Cyclic derivative as well as composition and application thereof

Abstract

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

Description

[0001] Cross-references to related applications

[0002] This invention claims the benefits of international applications filed on May 5, 2023 (PCT / CN2023 / 092300), June 26, 2023 (PCT / CN2023 / 102459), and September 28, 2023 (PCT / CN2023 / 122431), the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to cyclic derivatives as PolQ inhibitors and pharmaceutical compositions thereof. The invention also relates to methods for preparing the cyclic derivatives and their application in treating PolQ-mediated diseases, such as cancers with DNA repair defects. Background Technology

[0004] DNA damage repair processes are crucial for genome maintenance and cell viability. Double-strand breaks (DSBs) can be repaired through any of three main pathways: homologous recombination (HR), non-homologous end joining (NHEJ), and alternative non-homologous end joining (alt-NHEJ). Alternative non-homologous end joining (alt-NHEJ), also known as micro-homologous stage end joining (MMEJ), is often considered a "backup" DSB repair pathway when NHEJ or HR is impaired (Truong et al., PNAS 2013, 110(19), 7720-7725).

[0005] Abnormal DNA damage response (DDR) often sensitizes cancer cells to specific types of DNA damage. Therefore, defective DDR can be developed into targeted cancer therapies. DNA repair defects have become a proven and effective strategy in cancer treatment. For example, poly(ADP-ribose) polymerase (PARP) inhibitors have been successful in treating BRCA-deficient breast, ovarian, prostate, and pancreatic cancers (Audeh MW et al., Lancet (2010); 376(9737): 245-51).

[0006] Numerous genetic, cell biological, and biochemical studies have shown that DNA polymerase theta (PolQ, UniProtKB-075417 (DPOLQ_HUMAN)) is a key protein involved in MMEJ (Kent et al., Nature Structural & Molecular Biology (2015), 22(3), 230-237; Mateos-Gomez et al., Nature (2015), 518(7538), 254-257).

[0007] PolQ is unique among human DNA polymerases, containing an N-terminal helicase domain (SF2 HEL308 type) and a C-terminal low-fidelity DNA polymerase domain (type A) (Wood & Doublie DNA Repair (2016), 44, 22-32). In homologous recombination-deficient (HRD) cells, PolQ can perform error-prone DNA synthesis at DNA damage sites via the alt-NHEJ pathway. Studies have shown that the helicase domain of PolQ mediates the removal of RPA protein from the ssDNA terminus and stimulates annealing. PolQ's anti-recombinase activity promotes the alt-NHEJ pathway. Furthermore, the helicase domain of PolQ facilitates microhomology-mediated chain annealing (Chan SH et al., PLoS Genet. (2010); 6: el001005; and Kawamura K et al., Int. J. Cancer (2004); 109: 9-16). When the ssDNA overhang contains microhomology of >2 bp base pairs, PolQ can promote end joining in the alt-NHEJ pathway by utilizing this annealing activity (Kent T et al., Elife (2016); 5: el3740, and Kent T et al., Nat. Struct. Mol. Biol. (2015); 22: 230-237). This re-annealing activity is achieved through the mutual coupling of Rad51, followed by ATPase-mediated displacement of Rad51 from the DSB lesion site. After annealing, the polymerase domain extends the ssDNA end and fills the remaining gap.

[0008] PolQ is expressed at low levels in normal cells, but is significantly overexpressed in HRD ovarian cancer, uterine cancer, and breast cancer subsets, and PolQ overexpression is associated with poor prognosis (Higgins et al., Oncotarget (2010), 1, 175-184; Lemee et al., PNAS (2010), 107(30), 13390-13395; Ceccaldi et al., (2015), supra). Recent studies have shown that cancer cells deficient in HR, NHEJ, or ATM are highly dependent on PolQ expression (Ceccaldi R. et al., Nature (2015); 518: 258-62; Mateos-Gomez PA et al., Nature (2015); 518: 254-57; and Wyatt DW et al., Mol. Cell (2016); 63: 662-73). Therefore, PolQ inhibition may prevent the reversal of MMEJ-dependent function in BRCA1 or BRCA2 mutations, a reversal that underlies cisplatin and PARPi resistance in tumors (Zatreanu D. et al., Nature Communications (2021) 12: 3636). Thus, PolQ is an attractive target for synthetic lethal therapies against cancers with DNA repair defects. This invention provides a series of compounds with pharmaceutical properties. Summary of the Invention

[0009] This invention provides a compound represented by formula (I),

[0010]

[0011] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof; wherein the definitions of each variable are as defined in this invention.

[0012] On the other hand, the present invention also provides a pharmaceutical composition comprising: a compound of formula (I), or a pharmaceutically acceptable salt thereof, a solvate, a tautomer, a stereoisomer, a transisomer, an isotope derivative, a prodrug, an N-oxide or a deuterated compound, and at least one pharmaceutically acceptable carrier.

[0013] On the other hand, the present invention provides a method for suppressing PolQ, comprising:

[0014] Contact PolQ with the compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof.

[0015] 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 of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof.

[0016] Details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will become apparent from the specification and claims. Invention Details

[0018] The invention can be more fully understood by referring to the following description, including the definitions and embodiments. Certain features of the compositions and methods of the invention described in different contexts may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, various features of the compositions and methods of the invention described in the context of a single aspect may also be provided individually or in any sub-combination.

[0019] 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 in the present invention is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention.

[0020] This invention particularly relates to a compound represented by formula (I):

[0021]

[0022] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound, wherein:

[0023] Ring A is C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl or 5-14 heteroaryl groups;

[0024] Ring B is a partially unsaturated 5-14 membered heterocyclic group, C6-C 14 Aryl or 5-14 heteroaryl groups;

[0025] The ring C is an 8-14 member heteroaryl group, optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R. 6 Substituents; wherein the 8-14 membered heteroaryl group comprises at least one aromatic ring;

[0026] m is 1, 2, 3, 4 or 5;

[0027] n is 1, 2, 3, 4 or 5;

[0028] Each R1 The elements are selected independently from H, D, halogens, -CN, -NO2, N3, -SF5, oxo, and C. 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl, -NR C R D -OR A -SR A -NR C OR A , -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C C(O)R B , -S(O)R B -S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR C S(O)2NR C R D -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F ; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl are optionally represented by 1, 2, 3, 4, or 5 independently selected from R 1A Substituents; or

[0029] Two Rs 1 Together with the atoms it is attached to, it forms an oxo group, C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein, the C 3-C7 cycloalkyl or 4-7 membered heterocyclic groups are optionally surrounded by 1, 2, 3, 4 or 5 groups, each independently selected from R 1A Substituents of the substituents;

[0030] Each R 1A Each is independently selected from D, halogen, CN, -NO2, N3, oxo, OR a NR c R d C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C 3- C6 cycloalkyl or 4-6 membered heterocyclic groups may optionally be substituted with the following substituents: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a C 1- C6 alkyl, C 1- C6 haloalkyl;

[0031] Each R 2 Each element is independently selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, -NR C R D -OR A -SR A -NR C OR A , -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C C(O)R B , -S(O)R B -S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR C S(O)2NR C RD -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 2A Substituents; or

[0032] Two Rs 2 Together with the atoms to which it is attached, it forms an oxo, C3-C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group is optionally composed of 1, 2, 3 or 4 atoms, each independently selected from R 2A Substituents of the substituents;

[0033] Each R 2A Each of the following is independently selected from D, halogen, CN, OH, NH2, NO2, SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, NR c R d OR a SR 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 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)Rb S(O)NR c R d S(O)2R b NR c S(O)2R d 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with the following substituents: D, halogen, CN, OH, NH2, oxo, NR c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl;

[0034] R 3 For H, D, halogen, CN, oxo, NO2, SF5, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 heteroaryl, OR A SR A NR C OR A NR C R D C(O)R B C(O)NR C R D NR C C(O)R B NR C C(O)OR A NR C S(O)2R D NR C S(O)2NR C R D S(O)R B S(O)2R B ; wherein, the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 10 aryl, 5-14 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 4 Substituents of the substituents;

[0035] Each R 4 Each is independently selected from D, halogen, CN, NO2, N3, oxo, and NR. C R D OR A SR A NR C OR 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 C(O)R B NR C C(O)NR C R D NR C C(O)OR A S(O)R B S(O)2R B S(O)NR C R D NR C S(O)2R D S(O)2NR C R D NR C S(O)2NR C R D NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10Aryl, C3-C 10 Cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic groups optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R 5 Substituents of the substituents;

[0036] Each R 5 Independently selected from D, CN, halogen, NO2, SF5, oxo, selectively substituted C1-C6 alkyl, selectively substituted C2-C6 alkenyl, selectively substituted C2-C6 alkynyl, selectively substituted C3-C6 cycloalkyl, selectively substituted 4-6 membered heterocyclic groups, OR a SR 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)2R d S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ;

[0037] Each R 6 Each element is independently selected from H, D, halogen, CN, NO2, -N3, oxo, SF5, and NR. C R D OR A SR A SiR G R H R I B(OR)C (OR) D ), -P(O)R E R F C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group is optionally composed of 1, 2, 3, 4, or 5 groups, each independently selected from R 6A Substituents of the substituents;

[0038] Two Rs 6 Oxyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic groups are formed together on the same carbon atom; wherein, the C3-C7 cycloalkyl, 4-7 membered heterocyclic groups are optionally composed of 1, 2, 3 or 4 independently selected from R 6A Substituents of the substituents;

[0039] Two adjacent R 6 Together with the atoms to which they are attached, they form a C3-C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group is optionally composed of 1, 2, 3 or 4 atoms, each independently selected from R 6A Substituents of the substituents;

[0040] Each R 6A The groups are independently selected from D, halogen, CN, OH, NH2, NO2, SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, and NR. c R d OR a SR 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 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 Rd S(O)2R b NR c S(O)2R d 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl;

[0041] Each R A Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NRc 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 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 ;

[0042] Each R B Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a C(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)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 B(OR) c (OR) d );

[0043] R C and R D Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a OC(O)NR c R d NR c R d NR c C(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 B (OR) c (OR) d );

[0044] Or R C and R D Together with the N atom to which it is attached, it forms a 4-7 membered heterocyclic group, which may be optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;

[0045] R a and R a1 Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 alkyl group is a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C3-C6 alkyl group. 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, halogen, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl;

[0046] R b and R b1 Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic;

[0047] R c R d R c1 R d1 Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 Aryl, or bis(5-10 heteroaryl); wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 The aryl group, or bis(5-10 heteroaryl group), is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10Aryl, 5-10 heteroaryl, C(O)OR a1 C(O)R b1 S(O)2R b1 C1-C4 alkyl-O-C1-C4 alkyl or C1-C4 alkyl-O-C1-C4 alkyl-O-;

[0048] Or R c and R d Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkoxy-C1-C4 alkoxy;

[0049] Or R c1 and R d1 Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkoxy-C1-C4 alkoxy;

[0050] R E and R e Each of the following is 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 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 heterocyclic-C1-C4 alkyl;

[0051] R F and R fEach is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl groups, or 4-10 membered heterocyclic groups;

[0052] R G R H and R I Each is independently selected from selectively substituted C1-C4 alkyl groups or selectively substituted phenyl groups.

