Heterocyclic derivative and composition and application thereof

Abstract

The invention relates to a heterocyclic derivative as shown in a formula (I) and a composition, a preparation method and application of the heterocyclic derivative as a therapeutic agent. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to heterocyclic derivatives as PolQ inhibitors, and also relates to a preparation method and a composition of the heterocyclic derivatives, and an application of the heterocyclic derivatives in treating diseases associated with PolQ activity, such as cancer. Background Art

[0002] The DNA damage repair (DDR) process is essential for genome maintenance and cell viability. Double-strand breaks (DSBs) can be repaired by any of three major pathways: homologous recombination (HR), nonhomologous end joining (NHEJ), and alt-NHEJ. Nonhomologous end joining (alt-NHEJ), also known as end joining at the microhomology stage (MMEJ), is generally considered the “backup” DSB repair pathway when NHEJ or HR is impaired (Truong et al., 2013).

[0003] Aberrant DNA damage responses often sensitize cancer cells to specific types of DNA damage. Therefore, defective DDR can be developed into targeted cancer therapies. DNA repair defects have become a proven and effective strategy in cancer treatment, such as poly (ADP-ribose) polymerase (PARP) inhibitors have been successful in treating BRCA-deficient breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (Audeh MW et al., 2010).

[0004] Numerous genetic, cell biological and biochemical studies have shown that DNA PolQ (UniProtKB-075417(DPOLQ_HUMAN)) is a key protein involved in MMEJ (Kent et al., 2015, Mateos-Gomez et al., 2015).

[0005] PolQ is unique among human DNA polymerases, containing an N-terminal helicase domain (SF2 HEL308 type) and a C-terminal low-fidelity DNA polymerase domain (A type) (Wood and Doublie, 2016). In homologous recombination-deficient (HRD) cells, PolQ can perform error-prone DNA synthesis at DNA damage sites through the alt-NHEJ pathway. Studies have shown that the helicase domain of PolQ mediates the removal of replicative RPA proteins from ssDNA ends and stimulates annealing. The anti-recombinase activity of PolQ has a promoting effect on the MMEJ pathway. In addition, the helicase domain of PolQ facilitates microhomology-mediated strand annealing (Chan SH et al., 2010; Kawamura K et al., 2004). When the ssDNA overhang contains microhomology fragments of >2 base pairs (bp), PolQ can promote end joining in the alt-NHEJ pathway by utilizing this annealing activity (Kent T. et al., 2016; Kent T. et al., 2015). This reannealing activity is first achieved by ATPase-mediated displacement of Rad51 from the DSB lesion site and then by coupled interactions with Rad51. After annealing, the polymerase domain extends the ssDNA ends and fills in the remaining gap before the MMEJ repair junction is completed.

[0006] PolQ is lowly expressed or not expressed in normal cells, but is significantly overexpressed in HRD ovarian cancer, uterine cancer, and breast cancer subpopulations, and PolQ overexpression is associated with poor prognosis in breast cancer (Higgins et al., 2010, Lemee et al., 2010, Ceccaldi et al., 2015). Second, recent studies have shown that cancer cells with HR, NHEJ, or ATM defects are highly dependent on the expression of PolQ (Ceccaldi R. et al., 2015, Mateos-Gomez PA et al., 2015, and Wyatt DW et al., 2016). Finally, PolQ inhibition may prevent BRCA1 or BRCA2 mutations from undergoing MMEJ-dependent functional reversion mutations, which is the basis for the emergence of cisplatin and PARPi resistance in tumors (Zatreanu D. et al., 2021). Therefore, PolQ is an attractive target for synthetic lethal therapy against cancers containing DNA repair defects. Summary of the invention

[0007] The present invention relates to a compound represented by formula (I),

[0008]

[0009] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein the variables are respectively as defined in the present invention.

[0010] On the other hand, the present invention provides a pharmaceutical composition comprising: a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof and at least one pharmaceutically acceptable carrier.

[0011] In another aspect, the present invention provides a method for inhibiting PolQ, comprising:

[0012] PolQ is contacted with a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated product thereof.

[0013] On the other hand, the present invention provides a method for treating cancer, comprising: administering to a patient a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated product thereof.

[0014] The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the compositions and methods of the present invention described in different contexts may also be provided in a single aspect in a combined form. Alternatively, for the sake of brevity, various features of the compositions and methods of the present invention described in the context of a single aspect may also be provided individually or in any subcombination.

[0017] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described in the present invention, and it should also be understood that the terms used in the present invention are only used for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention. The present invention provides a compound shown in formula (I):

[0018]

[0019] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof, wherein:

[0020] Ring A is phenyl or a 5-6 membered heteroaryl group;

[0021] Ring B is a 5-6 membered heterocyclic group;

[0022] Ar 1 C 6 -C 10 Aryl or 5-10 membered heteroaryl; wherein the C 6 -C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by q independently selected from R 10 Substituents are substituted;

[0023] X is N or CR 5 ;

[0024] L 1 is absent, -C(O)-, *-(C(R 6 ) 2 ) p -C(R 7 ) 2 -,-C(O)C(R 7 ) 2 -,-C(O)NR 8 -, *-OC(O)-, or *-SC(O)-;

[0025] L 2 is not present, -(C(R 6 ) 2 ) t -,*-NR 9 C(R 7 ) 2 -,*-OC(R 7 ) 2 -, or *-SC(R 7 ) 2 -;

[0026] L 1 and L 2 do not exist simultaneously;

[0027] Wherein, the * and Y on ring A 1 or Y 2 connect;

[0028] Y 1 and Y 2 are independently selected from C or N; Y 1 and Y 2 Not all are N;

[0029] R 1 Selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 1A Substituents are substituted;

[0030] Every R 1A Independently selected from D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl or 5-10 membered heteroaryl, OR a , NR c R d , NHOR a , SR a , C(O)R b , C(O)NR c R d , NR c C(O)R b , C(O)OR a ,OC(O)R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b or S(O) 2 NR c R d ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O)2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 ;

[0031] Every R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , or NR C S(O) 2 NRC R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group; or

[0032] Two adjacent R 2 , together with the atoms to which it is attached, selectively forms C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0033] R 3 Selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D, NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , or NR C S(O) 2 NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 11 or

[0034] Two adjacent R 3 , together with the atoms to which it is attached, selectively forms C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0035] R 4 Selected from H, D, CN, C 1 -C 3 Alkyl, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl, wherein the C 1 -C 3 Alkyl, C 2 -C 3 Alkenyl, or C 2 -C3 The alkynyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of D, halogen, CN, OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl;

[0036] R 5 Selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , or NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group; or

[0037] R attached to adjacent carbons 5 and R 2 , together with the atoms to which it is attached, selectively forms C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0038] Every R 6independently selected from H, D, halogen, CN, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , NR C R D , C(O)R B , C(O)NR C R D , NR C C(O)R D , C(O)OR A , or OC(O)R B , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 or

[0039] Two R's 6 , together with the atoms to which it is attached, form C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0040] Every R 7 Independently selected from H, D, CN, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 1 , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 or

[0041] Two R's 7 , together with the atoms to which it is attached, form C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0042] R 8 Selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 1 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 Substituents are substituted;

[0043] R 9 Selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , C(O)R B , C(O)NR C R D , C(O)OR A , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , or S(O) 2 NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 or

[0044] R 9 and R 7 Together with the atoms to which they are attached, they selectively form C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0045] R 10 Selected from H, D, halogen, CN, NO 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , SR A , S.F. 5 , NHOR A , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), C(=NR C )NR C R D , NR D C(=NR C )NR C R D , NR DC(=NR C )R B , P(O)R E R F , P(O)OR E OR F OP(O)OR E OR F , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , NR C S(O) 2 NR C R D , or NR C S(O)(=NR B )R B ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 or

[0046] Two adjacent R 10 , together with the atoms to which it is attached, form C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups independently selected from R 12 Substituents are substituted;

[0047] Every R 11 Independently selected from D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6-Cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b , OP(O)OR e OR f , P(O)OR e OR f , S(O)(=NR b )R b , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , and NR c S(O) 2 NR c R d , NR c S(O)(=NR b )R b ;

[0048] Each R12 Independently selected from D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 -Cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , S.F. 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b ;

[0049] Cy 1 Selected from C 3- C 10Cycloalkyl, 4-10 membered heterocyclic group, C 6- C 10 Aryl or 5-10 membered heteroaryl, wherein the C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6- C 10 The aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 13 Substituents are substituted;

[0050] Every R 13 Independently selected from D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 -Cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , S.F. 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b OP(O)OR e OR f , P(O)ORe OR f , S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , NR c S(O)(=NR b )R b , phenyl, C 3 -C 10 Cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl;

[0051] Every R A Independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 0 -C 6 Alkyl-Cy 2 , wherein the C 1 -C 6 Alkyl, C 2 -C 4 Alkenyl, or C 2 -C 4 The alkynyl group is optionally substituted with 1, 2, or 3 independently selected from R 14 Substituents are substituted;

[0052] R B Independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 2 , wherein the C 1 -C 6 Alkyl, C 2 -C6 Alkenyl, or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, or 3 independently selected from R 14 Substituents are substituted;

[0053] R C and R D are independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 2 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, or 3 independently selected from R 14 or

[0054] R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of D, OH, oxo, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, C 1 -C 4 Cyanoalkyl, OC 1 -C 4 Alkyl, or OC 1 -C 4 Haloalkyl;

[0055] R E and R e are independently selected from H, D, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2-C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5-10 membered heteroaryl-C 1 -C 4 Alkyl, or 4-10 membered heterocyclyl-C 1 -C 4 alkyl;

[0056] R F and R f are independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4-10 membered heterocyclic group;

[0057] Every R a Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3 -C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclic group, wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, or C 1 -C 4 Haloalkoxy;

[0058] Every R b Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 Alkyl; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C4 The alkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy;

[0059] Every R a1 Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3 -C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclic group, wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, or C 1 -C 4 Haloalkoxy;

[0060] Every R b1 Independently selected from H, D, C 1 -C 4 Alkyl, C2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 Alkyl; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 The alkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy;

[0061] R c , R d , R c1 and R d1 are independently selected from H, D, C1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents independently selected from the following: D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl, and C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl-O-;

[0062] or R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group, which is optionally substituted by 1, 2, or 3 substituents independently selected from the following: D, OH, CN, -NH 2 , -NH(C 1 -C 4Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkoxy-C 1 -C 4 Alkyl, and C 1 -C 4 Alkoxy-C 1 -C 4 Alkoxy;

[0063] R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkoxy-C 1 -C4 Alkyl, and C 1 -C 4 Alkoxy-C 1 -C 4 Alkoxy;

[0064] Every R e1 Independently selected from H, D, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5-10 membered heteroaryl-C 1 -C 4 Alkyl, or 4-10 membered heterocyclyl-C 1 -C 4 alkyl;

[0065] Every R f1 Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4-10 membered heterocyclic group;

[0066] Cy 2 Selected from C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 3- C 7Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 14 Substituents are substituted;

[0067] Every R 14 independently selected from D, OH, CN, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, C 1 -C 4 Cyanoalkyl, NO 2 , oxo, OR a , SR a , S.F. 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR e )(OR f ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b , P(O)R e R f , P(O)OR e OR f OP(O)OR e OR f ,S(O)R b , S(O)NR c R d ,S(O) 2 R b, NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b ;

[0068] m is 1, 2 or 3;

[0069] n is 1, 2, 3 or 4;

[0070] p is 0 or 1;

[0071] q is 1, 2, 3 or 4;

[0072] t is 1 or 2.

[0073] In some embodiments, Ring A is phenyl.

[0074] In some embodiments, Ring A is a 5-membered heteroaryl.

[0075] In some embodiments, Ring A is a 6-membered heteroaryl.

[0076] In some embodiments, Ring A is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0077] In some embodiments, Ring B is a 5-membered heterocyclyl.

[0078] In some embodiments, Ring B is a 6-membered heterocyclyl.

[0079] In some embodiments, L 1 is not present, L 2 In some embodiments, L 1 In some embodiments, L 1 *-(C(R 6 ) 2 ) p -C(R 7 ) 2 -. In some embodiments, L 1 -C(O)C(R 7 ) 2 -. In some embodiments, L1 -C(O)NR 8 -. In some embodiments, L 1 is *-OC(O)-. In some embodiments, L 1 It is *-SC(O)-.

[0080] In some embodiments, p is 0. In some embodiments, p is 1.

[0081] In some embodiments, L 2 is not present, L 1 In some embodiments, L 2 -(C(R 6 ) 2 ) t -. In some embodiments, L 2 For *-NR 9 C(R 7 ) 2 -. In some embodiments, L 2 *-OC(R 7 ) 2 -. In some embodiments, L 2 *-SC(R 7 ) 2 -.

[0082] In some embodiments, t is 1. In some embodiments, t is 2.

[0083] In some embodiments, each R 6 independently selected from H, D, halogen, CN, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , NR C R D , C(O)R B , C(O)NR C R D , NR C C(O)R D , C(O)OR A , or OC(O)R B , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0084] In some embodiments, each R 6 Independently selected from H, D, halogen (eg F, Cl, Br, I), CN.

[0085] In some embodiments, each R 6 is H. In some embodiments, each R 6 is independently selected from D. In some embodiments, each R 6 is independently selected from halogen (e.g., F, Cl, Br, I). In some embodiments, each R 6 is independently selected from F. In some embodiments, each R 6 In some embodiments, each R 6 is independently selected from Br. In some embodiments, each R 6 are independently selected from I. In some embodiments, each R 6 Independently selected from CN.

[0086] In some embodiments, each R 6 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0087] In some embodiments, each R 6 Independently selected from C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0088] In some embodiments, each R 6 Independently selected from C 2 -C6 The alkenyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0089] In some embodiments, each R 6 Independently selected from C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0090] In some embodiments, each R 6 Independently selected from C 0 -C 6 Alkyl-Cy 1 .

[0091] In some embodiments, each R 6 Independently selected from OR A , NR C R D , C(O)R B , C(O)NR C R D , NR C C(O)R D , C(O)OR A , or OC(O)R B .

[0092] In some embodiments, each R 6 Independently selected from OR A In some embodiments, each R 6 Independently selected from NR C R D In some embodiments, each R 6 are independently selected from C(O)R B In some embodiments, each R 6 Independently selected from C(O)NR C R D In some embodiments, each R 6 Independently selected from NR C C(O)R D In some embodiments, each R 6 Independently selected from C(O)OR A In some embodiments, each R 6 Independently selected from OC(O)R B .

[0093] In some embodiments, both R 6 , together with the atoms to which it is attached, form C3- C 7 The cycloalkyl group is optionally substituted with 1, 2 or 3 groups independently selected from R 12 substituted by a substituent.

[0094] In some embodiments, both R 6 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2 or 3 independently selected R 12 substituted by a substituent.

[0095] In some embodiments, each R 7 is independently selected from H, D or CN. In some embodiments, each R 7 is independently selected from H. In some embodiments, each R 7 is independently selected from D. In some embodiments, each R 7 Independently selected from CN.

[0096] In some embodiments, each R 7 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 1 , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0097] In some embodiments, each R 7 Independently selected from C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0098] In some embodiments, each R 7 Independently selected from C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0099] In some embodiments, each R 7 Independently selected from C2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0100] In some embodiments, each R 7 Independently selected from C 0 -C 6 Alkyl-Cy 1 .

[0101] In some embodiments, both R 7 Together with the atoms to which it is attached, it forms C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups independently selected from R 12 substituted by a substituent.

[0102] In some embodiments, both R 7 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 independently selected R 12 substituted by a substituent.

[0103] In some embodiments, R 8 is H or D. In some embodiments, R 8 is H. In some embodiments, R 8 is D.

[0104] In some embodiments, R 8 C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 1 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0105] In some embodiments, R 8 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0106] In some embodiments, R 8 C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0107] In some embodiments, R 8 C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0108] In some embodiments, R 8 C 0 -C 6 Alkyl-Cy 1 .

[0109] In some embodiments, R 9 is H or D. In some embodiments, R 9 is H. In some embodiments, R 9 is D.

[0110] In some embodiments, R 9 C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 0 -C 6 Alkyl-Cy 1 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0111] In some embodiments, R 9 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0112] In some embodiments, R 9 C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0113] In some embodiments, R 9 C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0114] In some embodiments, R 9 C 0 -C 6 Alkyl-Cy 1 .

[0115] In some embodiments, R 9 C(O)R B , C(O)NR C R D , C(O)OR A , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , or S(O) 2 NR C R D In some embodiments, R 9 C(O)R B In some embodiments, R 9 C(O)NR C R D In some embodiments, R 9 C(O)OR A In some embodiments, R 9 S(O)(=NR B )R B In some embodiments, R 9 S(O)R B In some embodiments, R 9 S(O)NR C R D In some embodiments, R 9 S(O) 2 R B In some embodiments, R 9 S(O) 2 NR C R D .

[0116] In some embodiments, R 9 and R7 Together with the atoms to which it is attached, it forms C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups independently selected from R 12 substituted by a substituent.

[0117] In some embodiments, R 9 and R 7 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 independently selected R 12 substituted by a substituent.

[0118] In some embodiments, Y 1 and Y 2 Both are C.

[0119] In some embodiments, Y 1 is C; and Y 2 is N.

[0120] In some embodiments, Y 1 is N; and Y 2 For C.

[0121] In some embodiments, Ar 1 Selected from C 6 -C 10 The aryl group is optionally q independently selected from R 10 substituted by a substituent.

[0122] In some embodiments, Ar 1 phenyl, naphthyl; each substituent is optionally substituted by q independently selected from R 10 substituted by a substituent.

[0123] In some embodiments, Ar 1 is selected from phenyl optionally with q independently selected from R 10 substituted by a substituent.

[0124] In some embodiments, Ar 1 is selected from a 5-10 membered heteroaryl group optionally substituted by q independently selected from R 10 substituted by a substituent.

[0125] In some embodiments, Ar 1is selected from the group consisting of pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, benzo[c]thienyl, indazolyl, benzo[d]imidazolyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizin pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,4-c]pyridinyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furano[3,2-b]pyridinyl, furano[3,2-c]pyridinyl, c]pyridinyl, furo[2,3-c]pyridinyl, furo[2,3-b]pyridinyl, benzo[c]isoxazolyl, furo[3,4-b]pyridinyl, furo[3,4-c]pyridinyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, thieno[3,2-b]pyridinyl, thieno[3,4-c]pyridinyl, benzo[d] [1,2,3]triazolyl, pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-c]pyridinyl, Pyrrolo[3,2-c]pyridazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-d]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-c]pyridazinyl, pyrrolo[3,4-c]pyridazinyl, pyrrolo[3,4-d]pyrimidinyl, pyrrolo[3,4-b]pyrazinyl , pyrrolo[3,4-d]pyridazinyl, pyrrolo[3,4-d]pyrimidinyl, 6H-pyrrolo[3,4-c]pyridazinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyrazinyl, thiazolo[5,4-d]pyrimidinyl, thiazolo[4,5-d]pyrimidinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, oxazolo[5,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[5,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-b][1,2,4]thiadiazolyl, imidazo[1,2-b][1,2,4]thiadiazolyl, thiazo[5,4-d]thiazolyl, thiazo[4,5-d]thiazolyl, thiazo[3,2-b][1,2,4]triazolyl, isothiazolo[2,3-b][1,2,4]triazolyl, 2H-pyrazolo[4,3-d]thiazolyl, 4H-imidazo[4,5-d]thiazolyl, 2H-pyrazolo[3,4-d] thiazolyl, imidazo[5,1-b][1,3,4]thiadiazol-5(6H)-onyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-onyl; each substituent is optionally substituted by q independently selected from R, 10 substituted by a substituent.

