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 methods for preparing the heterocyclic derivatives and compositions thereof, as well as applications in treating diseases associated with PolQ activity, such as cancer. Background Art

[0002] The DNA damage repair (DDR) process is crucial 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. Alt-NHEJ, also known as microhomology-stage end joining (MMEJ), is often considered a "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 DDRs could be developed as targeted cancer therapies. DNA repair defects have become a proven and effective strategy in cancer treatment, exemplified by the successful use of poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of BRCA-deficient breast, ovarian, prostate, and pancreatic cancers (Audeh MW et al., 2010).

[0004] Numerous genetic, cell biological, and biochemical studies have shown that DNA polymerase theta (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, comprising an N-terminal helicase domain (SF2 HEL308 type) and a C-terminal low-fidelity DNA polymerase domain (A type) (Wood & Doublie, 2016). In homologous recombination-deficient (HRD) cells, PolQ can promote error-prone DNA synthesis at sites of DNA damage 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. PolQ's anti-recombinase activity promotes the MMEJ pathway. Furthermore, the helicase domain of PolQ facilitates microhomology-mediated strand annealing (Chan SH et al., 2010; Kawamura K et al., 2004). When ssDNA overhangs contain microhomology stretches greater than two 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, followed by a coupled interaction with Rad51. After annealing, the polymerase domain extends the ssDNA ends and fills the remaining gap before MMEJ repair ligation is complete.

[0006] PolQ is lowly expressed or absent in normal cells, but is significantly overexpressed in HRD ovarian, uterine, 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 PolQ expression (Ceccaldi R. et al., 2015, Mateos-Gomez PA et al., 2015, and Wyatt DW et al., 2016). Finally, PolQ inhibition may prevent the MMEJ-dependent functional reversion of BRCA1 or BRCA2 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 lethality therapy against cancers with DNA repair defects. Summary of the Invention

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

[0008]

[0009] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate 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 form 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 compound 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 from the 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 combination within a single aspect. 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 herein, and it should also be understood that the terminology used herein is only for the purpose of describing specific embodiments and is not intended to limit the scope of the present invention.

[0018] The present invention provides a compound represented by formula (I):

[0019]

[0020] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof, wherein:

[0021] L is Among them, * is connected to the N-atom, and ** is connected to the C-atom;

[0022] n is 1 or 2;

[0023] Ar 1 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by m independently selected R 10 Substituents substituted;

[0024] Ar 2 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by r independently selected from R 11 Substituents substituted;

[0025] R 1 is 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 independently selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl; or

[0026] R 1 and Ar 2 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl;

[0027] R 2 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 are optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A Substituents substituted;

[0028] Every R 2A 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-C10 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 with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)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 ;or

[0029] R 1 and R 2 and the atoms to which they are attached form a 5-7 membered heterocyclic radical optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl;

[0030] R 3 and R 4 are independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 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 Bwherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 or

[0031] R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-, -C(S)-, C3-C7 cycloalkyl, or 4-7 membered heterocyclyl; wherein the C3-C7 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl; or

[0032] R on adjacent carbon atoms 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl;

[0033] R 5 and R 6 are independently selected from H, D, halogen, CN, OR A , 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 independently selected R 12 or

[0034] R 5 and R 6 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group; wherein the C3-C7 cycloalkyl group, or the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d ;or

[0035] R 3 and R 5 、R 4 and R 5 、R 3 and R 6 or R 4 and R 6 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; wherein the C3-C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d ;

[0036] R 3 , R 4 , R 5 and R 6 Together with the carbon atom to which it is attached, it forms a C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a ,NR c R d , C(O)R b , C(O)NR c R d ,NR c C(O)R b ,NR c S(O)2R b , S(O)2NR c R d , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OR a , C1-C6 haloalkyl-OR a , C1-C6 alkyl-NR c R d ;

[0037] R 7 Selected from H, D, CN, OR A, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein, the C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by at least one substituent selected from the following: D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl; or

[0038] R 7 and R 5 or R 7 and R 6 The heterocyclic group which, taken together with the atoms to which it is attached, forms a 5-7 membered partially saturated group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, CF3, NO2, oxo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl;

[0039] R 8 Selected from H, D, CN, OR A ,C(O)OR A , C(O)R B , C(O)NR C R D , S(O)R B , S(O)NR C R D , S(O)2R B , S(O)2NR C R D , C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 or

[0040] R 3 and R 8 or R 4 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 Substituents substituted;

[0041] R 3 , R 4 and R 8 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3 or 4 independently selected R13 or

[0042] R 7 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 Substituents substituted;

[0043] R 9 is selected from phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein the phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted with at least one substituent independently selected from the group consisting of D, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl;

[0044] Every R 10 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)2NRC R D wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by a substituent independently selected from the group consisting of 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

[0045] Two adjacent R 10 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independently selected R 13 Substituents substituted;

[0046] Every R 11 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)ORE 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 independently selected R 12 or

[0047] Two adjacent R 11 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independently selected R 13 Substituents substituted;

[0048] Every R 12 D is independently selected from the group consisting of 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)ORa ,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 ;

[0049] Every R 13 D is independently selected from the group consisting of 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 ;

[0050] 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 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 Substituents substituted;

[0051] Every R 14 D is independently selected from the group consisting of 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)ORa ,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;

[0052] Every R A independently selected from H, D, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C0-C6 alkyl-Cy 2 wherein the C1-C6 alkyl, C2-C4 alkenyl or C2-C4 alkynyl is optionally substituted by 1, 2, or 3 independently selected R 15 Substituents substituted;

[0053] R B independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-Cy 2 wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, or 3 independently selected R 15 Substituents substituted;

[0054] R C and R Dare 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 independently selected R 15 or

[0055] R C and R D The 4-7 membered heterocyclyl formed together with the nitrogen atom to which it is attached is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkyl-OH, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;

[0056] R E and R e Each 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;

[0057] 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;

[0058] 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 independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;

[0059] 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 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

[0060] Every R a1 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 independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;

[0061] 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 independently 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;

[0062] 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 independently 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-;

[0063] or R c and R d The 4-7 membered heterocyclic radical formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently 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)Rb1 , S(O)2R b1 , C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy;

[0064] or R c1 and R d1 The 4-7 membered heterocyclic radical formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently 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;

[0065] 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;

[0066] 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;

[0067] Cy 2 Independently selected from C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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 independently selected R 15 Substituents substituted;

[0068] Every R 15Independently 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 ;

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

[0070] r is 1, 2, 3 or 4.

[0071] In some embodiments, n is 1.

[0072] In some embodiments, n is 2.

[0073] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0074] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0075] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0076] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0077] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0078] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0079] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0080] In some embodiments, L is Among them, * is connected to the N-atom and ** is connected to the C-atom.

[0081] In some embodiments, Ar 1 C6-C 10 Aryl is optionally substituted by m independently selected from R 10 The substituent replaces s.

[0082] In some embodiments, Ar 1 is phenyl, naphthyl; each substituent is optionally substituted by m independently selected R 10 substituted by a substituent.

[0083] In some embodiments, Ar 1 is phenyl optionally substituted by m independently selected R 10 substituted by a substituent.

[0084] In some embodiments, Ar 1is a 5-10 membered heteroaryl group optionally substituted by m independently selected R 10 substituted by a substituent.

[0085] In some embodiments, Ar 1 is a 5-6 membered heteroaryl group optionally substituted by m independently selected R 10 substituted by a substituent.

[0086] In some embodiments, Ar 1 is a 6-membered heteroaryl group optionally substituted by m independently selected R 10 substituted by a substituent.

[0087] In some embodiments, Ar 1 is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; each substituent is optionally substituted by m independently selected R 10 substituted by a substituent.

[0088] In some embodiments, Ar 1 is pyrimidinyl optionally substituted by m independently selected R 10 In some embodiments, Ar 1 is pyridyl optionally substituted by m independently selected R 10 substituted by a substituent.

[0089] In some embodiments, m is 1.

[0090] In some embodiments, m is 2.

[0091] In some embodiments, m is 3.

[0092] In some embodiments, m is 4.

[0093] In some embodiments, each R 10 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 ,NRC 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 optionally 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.

[0094] In some embodiments, each R 10 independently selected from H, D, CN, NO2, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, OR A ,NR C R D ; Wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally 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.

[0095] In some embodiments, each R 10 Independently selected from H, D, CN, NO2, SF5, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, OR A ,NR C R D; wherein, the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl are optionally substituted by substituents independently 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.

[0096] In some embodiments, each R 10 are independently selected from H. In some embodiments, each R 10 are independently selected from D. In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 Independently selected from SF5.

[0097] In some embodiments, each R 10 are independently selected from halogen (eg, F, Cl, Br, or I). In some embodiments, each R 10 is independently selected from F. In some embodiments, each R 10 In some embodiments, each R 10 is independently selected from Br. In some embodiments, each R 10 Independently selected from I.

[0098] In some embodiments, each R 10 Independently selected from C1-C6 alkyl optionally substituted with a substituent independently selected from 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. In some embodiments, for example, including but not limited to, each R 10 Independently selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CH3, CF2CF3, CH2CN, CH2OH, CH2OCH3, etc.

[0099] In some embodiments, each R 10 Independently selected from C3-C7 cycloalkyl optionally substituted by substituents independently selected from 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.

[0100] In some embodiments, each R 10 Independently selected from 4-7 membered heterocyclyl optionally substituted by substituents independently selected from 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.

[0101] In some embodiments, each R 10 Independently selected from OR A In some embodiments, for example, including but not limited to, each R 10 Independently selected from OH, OCH3, OCH2F, OCHF2, OCF3.

[0102] In some embodiments, each R 10 Independently selected from NR C R D .

[0103] In some embodiments, two adjacent R 10 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independently selected R 13 substituted by a substituent.

[0104] In some embodiments, two adjacent R 10 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl is optionally substituted by 1, 2, or 3 independently selected R 13 substituted by a substituent.

[0105] In some embodiments, two adjacent R 10 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group optionally substituted by 1, 2, or 3 members independently selected from R 13 substituted by a substituent.

[0106] In some embodiments, Ar 2 Selected from C6-C 10 Aryl is optionally substituted by r independently selected from R 11 substituted by a substituent.

[0107] In some embodiments, Ar 2 phenyl, naphthyl; each substituent is optionally substituted by r independently selected from R 11 substituted by a substituent.

[0108] In some embodiments, Ar 2is selected from phenyl optionally substituted by r independently selected from R 11 substituted by a substituent.

[0109] In some embodiments, Ar 2 Selected from 5-10 membered heteroaryl optionally substituted by r independently selected from R 11 substituted by a substituent.

[0110] In some embodiments, Ar 2selected from 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, indolizinyl, benzofu Pyrrolol[3,2-b]pyridinyl, pyrrolol[3,2-c]pyridinyl, pyrrolol[2,3-c]pyridinyl, pyrrolol[2,3-b]pyridinyl, pyrrolol[3,4-b]pyridinyl, pyrrolol[3,4-c]pyridinyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furo[3,2-b]pyridinyl, furo[3,2-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-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c 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, imidazole imidazo[1,2-b][1,2,4]thiadiazolyl, thiazo[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 replaced by r independently selected from R, 11 substituted by a substituent.

[0111] In some embodiments, r is 1.

[0112] In some embodiments, r is 2.

[0113] In some embodiments, r is 3.

[0114] In some embodiments, r is 4.

[0115] In some embodiments, each R 11 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 ORF ,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 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted by a substituent.

[0116] In some embodiments, each R 11 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 ,S(O)(=NR B )R B , S(O)R B , S(O)NR C R D , S(O)2R B ,NR C S(O)2RB , 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 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted by a substituent.

[0117] In some embodiments, each R 11 independently selected from H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-Cy 1 , OR A ,SF5,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 ,NR C C(O)OR A ,S(O)(=NR B )R B , 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 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14substituted by a substituent.

[0118] In some embodiments, each R 11 independently selected from H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-Cy 1 , OR A , SF5, NR 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 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted by a substituent.

[0119] In some embodiments, each R 11 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-Cy 1 , OR A , SF5; wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted by a substituent.

[0120] In some embodiments, each R 11 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

[0121] In some embodiments, each R 11 independently selected from H, D, halogen, CN, C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

[0122] In some embodiments, each R 11 are independently selected from H. In some embodiments, each R 11 are independently selected from D. In some embodiments, each R 11 In some embodiments, each R 11 Independently selected from CN.

[0123] In some embodiments, each R 11 independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 In some embodiments, for example, including but not limited to, each R 11 Independently selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH, CH(OH)CH3, CH2OCH3, CH2CH2OCH3, CH2CN, CH2CH2CN, etc.

[0124] In some embodiments, two adjacent R 11 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl is optionally substituted by 1, 2, or 3 independently selected R 13 substituted by a substituent.

[0125] In some embodiments, two adjacent R 11 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group optionally substituted by 1, 2, or 3 members independently selected from R 13 substituted by a substituent.

[0126] In some embodiments, R 1 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 independently selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0127] In some embodiments, R 1 In some embodiments, R 1 is D. In some embodiments, R 1 For H.

[0128] In some embodiments, R 1 C2-C3 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, halogen, CN, OH, -O-C1-C3 alkyl, and -OC1-C3 haloalkyl.

[0129] In some embodiments, R 1C2-C3 alkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, halogen, CN, OH, -O-C1-C3 alkyl, and -OC1-C3 haloalkyl.

[0130] In some embodiments, R 1 is C1-C3 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl. 1 is CH2CF3. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CH2OMe. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is Et. In some embodiments, R 1 For Me.

[0131] In some embodiments, R 1 and Ar 2 The heterocyclic group, taken together with the atoms to which it is attached, forms a 5-7 membered group and is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0132] In some embodiments, R 1 and Ar 2 The heterocyclic group, taken together with the atoms to which it is attached, forms a 7-membered heterocyclic group, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0133] In some embodiments, R 1 and Ar 2 The heterocyclic group, taken together with the atoms to which it is attached, forms a 6-membered heterocyclic group, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0134] In some embodiments, R 1 and Ar 2The heterocyclic group, taken together with the atoms to which it is attached, forms a 5-membered heterocyclic group, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0135] In some embodiments, R 2 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 are optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0136] In some embodiments, R 2 is H. In some embodiments, R 2 It is D.

[0137] In some embodiments, R 2 Selected from 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 are optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0138] In some embodiments, R 2 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl or phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl, or phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0139] In some embodiments, R 2 Independently selected from C1-C6 alkyl, C2-C6 alkynyl, C 3- C7 cycloalkyl or phenyl, wherein the C1-C6 alkyl, C 3- C7 cycloalkyl, or phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0140] In some embodiments, R 2 is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0141] In some embodiments, R 2 is phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A In some embodiments, R 2 It is a phenyl group.

[0142] In some embodiments, R 2 C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0143] In some embodiments, R 2 is cyclobutyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 2A In some embodiments, R 2 It is cyclobutyl.

[0144] In some embodiments, R 2 is cyclopropyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 2A In some embodiments, R 2 It is cyclopropyl.

[0145] In some embodiments, R 2 is C1-C6 alkyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0146] In some embodiments, R 2 is C1-C6 alkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, NR c R d , C(O)R b , C(O)NR c R d ,NR c C(O)R b ,C(O)OR a or OC(O)R b .

[0147] In some embodiments, R2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, -OC1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, or NR c R d .

[0148] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, -OC1-C6 alkyl, or NR c R d ;

[0149] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, or F.

[0150] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 D. In some embodiments, R 2 is i-C3D7. In some embodiments, R 2 In some embodiments, R 2 It is CD3.

[0151] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is Et. In some embodiments, R 2 For Me.

[0152] In some embodiments, each R 2A 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)ORa ,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 with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)Rb1 , 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 .

[0153] In some embodiments, each R 2A are independently selected from D. In some embodiments, each R 2A In some embodiments, each R 2A In some embodiments, each R 2A In some embodiments, each R 2A In some embodiments, each R 2A are independently selected from oxo.

[0154] In some embodiments, each R 2A independently selected from C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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(=NRc1 )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 .

[0155] In some embodiments, each R 2A independently selected from C2-C6 alkenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)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 .

[0156] In some embodiments, each R 2A independently selected from C2-C6 alkynyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)ORa1 ,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 .

[0157] In some embodiments, each R 2A 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, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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)NRc1 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 .

[0158] In some embodiments, each R 2A 4-10 membered heterocyclic radicals are optionally substituted by 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)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 .

[0159] In some embodiments, each R 2A Independently selected from C6-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, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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)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 .

[0160] In some embodiments, each R 2A Phenyl is independently selected from optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from: D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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 ,NRc1 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 .

[0161] In some embodiments, each R 2A 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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)NRc1 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 .

[0162] In some embodiments, each R 2A 5-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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)Rb1 ,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 .

[0163] In some embodiments, each R 2A 6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 ,C(O)ORa1 ,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 .

[0164] In some embodiments, each R 2A independently selected from 9-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, halogen, CN, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 Rd1 ,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 .

[0165] In some embodiments, each R 2A Independently selected from OR a In some embodiments, each R 2A Independently selected from NR c R d In some embodiments, each R 2A Independently selected from NHOR a In some embodiments, each R 2AIndependently selected from SR a .

[0166] In some embodiments, each R 2A independently selected from C(O)R b In some embodiments, each R 2A Independently selected from C(O)NR c R d In some embodiments, each R 2A Independently selected from NR c C(O)R b In some embodiments, each R 2A Independently selected from C(O)OR a In some embodiments, each R 2A Independently selected from OC(O)R b .

