Search

EP-4735447-A1 - AROMATIC NITROGEN-CONTAINING COMPOUNDS, PREPARATION METHODS AND MEDICINAL USES THEREOF

EP4735447A1EP 4735447 A1EP4735447 A1EP 4735447A1EP-4735447-A1

Abstract

Aromatic nitrogen-containing compounds, the preparation method thereof, pharmaceutical compositions comprising the compounds, and the pharmaceutical uses for the treatment of related diseases or disorders are disclosed.

Inventors

  • LIU, GANG
  • JING, Bingwen
  • ZHU, HUGH Y.

Assignees

  • Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A compound of formulas (I) , (I-1) , or (I-2) or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 are each independently selected from CH, NH, N, O, C or S; preferably, in formula (I) , Y 1 , Y 2 , Y 3 are N; in formula (I-1) , Y 1 , Y 2 , Y 3 , Y 6 are N, Y 4 , Y 5 , Y 7 , Y 8 are C; X 1 and X 2 are each independently CH or N; M 2 is CH, N; linking Y 2 and C atom with #is single bond or double bond, linking Y 3 and C atom with #is single bond or double bond, with the proviso that are not double bond simultaneously; each is independently single bond or double bond, with the proviso that adjacent are not double bond simultaneously; the represent vinylidene, which can be Z or E or its mixture; L a is selected from bond, -O-, -C (O) -, -S (O) -, -S (O) 2 -, -S-, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1a : -NH-, –NHC (O) CR 17 R 18 -, –NHC (O) (CR 17 R 18 ) n1 -, -CONH-, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 alkylene-NH-, C 2 -C 6 alkenylene-NH-, C 2 -C 6 alkynylene-NH-, C 1 -C 6 alkylene-O-, C 2 -C 6 alkenylene-O-, C 2 -C 6 alkynylene -O-, C 1 -C 6 alkylene-S-, C 2 -C 6 alkenylene-S-, C 2 -C 6 alkynylene -S-, C 1 -C 6 haloalkyl and -CON (R c ) -, -S (O) (NH) -, or any combination of two or three or more of them; each R 1 , R 3 R 4 , R 5 and R 7 , R A , R B , R 12 , R 16 , R 10A are identical or different, and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl and cycloalkyl, haloalkoxy, hydroxyalkoxy, -O-haloalkyl, aryl, heteroaryl, heterocyclyl; alternatively, two of R 3 together with atom (s) to which they are attached form a C 3 -C 10 cycloalkyl or C 1 -C 10 heterocyclyl or C 6 -C 10 aryl or C 1 -C 9 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or more R 1c ; alternatively, R 4 and R 5 , together with atom (s) to which they are attached form a C 3 -C 10 cycloalkyl or C 1 -C 10 heterocyclyl, wherein the cycloalkyl and heterocyclyl are unsubstituted or substituted with 1, 2, 3 or more R 1d ; alternatively, two of R 7 together with atom (s) to which they are attached form a C 3 -C 10 cycloalkyl or C 1 -C 10 heterocyclyl or C 6 -C 10 aryl or C 1 -C 9 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or more R 1e ; alternatively, two of R 12 together with atom (s) to which they are attached form a C 3 -C 10 cycloalkyl or C 1 -C 10 heterocyclyl or C 6 -C 10 aryl or C 1 -C 9 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or more R 1f ; L 2 is selected from bond, -O-, -C (O) -, -S (O) -, -S (O) 2 -, -S-, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1g : -NH-, -CONH-, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -C 1 -C 6 alkylene-NH-, -C 2 -C 6 alkenylene-NH-, -C 2 -C 6 alkynylene-NH-, -C 1 -C 6 alkylene-O-, -C 2 -C 6 alkenylene-O-, -C 2 -C 6 alkynylene -O-, -C 1 -C 6 alkylene-S-, -C 2 -C 6 alkenylene-S-, -C 2 -C 6 alkynylene -S-, C 1 -C 6 haloalkyl and -CON (R c ) -, -S (O) (NH) -, or any combination of two or three or more of them; R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl and alkynyl; ring C is aryl or heteroaryl or cycloalkyl or heterocyclyl; preferably, ring C is C 6 -C 10 aryl or C 2 -C 9 heteroaryl or C 3 -C 10 cycloalkyl or C 3 -C 10 heterocyclyl; R 10 is selected from the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1h : aryl or heteroaryl or cycloalkyl or heterocyclyl; preferably, R 10 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5, 6 or 7 ring carbon atoms which is optionally additionally fused to a heterocyclyl or cycloalkyl; or heterocyclyl, wherein said heterocyclyl is a 5, 6 or 7 membered fully saturated or partially unsaturated group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S, and wherein said heterocyclyl is unbridged or