[0126] In some embodiments, q is 1.

[0127] In some embodiments, q is 2.

[0128] In some embodiments, q is 3.

[0129] In some embodiments, q is 4.

[0130] In some embodiments, each R 10 Independently selected from H, D, halogen, CN, NO 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , SR A , S.F. 5 , NHOR A , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), C(=NR C )NR C R D , NR D C(=NR C )NR C R D , NR D C(=NRC )R B , P(O)R E R F , P(O)OR E OR F OP(O)OR E OR F , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , NR C S(O) 2 NR C R D , NR C S(O)(=NR B )R B , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 Substituents substituted, and Cy 1 Optionally, 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent.

[0131] In some embodiments, each R 10 is independently selected from H. In some embodiments, each R 10 is independently selected from D. In some embodiments, each R 10 is independently selected from halogen (e.g., F, Cl, Br, I). In some embodiments, each R 10 In some embodiments, each R 10 Independently selected from NO 2 .

[0132] In some embodiments, each R 10 Independently selected from C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11substituted by a substituent.

[0133] In some embodiments, each R 10 Independently selected from C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0134] In some embodiments, each R 10 Independently selected from C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0135] In some embodiments, each R 10 Independently selected from C 0 -C 6 Alkyl-Cy 1 Among them, Cy 1 Optionally, 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent.

[0136] In some embodiments, each R 10 Independently selected from OR A In some embodiments, each R 10 Independently selected from SR A In some embodiments, each R 10 Independently selected from SF 5 In some embodiments, each R 10 Independently selected from NHOR A .

[0137] In some embodiments, each R 10 are independently selected from C(O)R B In some embodiments, each R 10 Independently selected from C(O)NR C R D In some embodiments, each R 10 Independently selected from C(O)OR A In some embodiments, each R 10 Independently selected from OC(O)R B In some embodiments, each R 10 Independently selected from OC(O)NR C R D .

[0138] In some embodiments, each R10 Independently selected from NR C R D In some embodiments, each R 10 Independently selected from NR C C(O)R B In some embodiments, each R 10 Independently selected from NR C C(O)NR C R D In some embodiments, each R 10 Independently selected from NR C C(O)OR A .

[0139] In some embodiments, each R 10 Independently selected from B(OR E )(OR F In some embodiments, each R 10 Independently selected from C(=NR C )NR C R D In some embodiments, each R 10 Independently selected from NR D C(=NR C )NR C R D In some embodiments, each R 10 Independently selected from NR D C(=NR C )R B .

[0140] In some embodiments, each R 10 Independently selected from P(O)R E R F In some embodiments, each R 10 Independently selected from P(O)OR E OR F In some embodiments, each R 10 Independently selected from OP(O)OR E OR F .

[0141] In some embodiments, each R 10 Independently selected from S(O)(=NR B )R B In some embodiments, each R 10 Independently selected from S(O)R B In some embodiments, each R 10Independently selected from S(O)NR C R D In some embodiments, each R 10 Independently selected from S(O) 2 R B In some embodiments, each R 10 Independently selected from NR C S(O) 2 R B In some embodiments, each R 10 Independently selected from S(O) 2 NR C R D In some embodiments, each R 10 Independently selected from NR C S(O) 2 NR C R D In some embodiments, each R 10 Independently selected from NR C S(O)(=NR B )R B .

[0142] In some embodiments, each R 10 Independently selected from H, D, halogen, CN, NO 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , SR A , S.F. 5 , NHOR A , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A, S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , NR C S(O) 2 NR C R D , NR C S(O)(=NR B )R B , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 Substituents substituted, and Cy 1 Optionally, 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent.

[0143] In some embodiments, each R 10 Independently selected from H, D, halogen, CN, NO 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NRC C(O)OR A , S(O)(=NR B )R B ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , NR C S(O) 2 NR C R D , NR C S(O)(=NR B )R B , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 Substituents of Cy 1 Optionally, 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent.

[0144] In some embodiments, each R 10 Independently selected from H, D, halogen, CN, NO 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , S.F. 5 , NR C R D , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 Substituents of Cy 1 Optionally, 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent.

[0145] In some embodiments, each R 10 independently selected from H, D, halogen, CN, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 0 -C 6 Alkyl-Cy 1 , OR A , S.F. 5 , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 Substituents of Cy 1 Optionally, 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent.

[0146] In some embodiments, each R 10 independently selected from H, D, halogen, CN, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0147] In some embodiments, each R 10 independently selected from H, D, halogen, CN, C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0148] In some embodiments, two adjacent R 10 , together with the atoms to which it is attached, form C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups independently selected from R12 substituted by a substituent.

[0149] In some embodiments, two adjacent R 10 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 independently selected R 12 substituted by a substituent.

[0150] In some embodiments, each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , or NR C S(O) 2 NR C R D ; wherein, the C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0151] In some embodiments, each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , S(O)NR C R D ,S(O) 2 R B ,S(O) 2 NR C R D ; wherein, the C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0152] In some embodiments, each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0153] In some embodiments, each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 ,OC(O)R B , OC(O)NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0154] In some embodiments, each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0155] In some embodiments, each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, SF 5 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C6 Cycloalkyl, 4-6 membered heterocyclic group.

[0156] In some embodiments, each R 2 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0157] In some embodiments, each R 2 Independently selected from 4-7 membered heterocyclic groups optionally substituted by substituents selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0158] In some embodiments, each R 2 Independently selected from C 3 -C 7 The cycloalkyl group is optionally substituted with a substituent selected from the group consisting of D, CN, halogen, OH, NH 2 , C1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0159] In some embodiments, each R 2 Independently selected from C 2 -C 6 The alkynyl group is optionally substituted with a substituent selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0160] In some embodiments, each R 2 Independently selected from C 2 -C 6 The alkenyl group is optionally substituted with a substituent selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0161] In some embodiments, each R 2 Independently selected from C 1 -C 6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1-C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclyl. In some embodiments, for example, including but not limited to, each R 2 Independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 F, CHF 2 , C.F. 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 wait.

[0162] In some embodiments, each R 2 Independently selected from H, D, halogen, CN, SF 5 , C 1 -C 6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0163] In some embodiments, two adjacent R 2 , together with the atoms to which it is attached, form C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups independently selected from R 12 substituted by a substituent.

[0164] In some embodiments, two adjacent R 2 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 independently selected R 12 substituted by a substituent.

[0165] In some embodiments, X is N. In some embodiments, X is CR 5 .

[0166] In some embodiments, R 5 Selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , or NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0167] In some embodiments, R 5 Selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, or 4-7 membered heterocyclic group; wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0168] In some embodiments, R 5 Selected from H, D, halogen, CN, NO 2 , OR A , S.F. 5 , or NR C R D In some embodiments, R 5 Selected from H, D, halogen, CN, NO 2 , OR A , S.F. 5 In some embodiments, R 5 Selected from H, D, halogen, CN, NO 2 , S.F. 5 In some embodiments, R 5 Selected from H, D, halogen, CN, SF 5 In some embodiments, R 5 is selected from H, D, halogen, CN. In some embodiments, R 5 Selected from H, D, CN.

[0169] In some embodiments, R attached to adjacent carbons 5 and R 2 , together with the atoms to which it is attached, form C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups independently selected from R 12 substituted by a substituent.

[0170] In some embodiments, R attached to adjacent carbons 5 and R 2 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 independently selected R 12 substituted by a substituent.

[0171] In some embodiments, R 1 Independently selected from H, D, C1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 1A substituted by a substituent.

[0172] In some embodiments, R 1 is H. In some embodiments, R 1 is D.

[0173] In some embodiments, R 1 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 1A substituted by a substituent.

[0174] In some embodiments, R 1 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl or phenyl, wherein the C1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl, or phenyl is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 1A substituted by a substituent.

[0175] In some embodiments, R 1 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkynyl, C 3- C 7 Cycloalkyl or phenyl, wherein the C 1 -C 6 Alkyl, C 3- C 7 Cycloalkyl, or phenyl is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 1A substituted by a substituent.

[0176] In some embodiments, R 1 C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R 1A substituted by a substituent.

[0177] In some embodiments, R 1 is phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 1A In some embodiments, R 1 It is phenyl.

[0178] In some embodiments, R 1 C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R 1A substituted by a substituent.

[0179] In some embodiments, R 1 is cyclobutyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 1A In some embodiments, R 1 It is cyclobutyl.

[0180] In some embodiments, R 1 is cyclopropyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 1AIn some embodiments, R 1 It is cyclopropyl.

[0181] In some embodiments, R 1 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R 1A substituted by a substituent.

[0182] In some embodiments, R 1 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R 1A substituted by a substituent.

[0183] In some embodiments, R 1 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl-OH, C 1 -C 6 Haloalkyl -OH, or NR c R d .

[0184] In some embodiments, R 1 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, -OC 1 -C 6 Alkyl, or NR c R d ;

[0185] In some embodiments, R 1 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, or F.

[0186] In some embodiments, R 1 C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 D. In some embodiments, R 1 For iC 3D 7 In some embodiments, R 1 C 2 D 5 In some embodiments, R 1 For CD 3 .

[0187] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is Et. In some embodiments, R 1 For me.

[0188] In some embodiments, each R 1A Independently selected from D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl or 5-10 membered heteroaryl, OR a , NR c R d , NHOR a , SR a , C(O)R b , C(O)NR c R d , NR c C(O)R b , C(O)OR a ,OC(O)R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b or S(O) 2 NR c R d ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O)2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0189] In some embodiments, each R 1A is independently selected from D. In some embodiments, each R 1A is independently selected from halogen (e.g., F, Cl, Br, I). In some embodiments, each R 1A In some embodiments, each R 1A Independently selected from NO 2 In some embodiments, each R 1A Independently selected from SF 5 In some embodiments, each R 1A Independently selected from oxo.

[0190] In some embodiments, each R 1A Independently selected from C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1, NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0191] In some embodiments, each R 1A Independently selected from C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1, C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0192] In some embodiments, each R 1A Independently selected from C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )Rb1 .

[0193] In some embodiments, each R 1A Independently selected from C 3- C 10 The cycloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0194] In some embodiments, each R 1A independently selected from 4-10 membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)ORe1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0195] In some embodiments, each R 1A Independently selected from C 6 -C 10 The aryl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NRc1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0196] In some embodiments, each R 1A phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)Rb1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0197] In some embodiments, each R 1A independently selected from 5-10 membered heteroaryl (5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, NO 2 , S.F. 5 , oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, ORa1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ), C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )NR c1 R d1 , NR d1 C(=NR c1 )R b1 OP(O)OR e1 OR f1 , P(O)OR e1 OR f1 , S(O)(=NR b1 )R b1 ,S(O)R b1 , S(O)NR c1 R d1 ,S(O) 2 R b1 , NR c1 S(O) 2 R b1 ,S(O) 2 NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , NR c1 S(O)(=NR b1 )R b1 .

[0198] In some embodiments, each R 1A Independently selected from OR a In some embodiments, each R 1AIndependently selected from NR c R d In some embodiments, each R 1A Independently selected from NHOR a In some embodiments, each R 1A Independently selected from SR a .

[0199] In some embodiments, each R 1A are independently selected from C(O)R b In some embodiments, each R 1A Independently selected from C(O)NR c R d In some embodiments, each R 1A Independently selected from NR c C(O)R b In some embodiments, each R 1A Independently selected from C(O)OR a In some embodiments, each R 1A Independently selected from OC(O)R b .

[0200] In some embodiments, each R 1A Independently selected from S(O)R b In some embodiments, each R 1A Independently selected from S(O)NR c R d In some embodiments, each R 1A Independently selected from S(O) 2 R b In some embodiments, each R 1A Independently selected from NR c S(O) 2 R b In some embodiments, each R 1A Independently selected from S(O) 2 NR c R d .

[0201] In some embodiments, R 3 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , or NR C S(O) 2 NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0202] In some embodiments, R 3 are independently selected from H. In some embodiments, R 3 is independently selected from D. In some embodiments, R 3 In some embodiments, R 3In some embodiments, R 3 Independently selected from NO 2 In some embodiments, R 3 Independently selected from SF 5 .

[0203] In some embodiments, R 3 Independently selected from C 1 -C 6 The alkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0204] In some embodiments, R 3 Independently selected from C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0205] In some embodiments, R 3 Independently selected from C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 11 substituted by a substituent.

[0206] In some embodiments, R 3 Independently selected from C 3 -C 7 The cycloalkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from R 11 substituted by a substituent.

[0207] In some embodiments, R 3 independently selected from 4-7 membered heterocyclic groups optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 11 substituted by a substituent.

[0208] In some embodiments, R 3 Independently selected from OR A In some embodiments, R 3 Independently selected from SF 5 .

[0209] In some embodiments, R 3 are independently selected from C(O)R B In some embodiments, R 3 Independently selected from C(O)NR C R D In some embodiments, R 3 Independently selected from C(O)OR AIn some embodiments, R 3 Independently selected from OC(O)R B In some embodiments, R 3 Independently selected from OC(O)NR C R D .

[0210] In some embodiments, R 3 Independently selected from NR C R D In some embodiments, R 3 Independently selected from NR C C(O)R D In some embodiments, R 3 Independently selected from NR C C(O)NR C R D In some embodiments, R 3 Independently selected from NR C C(O)OR A .

[0211] In some embodiments, R 3 Independently selected from B(OR E )(OR F In some embodiments, R 3 Independently selected from S(O)(=NR B )R B In some embodiments, R 3 Independently selected from S(O)R B In some embodiments, R 3 Independently selected from S(O)NR C R D In some embodiments, R 3 Independently selected from S(O) 2 R B In some embodiments, R 3 Independently selected from NR C S(O) 2 R B In some embodiments, R 3 Independently selected from S(O) 2 NR C R D In some embodiments, R 3 Independently selected from NR C S(O) 2 NR C R D .

[0212] In some embodiments, two adjacent R 3 , together with the atoms to which it is attached, form C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from R 12 substituted by a substituent.

[0213] In some embodiments, two adjacent R 3 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 selected from R 12 substituted by a substituent.

[0214] In some embodiments, R 4 Selected from H, D, CN, C 1 -C 3 Alkyl, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl, wherein the C 1 -C 3 Alkyl, C 2 -C 3 Alkenyl, or C 2 -C 3 The alkynyl group is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of D, halogen, CN, OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Halogenated alkyl.

[0215] In some embodiments, R 4 C 2 -C 3 The alkynyl group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, halogen, CN, OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Halogenated alkyl.

[0216] In some embodiments, R 4 C 2 -C 3 The alkenyl group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, halogen, CN, OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Halogenated alkyl.

[0217] In some embodiments, R 4 C1 -C 3 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, halogen, CN, OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 In some embodiments, R 4 CH 2 CF 3 In some embodiments, R 4 For CF 3 In some embodiments, R 4 CH 2 In some embodiments, R 4 CH 2 OH. In some embodiments, R 4 In some embodiments, R 4 is Et. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is D. In some embodiments, R 4 For H.

[0218] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0219] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0220] In some embodiments, each R 11 Independently selected from D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 -Cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , S.F. 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b OP(O)OR e OR f , P(O)OR e OR f , S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b .

[0221] In some embodiments, R 11 is D. In some embodiments, R 11 In some embodiments, R 11 C 1 -C 6 In some embodiments, R 11 C 2 -C 6In some embodiments, R 11 C 2 -C 6 In some embodiments, R 11 C 1 -C 6 In some embodiments, R 11 C 1 -C 6 -cyanoalkyl. In some embodiments, R 11 In some embodiments, R 11 NO 2 In some embodiments, R 11 In some embodiments, R 11 OR a In some embodiments, R 11 For SR a In some embodiments, R 11 For SF 5 In some embodiments, R 11 For NHOR a In some embodiments, R 11 C(O)R b In some embodiments, R 11 C(O)NR c R d In some embodiments, R 11 C(O)OR a In some embodiments, R 11 OC(O)R b In some embodiments, R 11 OC(O)NR c R d In some embodiments, R 11 NR c R d In some embodiments, R 11 NR c C(O)R b In some embodiments, R 11 NR c C(O)NR c R d In some embodiments, R 11 NR c C(O)OR a In some embodiments, R 11 B(OR e )(OR f In some embodiments, R11 C(=NR c )NR c R d In some embodiments, R 11 NR d C(=NR c )NR c R d In some embodiments, R 11 NR d C(=NR c )R b In some embodiments, R 11 OP(O)OR e OR f In some embodiments, R 11 P(O)OR e OR f In some embodiments, R 11 S(O)(=NR b )R b In some embodiments, R 11 S(O)R b In some embodiments, R 11 S(O)NR c R d In some embodiments, R 11 S(O) 2 R b In some embodiments, R 11 NR c S(O) 2 R b In some embodiments, R 11 S(O) 2 NR c R d In some embodiments, R 11 NR c S(O) 2 NR c R d In some embodiments, R 11 NR c S(O)(=NR b )R b .

[0222] In some embodiments, R 12 Independently selected from D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2-C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 -Cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , S.F. 5 , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR e )(OR f ), S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b .

[0223] In some embodiments, R 12 is D. In some embodiments, R 12 In some embodiments, R 12 C 1 -C 6 In some embodiments, R 12 C 2 -C 6 In some embodiments, R12 C 2 -C 6 In some embodiments, R 12 C 1 -C 6 In some embodiments, R 12 C 1 -C 6 -cyanoalkyl. In some embodiments, R 12 In some embodiments, R 12 NO 2 In some embodiments, R 12 In some embodiments, R 12 OR a In some embodiments, R 12 For SR a In some embodiments, R 12 For SF 5 In some embodiments, R 12 C(O)R b In some embodiments, R 12 C(O)NR c R d In some embodiments, R 12 C(O)OR a In some embodiments, R 12 OC(O)R b In some embodiments, R 12 OC(O)NR c R d In some embodiments, R 12 NR c R d In some embodiments, R 12 NR c C(O)R b In some embodiments, R 12 NR c C(O)NR c R d In some embodiments, R 12 NR c C(O)OR a In some embodiments, R 12 B(OR e )(OR f In some embodiments, R 12 S(O)(=NR b )R b In some embodiments, R12 S(O)R b In some embodiments, R 12 S(O)NR c R d In some embodiments, R 12 S(O) 2 R b In some embodiments, R 12 NR c S(O) 2 R b In some embodiments, R 12 S(O) 2 NR c R d In some embodiments, R 12 NR c S(O) 2 NR c R d In some embodiments, R 12 NR c S(O)(=NR b )R b .