[0167] In some embodiments, each R 2A Independently selected from S(O)R b In some embodiments, each R 2A Independently selected from S(O)NR c R d In some embodiments, each R 2A Independently selected from S(O)2R b In some embodiments, each R 2A Independently selected from NR c S(O)2R b In some embodiments, each R 2A Independently selected from S(O)2NR c R d .

[0168] In some embodiments, R 1 and R 2 and the atoms to which they are attached form a 5-7 membered heterocyclic radical optionally substituted by 1, 2, 3 or 4 substituents independently selected from: D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0169] In some embodiments, R 1 and R 2and the atoms to which they are attached form a 7-membered heterocyclic radical optionally substituted by 1, 2, 3 or 4 substituents independently selected from: D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0170] In some embodiments, R 1 and R 2 and the atoms to which they are attached form a 5-membered heterocyclic radical optionally substituted by 1, 2, 3 or 4 substituents independently selected from: D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0171] In some embodiments, R 1 and R 2 and the atoms to which they are attached form a 6-membered heterocyclic radical optionally substituted by 1, 2, 3 or 4 substituents independently selected from: D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

[0172] In some embodiments, each R 3 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 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)RB wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0173] In some embodiments, each R 3 independently selected from H, D, CN, C1-C6 alkyl, C0-C6 alkyl-Cy 1 , OR A ,NR C R D , C(O)NR C R D ,NR C C(O)R D , or OC(O)R B , wherein the C1-C6 alkyl group is optionally replaced by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0174] In some embodiments, each R 3 are independently selected from H. In some embodiments, each R 3 are independently selected from D. In some embodiments, each R 3 Independently selected from CN.

[0175] In some embodiments, each R 3 independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

[0176] In some embodiments, each R 3 Independently selected from C0-C6 alkyl-Cy 1 .

[0177] In some embodiments, each R 3 Independently selected from OR A In some embodiments, for example, including but not limited to, each R 3 Independently selected from OH, OCH3.

[0178] In some embodiments, each R 3 Independently selected from NR C R D In some embodiments, each R 3 Independently selected from C(O)NR C R D In some embodiments, each R 3 Independently selected from NR CC(O)R D In some embodiments, each R 3 Independently selected from OC(O)R B .

[0179] In some embodiments, each R 4 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 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 C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0180] In some embodiments, each R 4 independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 independently selected R 12 substituted by a substituent.

[0181] In some embodiments, each R 4 are independently selected from H. In some embodiments, each R 4 Independently selected from D.

[0182] In some embodiments, each R 4 independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

[0183] In some embodiments, each R 4 independently selected from C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R12 substituted by a substituent.

[0184] In some embodiments, each R 4 independently selected from C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

[0185] In some embodiments, each R 4 independently selected from C(O)R B In some embodiments, each R 4 Independently selected from C(O)NR C R D In some embodiments, each R 4 Independently selected from NR C C(O)R D In some embodiments, each R 4 Independently selected from C(O)OR A In some embodiments, each R 4 Independently selected from OC(O)R B .

[0186] In some embodiments, R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-, -C(S)-, C3-C7 cycloalkyl, or 4-7 membered heterocyclyl; wherein the C3-C7 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl.

[0187] In some embodiments, R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-, or -C(S)-. In some embodiments, R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-.

[0188] In some embodiments, R 3 and R 4 Together with the carbon atom to which it is attached it forms a C3-C7 cycloalkyl group which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0189] In some embodiments, R 3 and R 4The heterocyclic group formed together with the carbon atom to which it is attached to form a 4-7 membered group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0190] In some embodiments, R of adjacent carbon atoms 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0191] In some embodiments, R on adjacent carbon atoms 3 and R 4 Together with the carbon atom to which it is attached it forms a C3-C7 cycloalkyl group which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0192] In some embodiments, R on adjacent carbon atoms 3 and R 4 The heterocyclic group formed together with the carbon atom to which it is attached to form a 4-7 membered group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0193] In some embodiments, R on adjacent carbon atoms 3 and R 4 Together with the carbon atom to which it is attached, it forms a C6-C 10 Aryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0194] In some embodiments, R on adjacent carbon atoms 3 and R 4 The 5-10 membered heteroaryl group, taken together with the carbon atom to which it is attached, is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0195] In some embodiments, each R 5 Independently selected from H, D, halogen, CN, OR A , 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 independently selected R 12 substituted by a substituent.

[0196] In some embodiments, each R 5 Independently selected from H, D, halogen, CN, OR A , C1-C6 alkyl, or C0-C6 alkyl-Cy 1 , wherein the C1-C6 alkyl group is optionally replaced by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0197] In some embodiments, each R 6 Independently selected from H, D, halogen, CN, OR A , 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 independently selected R 12 substituted by a substituent.

[0198] In some embodiments, each R 6 Independently selected from H, D, halogen, CN, OR A , C1-C6 alkyl, or C0-C6 alkyl-Cy 1 , wherein the C1-C6 alkyl group is optionally replaced by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0199] In some embodiments, R on adjacent carbon atoms 3 and R 5 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, or C1-C6 alkyl-NR c R d .

[0200] In other embodiments, R on adjacent carbon atoms 3 and R 6 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

[0201] In some embodiments, R on adjacent carbon atoms 4 and R 5 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

[0202] In other embodiments, R on adjacent carbon atoms 4 and R 6 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10Aryl or 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

[0203] In some embodiments, R 3 , R 4 , R 5 and R 6 Together with the carbon atom it is connected to, it forms a C6-C 10 Aryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a ,NR c R d , C(O)R b , C(O)NR c R d ,NR c C(O)R b ,NR c S(O)2R b , S(O)2NR c R d , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OR a , C1-C6 haloalkyl-OR a , C1-C6 alkyl-NR c R d .

[0204] In some embodiments, R 3 , R 4 , R 5 and R 6 Together with the carbon atoms to which it is connected, a 5-10 membered heteroaryl group is formed, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a ,NR c R d , C(O)R b , C(O)NRc R d ,NR c C(O)R b ,NR c S(O)2R b , S(O)2NR c R d , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OR a , C1-C6 haloalkyl-OR a , C1-C6 alkyl-NR c R d .

[0205] In some embodiments, R 7 Selected from H, D, CN, OR A , C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein, the C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by at least one substituent independently selected from the following: D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0206] In some embodiments, R 7 is H. In some embodiments, R 7 is D. In some embodiments, R 7 In some embodiments, R 7 OR A In some embodiments, R 7 is C1-C6 alkyl optionally substituted by a substituent independently selected from the group consisting of D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R 7 is -C1-C6 alkyl-C3-C7 cycloalkyl optionally substituted by a substituent independently selected from the group consisting of D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R 7-C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0207] In some embodiments, R 7 and R 5 The heterocyclic group which, together with the atoms to which it is attached, forms a 5-7 membered partially saturated group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0208] In other embodiments, R 7 and R 6 The heterocyclic group which, together with the atoms to which it is attached, forms a 5-7 membered partially saturated group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0209] In some embodiments, R 8 Selected from H, D, CN, OR A ,C(O)OR A , C(O)R B , C(O)NR C R D , S(O)R B , S(O)NR C R D , S(O)2R B , S(O)2NR C R D , C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0210] In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 In some embodiments, R 8 OR A In some embodiments, R 8C(O)OR A In some embodiments, R 8 C(O)R B In some embodiments, R 8 C(O)NR C R D In some embodiments, R 8 S(O)R B In some embodiments, R 8 S(O)NR C R D In some embodiments, R 8 is S(O)2R B In some embodiments, R 8 S(O)2NR C R D .

[0211] In some embodiments, R 8 Selected from C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally replaced by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0212] In some embodiments, R 8 Selected from C0-C6 alkyl-Cy 1 .

[0213] In some embodiments, R 8 Selected from Cy 1 In some embodiments, R 8 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, each ring is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, R 8 Selected from cyclopropyl, cyclobutyl, phenyl, pyridyl.

[0214] In some embodiments, R 8 C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 In some embodiments, for example, including but not limited to, R 8It is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2CH2OH, CH2CH2OCH3, etc.

[0215] In some embodiments, R 8 is C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent.

[0216] In some embodiments, R 8 is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

[0217] In some embodiments, R 3 and R 8 or R 4 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

[0218] In some embodiments, R 3 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

[0219] In other embodiments, R 4 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

[0220] In some embodiments, R 8 , R 3 and R 4 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

[0221] In some embodiments, R 7 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

[0222] In some embodiments, R 9Selected from phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein the phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by substituents independently selected from the following: D, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0223] In some embodiments, R 9 Phenyl is optionally substituted with substituents independently selected from the group consisting of D, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0224] In some embodiments, R 9 C1-C6 alkyl is optionally substituted by substituents independently selected from the group consisting of D, halogen, CN, OH, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, and -OC1-C6 haloalkyl.

[0225] In some embodiments, R 9 -C1-C6alkyl-C3-C7cycloalkyl is optionally substituted by substituents independently selected from the group consisting of D, halogen, CN, OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkyl-OH, -O-C1-C6alkyl, -OC1-C6haloalkyl.

[0226] In some embodiments, R 9 -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by substituents independently selected from the group consisting of D, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, and -OC1-C6 haloalkyl.

[0227] In some embodiments, each R 12 D is independently selected from the group consisting of 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 , or NR c S(O)(=NR b )R b .

[0228] In some embodiments, R 12 is D. In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 is C1-C6 haloalkyl. 12 In some embodiments, R 12In some embodiments, R 12 is NO2. In some embodiments, R 12 In some embodiments, R 12 OR a In some embodiments, R 12 SR a In some embodiments, R 12 In some embodiments, R 12 For NHOR a 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 C(=NR c )NR c R d In some embodiments, R 12 NR d C(=NR c )NR c R d In some embodiments, R 12 NR d C(=NR c )R bIn some embodiments, R 12 OP(O)OR e OR f In some embodiments, R 12 P(O)OR e OR f In some embodiments, R 12 S(O)(=NR b )R b In some embodiments, R 12 S(O)R b In some embodiments, R 12 S(O)NR c R d In some embodiments, R 12 is S(O)2R b In some embodiments, R 12 NR c S(O)2R b In some embodiments, R 12 S(O)2NR c R d In some embodiments, R 12 NR c S(O)2NR c R d In some embodiments, R 12 NR c S(O)(=NR b )R b .

[0229] In some embodiments, R 13 D is independently selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6-cyanoalkyl, CN, NO2, oxo, OR a , SR 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 b ,NR c C(O)NR c R d ,NR cC(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 ,NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0230] In some embodiments, R 13 is D. In some embodiments, R 13 is halogen (eg, F, Cl, Br, I). In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 is C1-C6 haloalkyl. 13 In some embodiments, R 13 In some embodiments, R 13 is NO2. In some embodiments, R 13 In some embodiments, R 13 OR a In some embodiments, R 13 SR a In some embodiments, R 13 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 13OC(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 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 is S(O)2R b In some embodiments, R 13 NR c S(O)2R b In some embodiments, R 13 S(O)2NR c R d In some embodiments, R 13 NR c S(O)2NR c R d In some embodiments, R 13 NR c S(O)(=NR b )R b .

[0231] 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, C6- C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 substituted by a substituent.

[0232] In some embodiments, Cy 1 C 3- C 10 Cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 substituted by a substituent.

[0233] In some embodiments, Cy 1 is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 substituted by a substituent.

[0234] In some embodiments, Cy 1 C 6- C 10 Aryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 substituted by a substituent.

[0235] In some embodiments, Cy 1 is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 14 substituted by a substituent.

[0236] In some embodiments, R 14 D is independently selected from the group consisting of 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.

[0237] 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 In some embodiments, R 14 is C1-C6 haloalkyl. 14 In some embodiments, R 14 In some embodiments, R 14 C3-C 10 In some embodiments, R 14 is a 5-10 membered heteroaryl. 14 It is a 4-10 membered heterocyclic group.

[0238] In some embodiments, R 14In some embodiments, R 14 is NO2. In some embodiments, R 14 In some embodiments, R 14 OR a In some embodiments, R 14 SR a In some embodiments, R 14 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 bIn some embodiments, R 14 OP(O)OR e OR f In some embodiments, R 14 P(O)OR e OR f In some embodiments, R 14 S(O)(=NR b )R b 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 is S(O)2R b In some embodiments, R 14 NR c S(O)2R b In some embodiments, R 14 S(O)2NR c R d In some embodiments, R 14 NR c S(O)2NR c R d In some embodiments, R 14 NR c S(O)(=NR b )R b .

[0239] In some embodiments, each R A independently selected from H, D, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C0-C6 alkyl-Cy 2 , wherein the C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally replaced by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0240] In some embodiments, each R A is H. In some embodiments, each R A It is D.

[0241] In some embodiments, each R A is C1-C6 alkyl optionally substituted by 1, 2, or 3 independently selected from R 15 substituted by a substituent.

[0242] In some embodiments, each R Ais C2-C4 alkenyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0243] In some embodiments, each R A is C2-C4 alkynyl optionally substituted by 1, 2, or 3 independently selected from R 15 substituted by a substituent.

[0244] In some embodiments, each R A C0-C6 alkyl-Cy 2 .

[0245] In some embodiments, R B independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-Cy 2 , wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0246] In some embodiments, R B is H. In some embodiments, R B It is D.

[0247] In some embodiments, R B is C1-C6 alkyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0248] In some embodiments, R B is C2-C6 alkenyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0249] In some embodiments, R B is C2-C6 alkynyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0250] In some embodiments, R B C0-C6 alkyl-Cy 2 .

[0251] In some embodiments, R C independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-Cy 2 wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0252] In some embodiments, R C is H. In some embodiments, R C It is D.

[0253] In some embodiments, R C is C1-C6 alkyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0254] In some embodiments, R C is C2-C6 alkenyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0255] In some embodiments, R C is C2-C6 alkynyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0256] In some embodiments, R C C0-C6 alkyl-Cy 2 .

[0257] In some embodiments, R D independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-Cy 2 wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

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

[0259] In some embodiments, R D is C1-C6 alkyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0260] In some embodiments, R D is C2-C6 alkenyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0261] In some embodiments, R D is C2-C6 alkynyl optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0262] In some embodiments, RD C0-C6 alkyl-Cy 2 .

[0263] In some embodiments, 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 independently 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.

[0264] In some embodiments, R E 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.

[0265] In some embodiments, R E is H. In some embodiments, R E It is D.

[0266] In some embodiments, R E In some embodiments, R E is C1-C4 haloalkyl. In some embodiments, R E In some embodiments, R E In some embodiments, R E In some embodiments, R E C6-C 10 In some embodiments, R E is a 5-10 membered heteroaryl. E C3-C 10 In some embodiments, R E In some embodiments, R E C6-C 10Aryl-C1-C4 alkyl. In some embodiments, R E C3-C 10 In some embodiments, R E is a 5-10 membered heteroaryl-C1-C4 alkyl. E It is a 4-10 membered heterocyclyl-C1-C4 alkyl group.

[0267] In some embodiments, R F 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.

[0268] In some embodiments, R F is H. In some embodiments, R F is D. In some embodiments, R F In some embodiments, R F In some embodiments, R F is a C2-C4 alkynyl group. 10 In some embodiments, R F is a 5-10 membered heteroaryl. F C3-C 10 In some embodiments, R F It is a 4-10 membered heterocyclic group.

[0269] In some embodiments, each R a are independently selected from H. In some embodiments, each R a Independently selected from D.

[0270] In some embodiments, each R a independently selected from 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 independently 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.

[0271] In some embodiments, each R b are independently selected from H. In some embodiments, each R b Independently selected from D.

[0272] In some embodiments, each R b independently selected from 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 is optionally substituted with 1, 2, or 3 substituents independently 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, and C1-C4 haloalkoxy.

[0273] In some embodiments, each R a1 are independently selected from H. In some embodiments, each R a1 Independently selected from D.

[0274] In some embodiments, each R a1 independently selected from 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 independently 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.

[0275] In some embodiments, each R b1 are independently selected from H. In some embodiments, each R b1 Independently selected from D.

[0276] In some embodiments, each R b1independently selected from 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 is optionally substituted with 1, 2, or 3 substituents independently 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, and C1-C4 haloalkoxy.

[0277] In some embodiments, each R c 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 independently 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-.

[0278] In some embodiments, each R d 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 independently 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-.

[0279] In some embodiments, each R c1 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 independently 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-.

[0280] In some embodiments, each R d1 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 independently 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)Rb1 , S(O)2R b1 , C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-.

[0281] In some embodiments, 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 independently 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.

[0282] In some embodiments, 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 independently 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.

[0283] In some embodiments, each R e 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.

[0284] In some embodiments, each R findependently 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.

[0285] In some embodiments, each 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.

[0286] In some embodiments, each 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.

[0287] In some embodiments, Cy 2 Independently selected from C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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 independently selected R 15 substituted by a substituent.

[0288] In some embodiments, Cy 2 C 3- C7 cycloalkyl is optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0289] In some embodiments, Cy 2 is a 4-7 membered heterocyclic group optionally substituted by 1, 2, or 3 members independently selected from R 15 substituted by a substituent.

[0290] In some embodiments, Cy 2 is phenyl optionally substituted by 1, 2, or 3 independently selected from R 15 substituted by a substituent.

[0291] In some embodiments, Cy 2 is a 5-6 membered heteroaryl group optionally substituted by 1, 2, or 3 independently selected R 15 substituted by a substituent.

[0292] In some embodiments, each R 15 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 Rd , or NR c S(O)(=NR b )R b .

[0293] In some embodiments, R 15 is D. In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 is C1-C4 haloalkyl. In some embodiments, R 15 It is a C1-C4 cyanoalkyl group.