[0053] In some implementations, ring A is C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl or 5-14 heteroaryl compounds.

[0054] In some implementations, ring A is C3-C 14 Cycloalkyl.

[0055] In some implementations, ring A is saturated C3-C 14 cycloalkyl or partially unsaturated C3-C 14 Cycloalkyl.

[0056] In some implementations, ring A is a 4-14 membered heterocyclic group.

[0057] In some embodiments, ring A is a saturated 4-14 membered heterocyclic group or a partially unsaturated 4-14 membered heterocyclic group.

[0058] In some implementations, ring A is C6-C. 14 Aryl. In some embodiments, ring A is C6-C. 10 Aryl.

[0059] In some embodiments, ring A is phenyl, naphthyl, anthraceneyl, or phenanthrene. In some embodiments, ring A is phenyl.

[0060] In some implementations, ring A is a 5-14 membered heteroaryl group.

[0061] In some embodiments, ring A is a 5-14 membered heteroaryl group having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.

[0062] In some embodiments, ring A is a 5-10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring A is a 5-10-membered heteroaryl group having one or two heteroatoms independently selected from N, O, or S. In some embodiments, ring A is a 5-6-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring A is a 6-membered heteroaryl group having 1, 2, or 3 heteroatoms independently selected from N.

[0063] In some embodiments, ring A is pyrroloyl, furanyl, thiophene, imidazoyl, oxazolyl, thiazoyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophene, benzo[c]thiophene, indolyl, benzo[d]imidazoyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3- c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,4-c]pyridyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, furano[2,3-b]pyridyl, benzo[c]isoxazolyl, furano[3,4-b]pyridyl, furano[3,4-c]pyridyl, benzo[d]isothiazolyl Benz[d]thiazolyl, thieno[3,2-b]pyridyl, thieno[3,4-c]pyridyl, benzo[d][1,2,3]triazolyl, pyrazolo[4,3-b]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-b]pyridyl, pyridyl 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. In some embodiments, ring A is pyridinyl.

[0064] In some embodiments, ring A is phenyl or a 6-membered heteroaryl group having one or two heteroatoms independently selected from N.

[0065] In some implementations, the It has the following structure: Among them, Z 1 Z 2 Z 3 Z 4 Z 5 Selected independently from N or CR 1 .

[0066] In some implementation schemes, Z 1 Z 2 Z 3 Z 4 Z 5 One of them is N.

[0067] In some implementation schemes, Z 1 Z 2 Z 3 Z 4 Z 5 Two of them are N.

[0068] In some implementation schemes, Z 1 Z 2 Z 3 Z 4 Z 5 All are CR 1 .

[0069] In some implementations, the It has the following structure:

[0070] In some implementations, the It has the following structure: In some implementations, the It has the following structure: In some implementations, the It has the following structure: In some implementations, the It has the following structure:

[0071] In some implementations, the It has the following structure: In some implementations, the It has the following structure:

[0072] In some implementations, the It has the following structure:

[0073] In some implementations, the It has the following structure:

[0074] In some implementations, ring B is a partially unsaturated 5-14 membered heterocyclic group, C6-C 14 Aryl or 5-14 heteroaryl compounds.

[0075] In some implementations, ring B is a partially unsaturated 5-14 membered heterocyclic group.

[0076] In some implementations, ring B is C6-C. 14 Aryl. In some embodiments, ring B is C6-C. 10 Aryl.

[0077] In some embodiments, ring B is phenyl, naphthyl, anthraceneyl, or phenanthryl. In some embodiments, ring B is phenyl.

[0078] In some embodiments, the cyclic B is a 5-14 membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, the cyclic B is a 5-10 membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, the cyclic B is a 5-6 membered heteroaryl group having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the cyclic B is a 5-6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, the cyclic B is a 5-6 membered heteroaryl group having 1 or 2 heteroatoms independently selected from N.

[0079] In some embodiments, ring B is pyrroloyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridyl, pyridyl, indolyl, isoindolyl, inazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophene, benzo[c]thiophene, indolyl, benzo[d]imidazolyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3- [b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,4-c]pyridyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, furano[2,3-b]pyridyl, benzo[c]isoxazolyl, furano[3,4-b]pyridyl, furano[3,4-c]pyridyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, thieno[3,2-b]pyridyl, thieno[d]isothiazolyl [3,4-c]pyridyl, benzo[d][1,2,3]triazolyl, pyrazolo[4,3-b]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-b]pyridyl, pyrrolo[3,2-c]pyridazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[3,2-c]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, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl or 1,2,4-triazin-5(4H)-keto.

[0080] In some embodiments, ring B is a 5- or 6-membered heteroaryl group. In some embodiments, ring A is imidazolyl, pyridinyl, or pyridazinyl. In some embodiments, ring A is imidazolyl or pyridinyl.

[0081] In some implementations, the It has the following structure: Among them, X 1 X 2 X 3 X 4 Selected independently from N or CR 2 ;X5 For NR 2 , O or S; the * is connected to -C(=O)NH-, and the ** is connected to ring A.

[0082] In some implementations, the It has the following structure: In some implementation schemes, X 1 X 2 X 3 X 4 One of them is N, where X 1 X 2 X 3 , and X 4 As defined in this invention. In some embodiments, X 1 X 2 X 3 , and X 4 One of them is N; the other three are independently selected from CR. 2 , where R 2 As defined in this invention. In some embodiments, X 1 X 2 X 3 , and X 4 Two of them are randomly selected as N; the other two are independently selected from CR. 2 , where R 2 As defined in this invention. In some embodiments, X 1 X 2 X 3 , and X 4 Selected independently from CR 2 , where R 2 As defined in this invention.

[0083] In some implementations, the It has the following structure: Where R 2 X 1 , and X 4 As defined in this invention.

[0084] In some implementations, the It has the following structure: Where X 1 X 2 , and X 3 As defined in this invention. In some embodiments, X 1 X 2 , and X 3 One of them is N; the other two are independently selected from CR. 2 , where R2 As defined in this invention. In some embodiments, X 1 X 2 , and X 3 Any two of them are N; and the other one is CR. 2 , where R 2 As defined in this invention. In some embodiments, X 1 X 2 , and X 3 Selected independently from CR 2 , where R 2 As defined in this invention.

[0085] In some implementations, the It has the following structure: Among them, each X 1 X 3 , and X 5 As defined in this invention. In some embodiments, each X 1 and X 3 Selected independently from CR 2 ; and X 5 For NR 2 , O or S; where each R 2 As defined in this invention. In some embodiments, X 1 For N; X 3 For CR 2 ; and X 5 For NR 2 , O or S; where each R 2 As defined in this invention. In some embodiments, X 1 For CR 2 ;X 3 For N; and X 5 For NR 2 , O or S; where each R 2 As defined in this invention. In some embodiments, X 1 For N; X 3 For N; and X 5 For NR 2 , O or S; where R 2 As defined in this invention.

[0086] In some implementations, the It has the following structure: Each of R 2 As defined in this invention.

[0087] In some implementations, the It has the following structure: in,

[0088] Each R 2 As defined in this invention.

[0089] In some implementations, the It has the following structure: Among them, each R 2 As defined in this invention.

[0090] In some implementations, the It has the following structure: Each of R 2 As defined in this invention. In some embodiments, the... It has the following structure: Each of R 2 As defined in this invention. In some embodiments, the... It has the following structure: Each of R 2 As defined in this invention. In some embodiments, the... It has the following structure: Among them, each R 2 As defined in this invention. In some embodiments, the... It has the following structure: Among them, each R 2 As defined in this invention.

[0091] In some implementations, the It has the following structure:

[0092] In some embodiments, the cyclic C is an 8-14 member heteroaryl group optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R. 6 Substituents are used to replace the 8-14 member heteroaryl group; wherein the heteroaryl group comprises at least one aromatic ring.

[0093] In some embodiments, the cyclic C is an 8-14 member heteroaryl group optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R. 6 Substituents are substituted.

[0094] In some embodiments, the cyclic C is an 8-14 member monoheteroaryl group optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R. 6 Substituents are substituted.

[0095] In some embodiments, the cyclic C is an 8-14 membered diheteroaryl group optionally surrounded by 1, 2, 3, 4, or 5 members, each independently selected from R. 6 Substituents are used to replace the 8-14 member heteroaryl group; wherein the heteroaryl group comprises at least one aromatic ring.

[0096] In some embodiments, the cyclic C is an 8-14 membered diheteroaryl group optionally surrounded by 1, 2, 3, 4, or 5 members, each independently selected from R. 6 The substituents are substituted; wherein the 8-14 membered heteroaryl group comprises at least one aromatic ring, and the other ring is an aromatic ring, a saturated heterocyclic group, a partially unsaturated heterocyclic group, a saturated cycloalkyl group, or a partially unsaturated cycloalkyl group.

[0097] In some embodiments, the cyclic C is an 8-10 membered diheteroaryl group optionally surrounded by 1, 2, 3, 4, or 5 members, each independently selected from R. 6 The substituents are substituted; wherein the 8-10 member heteroaryl group comprises at least one aromatic ring, and the other ring is an aromatic ring, a saturated heterocyclic group, a partially unsaturated heterocyclic group, a saturated cycloalkyl group, or a partially unsaturated cycloalkyl group.

[0098] In some embodiments, ring C is a 10-14 membered tricyclic heteroaryl group, optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R. 6 The substituents are substituted; wherein the 10-14 membered heteroaryl group comprises at least one aromatic ring, and the other two rings are independently selected from aromatic rings, saturated heterocyclic groups, partially unsaturated heterocyclic groups, saturated cycloalkyl groups, or partially unsaturated cycloalkyl groups.

[0099] In some implementations, ring C is

[0100] in, It can be a single bond or a double bond;

[0101] Y 1 Y 2 Y 3 Y 4 To be the same or different, each is independently either N or CH;

[0102] Y 5 It can be CH, NH, N or S;

[0103] Y 6 It can be CH, NH, N or S;

[0104] Y 7 Y 8 Y 9 Each is independently selected from CH, NH, N, and S;

[0105] p and q are each independently selected from 0, 1, or 2;

[0106] The * is connected to -NHC(=O)-, R 3 Connected at any position in ring C, any hydrogen atom in ring C is connected to R. 3 Replacement; ring C is optionally replaced by 1, 2, 3, 4 or 5 independently selected from R. 6 Substituents are substituted.

