol / dichloromethane) to give the crude product. The crude product was then purified using an XBridge Prep OBD C18 Column, 30×150 mm 5 μm column (eluent: 25%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a white solid (24.0 mg, 8.33% yield). LCMS (M+H) + :494.0. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0147] The following compounds were synthesized according to Example 4: [Table 3]

[0148] Example 5: 6-((1H-tetrazol-5-yl)oxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide [ka] Step 1: Preparation of ethyl 6-cyanatobenzofuran-3-carboxylate Ethyl 6-hydroxybenzofuran-3-carboxylate (1000 mg, 4.803 mmol) and BrCN (610.5 mg, 5.763 mmol, 1.2 equiv.) 2 To the 20O solution (10 mL), 3 N (972 mg, 9.606 mmol, 2 equiv.) was added at 0° C. The mixture was stirred at 0° C. for 3 h, quenched with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give the product as a white solid (309 mg, 54.7% yield).

[0149] Step 2: Preparation of ethyl 6-((1H-tetrazol-5-yl)oxy)benzofuran-3-carboxylate A solution of ethyl 6-cyanatobenzofuran-3-carboxylate (800 mg, 1.30 mmol) in toluene (1 mL) was added to TMSN 3 (448 mg, 3.89 mmol, 3 equiv.) and Bu 2 SnO (162 mg, 0.649 mmol, 0.5 equiv) was added. The reaction flask was evacuated and then refilled with nitrogen. The reaction was stirred at 100 °C for 3 h with N 2 The mixture was stirred under reduced pressure, 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 and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (261 mg, 73.3% yield).

[0150] Step 3: Preparation of 6-((1H-tetrazol-5-yl)methoxy)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)benzofuran-3-carboxamide 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 AlMe 3 (100 mg, 1.39 mmol, 1.2 equiv) was added at 0 °C. The resulting mixture was heated at 80 °C for 2 h with N 2 The reaction was stirred under reduced pressure. After the reaction was completed, it was cooled to room temperature, quenched with water, and concentrated. The residue was purified by column chromatography (eluent: 35%-55% (v / v) CH 3 CN and H 2 O and 10 mmol / L NH 4 HCO 3 ) to give the title compound as a pale yellow solid (158 mg, 29.4% yield). LCMS (M+H) + :480.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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), -NH was not observed.

[0151] Example 6: 6-((1H-tetrazol-5-yl)oxy)-N-(4-(3,3-difluorocyclobutoxy)-3-fluorophenyl)-5-fluorobenzofuran-3-carboxamide [ka] Step 1: Preparation of 4-(3,3-difluorocyclobutoxy)-3-fluoroaniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) - :216.0.

[0152] Step 2: Preparation of 5-fluoro-2-hydroxy-4-methoxybenzaldehyde N 2 To the ice-cold solution of 4-fluoro-3-methoxyphenol (1.42 g, 10.0 mmol) in MeCN (50 mL) below, anhydrous magnesium chloride (1.90 g, 20.0 mmol) was added portionwise. Solid paraformaldehyde (2.10 g, 69.9 mmol) was added to the reaction mixture, followed by dropwise addition of triethylamine (5.60 mL, 40.0 mmol). 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 successively with 1M HCl, water, and brine. The organic layer was extracted with anhydrous NaCl. 2 SO 4 Drying at 40° C. and concentration afforded the title compound (1.54 g, 91%) as an off-white solid. This material was used in the next step without further purification. LCMS (M+H) + :171.2.

[0153] Step 3: Preparation of ethyl 5-fluoro-6-methoxybenzofuran-3-carboxylate A solution of 5-fluoro-2-hydroxy-4-methoxybenzaldehyde (3.5 g, 21 mmol) in DCM (10 mL) was added to BF 4 ·OEt 2 (0.33 g, 2.1 mmol, 0.1 equiv.) and ethyl 2-diazoacetate (4.7 g, 41 mmol, 2 equiv.) were added at room temperature. The reaction was stirred for 30 min and then washed with H 2 SO 4 (2.0 g, 21 mmol, 1 equiv.) and stirred at room temperature for an additional 2 h. The reaction was quenched with water and extracted with DCM (3×100 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4The residue was purified by silica gel column to give the title compound (3.9 g, 80%).

[0154] Step 4: Preparation of ethyl 5-fluoro-6-hydroxybenzofuran-3-carboxylate To a solution of ethyl 5-fluoro-6-methoxybenzofuran-3-carboxylate (3.9 g, 16 mmol) was added 3,3-difluorocyclobutan-1-ol (4.1 g, 16 mmol). The reaction mixture was cooled to 0° C. and stirred at 0° C. for 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and washed with anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (2.9 g, 79% yield). LCMS (M+H) + :225.0.

[0155] Step 5: Preparation of ethyl 6-cyanato-5-fluorobenzofuran-3-carboxylate Ethyl 5-fluoro-6-hydroxybenzofuran-3-carboxylate (600 mg, 2.66 mmol) and BrCN (338 mg, 3.19 mmol, 1.2 equiv.) 2 To the 20O solution (10 mL), 3 N (537 mg, 5.32 mmol, 2 equiv.) was added at 0° C. The mixture was stirred at 0° C. for 3 h, quenched with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (200 mg, 30% yield).

[0156] Step 6: Preparation of ethyl 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylate Ethyl 6-cyanato-5-fluorobenzofuran-3-carboxylate (350 mg, 1.39 mmol) and Bu 2 A solution of SnO (173 mg, 697 μmol) in toluene (10 mL) was added to TMSN 3 (482 mg, 4.18 mmol) was added dropwise. The mixture was heated at 100 °C for 2 h with N 2 After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was then purified by column chromatography (eluent: 35%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a yellow solid (250 mg, 62% yield). LCMS (M+H) + :293.0.

[0157] Step 7: Preparation of 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylic acid Ethyl 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylate (230 mg, 0.787 mmol) in THF / MeOH / H 2 To a 200 mL (10 mL, v / v / v = 3 / 1 / 1) solution of HO (94 mg, 3.94 mmol, 5 equiv.) was added at 0 °C. The reaction was allowed to warm slowly to room temperature and stirred for 2 h. After adjusting the pH to about 7, the reaction was concentrated and purified by C18 column (eluent: 10%-30% (v / v) CH 3 CN and H 2 O and 10 mmol / L NH 4 HCO 3 ) to give the title compound (150 mg, 72%). LCMS (M+H) + :264.9.

[0158] Step 8: Preparation of 6-((1H-tetrazol-5-yl)oxy)-N-(4-(3,3-difluorocyclobutoxy)-3-fluorophenyl)-5-fluorobenzofuran-3-carboxamide To a solution of 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylic acid (130 mg, 492 μmol) and 4-(3,3-difluorocyclobutoxy)-3-fluoroaniline (107 mg, 492 μmol, 1 equiv.) in pyridine (10 mL) was added EDCI (113 mg, 591 μmol, 1.2 equiv.). The reaction was stirred at room temperature for 2 h, quenched with water, and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (eluent: 35%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a yellow solid (15.1 mg, 6.52% yield). LCMS (M+H) + :464.1. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0159] The following compounds were synthesized according to Example 6: [Table 4]

[0160] Example 7: 5-Fluoro-N-(3-fluoro-4-(1-methylcyclopropoxy)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-(3,3-difluorocyclobutoxy)-3-fluoroaniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :182.0.