[0294] In some embodiments, R 15 is NO2. In some embodiments, R 15 In some embodiments, R 15 OR a In some embodiments, R 15 SR a In some embodiments, R 15 In some embodiments, R 15 For NHOR a In some embodiments, R 15 C(O)R b In some embodiments, R 15 C(O)NR c R d In some embodiments, R 15 C(O)OR a In some embodiments, R 15 OC(O)R b In some embodiments, R 15 OC(O)NR c R d In some embodiments, R 15 NR c R d In some embodiments, R 15 NR c C(O)R b In some embodiments, R 15 NR c C(O)NR c R dIn some embodiments, R 15 NR c C(O)OR a In some embodiments, R 15 B(OR e )(OR f ). In some embodiments, R 15 C(=NR c )NR c R d In some embodiments, R 15 NR d C(=NR c )NR c R d In some embodiments, R 15 NR d C(=NR c )R b In some embodiments, R 15 P(O)R e R f In some embodiments, R 15 P(O)OR e OR f In some embodiments, R 15 OP(O)OR e OR f In some embodiments, R 15 S(O)R b In some embodiments, R 15 S(O)NR c R d In some embodiments, R 15 is S(O)2R b In some embodiments, R 15 NR c S(O)2R b In some embodiments, R 15 S(O)2NR c R d In some embodiments, R 15 NR c S(O)2NR c R d In some embodiments, R 15 NR c S(O)(=NR b )R b .

[0295] In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) is a stereoisomer. In some embodiments, the compound of formula (I) is a solvate. In some embodiments, the compound of formula (I) is an N-oxide of the compound of formula (I).

[0296] In some embodiments, the compound represented by formula (I) is represented by formula (II):

[0297]

[0298] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated form thereof; wherein L, Ar 1 ,Ar 2 , R 1 , R 2 , R 3 and R 4 The definition of is the same as that of formula (I).

[0299] In some embodiments, the compound represented by formula (I) is represented by formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and (IIh):

[0300]

[0301]

[0302] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The definition of is the same as that of formula (I).

[0303] In some embodiments, the compound represented by formula (I) is represented by formula (IIa), (IIb), (IIc), (IId), (IIe) and (IIf):

[0304]

[0305] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9的 The definition is the same as that of formula (I).

[0306] In some embodiments, the compound represented by formula (I) is represented by formula (IIb), (IIc), (IId), and (IIe):

[0307]

[0308]

[0309] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The definition of is the same as that of formula (I).

[0310] In some embodiments, the compound represented by formula (I) is represented by formula (IId), and (IIe):

[0311]

[0312] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The definition of is the same as that of formula (I).

[0313] In some embodiments, the compound represented by formula (I) is represented by formula (IIb), and (IIc):

[0314]

[0315] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 The definition of is the same as that of formula (I).

[0316] In some embodiments, the compound represented by formula (I) is represented by formula (III):

[0317]

[0318] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated form thereof; wherein L, Ar 1 ,Ar 2 R 1 , R 2 , R 3 and R 4 The definition of is the same as that of formula (I).

[0319] In some embodiments, the compound represented by formula (I) is represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg) and (IIIh):

[0320]

[0321] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The definition of is the same as that of formula (I).

[0322] In some embodiments, the compound represented by formula (I) is represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) and (IIIf):

[0323]

[0324] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The definition of is the same as that of formula (I).

[0325] In some embodiments, the compound represented by formula (I) is represented by formula (IIIa), (IIIb), (IIIc) and (IIIf):

[0326]

[0327] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The definition of is the same as that of formula (I).

[0328] In the compounds described by formula (IIIa), (IIIb), (IIIc) and (IIIf), each R 1 is 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 1-3 substituents independently selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl. In some embodiments, R 1 is H, D, or CN. In some embodiments, R 1is C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, wherein the C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl is optionally substituted by 1-3 substituents independently selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl. In some embodiments, R 1 is C1-C3 alkyl optionally substituted by 1-3 substituents independently selected from the group consisting of D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl. 1 In some embodiments, R 1 is D. In some embodiments, R 1 For H.

[0329] In some embodiments, the compound represented by formula (I) is represented by formula (IVa), (IVb), (IVc) and (IVf):

[0330]

[0331] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The definition of is the same as that of formula (I).

[0332] In some embodiments, the compound represented by formula (I) is represented by formula (Va), (Vb), (Vc) and (Vf):

[0333]

[0334] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The definition of is the same as that of formula (I).

[0335] In some embodiments, the compound represented by formula (I) is represented by formula (VIa), (VIb), (VIc) and (VIf):

[0336]

[0337] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 1 ,Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The definition of is the same as that of formula (I).

[0338] In some embodiments, in the formulas (VIa), (VIb), (VIc) and (VIf), Ar 1 Each independently selected from C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by m independently selected R 10 In some embodiments, Ar 1 C6-C 10 Aryl is optionally substituted by m independently selected from R 10 In some embodiments, Ar 1 is a 5-10 membered heteroaryl group optionally substituted by m independently selected R 10 In some embodiments, Ar 1 is pyrimidinyl optionally substituted by m independently selected R 10 In some embodiments, Ar 1 is pyridyl optionally substituted by m independently selected R 10 substituted by a substituent.

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

[0340]

[0341] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R8 , R 10 and m are defined the same as in formula (I).

[0342] In some embodiments, in Formula (VIIa), (VIIb), or (VIIc), each R 10 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 optionally substituted by substituents independently 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.

[0343] In some embodiments, each R 10 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 ,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 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 optionally substituted by substituents independently 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.

[0344] In some embodiments, each R 10 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, NR C R D ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by substituents independently 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.

[0345] In some embodiments, each R 10Independently selected from H, D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, SF5; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by substituents independently 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.

[0346] In some embodiments, each R 10 Independently selected from H, D, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, CN, SF5; wherein, the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by substituents independently 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.

[0347] In some embodiments, each R 10 Independently selected from H, D, halogen, C1-C6 alkyl, CN, SF5; wherein the C1-C6 alkyl is optionally substituted by substituents independently 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.

[0348] In some embodiments, each R 10 independently selected from C1-C6 alkyl optionally substituted by substituents independently selected from the group consisting of D, CN, halogen, OH, NH2, C1-C4 alkyl-OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl. In some embodiments, each R 10 independently selected from C1-C6 alkyl optionally substituted with substituents independently selected from the group consisting of D, CN, halogen, OH, NH2, C1-C4 alkyl-OH, C1-C4 haloalkyl, -O-C1-C4 alkyl. In some embodiments, each R 10 independently selected from C1-C6 alkyl optionally substituted with a substituent independently selected from: D or halogen. In some embodiments, each R 10 Independently selected from H, D, CN, halogen, C1-C6 alkyl and C1-C6 haloalkyl.

[0349] In some embodiments, each R10 are independently selected from H. In some embodiments, each R 10 are independently selected from D. In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 In some embodiments, each R 10 Independently selected from CF3.

[0350] In some embodiments, in Formula (VIIa), (VIIb), or (VIIc), R 2 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 are optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A Substituents substituted;

[0351] Every R 2A 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 with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)2R b1 ,NR c1 S(O)2R b1 , S(O)2NR c1 R d1 ,NR c1 S(O)2NR c1 Rd1 ,NR c1 S(O)(=NR b1 )R b1 ;

[0352] In some embodiments, R 2 is H. In some embodiments, R 2 It is D.

[0353] In some embodiments, R 2 independently selected from 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 are optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0354] In some embodiments, R 2 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl or phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3- C7 cycloalkyl, or phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0355] In some embodiments, R 2 Independently selected from C1-C6 alkyl, C2-C6 alkynyl, C 3- C7 cycloalkyl or phenyl, wherein the C1-C6 alkyl, C 3- C7 cycloalkyl, or phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0356] In some embodiments, R 2 is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0357] In some embodiments, R 2 is phenyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A In some embodiments, R 2 It is a phenyl group.

[0358] In some embodiments, R 2 C3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0359] In some embodiments, R 2 is cyclobutyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 2A In some embodiments, R 2 It is cyclobutyl.

[0360] In some embodiments, R 2 is cyclopropyl optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 2A In some embodiments, R 2 It is cyclopropyl.

[0361] In some embodiments, R 2 is C1-C6 alkyl optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2A substituted by a substituent.

[0362] In some embodiments, R 2 is C1-C6 alkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, NR c R d , C(O)R b , C(O)NR c R d ,NR c C(O)R b ,C(O)OR a or OC(O)R b .

[0363] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, -OC1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, or NR c R d .

[0364] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, halogen, CN, -OC1-C6 alkyl, or NR c Rd ;

[0365] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, or F.

[0366] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 D. In some embodiments, R 2 is i-C3D7. In some embodiments, R 2 In some embodiments, R 2 It is CD3.

[0367] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is Et. In some embodiments, R 2 For Me.

[0368] In some embodiments, each R 2A 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-C10 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, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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)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 .

[0369] In some embodiments, each R 2A are independently selected from D. In some embodiments, each R 2A In some embodiments, each R 2A In some embodiments, each R 2A In some embodiments, each R 2A In some embodiments, each R 2A are independently selected from oxo.

[0370] In some embodiments, each R 2A independently selected from C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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 )Rb1 , 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 .

[0371] In some embodiments, each R 2A independently selected from C2-C6 alkenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)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 .

[0372] In some embodiments, each R 2A independently selected from C2-C6 alkynyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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)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 .

[0373] In some embodiments, each R 2A 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, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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 )Rb1 ,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 .

[0374] In some embodiments, each R 2A Independently selected from 4-10 membered heterocyclic groups optionally substituted by 1, 2, 3, 4 or 5 substituents independently 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 heterocyclic group, 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 ,NRd1 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 .

[0375] In some embodiments, each R 2A Independently selected from C6-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, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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(=NRc1 )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 .

[0376] In some embodiments, each R 2A 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, NO2, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C7 cycloalkyl, 4-7 membered heterocyclic group, 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 Rd1 ,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 .

[0377] In some embodiments, each R 2A Independently selected from OR a In some embodiments, each R 2A Independently selected from NR c R d In some embodiments, each R 2A Independently selected from NHOR a In some embodiments, each R 2A Independently selected from SR a .

[0378] In some embodiments, each R 2A independently selected from C(O)R b In some embodiments, each R 2A Independently selected from C(O)NR c R d In some embodiments, each R 2A Independently selected from NR c C(O)R b In some embodiments, each R 2A Independently selected from C(O)OR a In some embodiments, each R 2AIndependently selected from OC(O)R b .

[0379] In some embodiments, each R 2A Independently selected from S(O)R b In some embodiments, each R 2A Independently selected from S(O)NR c R d In some embodiments, each R 2A Independently selected from S(O)2R b In some embodiments, each R 2A Independently selected from NR c S(O)2R b In some embodiments, each R 2A Independently selected from S(O)2NR c R d .

[0380] In some embodiments, the compound represented by formula (I) is represented by formula (VIIIa), (VIIIb), and (VIIIc):

[0381]

[0382] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 10 The definition of is the same as that of formula (I).

[0383] In some embodiments, in Formula (VIIIa), (VIIIb), or (VIIIc), R 10 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, NR C R D ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by substituents independently 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.

[0384] In some embodiments, R 10 Independently selected from H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6-cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, CN, SF5; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted by substituents independently 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.

[0385] In some embodiments, R 10 Independently selected from H, D, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, CN, SF5; wherein the C1-C6 alkyl, or C3-C7 cycloalkyl is optionally substituted by substituents independently 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.

[0386] In some embodiments, R 10 is H, D, SF5 or CN. In some embodiments, R 10 For SF5. 在 In some embodiments, R 10 In some embodiments, R 10 is D. In some embodiments, R 10 For H.

[0387] In some embodiments, in Formula (VIIIa), (VIIIb), or (VIIIc), Ar 2 Independently selected from C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by r independently selected from R 11 In some embodiments, Ar 2 is a 5-10 membered heteroaryl group optionally substituted by r independently selected from R 11 In some embodiments, Ar 2 C6-C 10 Aryl is optionally substituted by r independently selected from R 11 substituted by a substituent.

[0388] In some embodiments, the compound of formula (I) is represented by formula (IXa), (IXb), and (IXc):

[0389]

[0390] or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterate thereof; wherein each Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 The definition of is the same as that of formula (I).

[0391] In some embodiments, in Formula (IXa), (IXb), or (IXc), each R 3 and R 4 independently selected from H, D, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 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 C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 12 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0392] In some embodiments, each R 3 and R 4 independently selected from 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 independently selected R 12 Substituents substituted by: Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R14 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0393] In some embodiments, each R 3 and R 4 independently selected from C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 wherein each R 12 The definition of is the same as that of formula (I).

[0394] In some embodiments, each R 3 and R 4 Independently selected from C0-C6 alkyl-Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 14 The same definition as in formula (I). In some embodiments, Cy 1 C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 is a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 wherein each R 14 The definition of is the same as that of formula (I).

[0395] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 independently selected from 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 independently selected from the following R 12 Substituents substituted, Cy 1Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0396] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted with a substituent, wherein each R 12 The definition of is the same as that of formula (I).

[0397] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 independently selected from C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted with a substituent, wherein each R 12 The definition of is the same as that of formula (I).

[0398] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 independently selected from C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted with a substituent, wherein each R 12 The definition of is the same as that of formula (I).

[0399] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 Independently selected from C0-C6 alkyl-Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 14 The same definition as in formula (I). In some embodiments, Cy 1 C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 is a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 wherein each R 14 The definition of is the same as that of formula (I).

[0400] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 Independently selected from C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 substituted with a substituent, wherein each R 14 The definition of is the same as that of formula (I).

[0401] In some embodiments, assuming that one of the R 3 or R 4 is H, the remaining R 3 or R 4 independently selected from 4-7 membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 14 The definition of is the same as that of formula (I).

[0402] In some embodiments, R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-, -C(S)-, C3-C7 cycloalkyl, or 4-7 membered heterocyclyl; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0403] In some embodiments, each R 3 and R 4 In some embodiments, R 3 and R 4 are H or D. In some embodiments, R 3 and R 4 In some embodiments, R 3 and R 4 Both are H.

[0404] In some embodiments, in Formula (IXb), each R 5 and R 6 independently selected from H, D, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C0-C6 alkyl-Cy 1 , wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0405] In some embodiments, each R 5 and R 6 independently selected from C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 wherein each R 12 The definition of is the same as that of formula (I).

[0406] In some embodiments, each R 5 and R 6 C0-C6 alkyl-Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted with a substituent, wherein each R 14 The same definition as in formula (I). In some embodiments, Cy 1 C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 is a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 wherein each R 14 The definition of is the same as that of formula (I).

[0407] In some embodiments, assuming that one of the R5 or R 6 is H, the remaining R 5 or R 6 independently selected from 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 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0408] In some embodiments, assuming that one of the R 5 or R 6 is H, the remaining R 5 or R 6 independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted with a substituent, wherein each R 12 The definition of is the same as that of formula (I).

[0409] In some embodiments, assuming that one of the R 5 or R 6 is H, the remaining R 5 or R 6 independently selected from C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted with a substituent, wherein each R 12 The definition of is the same as that of formula (I).

[0410] In some embodiments, assuming that one of the R 5 or R 6 is H, the remaining R 5 or R 6 independently selected from C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted with a substituent, wherein each R 12 The definition of is the same as that of formula (I).

[0411] In some embodiments, assuming that one of the R 5 or R 6 is H, the remaining R 5 or R 6 Independently selected from C0-C6 alkyl-Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R14 wherein each R 14 The same definition as in formula (I). In some embodiments, Cy 1 C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl, or 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 is a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 wherein each R 14 The definition of is the same as that of formula (I).

[0412] In some embodiments, assuming that one of the R 5 or R 6 is H, the remaining R 5 or R 6 Independently selected from C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 substituted with a substituent, wherein each R 14 The definition of is the same as that of formula (I).

[0413] In some embodiments, assuming that one of the R 5 or R 6 is H, the remaining R 5 or R 6 independently selected from 4-7 membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 14 substituted with a substituent, wherein each R 14 The definition of is the same as that of formula (I).

[0414] In some embodiments, R 5 and R 6 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group; wherein the C3-C7 cycloalkyl group, or the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NRc R d .

[0415] In some embodiments, R 3 and R 5 、R 4 and R 5 、R 3 and R 6 or R 4 and R 6 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl, wherein the C3-C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

[0416] In some embodiments, R 3 , R 4 , R 5 and R 6 Together with the carbon atom it is connected to, it forms a C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

[0417] In some embodiments, each R 5 and R 6 are independently selected from H, D, or CN. In some embodiments, R 5 and R 6 are H, or D. In some embodiments, R 5 and R 6 In some embodiments, R 5 and R 6 Both are H.

[0418] In some embodiments, in the formula (IXc), R 8Independently selected from H, D, CN, OR A ,C(O)OR A , C(O)R B , C(O)NR C R D , S(O)R B , S(O)NR C R D , S(O)2R B , S(O)2NR C R D , C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0419] In some embodiments, in the formula (IXc), R 8 Independently selected from H, D, CN, OR A ,C(O)OR A , C(O)R B , C(O)NR C R D , S(O)R B , S(O)NR C R D , S(O)2R B , S(O)2NR C R D .

[0420] In some embodiments, in the formula (IXc), R 8 Independently selected from C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 Substituents substituted, Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 wherein each R 12 and R 14 The definition of is the same as that of formula (I).

[0421] In some embodiments, in the formula (IXc), R 8 independently selected from C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 wherein each R 12 The definition of is the same as that of formula (I).

[0422] In some embodiments, in the formula (IXc), R 8 C0-C6 alkyl-Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted with a substituent, wherein each R 14 The same definition as in formula (I). In some embodiments, Cy 1 Selected from C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclic group; wherein the C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 14 In some embodiments, Cy 1 C 3- C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1为 C 6- C 10 Aryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 14 In some embodiments, Cy 1 is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 14 wherein each R 14 The definition of is the same as that of formula (I).