[0107] In some embodiments, ring C is indolyl, isoindolyl, indazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indazole, benzo[d]imidazoyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,4-c]pyridyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, furano[2,3-b]pyridyl, benzo[c]isoxazolyl, furano[3,4-b] Pyridyl, furano[3,4-c]pyridyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, thieno[3,2-b]pyridyl, thieno[3,4-c]pyridyl, benzo[d][1,2,3]triazolyl, pyrazolo[4,3-b]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl Pyrazolo[3,4-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-b]pyridyl, 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, thiazo[5,4-]pyrrolo[2,3-]pyrimidinyl [b]pyridyl, thiazo[4,5-b]pyrazinyl, thiazo[5,4-d]pyrimidinyl, thiazo[4,5-d]pyrimidinyl, imidazo[2,1-b][1,3,4]thiadiazoleyl, imidazo[5,1-b][1,3,4]thiadiazoleyl, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoleyl, [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)-keto, 5,6-dihydro-4H-pyrrolo[3,[4-d]thiazolyl-4-one, benzo[d]thiazolyl, thiazo[4,5-b]pyridyl, thiazo[4,5-c]pyridyl, thiazo[5,4-c]pyridyl, thiazo[4,5-c]pyridazinyl, thiazo[4,5-d]pyrimidinyl, thiazo[5,4-c]pyridazinyl, thiazo[4,5-d]pyridazinyl, thiazo[5,4-e][1,2,4]triazinyl, thiazo[4,5-e][1,2,4]triazinyl, pyrazolo[5,1-b][1,3,4]thiadiazolyl, imidazo[1,5-b][1,2,4]thiadiazolyl, pyrazolo[1,5-b][1,2,4]thiadiazolyl, [1,2,4]triazolo[1,5-b] [1,2,4]thiadiazolyl, [1,2,4]triazolo[4,3-b][1,2,4]thiadiazolyl, spiro[cyclopropyl-1,6'-pyrrolo[3,4-d]thiazolyl]-4'(5'H)-keto, spiro[cyclobutyl-1,6'-pyrrolo[3,4-d]thiazolyl]-4'(5'H)-keto, thiazo[4,5-c]pyridin-4(5H)-keto, thiazo[5,4-d]pyrimidine-7(6H)-keto, 6,7-dihydrothiazo[4,5-c]pyridin-4(5H)-keto, 5',6'-dihydro-4'H-spiro[cyclopropyl-1,7'-thiazo[4,5-c]pyridin]-4'-keto, 5',6'-dihydro-4'H-spiro[ Cyclobutyl-1,7'-thiazo[4,5-c]pyridine-4'-keto, thiazo[4,5-c]pyridine-6(5H)-keto, thiazo[4,5-d]pyridazine-4(5H)-keto, thiazo[5,4-c]pyridine-6(5H)-keto, thiazo[4,5-d]pyrimidine-5(6H)-keto, thiazo[5 [4-c]pyridine-4(5H)-keto, thiazo[4,5-d]pyridazine-7(6H)-keto, 4,5-dihydro-6H-pyrrolo[3,4-d]thiazolyl-6-keto, spiro[cyclopropyl-1,4'-pyrrolo[3,4-d]thiazolyl]-6'(5'H)-keto, spiro[cyclobutyl-1,4'-pyrrolo[3,4-d] [Thiazolyl]-6'(5'H)-keto, 6,7-dihydrothiazolyl[5,4-c]pyridine-4(5H)-keto, 4,7-dihydrothiazolyl[5,4-c]pyridine-6(5H)-keto, 4,7-dihydrothiazolyl[4,5-c]pyridine-6(5H)-keto, 6,7-dihydrothiazolyl[5,4-d]pyrimidine-5(4H)-keto, 5',6'-dihydro-4'H-spiro[cyclopropyl-1,7'-thiazolyl[5,4-c]pyridine]-4'-keto, 5',6'-dihydro-4'H-spiro[cyclobutyl-1,7'-thiazolyl[5,4-c]pyridine]-4'-keto; each substituent is optionally selected from 1, 2, 3, 4 or 5 independently selected from R, 6 Substituents are substituted.

[0108] In some implementations, the ring Cis:

[0109] Wherein, the * is connected to -NHC(=O)-, R 3 Connected at any position of the ring C; the ring C is optionally composed of 1, 2, 3, 4, or 5 independently selected from R. 6 Substituents are substituted.

[0110] In some implementations, ring C is

[0111] In some implementations, ring C is Wherein, the * is connected to -NHC(=O)-, and the ** is connected to R. 3 Connected; ring C is optionally composed of 1, 2, 3, 4, or 5 elements independently selected from R. 6 Substituents are substituted.

[0112] In some implementations, ring C is Wherein, the * is connected to -NHC(=O)-, and the ** is connected to R. 3 Connected; ring C is optionally composed of 1, 2, 3, 4, or 5 elements independently selected from R. 6 Substituents are substituted.

[0113] In some implementations, ring C is Wherein, the * is connected to -NHC(=O)-, and the ** is connected to R. 3 Connected; ring C is optionally composed of 1, 2, 3, 4, or 5 elements independently selected from R. 6 Substituents are substituted.

[0114] In some implementations, m is 1.

[0115] In some implementations, m is 2.

[0116] In some implementations, m is 3.

[0117] In some implementations, m is 4.

[0118] In some implementations, m is 5.

[0119] In some implementations, n is 1.

[0120] In some implementations, n is 2.

[0121] In some implementations, n is 3.

[0122] In some implementations, n is 4.

[0123] In some implementations, n is 5.

[0124] In some implementation schemes, each R 1 Selected independently from H, D, halogens, -CN, -NO2, N3, -SF5, oxo, C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl, -NR C R D -OR A -SR A -NR C OR A , -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C C(O)R B , -S(O)R B -S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR C S(O)2NR C R D -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F ; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl are optionally represented by 1, 2, 3, 4, or 5 independently selected from R1A Substituents are substituted.

[0125] In some implementation schemes, each R 1 The elements are selected independently from H, D, halogen, -CN, -NO2, N3, -SF5, and oxo.

[0126] In some implementation schemes, each R 1 Each R is independently selected from H. In some implementations, each R 1 Each is selected independently from D.

[0127] In some implementation schemes, each R 1 Each R is independently selected from halogens. In some implementations, each R... 1 Each R is independently selected from F, Cl, Br, and I. In some implementations, each R 1 For F. In some implementations, each R 1 For Cl. In some implementations, each R 1 For Br. In some implementations, each R 1 For I.

[0128] In some implementation schemes, each R 1 Each R is independently selected from CN. In some implementations, each R 1 Each R is independently selected from NO2. In some implementations, each R 1 Each R is independently selected from N3. In some implementations, each R 1 Each is independently selected from SF5. In some implementations, each R... 1 They were each independently selected from the oxidative process.

[0129] In some implementation schemes, each R 1 Selected independently from NR C R D In some implementations, for example, each R 1 They are selected independently from NH2, NHCH3, NHCH(CH3)2, NHCH3, N(CH3)2, and N(CH2CH3)2, respectively.

[0130] In some implementation schemes, each R 1 Selected independently from OR A In some implementations, for example, each R 1Each R is independently selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, -CH(OH)CH3, OCH2CN, and OCH2CONH2. In some embodiments, each R 1 Each R is independently selected from OCH3. In some implementations, each R 1 Each R is independently selected from OCH2CH3. In some implementations, each R 1 Each is independently selected from OCH(CH3)2. In some implementations, each R... 1 Each is independently selected from OCF3. In some implementations, each R... 1 Each is independently selected from OCHF2. In some implementations, each R... 1 Each is independently selected from OCH2F. In some implementations, each R... 1 Each is independently selected from OCF3. In some implementations, each R... 1 Each is independently selected from OCH2CH2F. In some implementations, each R... 1 Each is independently selected from OCH2CHF2. In some implementations, each R... 1 Each is independently selected from OCH2CF3. In some implementations, each R... 1 Each is independently selected from OCH2CN. In some implementations, each R... 1 They were each independently selected from OCH2CONH2.

[0131] In some implementation schemes, each R 1 Selected independently from SR A In some implementations, each R 1 Each R is independently selected from SCH3. In some implementations, each R 1 They were each independently selected from SCH2CH3.

[0132] In some implementation schemes, each R 1 Selected independently from -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C R D -NR C C(O)R B , -S(O)R B-S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR C S(O)2NR C R D -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F .

[0133] In some implementation schemes, each R 1 Selected independently from C(O)R B In some implementations, each R 1 They are independently selected from CHO, C(O)CH3, and C(O)CH2CH3, respectively. In some implementation schemes, each R 1 Selected independently from C(O)NR C R D In some implementations, each R 1 They are independently selected from -CONH2, -CONHCH3, and -CON(CH3)2, respectively. In some implementation schemes, each R 1 Each is independently selected from -C(O)OR A In some implementations, each R 1 Each is independently selected from -COOH. In some embodiments, each R... 1 Selected independently from -OC(O)R B In some implementations, each R 1 Selected independently from NR C C(O)R B .

[0134] In some implementation schemes, each R 1 Selected independently from S(O)RB In some implementations, for example, each R 1 They are independently selected from S(O)CH3 and S(O)CH2CH3, respectively. In some implementation schemes, each R 1 Selected independently from S(O)2R B In some implementations, for example, each R 1 They were independently selected from S(O)2CH3 and S(O)2CH2CH3, respectively.

[0135] In some implementation schemes, each R 1 Selected independently from S(O)NR C R D In some implementations, for example, each R 1 They are selected independently from S(O)2NH2, S(O)2NHCH3, and S(O)2N(CH3)2, respectively.

[0136] In some implementation schemes, each R 1 Selected independently from -NR C S(O)2R D In some implementations, each R 1 Each is independently selected from NHS(O)2CH3. In some embodiments, each R... 1 Selected independently from -S(O)2NR C R D In some implementations, each R 1 Selected independently from -NR C S(O)2NR C R D In some implementations, each R 1 Selected independently from -NR C S(O)(=NR B )R B .

[0137] In some implementation schemes, each R 1 Selected independently from SiR G R H R I In some implementations, each R 1 Each independently selected from B(OR) C (OR) D In some implementations, each R 1 Selected independently from -P(O)R E R F In some implementations, each R1 Each is independently selected from -P(O)(CH3)2. In some implementations, each R 1 Selected independently from -P(O)OR E OR F In some implementations, each R 1 Each is independently selected from -OP(O)OR E OR F .

[0138] In some implementation schemes, each R 1 Selected independently from C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl are optionally represented by 1, 2, 3, 4, or 5 independently selected from R 1A Substituents are substituted.

[0139] In some implementation schemes, each R 1 Selected independently from C 1- The C6 alkyl group is optionally composed of 1, 2, 3, 4, or 5 atoms, each independently selected from R. 1A Substituents are substituted.

[0140] In some implementation schemes, each R 1 Each of the following is independently selected from CD3, CH3, CH2CH3, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, -CH(OH)CH3, CH2CH2OH, -CH2OCH3, -CH2OCHF2, -CH2OCH2F, -CH2OCF3, -CH(OCH3)CH3, CH2CH2NH2, -CH(NH2)CH3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CN.

[0141] In some implementation schemes, each R 1 Each and every alkenyl group is independently selected from C2-C6, optionally surrounded by 1, 2, 3, 4 or 5 elements independently selected from R. 1A Substituents are substituted. In some implementations, for example, each R... 1 They are selected independently from -CH=CH2 and -CH=CHCH3, respectively.

