Tricyclic derivatives and related uses

Abstract

The present disclosure relates to compounds of Formula (I'): (I), as well as prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of their manufacture. The compounds disclosed herein are useful for modulating Werner helicase (WRN) activity, and are useful for treating disorders involving WRN activity, such as cancer.

Claims

1. A compound of formula (I'): (I’)， Or its pharmaceutically acceptable salts, oxides, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein: X is N or C; Y is NR2 or CR2; Z is NR3 or CR3; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 1a replace; Each R 1a Independently, it is oxo, halogenated, cyano, -OH, -NH2, -NO2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NH-C(O) (C1-C6 alkyl), -S (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -S(O)2 (NH2), -C(O)(H), -C(O)NH2, -O (3 to 10 membered heterocyclic), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2-NH-C(O)(C1-C6 alkyl), -S(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -O(3- to 10-membered heterocyclic), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 1b replace; Each R 1b Independently, it can be oxo, halogenated, cyano, -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl), -O (C2-C6 alkenyl), -O (C2-C6 alkynyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NH (C1-C6 haloalkyl), -S (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -C(O)NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or optionally oxy-substituted 3- to 10-membered heterocyclic groups; R2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclic, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl group is a alkyl group. 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 2a replace; Each R 2a Independently, it is oxo, halogenated, cyano, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, -S(C1-C6 haloalkyl), -S(C1-C6 alkyl), C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, -S(C1-C6 haloalkyl), -S(C1-C6 alkyl), C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 2a1 replace; Each R 2a1 Independently, it is oxo, halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NH-C(O)(C1-C6 alkyl), -C(O)NH2 or -OC(O)(C1-C6 alkyl), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 alkyl is optionally substituted with one or more -OH groups; R3 and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains one or more additional N, O, or S, and is optionally surrounded by one or more R 3a replace; Each R 3a Independently, it can be cyano, halogenated, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C1-C6 haloalkyl), -NH-C(O)(C1-C6 alkyl), -O(C3-C 10 Cycloalkyl), -O (3 to 10-membered heterocyclic groups), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C1-C6 alkyl), or -S(C1-C6 haloalkyl), wherein -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C1-C6 haloalkyl), -NH-C(O)(C1-C6 alkyl), -O(C3-C 10 Cycloalkyl), -O (3 to 10-membered heterocyclic groups), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C1-C6 alkyl) or -S(C1-C6 haloalkyl) optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclic, -C(O)(C1-C6 alkyl), 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -N(R 3a1 )CO(R 3a2 -O(C3-C) 10 cycloalkyl), -O (C6-C) 10 Aryl), -O (5 to 10-membered heteroaryl) or -O (3 to 10-membered heterocyclic) substitution, or Two Rs 3a Together with the atoms to which they are attached, they form C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more C3-C6 groups. 10 cycloalkyl, 3 to 10-membered heterocyclic groups, C6-C 10 The aryl or 5- to 10-membered heteroaryl groups are substituted, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more C1-C6 alkyl groups; R 3a1 and R 3a2 Together with the atoms to which they are attached, they form 3- to 10-membered heterocyclic groups; R 4” yes , , , , , , , , , or ; R5 is H, halogenated, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. R6 is H, halogenated, cyano, -SO2 (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy group is optionally substituted with one or more -OH, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or -N (C1-C6 alkyl)2, or R5 and R6, together with the atoms to which they are attached, form C4-C. 10 Cycloalkenyl; and Each R7, R8, and R9 is independently H, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy group is optionally substituted with one or more oxo, halogen, cyano, -OH, -NH2, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), or -S(C1-C6 alkyl). R7 and R8, together with the atoms to which they are attached, form C3-C. 10 Cycloalkyl or 3 to 10-membered heterocyclic groups.