[0423] In some embodiments, in the formula (IXc), R 3 and R 8 or R 4 and R 8Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted with a substituent, wherein each R 13 The definition of is the same as that of formula (I).

[0424] In some embodiments, in the formula (IXc), R 3 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted with a substituent, wherein each R 13 The definition of is the same as that of formula (I).

[0425] In other embodiments, in the formula (IXc), R 4 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted with a substituent, wherein each R 13 The definition of is the same as that of formula (I).

[0426] In some embodiments, in the formula (IXc), R 8 、R 3 and R 4 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted with a substituent, wherein each R 13 The definition of is the same as that of formula (I).

[0427] The present invention also contemplates, describes and encompasses stereoisomers, pharmaceutical salts and solvates of the compound of Formula I. The present invention also describes uses of the compound of Formula I and pharmaceutical compositions thereof.

[0428] In some embodiments, the compound represented by formula (I) is:

[0429]

[0430] or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, the compound represented by formula (I) is:

[0432]

[0433]

[0434] or a pharmaceutically acceptable salt thereof.

[0435] 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.

[0436] The present invention also provides a method for treating and / or preventing a patient with a cancer having overexpressed PolQ, comprising: administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.

[0437] 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 MMEJDSB repair, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.

[0438] 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 or pharmaceutical composition of the present invention.

[0439] 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 or pharmaceutical composition of the present invention to the patient.

[0440] The present invention also provides a method for treating and / or preventing cancer, wherein the cancer has received or not received PARPi drug treatment and is resistant to PARPi treatment, comprising: administering a therapeutically effective amount of the compound or pharmaceutical composition of the present invention to the patient.

[0441] 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.

[0442] 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 in which PolQ is overexpressed in a patient.

[0443] 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 diseases that increase dependence on MMEJ-DSB repair.

[0444] 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, reduced or absent expression of HR-related genes.

[0445] The present invention also provides a use of the compound or pharmaceutical composition of the present invention in preparing a drug for treating cancer, wherein the cancer lacks the 53BP1 / Shieldin complex.

[0446] 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, characterized in that the cancer has received or not received PARPi drug treatment and is resistant to PARPi treatment.

[0447] 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.

[0448] definition

[0449] Unless otherwise stated, the following terms have the meanings set out below. Other terms are defined elsewhere throughout the specification.

[0450] 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 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 as "solely," "only," and the like in connection with recitation of claim elements or use of a "negative" limitation.

[0451] At various places in this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes -NR(CR'R")- and -(CR'R")NR-, and it is intended that each form 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" refers to a linked alkylene or arylene group, respectively.

[0452] The term "substituted" means that an atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any number of substitutions, for example, single-, double-, three-, four- or five-substitutions, if such substitutions are permitted. 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.

[0453] The term "Cn-Cm" refers to a range including the stated endpoints, where n and m are integers representing the number of carbon atoms. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. "C0 alkyl" refers to a covalent bond.

[0454] The compounds of the present invention are stable. As used herein, "stable" means that the compound is sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture, and preferably, the compound can be formulated into an efficacious therapeutic agent.

[0455] It should also be understood that certain features of the invention, which, for the sake of clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for the sake of brevity, are described in the context of a single embodiment, may also be provided individually or in any suitable subcombination.

[0456] As used herein, unless otherwise indicated, the term "alkyl", as part of a substituent or other 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, C1-C8 in C1-C8 alkyl 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), etc.

[0457] 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.

[0458] 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.

[0459] As used herein, unless otherwise indicated, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents. Exemplary haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0460] As used in the present invention, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon. In certain embodiments, the aryl group has about 6 to about 20 carbon atoms. In certain embodiments, the aryl group has about 6 to about 14 carbon atoms. In certain embodiments, the aryl group has about 6 to about 10 carbon atoms. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, etc.

[0461] 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, and cycloalkynyl. Cycloalkyl can include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring system, including fused rings, spirocycles, and bridged rings (e.g., bridged bicycloalkyl). In certain embodiments, the 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. The cycloalkyl can also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. The 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 to one or more aromatic rings (e.g., having a common bond with the cycloalkyl), for example, benzo derivatives of pentane, benzo derivatives of pentene, benzo derivatives of hexane, etc. It may be connected to an aromatic ring or a non-aromatic ring of a cycloalkyl group having one or more aromatic rings. One or more ring-forming carbon atoms of the cycloalkyl group may be oxidized, for example, with an oxo or thio substituent. In certain embodiments, the cycloalkyl group is a C3-C7 monocyclic cycloalkyl group. In certain embodiments, the cycloalkyl group is C 4- C 10Spirocyclic or bridged ring cycloalkyl. Exemplary cycloalkyl, include but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, 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 (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantyl (C 10 )wait.

[0462] The term "spirocycloalkyl" 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.

[0463] As used herein, unless otherwise indicated, "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 groups include, but are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, 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, indolinyl, etc. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and further, in some embodiments, 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.

[0464] As used herein, unless otherwise specified, "heterocyclyl" refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated) or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more ring-forming carbon atoms of the heterocyclyl may be replaced by a heteroatom selected from N, O, S, and B; and the ring-forming carbon atoms and heteroatoms of the heterocyclyl may be optionally replaced by one or more oxo or thio (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocyclyl includes monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocyclyl includes monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocyclyls. Heterocyclic groups also include spirocycles 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.

[0465] 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 a fused aromatic ring can be connected through any ring-forming atom, including the ring-forming atoms 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 having 1 or 2 heteroatoms independently selected from N, O, S and B, and having one or more ring atoms substituted with oxo.

[0466] 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, 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.

[0467] In some embodiments, the heterocyclic group 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 heterocyclic group can be attached through any heteroatom or carbon atom thereof, as long as a stable structure is generated. Exemplary heterocyclic groups include, but are not limited to, azepanyl, aziridine, azetidinyl, pyrrolidinyl, dioxolane, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxane, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, etc.

[0468] 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 of which is selected from heterocyclyl, and the two rings share one carbon atom.

[0469] As used herein, unless otherwise specified, "arylcycloalkyl" refers to a cycloalkyl group substituted with an aryl group.

[0470] As used herein, unless otherwise specified, "arylheterocyclyl" refers to a heterocyclyl group substituted with an aryl group.

[0471] As used herein, unless otherwise specified, "arylheteroaryl" refers to a heteroaryl group substituted with an aryl group.

[0472] As used herein, unless otherwise specified, "biaryl" refers to an aryl group substituted with an aryl group.

[0473] As used herein, unless otherwise specified, "heteroarylcycloalkyl" refers to a cycloalkyl group substituted with a heteroaryl group.

[0474] As used herein, unless otherwise specified, "heteroarylheterocyclyl" refers to a heterocyclyl group substituted with a heteroaryl group.

[0475] As used herein, unless otherwise specified, "heteroarylaryl" refers to an aryl group substituted with a heteroaryl group.

[0476] As used herein, unless otherwise specified, "biheteroaryl" refers to a heteroaryl group substituted with a heteroaryl group.

[0477] As used herein, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0478] As used herein, unless otherwise specified, "alkoxy" refers to -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0479] As used herein, unless otherwise specified, "hydroxyalkyl" refers to an alkyl group substituted with OH.

[0480] As used herein, unless otherwise specified, "cyanoalkyl" refers to an alkyl group substituted with CN.

[0481] As used herein, unless otherwise specified, "alkoxyalkyl" refers to an alkyl group substituted by an alkoxy group.

[0482] As used herein, unless otherwise specified, "alkoxyalkoxy" refers to an alkoxy group substituted by an alkoxy group.

[0483] As used herein, unless otherwise specified, "haloalkoxy" refers to -O-(haloalkyl).

[0484] 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.

[0485] 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.

[0486] As used herein, unless otherwise indicated, "oxo" refers to an oxygen substituent attached through a double bond (ie, =0).

[0487] As used herein, unless otherwise specified, the term "optionally substituted" means unsubstituted or substituted.

[0488] As used herein, unless otherwise specified, the term "substituted" refers to a group in which one or more hydrogen atoms are replaced by a substituent independently selected from the following substituents: -6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c R d , -(CH2CH2O) o C1-C6 alkyl; wherein o is 1-10; C 2-6 Alkenyl-NR c R d , C 2-6 Alkynyl-NR c R d , OC 2-6 Alkyl-NR c R d ,CN,NO2,N3,OR a , SR a , C(O)R b , C(O)NR c R d , -CH2C(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 , C(=NR c )NR c R d ,NR cC(=NR c )NR c R d , P(R f )2,P(OR e )2,P(O)R e R f , P(O)OR e OR f , S(O)R b ,-SO(=NR b ); S(O)NR c R d , S(O)2R b ,NR c S(O)2R b , S(O)2NR c R d ; aryl, heteroaryl, spiroalkyl, spiroheterocyclyl, cycloalkyl, or heterocyclyl, wherein the aryl, heteroaryl, spiroalkyl, spiroheterocyclyl, cycloalkyl, or heterocyclyl is optionally substituted by a substituent selected from the group consisting of D, halogen, oxo, C1-C -6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c R d , C 2-6 Alkenyl-NR c R d , C 2-6 Alkynyl-NR c R d , OC 2-6 Alkyl-NR c R d ,CN,NO2,N3,OR a , SR a , C(O)R b , C(O)NR c R d , -CH2C(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 , C(=NR c)NR c R d ,NR c C(=NR c )NR c R d , P(R f )2,P(OR e )2,P(O)R e R f , P(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 .

[0489] The compounds described herein 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. The compounds described herein 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 alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all stable isomers are also within the scope of the present invention. The cis and trans geometric isomers of the compounds described herein are also within the scope of the present invention and can be separated into mixtures of isomers or separated isomeric forms.

[0490] The compounds of the present invention also include tautomers. Tautomers are produced by the exchange of a single bond with an adjacent double bond 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. Protons in the ring structure can interconvert 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 can be fixed in space by suitable substitution to form a form.

[0491] In some cases, the compounds described herein may exist as rotational isomers. Descriptions of the compounds of the present invention are intended to encompass any individual rotational isomer, as well as mixtures of rotational isomers in any proportion, and are not intended to represent a specific rotational isomer. Descriptions of a specific rotational isomer are intended to encompass the described rotational isomer, substantially free of other rotational isomers.

[0492] The present invention further includes isotope-labeled 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.

[0493] 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 the environment at least partially or substantially separated.Partial separation can comprise for example rich in the composition of the compounds of this invention.In fact separation can comprise the 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 compound and their salt is conventional in this area.

[0494] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds described herein, wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Exemplary pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, 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; generally, 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.

[0495] The term "pharmaceutically acceptable" as used herein refers to those compounds, substances, 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.

[0496] A "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 a pharmaceutical agent 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 types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0497] "Solvate" refers to a compound of Formula I with one or more solvent molecules.

[0498] "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably in the present invention.

[0499] 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.

[0500] "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.

[0501] As used herein, the term "isotopic variant" refers to a compound that contains a ratio of isotopes greater than natural abundance at one or more of the atoms comprising 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 understood that in compounds subject to such isotopic substitution, the following atoms, if present, may vary so 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.

[0502] It will also be understood that compounds having the same molecular formula but differing in the nature or order of the bonding of the atoms or the arrangement of the atoms in space are referred to as "isomers". Isomers whose atoms are arranged differently 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 a chiral center is present in a structure, but the specific stereochemistry of the center is not shown, the structure includes both enantiomers, either individually or as a mixture of enantiomers. When more than one chiral center is present 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.

[0503] Pharmaceutical composition

[0504] 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.

[0505] 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 as an injectable (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 by 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 or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0506] Pharmaceutically acceptable excipients may be 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.

[0507] Pharmaceutically acceptable carriers can be, for example, solid, liquid, or gaseous. Exemplary solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Exemplary liquid carriers include syrup, peanut oil, olive oil, and water. Exemplary gaseous carriers include carbon dioxide and nitrogen. When preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavorings, preservatives, and colorants can be used to form oral liquid formulations, such as suspensions, elixirs, and solutions; and carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used to form oral solid formulations, such as powders, capsules, and tablets. Due to their ease of administration, tablets and capsules are preferred oral dosage forms when using solid pharmaceutical carriers. Optionally, tablets can be coated using standard aqueous or nonaqueous techniques.

[0508] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, wafers, or patches, such as buccal patches.

[0509] 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 hydroxypropyl methylcellulose, and starch such as corn starch. Tablets may also contain standard ingredients such as binders and granulating agents, 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 will not be described in detail here. The tablets are optionally mixed with one or more auxiliary ingredients or excipients and may be prepared by compression or molding. Compressed tablets can be compressed using suitable equipment, with the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be formed using a mixture of the powdered compound moistened with an inert liquid diluent and molded using suitable equipment. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation for oral human use may contain from about 0.5 mg to about 5 g of the active ingredient, mixed with an appropriate and convenient amount of carrier, which may vary from about 5% to about 95% of the total composition. Unit dosage forms typically contain from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0510] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. They may include a suitable surfactant, such as hydroxypropylcellulose. Dispersions can 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.

[0511] The pharmaceutical composition of the present invention suitable for injection includes sterile aqueous solutions or dispersions. In addition, the composition can be in the form of sterile powders for the temporary preparation of such sterile injectable solutions or dispersions. 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 preserved to prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0512] 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 use in a transdermal device. 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, a cream or ointment can be prepared by mixing a hydrophilic material and water with about 5wt% to about 10wt% of the compound to produce a cream or ointment with a desired consistency.

[0513] The pharmaceutical composition 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.

[0514] 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.

[0515] 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 symptoms associated with the disorders.

[0516] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form varies depending on the individual being treated and the specific route of administration. For example, a formulation 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, which can vary between about 5% to about 98% of the total composition weight.

[0517] 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.

[0518] Therefore, the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier and a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The compound represented by Formula I or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0519] 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, flavorings, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants) or the like, as appropriate. In addition, other adjuvants may be included to make the preparation and the blood of the intended recipient isotonic. Compositions containing the compound shown in Formula I or its pharmaceutically acceptable salt may also be prepared into powder or liquid concentrate form.

[0520] In general, dosage levels of about 0.01 mg / kg to about 150 mg / kg of body weight per day are useful for treating the above-mentioned 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.

[0521] However, it should be understood that lower or higher doses than those recited above 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 employed, 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.

[0522] These and other aspects will become apparent from the following description of the invention.

[0523] Described below are non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0524] Dosage

[0525] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising these compounds, can be administered to a subject by any convenient method of administration, whether systemically / peripherally or locally (ie, at the site of desired action).

[0526] 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); ophthalmic (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.

[0527] How to use

[0528] The method generally includes administering a therapeutically effective amount of the compound of the present invention to the subject. The therapeutically effective amount of the combination of target compound can be based on the intended application (in vitro or in vivo) or the subject and the disease condition being treated, for example, the subject's weight and age, the severity of the disease condition, the mode of administration, etc. and change, which can be easily determined by those of ordinary skill in the art. The term is also applicable to inducing a specific response in target cells, for example, the dosage of a reduction in the proliferation of the target protein or a reduction in the activity. The specific dosage will vary according to the specific compound selected, the dosage regimen followed, whether it is administered in combination with other compounds, the administration time, the tissue it is administered, and the physical delivery system it is carried.

[0529] As used herein, the term "IC 50 " refers to the half-maximal inhibitory concentration (IC50) 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 (IC60) of a substance (50% IC70 or IC80). 50 ).

[0530] In some embodiments, the test method uses an in vitro assay with an IC 50 In some embodiments, the PolQ inhibitor has an IC for PolQ inhibition of 50 value:

[0531] 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, 1μM or less, 1.1μM or less, 1.2μM or less, 1.3μM or less, 1.4μM or less, 1.5μM or less, 1.6μM or less, 1.7μM or less, 1.8μM or less, 1.9μM or less, 2μM or less, 5 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 value within the range defined by and including any two of the above numbers).

[0532] In some embodiments, the PolQ inhibitors of the present invention selectively inhibit PolQ with an IC of 50 Value: relative to the IC of Polα, Polβ, Polγ, Polη, Polν, Polδ, Polε and other DNA polymerases 50 s value, 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).

[0533] In some embodiments, the PolQ inhibitors of the present 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 a value within the range defined by and including any two of the above numbers).

[0534] The test methods can be used to treat diseases associated with PolQ. Any disease that is directly or indirectly caused by abnormal PolQ activity or expression levels may be a target disease.

[0535] 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, epithelial ovarian cancer, ovarian germ cell tumor, low-grade 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 adenocarcinoma, cervical adenosquamous carcinoma, small cell cervical carcinoma, cervical mucinous 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, estheneuroblastoma, 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, 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 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.

[0536] The compounds of the present invention are useful for treating and / or preventing a disease in a patient, wherein the disease is characterized by overexpression of PolQ.

[0537] 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 in the control cell, the amount of PolQ overexpression is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or 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.

[0538] The compounds of the present invention are useful for treating or preventing a disease in a patient characterized by an increased reliance on MMEJ DSB repair.

[0539] 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.

[0540] 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, and mixed carcinoma.

[0541] 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.

[0542] 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, and squamous cell prostate cancer.

[0543] 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, and pancreatic neuroendocrine cancer.

[0544] 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.

[0545] The compounds of the present invention are useful for treating or preventing cancers that are resistant to PARPi therapy, whether or not treated with a PARPi drug. 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.

[0546] The compounds of the present invention are useful for treating or preventing patients with 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.

[0547] 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 / ).

[0548] 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.