[0224] In some embodiments, Cy 1 Selected from C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6- C 10 Aryl or 5-10 membered heteroaryl, wherein the C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6- C 10 The aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 groups selected from R 13 substituted by a substituent.

[0225] In some embodiments, Cy 1 C 3- C 10 The cycloalkyl group is optionally substituted with 1, 2, 3, 4, or 5 groups selected from R 13 substituted by a substituent.

[0226] In some embodiments, Cy 1 is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 selected from R 13 substituted by a substituent.

[0227] In some embodiments, Cy 1 C 6- C10 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 groups selected from R 13 substituted by a substituent.

[0228] In some embodiments, Cy 1 is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members selected from R 13 substituted by a substituent.

[0229] In some embodiments, R 13 Independently selected from D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 -Cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , S.F. 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b OP(O)OR e OR f , P(O)OR e ORf , S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , NR c S(O)(=NR b )R b , phenyl, C 3 -C 10 Cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl.

[0230] In some embodiments, R 13 is D. In some embodiments, R 13 In some embodiments, R 13 C 1 -C 6 In some embodiments, R 13 C 2 -C 6 In some embodiments, R 13 C 2 -C 6 In some embodiments, R 13 C 1 -C 6 In some embodiments, R 13 C 1 -C 6 -cyanoalkyl. In some embodiments, R 13 In some embodiments, R 13 C 3 -C 10 In some embodiments, R 13 is a 5-10 membered heteroaryl. 13 It is a 4-10 membered heterocyclic group.

[0231] In some embodiments, R 13 In some embodiments, R 13 NO 2In some embodiments, R 13 In some embodiments, R 13 OR a In some embodiments, R 13 For SR a In some embodiments, R 13 For SF 5 In some embodiments, R 13 For NHOR a In some embodiments, R 13 C(O)R b In some embodiments, R 13 C(O)NR c R d In some embodiments, R 13 C(O)OR a In some embodiments, R 13 OC(O)R b In some embodiments, R 13 OC(O)NR c R d In some embodiments, R 13 NR c R d In some embodiments, R 13 NR c C(O)R b In some embodiments, R 13 NR c C(O)NR c R d In some embodiments, R 13 NR c C(O)OR a In some embodiments, R 13 B(OR e )(OR f In some embodiments, R 13 C(=NR c )NR c R d In some embodiments, R 13 NR d C(=NR c )NR c R d In some embodiments, R 13 NR d C(=NR c )R b In some embodiments, R 13OP(O)OR e OR f In some embodiments, R 13 P(O)OR e OR f In some embodiments, R 13 S(O)(=NR b )R b In some embodiments, R 13 S(O)R b In some embodiments, R 13 S(O)NR c R d In some embodiments, R 13 S(O) 2 R b In some embodiments, R 13 NR c S(O) 2 R b In some embodiments, R 13 S(O) 2 NR c R d In some embodiments, R 13 NR c S(O) 2 NR c R d In some embodiments, R 13 NR c S(O)(=NR b )R b .

[0232] In some embodiments, each R A Independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 0 -C 6 Alkyl-Cy 2 , wherein the C 1 -C 6 Alkyl, C 2 -C 4 Alkenyl, or C 2 -C 4 The alkynyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0233] In some embodiments, each RA is H. In some embodiments, each R A is D.

[0234] In some embodiments, each R A C 1 -C 6 The alkyl group is optionally replaced by 1, 2, or 3 groups selected from R 14 substituted by a substituent.

[0235] In some embodiments, each R A C 2 -C 4 The alkenyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0236] In some embodiments, each R A C 2 -C 4 The alkynyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0237] In some embodiments, each R A C 0 -C 6 Alkyl-Cy 2 .

[0238] In some embodiments, R B Independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 2 , wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl, optionally substituted by 1, 2, or 3 selected from R 14 substituted by a substituent.

[0239] In some embodiments, R B is H. In some embodiments, R B is D.

[0240] In some embodiments, R B C 1 -C 6The alkyl group is optionally replaced by 1, 2, or 3 groups selected from R 14 substituted by a substituent.

[0241] In some embodiments, R B C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0242] In some embodiments, R B C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0243] In some embodiments, R B C 0 -C 6 Alkyl-Cy 2 .

[0244] In some embodiments, R C Independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 2 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl, optionally substituted by 1, 2, or 3 selected from R 14 substituted by a substituent.

[0245] In some embodiments, R C is H. In some embodiments, R C is D.

[0246] In some embodiments, R C C 1 -C 6 The alkyl group is optionally replaced by 1, 2, or 3 groups selected from R 14 substituted by a substituent.

[0247] In some embodiments, R C C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, or 3 selected from R14 substituted by a substituent.

[0248] In some embodiments, R C C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0249] In some embodiments, R C C 0 -C 6 Alkyl-Cy 2 .

[0250] In some embodiments, R D Independently selected from H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 0 -C 6 Alkyl-Cy 2 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl, optionally substituted by 1, 2, or 3 selected from R 14 substituted by a substituent.

[0251] In some embodiments, R D is H. In some embodiments, R D is D.

[0252] In some embodiments, R D C 1 -C 6 The alkyl group is optionally replaced by 1, 2, or 3 groups selected from R 14 substituted by a substituent.

[0253] In some embodiments, R D C 2 -C 6 The alkenyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0254] In some embodiments, R D C 2 -C 6 The alkynyl group is optionally substituted with 1, 2, or 3 selected from R 14 substituted by a substituent.

[0255] In some embodiments, R D C 0 -C 6 Alkyl-Cy 2 .

[0256] In some embodiments, R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, oxo, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, or C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, C 1 -C 4 Cyanoalkyl, OC 1 -C 4 Alkyl, or OC 1 -C 4 Halogenated alkyl.

[0257] In some embodiments, R E Independently selected from H, D, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4Alkyl, 5-10 membered heteroaryl-C 1 -C 4 Alkyl, or 4-10 membered heterocyclyl-C 1 -C 4 alkyl.

[0258] In some embodiments, R E is H. In some embodiments, R E is D.

[0259] In some embodiments, R E C 1 -C 4 In some embodiments, R E C 1 -C 4 In some embodiments, R E C 2 -C 4 In some embodiments, R E For (C 1 -C 4 Alkoxy)-C 1 -C 4 In some embodiments, R E C 2 -C 4 In some embodiments, R E C 6 -C 10 In some embodiments, R E is a 5-10 membered heteroaryl. E C 3 -C 10 In some embodiments, R E is a 4-10 membered heterocyclyl. E C 6 -C 10 Aryl-C 1 -C 4 In some embodiments, R E C 3 -C 10 Cycloalkyl-C 1 -C 4 In some embodiments, R E is a 5-10 membered heteroaryl-C 1 -C 4 In some embodiments, R E is a 4-10 membered heterocyclic group-C 1 -C 4 alkyl.

[0260] In some embodiments, R F Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4-10 membered heterocyclic group.

[0261] In some embodiments, R F is H. In some embodiments, R F is D. In some embodiments, R F C 1 -C 4 In some embodiments, R F C 2 -C 4 In some embodiments, R F C 2 -C 4 In some embodiments, R F C 6 -C 10 In some embodiments, R F is a 5-10 membered heteroaryl. F C 3 -C 10 In some embodiments, R F It is a 4-10 membered heterocyclic group.

[0262] In some embodiments, each R a is independently selected from H. In some embodiments, each R a Independently selected from D.

[0263] In some embodiments, each R a Independently selected from C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3 -C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclic group, wherein the C 1 -C 4 Alkyl, C2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, or C 1 -C 4 Halogenated alkoxy.

[0264] In some embodiments, each R b is independently selected from H. In some embodiments, each R b Independently selected from D.

[0265] In some embodiments, each R b Independently selected from C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 Alkyl; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Halogenated alkoxy.

[0266] In some embodiments, each R a1 is independently selected from H. In some embodiments, each R a1 Independently selected from D.

[0267] In some embodiments, each R a1 Independently selected from C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3 -C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclic group, wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, or C 1 -C 4 Halogenated alkoxy.

[0268] In some embodiments, each R b1 is independently selected from H. In some embodiments, each R b1 Independently selected from D.

[0269] In some embodiments, each R b1 Independently selected from C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 Alkyl; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C 1 -C 4 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 4 Alkyl, 5-6 membered heteroaryl-C 1 -C 4 Alkyl, or 4-7 membered heterocyclyl-C 1 -C 4The alkyl group is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Halogenated alkoxy.

[0270] In some embodiments, each R c Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)Rb1 ,S(O) 2 R b1 , C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl, and C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl-O-.

[0271] In some embodiments, each R d Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkyl-OC 1 -C4 Alkyl, and C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl-O-.

[0272] In some embodiments, each R c1 Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl, and C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl-O-.

[0273] In some embodiments, each R d1 Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl, and C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl-O-.

[0274] In some embodiments, R c and R dTogether with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)OR a1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkoxy-C 1 -C 4 Alkyl, and C 1 -C 4 Alkoxy-C 1 -C 4 Alkoxy.

[0275] In some embodiments, R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, C 1 -C 4 Haloalkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C(O)ORa1 , C(O)R b1 ,S(O) 2 R b1 , C 1 -C 4 Alkoxy-C 1 -C 4 Alkyl, and C 1 -C 4 Alkoxy-C 1 -C 4 Alkoxy.

[0276] In some embodiments, each R e Independently selected from H, D, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5-10 membered heteroaryl-C 1 -C 4 Alkyl, or 4-10 membered heterocyclyl-C 1 -C 4 alkyl.

[0277] In some embodiments, each R f Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4-10 membered heterocyclic group.

[0278] In some embodiments, each R e1 Independently selected from H, D, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5-10 membered heteroaryl-C 1 -C 4 Alkyl, or 4-10 membered heterocyclyl-C 1 -C 4 alkyl.

[0279] In some embodiments, each R f1 Independently selected from H, D, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4-10 membered heterocyclic group.

[0280] In some embodiments, Cy 2 Independently selected from C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 3- C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 selected from R 14 substituted by a substituent.

[0281] In some embodiments, Cy 2 C 3- C 7 The cycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from R 14 substituted by a substituent.

[0282] In some embodiments, Cy 2 is a 4-7 membered heterocyclic group optionally substituted by 1, 2, or 3 selected from R 14 substituted by a substituent.

[0283] In some embodiments, Cy 2 The phenyl group is optionally replaced by 1, 2, or 3 groups selected from R 14 substituted by a substituent.

[0284] In some embodiments, Cy 2 is a 5-6 membered heteroaryl group optionally substituted by 1, 2, or 3 selected from R 14 substituted by a substituent.

[0285] In some embodiments, each R 14 independently selected from D, OH, CN, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, C 1 -C 4 Cyanoalkyl, NO 2 , oxo, OR a , SR a , S.F. 5 , NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR e )(OR f ), C(=NR c )NR c Rd , NR d C(=NR c )NR c R d , NR d C(=NR c )R b , P(O)R e R f , P(O)OR e OR f OP(O)OR e OR f ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b .

[0286] In some embodiments, R 14 is D. In some embodiments, R 14 In some embodiments, R 14 In some embodiments, R 14 In some embodiments, R 14 C 1 -C 4 In some embodiments, R 14 C 1 -C 4 In some embodiments, R 14 C 1 -C 4 In some embodiments, R 14 C 1 -C 4 Cyanoalkyl.

[0287] In some embodiments, R 14 NO 2 In some embodiments, R 14 In some embodiments, R 14OR a In some embodiments, R 14 For SR a In some embodiments, R 14 For SF 5 In some embodiments, R 14 For NHOR a In some embodiments, R 14 C(O)R b In some embodiments, R 14 C(O)NR c R d In some embodiments, R 14 C(O)OR a In some embodiments, R 14 OC(O)R b In some embodiments, R 14 OC(O)NR c R d In some embodiments, R 14 NR c R d In some embodiments, R 14 NR c C(O)R b In some embodiments, R 14 NR c C(O)NR c R d In some embodiments, R 14 NR c C(O)OR a In some embodiments, R 14 B(OR e )(OR f In some embodiments, R 14 C(=NR c )NR c R d In some embodiments, R 14 NR d C(=NR c )NR c R d In some embodiments, R 14 NR d C(=NR c )R b In some embodiments, R 14 P(O)R e R f In some embodiments, R14 P(O)OR e OR f In some embodiments, R 14 OP(O)OR e OR f In some embodiments, R 14 S(O)R b In some embodiments, R 14 S(O)NR c R d In some embodiments, R 14 S(O) 2 R b In some embodiments, R 14 NR c S(O) 2 R b In some embodiments, R 14 S(O) 2 NR c R d In some embodiments, R 14 NR c S(O) 2 NR c R d In some embodiments, R 14 NR c S(O)(=NR b )R b .

[0288] In some embodiments, the compound shown in formula (I) is a pharmaceutically acceptable salt. In some embodiments, the compound shown in formula (I) is a stereoisomer. In some embodiments, the compound shown in formula (I) is a solvate. In some embodiments, the compound shown in formula (I) is an N-oxide of the compound shown in formula (I).

[0289] In some embodiments, the compound represented by formula (I) is represented by formula (II):

[0290]

[0291] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3, m and n are as defined in formula (I).

[0292] In some embodiments, X is N or CR 5 In some embodiments, X is N. In other embodiments, X is CR 5 .

[0293] In some embodiments, the compound represented by formula (I) is represented by formula (III):

[0294]

[0295] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 , m and n are as defined in formula (I).

[0296] In some embodiments, in the formula (III), R 5 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , or NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group; or

[0297] In some embodiments, in the formula (III), R 5 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, or 4-7 membered heterocyclic group; wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0298] In some embodiments, in the formula (III), R 5 Independently selected from H, D, halogen, CN, NO 2 , OR A , S.F. 5 , or NR C R D In some embodiments, in the formula (III), R 5 Independently selected from H, D, halogen, CN, NO 2 , OR A , S.F. 5 In some embodiments, in the formula (III), R 5 Independently selected from H, D, halogen, CN, NO 2 , S.F. 5In some embodiments, in the formula (III), R 5 Independently selected from H, D, halogen, CN, SF 5 In some embodiments, in the formula (III), R 5 are independently selected from H, D, halogen, CN. In some embodiments, in the formula (III), R 5 Independently selected from H, D, CN.

[0299] In some embodiments, in the formula (III), R 5 and R 2 , together with the atoms to which it is attached, selectively forms C 3- C 7 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C 7 The cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 substituted by a substituent.

[0300] In some embodiments, the compound represented by formula (I) is represented by formula (IV):

[0301]

[0302] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 , m and n are as defined in formula (I).

[0303] In some embodiments, the compound represented by formula (I) is represented by formula (V):

[0304]

[0305] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R5 , m and n are as defined in formula (I).

[0306] In some embodiments, the compound represented by formula (I) is represented by formula (VI):

[0307]

[0308] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 and n are as defined in formula (I).

[0309] In some embodiments, the compound represented by formula (I) is represented by formula (VII):

[0310]

[0311] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 and R 5 is as defined in formula (I).

[0312] In some embodiments, in Formula (VII), each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D ,S(O) 2 R B , NR C S(O) 2 R B ,S(O) 2 NR C R D , or NR C S(O) 2 NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0313] In some embodiments, in Formula (VII), each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2-C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , S(O)NR C R D ,S(O) 2 R B ,S(O) 2 NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0314] In some embodiments, in Formula (VII), each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0315] In some embodiments, in Formula (VII), each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 ,OC(O)R B, OC(O)NR C R D ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0316] In some embodiments, in Formula (VII), each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR A , S.F. 5 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C6 Cycloalkyl, 4-6 membered heterocyclic group.

[0317] In some embodiments, in Formula (VII), each R 2 independently selected from H, D, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, CN, SF 5 ; wherein, the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0318] In some embodiments, in Formula (VII), each R 2 Independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group; wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl optionally substituted by substituents selected from the group consisting of: D, CN, halogen, OH, NH 2, C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0319] In some embodiments, in Formula (VII), each R 2 Independently selected from 4-7 membered heterocyclic groups optionally substituted by substituents selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0320] In some embodiments, in Formula (VII), each R 2 Independently selected from C 3 -C 7 The cycloalkyl group is optionally substituted with a substituent selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0321] In some embodiments, in Formula (VII), each R 2 Independently selected from C 2 -C 6 The alkynyl group is optionally substituted with a substituent selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0322] In some embodiments, in Formula (VII), each R 2 Independently selected from C 2 -C 6 The alkenyl group is optionally substituted with a substituent selected from the group consisting of D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0323] In some embodiments, in Formula (VII), each R 2 Independently selected from C 1 -C 6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: D, CN, halogen, OH, NH 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group.

[0324] In some embodiments, in Formula (VII), each R 2 Independently selected from H, D, halogen, CN, SF 5 .

[0325] In some embodiments, the compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIl), (VIIIm), (VIIIn), (VIIIo), and (VIIIp):

[0326]

[0327]

[0328] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein Y 1 , Y 2 , ring A, Ar 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined in formula (I).

[0329] In some embodiments, the compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIj), (VIIIk), (VIIIl), (VIIIm);

[0330]

[0331] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein Y 1 , Y 2 , ring A, Ar 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined in formula (I).

[0332] In some embodiments, the compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), (VIIIe), (VIIIj), (VIIIl), (VIIIm);

[0333]

[0334] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein Y 1 , Y 2 , Ring A, Ar 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined in formula (I).

[0335] In some embodiments, the compound represented by formula (I) is:

[0336]

[0337]

[0338] or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the compound represented by formula (I) is:

[0340]

[0341]

[0342] or a pharmaceutically acceptable salt thereof.

[0343] The present invention also provides a pharmaceutical composition, comprising: a compound represented by formula (I), or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0344] The present invention also provides a method for treating and / or preventing a patient with PolQ overexpressing cancer, comprising: administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0345] The present invention also provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by an increased dependence on MMEJ DSB repair, comprising: administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention.

[0346] The present invention also provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by HR-deficiency, reduced or absent expression of HR-related genes, comprising: administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0347] The present invention also provides a method for treating and / or preventing cancer, wherein the cancer lacks the 53BP1 / Shieldin complex, comprising: administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention, to the patient.

[0348] The present invention also provides a method for treating and / or preventing cancer, wherein the cancer has been treated with or has not been treated with PARPi drugs and is resistant to PARPi treatment, comprising: administering to the patient a therapeutically effective amount of the compound described in the present invention, or a pharmaceutical composition comprising the compound described in the present invention.