[0161] Step 2: Preparation of 5-fluoro-2-hydroxy-4-methoxybenzaldehyde 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, N 2 The reaction mixture was then cooled to 0° C. 4 ·OEt 2 (0.5 g, 3 mmol, 0.1 equiv.) and N 2 After removal of the volatile solvents, the residue was stirred under H 2 SO 4 The resulting mixture was stirred at 0° C. for 2 h, carefully quenched with water (50 mL) and extracted with DCM (100 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a yellow solid (3.5 g, 50% yield).

[0162] Step 3: Preparation of ethyl 5-fluoro-6-methoxybenzofuran-3-carboxylate Ethyl 6-chloro-5-fluorobenzofuran-3-carboxylate (1 g, 4 mmol) and Zn(CN) 2 (0.6g, 5mmol) and Zn (0.05g, 0.8mmol) and Pd 2 (dba) 3A reaction mixture of dppf (0.4 g, 0.4 mmol) and dppf (0.5 g, 0.8 mmol) in DMF (30 mL) was added to N 2 Degas by bubbling with N for 5 min and then at 100 °C for 2 hr. 2 After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The residue was then purified by silica gel column to give the title compound as a yellow solid (720 mg, 70% yield).

[0163] Step 4: Preparation of ethyl 5-fluoro-6-hydroxybenzofuran-3-carboxylate Ethyl 6-cyano-5-fluorobenzofuran-3-carboxylate (900 mg, 3.86 mmol) and Bu 2 A solution of SnO (480 mg, 1.93 mmol) in toluene (20 mL) was added to TMSN 3 (1.33 g, 11.6 mmol) was added dropwise. The mixture was heated at 100 °C for 2 h with N 2 After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (5%-20% methanol / DCM) to give the title compound as a yellow solid (810 mg, 71% yield). LCMS (M+H) + :277.1.

[0164] Step 5: Preparation of ethyl 6-cyanato-5-fluorobenzofuran-3-carboxylate Ethyl 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (770 mg, 2.79 mmol) in THF / H 2To the 20 solution (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 h. After the reaction was complete, the pH was adjusted to about 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.

[0165] Step 6: Preparation of ethyl 6-((1H-tetrazol-5-yl)oxy)-5-fluorobenzofuran-3-carboxylate To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (200 mg, 806 μmol) and 3-fluoro-4-(1-methylcyclopropoxy)aniline (146 mg, 806 μmol, 1 eq.) and HATU (367 mg, 967 μmol, 1.2 eq.) in DMF (10 mL) was added DIEA (312 mg, 2.42 mmol, 3 eq.) 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 (3×50 mL). The combined organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (eluent: 30%-50% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the crude product. The crude product was further purified by Xselect CSH OBD C18 Column, 30×150 mm 5 μm column (eluent: 40%-66% (v / v) acetonitrile and water with 0.05% TFA) to give the title compound as a pale yellow solid (45.6 mg, 13.7% yield). LCMS (M+H) + :412.0. 1 H NMR (300 MHz, DMSO-d 6) 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), -NH was not observed.

[0166] The following compounds were synthesized according to Example 7: [Table 5-1] [Table 5-2]

[0167] Example 8: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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 equiv.) in pyridine (10 mL) was added EDCI (185 mg, 967 μmol, 1.2 equiv.) at room temperature. The reaction was stirred at room temperature for 2 h, quenched with water, and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4The residue was then purified by column chromatography (eluent: 35%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a yellow solid (108.3 mg, 27.4% yield). LCMS (M+H) + :482.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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), -NH was not observed.

[0168] Example 9: N-(4-((4-chlorothiophen-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-chloro-2-((4-nitrophenoxy)methyl)thiophene To a solution of (4-chlorothiophen-2-yl)methanol (500 mg, 3.36 mmol) and 1-fluoro-4-nitrobenzene (712 mg, 5.05 μmol, 1.5 equiv) in THF (10 mL) was added t-BuOK (566 mg, 5.05 mmol, 1.5 equiv) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography to give the title compound as a white solid (800 mg, 88.2% yield).

[0169] Step 2: Preparation of 4-((4-chlorothiophen-2-yl)methoxy)aniline 4-Chloro-2-((4-nitrophenoxy)methyl)thiophene (750 mg, 2.78 mmol) in EtOH / H 2 NH2O solution (4:1, 12.5 mL) 4 Cl (1.5 g, 27.8 mmol, 10 equiv.) and Fe (0.78 g, 13.9 mmol, 5 equiv.) were added. After removing the air from the reaction flask, N 2 The reaction was then refilled with N for 2 h at 85 °C. 2 The mixture was stirred under reduced pressure for 20 min. It was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and diluted with anhydrous Na 2 SO 4 It was dried at 70° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (600 mg, 90% yield). LCMS (M+H) + :240.0.

[0170] Step 3: Preparation of N-(4-((4-chlorothiophen-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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-chlorothiophen-2-yl)methoxy)aniline (174 mg, 0.725 mmol, 1.2 equiv), HATU (275 mg, 0.725 mmol, 1.2 equiv) and DIEA (234 mg, 1.81 mmol, 3 equiv). The reaction was stirred at room temperature for 1 h, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 The crude product was purified by XBridge Prep C18 OBD Column (eluent: 22%-47% (v / v) CH 3 CN and H2 O and 10 mmol / L NH 4 HCO 3 ) to give the title compound as a white solid (20.1 mg, 6.93% yield). LCMS (M+H) + :470.1. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0171] Example 10: N-(4-((4-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-((4-chloro-3-fluorobenzyl)oxy)aniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :251.9.

[0172] Step 2: Preparation of N-(4-((4-chloro-3-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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 equiv.) and HATU (91 mg, 0.24 mmol, 1.2 equiv.) in DMF (5 mL) was added DIEA` (77 mg, 0.6 mmol, 3 equiv.) 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 brine and extracted with anhydrous Na 2 SO 4 The residue was then purified by XBridge Prep C18 OBD Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 30%B to 60%B in 7min to give the title compound as a white solid (11.9mg, 12.0% yield). LCMS (M+H) + :482.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0173] Example 11: N-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-((5-chloropyridin-2-yl)methoxy)aniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :235.2.

[0174] Step 2: Preparation of N-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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 equiv.) and HATU (97 mg, 0.26 mmol, 1.2 equiv.) in DMF (5 mL) was added DIEA (82 mg, 0.64 mmol, 3 equiv.) 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 (3×50 mL). The combined organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (eluent: 30%-50% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to obtain the crude product. Then, XBridge Prep OBD C18 Column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH 4 HCO 3 ), Mobile phase B: MeOH--HPLC; Flow rate: 25 mL / min; Gradient: 45% B to 65% B in 10 min to give the title compound as a white solid (13.9 mg, 14% yield). LCMS (M+H) + :465.0. 1 H NMR (300 MHz, DMSO-d 6) 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).