[0549] In other embodiments, the method is used to treat a disease selected from the group consisting of: a leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, a myeloproliferative disorder, chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or epidermoid carcinoma.

[0550] 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).

[0551] 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.

[0552] In other methods, the compounds described herein and pharmaceutical compositions thereof can be administered in combination with agonists of nuclear receptor agents.

[0553] In other methods, the compounds described herein and pharmaceutical compositions thereof can be administered in combination with antagonists of nuclear receptor agents.

[0554] In other methods, the compounds described herein and pharmaceutical compositions thereof can be administered in combination with an anti-proliferative agent.

[0555] Combination therapy

[0556] 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.

[0557] For the treatment of cancer and other proliferative diseases, the compounds of the present 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, dactinomycin, 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, leuprorelin and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole 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).

[0558] 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., the 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, vanillic aldehyde, 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 ( for example, RP6306), USP1 inhibitors (e.g., KSQ-4279), and PARG inhibitors (e.g., IDE161); antisense therapies, such as those acting on the above targets, such as ISIS2503, an anti-ras antisense; gene therapy approaches, including, for example, approaches to replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as approaches using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and approaches to increase 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 patient 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-β, CD73, CD39, A2AR, A2BR, IDO1, TD02, Arginase, B7-H3, B7-H4; methods using the above-mentioned 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.

[0559] synthesis

[0560] 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 those described below.

[0561] 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 technical staff of the organic synthesis field. 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. Given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the above-mentioned specific reactions step, those skilled in the art can select the solvent suitable for specific reactions step.

[0562] 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 appropriate 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).

[0563] The reaction can be monitored according to 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-visible), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0564] As used herein, expressions such as "ambient temperature," "room temperature," and "rt" generally refer to temperatures, such as reaction temperatures, in accordance with the understanding of the art, which refer to temperatures approximately in the space in which the reaction is performed, for example, a temperature of about 20°C to about 30°C.

[0565] The compounds of the present invention can be prepared according to various routes known in the literature. The following schemes provide general guidance for preparing the compounds of the present invention. It will be appreciated by those skilled in the art that the preparation methods described 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.

[0566] 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.

[0567] Synthesis scheme

[0568] A series of heterocyclic derivatives represented by formula (I), wherein n is an integer (e.g., 1, or 2) can be prepared by the method shown in Scheme 1. Compounds 1-3, wherein n is an integer (e.g., 1, or 2), can be prepared by reacting carboxylic acid 1-1, wherein n is an integer (e.g., 1, or 2) with an amine NHR 2 Ar 2 1-2 is prepared by reaction under standard amide coupling conditions (e.g., in the presence of an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T3P and a base such as Hunig's base, Et3N or pyridine). Alternatively, the carboxylic acid 1-1 is reacted with a chlorinating agent such as oxalyl chloride or thionyl chloride to give the corresponding acid chloride 1-4, which is further reacted with an appropriate amine NHR. 2 Ar 2 1-2 is coupled to generate the corresponding amide 1-3. Amide 1-3 is reacted with a suitable Ar 1 W 1-5, among which Ar 1 C6-C 10 Aryl or 5-10 membered heteroaryl derivatives and W is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), and Buchwald coupling is carried out under standard Buchwald coupling conditions (e.g., in the presence of a palladium catalyst such as BrettPhos PdG3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base such as t-BuOK, t-BuONa, Cs2CO3, or K2CO3) to give heterocyclic derivatives represented by formula (I).

[0569] Solution 1

[0570]

[0571] Alternatively, a series of heterocyclic derivatives represented by formula (I) can be prepared by the method shown in Scheme 2. Ester derivative 2-1 (wherein R is an alkyl group such as Me, Et, or t-Bu) and aromatic ring derivative Ar 1 W 2-2, where Ar 1For phenyl or 5-10 membered heteroaryl derivatives and W is halogen (e.g., Cl, Br, or I) or 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, Cs2CO3, or K2CO3) by Buchwald coupling to give compound 2-3. Saponification of compound 2-3 can give the corresponding acid 2-4, which is further reacted with a suitable amine NHR 2 Ar 2 2-5, in the presence of an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T3P and a base such as Hunig's base, Et3N or pyridine, to produce the corresponding amide of formula (I).

[0572] Option 2

[0573]

[0574] A series of heterocyclic intermediates represented by formula 3-2 can be prepared by the method shown in Scheme 3. Compound 3-1 reacts with a carbonyl reagent such as CDI, DSC [disuccinimidyl carbonate], triphosgene, phosgene, or phenyl chloroformate in the presence of a base such as triethylamine, Na2CO3, K2CO3, NaOH, or KOH to directly obtain the corresponding heterocyclic derivative 3-2.

[0575] Option 3

[0576]

[0577] A series of heterocyclic intermediates represented by formula 4-4 and formula 4-6 can be prepared by the method shown in Scheme 4. Sulfonyl chloride 4-3 can be prepared by reacting compound 4-1 or its diether 4-2 with chlorine in ethanol and chloroform. 4-3 undergoes intramolecular ring closure in the presence of a base such as Hunig's base or Et3N to obtain intermediate 4-4. Intermediate 4-6 can be prepared by a similar method. Compound 4-1 or its diether 4-2 is reacted with sulfonyl chloride in the presence of anhydrous acetic acid or trimethylsilyl acetate to obtain sulfinyl chloride 4-5, which is then subjected to ring closure in the presence of a base such as Hunig's base or Et3N to obtain intermediate 4-6.

[0578] Option 4

[0579]

[0580] A series of heterocyclic intermediates represented by formula 5-3 and formula 5-5 can be prepared by the method shown in Scheme 5. Sulfamic acid 5-1 is subjected to an imidization reaction with sodium azide in the presence of an acid such as sulfuric acid or HCl to obtain compound 5-3. Alternatively, sulfinamide 5-2 is subjected to an oxidation reaction with an oxidizing agent such as PhI(OAc)2 and carbamate amine to obtain compound 5-3. On the other hand, sulfonyl imide chloride 5-4 can be prepared by reacting sulfonamide 5-1 with Ph3PCl2 or SOCl2 in the presence of Et3N or Hunig's base, or by reacting 5-2 with tert-butyl hypochlorite in carbon tetrachloride. Sulfonyl imide chloride 5-4 is reacted with amine R 7 NH2 in the presence of a base such as triethylamine, Hunig's base or pyridine can give the sulfonimide amide 5-5. Alternatively, the sulfonamide 5-2 is reacted with R 7 NH2 reacts in the presence of an oxidizing agent such as PhI(OAc)2 and is directly converted to the sulfonimide amide 5-5.

[0581] Option 5

[0582]

[0583] A series of heterocyclic intermediates represented by formula 6-7 can be prepared by the method shown in Scheme 6. Amine-alcohol compound 6-1 is subjected to reductive amination reaction with benzaldehyde to obtain amino-protected compound 6-2, which is further converted into compound 6-3 by reacting with t-BuOH solution of chlorosulfonyl isocyanate in the presence of a base such as Hunig's base or Et3N. 6-3 is subjected to intramolecular Mitsunobo reaction under standard Mitsunobo reaction conditions (e.g., DIAD, or DEAD and Ph3P or Bu3P) to obtain the corresponding sulfonylurea 6-4. 6-4 is subjected to Boc group removal reaction in an acidic medium such as TFA in DCM solution, HCl in dioxane solution or other acidic medium to obtain the corresponding sulfonylurea 6-5. 6-5 is reacted with R 8 W 1 , where W 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs)], alkylation reaction is carried out under alkylation conditions (e.g., in the presence of a base such as NaH, NaOBu-t, KOBu-t, NaHMDS or KHMDS) to give compound 6-6. Compound 6-6 is hydrogenated in the presence of a palladium catalyst such as Pd / C or Pd(OH)2 / C to give the target intermediate 6-7.

[0584] Option 6

[0585]

[0586] A series of heterocyclic intermediates represented by formula 7-2 and formula 7-3 can be prepared by the method shown in Scheme 7. Heterocyclic intermediates 7-2 and 7-3 can be prepared by reacting diamine derivatives 7-1 with sulfonamide and dichlorothionyl in the presence of a base such as pyridine, Et3N or Hunig's base.

[0587] Option 7

[0588]

[0589] In a similar manner, a series of heterocyclic intermediates of formula 8-2 can be prepared by the method shown in Scheme 8. Heterocyclic intermediate 8-2 can be prepared by reacting diamine derivative 8-1 with sulfonimide 8-3 in the presence of a base such as pyridine, Et3N or Hunig's base.

[0590] Option 8

[0591]

[0592] A series of heterocyclic intermediates of formula 9-5 can be prepared by the method shown in Scheme 9. The reaction of sulfenyl chloride 9-1 with 2,2,2-trifluoroacetamide in the presence of a strong base such as NaHMDS, KHMDS, or LiBu can yield the corresponding N-sulfenyl-acetamide 9-2, which can be converted to compound 9-4 by sequential reaction with NCS, NBS, or NIS, and then with a 2-substituted 2-amino-malonic acid dimethyl ester 9-3 in the presence of a base such as Hunig's base or Et3N. Compound 9-4 can then undergo a ring-closure reaction in the presence of a base such as NaOMe or NaOEt to yield heterocyclic intermediate 9-5.

[0593] Option 9

[0594]

[0595] A series of heterocyclic intermediates represented by formula 10-3 can be prepared by the method shown in Scheme 10. Sulfonyl imide chloride 10-2 can be prepared by reacting sulfonamide 10-1 with Ph3PCl2 or SOCl2 in the presence of Et3N or Hunig's base. 7 Reaction of NH2 in the presence of a base such as triethylamine, Hunig's base, or pyridine can afford the sulfonimide amide 10-3.

[0596] Plan 10

[0597] Example

[0598] Example 1: (S)-N-(3-chloro-4-fluorophenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0599]

[0600] Step 1: 3-Chloro-4-fluoro-N-methylaniline

[0601]

[0602] At rt, to a solution of 3-chloro-4-fluoroaniline (1.00 g, 6.9 mmol) and NaOMe (1.48 g, 27.4 mmol) in MeOH (20 mL) was added paraformaldehyde (0.83 g, 27.4 mmol). The mixture was refluxed for 4 h under a nitrogen atmosphere. The mixture was cooled to 0 ° C (ice-water bath). NaBH4 (1.04 g, 27.5 mmol) was added. The resulting mixture was refluxed for 4 h. After cooling to rt, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (630 mg, 57% yield) as a yellow liquid. LCMS calculated value: C7H8ClFN[M+H] + : m / z = 160.0; found: 160.0.

[0603] Step 2: (S)-N-(3-chloro-4-fluorophenyl)-N,5-dimethyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0604]

[0605] To a suspension of (S)-5-methyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (170 mg, 0.944 mmol, intermediate 1) in DCM (10 mL) was added oxalyl chloride (240 mg, 1.89 mmol) and DMF (catalytic amount). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (10 mL) and a mixture of 3-chloro-4-fluoro-N-methylaniline (181 mg, 1.13 mmol) and pyridine (224 mg, 2.83 mmol) in DCM (20 mL) was added. The resulting mixture was stirred at 60 ° C overnight. The reaction mixture was then quenched with water (40 mL) and extracted with DCM (60 mLx3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC using EtOAc / PE (0-50%) as eluent to afford the title compound (90 mg, 30% yield) as a yellow solid. LCMS calculated value: C 11 H 14 ClFN3O3S[M+H] + : m / z = 322.0; found: 322.0.

[0606] Step 3: (S)-N-(3-chloro-4-fluorophenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0607]

[0608] (S)-N-(3-chloro-4-fluorophenyl)-N,5-dimethyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (45 mg, 0.140 mmol), copper (I) iodide (5.33 mg, 0.028 mmol), N 1 ,N 2-dimethylethyl-1,2-diamine (4.93 mg, 0.056 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (40.3 mg, 0.168 mmol), and Cs2CO3 (137 mg, 0.420 mmol) in 1,4-dioxane (8 mL) were degassed and filled with nitrogen, replaced 3 times. The mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. After cooling to rt, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mLx3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC using EtOAc / PE (1 / 1) as eluent to give the crude product, which was further purified by Prep-HPLC on a C18 column using MeCN / H2O (40-85%, 10 mmol / L NH4HCO3 + 0.1% NH3.H2O) as eluent to give the title compound (5.2 mg, 7.7% yield) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 7.26 (d, J = 6.5 Hz, 1H), 7.06 (s, 1H), 5.07 (t, J = 6.7 Hz, 1H), 3.48-3.34 (m, 2H), 3.30 (d, J = 2.6 Hz, 3H), 2.86 (d, J = 2.3 Hz, 3H), 2.59 (d, J = 2.4 Hz, 3H). LCMS calculated value C 18 H 18 ClF4N4O3S[M+H] + : m / z = 481.1; found: 481.1.

[0609] Example 2: (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[0610]

[0611] Step 1: (S)-Isothiazolidine-3-yl chloride 1,1-dioxide

[0612]

[0613] A solution of (S)-1,1-dioxo-1,2-thiazolidine-3-carboxylic acid (170 mg, 1.02 mmol, intermediate 2) and oxalyl chloride (261 mg, 2.05 mmol) in DCM (2 mL) and DMF (catalytic amount) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to afford the title compound (185 mg, crude) as a yellow semisolid, which was used directly in the next step without further purification.

[0614] Step 2: (S)-N-(3-chloro-4-fluorophenyl)-N-methylisothiazolidine-3-carboxamide 1,1-dioxide

[0615]

[0616] A solution of (S)-1,1-dioxo-1,2-thiazolidine-3-yl chloride (185 mg, 1.00 mmol), 3-chloro-4-fluoro-N-methylaniline (160 mg, 1.00 mmol) and pyridine (79.7 mg, 1.00 mmol) in tetrahydrofuran (3 mL) was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0–50%) to give the title compound (80.0 mg, 26% yield over 2 steps) as a white solid. LCMS calculated value: C 11 H 13 ClFN2O3S[M+H] + : m / z = 307.0; found: 307.1.

[0617] Step 3: (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[0618]

[0619] This compound was prepared in a similar manner to step 3 of Example 1 using (S)-N-(3-chloro-4-fluorophenyl)-N-methylisothiazolidine-3-carboxamide 1,1-dioxide and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine as starting materials. 1 H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 6.0 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.05 (s, 1H), 5.05-5.01 (m, 1H), 3.79-3.68 (m, 1H), 3.38-3.32 (m, 4H), 2.59 (s, 3H), 2.53-2.34 (m, 2H). LCMS calculated value C 18 H17 ClF4N3O3S[M+H] + : m / z = 466.1; found: 466.0.

[0620] Example 3: (R)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxothiazolidine-4-carboxamide

[0621]

[0622] Step 1: (R)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxothiazolidine-4-carboxamide

[0623]

[0624] This compound was prepared in a similar manner to step 2 of Example 1, using (R)-2-oxothiazolidine-4-carboxylic acid instead of (S)-5-methyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide. LCMS calculated value: C 11 H 11 ClFN2O2S[M+H] + : m / z = 289.0; found: 289.0.

[0625] Step 2: (R)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxothiazolidine-4-carboxamide

[0626]

[0627] A mixture of (R)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxothiazolidine-4-carboxamide (90.0 mg, 0.312 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (112 mg, 0.468 mmol), t-BuXPhos Pd G3 (37.1 mg, 0.047 mmol), t-BuXPhos (26.5 mg, 0.062 mmol), and Cs2CO3 (203 mg, 0.624 mmol) in 1,4-dioxane (10 mL) was degassed and filled with nitrogen, replaced 3 times. The mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. After cooling to rt, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC using EtOAc / PE (0-50%) as eluent to give the crude product, which was further purified by Prep-HPLC on a C18 column using MeCN / H2O (54-84%, 10 mmol / L NH4HCO3 + 0.1% NH3.H2O) as eluent to give the title compound (18.0 mg, 13% yield) as a white solid. 1 HNMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.76-7.61 (m, 1H), 7.44-7.27 (m, 2H), 7.12 (s, 1H), 5.53-5.41 (m, 1H), 3.35-3.17 (m, 5H), 2.63 (s, 3H). LCMS calculated value C 18 H 15 ClF4N3O2S[M+H] + : m / z = 448.0; found: 448.0.

[0628] Example 4: (S)-N-(3-chloro-4-fluorophenyl)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N,5-dimethyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0629]

[0630] This compound was prepared in a similar manner to that in Step 3 of Example 1, except that 2-bromo-3-cyano-6-methyl-4-(trifluoromethyl)pyridine was used instead of 2-bromo-6-methyl-4-(trifluoromethyl)pyridine. 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 1H), 7.25-7.16 (m, 2H), 7.08 (t, J = 8.6 Hz, 1H), 5.93-5.83 (m, 1H), 4.02-3.90 (m, 1H), 3.61-3.48 (m, 1H), 3.29 (s, 3H), 2.81 (s, 3H), 2.61 (s, 3H). LCMS calculated value C 19 H 17 ClF4N5O3S[M+H] + : m / z = 506.1; found: 506.1.

[0631] Example 5: (S)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0632]

[0633] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, N,3-dimethylaniline was used instead of 3-chloro-4-fluoro-N-methylaniline. 1 H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.26-7.14 (m, 3H), 7.04 (s, 1H), 5.11-5.03 (m, 1H), 3.41-3.34 (m, 2H), 3.30 (s, 3H), 2.85 (s, 3H), 2.59 (s, 3H), 2.42 (s, 3H). LCMS calculated value C 19 H 22 F3N4O3S[M+H] + : m / z = 443.1; found: 443.2.