[0349] The present invention also provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by NHEJ deficiency, reduced or absent expression of NHEJ-related genes, comprising: administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.

[0350] The present invention also provides a use of the compound or pharmaceutical composition of the present invention in the preparation of a drug for treating a patient's PolQ overexpression disease.

[0351] The present invention also provides a use of the compound or pharmaceutical composition of the present invention in the preparation of a drug for treating a disease with increased dependence on MMEJ-DSB repair.

[0352] The present invention also provides a use of the compound or pharmaceutical composition of the present invention in the preparation of a drug for treating cancer, wherein the cancer is characterized by HR-deficiency, reduction or loss of HR-related gene expression.

[0353] The present invention also provides an application of the compound or pharmaceutical composition of the present invention in the preparation of a drug for treating cancer, wherein the cancer lacks a 53BP1 / Shieldin complex.

[0354] The present invention also provides an application of the compound or pharmaceutical composition of the present invention in the preparation of a drug for treating cancer, characterized in that the cancer has received or not received PARPi drug treatment and is resistant to PARPi treatment.

[0355] The present invention also provides a use of the compound or pharmaceutical composition of the present invention in the preparation of a drug for treating cancer, wherein the cancer is characterized by NHEJ deficiency and reduced or absent expression of NHEJ-related genes.

[0356] definition

[0357] Unless otherwise stated, the following terms have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

[0358] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of such exclusive terminology, such as "solely," "only," and the like, in connection with recitation of claim elements or use of a "negative" limitation.

[0359] At various places in this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes -NR(CR'R")- and -(CR'R")NR-, and each form is intended to be disclosed separately. When a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" means a linked alkylene or arylene group, respectively.

[0360] The term "substituted" means that an atom or group of atoms replaces hydrogen as a "substituent" connected to another group. The term "substituted", unless otherwise specified, refers to any number of substitutions, for example, single-, double-, three-, four- or five-substitutions, if such substitutions are allowed. Substituents are independently selected, and substitutions can occur at any chemically possible position. It should be understood that substitutions at specific atoms are limited by valence. The term "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms.

[0361] The term "Cn-Cm" means a range including the endpoints, wherein n and m are integers representing the number of carbons. 1 -C 6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, and C 6 Alkyl. "C0 "Alkyl" refers to a covalent bond.

[0362] The compounds of the present invention are stable. As used herein, "stable" means that the compound is sufficiently stable to be isolated to a useful degree of purity from a reaction mixture, and preferably the compound can be formulated into an effective therapeutic agent.

[0363] It should also be understood that certain features of the present invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present invention described in the context of a single embodiment for simplicity may also be provided individually or in any suitable sub-combination.

[0364] As used herein, unless otherwise indicated, the term "alkyl", as a substituent or part of a substituent, refers to a straight or branched saturated hydrocarbon group. The alkyl group may contain from about 1 to about 20, from about 2 to about 20, from about 1 to about 10, from about 1 to about 8, from about 1 to about 6, from about 1 to about 4, or from about 1 to about 3 carbon atoms. Similarly, in C 1 -C 8 C in alkyl 1-8 It means that the group has 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched form. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, and t-butyl), pentyl (e.g., n-pentyl, isopentyl, and neopentyl) and the like.

[0365] As used herein, unless otherwise specified, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0366] As used herein, unless otherwise specified, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0367] As used herein, unless otherwise specified, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents. Exemplary haloalkyl groups include, but are not limited to, CF 3 , C 2 F 5 , CHF 2 , CH 2 F,CCl 3 , CHCl 2 , C 2 Cl5 wait.

[0368] As used in the present invention, unless otherwise indicated, the term "aryl" refers to unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbons. In certain embodiments, the aryl has about 6 to about 20 carbon atoms. In certain embodiments, the aryl has about 6 to about 14 carbon atoms. In certain embodiments, the aryl has about 6 to about 10 carbon atoms. Exemplary aryl, includes but is not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl etc.

[0369] As used in the present invention, unless otherwise indicated, the term "cycloalkyl" refers to an unsubstituted or substituted non-aromatic carbocyclic ring, including cycloalkyl, cycloalkenyl, cycloalkynyl. Cycloalkyl can include a monocyclic- or polycyclic (e.g., having 2, 3, or 4 fused rings) ring system, including fused rings, spiro rings, and bridged rings (e.g., bridged bicycloalkyl). In certain embodiments, cycloalkyl has about 3 to about 20 carbon atoms, about 3 to about 14 carbon atoms, about 3 to about 10 carbon atoms, or about 3 to 7 carbon atoms. Cycloalkyl can also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. Cycloalkyl can optionally be oxo or thio (e.g., -C(O)- or -C(S)-). The definition of cycloalkyl also includes a ring formed by cycloalkyl fused with one or more aromatic rings (e.g., having a common bond with cycloalkyl), for example, benzo derivatives of pentane, benzo derivatives of pentene, benzo derivatives of hexane, etc. The cycloalkyl radical may be connected to an aromatic ring or a non-aromatic ring of a cycloalkyl radical having one or more aromatic rings. One or more ring-forming carbon atoms of the cycloalkyl radical may be oxidized, for example, with an oxo or thio substituent. In certain embodiments, the cycloalkyl radical is C 3 -C 7 In certain embodiments, the cycloalkyl group is C 4- C 10 Spiro or bridged ring cycloalkyl. Exemplary cycloalkyl, include but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarbyl, cubic alkyl, adamantyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, and spiro [3.3] heptyl etc. In certain embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, cycloalkyl is a ring-containing, non-aromatic hydrocarbon group having 3 to 12 carbon atoms ("C 3- C 12 ”), preferably from 3 to 6 carbon atoms (“C 3- C6 ”). Exemplary cycloalkyl groups include, for example, cyclopropyl (C 3； 3-membered), cyclobutyl (C 4； 4-membered), cyclopropylmethyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), 1-methylcyclopropyl (C 4 ), 2-methylcyclopentyl (C 4 ), adamantyl (C 10 )wait.

[0370] The term "spirocyclic cycloalkyl" used alone or as part of a substituent group refers to a non-aromatic cycloalkyl group containing two cycloalkyl groups, wherein, typically, the two cycloalkyl groups share one carbon atom.

[0371] As used in the present invention, unless otherwise specified, "heteroaryl" refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member, such as boron, sulfur, oxygen, or nitrogen. Heteroaryl includes monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any N atom of a heteroaryl can be oxidized to form an N-oxide. Exemplary heteroaryl includes, but is not limited to, pyridyl, N-oxopyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolyl, etc. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and further, in some embodiments, has from 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0372] As used in the present invention, unless otherwise specified, "heterocyclyl" refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocyclyl may be replaced by a heteroatom selected from N, O, S, and B; the ring-forming carbon atoms and heteroatoms of the heterocyclyl may be optionally replaced by one or more oxo or thioxo (e.g., C(O), S(O), C(S), or S(O) 2Etc.). Heterocyclic groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Heterocyclic groups include monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocyclic groups. Heterocyclic groups also include spirocyclic and bridged rings (e.g., 5-10 membered bridged biheterocyclic groups, with one or more of the ring-forming carbon atoms being replaced by heteroatoms independently selected from N, O, S, and B). The heterocyclic group can be connected by ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocyclic group contains 0 to 3 double bonds. In some embodiments, the heterocyclic group contains 0 to 2 double bonds.

[0373] The heterocyclic group also includes a group having one or more aromatic rings fused to (i.e., having a common bond with the heterocyclic group) the non-aromatic heterocyclic ring, for example, piperidine, morpholine, benzo or thieno derivatives of azepane, etc. The heterocyclic group containing the fused aromatic ring can be connected by any ring-forming atom, including the ring-forming atom of the fused aromatic ring. In some embodiments, the heterocyclic group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocyclic group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocyclic group is a monocyclic 4-6 membered heterocyclic group with 1 or 2 heteroatoms independently selected from N, O, S and B, and has one or more ring atoms substituted with oxygen.

[0374] Exemplary heterocyclyl groups include, but are not limited to, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholine, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepine, 1,3-oxazolidinyl, 1,3-isoxazolidin-2-one ... 2,3,4-tetrahydroisoquinolyl, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl yl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, azaadamantyl, diazaadamantyl, oxaadamantyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxa-azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxa-azaspiro[3.4]octyl, Oxa-azaspiro[3.5]nonyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxa-azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxa-diazaspiro[4.4]nonyl, octahydropyrrolo[3,4-c]pyrrolyl and the like.

[0375] In some embodiments, heterocyclyl refers to any 3 to 10 membered monocyclic or bicyclic saturated ring structure, containing at least one heteroatom selected from O, N and S. The heterocyclyl can be connected through any heteroatom or carbon atom thereof, as long as a stable structure can be generated. Exemplary heterocyclyls include, but are not limited to, azepanyl, aziridine, azetidinyl, pyrrolidinyl, dioxolane, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, etc.

[0376] In some embodiments, the term "spirocyclic heterocyclyl" used alone or as part of a substituent group refers to a non-aromatic ring comprising two rings, at least one ring selected from heterocyclyl, and the two rings share one carbon atom.

[0377] As used herein, unless otherwise specified, "arylcycloalkyl" refers to a cycloalkyl group substituted with an aryl group.

[0378] As used herein, unless otherwise specified, "arylheterocyclyl" refers to a heterocyclyl group substituted with an aryl group.

[0379] As used herein, unless otherwise specified, "arylheteroaryl" refers to a heteroaryl group substituted with an aryl group.

[0380] As used herein, unless otherwise specified, "biaryl" refers to an aryl group substituted with an aryl group.

[0381] As used herein, unless otherwise specified, "heteroarylcycloalkyl" refers to a cycloalkyl group substituted with a heteroaryl group.

[0382] As used herein, unless otherwise specified, "heteroarylheterocyclyl" refers to a heterocyclyl substituted with a heteroaryl group.

[0383] As used herein, unless otherwise specified, "heteroarylaryl" refers to an aryl group substituted with a heteroaryl group.

[0384] As used herein, unless otherwise specified, "biheteroaryl" refers to a heteroaryl group substituted with a heteroaryl group.

[0385] As used in the present invention, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0386] As used herein, unless otherwise specified, "alkoxy" refers to -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, and the like.

[0387] As used herein, unless otherwise specified, "hydroxyalkyl" refers to an alkyl group substituted with OH.

[0388] As used herein, unless otherwise specified, "cyanoalkyl" refers to an alkyl group substituted with CN.

[0389] As used herein, unless otherwise specified, "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0390] As used herein, unless otherwise specified, "alkoxyalkoxy" refers to an alkoxy group substituted with an alkoxy group.

[0391] As used herein, unless otherwise specified, "haloalkoxy" refers to -O-(haloalkyl).

[0392] As used herein, unless otherwise specified, "arylalkyl" refers to an alkyl group substituted by an aryl group, and "cycloalkylalkyl" refers to an alkyl group substituted by a cycloalkyl group. An exemplary arylalkyl group is benzyl.

[0393] As used herein, unless otherwise specified, "heteroarylalkyl" refers to an alkyl group substituted by a heteroaryl group, and "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group.

[0394] As used herein, unless otherwise indicated, "oxo" refers to an oxygen substituent attached through a double bond (ie, =0).

[0395] As used in the present invention, unless otherwise specified, the term "optionally substituted" means unsubstituted or substituted.

[0396] As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms in a group are replaced with substituents independently selected from the same or different groups.

[0397] The compounds described in the present invention may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present invention. Compounds described in the present invention containing asymmetrically substituted carbon atoms may be optically active or racemates. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc., may also be present in the compounds described in the present invention, and all stable isomers are also within the scope of the present invention. The cis and trans geometric isomers of the compounds described in the present invention are also within the scope of the present invention and can be separated into mixtures of isomers or separated isomeric forms.

[0398] The compounds of the present invention also include tautomers. Tautomers are produced by the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomers include proton transfer tautomers, which have the same chemical formula and total charge. Exemplary proton transfer tautomers include keto-enol tautomerism, amide-imidic acid tautomerism, lactam-lactide tautomerism, amide-imidic acid tautomerism and enamine-imine tautomerism, and protons in the ring structure can be interconverted at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; tautomers can be balanced, or they can be fixed in space by suitable substitution to form a form.

[0399] In some cases, the compounds of the present invention may exist in the form of rotational isomers. The description of the compounds of the present invention is intended to cover any single rotational isomer, as well as any proportion of rotational isomer mixtures, and does not represent a specific rotational isomer. The description of a specific rotational isomer means that the rotational isomer described is substantially free of other rotational isomers.

[0400] The present invention further includes isotope labels of the compounds or intermediates of the present invention. "Isotope" refers to atoms with the same atomic number but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0401] In certain embodiments, compound of the present invention or its salt is substantially separated.With regard to " substantially separated ", it refers to that compound is formed from it or is detected in the environment at least partially or substantially separated.Partial separation may include, for example, a composition rich in the compounds of this invention.Substantially separation may include a composition containing at least about 50 % by weight, at least about 60 % by weight, at least about 70 % by weight, at least about 80 % by weight, at least about 90 % by weight, at least about 95 % by weight, at least about 97 % by weight or at least about 99 % by weight of the compounds of this invention or its salt.The method for separating compounds and their salts is conventional in the art.

[0402] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds described herein, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Exemplary pharmaceutically acceptable salts include, but are not limited to, mineral acids or organic acid salts of basic residues such as amines; alkali salts or organic salts of acidic residues such as carboxylic acids, etc. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed by non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, the salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0403] The term "pharmaceutically acceptable" is used in the present invention to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0404] "Pharmaceutically acceptable excipient" refers to a substance, such as an inert substance, that is added to a pharmacological composition or otherwise used as a vehicle, carrier or diluent to facilitate administration of the medicament and is compatible therewith, that is non-toxic, biologically tolerable and otherwise biologically suitable for administration to a subject. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0405] "Solvate" refers to a compound of Formula I with one or more solvent molecules.

[0406] "Subject" includes humans. The terms "human", "patient" and "subject" are used interchangeably in the present invention.

[0407] In one embodiment, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., preventing or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter that the subject may not be able to discern. In another embodiment, "treating" refers to regulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In another embodiment, "treating" refers to delaying the onset of a disease or disorder.

[0408] "Compounds of the present invention" and equivalent expressions are intended to cover the compounds of Formula I described in the present invention, and their respective subgenera. Where the context permits, the expression includes stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds of Formula I and pharmaceutically acceptable salts.

[0409] As used herein, the term "isotopic variant" refers to a compound that contains an isotopic ratio greater than the natural abundance at one or more of the atoms that make up the compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more radioactive isotopes, or may be labeled with a non-radioactive isotope such as, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15It will be appreciated that in compounds subject to such isotopic substitution, if present, the following atoms may vary, such that, for example, any hydrogen may be 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and position of such atoms can be determined within the capabilities of those skilled in the art.

[0410] It is also understood that compounds having the same molecular formula but differing in the nature or order of bonding of the atoms or the arrangement of the atoms in space are referred to as "isomers". Isomers that differ in the arrangement of atoms in space are referred to as "stereoisomers", such as diastereomers, enantiomers, and rotamers. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers at each asymmetric center or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof, racemic or otherwise. When there is one chiral center in a structure, but the specific stereochemistry of the center is not shown, the structure includes two enantiomers, either individually or as a mixture of enantiomers. When there is more than one chiral center in a structure, but the specific stereochemistry of the center is not shown, the structure includes all enantiomers and diastereomers, either individually or as a mixture. Methods for testing stereochemistry and separating stereoisomers are well known in the art.

[0411] Pharmaceutical composition

[0412] The present invention also provides a pharmaceutical composition, comprising: a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, and a pharmaceutically acceptable carrier.

[0413] The pharmaceutical composition can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), can be used for injection (e.g., aqueous or oily suspensions, or emulsions, containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar pharmaceutical carriers), can be used topically (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), can be used for inhalation (e.g., fine powders or liquid aerosols), can be administered by insufflation (e.g., fine powders), or can be administered parenterally (e.g., sterile aqueous oil solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0414] Pharmaceutically acceptable excipients may be excipients such as carriers (e.g., solid, liquid or semisolid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release controlling agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, stabilizers or any other conventional excipients useful in pharmaceutical compositions.

[0415] Pharmaceutically acceptable carriers can be, for example, solid, liquid or gas. Exemplary solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Exemplary liquid carriers include syrup, peanut oil, olive oil, water. Exemplary gaseous carriers include carbon dioxide and nitrogen. When preparing the composition for oral dosage form, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives and colorants can be used to form oral liquid preparations, such as suspensions, elixirs and solutions; for example, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrant carriers can be used to form oral solid preparations, such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are preferred oral dosage forms when solid pharmaceutical carriers are used. Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

[0416] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard shell or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, wafers or patches, such as buccal patches.

[0417] Thus, tablet compositions may contain a unit dose of active compound and an inert diluent or carrier, such as a sugar or sugar alcohol, for example, lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, and hydroxypropylmethylcellulose, and starch such as corn starch. Tablets may also contain standard ingredients such as binders and granulators, such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures. Such excipients are well known and are not described in detail herein. The tablets are optionally mixed with one or more auxiliary ingredients or excipients and can be prepared by compression or molding. Compressed tablets can be compressed by suitable equipment, and the active ingredient is in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. The mixture of the molded tablet with the wetted powdered compound and the inert liquid diluent can be molded by suitable equipment. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, a formulation for oral use by humans may contain about 0.5 mg to about 5 g of the active ingredient, which is mixed with an appropriate and convenient amount of carrier, and the amount of the carrier may vary between about 5% and about 95% of the total composition. The unit dosage form usually contains about 1 mg to about 2 g of the active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0418] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. It may include a suitable surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. In addition, preservatives may be included to prevent the harmful growth of microorganisms.

[0419] The pharmaceutical composition of the present invention suitable for injection includes sterile aqueous solution or dispersion. In addition, the composition can be in the form of sterile powder for the temporary preparation of such sterile injectable solution or dispersion. In all cases, the final injection form must be sterile and must be an effective fluid for injection. The pharmaceutical composition must be stable under manufacturing and storage conditions; therefore, it is preferably stored to prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0420] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, etc. In addition, the composition can be in a form suitable for transdermal devices. These preparations can be prepared by conventional processing methods using the compound shown in Formula I of the present invention or a pharmaceutically acceptable salt thereof. Exemplarily, an emulsion or ointment is prepared by mixing a hydrophilic material and water with about 5wt% to about 10wt% of the compound to produce an emulsion or ointment with a desired consistency.

[0421] Pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be formed by mixing the composition with a softened or melted carrier, then cooling and molding in a mold.

[0422] The compositions can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and / or preservatives.