2. A compound of formula (I): (I)， Or its pharmaceutically acceptable salts, oxides, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein: X is N or C; Y is NR2 or CR2; Z is NR3 or CR3; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 1a replace; Each R 1a Independently, it is oxo, halogenated, cyano, -OH, -NH2, -NO2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NH-C(O) (C1-C6 alkyl), -S (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -S(O)2 (NH2), -C(O)(H), -C(O)NH2, -O (3 to 10 membered heterocyclic), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-C(O)(C1-C6 alkyl), -S(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -O(3- to 10-membered heterocyclic), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 1b replace; Each R 1b Independently, it can be oxo, halogenated, cyano, -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl), -O (C2-C6 alkenyl), -O (C2-C6 alkynyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NH (C1-C6 haloalkyl), -S (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -C(O)NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or optionally oxy-substituted 3- to 10-membered heterocyclic groups; R2 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclic, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl group is a alkyl group. 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 2a replace; Each R 2a Independently, it is oxo, halogenated, cyano, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(O)2NH2, -SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, -S(C1-C6 haloalkyl), -S(C1-C6 alkyl), C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, -S(C1-C6 haloalkyl), -S(C1-C6 alkyl), C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be occupied by one or more R 2a1 replace; Each R 2a1 Independently, it is oxo, halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NH-C(O)(C1-C6 alkyl), -C(O)NH2 or -OC(O)(C1-C6 alkyl), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 alkyl is optionally substituted with one or more -OH groups; R3 and R4, together with the atoms to which they are attached, form a 6- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains one or more additional N, O, or S, and is optionally surrounded by one or more R 3a replace; Each R 3a Independently, it can be cyano, halogenated, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C1-C6 haloalkyl), -NH-C(O)(C1-C6 alkyl), -O(C3-C 10 Cycloalkyl), -O (3 to 10-membered heterocyclic groups), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C1-C6 alkyl), or -S(C1-C6 haloalkyl), wherein -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C1-C6 haloalkyl), -NH-C(O)(C1-C6 alkyl), -O(C3-C 10 Cycloalkyl), -O (3 to 10-membered heterocyclic groups), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl, -S(O)(=NH)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C1-C6 alkyl) or -S(C1-C6 haloalkyl) optionally substituted with one or more oxo, cyano, 3- to 10-membered heterocyclic, -C(O)(C1-C6 alkyl), 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -N(R 3a1 )CO(R 3a2 -O(C3-C) 10 cycloalkyl), -O (C6-C) 10 Aryl), -O (5 to 10-membered heteroaryl) or -O (3 to 10-membered heterocyclic) substitution, or Two Rs 3a Together with the atoms to which they are attached, they form C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more C3-C6 groups. 10 cycloalkyl, 3 to 10-membered heterocyclic groups, C6-C 10 The aryl or 5- to 10-membered heteroaryl groups are substituted, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more C1-C6 alkyl groups; R 3a1 and R 3a2 Together with the atoms to which they are attached, they form 3- to 10-membered heterocyclic groups; R5 is H, halogenated, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. R6 is H, halogenated, cyano, -SO2 (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy group is optionally substituted with one or more -OH, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or -N (C1-C6 alkyl)2, or R5 and R6, together with the atoms to which they are attached, form C4-C. 10 Cycloalkenyl; and Each R7, R8, and R9 is independently H, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy group is optionally substituted with one or more oxo, halogen, cyano, -OH, -NH2, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 haloalkyl), or -S(C1-C6 alkyl). R7 and R8, together with the atoms to which they are attached, form C3-C. 10 Cycloalkyl or 3 to 10-membered heterocyclic groups.