[0175] Example 12: N-(4-((4-chloro-3,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-((4-chloro-3,5-difluorobenzyl)oxy)aniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :270.1.

[0176] Step 2: Preparation of N-(4-((4-chloro-3,5-difluorobenzyl)oxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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 equiv.) and HATU (85 mg, 0.22 mmol, 1.2 equiv.) in DMF (5 mL) was added DIEA (72 mg, 0.56 mmol, 3 equiv.) at room temperature. The reaction was stirred at room temperature for 2 h, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4The residue was purified by column chromatography (eluent: 30%-50% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to obtain the crude product. Then, XBridge Prep C18 OBD Column, 30*100mm, 5μm; Mobile phase A: water (10mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 53% B in 9 min to give the title compound as a white solid (14.2 mg, 15% yield). LCMS (M+H) + :500.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0177] The following compounds were synthesized according to Example 12: [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0178] Example 13: N-(4-cyclopentyl-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 1-(cyclopent-1-en-1-yl)-2-fluoro-4-nitrobenzene 1-Bromo-2-fluoro-4-nitrobenzene (1g, 5mmol) in 1,4-dioxane / H 2 In a 3:1 mixture of 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9 g, 5 mmol, 1 equiv.), Pd(dppf)Cl 2 (0.3 g, 0.5 mmol, 0.1 equiv.), and K 2 CO 3 (1 g, 9 mmol, 2 equiv.) was added. After removing the air from the reaction flask, N 2 The reaction was then refilled with N for 30 min at 110 °C. 2 After the reaction was completed, it was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and diluted with anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the product as a white solid (800 mg, 60% yield).

[0179] Step 2: Preparation of 4-cyclopentyl-3-fluoroaniline To a solution (10 mL) of 1-(cyclopent-1-en-1-yl)-2-fluoro-4-nitrobenzene (800 mg, 3.86 mmol) in MeOH, wet Pd / C (400 mg, 0.5 equivalents) was added at room temperature. After removing the air from the reaction flask, N 2 The above process was repeated three times, and then the reaction flask was refilled with H 2 The reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was carefully filtered through a pad of Celite. The filtrate was concentrated to give the crude product (650 mg, 88% yield), which was used directly in the next step. LCMS (M+H) + :180.1.

[0180] Step 3: Preparation of N-(4-cyclopentyl-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (200 mg, 806 μmol) and 4-cyclopentyl-3-fluoroaniline (144 mg, 806 μmol, 1 equiv.) and HATU (367 mg, 967 μmol, 1.2 equiv.) in DMF (10 mL), DIEA (312 mg, 2.42 mmol, 3 equiv.) was added at room temperature. The reaction was stirred at room temperature for 2 h. After the reaction was completed, it was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then purified by C18 column (eluent: 35%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a yellow solid (40.1 mg, 11.9% yield). LCMS (M+H) + :410.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0181] Example 14: (S)-5-Fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of (S)-1-(2-fluoro-4-nitrophenyl)-2-(trifluoromethyl)pyrrolidine A solution of 1-bromo-2-fluoro-4-nitrobenzene (1 g, 5 mmol) in 1,4-dioxane (40 mL) was added with (S)-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 Cs 2 CO 3 (3g, 9mmol) was added. The reaction was stirred at 90°C for 2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel chromatography to give the title compound as an off-white solid (1g, 80% yield). LCMS (M+H) + :279.2.

[0182] Step 2: Preparation of (S)-3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)aniline The title compound was prepared according to step 2 of example 1. LCMS (MH) + :249.1.

[0183] Step 3: Preparation of (S)-5-fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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 equiv.) in toluene (10 mL), was added AlMe 3 (104 mg, 1.45 mmol, 2 equiv.) was added at 0 °C. The reaction was heated at 80 °C for 2 h with N 2After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was then purified by column chromatography (eluent: 35%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a pink solid (34.7 mg, 9.85% yield). LCMS (M+H) + :479.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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), -NH was not observed.

[0184] The following compounds were synthesized according to Example 14: [Table 7]

[0185] Example 15: N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-6-cyano-5-fluorobenzofuran-3-carboxamide 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 equiv.) in toluene (10 mL) was added with AlMe 3 (57 mg, 788 μmol, 1.2 equiv.) was added at 0° C. The reaction was heated at 80° C. for 2 h with N 2 The mixture was stirred under reduced pressure. After the reaction was completed, it was cooled to room temperature and quenched with water. The resulting mixture was then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (eluent: 35%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound (84 mg, 30%). LCMS (M+H) + :439.0.

[0186] Step 2: Preparation of (Z)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(N'-hydroxycarbamimidoyl)benzofuran-3-carboxamide H 2 NOH-HCl (79 mg, 1.14 mmol, 2.5 equiv.) and K 2 CO 3 To a solution of (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 reaction was stirred at 70° C. for 4 h. After the reaction was complete, it was cooled to room temperature, quenched with water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound as an off-white solid (200 mg, 65% yield). LCMS (M+H) +:472.0.

[0187] Step 3: Preparation of N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzofuran-3-carboxamide To a solution of (Z)-N-(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluoro-6-(N'-hydroxycarbamimidoyl)benzofuran-3-carboxamide (200 mg, 424 μmol) and di(1H-imidazol-1-yl)methanone (82.5 mg, 509 μmol, 1.2 equiv) in dioxane (10 mL) was added DBU (71 mg, 466 μmol, 1.1 equiv). The reaction was stirred at 100° C. for 3 h and then cooled to 5° C. with N 2 The mixture was cooled to room temperature under reduced pressure. After the reaction was completed, its pH was adjusted to about 2 with 2M HCl. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was then purified by C18 reverse phase column to give the title compound as an off-white solid (37.7 mg, 17.5% yield). LCMS (MH) - :495.9. 1 H NMR (300 MHz, DMSO-d 6 ) 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), -NH was not observed.

[0188] Example 16: N 3 -(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3,6-dicarboxamide [ka] Step 1: 3 Preparation of -(4-((2-chloro-4-fluorobenzyl)oxy)phenyl)-5-fluorobenzofuran-3,6-dicarboxamide 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 treated with (E)-acetaldehyde oxime (16.2 mg, 273 μmol, 1 equiv.) and Pd(AcO) 2 (6.14 mg, 27.3 μmol, 0.1 equivalents) and PPh 3 (71.7 mg, 273 μmol, 1 equiv.) was added. The resulting mixture was heated at 80° C. for 2 h with N 2 After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated. The residue was purified by silica gel column to give the crude product. The crude product was purified by XBridge Prep OBD C18 Column, 30×150 mm 5 μm column (eluent: 43%-68% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a pale yellow solid (32.4 mg, 25.7% yield). LCMS (M+H) + :457.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.21 (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).

[0189] 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 [ka] Step 1: Preparation of 4-((3,3-difluorocyclopentyl)oxy)-3-fluoroaniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :232.2.