[0142] In some implementation schemes, each R 1Each group is independently selected from C2-C6 ynylene, optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from R. 1A Substituents are substituted. In some implementations, for example, each R... 1 They are independently selected from -C≡CH and -C≡CCH3, respectively.

[0143] In some implementation schemes, each R 1 Each cycloalkyl group is independently selected from C3-C6, optionally surrounded by 1, 2, 3, 4, or 5 atoms, each independently selected from R. 1A Substituents are substituted. In some embodiments, each R... 1 The compounds are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, respectively, and each ring is optionally composed of 1, 2, 3, 4, or 5 independently selected from R. 1A Substituents are substituted.

[0144] In some implementation schemes, each R 1 The heterocyclic groups are each independently selected from 4-6 membered heterocyclic groups, each having one or two heteroatoms independently selected from N, O, S, and B, wherein the heteroatoms may optionally be oxidized by one or more oxo groups (e.g., S(O), or S(O)2), and may optionally be oxidized by 1, 2, 3, 4, or 5 oxo groups selected from R. 1A Substituents are substituted.

[0145] In some implementation schemes, each R 1 Each ring is independently selected from nitrogen-heterobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, morpholinyl, or thiomorpholine dioxide, and each ring is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 1A Substituents are substituted. In some embodiments, one of the R groups is... 1 for

[0146] In some implementation schemes, each R 1 Each and every one is independently selected from phenyl, optionally by 1, 2, 3, 4 or 5 molecules, each and every one is independently selected from R. 1A Substituents are substituted. In some embodiments, one of the R groups is... 1 It is a phenyl group.

[0147] In some implementation schemes, each R 1 Each of the following is independently selected from 5-6 heteroaryl groups, with 1, 2, 3, 4, or 5 groups independently selected from R 1A Substituents are substituted. In some embodiments, each R... 1Each substituent is independently selected from pyrrole, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, and pyrazinyl; each substituent is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 1A Substituents are substituted. In some embodiments, one of the R groups is... 1 for

[0148] In some implementation schemes, each R 1 Each is independently selected from (i) H, D, halogen, or –OR A ; or (ii) C1-C6 alkyl, C2-C6 alkynyl; each substituent is optionally selected from 1, 2, 3, 4, or 5 independently selected from R 1A Substituents of R; where R A and R 1A As defined in this invention. In some embodiments, each R 1 Each is independently selected from (i) H, D, halogen, or –OR A ; or (ii) C1-C6 alkyl groups optionally composed of 1, 2, 3, 4, or 5 molecules, each independently selected from R 1A Substituents of R; where R A and R 1A As defined in this invention. In some embodiments, each R 1 Each R is independently selected from H, –F, –Cl, –CH3, –CHF2, –CF3, –OCH3, –OCHF2, –OCF3, or -C≡CH. In some embodiments, each R 1 Each is independently selected from H, –F, –Cl, –CH3, –CF3, or –OCH3.

[0149] In some implementations, one of the R 1 It is –OCH3 or -C≡CH. In some implementations, one of the R... 1 The values ​​are –F, –Cl, –CH3, –CHF2, –CF3, –OCH3, –OCHF2, or –OCF3.

[0150] In some implementations, one of the R 1 For –F. In some implementations, one of the R... 1 It can be –Cl, –CH3, or –CF3. In some implementations, one of the R... 1 It is –OCH3.

[0151] In some implementations, three R 1 Not H. In some implementations, three Rs are... 1Not H; the first of the three is –F; the second of the three is –Cl, –CH3, or –CF3; the third of the three is –OCH3. In some implementations, the three Rs are... 1 It is not H; the first of the three is –F; the second of the three is –Cl; the third of the three is –OCH3.

[0152] In some implementations, two R 1 Together with the atoms it is attached to, it forms an oxo group, C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein, the C 3- C7 cycloalkyl or 4-7 membered heterocyclic groups are optionally surrounded by 1, 2, 3, 4 or 5 groups, each independently selected from R 1A Substituents are substituted.

[0153] In some implementations, two R 1 Together with the atoms it is attached to, it forms an oxo group.

[0154] In some implementations, two R 1 Together with the atoms it is attached to, they form C 3- The C7 cycloalkyl group is optionally composed of 1, 2, 3, 4, or 5 groups, each independently selected from R. 1A Substituents are substituted.

[0155] In some implementations, two R 1 Together with the atoms to which they are attached, they form 4-7 membered heterocyclic groups, optionally composed of 1, 2, 3, 4, or 5 atoms, each independently selected from R. 1A Substituents are substituted.

[0156] In some implementation schemes, each R 1A Each is independently selected from D, halogen, CN, -NO2, N3, oxo, OR a NR c R d C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C 3- The C6 cycloalkyl group or the 4-6 membered heterocyclic group is optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a C 1- C6 alkyl, C 1- C6 haloalkyl.

[0157] In some implementation schemes, each R 1A Each is independently selected from D, halogen, CN, -NO2, N3, oxo, OR a NR c R d In some implementations, each R 1A Each R is independently selected from D. In some implementations, each R 1A Each R is independently selected from halogens (e.g., F, Cl, Br, I). In some embodiments, each R 1A Each R is independently selected from CN. In some implementations, each R 1A Each is independently selected from -NO2. In some implementations, each R... 1A Each R is independently selected from N3. In some implementations, each R 1A Each R is independently selected from oxygen. In some implementations, each R... 1A Selected independently from OR a (e.g., OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2F, OCHF2, OCF3). In some embodiments, each R 1A Selected independently from NR c R d (NH2, NHCH3, N(CH3)2, NHCH2CH2OH, N(CH3)CH2CH2OH).

[0158] In some implementation schemes, each R 1A Selected independently from C 1- The C6 alkyl group may optionally be substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a .

[0159] In some implementation schemes, each R 1A Each of the C2-C6 alkenyl groups is independently selected and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a .

[0160] In some implementation schemes, each R 1A Each group is independently selected from C2-C6 alkynyl groups, optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R dOR a SR a .

[0161] In some implementation schemes, each R 1A Each cycloalkyl group is independently selected from C3-C6 and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a C 1- C6 alkyl, C 1- C6 haloalkyl.

[0162] In some implementation schemes, each R 1A Each of the 4-6 membered heterocyclic groups is independently selected and optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a C 1- C6 alkyl, C 1- C6 haloalkyl.

[0163] In some implementation schemes, each R 2 Each element is independently selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, -NR C R D -OR A -SR A -NR C OR A , -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C C(O)R B , -S(O)R B -S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR CS(O)2NR C R D -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 2A Substituents are substituted.

[0164] In some implementation schemes, each R 2 Each R is independently selected from H, D, CN, NO2, N3, oxo, SF5, and halogen. In some embodiments, each R 2 Each R is independently selected from H. In some implementations, each R 2 Each R is independently selected from D. In some implementations, each R 2 Each R is independently selected from CN. In some implementations, each R 2 Each R is independently selected from NO2. In some implementations, each R 2 Each R is independently selected from N3. In some implementations, each R 2 Each was selected independently from SF5.

[0165] In some implementation schemes, each R 2 Each R is independently selected from halogens. In some implementations, each R... 2 Each R is independently selected from F, Cl, Br, or I. In some embodiments, each R 2 Each R is independently selected from F. In some implementations, each R 2 Each is independently selected from Cl. In some implementations, each R... 2 Each R is independently selected from Br. In some implementations, each R 2 Each is selected independently from I.

[0166] In some implementation schemes, each R 2Selected independently from -NR C R D In some implementations, each R 2 They are independently selected from NH2, NHCH3, N(CH3)2, NHCH2CH3, N(CH2CH3)2, NHCH2CH2CH3, N(CH2CH2CH3)2, NHCH(CH3)2, and NHCH2CH2OH.

[0167] In some implementation schemes, each R 2 Selected independently from OR A In some implementations, each R 2 Each of the following is independently selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2F, OCHF2, and OCF3.

[0168] In some implementation schemes, each R 2 Selected independently from SR A In some implementations, each R 2 Each was selected independently from SMe.

[0169] In some implementation schemes, each R 2 Selected independently from -NR C OR A In some implementations, each R 2 Selected independently from -C(O)R B In some implementations, R 2 is -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2,

[0170] In some implementation schemes, each R 2 Selected independently from -C(O)NR C R D In some implementations, R 2 The values ​​are -C(O)NH2, -C(O)NHCH3, and -C(O)N(CH3)2.

[0171] In some implementation schemes, each R 2 Each is independently selected from -C(O)OR A In some implementations, each R 2 Selected independently from -OC(O)R B .

[0172] In some implementation schemes, each R2 Selected independently from -NR C C(O)R B In some implementations, R 2 is -NHC(O)CH3, -NCH3C(O)CH3,

[0173] In some implementation schemes, each R 2 Selected independently from -S(O)R B In some implementations, each R 2 Selected independently from -S(O)2R B In some implementations, each R 2 Selected independently from -S(O)NR C R D In some implementations, each R 2 Selected independently from -NR C S(O)2R D In some implementations, each R 2 Selected independently from -S(O)2NR C R D In some implementations, each R 2 Selected independently from -NR C S(O)2NR C R D In some implementations, each R 2 Selected independently from -NR C S(O)(=NR B )R B In some implementations, each R 2 Selected independently from SiR G R H R I In some implementations, each R 2 Each independently selected from B(OR) C (OR) D In some implementations, each R 2 Selected independently from -P(O)R E R F In some implementations, each R 2 Selected independently from -P(O)OR E OR F In some implementations, each R 2 Each is independently selected from -OP(O)OR E OR F .

[0174] In some implementation schemes, each R 2 Alkyl groups, each independently selected from C1-C6, optionally surrounded by 1, 2, 3, 4, or 5 molecules, each independently selected from R 2A Substituents are substituted. In some embodiments, for example, but not limited to, R 2 The derivatives are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CD3, CH2OH, CH2OMe, CH2CN. In some implementation schemes, R 2 It is either methyl or CD3.

[0175] In some implementation schemes, each R 2 Each and every alkenyl group is independently selected from C2-C6, optionally surrounded by 1, 2, 3, 4 or 5 elements independently selected from R. 2A Substituents are substituted.

[0176] In some implementation schemes, each R 2 Each group is independently selected from C2-C6 ynylene, optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from R. 2A Substituents are substituted. In some embodiments, R 2 for

[0177] In some implementation schemes, each R 2 Selected independently from C3-C 10 The cycloalkyl group is optionally composed of 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted.

[0178] In some implementation schemes, each R 2 Each was independently selected from saturated C3-C 10 cycloalkyl or partially unsaturated C3-C 10 Cycloalkyl; each substituent is optionally selected from 1, 2, 3, 4 or 5 independently selected from R 2A Substituents are substituted.

[0179] In some implementation schemes, each R 2 Each substituent is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; each substituent is optionally replaced by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted. In some embodiments, one of the R groups is... 2 for

[0180] In some implementation schemes, each R 2 Each heterocyclic group is independently selected from 4-10 membered heterocyclic groups, optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R. 2A Substituents are substituted.