3. The compound according to claim 1 or claim 2, wherein: X is N or C; Y is NR2 or CR2; Z is NR3 or CR3; R1 is C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10-membered heteroaryl, of which C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl groups are substituted with one or more R groups. 1a replace; Each R 1a Independently, it can be oxo, halogenated, cyano, -OH, -NH2, -NH (C1-C6 alkyl), -NO2, -S (C1-C6 alkyl), -S(O)2(NH2), -C(O)NH2, -O (3 to 10 membered heterocyclic groups), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein -NH (C1-C6 alkyl), -S (C1-C6 alkyl), -O (3- to 10-membered heterocyclic), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be represented by one or more R groups. 1b replace; Each R 1b It can be independently a halogenated, cyano, -OH, -O (C1-C6 alkyl), -C(O)NH2 or a 3 to 10-membered heterocyclic group; R2 is a C1-C6 alkyl group, C3-C6 alkyl group. 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 2a replace; Each R 2a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -S(C1-C6 alkyl), wherein the C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -S (C1-C6 alkyl) may optionally be represented by one or more R 2a1 replace; Each R 2a1 It is either halogenated or -OH on its own; Each R 3a Independently, it is halogenated, -OH, -O (C3-C) 10 Cycloalkyl), -O (3 to 10-membered heterocyclic), C1-C6 alkyl, C1-C6 alkoxy, 5 to 10-membered heteroaryl, wherein the -O (C3-C 10 Cycloalkyl), -O (3 to 10-membered heterocyclic), C1-C6 alkyl, C1-C6 alkoxy, 5 to 10-membered heteroaryl, optionally substituted with one or more oxo, cyano, 3 to 10-membered heterocyclic, -C(O) (C1-C6 alkyl), 5 to 10-membered heteroaryl substituted with C1-C6 alkyl, or C1-C6 alkyl substituted with C1-C6 alkoxy, or Two Rs 3a Together with the atoms to which they are attached, they form C3-C 10 cycloalkyl or 3 to 10-membered heterocyclic groups, wherein the C3-C 10 The cycloalkyl or 3- to 10-membered heterocyclic group is optionally substituted with one or more 5- to 10-membered heteroaryl groups, wherein the 5- to 10-membered heteroaryl group is optionally substituted with one or more C1-C6 alkyl groups; R 4” yes , or ; R5 is H or halogenated. R6 is a C1-C6 alkyl group that is H, halogenated, -SO2 (C1-C6 alkyl), or optionally substituted with one or more -O (C1-C6 alkyl) or -N (C1-C6 alkyl)2, or R5 and R6, together with the atoms to which they are attached, form C4-C. 10 Cycloalkenyl; and Each of R7, R8 and R9 is independently H or C1-C6 alkyl.

4. The compound as claimed in any of the preceding claims, wherein X is C.

5. The compound as claimed in any of the preceding claims, wherein Y is NR2.

6. The compound as claimed in any of the preceding claims, wherein Z is CR3.

7. The compound as claimed in any of the preceding claims, wherein R1 is C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C3-C 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl groups are substituted with one or more R groups. 1a replace.

8. The compound as claimed in any of the preceding claims, wherein R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

9. The compound as claimed in any one of the preceding claims, wherein R 1a Independently, it can be oxo, halogenated, cyano, -OH, -NH2, -NH (C1-C6 alkyl), -NO2, -S (C1-C6 alkyl), -S(O)2(NH2), -C(O)NH2, -O (3 to 10 membered heterocyclic groups), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic, wherein -NH (C1-C6 alkyl), -S (C1-C6 alkyl), -O (3- to 10-membered heterocyclic), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic group may optionally be represented by one or more R groups. 1b replace.

10. The compound as claimed in any one of the preceding claims, wherein R 1a Independently, it can be oxo, fluorine, chlorine, bromine, cyano, -OH, -OCH3, -OCHF2, -OCF3, -OCH2CF3, -OCH(CH3)2, or -OCH2C(O)NH. 2、 -SCH3, -SCF3, -NH2, -NH(CH3) 、 -NH(CH2CF3), -NO2, -CH3, -CH2OH, -(CH2)2OH 、 -(CH2)2OCH 3、 -CHF2、-CF2CH 3、 -CH2CF 3、 -CF3, -S(O)2(NH2), -C(O)NH2, , , , , or .

11. The compound as claimed in any of the preceding claims, wherein R2 is a C1-C6 alkyl, C3-C6 alkyl, C4-C5 alkyl, C6-C6 alkyl, C6-C5 ... 10 cycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 2a replace.

12. The compound as claimed in any of the preceding claims, wherein R2 is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

13. The compound as claimed in any of the preceding claims, wherein each R 2a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -S(C1-C6 alkyl), wherein the C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -S (C1-C6 alkyl) may optionally be represented by one or more R 2a1 replace.