[0190] Step 2: Preparation of (Rac)-N-(4-((3,3-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide To a solution of 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (280 mg, 1.13 mmol), 4-((3,3-difluorocyclopentyl)oxy)-3-fluoroaniline (287 mg, 1.24 mmol, 1.1 equiv.) and HATU (514 mg, 1.35 mmol, 1.2 equiv.) in DMF (10 mL) was added DIEA (437 mg, 3.38 mmol, 3 equiv.) 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 (3×50 mL). The combined organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (eluent: 25%-55% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a yellow solid (300 mg, 57.3% yield). LCMS (M+H) + :462.2.

[0191] Step 3: Preparation of (S)-5-fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide and (R)-5-fluoro-N-(3-fluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide 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: Hex(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 (31.9 mg, 99.511% purity, 99.7% ee) as an off-white solid (second peak) and the (R) isomer (first peak). Stereochemistry was 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 not observed. (R) isomer: LCMS (M+H) + :462.0.1H NMR (300 MHz, DMSO-d 6) δ 8.96 (s, 1H), 8.39 (d, J = 5.4 Hz, 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.

[0192] The following compounds were synthesized according to Example 17: [Table 8]

[0193] Example 18: N-(4-(2-chloro-4-fluorophenoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-(2-chloro-4-fluorophenoxy)aniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :238.1.

[0194] Step 2: Preparation of N-(4-(2-chloro-4-fluorophenoxy)phenyl)-5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxamide A solution of ethyl 5-fluoro-6-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (232 mg, 842 μmol) and 4-(2-chloro-4-fluorophenoxy)aniline (200 mg, 842 μmol, 1 equiv.) in toluene (10 mL) was added with AlMe 3 (72.8 mg, 1.01 mmol, 1.2 equiv) was added at 0 °C. The reaction was heated at 80 °C for 2 h with N2 The mixture was stirred under reduced pressure. After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by C18 reverse phase column to give the title compound as a white solid (42.3 mg, 10.7% yield). LCMS (M+H) + :468.0. 1 H NMR (300 MHz, DMSO-d 6 ) 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.

[0195] Example 19: N-(4-(cyclopentyloxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide [ka] Step 1: Preparation of 4-(cyclopentyloxy)-3-fluoroaniline The title compound was prepared according to steps 1 and 2 of example 1. LCMS (MH) + :195.9.

[0196] Step 2: Preparation of ethyl 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylate A solution of ethyl 7-cyanobenzofuran-3-carboxylate (1 g, 4 mmol) in toluene (20 mL) was added to TMSN 3 (2 g, 0.01 mmol, 3 equiv.) and Bu 2SnO (0.5 g, 2 mmol, 0.5 equiv.) was added. The reaction flask was evacuated under vacuum and then refilled with nitrogen. The reaction was stirred at 100° C. for 2 h. After the reaction was complete, it was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound as a white solid (1.05 g, 80% yield). LCMS (M+H) + :259.0.

[0197] Step 3: Preparation of 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid Ethyl 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylate (980 mg, 3.79 mmol) in THF / MeOH / H 2 To the 2H2O solution (10 mL, v / v / v=3 / 1 / 1), LiOH (182 mg, 7.59 mmol) was added at 0 °C. The solution was then slowly warmed to room temperature and stirred for 2 h. After the reaction was completed, its pH was adjusted to about 7. The crude product precipitated during the pH adjustment. The solid product was filtered, collected, and purified by C18 column (eluent: 25%-45% (v / v) CH4O). 3 CN and H 2 O and 10 mmol / L NH 4 HCO 3 ) to give the title compound (1.0 g, 90%). LCMS (M+H) + :231.0.

[0198] Step 4: Preparation of N-(4-(cyclopentyloxy)-3-fluorophenyl)-7-(1H-tetrazol-5-yl)benzofuran-3-carboxamide To a solution of 7-(1H-tetrazol-5-yl)benzofuran-3-carboxylic acid (300 mg, 1.3 mmol), 4-(cyclopentyloxy)-3-fluoroaniline (254 mg, 1.3 mmol, 1 equiv.) and HATU (594 mg, 1.56 mmol, 1.2 equiv.) in DMF (10 mL) was added DIEA (505 mg, 3.91 mmol, 3 equiv.) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine and washed with anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was then purified by silica gel chromatography (15%-40% methanol / DCM) to give the crude product. The crude product was then further purified by XBridge Prep OBD C18 Column, 30×150 mm 5 μm column (eluent: 20%-50% (v / v) acetonitrile and water with 10 mmol / L NH4HCO3) to give the title compound as a white solid (97.7 mg, 18.2% yield). LCMS (M+H) + :408.1. 1 H NMR (400 MHz, DMSO-d 6 ) 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), NH not observed.

[0199] The following compounds were synthesized according to Example 19: [Table 9]

[0200] Example 20: N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide [ka] Step 1: Preparation of ethyl 6-cyanobenzo[b]thiophene-3-carboxylate A solution of ethyl 6-bromobenzo[b]thiophene-3-carboxylate (800 mg, 2.81 mmol) in DMA (10 mL) was added to Zn(CN) 2 (394mg, 3.37mmol), Zn (36mg, 561μmol), Pd 2 (dba) 3 (257 mg, 281 μmol) and dppf (311 mg, 561 μmol) were added under an inert atmosphere. The resulting mixture was heated at 100° C. for 2 h with N 2 After the reaction was completed, it was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (10% to 55% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (500 mg, 73.2%).

[0201] Step 2: Preparation of ethyl 6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxylate Ethyl 6-cyanobenzo[b]thiophene-3-carboxylate (490 mg, 2.12 mmol) and Bu 2 A solution of SnO (264 mg, 1.06 mmol) in toluene (10 mL) was added to TMSN 3 (732 mg, 6.36 mmol) was added dropwise. The resulting mixture was heated at 100 °C for 2 h with N 2The mixture was stirred under reduced pressure. 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 as a white solid (490 mg, 83.5% yield). LCMS (M+H) + :275.9.

[0202] Step 3: Preparation of N-(4-cyclopentyl-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide 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 equiv.) in toluene (10 mL) was added with AlMe 3 (69.4 mg, 962 μmol, 1.2 equiv.) was added at 0° C. The resulting mixture was heated at 80° C. for 2 h with N 2 The reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (eluent: 35%-55% (v / v) CH 3 CN and H 2 O and 10 mmol / L NH 4 HCO 3 The crude product was purified by XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm column (eluent: 38% to 58% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) 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-d 6) 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), -NH was not observed.