[0181] In some implementation schemes, each R 2 Each substituent is independently selected from saturated 4-10 membered heterocyclic groups or partially unsaturated 4-10 membered heterocyclic groups; each substituent is optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 2A Substituents are substituted.

[0182] In some implementation schemes, each R 2 Each substituent is independently selected from nitrogen-heterobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, imidazoalkyl, and pyrazolyl; each substituent is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted.

[0183] In some implementation schemes, each R 2 Selected independently from C6-C 10 The aryl group is optionally composed of 1, 2, 3, 4, or 5 independently selected from R. 2A Substituents are substituted. In some embodiments, each R... 2 Independently selected from phenyl, naphthyl is optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 2A Substituents are substituted. In some embodiments, one of the R groups is... 2 for

[0184] In some implementation schemes, each R 2 Each of the following is independently selected from 5-10 heteroaryl groups, with 1, 2, 3, 4, or 5 groups independently selected from R 2A Substituents are substituted.

[0185] In some implementation schemes, each R 2Each of the following groups is independently selected from pyrroloyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxiadiazolyl, pyridinyl, pyrazinyl, pyrazinyl, indolyl, isoindolyl, indolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophene, benzo[c]thiophene, indolyl, benzo[d]imidazolyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2 [3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,4-c]pyridyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, furano[2,3-b]pyridyl, benzo[c]isoxazolyl, furano[3,4-b]pyridyl, furano[3,4-c]pyridyl, benzo[d]thiazolylisothiazolyl, benzo[d]thiazolyl, thieno[3,4-b]pyridyl, benzo[d]thiazolyl, thieno[3,4-c]pyridyl, benzo[d]thiazolyl, thieno[3,4-b]pyridyl, benzo[d]thiazolyl, thieno[3,4-b]pyridyl, benzo[d]thiazolyl, benzo[d]thiazolyl, thieno[3,4-b]pyridyl, benzo[d]thiazolyl, benzo[d]thiazolyl, benzo[d]thiazolyl, benzo[d]thiazolyl [2-b]pyridyl, thieno[3,4-c]pyridyl, benzo[d][1,2,3]triazolyl, pyrazolo[4,3-b]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-b]pyridyl, 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; each substituent is optionally selected from 1, 2, 3, 4 or 5 independently selected from R 2A Substituents are substituted. In some embodiments, one of the R groups is... 2 for

[0186] In some implementation schemes, each R 2 Each substituent is independently selected from (i) H, D, –CN, or halogen; or (ii) C1-C6 alkyl or 5-10 heteroaryl, each substituent optionally being composed of 1, 2, 3, 4, or 5 independently selected from R 2A Substituents of R, wherein R 2A As defined in this invention. In some embodiments, each R 2Each substituent is independently selected from (i) H, D, or –CN; or (ii) C1-C6 alkyl or 5-heteroaryl, each substituent optionally being replaced by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents of R, wherein R 2A As defined in this invention. In some embodiments, each R 2 Each R is independently selected from H, D, –CN, methyl, or 1-methyl-pyrazolyl. In some embodiments, each R 2 Each is independently selected from H or methyl.

[0187] In some implementations, one of the R 2 It is (i) –CN or halogen; or (ii) C1-C6 alkyl or 5-10 heteroaryl, each substituent optionally being 1, 2, 3, 4, or 5 independently selected from R 2A Substituents of R, wherein R 2A As defined in this invention. In some embodiments, one of the R 2 It is –CN, methyl, or 1-methylpyrazolyl. In some embodiments, one of the R 2 It is a methyl group.

[0188] In some implementations, one of the R 2 It is (i) –CN or halogen; or (ii) C1-C6 alkyl or 5-10 heteroaryl, each substituent optionally being 1, 2, 3, 4, or 5 independently selected from R 2A Substituents of R, wherein R 2A As defined in this invention; Remaining R 2 For H. In some implementations, one of the R 2 –CN, methyl, or 1-methylpyrazolyl; the remaining R 2 For H. In some implementations, one of the R 2 Methyl; remaining R 2 For H.

[0189] In some implementations, two R 2 Together with the atoms to which it is attached, it forms an oxo, C3-C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group is optionally composed of 1, 2, 3 or 4 atoms, each independently selected from R 2A Substituents are substituted.

[0190] In some implementations, two R 2 Together with the atoms it is attached to, it forms an oxo group.

[0191] In some implementations, two R 2Together with the atoms to which they are attached, they form C3-C7 cycloalkyl groups, optionally separated by 1, 2, 3, or 4 atoms, each independently selected from R. 2A Substituents are substituted.

[0192] In some implementations, two R 2 Together with the atoms to which they are attached, they form 4-7 membered heterocyclic groups, optionally composed of 1, 2, 3, or 4 atoms, each independently selected from R. 2A Substituents are substituted.

[0193] In some implementation schemes, each R 2A Each of the following is independently selected from D, halogen, CN, OH, NH2, NO2, SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, NR c R d OR a SR 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 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)2R d 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with the following substituents: D, halogen, CN, OH, NH2, oxo, NR c1 R d1OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0194] In some implementation schemes, each R 2A They are independently selected from D, halogen, CN, OH, NH2, NO2, SF5, and oxo.

[0195] In some implementation schemes, each R 2A Each is independently selected from C1-C4 alkyl groups, optionally prefixed with D, halogen, CN, OH, NH2, oxo, or NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl. In some embodiments, each R 2A Each of the following is independently selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CH3, CF2CF3, CF2CH2CH3, CH2OH, CH2CH2OH, CH(OH)CH3, CH2CH2CH2OH, CH(OH)CH2CH2OH, CH2CN, CH2CH2CN, CH2CH2CH2CN.

[0196] In some implementation schemes, each R 2A Each of the C2-C4 alkenyl groups is independently selected and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0197] In some implementation schemes, each R 2A Each group is independently selected from C2-C4 alkynyl groups, optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0198] In some implementation schemes, each R 2A Each cycloalkyl group is independently selected from C3-C6 and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0199] In some implementation schemes, each R 2A Each of the 4-6 membered heterocyclic groups is independently selected and optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0200] In some implementation schemes, each R 2A Each is independently selected from phenyl and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0201] In some implementation schemes, each R 2A Each of the 5-6 membered heteroaryl groups is independently selected and optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0202] In some implementation schemes, each R 2A Selected independently from NR c R d In some implementations, each R 2A Selected independently from OR a In some implementations, each R 2A Selected independently from SR a .

[0203] In some implementation schemes, each R 2A Selected independently from C(O)R b In some implementations, each R 2A Selected independently from C(O)NR c R d In some implementations, each R 2A Selected independently from C(O)OR a In some implementations, each R 2A Selected independently from OC(O)R b In some implementations, each R 2A Selected independently from OC(O)NR c R d .

[0204] In some implementation schemes, each R 2A Selected independently from NR c C(O)R b In some implementations, each R 2A Selected independently from NR c C(O)NR c R d In some implementations, each R 2A Selected independently from NR c C(O)OR a .

[0205] In some implementation schemes, each R 2A Each is independently selected from S(O)(=NR) b )R b In some implementations, each R 2A Selected independently from S(O)R b In some implementations, each R 2A Selected independently from S(O)NR c R d In some implementations, each R 2A Selected independently from S(O)2R b In some implementations, each R 2A Selected independently from NR c S(O)2R d In some implementations, each R 2A Selected independently from S(O)2NR c R d In some implementations, each R 2A Selected independently from NR c S(O)2NRc R d In some implementations, each R 2A Selected independently from NR c S(O)(=NR b )R b .

[0206] In some implementation schemes, R 3 For H, D, halogen, CN, oxo, NO2, SF5, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 heteroaryl, OR A SR A NR C OR A NR C R D C(O)R B C(O)NR C R D NR C C(O)R B NR C C(O)OR A NR C S(O)2R D NR C S(O)2NR C R D S(O)R B S(O)2R B ; wherein, the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 10 aryl, 5-14 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 4 Substituents are substituted.

[0207] In some implementation schemes, R 3 For example, H, D, halogen, CN, oxo, NO2, SF5. In some embodiments, R 3 For H. In some implementations, R 3 For D. In some implementations, R 3 It is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R 3For F. In some implementations, R 3 For Cl. In some implementations, R 3 For Br. In some implementations, R 3 For I. In some implementations, R 3 For CN. In some implementations, R 3 For oxygenation. In some implementations, R 3 For NO2. In some implementations, R 3 It is SF5.

[0208] In some implementation schemes, R 3 For C1-C 10 The alkyl group is optionally selected independently from R by 1, 2, 3, 4 or 5 groups. 4 Substituents are substituted.

[0209] In some implementation schemes, R 3 The is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3; each is optionally selected independently by 1, 2, 3, 4 or 5 from R 4 Substituents are substituted.

[0210] In some implementation schemes, R 3 for CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2F, CHF2, CF3, CH2CH2F , CH2CHF2, CH2CF3, CF2CH3, CF2CF3, CF2CH2CH3, CH2CH2OH, CH2CH2CH2OH, CH2CH2OCH3, CH2CH2CH2OCH3.

[0211] In some implementation schemes, R 3 For C2-C 10 The alkenyl group is optionally composed of 1, 2, 3, 4, or 5 groups, each independently selected from R. 4 Substituents are substituted.

[0212] In some implementation schemes, R 3 For C2-C 10 The alkynyl group is optionally composed of 1, 2, 3, 4, or 5 groups, each independently selected from R. 4 Substituents are substituted.

[0213] In some implementation schemes, R 3 For C3-C 14 The cycloalkyl group is optionally composed of 1, 2, 3, 4, or 5 independently selected from R4 Substituents are substituted.

[0214] In some implementation schemes, R 3 The substituents are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each substituent is optionally selected from 1, 2, 3, 4, or 5 independently selected from R. 4 Substituents are substituted.

[0215] In some implementation schemes, R 3 The 4-14 membered heterocyclic group is optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 4 Substituents are substituted.

[0216] In some implementation schemes, R 3 The substituents are azirrobutyl, oxohexacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, dioxanecycloalkyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, azirroheptanyl, or 1,4-diazaheptanyl; each substituent is optionally selected from 1, 2, 3, 4, or 5 independently selected from R. 4 Substituents are substituted.

[0217] In some implementation schemes, R 3 For C6-C 14 The aryl group is optionally composed of 1, 2, 3, 4, or 5 independently selected from R. 4 Substituents are substituted. In some embodiments, R 3 The substituents are phenyl, naphthyl, anthracene, or phenanthrene; each substituent is optionally replaced by 1, 2, 3, 4, or 5 independently selected from R. 4 Substituents are substituted.

[0218] In some implementation schemes, R 3 The 5-14 heteroaryl group is optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 4 Substituents are substituted.

[0219] In some implementation schemes, R 3 The substituents are pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, oxiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophene, benzo[c]thiophene, inzolyl; each substituent is optionally selected independently from R by 1, 2, 3, 4 or 5, respectively. 4 Substituents are substituted.