bridged, and said bridge is 1 or 2 carbon atoms; or heteroaryl, wherein said heteroaryl is a 5 or 6 membered fully unsaturated monocyclic group comprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteraoms, wherein the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1; or phenyl; wherein said cycloalkenyl, heterocyclyl, heteroaryl, phenyl are unsubstituted or substituted by one or more substituents selected from halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; or, R 10 is C 2 -C 4 alkenyl, optional substituted by R 19 or –O-R 20 ; each R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h are identical or different, and are independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R p : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) R 21 , -C (O) OR 22 , -OC (O) R 23 , -S (O) 2 R 24 , -S (O) 2 OR 25 , -OS (O) 2 R 26 , -B (OR 27 ) (OR 28 ) , -P (O) (OR 29 ) (OR 30 ) ; each R p is identical or different, and is independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO2, oxo (═O) , thio (═S) , and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R q : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 3-40 cycloalkenylthio, C 3-40 cycloalkynylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) R 31 , -C (O) OR 32 , -OC (O) R 33 , -S (O) 2 R 34 , -S (O) 2 OR 35 , -OS (O) 2 R 36 , -B (OR 37 ) (OR 38 ) , -P (O) (OR 39 ) (OR 40 ) and –S (O) (NH) -R 41 ; each R q is identical or different, and is independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) C 1-40 alkyl, -C (O) NH2, -C (O) NHC 1-40 alkyl, -C (O) -NH-OH, -COOC 1-40 alkyl, -COOH, -OC (O) C 1-40 alkyl, -OC (O) H, - S (O) 2 C 1-40 alkyl, S (O) 2 H, -S (O) 2 OC 1-40 alkyl, -OS (O) 2 C 1-40 alkyl, -P (O) (OH) 2 , -B (OH) 2 , and –S (O) (NH) C 1-40 alkyl; R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 and R 41 are identical or different, and are each independently selected from H, deuterium, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, and NH 2 ; p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4 or 5; r is 0, 1, 2 or 3; t is 0, 1, 2 or 3; w is 0, 1, 2 or 3; n 1 is 0, 1, 2 or 3; n 2 is 0, 1, 2 or 3.
  2. The compound is of formula (I) , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis-or trans-isomers, mesomers, racemates, enantiomers, diastereomers, deuterated derivative, or mixtures thereof: Y 1 is CH, NH, N, O or S; Y 2 is CH, NH, N, O or S; Y 3 is CH, NH, N, O or S; X 1 and X 2 are each independently CH or N; M 2 is each independently CH, N; is single bond or double bond, with the proviso that are not double bond simultaneously; R 1 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; R 7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; or, two of R 7 together with atom to which they are bound with form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocyclyl, L 2 is bond, O, -C (O) , -CONH-, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -C 1 -C 6 alkyl-NH-, -C 2 -C 6 alkenyl-NH-, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl and -CON (R c ) -; R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; ring C is C 6 -C 10 aryl or C 2 -C 9 heteroaryl; R 10 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms; or heterocyclyl, wherein said heterocyclyl is a 5 or 6 membered fully saturated or partially unsaturated group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S, and wherein said heterocyclyl is unbridged or bridged, and said bridge is 1 or 2 carbon atoms; or heteroaryl, wherein said heteroaryl is a 5 or 6 membered fully unsaturated monocyclic group comprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteraoms, wherein the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1; or phenyl; wherein said cycloalkenyl, heterocyclyl, heteroaryl, phenyl are unsubstituted or substituted by one of more substituents selected from halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; or, R 10 is C 2 -C 4 alkenyl, optional substituted by R 4 or –O-R 4 ; R 12 are each selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl and -O-haloalkyl; R 16 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl and -O-haloalkyl; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; t is 0, 1, 2 or 3; w is 0, 1, 2 or 3.