14. The compound as claimed in any of the preceding claims, wherein each R 2a Independently, it can be fluorine, chlorine, cyano, -OH, -NH2, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCHF2, -SCF3, -CH3, -CH(CH3)2, -CH2OH, -CF3, -CH(CF3)2. or .

15. The compound as claimed in any of the preceding claims, wherein R3 and R4, together with the atoms to which they are attached, are optionally formed by one or more R... 3a Substituted 6-membered heterocyclic group.

16. The compound as claimed in any of the preceding claims, wherein R3 and R4, together with the atoms to which they are attached, are optionally formed by one or more R... 3a Substituted 7-membered heterocyclic group.

17. The compound of any one of the preceding claims, wherein R3 and R4 together with the atoms to which they are attached form an 8-membered heterocyclic group, wherein the heterocyclic group optionally comprises one or more additional O atoms and is optionally surrounded by one or more R atoms. 3a replace.

18. The compound as claimed in any of the preceding claims, wherein each R 3a Independently, it is halogenated, -OH, -O (C3-C) 10 Cycloalkyl), -O (3 to 10-membered heterocyclic), C1-C6 alkyl, C1-C6 alkoxy, 5 to 10-membered heteroaryl, wherein the -O (C3-C 10 Cycloalkyl), -O (3 to 10-membered heterocyclic), C1-C6 alkyl, C1-C6 alkoxy, 5 to 10-membered heteroaryl, optionally substituted with one or more oxo, cyano, 3 to 10-membered heterocyclic, -C(O) (C1-C6 alkyl), 5 to 10-membered heteroaryl substituted with C1-C6 alkyl, or C1-C6 alkyl substituted with C1-C6 alkoxy.

19. The compound as claimed in any of the preceding claims, wherein each R 3a Independently, it consists of F, CH3, -OH, -OCH3, -O (cyclopropyl). , , , , , , , , , or .

20. The compound as claimed in any of the preceding claims, wherein R5 is H or halogenated.

21. The compound of any one of the preceding claims, wherein R6 is a C1-C6 alkyl group substituted with H, chlorine, -SO2 (C1-C6 alkyl), or optionally -N (C1-C6 alkyl)2 or -O (C1-C6 alkyl).

22. The compound of any one of the preceding claims, wherein R5 and R6 together with the atoms to which they are attached form a C4 cycloalkenyl group.

23. The compound as claimed in any of the preceding claims, wherein each of R7, R8 and R9 is independently H.

24. The compound of any one of the preceding claims, wherein the compound has the formula (II-a), (II-b), (II-c), (II-d), or (II-e): (II-a), (II-b), (II-c), (II-d), or (II-e), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein q is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3 or 4.

25. The compound of claim 1 or claim 2, wherein the compound has the formula (II-a1), (II-b1), (II-c1), (II-d1), or (II-e1): (II-a1), (II-b1), (II-c1), (II-d1), or (II-e1), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein n is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4 or 5; and r is 0, 1, 2, 3 or 4.

26. The compound of claim 1 or claim 2, wherein the compound has the formula (III-a'), (III-b'), (III-c'), (III-a), (III-b), or (III-c): (III-a), (III-b'), (III-c'), (III-a), (III-b), or (III-c), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4 and p is 0, 1, 2, 3, 4, 5 or 6.

27. The compound of claim 1 or claim 2, wherein the compound has the formula (III-a”'), (III-b”'), (III-c”'), (III-a”), (III-b”) or (III-c”): (III-a”'), (III-b”'), (III-c”'), (III-a”), (III-b”), or (III-c”), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4 and p is 0, 1, 2, 3, 4, 5 or 6.

28. The compound of claim 1 or claim 2, wherein the compound has the formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), or (IV-i): (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), or (IV-i), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5 or 6; and r is 0, 1, 2, 3 or 4.

29. The compound of claim 1 or claim 2, wherein the compound has the formula (IV-a'), (IV-b'), (IV-c'), (IV-d'), (IV-e'), (IV-f'), (IV-g'), (IV-h'), or (IV-i'): (IV-a'), (IV-b'), (IV-c'), (IV-d'), (IV-e'), (IV-f'), (IV-g’), (IV-h’), or (IV-i’), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5 or 6; and r is 0, 1, 2, 3 or 4.