[0220] In some implementation schemes, R 3 OR A RA It is H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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(=NRc )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 .

[0221] In some implementation schemes, R 3 OR A R A The C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, OR a SR 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 ), P(O)R e R f P(O)OR e OR fOP(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 .

[0222] In some implementation schemes, R 3 OR A R A The C2-C6 alkenyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, OR a SR 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 ), 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)2Rb 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 .

[0223] In some implementation schemes, R 3 OR A R A The C2-C6 alkynyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, OR a SR 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 ), 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 cS(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0224] In some implementation schemes, R 3 OR A R A For C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 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 dS(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 .

[0225] In some implementation schemes, R 3 OR A R A The 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 P(O)R e R f P(O)OR e OR fOP(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 .

[0226] In some implementation schemes, R 3 OR A R A For C6-C 10 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 dC(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)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 .

[0227] In some implementation schemes, R 3 OR A R A The 5-10-membered heteroaryl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 Rd NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)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 implementation schemes, R 3 OR A R A For C6-C 10 The aryl-C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 dNR 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 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 .

[0229] In some implementation schemes, R 3 OR A R A The 5-10-membered heteroaryl-C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 cR 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 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 .

[0230] In some implementation schemes, R 3 OR A R A For C3-C 10 The cycloalkyl-C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NRc 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 ,P(O)R e R f ,P(O)OR e OR<00,01921>,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 。

[0231] In some embodiments, R 3 is OR A ,R AThe 4-10 membered heterocyclic -C1-C6 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 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 .

[0232] In some implementation schemes, R 3 for OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCF 2CF3, OCH2CH2OH, OCH2CH2OCH3, OCH2CH2OCH2CH3, OCH(CH3)CH2OH, OCH2CH(CH3)OH, OCH2C(CH3)2OH.

[0233] In some implementation schemes, R 3 For SR A .

[0234] In some implementation schemes, R 3 It is SCH3, SCH2CH2CN, SCH2CH2CH2CN, SCH2CH2OH, SCH2CH2OCH3, SCH2CH(CH3)OH.

[0235] In some implementation schemes, R 3 For NR C OR A .

[0236] In some implementation schemes, R 3 For NR C R D R C and R D Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a OC(O)NR c R d NR c R d NR c C(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 B (OR) c (OR) d ).

[0237] In some implementation schemes, R 3 For NR C R D ;R C H, D, C1-C6 alkyl, optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a OC(O)NR c R d NR c R d NR c C(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 B (OR) c (OR)d ), R D Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a OC(O)NR c R d NR c R d NR c C(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 B (OR) c (OR) d ).

[0238] In some implementation schemes, R 3is NH2, NHCH3, N(CH3)2, NHCH2CH3, N(CH2CH3)2, NHCH2CH2CH3, N(CH2CH2CH3)2, NHCH(CH3)2, NHCH2CH2OH, N(CH3)CH2CH2OH, NHCH2CH2OCH3, N(CH3)CH2CH2OCH3,

[0239] In some implementation schemes, R 3 For C(O)R B In some implementations, R 3 For C(O)NR C R D In some implementations, R 3 For NR C C(O)R B In some implementations, R 3 For NR C C(O)OR A .

[0240] In some implementation schemes, R 3 For NR C S(O)2R D In some implementations, R 3 For NR C S(O)2NR C R D In some implementations, R 3 S(O)R B In some implementations, R 3 is S(O)2R B .

[0241] In some implementation schemes, R 3 H, D, halogen, CN, oxo, NO2, SF5, OR A NR C R D SR A C1-C 10 Alkyl, C3-C 14 Cycloalkyl, or 4-14 membered heterocyclic group; wherein, the C1-C 10 Alkyl, C3-C 14 The cycloalkyl group, or a 4-14 membered heterocyclic group, is optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R. 4 Substituents are substituted.

[0242] In some implementation schemes, R 3for H, D, halogen, CN, oxo, NO2, SF5, CH3, CH2CH3, CH2CH2OH, CH2CH2OCH3, OH, OCH3, OCH2CH3, OCH2CF3, OCF2CF3, OCH2CH2OH, OCH2CH2OCH3, OCH2CH2OCH2CH3, OCH2C(CH3)2OH, NH2, NHCH3, N(CH3)2, NHCH2CH3, N(CH2CH3)2, N(CH3)CH2CH2OCH3,

[0243] In some implementation schemes, each R 4 Each R is independently selected from H, D, halogen, CN, NO2, N3, and oxo. In some embodiments, each R 4 Each R is independently selected from H. In some implementations, each R 4 Each R is independently selected from D. In some implementations, each R 4 Each R is independently selected from halogens (e.g., F, Cl, Br, or I). In some embodiments, each R 4 Each R is independently selected from CN. In some implementations, each R 4 Each R is independently selected from NO2. In some implementations, each R 4 Each R is independently selected from N3. In some implementations, each R 4 They were each independently selected from the oxidative process.

[0244] In some implementation schemes, each R 4 Selected independently from NR C R D In some implementations, each R 4 Selected independently from OR A In some implementations, each R 4 Selected independently from SR A In some implementations, each R 4 Selected independently from NR C OR A .

[0245] In some implementation schemes, each R 4 Selected independently from C(O)R B In some implementations, each R 4 Selected independently from C(O)NR C R D In some implementations, each R 4 Selected independently from C(O)ORA In some implementations, each R 4 Selected independently from OC(O)R B In some implementations, each R 4 Selected independently from OC(O)NR C R D .

[0246] In some implementation schemes, each R 4 Selected independently from NR C C(O)R B In some implementations, each R 4 Selected independently from NR C C(O)NR C R D In some implementations, each R 4 Selected independently from NR C C(O)OR A .

[0247] In some implementation schemes, each R 4 Selected independently from S(O)R B In some implementations, each R 4 Selected independently from S(O)2R B In some implementations, each R 4 Selected independently from S(O)NR C R D In some implementations, each R 4 Selected independently from NR C S(O)2R D In some implementations, each R 4 Selected independently from S(O)2NR C R D In some implementations, each R 4 Selected independently from NR C S(O)2NR C R D In some implementations, each R 4 Selected independently from NR C S(O)(=NR B )R B .

[0248] In some implementation schemes, each R 4 Selected independently from SiR G R H R I In some implementations, each R4 Each independently selected from B(OR) C (OR) D In some implementations, each R 4 Selected independently from -P(O)R E R F .

[0249] In some implementation schemes, each R 4 Alkyl groups, each independently selected from C1-C6, are optionally surrounded by 1, 2, 3, 4, or 5 molecules, each independently selected from R. 5 Substituents are substituted.

[0250] In some implementation schemes, each R 4 The alkenyl groups are independently selected from C2-C6, and are optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R. 5 Substituents are substituted.

[0251] In some implementation schemes, each R 4 Each group is independently selected from C2-C6 ynyl groups, optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from R. 5 Substituents are substituted.

[0252] In some implementation schemes, each R 4 Selected independently from C6-C 10 The aryl group is optionally composed of 1, 2, 3, 4, or 5 independently selected from R. 5 Substituents are substituted. In some embodiments, each R... 4 Each substituent is independently selected from phenyl or naphthyl; each substituent is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R 5 Substituents are substituted.

[0253] In some implementation schemes, each R 4 Selected independently from C3-C 10 The cycloalkyl group is optionally composed of 1, 2, 3, 4, or 5 independently selected from R 5 Substituents are substituted.

[0254] In some implementation schemes, each R 4 Each of the five- to ten heteroaryl groups is independently selected from R, with 1, 2, 3, 4, or 5 groups independently selected from R. 5 Substituents are substituted.

[0255] In some implementation schemes, each R 4 Each heterocyclic group is independently selected from 4-10 membered heterocyclic groups, optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from R. 5 Substituents are substituted.

[0256] In some implementation schemes, each R 5 Each R is independently selected from D, CN, halogen, NO2, SF5, and oxo. In some embodiments, each R... 5 Each R is independently selected from D. In some implementations, each R 5 Each R is independently selected from CN. In some implementations, each R 5 Each R is independently selected from halogens (e.g., F, Cl, Br, or I). In some embodiments, each R 5 Each R is independently selected from NO2. In some implementations, each R 5 Each is independently selected from SF5. In some implementations, each R... 5 They were each independently selected from the oxidative process.

[0257] In some implementation schemes, each R 5 Each is independently selected from selectively substituted C1-C6 alkyl groups.

[0258] In some implementation schemes, each R 5 Each is independently selected from selectively substituted C2-C6 alkenyl groups.

[0259] In some implementation schemes, each R 5 Each group is independently selected from selectively substituted C2-C6 ynyl groups.

[0260] In some implementation schemes, each R 5 Each is independently selected from selectively substituted C3-C6 cycloalkyl groups.

[0261] In some implementation schemes, each R 5 Each is independently selected from selectively substituted 4-6 membered heterocyclic groups.

[0262] In some implementation schemes, each R 5 Selected independently from OR a In some implementations, each R 5 Selected independently from SR a .

[0263] In some implementation schemes, each R 5 Selected independently from C(O)R b In some implementations, each R 5 Selected independently from C(O)NR c R d In some implementations, each R 5 Selected independently from C(O)OR aIn some implementations, each R 5 Selected independently from OC(O)R b In some implementations, each R 5 Selected independently from OC(O)NR c R d .

[0264] In some implementation schemes, each R 5 Selected independently from NR c R d In some implementations, each R 5 Selected independently from NR c C(O)R b In some implementations, each R 5 Selected independently from NR c C(O)NR c R d In some implementations, each R 5 Selected independently from NR c C(O)OR a .

[0265] In some implementation schemes, each R 5 Each is independently selected from S(O)(=NR) b )R b In some implementations, each R 5 Selected independently from S(O)R b In some implementations, each R 5 Selected independently from S(O)NR c R d In some implementations, each R 5 Selected independently from S(O)2R b In some implementations, each R 5 Selected independently from NR c S(O)2R d In some implementations, each R 5 Selected independently from S(O)2NR c R d In some implementations, each R 5 Selected independently from NR c S(O)2NR c R d In some implementations, each R 5 Selected independently from NR c S(O)(=NR b )R b .

[0266] In some implementation schemes, each R 6 Each element is independently selected from H, D, halogen, CN, NO2, -N3, oxo, SF5, and NR. C R D OR A SR A SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group is optionally composed of 1, 2, 3, 4, or 5 groups, each independently selected from R 6A Substituents are substituted.

[0267] In some implementation schemes, each R 6 Each R is independently selected from H. In some implementations, each R 6 Each R is independently selected from D. In some implementations, each R 6 Each R is independently selected from halogens (e.g., F, Cl, Br, I). In some embodiments, each R 6 Each R is independently selected from CN. In some implementations, each R 6 Each R is independently selected from NO2. In some implementations, each R 6 Each is independently selected from -N3. In some implementations, each R 6 They were each independently selected from the oxidative process.