[0203] Example 21: N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide [ka] Step 1: Preparation of N-(4-((2-chloro-4-fluorobenzyl)oxy)-3-fluorophenyl)-6-(1H-tetrazol-5-yl)benzo[b]thiophene-3-carboxamide 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 equiv.) in toluene (10 mL), was added AlMe 3 (63.1 mg, 875 μmol, 1.2 equiv) was added at 0° C. The reaction was then heated at 80° C. for 2 h with N 2 The mixture was stirred under reduced pressure. After the reaction was completed, it was cooled to room temperature and quenched with water. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated. The residue was purified by silica gel chromatography (20% to 50% methanol / DCM) to give the crude product. The crude product was purified by C18 column (eluent: 25% to 60% (v / v) acetonitrile and water with 10 mmol / L NH 4 HCO 3 ) to give the title compound as a white solid (49.9 mg, 13.6% yield). LCMS (M+H) + :497.9. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0204] Example 22: Luciferase reporter assay HEK293 cells stably transfected with human GPR35 were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS, 300 μg / mL Zeocin and 200 μg / mL Hygromycin at 37°C and 10% CO 2Cells were maintained at 4°C for 12 h. 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. The following day, cells were transfected with luciferase reporter plasmid DNA containing the YAP response element using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. After 6 h of transfection, cells were treated with fasting DMEM medium (phenol red-free, FBS-free) containing test compounds at various compound concentrations ranging from 10 μM to 169 pM in a 3-fold serial dilution format. 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 4-parameter logistic curve using GraphPad Prism.

[0205] Luciferase IC 50 The data are shown in Table 2. The symbol "+" indicates IC 50 "++" indicates IC 50 "+++" indicates IC 50 is less than 100 nM. [Table 10]

[0206] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will readily occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0207] Additional Numbered Embodiments

[0208] 1. Formula (I): [ka] or a pharma- ceutical acceptable salt thereof, X is CR 6 and N; Y is CR 12 and N; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 2 teeth, 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) 2 R 10 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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)R10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 teeth, C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); If Q is -W-, then R 3 may additionally be 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) 2 R 10 , -NO 2 -CN; Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 5 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; Each R 7 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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)2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 8 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 9 teeth, 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) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =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 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] are independently selected from Each R 10 teeth, Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl; W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10optionally substituted with one or more substituents independently selected from: carbocycle, and 3- to 10-membered heterocycle; R 12 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 alkyl; When Z is NH, R 4 NH 2 Instead, Z is O or S, and R 4 -OR 3 and R 5 If H, WR 3 Additionally, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl].

[0209] 2. The compound or salt of embodiment 1, wherein Z is selected from -O- and -S-.

[0210] 3. The compound or salt of embodiment 1 or 2, wherein Z is -O-.

[0211] 4. X is CR 6 4. The compound or salt of any one of embodiments 1 to 3, wherein

[0212] 5. Y is CR 12 5. The compound or salt of any one of embodiments 1 to 4, wherein

[0213] 6. The compound or salt of any one of embodiments 1-5, wherein Q is absent or selected from -W-, -O-, -OW-, and -WO-.

[0214] 7. The compound or salt of any one of embodiments 1-6, wherein Q is absent or -O-.

[0215] 8. The compound or salt of any one of embodiments 1-7, wherein Q is absent.

[0216] 9. The compound or salt according to any one of embodiments 1 to 8, wherein m is selected from 1 and 2.

[0217] 10. The compound or salt of any one of embodiments 1 to 9, wherein m is 1.

[0218] 11. A compound or salt according to any one of embodiments 1 to 10, wherein R 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C1-6 The compound or salt thereof is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0219] 12. R 1 is hydrogen and C 1-3 12. The compound or salt according to any one of embodiments 1 to 11, wherein:

[0220] 13. A compound or salt according to any one of embodiments 1 to 12, wherein R 2 teeth, hydrogen; Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6The compound or salt thereof is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0221] 14. A compound or salt according to any one of embodiments 1 to 13, wherein R 2 teeth, hydrogen; Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle 1-6 Alkyl; and C 6 A compound or salt thereof selected from a carbocycle, and a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen.

[0222] 15. A compound or salt according to any one of embodiments 1 to 14, wherein R 2 teeth, hydrogen; Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle 1-6 The compound or salt thereof, wherein the compound or salt is selected from the group consisting of alkyl, aryl ... and alkyl.

[0223] 16. R 2 is hydrogen, halogen, and C 1-3 16. The compound or salt according to any one of embodiments 1 to 15, wherein:

[0224] 17. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-6 Carbocyclic ring, C 1-6Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 17. The compound or salt according to any one of embodiments 1 to 16, optionally substituted by:

[0225] 18. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 17. The compound or salt according to any one of embodiments 1 to 16, optionally substituted by:

[0226] 19. R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 17. The compound or salt of any one of embodiments 1-16, wherein R is phenyl optionally substituted with one or more substituents independently selected from: alkyl.

[0227] 20. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 17. The compound or salt according to any one of embodiments 1 to 16, optionally substituted by:

[0228] 21. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 17. The compound or salt according to any one of embodiments 1 to 16, optionally substituted by:

[0229] 22. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 6-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 17. The compound or salt according to any one of embodiments 1 to 16, optionally substituted by:

[0230] 23. R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 17. The compound or salt of any one of embodiments 1-16, wherein the heterocyclic ring is a 6-membered heterocycle optionally substituted with one or more substituents independently selected from:

[0231] 24. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 17. The compound or salt according to any one of embodiments 1 to 16, optionally substituted by:

[0232] 25. R 3 are halogens, -CN, -OH, =O, =S, =NH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl), and C 1-6 The compound or salt of any one of embodiments 1-16, which is a 5-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl.

[0233] 26. R 3 isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, and thiazole (each of which may contain one or more R 9 17. The compound or salt of any one of embodiments 1-16, wherein the heterocycle is a 5-membered heterocycle selected from

[0234] 27. R 3 The compound or salt of any one of embodiments 1-16, wherein is a 5-membered heterocycle selected from tetrazole and oxadiazole.

[0235] 28. R3 isothiazol-3-ol, isoxazol-3-ol, squaric acid, thiazolidinedione, oxazolidinedione, tetrazole, 1,2,4-oxadiazol-5(4H)-one, 1,2,4-thiadiazol-5(4H)-one, 1,2,4-oxadiazol-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5-oxathiadiazole-2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole, or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one, and tetramic acid (each of which may contain one or more R 9 17. The compound or salt of any one of embodiments 1-16, wherein the heterocycle is a 5-membered heterocycle selected from

[0236] 29. R 3 is one or more R 9 is optionally replaced by [ka] 17. The compound or salt of any one of embodiments 1-16, wherein the five-membered heterocycle is selected from:

[0237] 30. R 3 teeth, [ka] 17. The compound or salt according to any one of embodiments 1 to 16, selected from:

[0238] 31. A compound or salt according to any one of embodiments 1 to 16, Q is -W-; R 3 may additionally be 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) 2 R 10 , -NO 2 , -CN; -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The compound or salt thereof, wherein the compound or salt is an alkylene.

[0239] 32. A compound or salt according to any one of embodiments 1 to 16, Q is -W-; R 3 may additionally include halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl), -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The compound or salt thereof, wherein the compound or salt is an alkylene.

[0240] 33. A compound or salt according to any one of embodiments 1 to 16, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1 The compound or salt thereof, wherein the compound or salt is an alkylene.

[0241] 34. A compound or salt according to any one of embodiments 1 to 16, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); The compound or salt thereof, wherein -W- is -C(=O)-.

[0242] 35. A compound or salt according to any one of embodiments 1 to 34, wherein each R 4 teeth, Halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 wherein each of the compounds or salts is independently selected from the group consisting of aryl, aryl, arylalkyl, and arylsulfates.