  3. The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the compound is of formula (I-A) , (I-B) , (I-C) , (I-D) , (II) , (II-A) or (II-B) , (III) , (IV) , (IV-A) or (IV-B) , (V) , (V-A) , (V-B) or (V-C) , (VI) or (VI-A) , (VII) , (VII-A) or (VII-B) , (VII-C) ,
  4. The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the compound is of formula (VIII) - (X) , wherein, p 1 is 0, 1, 2 or 3; each R 3a is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1a : amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl and cycloalkyl, haloalkoxy, hydroxyalkoxy, -O-haloalkyl, aryl, heteroaryl, heterocyclyl; ring H is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5, 6 or 7 ring carbon atoms which is optionally additionally fused to a heterocyclyl or cycloalkyl; or heterocyclyl, wherein said heterocyclyl is a 5, 6 or 7 membered fully saturated or partially unsaturated group comprising ring carbon atoms and 1 or 2 ring oxygen atoms, wherein when the heterocyclyl is partially unsaturated, there is only one unsaturated bond; preferably, is selected from more preferably, is selected from most preferably, is selected from
  5. The compound of any one of claims 1-3, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R 10 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5, 6 or 7 ring carbon atoms which is optionally additionally fused to a C 2 -C 5 heterocyclyl or C 3 -C 6 cycloalkyl; or heterocyclyl, wherein said heterocyclyl is a 5, 6 or 7 membered fully saturated or partially unsaturated group comprising ring carbon atoms and 1 or 2 ring oxygen atoms, wherein said cycloalkenyl, heterocyclyl are unsubstituted or substituted by one or more substituents selected from halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; wherein when the heterocyclyl is partially unsaturated, there is only one unsaturated bond; preferably, R 10 is selected from more preferably, R 10 is selected from most preferably, R 10 is selected from wherein, p 1 is 0, 1, 2 or 3; each R 3a is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1a : amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl and cycloalkyl, haloalkoxy, hydroxyalkoxy, -O-haloalkyl, aryl, heteroaryl, heterocyclyl.
  6. The compound of claim 4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or R 10 is selected from
  7. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R 1 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl and C 3 -C 6 cycloalkyl; preferably, R 1 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 3 alkyl, -CF 3 .
  8. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R 7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 hydroxyalkyl; preferably, R 7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 3 alkyl, -CF 3 , -CH 2 F, CHF 2 , more preferably, C 1 -C 3 alkyl.
  9. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R 12 , R 16 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl and C 2 -C 6 alkenyl; preferably, R 12 , R 16 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 3 alkyl, -CF 3 .
  10. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, L 2 is bond, O, -C (O) -, -CONH-, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -C 1 -C 3 alkyl-NH-, -C 2 -C 3 alkenyl-NH-, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkyl and -CON (R c ) -; preferably, L2 is -C (O) -; R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl and C 1 -C 3 hydroxyalkyl.
  11. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, is selected from
  12. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, ring C is or fused C 1 -C 12 heteroaryl or bicyclo [1.1.1] pentane; and ring C is optionally substituted by (R 12 ) q ; preferably, or R B is selected from more preferably, or R B is selected from
  13. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, w is 0, 1; p is 0, 1, 2; t is 1; r is 1; q is 0, 1, 2; p1 is 0, 1.