[0423] An effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent the proliferative disorders mentioned in the present invention, slow down their progression and / or alleviate the symptoms associated with the disorders.

[0424] The amount of active ingredient combined with one or more excipients to produce a single dosage form varies according to the individual being treated and the specific route of administration. For example, a preparation for oral administration to humans typically contains, for example, 0.1 mg to 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an appropriate and convenient amount of excipient, the amount of which can vary between about 5% to about 98% of the total composition weight.

[0425] The dosage of the compound of formula (I) for therapeutic or preventive purposes will vary according to known medical principles, the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration.

[0426] Therefore, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with the following substances: one or more other therapeutically active compounds.

[0427] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants) etc. as appropriate. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compound shown in Formula I or its pharmaceutically acceptable salt may also be prepared into powder or liquid concentrate forms.

[0428] Generally speaking, dosage levels of about 0.01 mg / kg to about 150 mg / kg of body weight per day are useful for treating the above conditions, or about 0.5 mg to about 7 g per patient per day. For example, colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T-cell lymphoma, melanoma, pancreatic cancer or lung cancer can be effectively treated by administering about 0.01 to 50 mg of the compound per kilogram of body weight per day, or about 0.5 mg to about 3.5 g per patient per day.

[0429] However, it should be understood that lower or higher doses than the above doses may be required. The specific dosage level and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, severity and course of the specific disease being treated, the subject's predisposition to the disease, and the judgment of the attending physician.

[0430] These and other aspects will become apparent from the following description of the invention.

[0431] Described below are non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0432] Dosage

[0433] The compound represented by formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition comprising these compounds can be administered to the subject by any convenient administration method, whether systemically / peripherally or locally (ie, at the desired site of action).

[0434] Methods of administration include, but are not limited to: oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., by aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrathoracic; implantation of a depot or reservoir, e.g., subcutaneous or intramuscular.

[0435] How to use

[0436] The method generally includes administering a therapeutically effective amount of the compound of the present invention to a subject. The therapeutically effective amount of the combination of the target compound can be varied according to the intended application (in vitro or in vivo) or the subject and the disease condition to be treated, for example, the subject's weight and age, the severity of the disease condition, the mode of administration, etc., which can be easily determined by a person of ordinary skill in the art. The term is also applicable to the dosage of inducing a specific response in the target cell, for example, a reduction in the proliferation of the target protein or a reduction in the activity. The specific dosage will vary according to the selected specific compound, the dosage regimen followed, whether it is administered in combination with other compounds, the administration time, the tissue to which it is administered, and the physical delivery system to which it is carried.

[0437] As used herein, the term "IC 50 " refers to the half-maximal inhibitory concentration of an inhibitor in inhibiting a biological activity or biochemical function. This quantitative measure indicates how much of a particular inhibitor is required to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC or IC 50 ).

[0438] In some embodiments, the test method uses a test sample having an IC 50 In some embodiments, the PolQ inhibitor has an IC for PolQ inhibition of 50Value: about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less , 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1μΜ or less, 1.1μΜ or less, 1.2μΜ or less, 1.3μΜ or less, 1.4μΜ or less, 1.5μΜ or less, 1.6μΜ or less, 1.7μΜ or less, 1.8μΜ or less, 1.9μΜ or less, 2μ In some embodiments, the present invention relates to an aqueous solution of at least 5 μM or less, 5 μM or less, 6 μM or less, 7 μM or less, 8 μM or less, 9 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or less (or a numerical value within the range defined by and including any two of the above numbers).

[0439] In some embodiments, the PolQ inhibitors of the invention selectively inhibit PolQ with an IC of 50 Value: relative to IC of Polα, Polβ, Polγ, Polη, Polν, Polδ, Polε and other DNA polymerases 50 The value of s is at least 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 100 times, or 1000 times smaller (or in the range defined by and including any two of the above numbers).

[0440] In some embodiments, the PolQ inhibitors of the invention selectively inhibit PolQ with an IC of 50Values: less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950nM, 1μM, 1.1μM, 1.2μM, 1.3μM, 1.4μM, 1.5μM, 1.6μM, 1.7μM, 1.8μM, 1. 9μM, 2μM, 5μM, 10μM, 15μM, 20μM, 25μM, 30μM, 40μM, 50μM, 60μM, 70μM, 80μ IC of M, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM (or a value within a range defined by and including any two of the above numbers), relative to Polα, Polβ, Polγ, Polη, Polν, Polδ, Polε, and other DNA polymerases 50 s value, the IC 50 The value is at least 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 100 times, or 1000 times smaller (or within the range defined by and including any two of the above numbers).

[0441] The test methods can be used to treat diseases associated with PolQ. Any disease that is directly or indirectly caused by abnormal activity or expression level of PolQ may be a desired disease.

[0442] Non-limiting examples of such conditions include, but are not limited to, breast cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma of the breast, Paget's disease of the breast, hereditary breast cancer syndrome, medullary carcinoma of the breast, mucinous breast cancer, inflammatory breast cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumor, low malignant potential ovarian tumor, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor, gastrointestinal stromal tumor, prostate cancer, prostate acinar adenocarcinoma, prostate ductal adenocarcinoma, prostate sarcoma, small cell prostate cancer, squamous cell prostate cancer, pancreatic cancer, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, uterine cancer, uterine sarcoma, uterine corpus sarcoma, cervical cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, small cell cervical carcinoma, mucinous cervical tumor, clear cell cervical carcinoma, cervical lymphoma, cervical sarcoma, endometrial carcinoma, endometrial carcinoma, endometrioid tumor, lung cancer, non-small cell lung cancer, small cell lung cancer, brain cancer stem cell glioma, brain cancer, cerebellar astrocytoma, brain astrocytoma, head and neck cancer, glioblastoma multiforme, glioma, glioma cerebri, ganglioglioma, ganglioneuroma, paraganglioma, primitive neuroectodermal tumor, supratentorial primitive neuroectodermal tumor, visual pathway glioma, schwannoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, esthesia neuroblastoma, extrahepatic bile duct carcinoma, Bellini duct carcinoma, bile duct carcinoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, Acute lymphocytic leukemia, acute megakaryocyte leukemia, acute monocytic leukemia, acute myeloid leukemia, mature acute myeloid leukemia, acute myeloid dendritic cell leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aggressive NK-cell leukemia, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelocytic leukemia, chronic myeloproliferative disease, chronic neutrophilic leukemia, erythroleukemia, hairy cell leukemia, leukemia, lymphoid leukemia, lymphoma, macroglobulinemia, mast cell leukemia, monocytic leukemia, granulocytic leukemia, T-cell acute lymphocytic leukemia, T-cell large granulocytic lymphocytic leukemia, T-cell leukemia blood disease, T-cell prolymphocytic leukemia, AIDS-related lymphoma, angioimmunoblastic T-cell lymphoma, B-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, Hodgkin's lymphoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma, precursor T-lymphocytic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, small cell lymphoma, T-cell lymphoma, terminal lymphoma.

[0443] The compounds of the invention are useful for treating and / or preventing a disease in a patient, wherein the disease is characterized by overexpression of PolQ.

[0444] The term "PolQ overexpression" refers to increased expression or activity of the PolQ enzyme in a diseased cell, e.g., a cancer cell, relative to the expression or activity of the PolQ enzyme in a control cell (e.g., a non-diseased cell of the same type). Relative to the PolQ expression of the control cell, the PolQ overexpression is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, the PolQ overexpression is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, at least 20-fold, or at least 50-fold. Exemplary PolQ overexpressing cancers include, but are not limited to, ovarian cancer, breast cancer, cervical cancer, uterine cancer, pancreatic cancer, lung cancer, colorectal cancer, gastric cancer, bladder cancer, and prostate cancer.

[0445] The compounds of the invention are useful for treating or preventing a disease in a patient characterized by an increased reliance on MMEJ DSB repair.

[0446] The compounds of the present invention are useful for treating or preventing a disease in a patient characterized by HR-deficiency, decreased or absent expression of HR-related genes, including, but not limited to, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, CtIP (BCL11A), ERCC4 (FANCQ), FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (PALB2), FANCP (SLX4), LIG1, MRE11, NBS1, NBN, PTEN, RAD50, RAD51B, RAD51C, RAD54, RECQL4, RPA1, RPA2, SMARCA2, SMARCA4, WRN, and XRCC2.

[0447] In some embodiments, the method is used to treat or prevent HR-deficient breast cancer, including but not limited to, lobular carcinoma in situ, ductal carcinoma in situ, invasive ductal carcinoma of the breast, triple-negative breast cancer, HER-positive breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, HER and estrogen receptor-positive breast cancer, HER and estrogen receptor and progesterone receptor-positive breast cancer, inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, poorly differentiated adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma.

[0448] In some embodiments, the method is used to treat or prevent HR-deficient ovarian cancer, including, but not limited to, epithelial ovarian cancer, mature teratoma, dysgerminoma, endodermal sinus tumor, granulosa-theca tumor, Sertoli-Leydig cell tumor, and primary peritoneal cancer.

[0449] In some embodiments, the method is used to treat or prevent HR-deficient prostate cancer, including but not limited to, prostate cancer, prostate acinar adenocarcinoma, prostate ductal adenocarcinoma, prostate sarcoma, small cell prostate cancer, squamous cell prostate cancer.

[0450] In some embodiments, the method is used to treat or prevent HR-deficient pancreatic cancer, including but not limited to, pancreatic cancer, exocrine pancreatic cancer, pancreatic neuroendocrine cancer.

[0451] The compounds of the present invention are useful for treating or preventing patients with cancers that lack the 53BP1 / Shieldin complex. Exemplary cancers include, but are not limited to, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, gastrointestinal cancer, and colorectal cancer.

[0452] The compounds of the present invention are used to treat or prevent cancers that are resistant to PARPi treatment, either with or without PARPi drug treatment. Exemplary cancers that are resistant to PARP inhibitors include, but are not limited to, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, gastrointestinal cancer, and colorectal cancer.

[0453] The compounds of the present invention are useful for treating or preventing a patient having a cancer characterized by NHEJ deficiency, decreased or absent expression of NHEJ-related genes, including, but not limited to, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5 and XRCC6.

[0454] In some embodiments, the method is used to treat or prevent the following diseases: lymphoma, soft tissue tumor, rhabdomyomas, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive system cancer, leukemia, kidney cancer, skin cancer, esophageal cancer and pancreatic cancer (data from large-scale screening of cancer cell lines indicate that some cell lines of the above cancers depend on PolQ for proliferation, see https: / / depmap.org / portal / ).

[0455] In other embodiments, the method is used to treat a disease selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0456] In other embodiments, the method is used to treat a disease selected from the group consisting of: leukemias such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS) or epidermoid carcinoma.

[0457] The compounds of the present invention and pharmaceutical compositions comprising them can be administered alone or in combination with medical therapy to treat any of the diseases described. Medical therapy includes, for example, surgery and radiation therapy (e.g., gamma-irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

[0458] In other aspects, the compounds and pharmaceutical compositions described herein can be administered alone or in combination with one or more other pharmaceutical agents to treat any of the aforementioned diseases.

[0459] In other methods, the compounds described herein and pharmaceutical compositions thereof may be administered in combination with agonists of nuclear receptor agents.

[0460] In other methods, the compounds described herein and pharmaceutical compositions thereof may be administered in combination with antagonists of nuclear receptor agents.

[0461] In other methods, the compounds described herein and pharmaceutical compositions thereof may be administered in combination with an anti-proliferative agent.

[0462] Combination therapy

[0463] The compounds of the present invention can be used as a single agent or in combination with other treatments. Such treatments may include one or more of the following cancer therapies: for example, surgery, chemotherapy, radiotherapy, targeted therapy (e.g., growth factor inhibitors, kinase inhibitors, cyclin-dependent kinase inhibitors, etc.), other DDR regulators (e.g., PARP inhibitors, DNA-PK inhibitors, ATM inhibitors, ATR inhibitors, CHK1 inhibitors, WEE1 inhibitors, CDK1 inhibitors, LIG4 inhibitors, HIF-1 inhibitors, HDAC inhibitors, RAD51 inhibitors, WRN inhibitors, PRMT5 inhibitors, MAT2A inhibitors, USP1 inhibitors, PARG inhibitors and PKMYT1 inhibitors, etc.), immunotherapy, gene and cell therapy.

[0464] For the treatment of cancer and other proliferative diseases, the compounds of the invention can be used in combination with medical therapies such as surgery, radiotherapy or chemotherapy. Exemplary radiotherapy includes gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes. Exemplary suitable chemotherapeutic agents include one or more anti-tumor agents from the following classes: other anti-proliferative / antineoplastic drugs used in medical oncology and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); anti-tumor antibiotics (e.g., anthracyclines such as bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, actinomycin, and mithramycin); anti-mitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and anti-tumor drugs such as paclitaxel and taxotere and polo kinase inhibitors); topoisomerase inhibitors ( For example, podophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin); cytostatic agents such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazol and exemestane) and 5α-reductase inhibitors such as finasteride; anti-invasive agents such as inhibitors of the c-Src kinase family (AZD0530, dasatinib and bosutinib), and the metalloproteinase family (e.g., marimastat, family of urokinase plasminogen activator receptor function or heparanase antibodies).

[0465] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies, including growth factor function inhibitors (e.g., anti-erbB2 antibody trastuzumab, anti-EGFR antibody panitumumab, anti-erbB antibody cetuximab, and any growth factor or growth factor antibody disclosed by Stem et al. (Critical reviews in oncology / haematology, 2005, Vo1.54, ppl1-29); such inhibitors also include tyrosine kinase inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib and CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib; serine / threonine kinase inhibitors (such as the Ras / Raf inhibitors sorafenib, tipifarnib and lonafarnib), cell proliferation inhibitors through MEK and / or AKT kinases; c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Fl t3 kinase inhibitors, CSF-1R kinase inhibitors; Aurora kinase inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 / 6 inhibitors; anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor (e.g. anti-vascular endothelial growth factor antibody bevacizumab); , such as VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib and AZD2171, compounds disclosed in international patent applications WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354 and compounds that act by other mechanisms (such as linomide, integrin avβ3 function inhibitors and angiostatin); vascular damaging agents, such as combretastatin A4 and the compounds disclosed in international patent applications WO99 / Compounds disclosed in WO02166, WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; endothelin receptor antagonists, such as zilpotentan or atrasentan; PARP inhibitors such as olaparib, rucaparib, niraparib, talazoparib, veliparib, and pamiparib; PARP1 selective inhibitors such as AZD9547, AZD5305, AG-14361 and NMS-P118;Other DNA damage repair modulators such as DNA-PK inhibitors (e.g., LY294002, NU7026, NU7441, IC86621, IC87102, IC87361, OK-1035, SU11752, vanillin, NK314, IC486241, BVAN08, M3814, AZD7648, VX-984, doxycycline), ATM inhibitors (e.g., caffeine, wortmannin, CP-466722, KU-55933, KU-60019, and KU-559403), ATR inhibitors (e.g., schisandrin B, NU6027, NVP-BEZ235, VE-821, VE-822, AZ20, Elimusertib, RP-3500 and AZD6738), CHK1 inhibitors (e.g. LY2606368, PF-00477736, SRA737, SCH900776, MK8776, CCT244747 and AZD6738), WEE1 inhibitors (e.g. AZD1775, ZN-c3 and PD0166285), CDK1 (e.g. AZD5438, RO-3306, JNJ-7706621 and MER162), DNA LIG4 inhibitors (e.g. SCR7), HIF-1 inhibitors (e.g. LW6 and PX-478), HDAC inhibitors (e.g. short-chain fatty acids, benzamides, hydroxamic acids, and cyclic tetrapeptides, suberoylanilide hydroxamic acid (SAHA), trichostatin A), RAD51 inhibitors (e.g. CYT-0851, SCR-6992, SAT-93 / 101, CAM833, JKYN-1 (IBR120-series, B02-iso)), WRN inhibitors (e.g. NCGC00029283), PKMYT1 inhibitors ( such as RP6306), USP1 inhibitors (such as KSQ-4279) and PARG inhibitors (such as IDE161); antisense therapy, such as therapy acting on the above targets, such as ISIS2503, an anti-ras antisense; gene therapy methods, including methods such as replacing abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods, such as methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods for increasing a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy;and immunotherapy methods, including, for example, in vitro and in vivo methods to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor, methods to reduce T cell anergy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines and methods using anti-idiotypic antibodies, methods using immune checkpoint inhibitors, such as CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX4 0, 41BB, VISTA, CD96, TGF, CD73, CD39, A2AR, A2BR, IDO1, TD02, Arginase, B7-H3, B7-H4; Methods using the above immune checkpoint receptor and ligand inhibitors, such as ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab; Methods using cGAS-STING signaling pathway agonists, such as ADU-S100, BMS-986301, and MK-1454, etc.;

[0466] synthesis

[0467] The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as the schemes described below.

[0468] The reaction of preparing the compounds of this invention can be carried out in a suitable solvent, and the solvent can be easily selected by the technician in the field of organic synthesis. Suitable solvent can be substantially unreacted with starting material (reactant), intermediate or product at the temperature of carrying out the reaction, for example, the temperature range can be from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the above-mentioned specific reaction steps, those skilled in the art can select the solvent suitable for the specific reaction steps.

[0469] The preparation of the compounds of the present invention may involve the above-mentioned protection and deprotection of various chemical groups. The above-mentioned protection and deprotection selection, as well as the selection of suitable protecting groups, can be easily determined by those skilled in the art. Disclosed chemical protecting groups are as follows, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith el ah, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al, "Protecting Groups in Carbohydrate Chemistry," J Chem. Educ., 1997, 74 (11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0470] The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-Vis), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0471] As used herein, expressions such as "ambient temperature", "room temperature" and "rt" generally refer to temperature, such as reaction temperature, which is approximately the temperature of the space in which the reaction is performed, for example, a temperature of about 20°C to about 30°C, as understood in the art.

[0472] The compounds of the present invention can be prepared according to various routes known in the literature. The following schemes provide general guidance related to the preparation of the compounds of the present invention. It should be understood by those skilled in the art that the preparation methods in the following schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are shown in the following schemes.

[0473] The following examples are provided to illustrate some of the above concepts described in this summary. While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein.

[0474] Synthesis scheme

[0475] A series of heterocyclic derivatives of formula (I), wherein each m and n is an integer (e.g., 1, 2, or 3), can be prepared according to the method described in Scheme 1. Compound 1-3, wherein n is an integer (e.g., 1, 2, 3, or 4), can be prepared by reacting carboxylic acid 1-1 with an amine NHR 1 Ar 1 1-2 Under standard amide coupling conditions (e.g., in the presence of an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T 3 P and bases such as Hunig's base, Et 3 Alternatively, the carboxylic acid 1-1 can be reacted with a chlorinating agent such as (1-chloro-2-methylprop-1-en-1-yl)dimethylamine, oxalyl chloride or thionyl chloride to obtain the corresponding acid chloride 1-4, which can be reacted with the corresponding amine NHR 1 Ar 1 The amide 1-3 is coupled with the appropriate 1-5 wherein W is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) under standard Buchwald coupling conditions (e.g., in the presence of a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3 The heterocyclic derivative represented by formula (I) can be obtained by Buchwald coupling in the presence of .