[0634] Example 6: (S)-N-(4-chloro-3-methylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0635]

[0636] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, 4-chloro-N,3-dimethylaniline was used instead of 3-chloro-4-fluoro-N-methylaniline. 1H NMR (300 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.35 (s, 1H), 7.22-7.19 (d, J = 4.5 Hz, 1H), 7.07 (s, 1H), 5.13-5.09 (m, 1H), 3.45-3.35 (m, 2H), 3.31 (s, 3H), 2.87 (s, 3H), 2.60 (s, 3H), 2.45 (s, 3H). LCMS calculated value C 19 H 21 ClF3N4O3S[M+H] + : m / z = 477.1; found: 477.0.

[0637] Example 7: (S)-N-(5-chloro-2,4-difluorophenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0638]

[0639] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, 5-chloro-2,4-difluoro-N-methylaniline was used instead of 3-chloro-4-fluoro-N-methylaniline. 1 H NMR (300 MHz, CDCl3) δ 7.88-7.82 (m, 1H), 7.52-7.41 (d, J = 16.5 Hz, 1H), 7.22-7.07 (m, 2H), 5.09-5.01 (m, 1H), 3.61-3.38 (m, 2H), 3.20-3.28 (d, J = 3.0 Hz, 3H), 2.91 (s, 3H), 2.63-2.51 (m, 3H). LCMS calculated value C 18 H 17 ClF5N4O3S[M+H] + : m / z = 499.1; found: 499.0.

[0640] Example 8: (S)-N-(4-fluoro-3-methylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0641]

[0642] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, 4-fluoro-N,3-dimethylaniline was used instead of 3-chloro-4-fluoro-N-methylaniline. 1H NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 7.13-7.10 (m, 1H), 7.07-7.04 (s, 1H), 5.11-5.06 (m, 1H), 3.44-3.34 (m, 2H), 3.30 (s, 3H), 2.87 (s, 3H), 2.60 (s, 3H), 2.36 (d, J = 1.5 Hz, 3H). LCMS calculated value C 19 H 21 F4N4O3S[M+H] + : m / z = 461.1; found: 461.1.

[0643] Example 9: (S)-N-(2,4-difluoro-5-methylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0644]

[0645] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, 2,4-difluoro-N,3-dimethylaniline was used instead of 3-chloro-4-fluoro-N-methylaniline. 1 H NMR (300 MHz, CDCl3) δ 7.58-7.40 (m, 2H), 7.09-6.89 (m, 2H), 5.06-4.96 (m, 1H), 3.52-3.32 (m, 2H), 3.26 (d, J = 2.3 Hz, 3H), 2.88 (d, J = 1.4 Hz, 3H), 2.54 (d, J = 27.6 Hz, 3H), 2.33-2.25 (m, 3H). LCMS calculated value C 19 H 20 F5N4O3S[M+H] + : m / z = 479.1; found: 479.1.

[0646] Example 10: (S)-N,5-dimethyl-N-(1-methyl-1H-indol-6-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0647]

[0648] Step 1: Benzyl N-(1H-indol-6-yl)carbamate

[0649]

[0650] A solution of 1H-indole-6-amine (500 mg, 3.78 mmol), benzyl chloroformate (1.55 g, 9.08 mmol) and pyridine (781 mg, 9.87 mmol) in DCM (20 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0–30%) to give the title compound (950 mg, 94% yield) as a white solid. LCMS calculated value C 16 H 15 N2O2[M+H] + : m / z = 267.1; found: 267.0.

[0651] Step 2: Benzyl N-methyl-N-(1-methylindol-6-yl)carbamate

[0652]

[0653] At 0 ° C, to a solution of benzyl N-(1H-indol-6-yl)carbamate (300 mg, 1.12 mmol) in DMF (5 mL), 60% sodium hydride (90.1 mg, 2.25 mmol) was added in batches. The reaction mixture was stirred at 0 ° C for 20 min. At 0 ° C, iodomethane (318 mg, 2.24 mmol) was added dropwise. The resulting mixture was stirred at rt for 4 h. under a nitrogen atmosphere and then quenched with ice / water (30 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (50 mLx3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (300 mg, crude product). LCMS calculated value C 18 H 19 N2O2[M+H] + : m / z = 295.1; found: 295.1.

[0654] Step 3: N,1-dimethylindole-6-amine

[0655]

[0656] A mixture of benzyl N-methyl-N-(1-methylindol-6-yl)carbamate (60.0 mg, 0.204 mmol) and 10% Pd / C (10.8 mg) in methanol (20 mL) was stirred at 60 ° C for 3 h under a hydrogen atmosphere (hydrogen bag, 2-3 atm). The solid was removed by filtration and the filter cake was rinsed with methanol (10 mL x 3). The combined organic phases were concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (0-30%) to give the title compound (20.0 mg, 61% yield) as a white solid. LCMS calculated value C 10 H 13 N2[M+H] + : m / z = 161.1; found: 161.1.

[0657] Step 4: (S)-N,5-Dimethyl-N-(1-methyl-1H-indol-6-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0658] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, N,1-dimethyl-1H-indol-6-amine was used instead of 3-chloro-4-fluoro-N-methylaniline. 1 H NMR (300 MHz, CDCl3) δ 7.73-7.70 (d, J = 4.5 Hz, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.28-7.27 (d, J = 1.5 Hz, 1H), 7.21-7.20 (m, 1H), 7.06 (s, 1H), 6.58-6.57 (m, 1H), 5.22-5.18 (m, 1H), 3.86-3.85 (m, 3H), 3.46-3.23 (m, 5H), 2.85-2.83 (m, 3H), 2.67 (s, 3H). LCMS calculated value C 21 H 23 F3N5O3S[M+H] + : m / z = 482.1; found: 482.1.

[0659] Example 11: (S)-N-(3-chloro-2,4-difluorophenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0660]

[0661] Step 1: 3-Chloro-2,4-difluoro-N-methylaniline

[0662]

[0663] This compound was prepared in a similar manner to that in step 1 of Example 1, using 3-chloro-2,4-difluoro-aniline instead of 3-chloro-4-fluoro-aniline. LCMS calculated value: C7H7ClF2N[M+H] + : m / z = 178.0; found: 178.0.

[0664] Step 2: (S)-N-(3-chloro-2,4-difluorophenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0665] This compound was prepared in a similar manner to Steps 2-3 of Example 1, except that in Step 2, 3-chloro-2,4-difluoro-N-methylaniline was used instead of 3-chloro-4-fluoro-N-methylaniline. 1 H NMR (300 MHz, CDCl3) δ 7.61 (td, J = 8.6, 5.4 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.17-7.07 (m, 1H), 7.05 (s, 1H), 5.07-4.93 (m, 1H), 3.49-3.39 (m, 2H), 3.28 (d, J = 2.8 Hz, 3H), 2.88 (d, J = 3.1 Hz, 3H), 2.54 (d, J = 14.6 Hz, 3H). LCMS calculated value C 18 H 17 ClF5N4O3S[M+H] + : m / z = 499.1; found: 499.1.

[0666] Example 12: (S)-N,5-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0667]

[0668] Step 1: N,1-dimethylpyrrolo[2,3-b]pyridin-6-amine

[0669]

[0670] This compound was prepared in a similar manner to steps 1-3 of Example 10, except that 1H-pyrrolo[2,3-b]pyridin-6-amine was used instead of 1H-indol-6-amine in step 1. LCMS calculated value: C9H 12 N3[M+H] +: m / z = 162.1; found: 162.1.

[0671] Step 2: (S)-N,5-Dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0672] This compound was prepared in a similar manner to Steps 2-3 of Example 1, wherein in Step 2, N,1-dimethyl-1H-pyrrolo[2,3-b]pyridin-6-amine was used instead of 3-chloro-4-fluoro-N-methylaniline. 1 H NMR (300 MHz, CDCl3) δ 8.04 (dd, J = 8.2, 1.3 Hz, 1H), 7.44 (s, 1H), 7.31-7.22 (m, 1H), 7.14 (dd, J = 8.2, 1.3 Hz, 1H), 6.97 (s, 1H), 6.52 (dd, J = 3.6, 1.3 Hz, 1H), 5.02 (td, J = 5.8, 5.1, 2.8 Hz, 1H), 4.08-3.64 (m, 5H), 3.46 (d, J = 1.4 Hz, 3H), 2.98 (d, J = 1.4 Hz, 3H), 2.47 (d, J = 1.3 Hz, 3H). LCMS calculated value C 20 H 22 F3N6O3S[M+H] + : m / z = 483.1; found: 483.1.

[0673] Example 13: (S)-N-(3-chloro-4-fluorophenyl)-5-ethyl-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0674]

[0675] This compound was prepared by a method similar to steps 2-3 of Example 1, wherein in step 2, (S)-5-ethyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (intermediate 3) was used instead of (S)-5-methyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (intermediate 1). 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.48 (s, 1H), 7.29 (s, 2H), 7.06 (s, 1H), 5.08-5.05 (m, 1H), 3.43-3.40 (m, 2H), 3.29 (s, 4H), 3.15-3.11 (m, 1H), 2.59 (s, 3H), 1.28-1.26 (m, 3H). LCMS calculated value C 19 H 20 ClF4N4O3S[M+H] + : m / z = 495.1; found: 495.1.

[0676] Example 14: (S)-N-(4-chloro-3-methylphenyl)-5-ethyl-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0677]

[0678] This compound was prepared in a similar manner to Steps 2-3 of Example 1. In Step 2, (S)-5-ethyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (Intermediate 3) and 4-chloro-N,3-dimethylaniline were used. 1 H NMR (300 MHz, methanol-d4) δ 7.54-7.50 (m, 2H), 7.38-7.36 (m, 1H), 7.33 (s, 1H), 7.20 (d, J = 1.0 Hz, 1H), 5.00-4.98 (m, 1H), 3.56-3.50 (m, 2H), 3.26 (s, 3H), 3.24-3.10 (m, 2H), 2.61 (s, 3H), 2.43 (s, 3H), 1.24-1.20 (m, 3H). LCMS calculated value C 20 H 23 ClF3N4O3S[M+H] + : m / z = 491.1; found: 491.1.

[0679] Example 15: (S)-N-(4-chloro-2-fluoro-5-methylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0680]

[0681] Step 1: 4-Chloro-2-fluoro-N,5-dimethylaniline

[0682]

[0683] A mixture of 4-chloro-2-fluoro-5-methylaniline (300 mg, 1.88 mmol), MeONa (406 mg, 7.52 mmol) and paraformaldehyde (169 mg, 5.64 mmol) in MeOH (5 mL) was stirred at 70 ° C overnight under a nitrogen atmosphere. NaBH4 (213 mg, 5.64 mmol) was added to the above mixture in small batches at 0 ° C. The resulting mixture was stirred at 70 ° C overnight and then concentrated under reduced pressure. The residue was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EA / PE (0-10%) to give 4-chloro-2-fluoro-N,5-dimethylaniline (120 mg, 37% yield) as a yellow oil. LCMS calculated for C8H 10 ClFN[M+H] + : m / z = 174.1; found: 174.1.

[0684] Step 2: (S)-5-Methyl-1,2,5-thiadiazolidine-3-yl chloride 1,1-dioxide

[0685]

[0686] To a mixture of (S)-5-methyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (40.0 mg, 0.222 mmol, Intermediate 1) and oxalyl chloride (33.8 mg, 0.266 mmol) in DCM (2 mL) was added DMF (0.05 mL). The resulting mixture was stirred at rt for 2 h and concentrated under reduced pressure to afford the title compound (45 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0687] Step 3: (S)-N-(4-chloro-2-fluoro-5-methylphenyl)-N,5-dimethyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0688]

[0689] To a mixture of 4-chloro-2-fluoro-N,5-dimethylaniline (78.7 mg, 0.454 mmol) and 60% NaH (21.8 mg, 0.545 mmol) in THF (5 mL) at 0°C under nitrogen was added (S)-5-methyl-1,2,5-thiadiazolidine-3-yl chloride 1,1-dioxide (45.0 mg, 0.227 mmol). The resulting mixture was stirred at rt under nitrogen for 4 h and then quenched with ice / water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with PE / EA (0-50%) to give the target compound (17 mg, 22% yield) as a yellow solid. LCMS calculated value: C 12 H 16 ClFN3O3S[M+H] + : m / z = 336.1; found: 335.9.

[0690] Step 4: (S)-N-(4-chloro-2-fluoro-5-methylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0691] This compound was prepared in a similar manner to step 3 of Example 1 using (3S)-N-(4-chloro-2-fluoro-5-methylphenyl)-N,5-dimethyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine as starting materials. 1 HNMR (300 MHz, CDCl3) δ 7.55-7.41 (m, 2H), 7.31-7.28 (m, 1H), 7.12-6.99 (m, 1H), 5.06-4.98 (m, 1H), 3.48-3.36 (m, 2H), 3.26 (s, 3H), 2.87 (s, 3H), 2.64-2.48 (m, 3H), 2.38 (s, 3H). LCMS calculated value C 19 H 20 ClF4N4O3S[M+H] + : m / z = 495.1; found: 495.1.

[0692] Example 16: (S)-N-(2,4-dichloro-5-methylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0693]

[0694] This compound was prepared in a similar manner to Steps 1 to 4 of Example 15, except that 2,4-dichloro-5-methylaniline was used in place of 4-chloro-2-fluoro-5-methylaniline in Step 1. 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.61-7.43 (m, 2H), 7.08 (s, 1H), 5.07 (d, J = 6.1 Hz, 1H), 3.46 (dd, J = 18.0, 6.6 Hz, 2H), 3.27 (d, J = 4.1 Hz, 3H), 2.88 (t, J = 3.8 Hz, 3H), 2.64 (d, J = 4.0 Hz, 3H), 2.42 (d, J = 4.1 Hz, 3H). LCMS calculated value C 19 H 20 Cl2F3N4O3S[M+H] + : m / z = 511.1; found: 511.0.

[0695] Example 17: (S)-N-(4-chloro-2,5-dimethylphenyl)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0696]

[0697] This compound was prepared in a similar manner to Steps 1 to 4 of Example 15, except that 4-chloro-2,5-dimethylaniline was used in place of 4-chloro-2-fluoro-5-methylaniline in Step 1. 1 H NMR (300 MHz, CDCl3) δ 7.57 (s, 0.5H), 7.48 (s, 1H), 7.33 (d, J = 5.6 Hz, 1H), 7.07 (d, J = 9.9 Hz, 1H), 6.97 (s, 0.5H), 5.29-5.00 (m, 1H), 3.52-3.33 (m, 1H), 3.33-3.26 (m, 1H), 3.22 (d, J = 0.9 Hz, 3H), 2.84 (d, J = 2.9 Hz, 3H), 2.64 (s, 1.5H), 2.50 (d, J = 11.1 Hz, 3H), 2.38 (s, 3H), 2.26 (s, 1.5H). LCMS calculated value C 20 H 23 ClF3N4O3S[M+H] + : m / z = 491.1; found: 491.1.

[0698] Example 18: (S)-N-(4-chloro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxamide

[0699]

[0700] Step 1: (3S)-2-Benzyl-5-propyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester

[0701]

[0702] This compound was prepared in a similar manner to that of Intermediate 1, Step 5, using 1-iodopropane instead of iodomethane. LCMS calculated value: C 14 H 21 N2O4S[M+H] + : m / z = 313.1; found: 313.2.

[0703] Step 2: (3S)-2-Benzyl-5-propyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid

[0704]

[0705] This compound was prepared by a similar method to that of Step 7 of Intermediate 1, using (3S)-2-benzyl-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester and lithium hydroxide monohydrate in water / MeOH (v / v=1 / 5). LCMS calculated value: C 13 H 19 N2O4S[M+H] + : m / z = 299.1; found: 299.1.

[0706] Step 3: (3S)-2-Benzyl-N-(4-chloro-3-methylphenyl)-N-methyl-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxamide

[0707]

[0708] A mixture of (3S)-2-benzyl-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxylic acid (380 mg, 1.27 mmol), 4-chloro-N,3-dimethylaniline (238 mg, 1.53 mmol), TCFH (429 mg, 1.53 mmol) and NMI (366 mg, 4.46 mmol) in DMF (4 mL) was stirred at rt overnight. The resulting mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (5 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA / PE (0-50%) to give the title compound (180 mg, 32% yield) as a colorless oil. LCMS calculated value C 21 H 27 ClN3O3S[M+H] + : m / z = 436.2; found: 436.1.

[0709] Step 4: (S)-N-(4-chloro-3-methylphenyl)-N-methyl-5-propyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0710]

[0711] A mixture of (3S)-2-benzyl-N-(4-chloro-3-methylphenyl)-N-methyl-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxamide (180 mg, 0.413 mmol) and 10% Pd / C (20 mg) in MeOH (4 mL) and 4.0 M HCl / dioxane (0.5 mL) was stirred at rt under a hydrogen atmosphere (2-3 atm) for 2 h. The mixture was filtered and the filter cake was washed with MeOH (20 mL x 3). The filtrate was concentrated under reduced pressure to give the title compound (140 mg, crude product) as a colorless liquid, which was used directly in the next step without further purification. LCMS calculated value: C 14 H 21 ClN3O3S[M+H] + : m / z = 346.1; found: 346.1.

[0712] Step 5: (S)-N-(4-chloro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxamide

[0713]

[0714] This compound was prepared in a similar manner to step 3 of Example 1 by reacting (3S)-N-(4-chloro-3-methylphenyl)-N-methyl-1,1-dioxo-5-propyl-1,2,5-thiadiazolidine-3-carboxamide and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine to give the desired product as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.51-7.44 (m, 2H), 7.35 (s, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 5.12-5.09 (m, 1H), 3.48-3.35 (m, 2H), 3.30 (s, 3H), 3.26-3.17 (m, 1H), 3.06-3.04 (m, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 1.75-1.63 (m, 2H), 1.02-0.99 (m, 3H). LCMS calculated value C 21 H 25 ClF3N4O3S[M+H] + : m / z = 505.1; found: 505.1.