  14. The compound of any one of claims 1-4, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, or R A is selected from
  15. The compound of claim 1, selected from the group consisting of: or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 15 or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
  17. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1-15, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt solvate, or prodrug thereof, or the pharmaceutical composition of claim 16; preferably, the cancer is selected from the group consisting of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) ; more preferably the microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, colon, kidney and ovarian cancer, further preferably the microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from prostate cancer, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
  18. A method of treating a disorder or disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 15, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt solvate, or prodrug thereof, or the pharmaceutical composition of claim 16, preferably, the disorder or disease is cancer; more preferably, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) ; further preferably, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, colon, kidney and ovarian cancer; further preferably, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from prostate cancer, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
  19. A compound of formulas (XI) or (XII) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or salt or solvate thereof, R B is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl and cycloalkyl, haloalkoxy, hydroxyalkoxy, -O-haloalkyl, aryl, heteroaryl, heterocyclyl; each R 10A is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl and cycloalkyl, haloalkoxy, hydroxyalkoxy, -O-haloalkyl, aryl, heteroaryl, heterocyclyl; M 2 is CH, N; L a is selected from bond, -O-, -C (O) -, -S (O) -, -S (O) 2 -, -S-, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1a : -NH-, –NHC (O) CR 17 R 18 -, –NHC (O) (CR 17 R 18 ) n1 -, -CONH-, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 alkylene-NH-, C 2 -C 6 alkenylene-NH-, C 2 -C 6 alkynylene-NH-, C 1 -C 6 alkylene-O-, C 2 -C 6 alkenylene-O-, C 2 -C 6 alkynylene -O-, C 1 -C 6 alkylene-S-, C 2 -C 6 alkenylene-S-, C 2 -C 6 alkynylene -S-, C 1 -C 6 haloalkyl and -CON (R c ) -, -S (O) (NH) -, or any combination of two or three or more of them; R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, deuterated hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl and alkynyl; R 42 is hydrogen, deuterium, or a nitrogen protecting group; R 43 is hydrogen, deuterium, or carboxylic acid protecting group; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 are each independently selected from CH, NH, N, O, C or S; each is independently single bond or double bond, with the proviso that adjacent are not double bond simultaneously; R 1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 3-10 cycloalkyl, C 1-12 haloalkoxy, C 1-12 hydroxyalkoxy, -O-C 1-12 haloalkyl, C 6-10 aryl, C 1-10 heteroaryl, C 1-10 heterocyclyl; R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 3-10 cycloalkyl, C 1-12 haloalkoxy, C 1-12 hydroxyalkoxy, -O-C 1-12 haloalkyl, C 6-10 aryl, C 1-10 heteroaryl, C 1-10 heterocyclyl; R 5 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 3-10 cycloalkyl, C 1-12 haloalkoxy, C 1-12 hydroxyalkoxy, -O-C 1-12 haloalkyl, C 6-10 aryl, C 1-10 heteroaryl, C 1-10 heterocyclyl; R 7 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 3-10 cycloalkyl, C 1-12 haloalkoxy, C 1-12 hydroxyalkoxy, -O-C 1-12 haloalkyl, C 6-10 aryl, C 1-10 heteroaryl, C 1-10 heterocyclyl; R 16 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 3-10 cycloalkyl, C 1-12 haloalkoxy, C 1-12 hydroxyalkoxy, -O-C 1-12 haloalkyl, C 6-10 aryl, C 1-10 heteroaryl, C 1-10 heterocyclyl; alternatively, R 4 and R 5 , together with atom (s) to which they are attached to form a C 3 -C 10 cycloalkyl or C 1 -C 10 heterocyclyl, wherein the cycloalkyl and heterocyclyl are unsubstituted or substituted with 1, 2, 3 or more R 1d ; alternatively, two of R 7 together with atom (s) to which they are attached form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocyclyl or C 6 -C 10 aryl or C 1 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or more R 1e ; R 10 is selected from the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1h : C 6 -C 10 aryl or C 1 -C 9 heteroaryl or C 3 -C 10 cycloalkyl or C 1 -C 9 heterocyclyl; preferably, R 10 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5, 6 or 7 ring carbon atoms which is optionally additionally fused to a heterocyclyl or cycloalkyl; or heterocyclyl, wherein said heterocyclyl is a 5, 6 or 7 membered fully saturated or partially unsaturated group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S, and wherein said heterocyclyl is unbridged or bridged, and said bridge is 1 or 2 carbon atoms; or heteroaryl, wherein said heteroaryl is a 5 or 6 membered fully unsaturated monocyclic group comprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteraoms, wherein the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1; or phenyl; wherein said cycloalkenyl, heterocyclyl, heteroaryl, phenyl are unsubstituted or substituted by one or more substituents selected from halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl; or, R 10 is C 2 -C 4 alkenyl, optional substituted by R 19 or –O-R 20 ; each R 1a , R 1b , R 1d , R 1e , R 1h are identical or different, and are independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R p : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) R 21 , -C (O) OR 22 , -OC (O) R 23 , -S (O) 2 R 24 , -S (O) 2 OR 25 , -OS (O) 2 R 26 , -B (OR 27 ) (OR 28 ) , -P (O) (OR 29 ) (OR 30 ) ; each R p is identical or different, and is independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , and the following groups unsubstituted or optionally substituted with 1, 2 or more R q : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 3-40 cycloalkenylthio, C 3-40 cycloalkynylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) R 31 , -C (O) OR 32 , -OC (O) R 33 , -S (O) 2 R 34 , -S (O) 2 OR 35 , -OS (O) 2 R 36 , -B (OR 37 ) (OR 38 ) , -P (O) (OR 39 ) (OR 40 ) and –S (O) (NH) -R 41 ; each R q is identical or different, and is independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) C 1-40 alkyl, -C (O) NH2, -C (O) NHC 1-40 alkyl, -C (O) -NH-OH, -COOC 1-40 alkyl, -COOH, -OC (O) C 1-40 alkyl, -OC (O) H, -S (O) 2 C 1-40 alkyl, S (O) 2 H, -S (O) 2 OC 1-40 alkyl, -OS (O) 2 C 1-40 alkyl, -P (O) (OH) 2 , -B (OH) 2 , and –S (O) (NH) C 1-40 alkyl; R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 and R 41 are identical or different, and are each independently selected from H, deuterium, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, and NH 2 ; w is 0, 1, 2 or 3; n 1 is 0, 1, 2 or 3; n 2 is 0, 1, 2 or 3; r is 0, 1, 2 or 3; t is 0, 1, 2 or 3; preferably one R 7 or two R 7 is substituted on the *position; the represent vinylidene, which can be Z or E or its mixture; preferably, the compound is selected from:
  20. A method for preparing a compound of formula (I-2) or formula (I-2’) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising: R W is a leaving group, preferably, halogen or OH; L 2 is selected from bond, -O-, -C (O) -, -S (O) -, -S (O) 2 -, -S-, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1g : -NH-, -CONH-, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -C 1 -C 6 alkylene-NH-, -C 2 -C 6 alkenylene-NH-, -C 2 -C 6 alkynylene-NH-, -C 1 -C 6 alkylene-O-, -C 2 -C 6 alkenylene-O-, -C 2 -C 6 alkynylene -O-, -C 1 -C 6 alkylene-S-, -C 2 -C 6 alkenylene-S-, -C 2 -C 6 alkynylene -S-, C 1 -C 6 haloalkyl and -CON (R c ) -, -S (O) (NH) -, or any combination of two or three or more of them; R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, deuterated hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl and alkynyl; R A is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, deuterated hydroxy, cyano, NO 2 , oxo, and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R 1b : amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl and cycloalkyl, haloalkoxy, hydroxyalkoxy, -O-haloalkyl, aryl, heteroaryl, heterocyclyl; R 1b , R 1g are identical or different, and are independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R p : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) R 21 , -C (O) OR 22 , -OC (O) R 23 , -S (O) 2 R 24 , -S (O) 2 OR 25 , -OS (O) 2 R 26 , -B (OR 27 ) (OR 28 ) , -P (O) (OR 29 ) (OR 30 ) ; each R p is identical or different, and is independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO2, oxo (═O) , thio (═S) , and the following groups unsubstituted or optionally substituted with 1, 2, 3 or more R q : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 3-40 cycloalkenylthio, C 3-40 cycloalkynylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) R 31 , - C (O) OR 32 , -OC (O) R 33 , -S (O) 2 R 34 , -S (O) 2 OR 35 , -OS (O) 2 R 36 , -B (OR 37 ) (OR 38 ) , -P (O) (OR 39 ) (OR 40 ) and –S (O) (NH) -R 41 ; each R q is identical or different, and is independently selected from H, deuterium, halogen, OH, deuterated hydroxy, CN, NO 2 , oxo (═O) , thio (═S) , C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 6-20 aryloxy, 5-to 20-membered heteroaryloxy, 3-to 20-membered heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 6-20 arylthio, 5-to 20-membered heteroarylthio, 3-to 20-membered heterocyclylthio, NH 2 , -C (O) C 1-40 alkyl, -C (O) NH2, -C (O) NHC 1-40 alkyl, -C (O) -NH-OH, -COOC 1-40 alkyl, -COOH, -OC (O) C 1-40 alkyl, -OC (O) H, -S (O) 2 C 1-40 alkyl, S (O) 2 H, -S (O) 2 OC 1-40 alkyl, -OS (O) 2 C 1-40 alkyl, -P (O) (OH) 2 , -B (OH) 2 , and –S (O) (NH) C 1-40 alkyl; R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 and R 41 are identical or different, and are each independently selected from H, deuterium, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-to 20-membered heteroaryl, 3-to 20-membered heterocyclyl, and NH 2 ; formula (XI) and formula (XII) are as defined in claim 19.