[0476] Solution 1

[0477]

[0478] Alternatively, a series of heterocyclic derivatives represented by formula (I) can be prepared according to the method described in Scheme 2. Ester derivative 2-1 (wherein R is an alkyl group such as Me, Et, or t-Bu) is reacted with aromatic ring derivative 2-2, where W is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) under standard Buchwald coupling conditions (e.g., in the presence of a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2CO 3 Compound 2-3 can be obtained by Buchwald coupling in the presence of 2-6 (NH4OH) or 2-7. Compound 2-3 can be saponified to obtain the corresponding acid 2-4, which can be further reacted with a suitable amine NHR 1 Ar 1 2-5 Use activation reagents such as BOP, PyBOP, HATU, HBTU, EDCI, or T 3 P and bases such as Hunig's base, Et 3 N or pyridine coupling can give the amide represented by formula (I).

[0479] Solution 2

[0480]

[0481] The heterocyclic intermediates of formula 3-5, 3-6 and 3-7 can be prepared according to the method described in Scheme 3. 2,3-dibromopropionic acid alkyl ester 3-1 reacts with compounds 3-2, 3-3 and 3-4 in the presence of a base such as Hunig's base, triethylamine, DBU, t-BuONa or NaH to obtain the corresponding heterocyclic intermediates of formula 3-5, 3-6 and 3-7.

[0482] Solution 3

[0483]

[0484] A series of heterocyclic intermediates of formula 4-5 can be prepared according to the method described in Scheme 4. Compound 4-1 (W is H, Br, or I) is lithiation with a strong base such as butyl lithium, and then sulfenamide 4-2 is added to obtain the corresponding acid 4-3, which can be converted into the lactam 4-4 under amide coupling conditions in the presence of a coupling reagent (e.g., N,N'-dicyclohexyl-carbodiimide or HATU, etc.). In the presence of an acid such as a solution of TFA in DCM or a solution of HCl in dioxane, the sulfenamide group is removed to obtain lactam 4-5.

[0485] Solution 4

[0486]

[0487] A series of heterocyclic intermediates of formula 5-7 can be prepared according to the method described in Scheme 5. Heterocyclic acid 5-1 (W is H, Br, or I) is reacted with a suitable amine PGNH 2In the presence of a coupling reagent (e.g., N,N'-dicyclohexylcarbodiimide or HATU) and optionally an additive (e.g., 1-hydroxybenzotriazole or 4-dimethylaminopyridine) and optionally a base (e.g., pyridine or N,N-diisopropylethylamine), amide 5-2 can be obtained by amide coupling. Acid 5-2 is lithiated with a strong base such as butyl lithium, and then a formyl conversion reagent such as N,N-dimethyl-formamide, N-methoxy-N-methylformamide or N-formylmorpholine is added to give aldehyde 5-3, which can be directly converted to alcohol 5-4 by reaction with a CN reagent such as NaCN, KCN, TMSCN, or TBSCN. Alcohol 5-4 is halogenated with a suitable reagent such as thionyl chloride or phosphine tribromide or triphenylphosphine and iodine to give compound 5-5, wherein W 1 is halogen (e.g., Cl, Br, or I). Compound 5-5 is subjected to ring-closing reaction under alkaline conditions (e.g., in the presence of sodium hydride or lithium bis(trimethylsilyl)amide) to obtain lactam 5-6. 5-6 is reacted with an acid such as TFA or hydrogenated in the presence of a palladium catalyst such as Pd / C, the protecting group is removed, and then hydrolyzed to obtain heterocyclic intermediate 5-7.

[0488] Solution 5

[0489]

[0490] Alternatively, the heterocyclic intermediate 6-6 can be prepared according to the method described in Scheme 6. Carboxylic acid 6-1 (W is H, Br, or I) is esterified with a suitable alcohol such as MeOH or EtOH to give the corresponding heterocyclic ester 6-2. Acid 6-2 is lithiated with a strong base such as butyl lithium, followed by the addition of a formyl conversion reagent such as N,N-dimethylformamide, N-methoxy-N-methylformamide or N-formylmorpholine to give aldehyde 6-3, which is reacted with a CN reagent such as NaCN, KCN, TMSCN, or TBSCN in the presence of an ammonia medium such as NH 3 methanol solution or NH 4 Cl aqueous solution can be directly converted to lactam 6-5. The CN group of 6-5 is reacted with an acid such as H 2 SO 4 , or hydrolysis in the presence of HCl can give the heterocyclic intermediate 6-6.

[0491] Solution 6

[0492]

[0493] A series of heterocyclic intermediates The heterocyclic intermediate 7-4 shown in the formula can be prepared according to the method described in Scheme 7. Compound 7-1 (W 1Br or I) with alkyl acrylate 7-2 (R = Me, Et, or t-Bu) in the presence of a catalyst such as Pd(PPh 3 ) 2 Cl 2 or Pd(OAc) 2 / PPh 3 The cross-coupling reaction was carried out in the presence of Pd / C or Pd(OH) 2 Compound 7-3 can be prepared by hydrogenation in the presence of Pd(OAc) at high temperature. 2 As catalyst and PhI(OAc) 2 As an oxidizing agent for intramolecular amination, compound 7-4 can be obtained. Alternatively, the corresponding compound 7-5 is reacted in the presence of a palladium catalyst such as Pd / C or Pd(OH) 2 Compound 7-4 can be prepared by hydrogenation in the presence of / C.

[0494] Solution 7

[0495]

[0496] A series of heterocyclic intermediates The heterocyclic intermediates shown in formula 8-5 and 8-9 can be prepared according to the method described in Scheme 8. Compound 8-1 (W 2 H, Br, or I) with a strong base such as butyl lithium for lithiation, and then add sulfenamide 8-2 to obtain the corresponding compound 8-3. In the presence of an acid such as TFA in DCM, or HCl in dioxane, the protecting group can be removed to obtain diamine 8-4. Diamine 8-4 reacts with CDI or triphosgene to be converted into urea 8-5. Similarly, compound 8-9 can be prepared from the corresponding compound 8-6.

[0497] Solution 8

[0498]

[0499] A series of heterocyclic intermediates 9-7 and 9-8 can be prepared according to the method described in Scheme 9. 4 Reduction reaction and chlorination with thionyl chloride can convert it into bis(chloromethyl) derivative 9-3. Alkylation reaction of dialkyl acetamidomalonate 9-4 with compound 9-3 in the presence of sodium hydride can obtain bicyclic ester, which is a mixture of two isomers 9-5 and 9-6. The mixture is hydrolyzed with 6N hydrochloric acid under heating conditions to form a mixture of bicyclic amino acids 9-7 and 9-8.

[0500] Solution 9

[0501]

[0502] A series of heterocyclic intermediates represented by formula 10-5 can be prepared according to the method described in Scheme 10. 2,3-Dimethylpyrazine 10-1 is subjected to chlorination reaction with N-chlorosuccinimide (NCS) in carbon tetrachloride to obtain 2,3-bis(chloromethyl)pyrazine 10-2. Diethyl acetamidomalonate 10-3 and compound 10-2 are subjected to cyclization reaction in the presence of cesium carbonate to obtain compound 10-4. 10-4 is heated in hydrochloric acid for hydrolysis and decarboxylation to obtain compound 10-5.

[0503] Solution 10

[0504]

[0505] A series of heterocyclic intermediates represented by formula 11-2 can be prepared according to the method described in Scheme 11. 7 CHO undergoes a Pictet–Spengler reaction in the presence of hydrochloric acid to obtain compound 11-2.

[0506] Solution 11

[0507]

[0508] A series of heterocyclic intermediates represented by formula 12-4, 12-5, 12-6 and 12-8 can be prepared according to the method described in Scheme 12. Ketone compound 12-1 is heated with 1-alkoxy-N,N,N',N'-tetramethylmethanediamine 12-2 (R is Me, Et or t-Bu) or 1,1-dialkoxy-N,N-dimethylmethylamine to obtain the corresponding enaminoketone 12-3, which is reacted with hydrazine R 3 NHNH 2 It can be converted into pyrazole derivative 12-4 by reaction with hydroxylamine to be converted into isoxazole derivative 12-5, and can be converted into pyrimidine derivative 12-8 by reaction with carboximide 12-7. 2 NOSO 3 H in bases such as NaHCO 3 The isothiazole derivative 12-6 can be prepared by reacting with an aqueous solution of NaSH in the presence of 1H-2O-2.

[0509] Solution 12

[0510]

[0511] Similarly, the heterocyclic intermediates represented by formula 13-4, 13-5, 13-6 and 13-8 can be prepared according to the method described in Scheme 13. Ketone compound 13-1 (t is 1 or 2) reacts with 1-alkoxy-N,N,N',N'-tetramethylmethanediamine 13-2 (R is Me, Et or t-Bu) under heating conditions to obtain the corresponding enamino ketone 13-3, which can be converted into pyrazole derivatives 12-4, isoxazole derivatives 12-5, pyrimidine derivatives 12-8 and isothiazole derivatives 12-6 according to the method described in Scheme 12.

[0512] Solution 13

[0513]

[0514] Heterocyclic intermediates of formula 14-3, 14-5, 14-7, 14-9, 14-11 and 14-12 can be prepared by the method described in Scheme 14. Ethyl 2,3-dibromopropionate 14-1 is reacted with various aminoazole derivatives 14-2, 14-4, 14-6 and 14-8 in the presence of a base such as Hunig's base, triethylamine, DBU, t-BuONa, NaH or Cs 2 CO 3 The reaction is carried out in the presence of to give the corresponding heterocyclic intermediates 14-3, 14-5, 14-7, and 14-9. The reaction of 14-1 with the 4H-1,2,4-triazole-3-amine derivative 14-10 can give a mixture of two isomers 14-11 and 14-12.

[0515] Solution 14

[0516]

[0517] Example 1: (S)-N-(4-chloro-3-methylphenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide

[0518]

[0519] Step 1: 4-Chloro-N,3-dimethylaniline

[0520]

[0521] To a solution of 4-chloro-3-methylaniline (500 mg, 3.53 mmol) and NaOMe (572 mg, 10.5 mmol) in MeOH (20 mL) was added paraformaldehyde (424 mg, 14.1 mmol) at rt. The resulting mixture was stirred at reflux for 4 h under nitrogen atmosphere. The mixture was cooled to 0 °C (ice-water bath). NaBH was added in small batches at 0 °C.4 (400 mg, 10.5 mmol). The resulting mixture was stirred at reflux for 4 h. Then cooled to rt, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with saturated brine and purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to obtain the desired product (280 mg, 50% yield) as a yellow liquid. LCMS calculated value C 8 H 11 ClN[M+H] + :m / z=156.0; measured value: 156.1.

[0522] Step 2: (2S)-1-(tert-Butyloxycarbonyl)-2,3-dihydroindole-2-carboxylic acid

[0523]

[0524] At 0°C, (S)-indoline-2-carboxylic acid (300 mg, 1.75 mmol) and (Boc 2 To a solution of 1,4-dioxane (25 mL) of 1,4-dioxane (420 mg, 1.93 mmol) was added dropwise a solution of NaOH (140 mg, 3.50 mmol) in water (10 mL). The reaction mixture was stirred at rt for 3 h. and then concentrated under reduced pressure. The residue was diluted with water (50 mL), adjusted to pH 6 with HCl (1 M), and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with saturated brine and purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0-40%) to give the desired product (311 mg, 67% yield). LCMS calculated value C 14 H 18 NO 4 [M+H-56] + :m / z=208.1; Found: 208.1.

[0525] Step 3: (2S)-tert-butyl 2-[(4-chloro-3-methylphenyl)(methyl)carbamoyl]-2,3-dihydroindole-1-carboxylate

[0526]

[0527] To a suspension of (2S)-1-(tert-butyloxycarbonyl)-2,3-dihydroindole-2-carboxylic acid (50.0 mg, 0.190 mmol) in THF (5 mL) was added (1-chloro-2-methylprop-1-en-1-yl)dimethylamine (30.4 mg, 0.228 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was added to a mixture of 4-chloro-N,3-dimethylaniline (35.5 mg, 0.228 mmol) and pyridine (45.1 mg, 0.570 mmol) in THF (5 mL). The resulting mixture was stirred at 60 ° C overnight. After cooling, the reaction mixture was quenched with water (40 ml) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with saturated brine and purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. The residue was purified by Prep-TLC, eluting with EtOAc / PE (1 / 1) to give the desired product (61 mg, 80% yield) as a yellow solid. LCMS calculated value C 22 H 26 C1N 2 O 3 [M+H-56] + :m / z=345.2; measured value: 345.2.

[0528] Step 4: (2S)-N-(4-chloro-3-methylphenyl)-N-methyl-2,3-dihydro-1H-indole-2-carboxamide

[0529]

[0530] To a solution of tert-butyl (2S)-2-[(4-chloro-3-methylphenyl)(methyl)carbamoyl]-2,3-dihydroindole-1-carboxylate (61.0 mg, 0.152 mmol) in 1,4-dioxane (12 mL) was added HCl (gas) in 1,4-dioxane (4 M, 4 mL). The resulting mixture was stirred at rt for 8 h. It was then concentrated under reduced pressure to afford the desired product as the HCl salt (63.0 mg) as a yellow solid. LCMS calculated value C 17 H 18 C1N 2 O[M+H] + :m / z=301.1; measured value: 301.0.

[0531] Step 5: (2S)-N-(4-chloro-3-methylphenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,3-dihydroindole-2-carboxamide

[0532] (2S)-N-(4-chloro-3-methylphenyl)-N-methyl-2,3-dihydro-1H-indole-2-carboxamide hydrochloride (63.0 mg, 0.187 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (53.8 mg, 0.224 mmol), Pd 2 (dba) 3 (25.7 mg, 0.028 mmol), Xantphos (32.4 mg, 0.056 mmol) and K 3 PO 4 (119 mg, 0.561 mmol) in 1,4-dioxane (3 mL), degassed and filled with nitrogen, replaced 3 times. The resulting mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. Then cooled to rt, the mixture was quenched with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with saturated brine and purified by Na 2 SO 4 The residue was purified by Prep-TLC using EtOAc / PE (1 / 1) as eluent to give a crude product, which was further purified by Prep-HPLC on a C18 column using MeCN / H 2 O (75% to 95%, 10mmol / L NH 4 HCO 3 +0.1% NH 3 .H 2 O) to give the desired product (33.2 mg, 39% yield) as an off-white solid. 1 H NMR (300 MHz, CDCl 3 )δ7.61 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.24-7.03 (m, 4H), 6.97-6.77 (m, 2H), 5.18-5.04 (m, 1H), 3.29 (s, 3H), 3.25-3.07 (m, 2H), 2.59 (s, 3H), 2.43 (s, 3H). LCMS calculated value C 24 H 22 CIF 3 N 3 O[M+H] + :m / z=460.1; measured value: 460.1.

[0533] Example 2: (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide

[0534]

[0535] This compound was prepared in a similar manner to Steps 1 to 5 of Example 1, wherein in Step 1, 3-chloro-4-fluoroaniline was used instead of 4-chloro-3-methylaniline. 1 H NMR (300 MHz, CDCl 3 )δ7.59 (d, J=6.5 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.40-7.29 (m, 1H), 7.25-7.09 (m, 4H), 6.97-6.81 (m, 2H), 5.17-5.05 (m, 1H), 3.29 (s, 3H), 3.25-3.06 (m, 2H), 2.59 (s, 3H). LCMS calculated value C 23 H 19 CIF 4 N 3 O[M+H] + :m / z=464.1; Found: 464.1.

[0536] Example 3: (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide

[0537]

[0538] This compound was prepared in a similar manner to Steps 1-5 of Example 1, wherein in Step 1, 5-chloro-2,4-difluoroaniline was used instead of 4-chloro-3-methylaniline. 1 H NMR (400 MHz, CDCl 3 )δ8.02-7.65 (m, 1H), 7.46-7.29 (m, 1H), 7.27-7.08 (m, 3H), 7.04-6.79 (m, 3H), 5.18-4.96 (m, 1H), 3.46-3.06 (m, 5H), 2.67-2.51 (m, 3H). LCMS calculated value C 23 H 18 CIF 5 N 3 O[M+H] + :m / z=482.1; Found: 482.1.

[0539] Example 4: (S)-N-(4-chloro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isoindoline-1-carboxamide

[0540]

[0541] This compound was prepared in a similar manner to steps 1 to 5 of Example 1, except that (S)-isoindoline-1-carboxylic acid was used instead of (S)-indoline-2-carboxylic acid in step 2. 1H NMR (400 MHz, CDCl 3 )δ7.31-7.25 (m, 5H), 7.09-6.99 (m, 1H), 6.74 (s, 1H), 6.43 (s, 1H), 6.10 (s, 1H), 4.59 (d, J=13.1 Hz, 1H), 4.30 (s, 1H), 3.68 (s, 1H), 3.24 (s, 3H), 2.60 (s, 3H), 2.33 (s, 3H). LCMS calculated value C 24 H 22 CIF 3 N 3 O[M+H] + :m / z=460.1; measured value: 460.1.

[0542] Example 5: (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isoindoline-1-carboxamide

[0543]

[0544] This compound was prepared in a similar manner to Steps 1-5 of Example 1, wherein in Step 1, 3-chloro-4-fluoroaniline was used instead of 4-chloro-3-methylaniline, and in Step 2, (S)-isoindoline-1-carboxylic acid was used instead of (S)-indoline-2-carboxylic acid. 1 HNMR (400 MHz, CDCl 3 )δ7.32 (m, J=8.4 Hz, 4H), 7.17 (s, 2H), 6.75 (s, 1H), 6.45 (s, 1H), 6.08 (s, 1H), 4.61 (d, J=12.9 Hz, 1H), 4.41 (s, 1H), 3.82 (s, 1H), 3.26 (s, 3H), 2.60 (s, 3H). LCMS calculated value C 23 H 19 CIF 4 N 3 O[M+H] + :m / z=464.1; Found: 464.1.

[0545] Example 6: N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide

[0546]

[0547] Step 1: 1-tert-Butyloxycarbonyl 6-methoxyindole-2-carboxylic acid methyl ester

[0548]

[0549] At rt, a solution of di-tert-butyl dicarbonate (957 mg, 4.39 mmol) in THF (2 mL) was added dropwise to a solution of 6-methoxy-1H-indole-2-methylformate (600 mg, 2.92 mmol) and DMAP (17.9 mg, 0.146 mmol) in THF (10 mL). The reaction mixture was stirred overnight at rt. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with saturated brine and purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / hexane (0-40%) to give the desired product (800 mg, 90% yield). LCMS calculated value C 12 H 12 NO 5 [M+H-56] + :m / z=250.1; measured value: 250.0.