[0243] 36. R 4 -OR 7 , -SR 7 , and -N(R 7 ) 2 The compound or salt according to any one of embodiments 1 to 35, independently selected from:

[0244] 37. m is 1 and R 4 -OR 7 37. The compound or salt of any one of embodiments 1-36, wherein

[0245] 38. A compound or salt according to any one of embodiments 1 to 37, wherein each R 7 teeth, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 and optionally substituted by

[0246] 39. A compound or salt according to any one of embodiments 1 to 38, wherein each R 7 teeth, 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)2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl (C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 and optionally substituted by

[0247] 40. A compound or salt according to any one of embodiments 1 to 39, wherein each R7 teeth, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl (C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -CN, and one or more R 9 C optionally replaced by 1-6 and optionally substituted with one or more substituents independently selected from alkyl.

[0248] 41. R 7 is C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 alkyl, 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 41. The compound or salt of any one of embodiments 1-40, optionally substituted with one or more substituents independently selected from:

[0249] 42. R 7 is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 alkyl, 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 42. The compound or salt of any one of embodiments 1-41, optionally substituted with one or more substituents independently selected from:

[0250] 43. R 7 is C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 41. The compound or salt of any one of embodiments 1-40, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0251] 44. R 5 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 44. The compound or salt of any one of embodiments 1-43, wherein said compound or salt is selected from:

[0252] 45. R 5 The compound or salt of any one of embodiments 1-44, wherein is hydrogen.

[0253] 46. ​​R 6 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 46. ​​The compound or salt of any one of embodiments 1-45, wherein the compound or salt is selected from:

[0254] 47. R 6 The compound or salt of any one of embodiments 1-46, wherein is selected from hydrogen and halogen.

[0255] 48. Z is -NR 8 - 48. The compound or salt of any one of embodiments 1-47, wherein

[0256] 49. R 8 The compound or salt of any one of embodiments 1-48, wherein is selected from hydrogen.

[0257] 50. R 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally substituted by:

[0258] 51. R 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 49. The compound or salt of any one of embodiments 1-48, wherein the ring is selected from the group consisting of: carbocycle, 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from:

[0259] 52. R 8 is halogen, -CN, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 The compound or salt according to any one of embodiments 1 to 48, wherein R is selected from alkyl.

[0260] 53. R 8 is C 1-6 The compound or salt according to any one of embodiments 1 to 48, wherein R is selected from alkyl.

[0261] 54. R 8is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-10 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The compound or salt according to any one of embodiments 1 to 48, optionally substituted by:

[0262] 55. R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 3-10 The compound or salt according to any one of embodiments 1 to 48, wherein the ring is selected from carbocycle.

[0263] 56. R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The compound or salt according to any one of embodiments 1 to 48, optionally substituted by:

[0264] 57. R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 49. The compound or salt of any one of embodiments 1-48, wherein the heterocycle is selected from 3-10 membered heterocycle optionally substituted with one or more substituents independently selected from: alkyl.

[0265] 58. R 8 The compound or salt of any one of embodiments 1-57, wherein is hydrogen.

[0266] 59. A compound or salt according to any one of embodiments 1 to 58, wherein each R 9 teeth, Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); and Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-3 The compound or salt thereof, wherein the compound or salt is selected from the group consisting of alkyl, aryl ... and alkyl.

[0267] 60. Each R 10 The compound or salt of any one of embodiments 1-59, wherein is hydrogen.

[0268] 61. W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0269] 62. W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0270] 63. W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0271] 64. W is for C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0272] 65. W is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 5-membered heterocycles 1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0273] 66. W is for C 3-6 C substituted with one or more substituents independently selected from carbocycles1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0274] 67. W is [ka] 61. The compound or salt according to any one of embodiments 1 to 60, selected from:

[0275] 68. W is for C 1-6 The compound or salt of any one of embodiments 1-60, wherein:

[0276] 69. R 12 The compound or salt of any one of embodiments 1-68, wherein is selected from hydrogen and halogen.

[0277] 70. A compound or salt according to embodiment 1, [ka] [ka] [ka] [ka] [ka] [ka] [ka] and combinations thereof.

[0278] 71. A pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 70, and a pharma- ceutically acceptable excipient.

[0279] 72. A method for treating cancer, comprising administering to a subject in need thereof a compound or salt described in any one of embodiments 1 to 70.

[0280] 73. A method for treating cancer, comprising administering to a subject in need thereof a compound of formula (II): [ka] or a pharma- ceutical acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are CQR 3 , C.R. 6 and N are independently selected; Z is -O-, -S-, or -NR 8 - Selected from; Q is absent or -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 )0-, -OC(O)N(R 10 )-, -N(R 10 )C(O)O-, -S(O)-, -S(O) 2 - and -P(O) 2 Selected from O-; m is selected from 1, 2, 3, 4, and 5; R 1 teeth, hydrogen; C1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 2 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); R 3 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 4 teeth, 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) 2 R 7 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by Each R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 -CN; and Halogen, -OR 10 , -SR 10, -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1-6 independently selected from alkyl; Each R 7 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -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 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally substituted by R 8 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 (optionally replaced by); Each R 9 teeth, 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) 2 R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =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 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and C 3-10Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 Optionally substituted with one or more substituents independently selected from -CN; and [ka] are independently selected from; Each R 10 teeth, Hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-10Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 rings, 3- to 10-membered heterocyclic rings, and C 1-6 haloalkyl; W is C 1-6 Alkylene, C 2-6 Alkenylene, and C 2-6 Alkynylene (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 and optionally substituted with one or more substituents independently selected from: carbocycle, and 3- to 10-membered heterocycle.

[0281] 74. When Z is NH, R 4 NH 2 74. The method of embodiment 73, wherein said method is not

[0282] 75. Z is O or S and R 4 -OR 3 and R 5 If H, WR 3 Additionally, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 74. The method of embodiment 73, wherein said at least one alkyl group is selected from alkynyl.

[0283] 76. X 1 , X 2 , and X 3 are each independently CR 6 and X 4 is CQR 3 75. The method of embodiment 73 or 74, wherein

[0284] 77. The method of embodiment 73, wherein Z is selected from -O- and -S-.

[0285] 78. The method of embodiment 73 or 76, wherein Z is -O-.

[0286] 79. X is CR 6 The method of any one of embodiments 73 to 78, wherein

[0287] 80. Y is CR 12 The method of any one of embodiments 73 to 79, wherein

[0288] 81. The method of any one of embodiments 73-80, wherein Q is absent or selected from -W-, -O-, -OW-, and -WO-.

[0289] 82. The method of any one of embodiments 73-81, wherein Q is absent or -O-.

[0290] 83. The method of any one of embodiments 73-82, wherein Q is absent.

[0291] 84. The method of any one of embodiments 73 to 83, wherein m is selected from 1 and 2.

[0292] 85. The method of any one of embodiments 73 to 84, wherein m is 1.