[0268] In some implementation schemes, each R 6 Selected independently from NR C R D In some implementations, each R 6 Selected independently from OR A In some implementations, each R 6 Selected independently from SR A .

[0269] In some implementation schemes, each R 6 Selected independently from SiR G R H R IIn some implementations, each R 6 Each independently selected from B(OR) C (OR) D In some implementations, each R 6 Selected independently from -P(O)R E R F .

[0270] In some implementation schemes, each R 6 Alkyl groups, each independently selected from C1-C6, optionally surrounded by 1, 2, 3, 4, or 5 molecules, each independently selected from R 6A Substituents are substituted.

[0271] In some implementation schemes, each R 6 Each and every alkenyl group is independently selected from C2-C6, optionally surrounded by 1, 2, 3, 4 or 5 elements independently selected from R. 6A Substituents are substituted. In some embodiments, each R... 6 Each group is independently selected from C2-C6 ynylene, optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from R. 6A Substituents are substituted.

[0272] In some implementation schemes, each R 6 Each and every one is independently selected from phenyl, optionally by 1, 2, 3, 4 or 5 molecules, each and every one is independently selected from R. 6A Substituents are substituted. In some embodiments, each R... 6 Each cycloalkyl group is independently selected from C3-C7, optionally surrounded by 1, 2, 3, 4, or 5 atoms, each independently selected from R. 6A Substituents are substituted. In some embodiments, each R... 6 Each of the following is independently selected from 5-6 heteroaryl groups, with 1, 2, 3, 4, or 5 groups independently selected from R 6A Substituents are substituted. In some embodiments, each R... 6 Each heterocyclic group is independently selected from 4-7 membered heterocyclic groups, optionally surrounded by 1, 2, 3, 4, or 5 independently selected from R. 6A Substituents are substituted.

[0273] In some implementations, two R 6 They form oxygen on the same carbon atom.

[0274] In some implementations, two R 6 C3-C7 cycloalkyl groups are formed together on the same carbon atom, optionally by 1, 2, 3 or 4 independently selected from R 6A Substituents are substituted.

[0275] In some implementations, two R6 The 4-7 membered heterocyclic groups formed together on the same carbon atom are optionally composed of 1, 2, 3, or 4 independently selected from R 6A Substituents are substituted.

[0276] In some implementations, two adjacent R 6 Together with the atoms to which they are attached, they form C3-C7 cycloalkyl groups, optionally separated by 1, 2, 3, or 4 atoms, each independently selected from R. 6A Substituents are substituted.

[0277] In some implementations, two adjacent R 6 Together with the atoms to which they are attached, they form 4-7 membered heterocyclic groups, optionally composed of 1, 2, 3, or 4 atoms, each independently selected from R. 6A Substituents are substituted.

[0278] In some implementation schemes, each R 6A Each of the following is independently selected from D, halogen, CN, OH, NH2, NO2, SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, NR c R d OR a SR 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 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)2R d S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NRb )R b ; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0279] In some implementation schemes, each R 6A It is independently selected from D, halogen, CN, OH, NH2, NO2, SF5, and oxo.

[0280] In some implementation schemes, each R 6A The alkyl group is independently selected from C1-C4 and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0281] In some implementation schemes, each R 6A Each of the C2-C4 alkenyl groups is independently selected and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0282] In some implementation schemes, each R 6A Each group is independently selected from C2-C4 alkynyl groups, optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0283] In some implementation schemes, each R 6A Each cycloalkyl group is independently selected from C3-C6 and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR.c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0284] In some implementation schemes, each R 6A Each and every one is independently selected from 4- to 6-membered heterocyclic groups (e.g., 4-membered, 5-membered, and 6-membered heterocyclic groups) and optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0285] In some implementation schemes, each R 6A Each is independently selected from phenyl and optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0286] In some implementation schemes, each R 6A Each of the following groups is independently selected from 5- or 6-membered heteroaryl groups (e.g., 5-membered heterocyclic group, 6-membered heterocyclic group) and optionally substituted by substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl.

[0287] In some implementation schemes, each R 6A Selected independently from NR c R d In some implementations, each R 6A Selected independently from OR a In some implementations, each R 6A Selected independently from SR a .

[0288] In some implementation schemes, each R 6A Selected independently from C(O)R bIn some implementations, each R 6A Selected independently from C(O)NR c R d In some implementations, each R 6A Selected independently from C(O)OR a In some implementations, each R 6A Selected independently from OC(O)R b In some implementations, each R 6A Selected independently from OC(O)NR c R d .

[0289] In some implementation schemes, each R 6A Selected independently from NR c C(O)R b In some implementations, each R 6A Selected independently from NR c C(O)NR c R d In some implementations, each R 6A Selected independently from NR c C(O)OR a .

[0290] In some implementation schemes, each R 6A Each is independently selected from S(O)(=NR) b )R b In some implementations, each R 6A Selected independently from S(O)R b In some implementations, each R 6A Selected independently from S(O)NR c R d In some implementations, each R 6A Selected independently from S(O)2R b In some implementations, each R 6A Selected independently from NR c S(O)2R d In some implementations, each R 6A Selected independently from S(O)2NR c R d In some implementations, each R 6A Selected independently from NR c S(O)2NR c R d In some implementations, each R 6ASelected independently from NR c S(O)(=NR b )R b .

[0291] In some implementation schemes, each R A They are selected independently from H and D, respectively.

[0292] In some implementation schemes, each R A Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 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 .

[0293] In some implementation schemes, each R B They are selected independently from H and D, respectively.

[0294] In some implementation schemes, each R B Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 alkyl group is a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C3-C6 alkyl group. 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a C(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)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 B(OR) c (OR) d ).

[0295] In some implementation schemes, R C and R D They are selected independently from H and D, respectively.

[0296] In some implementation schemes, R C and R D Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a OC(O)NR c R d NR c R d NR c C(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 B(OR) c (OR) d ).

[0297] In some implementation schemes, R C and R D Together with the N atom to which it is attached, it forms a 4-7 membered heterocyclic group, which may optionally be substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.

[0298] In some implementation schemes, each R a They are selected independently from H and D, respectively.

[0299] In some implementation schemes, each R a Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, halogen, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl.

[0300] In some implementation schemes, each R a1 They are selected independently from H and D, respectively.

[0301] In some implementation schemes, each R a1 Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, halogen, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl.

[0302] In some implementation schemes, each R b They are selected independently from H and D, respectively.

[0303] In some implementation schemes, each R b Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 alkyl group is a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C3-C6 alkyl group. 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic.

[0304] In some implementation schemes, each R b1 They are selected independently from H and D, respectively.

[0305] In some implementation schemes, each R b1 Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 alkyl group is a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C3-C6 alkyl group. 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic.

[0306] In some implementation schemes, R c and R d They are selected independently from H and D, respectively.

[0307] In some implementation schemes, R c and R d Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 Aryl, or bis(5-10 heteroaryl); wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 The aryl group, or bis(5-10 heteroaryl group), is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, 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-.

[0308] In some implementation schemes, R c and R d Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkoxy-C1-C4 alkyl, or C1-C4 alkoxy-C1-C4 alkoxy.

[0309] In some implementation schemes, R c1 and R d1 They are selected independently from H and D, respectively.

[0310] In some implementation schemes, R c1 and R d1 Each is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 Aryl, or bis(5-10 heteroaryl); wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 The aryl group, or bis(5-10 heteroaryl group), is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, 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-.

[0311] In some implementation schemes, R c1 and R d1Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkoxy-C1-C4 alkyl, or C1-C4 alkoxy-C1-C4 alkoxy.

[0312] In some implementation schemes, each R E They are selected independently from H and D, respectively.

[0313] In some implementation schemes, each R E Each of the following is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 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 heteroaryl-C1-C4 alkyl, or 4-10 heterocyclic-C1-C4 alkyl.

[0314] In some implementation schemes, each R F They are selected independently from H and D, respectively.

[0315] In some implementation schemes, each R F Each is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic groups.

[0316] In some implementation schemes, each R e They are selected independently from H and D, respectively.

[0317] In some implementation schemes, each R e Each of the following is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 heteroaryl-C1-C4 alkyl, or 4-10 heterocyclic-C1-C4 alkyl.

[0318] In some implementation schemes, each R f They are selected independently from H and D, respectively.

[0319] In some implementation schemes, each R f Each is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic groups.

[0320] In some implementation schemes, R G R H and R I Each is independently selected from selectively substituted C1-C4 alkyl groups or selectively substituted phenyl groups.

[0321] In some implementation schemes, R G It is a selectively substituted C1-C4 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl) or phenyl. In some embodiments, R G It can be methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0322] In some implementation schemes, R H It is a selectively substituted C1-C4 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl) or phenyl. In some embodiments, R H It can be methyl, ethyl, propyl (e.g., n-propyl, i-propyl), or butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0323] In some implementation schemes, R I It is a selectively substituted C1-C4 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl) or phenyl. In some embodiments, R I It can be methyl, ethyl, propyl (e.g., n-propyl, i-propyl), or butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0324] In some embodiments, the compound represented by formula (I) is as shown in formula (IIa), (IIb), (IIc), (IId), or (IIe):

[0325]

[0326] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof;

[0327] X 1 For N or CR 2 ;

[0328] X 2 For N or CR 2 ;

[0329] X 3 For N or CR 2 ;

[0330] X 4 For N or CR 2 ;

[0331] Among them, ring A, ring C, and ring R 1 R 2 R 3 And m is as defined in the present invention (I).

[0332] In some embodiments, the compound represented by formula (I) is as shown in formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf):

[0333]

[0334] Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof;

[0335] Among them, ring A, ring C, and ring R 1 R 2 R 3 And m is as defined in the present invention (I).

[0336] In some embodiments, the compound represented by formula (I) is as shown in formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf):

[0337]

[0338] Z 3 For N or CR 1 ;

[0339] Among them, rings C and R 1 R 2 R 3 And m is as defined in the present invention (I).

[0340] In some embodiments, the compound represented by formula (I) is:

[0341]

[0342]

[0343]

[0344] Or its pharmaceutically acceptable salt.

[0345] The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0346] The present invention also provides a method for treating or preventing PolQ overexpression cancer, comprising: administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0347] The present invention also provides a method for treating or preventing cancer, wherein the cancer is characterized by an increased dependence on MMEJ-DSB repair, comprising: administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0348] The present invention also provides a method for treating or preventing cancer, wherein the cancer is characterized by HR deficiency, a reduction or absence of HR-related gene expression, comprising: administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0349] The present invention also provides a method for treating or preventing cancer, wherein the cancer lacks the 53BP1 / Shieldin complex, comprising: administering to the patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0350] The present invention also provides a method for treating or preventing cancer, said cancer being treated or not treated with PARPi drugs and being resistant to PARPi treatment, comprising: administering to said patient a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0351] The present invention also provides a method for treating or preventing cancer, 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 of the present invention, or a pharmaceutical composition comprising the compound of the present invention.

[0352] The present invention also provides the use of the compound or pharmaceutical composition described herein in the preparation of a medicament for treating PolQ overexpression diseases.