[0550] Step 2: 1-tert-Butyloxycarbonyl 6-methoxy-2,3-dihydroindole-2-carboxylic acid methyl ester

[0551]

[0552] To a suspension of 1-tert-butyloxycarbonyl 6-methoxyindole-2-carboxylic acid methyl ester (800 mg, 2.62 mmol) in MeOH (20 mL) was added 10% Pd / C (279 mg). The resulting mixture was stirred at 60 ° C overnight under hydrogen (2-3 atm). The mixture was filtered and the filter cake was washed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure to give the desired product (744 mg, 92% yield) as a yellow oil. LCMS calculated value C 12 H 14 NO 5 [M+H-56] + :m / z=252.1; measured value: 252.1.

[0553] Step 3: 1-(tert-Butyloxycarbonyl)-6-methoxy-2,3-dihydroindole-2-carboxylic acid

[0554]

[0555] To a solution of methyl 1-tert-butoxycarbonyl 6-methoxy-2,3-dihydroindole-2-carboxylate (744 mg, 2.4 mmol) in MeOH (10 mL) was added NaOH (194 mg, 4.8 mmol) in H 2 O (2 mL) solution. The resulting mixture was stirred at rt overnight. The mixture was quenched with water (30 mL), adjusted to pH 5 with 1 M HCl, and extracted with EtOAc (30 mL x 3). The combined organic phases were purified by Na 2 SO 4 The mixture was dried, filtered, and the filtrate was concentrated under reduced pressure to give the desired product (542 mg, crude product) as a yellow oil. LCMS calculated value: C 11 H 12 NO 5 [M+H-56] + :m / z=238.1; Found: 238.1.

[0556] Step 4: tert-Butyl 2-[(4-chloro-3-methylphenyl)(methyl)carbamoyl]-6-methoxy-2,3-dihydroindole-1-carboxylate

[0557]

[0558] This compound was prepared in a similar manner to step 3 of Example 1, using 1-(tert-butyloxycarbonyl)-6-methoxy-2,3-dihydroindole-2-carboxylic acid instead of (2S)-1-(tert-butyloxycarbonyl)-2,3-dihydroindole-2-carboxylic acid to obtain the desired product as a yellow solid. LCMS calculated value C 23 H 28 C1N 2 O 4 [M+H] + :m / z=431.2; measured value: 431.1.

[0559] Step 5: N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-2,3-dihydro-1H-indole-2-carboxamide

[0560]

[0561] This compound was prepared in a similar manner to step 4 of Example 1 to give the desired product (HCl salt) as a brown solid.

[0562] LCMS calculated value C 18 H 20 C1N 2 O 2 [M+H] + :m / z=331.1; measured value: 331.0.

[0563] Step 6: N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,3-dihydroindole-2-carboxamide

[0564]

[0565] This compound was prepared in a similar manner to step 5 of Example 1, using N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-2,3-dihydro-1H-indole-2-carboxamide HCl salt and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine as starting materials to give the desired product as a white solid. 1 H NMR (300 MHz, CDCl 3 )δ7.49-7.37 (m, 2H), 7.31 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.06-6.93 (m, 2H), 6.84 (s, 1H), 6.44 (dd, J=8.1, 2.3 Hz, 1H), 5.03 (dd, J=10.3, 5.3 Hz, 1H), 3.82 (d, J=1.6 Hz, 3H), 3.30 (s, 3H), 3.24-3.09 (m, 2H), 2.58 (s, 3H), 2.44 (s, 3H). LCMS calculated value C 25 H 24 CIF 3 N 3 O 2 [M+H] + :m / z=490.2; Found: 490.2.

[0566] Example 7: N-(4-chloro-3-methylphenyl)-6-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide

[0567]

[0568] To a solution of N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,3-dihydroindole-2-carboxamide (160 mg, 0.327 mmol, Example 6) in DCM (10 mL) at 0°C was added BBr 3 (164 mg, 0.65 mmol). The resulting mixture was stirred at rt overnight. The mixture was washed with saturated NaHCO 3 (aq., 20 mL), stirred at rt for 2 h., and washed with CH 2 Cl 2(50mL x 3) extraction. The combined organic phase was purified by Na 2 SO 4 The residue was purified by Prep-TLC using PE / EA (1 / 1) as eluent to give a crude product, which was further purified by PrepHPLC using ACN / H 2 O (55% to 85% containing 10 mmol / L NH 4 HCO 3 +0.1% NH 3 .H 2 O) to give the desired product (20.8 mg, 13% yield) as a white solid. 1 H NMR (300 MHz, methanol-d 4 )δ7.55-7.42 (m, 2H), 7.32 (d, J=8.5 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.02 (s, 1H), 6.96 (d, J=6.7 Hz, 2H), 6.37-6.27 (d, 1H), 5.04 (t, J=6.3 Hz, 1H), 3.27 (s, J=1.1 Hz, 3H), 3.19-3.05 (m, 2H), 2.61 (s, 3H), 2.44 (s, 3H). LCMS calculated value C 24 H 22 CIF 3 N 3 O 2 [M+H] + :m / z=476.1; Found: 476.1.

[0569] Example 8: N-(4-chloro-3-methylphenyl)-5-fluoro-6-methoxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide

[0570]

[0571] To a solution of N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (14.6 mg, 0.03 mmol, Example 6) in DCM (4 mL) was added N-fluoropyridinium trifluoromethanesulfonate (24.6 mg, 0.1 mmol). The reaction mixture was stirred at 40 ° C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-TLC on a silica gel column and eluted with EtOAc / PE (1:4) to give the target product (4.0 mg, Rf = 0.55). LCMS calculated value C 25 H 23 CIF4 N 3 O 2 [M+H] + :m / z=508.1; measured value: 508.2.

[0572] Example 9: N-(4-chloro-3-methylphenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0573]

[0574] This compound was prepared in a similar manner to steps 1-6 of Example 6, where in step 1, 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester was used instead of 6-methoxy-1H-indole-2-carboxylic acid methyl ester to give the desired product as a white solid. 1 H NMR (300 MHz, CDCl 3 )δ9.05 (s, 1H), 8.17-8.09 (m, 1H), 7.53-7.40 (m, 2H), 7.35 (d, J=1.6 Hz, 1H), 7.32 (d, J=3.1 Hz, 1H), 6.92 (s, 1H), 6.75 (dd, J=7.2, 5.2 Hz, 1H), 5.27 (dd, J=9.1, 7.0 Hz, 1H), 3.31 (d, J=2.1 Hz, 3H), 3.12 (d, J=8.0 Hz, 2H), 2.60 (d, J=2.1 Hz, 3H), 2.47 (s, 3H). LCMS calculated value C 23 H 21 CIF 3 N 4 O[M+H] + :m / z=461.1; measured value: 461.1.

[0575] Example 10: N-(4-chloro-3-methylphenyl)-6-methoxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0576]

[0577] This compound was prepared in a similar manner to steps 1-6 of Example 6, where 6-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester was used in step 1 to replace 6-methoxy-1H-indole-2-carboxylic acid methyl ester to give the desired product as a yellow solid. 1 HNMR (400 MHz, DMSO-d 6)δ8.90 (s, 1H), 7.68-7.53 (m, 2H), 7.44 (dd, J = 14.1, 8.1 Hz, 2H), 7.12 (s, 1H), 6.29 (d, J = 7.9 Hz, 1H), 5.35-4.90 (m, 1H), 3.89 (s, 3H), 3.16 (s, 3H), 3.07 (d, J = 5.4 Hz, 2H), 2.56 (s, 5H), 2.39 (s, 3H). LCMS calculated value C 24 H 23 CIF 3 N 4 O 2 [M+H] + :m / z=491.4; Found: 491.4.

[0578] Example 11: (S)-N-(4-chloro-3-methylphenyl)-N,1-dimethyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-4-carboxamide

[0579]

[0580] Step 1: 1-tert-Butylcarbonyl (2S,3E)-3-[(dimethylamino)methylene]-4-oxopyrrole-2-carboxylic acid methyl ester

[0581]

[0582] A mixture of 1-tert-butyloxycarbonyl (2S)-4-oxopyrrole-2-carboxylic acid methyl ester (2.00 g, 8.22 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (20 mL) was stirred at rt for 1 h. The resulting mixture was diluted with EtOAc (350 mL), washed with water (60 mL x 3), and dried over anhydrous Na 2 SO 4 The mixture was dried, filtered, and the filtrate was concentrated under reduced pressure to give the desired product (2.26 g, crude product) as a yellow oil. LCMS calculated value: C 14 H 23 N 2 O 5 [M+H] + :m / z=299.2; Found: 299.1.

[0583] Step 2: 5-tert-Butylcarbonyl (4S)-1-methyl-4H,6H-pyrrolo[3,4-c]pyrrole-4-carboxylic acid methyl ester

[0584]

[0585] A mixture of 1-tert-butyloxycarbonyl (2S, 3E)-3-[(dimethylamino)methylene]-4-oxopyrrole-2-carboxylic acid methyl ester (1.00 g, 3.35 mmol) and methylhydrazine (1.0 mL, 1.34 mmol, 40% in water) in MeOH (10 mL) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL), acidified to pH 5 with 1N HCl (aq.), and extracted with EtOAc (50 mL x 3). The combined organic phases were purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using CH 2 Cl 2 / MeOH (10 / 1) to give the desired product (416 mg, 44% yield) as a yellow solid. LCMS calculated value C 13 H 20 N 3 O 4 [M+H] + :m / z=282.1; Found: 282.1.

[0586] Step 3: (4S)-5-(tert-Butyloxycarbonyl)-1-methyl-4H,6H-pyrrolo[3,4-c]pyrrole-4-carboxylic acid

[0587]

[0588] 5-tert-Butyloxycarbonyl (4S)-1-methyl-4H,6H-pyrrolo[3,4-c]pyrrole-4,5-carboxylic acid methyl ester (370 mg, 1.32 mmol), LiOH.H 2 O (110 mg, 2.63 mmol) and H 2 A mixture of 10% 4H2O (1 mL) and MeOH (4 mL) was stirred at rt for 4 h. and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The aqueous phase was adjusted to pH 6 with HCl (1 M) and extracted with EtOAc (20 mL x 3). The combined organic phases were purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to obtain the desired product (230 mg, 65% yield) as a yellow solid. LCMS calculated value C 12 H 18 N 3 O 4 [M+H] + :m / z=268.1; Found: 268.1.

[0589] Step 4: (4S)-4-[(4-chloro-3-methylphenyl)(methyl)carbamoyl]-1-methyl-4H,6H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester

[0590]

[0591] This compound was prepared in a similar manner to step 3 of Example 1, using (4S)-5-(tert-butyloxycarbonyl)-1-methyl-4H,6H-pyrrolo[3,4-c]pyrrole-4-carboxylic acid and 4-chloro-N,3-dimethylaniline as raw materials to obtain the target product as a yellow solid. LCMS calculated value C 20 H 26 C1N 4 O 3 [M+H] + :m / z=405.2; Found: 405.2.

[0592] Step 5: (4S)-N-(4-chloro-3-methylphenyl)-N,1-dimethyl-4H,5H,6H-pyrrolo[3,4-c]pyrrole-4-carboxamide hydrochloride

[0593]

[0594] This compound was prepared in a similar manner to step 4 of Example 1 to obtain the target product as a yellow solid. LCMS calculated value C 15 H 18 C1N 4 O[M+H] + :m / z=305.1; measured value: 305.1.

[0595] Step 6: (S)-N-(4-chloro-3-methylphenyl)-N,1-dimethyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-4-carboxamide

[0596]

[0597] This compound was prepared in a similar manner to step 5 of Example 1, using (4S)-N-(4-chloro-3-methylphenyl)-N,1-dimethyl-4H,5H,6H-pyrrolo[3,4-c]pyrrole-4-carboxamide hydrochloride and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine as raw materials to obtain the target product as an off-white solid. 1 H NMR (300 MHz, CDCl 3)δ7.46 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 7.20 (s, 2H), 6.70 (s, 1H), 6.35 (s, 1H), 5.60 (s, 1H), 4.58-4.44 (m, 2H), 3.83 (s, 3H), 3.25 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H). LCMS calculated value C 22 H 22 CIF 3 N 5 O[M+H] + :m / z=464.2; Found: 464.2.

[0598] Example 12: N-(4-chloro-3-methylphenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-2-carboxamide

[0599]

[0600] Step 1: 1,2,3,4-Tetrahydroquinoline-2-carboxylic acid

[0601]

[0602] 4-Hydroxyquinoline-2-carboxylic acid (2.0 g, 11.5 mmol) and PtO 2 A mixture of (262 mg, 1.16 mmol) in MeOH (20 mL) was stirred at rt under a hydrogen atmosphere (2-3 atm) for 1.5 h. The solid was filtered and the filter cake was rinsed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure to give 1,2,3,4-tetrahydroquinoline-2-carboxylic acid (2.0 g, crude) as a yellow oil. LCMS calculated value C 10 H 12 NO 2 [M+H] + :m / z=178.1; Found: 178.1.

[0603] Step 2: N-(4-chloro-3-methylphenyl)-N-methyl-1,2,3,4-tetrahydroquinoline-2-carboxamide

[0604]

[0605] A mixture of 1,2,3,4-tetrahydroquinoline-2-carboxylic acid (200 mg, 1.13 mmol), 4-chloro-N,3-dimethylaniline (176 mg, 1.13 mmol), TCFH (380 mg, 1.36 mmol) and NMI (324 mg, 3.95 mmol) in DMF (6 mL) was stirred at rt for 2 h. The resulting mixture was diluted with EtOAc (50 mL), washed with water (20 mL x 3), and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. The crude residue was purified by flash chromatography on a silica gel column using PE / EA (5 / 1) as eluent to give the desired product (116 mg, 33% yield) as a yellow solid. LCMS calculated value: C 18 H 20 C1N 2 O[M+H] + :m / z=315.1; measured value: 315.1.

[0606] Step 3: N-(4-chloro-3-methylphenyl)-N-methyl-1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3,4-dihydro-2H-quinoline-2-carboxamide

[0607]

[0608] N-(4-chloro-3-methylphenyl)-N-methyl-1,2,3,4-tetrahydroquinoline-2-carboxamide (85.0 mg, 0.270 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (64.8 mg, 0.270 mmol), Xantphos (31.3 mg, 0.0540 mmol), Pd 2 (dba) 3 (24.7 mg, 0.0270 mmol) and K 3 PO 4 A mixture of 1,4-dioxane (8 mL) and 172 mg (172 mg, 0.810 mmol) was stirred at 100 °C overnight under a nitrogen atmosphere. After cooling, the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using PE / EA (3 / 1) as eluent to give the desired product, which was further purified by Prep-HPLC using ACN / H 2 O (80% to 95% containing 0.1% FA) to afford the desired product (8.4 mg, 7% yield) as a white solid. 1HNMR (300 MHz, CDCl 3 )δ7.61-7.37 (m, 3H), 7.25 (d, J=4.2 Hz, 2H), 7.24-7.19 (m, 1H), 7.15-7.11 (m, 1H), 7.03-6.91 (m, 1H), 6.74 (s, 1H), 4.96-4.90 (m, 1H), 3.29-2.81 (m, 3H), 2.67-2.54 (m, 3H), 2.42-2.21 (m, 4H), 2.15-2.02 (m, 1H), 1.65-1.56 (m, 2H). LCMS calculated value C 25 H 24 CIF 3 N 3 O[M+H] + :m / z=474.2; Found: 474.1.

[0609] Example A: Biological Tests

[0610] PolQ polymerase test

[0611] The PolQ polymerase assay was used to test the ability of compounds to inhibit PolQ-C-terminal activity in vitro. C-terminal His6-tag PolQ (AA: 1819-2590) expressed in insect cells was purified and stored in aliquots at -80°C. The assay was performed using 1× buffer containing 25 mM Tris-HCl (pH 7.5), 12.5 mM NaCl, 0.5 mM MgCl 2, 5% glycerol, 0.01% TritonX-100, 0.01% BSA, 1mM DTT. Using a dispenser (Labcyte, Echo665), the compound dissolved in DMSO was transferred to two wells in a 384-well test plate (PerkinElmer, Catalog #: 6008269) and tested at 10 concentrations of 3-fold serial dilution. Add 5 μL of enzyme mixture [h PolQ-C (C-terminalHis6-tag, 29.3 μM), final concentration 2.5 nM] to the test well. Cover the test plate and incubate at room temperature for 15 minutes, then add 5 μL of substrate mixture [dNTP (100 mM, final concentration 40 μM) and dsDNA (10 μM, final concentration 15 nM)] to start the reaction. Incubate at room temperature for 60 minutes, add 5 μL PicoGreen solution (Thermo, Catalog #: P7581) to the test plate, and incubate at room temperature for 90 minutes. Read on a multi-plate reader (BMG, PHERAstar FSX) in fluorescence mode, with an excitation wavelength of 485 nm and an emission wavelength of 520 nm. Calculate the average fluorescence signal of the high control group (wells containing 1% DMSO) as the high control group (HC). Calculate the average fluorescence signal of the low control group (no enzyme) as the low control group (LC).

[0612] %Inhibition=(Signal Ave_HC -Signal cmpd ) / (Signal Ave_HC -Signal Ave_LC )×100%.IC 50 Values ​​were determined by fitting the data to a standard 4-parameter using Hill Slope using GraphPad Prism software.

[0613] +++<=0.1μM, 0.1μM<++<=1μM, +>1μM.

[0614] Table 1. PolQ polymerase

[0615]

[0616] Cell viability test

[0617] Cell viability studies were performed on Ishikawa cells. Cells were cultured in medium supplemented with 5% v / v FBS (AusGeneX, Catalog #: FBS500-S), 1% GlutaMAX TM(Gibco, Catalog #: 35050061), 1% MEM Non-Essential Amino Acids (Gibco, Catalog #: 11140050), 1% v / v Penicillin Streptomycin (Gibco, Catalog #: 15140122) in MEM (Hyclone, Catalog #: SH30024.01). Cells were seeded into 96-well assay plates (PerkinElmer, Catalog #: 6005680) at a density of 600 cells / well. Compounds dissolved in DMSO were pipetted into two wells of the assay plate using a multichannel pipette and tested at 9 concentration points in 3-fold serial dilutions. Cells were incubated in an active humidified incubator at 37°C, 5% CO 2 Incubate for 7 days under 4% paraformaldehyde (pH 7.0) conditions. Cell viability was tested using the Cell Titer-Glo reagent (Promega, Catalog #: G7573) according to the manufacturer's instructions. Fluorescence signals were tested using a multi-template tester (Perkin Elmer, Envision 2105 or BMG, ClarioStar Plus). The average of the wells treated with DMSO in the test plate was calculated as the high control group (HC). The average of the medium-only wells in the test plate was calculated as the low control group.