[0293] 86. The method of any one of embodiments 73 to 85, comprising: 1 teeth, hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any of the preceding claims, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0294] 87. R 1 is hydrogen and C 1-3 The method of any one of embodiments 73-84, wherein the alkyl is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0295] 88. The method of any one of embodiments 73 to 86, comprising: 2 teeth, hydrogen; Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 2-6Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any of the preceding claims, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0296] 89. The method of any one of embodiments 73 to 85, comprising: 2 teeth, hydrogen; Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10C optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle 1-6 Alkyl; and C 6 carbocycle, and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen.

[0297] 90. The method according to any one of embodiments 73 to 86, comprising: 2 teeth, hydrogen; Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 alkyl); Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The method according to claim 1, wherein the alkyl group is selected from alkyl.

[0298] 91. R 2 is hydrogen, halogen, and C 1-3 The method of any one of embodiments 73-86, wherein the alkyl is selected from the group consisting of aryl, aryl, aryl and alkyl.

[0299] 92. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 91, optionally substituted by:

[0300] 93. R 3 is 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) 2 R 10, -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 6 Carbocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 91, optionally substituted by:

[0301] 94. R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any one of embodiments 73-91, wherein R is phenyl optionally substituted with one or more substituents independently selected from: alkyl.

[0302] 95. R 3 is 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) 2 R10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 91, optionally substituted by:

[0303] 96. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9The method of any one of embodiments 73 to 91, optionally substituted by:

[0304] 97. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 6-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 91, optionally substituted by:

[0305] 98. R 3 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6The method of any one of embodiments 73-91, wherein the heterocyclic ring is a 6-membered heterocycle optionally substituted with one or more substituents independently selected from: alkyl.

[0306] 99. R 3 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is a 5-membered heterocycle optionally substituted by one or more substituents independently selected from alkynyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 91, optionally substituted by:

[0307] 100. R 3 are halogens, -CN, -OH, =O, =S, =NH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C1-6 alkyl), and C 1-6 The method of any one of embodiments 73-91, wherein the heterocycle is a 5-membered ring optionally substituted with one or more substituents independently selected from alkyl.

[0308] 101. R 3 isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, and thiazole (each of which may contain one or more R 9 The method of any one of embodiments 73-91, wherein the heterocyclic ring is a 5-membered ring selected from

[0309] 102. R 3 The method of any one of embodiments 73-91, wherein is a 5-membered heterocycle selected from tetrazole and oxadiazole.

[0310] 103. R 3 isothiazol-3-ol, isoxazol-3-ol, squaric acid, thiazolidinedione, oxazolidinedione, tetrazole, 1,2,4-oxadiazol-5(4H)-one, 1,2,4-thiadiazol-5(4H)-one, 1,2,4-oxadiazol-5(4H)-thione, 2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3H-1,2,3,5-oxathiadiazole-2-oxide, 3-(methylsulfonyl)-4H-1,2,4-triazole, or 1,4-dihydro-5H-tetrazol-5-one, 3-hydroxyquinolin-2-one, and tetramic acid (each of which may contain one or more R 9 The method of any one of embodiments 73-91, wherein the heterocyclic ring is a 5-membered ring selected from

[0311] 104. R 3 teeth, [ka] The method of any one of embodiments 73-91, wherein the five-membered heterocycle is selected from:

[0312] 105. R 3 teeth, [ka] 92. The compound or salt according to any one of embodiments 73 to 91, selected from:

[0313] 106. Q is -O- and R 3 The method of any one of embodiments 73-91, wherein is tetrazole.

[0314] 107. The method according to any one of embodiments 73 to 91, comprising: Q is -W-; R 3 may additionally be 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) 2 R 10 , -NO 2 , -CN; -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The method according to claim 1, wherein the alkylene is

[0315] 108. The method according to any one of embodiments 73 to 91, comprising: Q is -W-; R 3 may additionally include halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl), -W- is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The method according to claim 1, wherein the alkylene is

[0316] 109. The method according to any one of embodiments 73 to 91, comprising: Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); -W- is halogen, -CN, -OH, -SH, -NO 2, -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1 The method according to claim 1, wherein the alkylene is

[0317] 110. The method according to any one of embodiments 73 to 91, Q is -W-; R 3 may additionally include -OH, -SH, -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); The method, wherein -W- is -C(=O)-.

[0318] 111. The method of any one of embodiments 73 to 110, wherein each R 4 teeth, Halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -NO 2 , and -CN; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10Optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle; and C 3-6 Carbocycles and 3- to 6-membered heterocycles (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 wherein each of the aryl, aryl and alkyl groups is independently selected from the group consisting of aryl, aryl and alkyl.

[0319] 112. R 4 -OR 7 , -SR 7 , and -N(R 7 ) 2 The method of any one of embodiments 73 to 110, independently selected from:

[0320] 113. m is 1 and R 4 -OR 7 The method of any one of embodiments 73 to 110, wherein

[0321] 114. The method of any one of embodiments 73 to 113, wherein each R 7 teeth, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9wherein the compound is selected from the group consisting of

[0322] 115. The method of any one of embodiments 73 to 113, wherein each R 7 teeth, 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl (C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Optionally substituted by one or more substituents independently selected from alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 wherein the compound is selected from the group consisting of

[0323] 116. The method of any one of embodiments 73 to 113, wherein each R 7 teeth, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl (C 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 Optionally replaced by C 3-10 Carbocyclic rings and 3-10 membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -CN, and one or more R 9 C optionally replaced by 1-6 and optionally substituted with one or more substituents independently selected from alkyl.

[0324] 117. R 7 is C 3-10C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 alkyl, 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any one of embodiments 73-113, optionally substituted with one or more substituents independently selected from: alkyl.

[0325] 118. R 7 is C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 alkyl, 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any one of embodiments 73-113, optionally substituted with one or more substituents independently selected from: alkyl.

[0326] 119. R 7 is C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6The method of any one of embodiments 73-113, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl, and alkyl.

[0327] 120. R 6 are hydrogen, halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any one of embodiments 73 to 45, wherein the alkyl group is selected from the group consisting of aryl, arylalkyl, arylsulfuryl ...

[0328] 121. R 6 The method of any one of embodiments 73-120, wherein is selected from hydrogen and halogen.

[0329] 122. Z is -NR 8 The method of any one of embodiments 73 to 121, wherein

[0330] 123. R 8 The method of any one of embodiments 73-121, wherein is selected from hydrogen.

[0331] 124. R 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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(R10 ) 2 , -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3-10 Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3-10 The carbocycle and the 3- to 10-membered heterocycle each have one or more R 9 The method of any one of embodiments 73 to 121, wherein the R is selected from the group consisting of R and R, and optionally substituted with

[0332] 125. R 8 is C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of these is a halogen, -CN, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 The method of any one of embodiments 73-121, wherein the ring is selected from the group consisting of a cyclic ring, a cyclic ring, a 3- to 10-membered heterocycle, and optionally substituted with one or more substituents independently selected from the group consisting of a cyclic ring, ...

[0333] 126. R 8 is halogen, -CN, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 The method of any one of embodiments 73-121, wherein the alkyl group is selected from alkyl.

[0334] 127. R 8 is C 1-6 The method of any one of embodiments 73-121, wherein the alkyl group is selected from alkyl.