30. The compound of claim 1 or claim 2, wherein the compound has the formula (V-a'), (V-b'), (V-c'), (V-d'), (V-e'), or (V-f'): (V-a’), (V-b’), (V-c'), or (V-d'), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4 or 5; and r is 0, 1, 2, 3 or 4.

31. The compound of claim 1 or claim 2, wherein the compound has the formula (VI-a'), (VI-b'), (VI-c'), or (VI-d'): (VI-a'), (VI-b'), (VI-c’), or (VI-d’), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4 or 5; and r is 0, 1, 2, 3 or 4.

32. The compound of claim 1 or claim 2, wherein the compound has the formula (VII-a'), (VII-b'), (VII-c'), or (VII-d'): (VII-a'), (VII-b'), (VII-c'), or (VII-d'), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4 or 5; and r is 0, 1, 2, 3 or 4.

33. The compound of claim 1 or claim 2, wherein the compound has the formula (VIII-a'), (VIII-b'), (VIII-c'), or (VIII-d'): (VIII), (VIII-b'), (VIII-c') or (VIII-d'), Or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer, wherein m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4 or 5; and r is 0, 1, 2, 3 or 4.

34. The compound of any of the preceding claims, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 1A or Table 2A, or pharmaceutically acceptable salts thereof.

35. The compound of any of the preceding claims, wherein the compound is compound numbered 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220, or 228, or a pharmaceutically acceptable salt thereof.

36. The compound of any of the preceding claims, wherein the compound is compound numbered 128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A, or 228A, or a pharmaceutically acceptable salt thereof.

37. A compound that can be obtained by or through the methods described herein; optionally, the methods include one or more steps described in any one of schemes 1-18.

38. A pharmaceutical composition comprising a compound as described in any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

39. The pharmaceutical composition of claim 38, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 1A or Table 2A.

40. The pharmaceutical composition of claim 38 or claim 39, wherein the compound is compound numbered 128, 163, 166, 178, 182, 183, 184, 186, 187, 190, 191, 194, 195, 196, 202, 203, 206, 208, 210, 211, 218, 220 or 228, or a pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition of claim 38 or claim 39, wherein the compound is compound numbered 128A, 163A, 166A, 178A, 182A, 183A, 186A, 191A, 194A, 196A, 202A, 203A, 206A, 208A, 210A, 211A, 218A, 220A or 228A, or a pharmaceutically acceptable salt thereof.

42. A method for modulating WRN activity, comprising contacting cells with a compound as described in any one of claims 1 to 37 or a pharmaceutical composition as described in any one of claims 38 to 41.

43. The compound of any one of claims 1 to 37 or the pharmaceutical composition of any one of claims 38 to 41, for modulating WRN activity.

44. Use of the compound of any one of claims 1 to 37 in the manufacture of a medicament for modulating WRN activity.

45. A method of treating or preventing a disease or condition in a subject in need, comprising administering to the subject a compound as described in any one of claims 1 to 37 or a pharmaceutical composition as described in any one of claims 38 to 41.

46. ​​The compound of any one of claims 1 to 37 or the pharmaceutical composition of any one of claims 38 to 41, for the treatment or prevention of a disease or condition.

47. Use of the compound of any one of claims 1 to 37 in the manufacture of a medicament for treating or preventing a disease or ailment.

48. The method, compound, pharmaceutical composition, or use as claimed in any one of claims 45 to 47, wherein the disease or condition is related to the WRN activity involved.

49. The method, compound, pharmaceutical composition, or use as claimed in any one of claims 45 to 48, wherein the disease or condition is cancer.

50. The method, compound, pharmaceutical composition, or use of claim 49, wherein the cancer is an MSI, MSI-H, and / or MMR-deficient cancer.

51. The method, compound, pharmaceutical composition, or use of claim 49, wherein the cancer is a TA repeat sequence amplified tumor.

52. The method, compound, pharmaceutical composition, or use as described in any one of claims 42 to 51, wherein the subject is a human.

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