[0715] Example 19: (S)-N-(4-chloro-3-methylphenyl)-5-isopropyl-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide

[0716]

[0717] This compound was prepared in a similar manner to Steps 1 to 5 of Example 18, except that 2-iodopropane was used in place of 1-iodopropane in Step 1. 1 H NMR (300 MHz, CDCl3) δ 7.45 (d, J = 8.7 Hz, 2H), 7.36 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.04 (s, 1H), 5.08 (t, J = 7.3 Hz, 1H), 3.86-3.74 (m, 1H), 3.48-3.19 (m, 5H), 2.58 (s, 3H), 2.43 (s, 3H), 1.32-1.25 (m, 6H). LCMS calculated value C 21 H 25 ClF3N4O3S[M+H]+: m / z=505.1; found: 505.1.

[0718] Example 20: (S)-N-(3-chloro-4-fluorophenyl)-5-(2-hydroxyethyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0719]

[0720] Step 1: (3S)-2-Benzyl-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester

[0721]

[0722] A mixture of (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (400 mg, 1.48 mmol, Intermediate 1, Step 4), (2-bromoethoxy)(tert-butyl)dimethylsilane (708 mg, 2.96 mmol) and K2CO3 (614 mg, 4.44 mmol) in DMF (7 mL) was stirred at rt overnight. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0–20%) to give the title compound (300 mg, 47% yield) as a yellow oil. LCMS calculated value: C 19 H 33 N2O5SSi[M+H] + : m / z = 429.2; found: 429.1.

[0723] Step 2: (S)-methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,5-thiadiazolidine-3-carboxylate 1,1-dioxide

[0724]

[0725] A mixture of (3R)-2-benzyl-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (300 mg, 0.700 mmol), Pd / C (30.0 mg) and AcOH (1 mL) in EtOAc (5 mL) was stirred at 60°C under a hydrogen atmosphere (2–3 atm) for 2 days. The mixture was filtered and the filter cake was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated under reduced pressure to give the title compound (250 mg, crude) as a yellow oil. LCMS calculated value: C 12 H 27 N2O5SSi[M+H] + : m / z = 339.1; found: 339.1.

[0726] Step 3: (S)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide

[0727]

[0728] A mixture of (S)-methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,5-thiadiazolidine-3-carboxylate 1,1-dioxide (250 mg, 0.739 mmol), lithium hydroxide monohydrate (62.0 mg, 1.48 mmol) and H2O (1 mL) in MeOH (5 mL) was stirred at 60°C for 6 h and then concentrated under reduced pressure. The residue was diluted with water (50 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. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (180 mg, 75% yield) as a yellow oil. LCMS calculated value: C 11 H 25 N2O5SSi[M+H] + : m / z = 325.1; found: 325.0.

[0729] Step 4: (S)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0730]

[0731] A mixture of (S)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (180 mg, 0.491 mmol) and (1-chloro-2-methylprop-1-en-1-yl)dimethylamine (78.8 mg, 0.589 mmol) in DCM (4 mL) was stirred at rt for 2 h. At 0°C, the above mixture was added dropwise to a mixture of 3-chloro-4-fluoro-N-methylaniline (94.1 mg, 0.589 mmol) and pyridine (77.7 mg, 0.982 mmol). The resulting mixture was stirred at rt overnight and concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (50 mL), washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0-50%) to afford the title compound (15 mg, 7% yield) as a yellow solid. LCMS calculated value: C 18 H 30ClFN3O4SSi[M+H] + : m / z = 466.1; found: 466.1.

[0732] Step 5: (S)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0733]

[0734] (S)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (15 mg, 0.032 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (8.50 mg, 0.035 mmol), N 1 ,N 2 A mixture of 1,4-dioxane (2 mL) of 1,4-dioxane (1.13 mg, 0.013 mmol), CuI (1.23 mg, 0.006 mmol) and Cs2CO3 (31.46 mg, 0.096 mmol) was stirred at 100 ° C under nitrogen overnight and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (0-50%) to give the title compound (8.0 mg, 40% yield) as a yellow solid. LCMS calculated value C 25 H 34 ClF4N4O4SSi[M+H] + : m / z = 625.17; found: 625.1.

[0735] Step 6: (S)-N-(3-chloro-4-fluorophenyl)-5-(2-hydroxyethyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0736]

[0737] A mixture of (S)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (8 mg, 0.013 mmol) in 4.0 M HCl / dioxane (2 mL) was stirred at rt for 4 h and then concentrated under reduced pressure. The crude product was purified by Prep-HPLC using ACN / H2O (40% to 70% containing 0.1% NH4HCO3 + 0.1% NH3.H2O) to afford the title compound (1.3 mg, 19% yield) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 7.47 (s, 1H), 7.29 (s, 2H), 7.05 (d, J = 7.5 Hz, 1H), 5.12-5.08 (m, 1H), 3.88-3.71 (m, 2H), 3.63 (d, J = 5.7 Hz, 2H), 3.52-3.48 (m, 2H), 3.39-3.30 (m, 3H), 2.58 (s, 3H), 2.38 (d, J = 7.5 Hz, 1H). LCMS calculated value C 19 H 20 ClF4N4O4S[M+H] + : m / z = 511.08; found: 511.1.

[0738] Example 21: (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide and

[0739] Example 22: (S)-N-(4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0740]

[0741] Step 1: (S)-2-Benzyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide

[0742]

[0743] To a mixture of (S)-2-benzyl-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester 1,1-dioxide (270 mg, 0.729 mmol, intermediate 1 step 4) in water / MeOH (30 mL, v / v=1 / 5) at 0°C was added lithium hydroxide monohydrate (61.2 mg, 1.46 mmol). The resulting mixture was stirred at rt overnight, concentrated under reduced pressure, and then diluted with water (60 mL). The mixture was acidified to pH 4 with AcOH and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound (201 mg, crude product) as a yellow semi-solid, which was used directly in the next step without further purification. LCMS calculated value C 10 H 13 N2O4S[M+H] + : m / z = 257.1; found: 257.1.

[0744] Step 2: (S)-2-Benzyl-1,2,5-thiadiazolidine-3-yl chloride 1,1-dioxide

[0745]

[0746] To a suspension of (S)-2-benzyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide (170 mg, 0.477 mmol) in dry dichloromethane (5 mL) was added oxalyl chloride (121 mg, 0.954 mmol) and DMF (catalytic amount). The resulting mixture was stirred at rt for 2 h and then concentrated under reduced pressure to afford the title compound (173 mg, crude product) as a yellow solid, which was used directly in the next step without further purification.

[0747] Step 3: (S)-2-Benzyl-N-(3-chloro-4-fluorophenyl)-N-methyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0748]

[0749] A mixture of (S)-2-benzyl-1,2,5-thiadiazolidine-3-chloride 1,1-dioxide (173 mg, 0.630 mmol) in dry dichloromethane (5 ml) was added dropwise to a solution of 3-chloro-4-fluoro-N-methylaniline (121 mg, 0.756 mmol) and pyridine (149 mg, 1.89 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred at 60 ° C overnight, then quenched with water (40 mL) and extracted with dichloromethane (50 mLx3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC and eluted with PE / EA (1 / 2) to give the target compound (71 mg, 28% yield) as an off-white solid. LCMS calculated value C 17 H 18 ClFN3O3S[M+H] + : m / z = 398.1; found: 398.0.

[0750] Step 4: (S)-2-Benzyl-N-(3-chloro-4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0751]

[0752] (S)-2-Benzyl-N-(3-chloro-4-fluorophenyl)-N-methyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (50 mg, 0.126 mmol), N 1 ,N 2 A mixture of 1,4-dioxane (3 mL) of 2-dimethylethyl-1,2-diamine (4.4 mg, 0.05 mmol), 2-bromopyridine (23.8 mg, 0.151 mmol), CuI (4.8 mg, 0.025 mmol) and Cs2CO3 (123 mg, 0.378 mmol) was stirred at 100 ° C under nitrogen overnight. The resulting mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with PE / EA (1:1) to give the target compound (49 mg, 82% yield) as a white solid. LCMS calculated value C 22 H 21 ClFN4O3S[M+H] + m / z = 475.1; found: 475.1.

[0753] Step 5: (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide and (S)-N-(4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[0754]

[0755] A mixture of (S)-2-benzyl-N-(3-chloro-4-fluorophenyl)-N-methyl-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (45.0 mg, 0.095 mmol) and Pd / C (10 mg) in EtOAc (3 mL) was stirred at 60°C under a hydrogen atmosphere (2-3 atm) for 2 h. The mixture was filtered and the filter cake was washed with EtOAc (15 mL x 3). The filtrate was concentrated under reduced pressure to give (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide as a yellow solid. LCMS calculated value: C 15 H 15 ClFN4O3S[M+H] + : m / z = 385.1; found: 385.0; and (S)-N-(4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (20 mg, 55% yield) as a yellow solid. LCMS calculated value C 15 H 16 FN4O3S[M+H] + : m / z = 351.1; found: 351.1.

[0756] Step 3: (3S)-N-(3-Chloro-4-fluorophenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-1,1-dioxo-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide and (3S)-N-(4-fluorophenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-1,1-dioxo-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide

[0757] (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide and (S)-N-(4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (20 mg, 0.052 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (15.0 mg, 0.062 mmol), N 1 ,N 2 A mixture of 1,4-dioxane (3 mL) containing 1,4-dioxane (1.83 mg, 0.021 mmol), CuI (1.98 mg, 0.010 mmol), and CsCO (50.8 mg, 0.156 mmol) was stirred at 100°C under nitrogen for 3 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous NaSO, filtered, and the filtrate concentrated and filtered under reduced pressure. The residue was purified by Prep-HPLC using ACN / H2O (62% to 92% containing 0.1% NH4HCO3 + 0.1% NH3.H2O) as the eluent to afford two products: P1 (1.9 mg, 7% yield, earlier eluting fraction) as a white solid and P2 (1.1 mg, 4% yield, later eluting fraction) as a white solid.

[0758] P1 is (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide. 1 H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 5.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.52-7.48 (m, 2H), 7.39 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.11-7.07 (m, 2H), 5.30-5.26 (m, 1H), 4.28-4.23 (m, 1H), 4.17-4.10 (m, 1H), 3.31 (s, 3H), 2.63 (s, 3H). LCMS calculated value C 22 H 19 ClF4N5O3S[M+H] + : m / z = 544.1; Found: 544.1;

[0759] P2 is (S)-N-(4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(pyridin-2-yl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide.1 H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 4.8 Hz, 1H), 7.73-7.61 (m, 1H), 7.53-7.48 (m, 4H), 7.22-7.14 (m, 2H), 7.10-7.04 (m, 2H), 5.26-5.22 (m, 1H), 4.26-4.21 (m, 1H), 4.12-4.05 (m, 1H), 3.32 (s, 3H), 2.61 (s, 3H). LCMS calculated value C 22 H 20 F4N5O3S[M+H] + : m / z = 510.1; found: 510.1.

[0760] Intermediate 1: (S)-5-methyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide

[0761]

[0762] Step 1: Benzyl-L-serine methyl ester

[0763]

[0764] To a solution of (2S)-methyl 2-amino-3-hydroxypropanoate hydrochloride (5.00 g, 32.1 mmol) and Et3N (3.90 g, 38.6 mmol) in DCM (150 mL) was added benzaldehyde (4.09 g, 38.6 mmol). The mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was diluted with MeOH (200 mL) and NaBH4 (2.43 g, 64.3 mmol) was added in small portions at 0°C. The resulting mixture was stirred at rt for 2 h. and then concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with NaHCO3 aq. (8%) (3 x 200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (5.11 g) as a light yellow oil. LCMS calculated value C 11 H 16 NO3[M+H] + : m / z = 210.1; found: 210.0.

[0765] Step 2: N-Benzyl-N-(N-(tert-butylcarbonyl)sulfamoyl)-L-serine methyl ester

[0766]

[0767] At 0 ° C, to a solution of tert-butanol (2.17 g, 29.3 mmol) in DCM (25 mL), a solution of chlorosulfonyl isocyanate (4.15 g, 29.3 mmol) in DCM (30 mL) was added dropwise. Stirred at 0 ° C for 15 min., the resulting mixture was added dropwise to a solution of (2S)-2-(benzylamino)-3-hydroxypropionic acid methyl ester (5.11 g, 24.4 mmol) and TEA (2.97 g, 29.3 mmol) in DCM (60 mL) at 0 ° C. The mixture was stirred at rt overnight. The reaction mixture was washed with water. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane / methanol (4 / 1) to give the target compound (4.8 g, 51% yield) as a light yellow oil. LCMS calculated value C 16 H 25 N2O7S[M+H] + : m / z = 389.1; found: 389.0.

[0768] Step 3: 2-(tert-Butyl)4-methyl(S)-5-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-2,4-dicarboxylic acid methyl ester

[0769]

[0770] At 0 ° C, to a solution of (2S)-2-{benzyl[(tert-butylcarbonyl)aminosulfonyl]amino}-3-hydroxypropionic acid methyl ester (4.80 g, 12.4 mmol) and PPh3 (3.89 g, 14.8 mmol) in DCM (20 mL) was added dropwise. The reaction mixture was stirred at rt overnight and quenched with water (60 mL). The mixture was extracted with DCM (100 mLx3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column and eluted with DCM / hexane (1 / 1) to give the target compound (3.80 g, 83% yield) as an off-white solid. LCMS calculated value C 16 H 23 N2O6S[M+H] + : m / z = 371.1; found: 371.1.

[0771] Step 4: (S)-2-Benzyl-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester 1,1-dioxide

[0772]

[0773] To a solution of 2-tert-butyl 4-methyl (4S)-5-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-2,4-dicarboxylic acid methyl ester (3.8 g, 10.3 mmol) in DCM (50 mL) was added TFA (2.5 mL). The resulting mixture was stirred at rt for 4 h. and then concentrated under reduced pressure to give the title compound (2.5 g, crude product) as a light yellow semi-solid, which was used directly in the next step without further purification. LCMS calculated value C 11 H 15 N2O4S[M+H] + : m / z = 271.1; found: 271.1.

[0774] Step 5: (S)-2-Benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester

[0775]

[0776] To a solution of (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (2.50 g, 9.25 mmol) and K2CO3 (3.83 g, 27.7 mmol) in DMF (40 ml) was added CH3I (6.56 g, 46.2 mmol). The mixture was stirred at rt overnight, quenched with water (100 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with DCM / petroleum ether (0-100%) to give the target compound (1.80 g, 68% yield) as a yellow semisolid. LCMS calculated value C 12 H 17 N2O4S[M+H] + : m / z = 285.1; found: 285.1.

[0777] Step 6: (S)-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester

[0778]

[0779] A mixture of (3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (1.00 g, 3.52 mmol), 10% Pd / C (100 mg) and 4M HCl / dioxane (2 mL) in methanol (100 mL) was degassed and filled with hydrogen, replacing 3 times. The mixture was stirred at 60 ° C under a hydrogen atmosphere (2-3 atm) overnight. After cooling, the mixture was filtered and washed with methanol (100 mL x 2). The filtrate was concentrated under reduced pressure to give the target compound (860 mg) as a yellow semi-solid. LCMS calculated value: C5H 11 N2O4S[M+H] + : m / z = 195.0; found: 195.0.

[0780] Step 7: (S)-5-Methyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide

[0781]

[0782] A mixture of (3S)-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (650 mg, 3.35 mmol) and lithium hydroxide monohydrate (281 mg, 6.69 mmol) in water / methanol (50 mL, v / v = 1 / 5) was stirred at rt overnight. The mixture was diluted with water (60 mL) and the pH was adjusted to 3 with HCl (aq. 1 mol / L). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (180 mg, crude product) as a yellow semisolid. LCMS calculated value: C4H9N2O4S [M+H] + : m / z = 181.0; found: 181.0.

[0783] Intermediate 2: (S)-1,1-dioxo-1,2-thiazolidine-3-carboxylic acid

[0784]

[0785] Step 1: 4,4'-disulfanyl (2S,2'S)-bis(2-aminobutyric acid methyl ester) dihydrochloride

[0786]

[0787] To a solution of (2S,2'S)-4,4'-disulfanyl-bis(2-aminobutyric acid) (5.00 g, 18.6 mmol) in methanol (60 mL) was added thionyl chloride (5.10 g, 42.8 mmol) dropwise at 0° C. The resulting mixture was stirred at rt overnight and then concentrated under reduced pressure to afford the title compound (5.00 g, 73% yield) as an orange semisolid, which was used directly in the next step without further purification.

[0788] Step 2: (S)-methyl 2-amino-4-(chlorosulfonyl)butanoate hydrochloride

[0789]

[0790] A solution of 4,4'-disulfanyl (2S,2'S)-bis(methyl 2-aminobutyrate) dihydrochloride (2.00 g, 5.47 mmol) in ethanol (10 mL) and chloroform (20 mL) was stirred at 0°C for 4 h under a chlorine atmosphere (1-2 atm). The white precipitate was collected by filtration and rinsed with chloroform. The white solid was dried to obtain the title compound (1.20 g, 88% yield). 1 H NMR (300MHz, DMSO-d6) δ 11.35 (s, 1H), 8.57 (s, 1H), 3.75-3.68 (m, 3H), 3.35-2.92 (m, 1H), 2.69-2.55 (m, 2H), 2.41-1.80 (m, 2H).