[0618] (LC). %inhibition=(Signal Ave_HC -Signal cmpd ) / (Signal Ave_HC -Signal Ave_LC )×100%.IC 50 The value is passed

[0619] GraphPad Prism software was used to fit the data to a standard 4-parameter Hill Slope determination.

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof, wherein: Ring A is phenyl or a 5-6 membered heteroaryl group; Ring B is a 5-6 membered heterocyclic group; Ar 1 C6-C 10 Aryl or 5-10 membered heteroaryl; wherein, The C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted by q selected from R 10 Substituents are substituted; X is N or CR 5 ; L 1 is absent, -C(O)-, *-(C(R 6 )2) p -C(R 7 )2-,-C(O)C(R 7 )2-,-C(O)NR 8 -, *-OC(O)-, or *-SC(O)-; L 2 is not present, -(C(R 6 )2) t -,*-NR 9 C(R 7 )2, *-OC(R 7 )2-, or *-SC(R 7 )2-; L 1 and L 2 do not exist simultaneously; Wherein, the * and Y on ring A 1 or Y 2 connect; Y 1 and Y 2 are independently selected from C or N; Y 1 and Y 2 Not all are N; R 1 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 selected from R 1A Substituents are substituted; Every R 1A independently selected from D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, OR a , NR c R d , NHOR a , SR a , C(O)R b , C(O)NR c R d , NR c C(O)R b , C(O)OR a ,OC(O)R b ,S(O)R b , S(O)NR c R d , S(O)2R b , NR c S(O)2R b or S(O)2NR c R d ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , B(OR c1 )(OR d1 ),C(=NR c1 )NR c1 R d1 ,NR d1 C(=NR c1 )NR c1 R d1 ,NR d1 C(=NR c1 )R b1 ,OP(O)OR e1 OR f1 ,P(O)OR e1 OR f1 ,S(O)(=NR b1 )R b1 ,S(O)R b1 ,S(O)NR c1 R d1 ,S(O)2R b1 ,NR c1 S(O)2R b1 ,S(O)2NR c1 R d1 ,NR c1 S(O)2NR c1 R d1 ,NR c1 S(O)(=NR b1 )R b1 ; Every R 2 independently selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, NO2, OR A , SF5, C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , or NR C S(O)2NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is selectively substituted by a substituent selected from the following: D, CN, halogen, OH, NH2, C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl; or Two adjacent R 2 , together with the atoms to which it is attached, selectively forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; R 3 independently selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, NO2, OR A , SF5, C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , or NR C S(O)2NR C R D wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 or Two adjacent R 3 , together with the atoms to which it is attached, selectively forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; R 4 Selected from H, D, CN, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, wherein the C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl is optionally substituted with 1, 2 or 3 substituents selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl; R 5 independently selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, NO2, OR A , SF5, or NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is selectively substituted by a substituent selected from the following: D, CN, halogen, OH, NH2, C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl; or R attached to adjacent carbons 5 and R 2 , together with the atoms to which it is attached, selectively forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; Every R 6 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-C 1 , OR A , NR C R D , C(O)R B , C(O)NR C R D , NR C C(O)R D , C(O)OR A , or OC(O)R B , wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 or Two R's 6 , together with the atoms to which it is attached, form C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; Every R 7 independently selected from H, D, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-C 1 , wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 or Two R's 7 , together with the atoms to which it is attached, form C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; R 8 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-C 1 wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 Substituents are substituted; R 9 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-C 1 , C(O)R B , C(O)NR C R D , C(O)OR A , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , or S(O)2NR C R D wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 or R 9 and R 7 Together with the atoms to which they are attached, they selectively form C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; R 10 independently selected from H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-Cy 1 , OR A , SR A , SF5, NHOR A , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), C(=NR C )NR C R D , NR D C(=NR C )NR C R D , NR D C(=NR C )R B , P(O)R E R F , P(O)OR E OR F OP(O)OR E OR F , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , NR C S(O)2NR C R D , or NR C S(O)(=NR B )R B wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 or Two adjacent R 10 , together with the atoms to which it is attached, form C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 Substituents are substituted; Every R 11 D is independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6-cyanoalkyl, CN, NO2, oxo, OR a , SR a , SF5, NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b OP(O)OR e OR f , P(O)OR e OR f , S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d , S(O)2R b , NR c S(O)2R b , S(O)2NR c R d , and NR c S(O)2NR c R d , NR c S(O)(=NR b )R b ; Every R 12 D is independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6-cyanoalkyl, CN, NO2, oxo, OR a , SR a , SF5, NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d , S(O)2R b , NR c S(O)2R b , S(O)2NR c R d , NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ; Cy 1 Selected from C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6- C 10 Aryl or 5-10 membered heteroaryl, wherein the C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6- C 10 The aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 groups selected from R 13 Substituents are substituted; Every R 13 D is independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6-cyanoalkyl, CN, NO2, oxo, OR a , SR a , SF5, NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR c )(OR d ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b OP(O)OR e OR f , P(O)OR e OR f , S(O)(=NR b )R b ,S(O)R b , S(O)NR c R d , S(O)2R b , NR c S(O)2R b , S(O)2NR c R d , NR c S(O)2NR c R d , NR c S(O)(=NR b )R b , phenyl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl; Every R A independently selected from H, D, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C0-C6 alkyl-C 2 , wherein the C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally replaced by 1, 2, or 3 selected from R 14 Substituents are substituted; R B independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-C 2 , wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, or 3 selected from R 14 Substituents are substituted; R C and R D are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-C 2 wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, or 3 selected from R 14 or R C and R D The 4-7 membered heterocyclic group formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, or C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl; R E and R e are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocyclyl-C1-C4 alkyl; R F and R f are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group; Every R a is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; Every R b independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C1-C4 alkyl, C3-C7 cycloalkyl-C1-C4 alkyl, 5-6 membered heteroaryl-C1-C4 alkyl, or 4-7 membered heterocyclyl-C1-C4 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C1-C4 alkyl, C3-C7 cycloalkyl-C1-C4 alkyl, 5-6 membered heteroaryl-C1-C4 alkyl, or 4-7 membered heterocyclyl-C1-C4 alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; Every R a1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; Every R b1 independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, phenyl-C1-C4 alkyl, C3-C7 cycloalkyl-C1-C4 alkyl, 5-6 membered heteroaryl-C1-C4 alkyl, or 4-7 membered heterocyclyl-C1-C4 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, phenyl-C1-C4 alkyl, C3-C7 cycloalkyl-C1-C4 alkyl, 5-6 membered heteroaryl-C1-C4 alkyl, or 4-7 membered heterocyclyl-C1-C4 alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; R c , R d , R c1 and R d1 are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, 5-6 membered heteroaryl, C 3- C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C(O)OR a1 , C(O)R b1 , S(O)2R b1 , C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-; or R c and R d The 4-7 membered heterocyclic group formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C(O)OR a1 , C(O)R b1 , S(O)2R b1 , C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy; R c1 and R d1 The 4-7 membered heterocyclic group formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C(O)OR a1 , C(O)R b1 , S(O)2R b1 , C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy; Every R e1 independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocyclyl-C1-C4 alkyl; Every R f1 independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group; Cy 2 Independently selected from C 3- C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 3- C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 selected from R 14 Substituents are substituted; Every R 14 independently selected from D, OH, CN, halogen, C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, C1-C4 cyanoalkyl, NO2, oxo, OR a , SR a , SF5, NHOR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , B(OR e )(OR f ), C(=NR c )NR c R d , NR d C(=NR c )NR c R d , NR d C(=NR c )R b , P(O)R e R f , P(O)OR e OR f OP(O)OR e OR f ,S(O)R b , S(O)NR c R d , S(O)2R b , NR c S(O)2R b , S(O)2NR c R d , NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ; m is 1, 2 or 3; n is 1, 2, 3 or 4; p is 0 or 1; q is 1, 2, 3 or 4; t is 1 or 2.

2. The compound according to claim 1, characterized in that R 4 Selected from H, D, CN, C1-C3 alkyl optionally substituted with 1, 2 or 3 substituents selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

3. The compound according to claim 2, characterized in that R 4 For H.

4. The compound according to any one of claims 1 to 3, characterized in that X is N.

5. The compound according to any one of claims 1 to 3, characterized in that X is CR 5 .

6. The compound according to claim 1 or 5, characterized in that R 5 Selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, NO2, OR A , SF5, or NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl are selectively substituted by substituents selected from the following: D, CN, halogen, OH, NH2, C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl.

7. The compound according to claim 1 or 5, characterized in that R attached to adjacent carbons 5 and R 2 , together with the atoms to which it is attached, form C 3- The C7 cycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from R 12 substituted by a substituent.

8. The compound according to claim 1 or 5, characterized in that R attached to adjacent carbons 5 and R 2 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 selected from R 12 substituted by a substituent.

9. The compound according to any one of claims 1 to 8, characterized in that Ring A is phenyl.

10. The compound according to any one of claims 1 to 8, characterized in that Ring A is a 5-membered heteroaryl group.

11. The compound according to any one of claims 1 to 8, characterized in that Ring A is a 6-membered heteroaryl group.

12. The compound according to any one of claims 1 to 11, characterized in that Ring B is a 5-membered heterocyclic group.

13. The compound according to claim 12, characterized in that L 1 is not present, L 2 -(C(R 6 )2) t -, t = 1; or L 2 is not present, L 1 is absent, -C(O)-, *-(C(R 6 )2) p -C(R 7 )2-, p=0.

14. The compound according to any one of claims 1 to 11, characterized in that Ring B is a 6-membered heterocyclic group.

15. The compound according to claim 14, characterized in that L 1 is not present, L 2 -(C(R 6 )2) t -,*-NR 9 C(R 7 )2, *-OC(R 7 )2-, or *-SC(R 7 )2-, t=2; or L 2 is not present, L 1 *-(C(R 6 )2) p -C(R 7 )2-,-C(O)C(R 7 )2-,-C(O)NR 8 -, *-OC(O)-, or *-SC(O)-, p=1; or L 1 -C(O)-, *-(C(R 6 )2) p -C(R 7 )2-,L 2 -(C(R 6 )2) t -, p=0, t=1.

16. The compound according to any one of claims 1 to 15, characterized in that Every R 6 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-C 1 , OR A , NR C R D , C(O)R B , C(O)NR C R D , NR C C(O)R D , C(O)OR A , or OC(O)R B , wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 substituted by a substituent.

17. The compound according to any one of claims 1 to 15, characterized in that Two R's 6 , selectively forming C 3- The C7 cycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from R 12 substituted by a substituent.

18. The compound according to any one of claims 1 to 15, characterized in that Two R's 6 , and the atoms to which they are attached selectively form a 4-7 membered heterocyclic group, which is selectively substituted by 1, 2, or 3 selected from R 12 substituted by a substituent.

19. The compound according to any one of claims 1 to 18, characterized in that Every R 7 independently selected from H, D, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-C 1 , wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 substituted by a substituent.

20. The compound according to any one of claims 1 to 18, characterized in that Two R's 7 , together with the atoms to which it is attached, form C 3- The C7 cycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from R 12 substituted by a substituent.

21. The compound according to any one of claims 1 to 18, characterized in that Two R's 7 , together with the atoms to which they are attached, form a 4-7 membered heterocyclic group, optionally substituted by 1, 2, or 3 selected from R 12 substituted by a substituent.

22. The compound according to any one of claims 1 to 21, characterized in that R 8 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-C 1 wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 substituted by a substituent.

23. The compound according to any one of claims 1 to 22, characterized in that R 9 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-C 1 , C(O)R B , C(O)NR C R D , C(O)OR A , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , or S(O)2NR C R D wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 substituted by a substituent.

24. The compound according to any one of claims 1 to 22, characterized in that R 9 and R 7 Together with the atoms to which they are attached, they selectively form C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 substituted by a substituent.

25. The compound according to any one of claims 1 to 24, characterized in that Y 1 and Y 2 Both are C.

26. The compound according to any one of claims 1 to 24, characterized in that Y 1 C; and Y 2 is N.

27. The compound according to any one of claims 1 to 24, characterized in that Y 1 is N; and Y 2 For C.

28. The compound according to any one of claims 1 to 27, characterized in that Ar 1 Selected from C6-C 10 The aryl group is optionally selected from R 10 substituted by a substituent.

29. The compound according to any one of claims 1 to 27, characterized in that Ar 1 is selected from a 5-10 membered heteroaryl group optionally substituted by q selected from R 10 substituted by a substituent.

30. The compound according to any one of claims 1 to 29, characterized in that Every R 10 independently selected from H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-Cy 1 , OR A , SR A , SF5, NHOR A , C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), C(=NR C )NR C R D , NR D C(=NR C )NR C R D , NR D C(=NR C )R B , P(O)R E R F , P(O)OR E OR F OP(O)OR E OR F , S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , NR C S(O)2NR C R D , NR C S(O)(=NR B )R B , wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 Substituents of Cy 1 Optionally, 1, 2, 3, 4, or 5 selected from R 13 substituted by a substituent.

31. The compound according to any one of claims 1 to 29, characterized in that Two adjacent R 10 , together with the atoms to which it is attached, form C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 substituted by a substituent.

32. The compound according to any one of claims 1 to 31, characterized in that m is 2.

33. The compound according to any one of claims 1 to 32, characterized in that n is 1.

34. The compound according to any one of claims 1 to 33, characterized in that R 1 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 selected from R 1A substituted by a substituent.

35. The compound according to any one of claims 1 to 34, characterized in that Every R 2 independently selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, NO2, OR A , SF5, C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , or NR C S(O)2NR C R D ; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl are selectively replaced by D, CN, halogen, OH, NH2, C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl.

36. The compound according to any one of claims 1 to 34, characterized in that Two adjacent R 2 , together with the atoms to which it is attached, selectively forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- The C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from R 12 substituted by a substituent.

37. The compound according to any one of claims 1 to 36, characterized in that R 3 independently selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, NO2, OR A , SF5, C(O)R B , C(O)NR C R D , C(O)OR A ,OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , NR C C(O)OR A , B(OR E )(OR F ), S(O)(=NR B )R B ,S(O)R B , S(O)NR C R D , S(O)2R B , NR C S(O)2R B , S(O)2NR C R D , or NR C S(O)2NR C R D wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 selected from R 11 substituted by a substituent.

38. The compound according to any one of claims 1 to 37, characterized in that The compound shown in formula (I) is shown in formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , m and n are as defined in formula (I).

39. The compound according to claim 38, characterized in that The compound shown in formula (I) is shown in formula (III): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 , m and n are as defined in formula (I).

40. The compound according to claim 39, characterized in that The compound shown in formula (I) is shown in formula (IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 , m and n are as defined in formula (I).

41. The compound according to claim 39, characterized in that The compound shown in formula (I) is shown in formula (V): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 , m and n are as defined in formula (I).

42. The compound according to claim 41, characterized in that The compound shown in formula (I) is shown in formula (VI): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 , R 5 and n are as defined in formula (I).

43. The compound according to claim 42, characterized in that The compound shown in formula (I) is shown in formula (VII): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein L 1 , L 2 , Y 1 , Y 2 , Ring A, Ring B, Ar 1 , R 1 , R 2 , R 3 and R 5 is as defined in formula (I).

44. The compound according to claim 43, characterized in that The compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIl), (VIIIm), (VIIIn), (VIIIo), and (VIIIp): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein Y 1 , Y 2 , Ring A, Ar 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined in formula (I).

45. The compound according to claim 44, characterized in that The compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIj), (VIIIk), (VIIIl), (VIIIm); or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein Y 1 , Y 2 , Ring A, Ar 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined in formula (I).

46. ​​The compound according to claim 45, characterized in that The compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), (VIIIe), (VIIIj), (VIIIl), (VIIIm) are shown as: or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated substance thereof; wherein Y 1 , Y 2 , Ring A, Ar 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9的 As defined in formula (I).

47. The compound according to any one of claims 1 to 46, characterized in that The compound is: or a pharmaceutically acceptable salt thereof.

48. The compound according to claim 47, characterized in that The compound is: or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

50. A method for treating and / or preventing a patient having a cancer with overexpression of PolQ, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 48, or a pharmaceutical composition according to claim 49.

51. A method for treating and / or preventing cancer in a patient, characterized in that The cancer is characterized by an increased reliance on MMEJ DSB repair, and the method comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 48, or a pharmaceutical composition according to claim 49.

52. A method for treating and / or preventing cancer in a patient, characterized in that The cancer is characterized by HR-deficiency, reduction or absence of HR-related gene expression, comprising: administering a therapeutically effective amount of the compound of any one of claims 1-48, or the pharmaceutical composition of claim 49 to the patient.

53. A method for treating and / or preventing cancer, characterized in that: The cancer lacks the 53BP1 / Shieldin complex, comprising: administering a therapeutically effective amount of the compound of any one of claims 1-48, or the pharmaceutical composition of claim 49 to the patient.

54. A method for treating and / or preventing cancer, characterized in that: The cancer has or has not been treated with PARPi drugs and is resistant to PARPi treatment, comprising: administering to the patient a therapeutically effective amount of the compound of any one of claims 1-48, or the pharmaceutical composition of claim 49.

55. A method for treating and / or preventing cancer in a patient, characterized in that The cancer is characterized by NHEJ deficiency, reduced or absent expression of NHEJ-related genes, comprising: administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 48, or the pharmaceutical composition of claim 49.

56. Use of the compound according to any one of claims 1 to 48 or the pharmaceutical composition according to claim 49 in the preparation of a drug for treating a disease in which PolQ is overexpressed in a patient.

57. Use of the compound of any one of claims 1 to 48 or the pharmaceutical composition of claim 49 in the preparation of a medicament for treating a disease with increased dependence on MMEJ-DSB repair.

58. Use of the compound 1-48 according to any one of claims 1 to 48 or the pharmaceutical composition according to claim 49 in the preparation of a drug for treating cancer, characterized in that: Such cancers are characterized by HR-deficiency, reduced or absent expression of HR-related genes.

59. Use of the compound according to any one of claims 1 to 48 or the pharmaceutical composition according to claim 49 in the preparation of a drug for treating cancer, characterized in that: The cancer lacks the 53BP1 / Shieldin complex.

60. Use of the compound according to any one of claims 1 to 48 or the pharmaceutical composition according to claim 49 in the preparation of a drug for treating cancer, characterized in that: The cancer may or may not have been treated with a PARPi drug and may be resistant to PARPi treatment.

61. Use of the compound according to any one of claims 1 to 48 or the pharmaceutical composition according to claim 49 in the preparation of a drug for treating cancer, characterized in that: Such cancers are characterized by NHEJ deficiency, reduced or absent expression of NHEJ-related genes.

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