[0335] 128. R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 C optionally substituted with one or more substituents independently selected from alkynyl 3-10 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 121, optionally substituted with:

[0336] 129. R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 3-10 The method of any one of embodiments 73-121, wherein the ring is selected from carbocycle.

[0337] 130. R 8 is 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) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl may be one or more R 9 The method of any one of embodiments 73 to 121, optionally substituted with:

[0338] 131. R 8 are halogens, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 The method of any one of embodiments 73-121, wherein the heterocycle is selected from 3-10 membered heterocycles optionally substituted with one or more substituents independently selected from: alkyl.

[0339] 132. R 8 The method of any one of embodiments 73-121, wherein is hydrogen.

[0340] 133. The method of any one of embodiments 73 to 132, wherein each R 9 teeth, Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 alkyl); and Halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-3 The method according to claim 1, wherein the alkyl group is selected from alkyl.

[0341] 134. Each R 10 The method of any one of embodiments 73-133, wherein is hydrogen.

[0342] 135. W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The method of any one of embodiments 73-134, wherein the alkylene is alkylene.

[0343] 136. W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The method of any one of embodiments 73-134, wherein the alkylene is alkylene.

[0344] 137. W is halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from 1-6 The method of any one of embodiments 73-134, wherein the alkylene is alkylene.

[0345] 138. W is C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 The method of any one of embodiments 73-134, wherein the alkylene is alkylene.

[0346] 139. W is for C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 5-membered heterocycles1-6 The method of any one of embodiments 73-134, wherein the alkylene is alkylene.

[0347] 140. W is C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 The method of any one of embodiments 73-134, wherein the alkylene is alkylene.

[0348] 141. W is [ka] The method according to any one of embodiments 73 to 134, wherein the method is selected from the group consisting of:

[0349] 142. R 12 The method of any one of embodiments 73-141, wherein is selected from hydrogen and halogen.

[0350] 143. The method of any one of embodiments 73 to 141, wherein the method for treating cancer is cancer immunotherapy.

[0351] 144. The method of any one of embodiments 73 to 143, wherein the cancer is a solid tumor.

[0352] 145. The method of embodiment 143, wherein the solid tumor is a sarcoma, carcinoma, or lymphoma.

[0353] 146. The method of embodiment 143, wherein the solid tumor is in the breast, brain, kidney, ovary, cervix, pancreas, thyroid, colon, bladder, prostate, liver, stomach, or lung.

Claims

1. Equation (I): 【Chemistry 1】 A compound represented by, or a pharmaceutically acceptable salt thereof [wherein, X is CR ６ and selected from N; Y is CH; Z is -O-, -S-, and -NR ８ - Selected from; Q does not exist, or Selected from -O-, -W-, and -O-W-; m is selected from 1, 2, 3, 4, and 5; R １ is hydrogen, or C １－６ It is alkyl; R ２ is hydrogen; R ３ teeth, 【Chemistry 2】 is a 5-membered heterocyclic ring selected from, and when Q is -W-, R ３ is additionally selected from halogen, -OR １０ , -SR １０ , -N(R １０ ), -C(O)R ２ , -C(O)N(R １０ ), -N(R １０ ), -N(R ２ ), -N(R １０ )C(O)R １０ , -N(R １０ )C(O)N(R １０ ), -OC(O)N(R ２ ), -N(R １０ )C(O)OR ２ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O １０ )R １０ , -NO ２ ), and -CN;​​​​ Each R ４ teeth, halogen; -OR7; C １－６ Alkyl (this is halogen, C) ３－１０ The C is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle. ３－１０ The carbon ring and the 3- to 10-membered heterocycle each have 1 to 3 R groups. ９ (Optionally replaced by); and C ３－１０ Carbon rings and 3- to 10-membered heterocycles (these are halogens, -CN, and C, respectively). １－６ The C is optionally substituted with one to three substituents independently selected from alkyl groups. １－６ Alkyl groups have 1 to 3 R's. ９ (This is being replaced by an optional choice.) Selected independently from; R ５ is hydrogen; R ６ is hydrogen or a halogen; Each R ７ teeth, C １－６ Alkyl (this is halogen, C) ３－１０ The C is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle. ３－１０ The carbon ring and the 3- to 10-membered heterocycle each have 1 to 3 R groups. ９ (Optionally replaced by); and C ３－１０ Carbon rings and 3- to 10-membered heterocycles (these are halogens, -CN, and C, respectively). １－６ The C is optionally substituted with one to three substituents independently selected from alkyl groups. １－６ Alkyl is one or more R ９ (This is being replaced by an optional choice.) Selected independently from; R ８ C is optionally substituted with hydrogen or one to three halogens. １－６ It is alkyl; Each R ９ These include halogens, -CN, and C １－３ Alkyl (which is optionally substituted with one to three substituents independently selected from halogens and -CN) Selected independently from, Each R １０ is hydrogen, and C １－６ Alkyl (this is -CN, -OH, -SH, -NO) ２ , -NH ２ , =O, =S, -O-C １－６ Alkyl, -S-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ ,-NH(C １－６ Alkyl), C ３－１０ (Optionally substituted with one or more substituents independently selected from a carbon ring or a 3- to 10-membered heterocycle); and W is C １－６ [It is alkylene, or -C(O)-].

2. The compound or salt according to claim 1, wherein Z is -O-.

3. X is CR ６ The compound or salt according to claim 1.

4. The compound or salt according to claim 1, wherein Q is absent or -O-.

5. Q is a compound or salt according to claim 1 that does not exist.

6. m is a compound or salt according to claim 1, selected from 1 and 2.

7. R ３ teeth, 【Transformation 3】 The compound or salt according to claim 1.

8. R3 is, 【Chemistry 4】 The compound or salt according to claim 1.

9. The compound or salt according to claim 1, wherein m is 1 or 2 and one R 4 is a halogen.

10. m is 1 or 2, and one R ４ ha-OR ７ The compound or salt according to claim 1.

11. The compound or salt according to claim 1, wherein m is 1 or 2, and one R4 is a C1-6 alkyl group (which is optionally substituted with one or more substituents independently selected from halogens, C3-10 carbocyclic groups and 3-10 membered heterocyclic groups, each of which is optionally substituted with 1-3 R9 groups).

12. R ６ The compound or salt according to claim 1, wherein is hydrogen.

13. R ６ The compound or salt according to claim 1, wherein is a halogen. 【Request Item 14】 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Transformation 5-5】 [Transformation 5-6] [Transformation 5-7] [Transformation 5-8] 【Chemistry 5-9】 A compound or salt according to claim 1, selected from the above.

15. A pharmaceutical composition comprising the compound or salt described in claim 1 and a pharmaceutically acceptable excipient.

16. A method for treating cancer, comprising administering the compound or salt described in claim 1 to a subject in need thereof.

17. The method according to claim 16, wherein the method for treating cancer is cancer immunotherapy.

18. The method according to claim 16, wherein the cancer is a solid tumor.

19. The method according to claim 18, wherein the solid tumor is a sarcoma, carcinoma, or lymphoma.

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