[0791] Step 3: Methyl (3S)-1,1-dioxo-1,2-thiazolidine-3-carboxylate

[0792]

[0793] A solution of (2S)-2-amino-4-sulfobutyric acid methyl ester hydrochloride (1.20 g, 4.80 mmol) and DIEA (2.16 g, 14.4 mmol) in DCM (20 mL) was stirred at rt overnight and then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (660 mg, 76% yield) as a yellow semisolid. LCMS calculated for C5H 10 NO4S[M+H] + : m / z = 180.0; found: 180.1.

[0794] Step 4: (S)-1,1-dioxo-1,2-thiazolidine-3-carboxylic acid

[0795]

[0796] A solution of (3S)-1,1-dioxo-1,2-thiazolidine-3-carboxylic acid methyl ester (200 mg, 1.11 mmol) and lithium hydroxide monohydrate (93.6 mg, 2.23 mmol) in ethanol (5 mL) and water (1 mL) was stirred at rt for 4 h. The reaction mixture was adjusted to pH ~4 with 1 M HCl aq., diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (170 mg, 92% yield) as a yellow semisolid.

[0797] Intermediate 3: (S)-5-ethyl-1,2,5-thiadiazolidine-3-carboxylic acid 1,1-dioxide

[0798]

[0799] This compound was prepared in a similar manner to Intermediate 1, Steps 5-7, except that iodoethane was used instead of iodomethane in Step 5. LCMS calculated value: C5H 11 N2O4S[M+H] + : m / z = 195.0; found: 195.1.

[0800] Example A: Biological Testing

[0801] PolQ polymerase test

[0802] The PolQ polymerase assay was used to test compounds for their ability to inhibit PolQ C-terminal activity in vitro. C-terminal His6-tagged 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 MgCl2, 5% glycerol, 0.01% Triton X-100, 0.01% BSA, and 1 mM DTT. Compounds dissolved in DMSO were pipetted into two wells of a 384-well assay plate (PerkinElmer, Catalog #: 6008269) using a dispenser (Labcyte, Echo665) and tested at 10 concentrations in a 3-fold serial dilution. Add 5 μL of enzyme mix [h PolQ-C (C-terminal His6-tag, 29.3 μM), final concentration 2.5 nM] to the test wells. Cover the test plate and incubate at room temperature for 15 minutes, then add 5 μL of substrate mix [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 of 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).

[0803] %Inhibition=(Signal Ave_HC -Signal cmpd ) / (Signal Ave_HC -Signal Ave_LC )×100%.

[0804] IC 50 The values ​​were determined by fitting the data to a standard 4-parameter using Hill Slope using GraphPad Prism software.

[0805] +++<=0.1μM, 0.1μM<++<=1μM, +>1μM.

[0806] Table 1. PolQ polymerase

[0807]

[0808] Cell viability test

[0809] Cell viability studies were performed on Ishikawa cells. Cells were grown in a 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 at 600 cells / well in 96-well assay plates (PerkinElmer, Catalog #: 6005680). Compounds dissolved in DMSO were pipetted into two wells of the assay plate using a multichannel pipette and tested at nine concentration points in a 3-fold serial dilution. Cells were incubated for 7 days in a humidified incubator at 37°C with 5% CO2. Cell viability was assessed using the Cell Titer-Glo reagent (Promega, Catalog #: G7573) according to the manufacturer's instructions. Fluorescence signals were measured using a multi-plate tester (Perkin Elmer, Envision 2105 or BMG, ClarioStar Plus). The average value of the wells treated with DMSO in the test plate was calculated as the high control (HC). The average value of the wells treated with medium alone in the test plate was calculated as the low control (LC).

[0810] %inhibition=(Signal Ave_HC -Signal cmpd ) / (Signal Ave_HC -Signal Ave_LC )×100%.

[0811] IC 50 The values ​​were determined by fitting the data to a standard 4-parameter using Hill Slope using GraphPad Prism software.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof, characterized in that: in: L is Among them, * is connected to the N-atom, and ** is connected to the C-atom; Ar 1 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by m independently selected from R 10 Substituents are substituted; Ar 2 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by r independently selected from R 11 Substituents are substituted; R 1 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 independently selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl; or R 1 and Ar 2 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl; R 2 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 independently selected from R 2A Substituents are substituted; Every R 2A 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 independently 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 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)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 ; or R 1 and R 2 The heterocyclic group, taken together with the atoms to which it is attached, forms a 5-7 membered heterocyclic group, optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl; R 3 and R 4 are 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 independently selected from R 12 or R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-, -C(S)-, C3-C7 cycloalkyl, or 4-7 membered heterocyclyl, wherein the C3-C7 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl; or R on adjacent carbon atoms 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl; R 5 and R 6 are independently selected from H, D, halogen, CN, OR A , 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 independently selected from R 12 or R 5 and R 6 The C3-C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d ;or R 3 and R 5 , R 4 and R 5 , R 3 and R 6 or R 4 and R 6 The C3-C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d ; R 3 , R 4 , R 5 and R 6 Together with the carbon atom it is attached to, it forms a C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , NR c R d , C(O)R b , C(O)NR c R d , NR c C(O)R b , NR c S(O)2R b , S(O)2NR c R d , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OR a , C1-C6 haloalkyl-OR a , C1-C6 alkyl-NR c R d ; R 7 Selected from H, D, CN, OR A , C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein the C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by at least one substituent selected from the following: D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl; or R 7 and R 5 or R 7 and R 6 The 5-7 membered partially saturated heterocyclyl group, together with the atoms to which it is attached, is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, CF3, NO2, oxo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl; R 8 Independently selected from H, D, CN, OR A , C(O)OR A , C(O)R B , C(O)NR C R D ,S(O)R B , S(O)NR C R D , S(O)2R B , S(O)2NR C R D , C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 or R 3 and R 8 or R 4 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group which is optionally substituted by 1, 2, 3 or 4 independently selected R 13 Substituents are substituted; R 3 , R 4 and R 8 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl group which is optionally substituted by 1, 2, 3 or 4 independently selected R 13 or R 7 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group which is optionally substituted by 1, 2, 3 or 4 independently selected R 13 Substituents are substituted; R 9 is selected from phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein the phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by at least one substituent independently selected from the following: D, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl; Every R 10 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 optionally substituted by a substituent independently 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 10 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein the C 3- C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, or 3 independently selected from R 13 Substituents are substituted; Every R 11 independently selected from H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-C 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 independently selected from R 12 or Two adjacent R 11 Together with the atoms to which it is attached, it forms C 3- C7 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3- C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, or 3 independently selected from R 13 Substituents are substituted; 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 ), 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 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 ), 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 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 14 Substituents are substituted; Every R 14 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, 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 substituted by 1, 2, or 3 independently selected from R 15 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 independently selected from R 15 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 independently selected from R 15 or R C and R D The 4-7 membered heterocyclyl formed together with the N atom to which it is attached is optionally substituted with 1, 2, or 3 substituents independently 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 independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), 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 is optionally substituted with 1, 2, or 3 substituents independently 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 independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), 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 independently selected from: 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 independently 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 heterocyclic group formed by the N atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently 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, C1-C4 alkoxy-C1-C4 alkoxy; or R c1 and R d1 The heterocyclic group formed by the N atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently 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 independently selected from R 15 Substituents are substituted; Every R 15 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, 3 or 4; n is 1 or 2; r is 1, 2, 3 or 4.

2. The compound according to claim 1, characterized in that R 1 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 independently selected from the following: D, halogen, CN, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

3. The compound according to claim 1 or 2, characterized in that R 2 is 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 independently selected from R 2A substituted by a substituent.

4. The compound according to claim 1 or 2, characterized in that R 1 and R 2 The heterocyclic group, taken together with the atoms to which it is attached, forms a 5-7 membered heterocyclic group, optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, C1-C3 alkyl-OH, C1-C3 haloalkyl-OH, C1-C3 alkyl-NR c R d , C1-C3 haloalkyl-NR c R d , -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

5. The compound according to any one of claims 1 to 4, characterized in that Ar 1 C6-C 10 The aryl group is optionally substituted by m independently selected from R 10 Preferably, Ar 1 is phenyl or naphthyl, each of which is optionally substituted by m independently selected from R 10 Preferably, Ar 1 is phenyl optionally substituted by m independently selected from R 10 substituted by a substituent.

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

7. The compound according to claim 6, characterized in that Ar 1 is a 5-6 membered heteroaryl group optionally substituted by m independently selected from R 10 substituted by a substituent.

8. The compound according to claim 7, characterized in that Ar 1 is a 6-membered heteroaryl group optionally substituted by m independently selected from R 10 substituted by a substituent.

9. The compound according to claim 8, characterized in that Ar 1 is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; each substituent is optionally substituted by m independently selected from R 10 Preferably, Ar 1 is pyridyl or pyrimidinyl; each substituent is optionally substituted by m independently selected from R 10 substituted by a substituent.

10. The compound according to any one of claims 1, 5 to 9, characterized in that Every R 10 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 optionally substituted by substituents independently 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.

11. The compound according to any one of claims 1 to 10, characterized in that Ar 2 C6-C 10 Aryl is optionally substituted by r independently selected from R 11 Preferably, Ar 2 is phenyl or naphthyl, each substituent is optionally substituted by r independently selected from R 11 Preferably, Ar 2 is phenyl optionally with r independently selected from R 11 substituted by a substituent.

12. The compound according to any one of claims 1 to 10, characterized in that Ar 2 is a 5-10 membered heteroaryl group optionally substituted by r independently selected from R 11 Preferably, Ar 2 is 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, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, [2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,4-c]pyridinyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furo[3,2-b]pyridinyl, furo[3,2-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, 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[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] thiazolyl, thiazolo[5,4-d]thiazolyl, thiazolo[4,5-d]thiazolyl, thiazolo[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 replaced by r independently selected from R; 11 substituted by a substituent.

13. The compound according to any one of claims 1, 11-12, characterized in that Every R 11 independently selected from H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkyl-C 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, C3-C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 Substituents of Cy 1 Optionally 1, 2, 3, 4, or 5 independently selected from R 14 substituted by a substituent.

14. The compound according to any one of claims 1 to 10, characterized in that R 1 and Ar 2 The heterocyclic group formed together with the atoms to which it is attached to form a 5-7 membered group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, oxo, OH, -O-C1-C3 alkyl, -OC1-C3 haloalkyl.

15. The compound according to any one of claims 1 to 14, characterized in that Every R 3 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 independently selected from R 12 substituted by a substituent.

16. The compound according to any one of claims 1 to 15, characterized in that Every R 4 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 independently selected from R 12 substituted by a substituent.

17. The compound according to any one of claims 1 to 14, characterized in that R 3 and R 4 Together with the carbon atom to which it is attached, it forms -C(O)-, -C(S)-, C3-C7 cycloalkyl, or 4-7 membered heterocyclyl; wherein the C3-C7 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl; or R on the adjacent carbon atom 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl, a 4-7 membered heterocyclic group, a C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

18. The compound according to any one of claims 1 to 17, characterized in that R 5 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 independently selected from R 12 substituted by a substituent.

19. The compound according to any one of claims 1 to 18, characterized in that R 6 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 independently selected from R 12 substituted by a substituent.

20. The compound according to any one of claims 1 to 17, characterized in that R 5 and R 6 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group; wherein the C3-C7 cycloalkyl group, or the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

21. The compound according to any one of claims 1 to 17, characterized in that R 3 and R 5 , R 4 and R 5 , R 3 and R 6 or R 3 and R 6 The C3-C7 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 haloalkyl-OH, C1-C6 alkyl-NR c R d .

22. The compound according to any one of claims 1 to 17, characterized in that R 3 , R 4 , R 5 and R 6 Together with the carbon atom it is attached to, it forms a C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , NR c R d , C(O)R b , C(O)NR c R d , NR c C(O)R b , NR c S(O)2R b , S(O)2NR c R d , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl-OR a , C1-C6 haloalkyl-OR a , C1-C6 alkyl-NR c R d .

23. The compound according to any one of claims 1 to 22, characterized in that R 7 Selected from H, D, CN, OR A , C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein, the C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by at least one substituent independently selected from the following: D, halogen, CN, NO2, oxo, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

24. The compound according to any one of claims 1 to 22, characterized in that R 7 and R 5 or R 7 and R 6 The partially saturated heterocyclyl group, which together with the atoms to which it is attached forms a 5-7 membered group, is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, CF3, NO2, oxo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

25. The compound according to any one of claims 1 to 24, characterized in that R 8 Independently selected from H, D, CN, OR A , C(O)OR A , C(O)R B , C(O)NR C R D ,S(O)R B , S(O)NR C R D , S(O)2R B , S(O)2NR C R D , C0-C6 alkyl-Cy 1 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent.

26. The compound according to any one of claims 1 to 24, characterized in that R 3 and R 8 or R 4 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group which is optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

27. The compound according to any one of claims 1 to 24, characterized in that R 3 , R 4 and R 8 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl group which is optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

28. The compound according to any one of claims 1 to 24, characterized in that R 7 and R 8 Together with the atoms to which they are attached, they form a 5-7 membered heterocyclic group which is optionally substituted by 1, 2, 3 or 4 independently selected R 13 substituted by a substituent.

29. The compound according to any one of claims 1 to 28, characterized in that R 9 is phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl; wherein the phenyl, C1-C6 alkyl, -C1-C6 alkyl-C3-C7 cycloalkyl or -C1-C6 alkyl-4-7 membered heterocyclyl is optionally substituted by at least one substituent independently selected from the following: D, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

30. The compound according to any one of claims 1 to 29, characterized in that The compound represented by formula (I) is represented by formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein L, Ar 1 ,Ar 2 , R 1 , R 2 , R 3 and R 4 The same as defined in formula (I).

31. The compound according to claim 30, characterized in that The compound represented by formula (I) is as follows: (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and (IIh): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The same as defined in formula (I).

32. The compound according to claim 31, characterized in that The compound represented by formula (I) is as follows: (IIa), (IIb), (IIc), (IId), (IIe) and (IIf): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The same as defined in formula (I).

33. The compound according to claim 32, characterized in that The compound represented by formula (I) is as follows: (IIb), (IIc), (IId), and (IIe): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The same as defined in formula (I).

34. The compound according to claim 33, characterized in that The compound represented by formula (I) is represented by formula (IId) and (IIe): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The same as defined in formula (I).

35. The compound according to claim 33, characterized in that The compound represented by formula (I) is represented by formula (IIb) and (IIc): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 The same as defined in formula (I).

36. The compound according to any one of claims 1 to 29, characterized in that The compound represented by formula (I) is represented by formula (III): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , and L are defined as in formula (I).

37. The compound according to claim 36, characterized in that The compound represented by formula (I) is represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg) and (IIIh): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The same as defined in formula (I).

38. The compound according to claim 37, characterized in that The compound represented by formula (I) is represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) and (IIIf) are shown as follows: or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The same as defined in formula (I).

39. The compound according to claim 38, characterized in that The compound represented by formula (I) is represented by formula (IIIa), (IIIb), (IIIc) and (IIIf) are shown as follows: or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The same as defined in formula (I).

40. The compound according to any one of claims 1 to 39, characterized in that The compound represented by formula (I) is as follows (IVa), (IVb), (IVc) and (IVf) are shown as follows: or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The same as defined in formula (I).

41. The compound according to claim 40, characterized in that The compound represented by formula (I) is as follows: (Va), (Vb), (Vc) and (Vf) are shown as follows: or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The same as defined in formula (I).

42. The compound according to claim 41, characterized in that The compound represented by formula (I) is as follows: (VIa), (VIb), (VIc) and (VIf) are shown as follows: or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 1 ,Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 The same as defined in formula (I).

43. The compound according to claim 42, characterized in that The compound represented by formula (I) is represented by formula (VIIa), (VIIb), and (VIIc): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 10 and m are the same 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), and (VIIIc): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 10 The same 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 (IXa), (IXb), and (IXc): or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer, isotopic variant, prodrug, N-oxide or deuterated compound thereof; wherein each Ar 2 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 The same as defined in formula (I).

46. ​​The compound according to any one of claims 1 to 45, characterized in that The compound is: or a pharmaceutically acceptable salt thereof.

47. The compound according to claim 46, characterized in that The compound is: or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

49. A method for treating and / or preventing a patient having a PolQ overexpressing cancer, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutical composition according to claim 48.

50. 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 47, or a pharmaceutical composition according to claim 48.

51. 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 to the patient a therapeutically effective amount of the compound according to any one of claims 1-47, or the pharmaceutical composition according to claim 48.

52. 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 according to any one of claims 1-47, or the pharmaceutical composition according to claim 48 to the patient.

53. 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 a compound according to any one of claims 1-47, or a pharmaceutical composition according to claim 48.

54. 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 according to any one of claims 1-47, or the pharmaceutical composition according to claim 48.

55. Use of the compound according to any one of claims 1 to 47 or the pharmaceutical composition according to claim 48 in the preparation of a drug for treating a disease in which PolQ is overexpressed in a patient.

56. Use of the compound of any one of claims 1 to 47 or the pharmaceutical composition of claim 48 in the preparation of a medicament for treating a disease with increased dependence on MMEJ-DSB repair.

57. Use of the compound according to any one of claims 1 to 47 or the pharmaceutical composition according to claim 48 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.

58. Use of the compound according to any one of claims 1 to 47 or the pharmaceutical composition according to claim 48 in the preparation of a drug for treating cancer, characterized in that: The cancer lacks the 53BP1 / Shieldin complex.

59. Use of the compound according to any one of claims 1 to 47 or the pharmaceutical composition according to claim 48 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.

60. Use of the compound according to any one of claims 1 to 47 or the pharmaceutical composition according to claim 48 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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