Description

AROMATIC NITROGEN-CONTAINING COMPOUNDS, PREPARATION METHODS AND MEDICINAL USES THEREOF FIELD OF THE INVENTION The present invention belongs to the field of medicine, and relates to aromatic nitrogen-containing compound, preparation methods thereof, pharmaceutical compositions comprising the compounds, and medical uses thereof. BACKGROUD OF THE INVENTION Cells in any living organism possess multiple DNA repair machineries to maintain the genome stability and integrity, which is essential for survival. DNA mismatch repair (MMR) is a highly conserved pathway that plays a critical role in maintaining genomic stability by correcting errors occurred during DNA replication, recombination, and repairing processes. (Pecina-Slaus, N., Kafka, A., Salamon, I. &Bukovac, A. Mismatch Repair Pathway, Genome Stability and Cancer. Front Mol. Biosci. 7, 122 (2020) ) . Deficiency in MMR machinery creates genomic hypermutation and instability, manifested as the high frequency of insertion and deletions at short tracts of repetitive DNA sequences (microsatellites) throughout the genome, a phenomenon known as microsatellite instability (MSI) . (Kim, T.M., Laird, P.W. &Park, P.J. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858–868 (2013) , Vernole, P. et al. Common fragile sites in colon cancer cell lines: role of mismatch repair, RAD51 and poly (ADP-ribose) polymerase-1. Mutat. Res 712, 40–48 (2011) ) . . Microsatellites are generated by DNA polymerase slippage during replication or mismatch repair and are susceptible to misalignment and frame shift mutation, which can be recognized and corrected by MMR process in normal cells. However, in cancer cells lacking normal MMR machinery, errors occurred during replication or repair processes are accumulated and the mutation rate in genome is increased (Lower, S.S., McGurk, M.P., Clark, A.G., et al, Satellite DNA evolution: old ideas, new approaches. Curr. Opin. Genet. Dev., 2018; 49: 70-78) . High frequency of deletion and insertion in microsatellites lead to MSI, which contributes to the  development of 10-30%of ovarian, colon, gastric and endometrial cancers (Aaltonen, L.A. et al. Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993) , Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 1: PO. 17.00073 (2017) ) . While MSI-high (MSI-H) cancer patients show a better overall prognosis and reduced metastatic potential with higher tumor mutation burden and immunogenicity comparing to MSS cancers (Kang, S. et al. The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. Med. (Baltim. ) 97, e0019 (2018) ) , MSI-H tumors tend to develop resistance to immunotherapy and chemotherapy (Le, D.T. et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J. Clin. Oncol. 38, 11–19 (2020) , Overman, M.J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142) : an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017) , Fuca, G. et al. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. J. Immunother. Cancer 10, 4001 (2022) ) . Recently, multiple independent large scale functional genomics screen using more than 300 human cancer cell lines identified Werner syndrome RecQ helicase (WRN) as being selectively required for survival of MSI-H cells (Behan, F.M. et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511–516 (2019) , McDonald E.R. et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170 (3) : 577-592 (2017) , Chan, E.M. et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551–556 (2019) ) . WRN, one of 5 RecQ-like helicases in human, is a multifunctional enzyme with helicase and exonuclease activities and plays important roles in multiple pathways of DNA repair and maintenance of genome integrity including DNA replication, transcription, DNA repair, and telomere maintenance (Bohr, V.A. Rising from the RecQ-age: the role of human  RecQ helicases in genome maintenance. Trends Biochem Sci. 33, 609–620 (2008) , Singh, D.K., Ahn, B. &Bohr, V.A. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology 10, 235–252 (2009) , Rossi, M.L., Ghosh, A.K. &Bohr, V.A. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair (Amst. ) 9, 331–344 (2010) ) . Deletion of WRN leads various defects in cell and genomic structure including cell cycle arrest, DNA breaks, mitotic defects