[0353] The present invention also provides the use of the compound or the pharmaceutical composition thereof in the preparation of a medicament for treating diseases that increase dependence on MMEJ-DSB repair.

[0354] The present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for treating cancer, wherein the cancer is characterized by HR deficiency, a reduction or absence of HR-related gene expression.

[0355] The present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for treating cancer, wherein the cancer lacks the 53BP1 / Shieldin complex.

[0356] The present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for treating cancer, wherein the cancer has been treated with or not with PARPi drugs and is resistant to PARPi treatment.

[0357] The present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for treating cancer, wherein the cancer is characterized by NHEJ deficiency, with reduced or absent expression of NHEJ-related genes.

[0358] definition

[0359] Unless otherwise stated, the following terms have the meanings described below. Other terms are defined elsewhere throughout this specification.

[0360] Unless the context clearly indicates otherwise, as used herein, the singular forms "a," "an," and "the" include the plural objects referred to. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a prior basis for the use of such exclusive terms, such as "unique," "only," etc., in connection with reference to claim elements or the use of the word "negative" limitation.

[0361] In various places within 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-, with each form intended to be disclosed separately. When a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," then it should be understood that "alkyl" or "aryl" respectively represents the linked alkylene or aryl group.

[0362] The term "substituted" means that one atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substitution," unless otherwise specified, refers to any number of substitutions, such as mono-, di-, tri-, tetra-, or penta-substitution, if such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically possible position. It should be understood that substitution at a particular atom is limited by valence. The term "optionally substituted" means either unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms.

[0363] The term "Cn-Cm" represents a range including the 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.

[0364] The compounds of the present invention are stable. As used herein, “stable” means that the compound is sufficiently stable during the separation of the compound from the reaction mixture to obtain useful purity, and preferably means that the compound can be formulated into an effective therapeutic agent.

[0365] It should also be understood that, for clarity, certain features of the invention described in the context of individual embodiments may also be provided in combination with individual embodiments. Conversely, for the sake of brevity, various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0366] As used herein, unless otherwise specified, the term "alkyl," either alone or as part of another substituent, refers to a straight-chain or branched saturated hydrocarbon group. An alkyl group may contain 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. Exemplarily, an alkyl group may contain any number of carbon atoms, such as C1... 1-2 Alkyl, C 1-3 Alkyl, C 1-4 Alkyl, C 1-5 Alkyl, C 1-6 Alkyl, C 1-7 Alkyl, C 1-8 Alkyl, C 1-9 Alkyl, C 1-10 Alkyl, C 2-3 Alkyl, C 2-4 Alkyl, C 2-5 Alkyl, C 2-6 Alkyl, C 3-4Alkyl, C 3-5 Alkyl, C 3-6 Alkyl, C 4-5 Alkyl, C 4-6 Alkyl and C 5-6 Alkyl group. Similarly, C 1-8 C 1-8 An alkyl group is defined as having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain. 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, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, heptyl, octyl, etc.

[0367] As used herein, unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Alkenyl groups can contain any number of carbon atoms, for example, C1... 2-3 alkenyl, C 2-4 alkenyl, C 2-5 alkenyl, C 2-6 alkenyl, C 2-7 alkenyl, C 2-8 alkenyl, C 2-9 alkenyl, C 2-10 alkenyl, C 3-4 alkenyl, C 3-5 alkenyl, C 3-6 alkenyl, C 4-5 alkenyl, C 4-6 alkenyl and C 5-6 Alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, etc. The one or more carbon-carbon double bonds may be in the chain (e.g., 2-butene) or at the end (e.g., 1-butene).

[0368] As used herein, unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group can contain any number of carbon atoms, for example, C0... 2-3 alkynyl group, C 2-4 alkynyl group, C 2-5 alkynyl group, C 2-6 alkynyl group, C 2-7 alkynyl group, C 2-8 alkynyl group, C 2-9 alkynyl group, C 2-10 alkynyl group, C 3-4 alkynyl group, C 3-5 alkynyl group, C 3-6 alkynyl group, C 4-5 alkynyl group, C 4-6 alkynyl group and C 5-6Alkynyl group. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc. The one or more carbon-carbon triple bonds may be in the chain (e.g., 2-butyne) or at the end (e.g., 1-butyne).

[0369] As used herein, unless otherwise specified, “halogenated alkyl” refers to an alkyl group having one or more halogen substituents. Exemplary halogenated alkyl groups include, but are not limited to, CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc.

[0370] As used herein, unless otherwise specified, "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings). In some embodiments, the aryl group has 6 to about 20 carbon atoms. In some embodiments, the aryl group has 6 to about 14 carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthryl, indene, indenyl, etc.

[0371] As used herein, unless otherwise specified, “cycloalkyl” refers to an unsubstituted or substituted non-aromatic carbon ring, including cyclic alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., bridged bicyclic alkyl rings). In some embodiments, the cycloalkyl group may have 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to about 7 carbon atoms. The cycloalkyl group may also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. The cycloalkyl group may also optionally be oxidized or thiolated (e.g., -C(O)- or -C(S)-). The definition of cycloalkyl also includes groups having one or more aromatic rings fused to (i.e., having bonds shared with the cycloalkyl group) the cycloalkyl group, such as cyclopentyl, cyclopentenyl, cyclohexyl benzo[a] derivatives, etc. A cycloalkyl group having one or more fused aromatic rings can be linked by either an aromatic ring moiety or a non-aromatic ring moiety. One or more cyclic carbon atoms of the cycloalkyl group can be oxidized, for example, to form oxo or thio substituents. In some embodiments, the cycloalkyl group is selected from C10. 3- C7 monocyclic cycloalkyl groups. In some embodiments, the cycloalkyl group is selected from C7... 4- C 10Spirocyclic or bridged cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcarelyl, cubic, adamantyl, bicyclo

[111] pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group is a cyclic non-aromatic hydrocarbon group having 3 to 12 carbon atoms (“C…”). 3- C 12 Preferably, 3 to 6 carbon atoms (“C”) 3- Exemplary cycloalkyl groups include, for example, cyclopropyl (C3; 3-membered), cyclobutyl (C4; 4-membered), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantyl (C6) 10 )wait.

[0372] When used alone or as part of a substituent, the term "spirocycloalkyl" refers to a non-aromatic cycloalkyl group containing two cycloalkyl groups, wherein, typically, the two cycloalkyl groups share a single carbon atom.

[0373] As used herein, unless otherwise specified, “heteroaryl” refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member, such as boron, silicon, sulfur, oxygen, nitrogen, or phosphorus. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any N atom of a heteroaryl group can be oxidized to form an N-oxide. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, N-oxopyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purine, carbazoleyl, benzimidazolyl, indololinyl, etc. A heteroaryl group containing a non-aromatic ring can be fused with a non-aromatic ring by arbitrary atom substitution. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms, and further, in some embodiments, has from 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group comprises 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.

[0374] As used herein, unless otherwise specified, "heterocyclic alkyl" 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), wherein one or more cyclic carbon atoms of the heterocyclic alkyl group may be replaced by heteroatoms selected from N, O, P, S, Si, and B; and the cyclic carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be oxidized or thiolated (e.g., C(O), P(O), S(O), C(S), or S(O)2, etc.). Heterocyclic alkyl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Heterocyclic alkyl groups include monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocyclic alkyl groups. Heterocyclic alkyl groups also include spirocyclic and bridged rings (e.g., 5-10 membered bridged bicyclic alkyl groups, where one or more of the cyclic carbon atoms are replaced by heteroatoms independently selected from N, O, P, S, Si, and B). The heterocyclic alkyl groups can be linked by cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds.

[0375] The heterocyclic alkyl group further includes a group having one or more aromatic rings fused to (i.e., having a shared bond with the heterocyclic alkyl group) the non-aromatic heterocycle, such as piperidine, morpholine, benzo[a] or thieno[b] derivatives of azaheptanes. The heterocyclic alkyl group containing the fused aromatic ring can be linked by any cyclic atoms, including the cyclic atoms of the fused aromatic ring. In some embodiments, the heterocyclic alkyl group contains 3 to 10 cyclic atoms, 4 to 10 cyclic atoms, 3 to 7 cyclic atoms, or 5 to 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatomum. In some embodiments, the heterocyclic alkyl group is a monocyclic 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms independently selected from N, O, S, and B, while having one or more oxygenated ring atoms.

[0376] Exemplary heterocyclic alkyl groups include, but are not limited to, pyrrolidine-2-one, 1,3-isooxazolidine-2-one, pyranyl, tetrahydropyranyl, oxacyclobutyl, aziridine, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, aziridine-heptyl, and benzozapentenyl. ,1,2,3,4-Tetrahydroisoquinolinyl, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.l]hexyl, azabicyclo[2.2.l]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.l]heptyl, diazabicyclo[3.1.l]heptyl, azabicyclo[3.2.l]octyl, diazabicyclo[3.2.1] Octyl, 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]pyrrol, etc.

[0377] In some embodiments, a heterocyclic alkyl 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 alkyl group can be linked by any heteroatom or carbon atom, as long as a stable structure can be generated. Exemplary heterocyclic alkyl groups include, but are not limited to, aziridine, aziridine propyl, aziridine butyl, pyrrolidinyl, dioxocyclopentyl, imidazoalkyl, pyrazolyl, piperazinyl, piperidinyl, dioxohexacycloyl, morpholinyl, dithiaalkyl, thiomorpholinyl, oxazaheptanyl, ethylene oxide, oxazabutyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, etc.

[0378] In some embodiments, the term "spirocyclic heterocyclic alkyl" when used alone or as part of a substituent refers to a non-aromatic ring comprising two rings, at least one of which is selected from heterocyclic alkyl groups, the two rings sharing a single carbon atom.

[0379] As used herein, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0380] 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, etc.

[0381] As used herein, unless otherwise specified, “hydroxyalkyl” refers to an alkyl group substituted with OH.

[0382] As used herein, unless otherwise specified, “cyanoalkyl” refers to an alkyl group substituted with CN.

[0383] As used herein, unless otherwise specified, “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group.

[0384] As used herein, unless otherwise specified, “haloalkoxy” refers to –O-(haloalkyl).

[0385] As used herein, unless otherwise specified, “arylalkyl” refers to an alkyl group substituted with an aryl group, and “cycloalkyl” refers to an alkyl group substituted with a cycloalkyl group. An exemplary arylalkyl group is benzyl.

[0386] As used herein, unless otherwise specified, “heteroarylalkyl” means an alkyl group substituted with a heteroaryl group, and “heterocyclic alkylalkyl” means an alkyl group substituted with a heterocyclic alkyl group.

[0387] As used herein, unless otherwise specified, “oxo” refers to an oxygen substituent (i.e., =O) linked by a double bond.

[0388] The compounds described in this invention may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this invention. The compounds containing asymmetrically substituted carbon atoms described in this invention can be isolated as optical isomers or racemates. Methods for preparing optically active forms of products from optically active starting materials are known in the art, for example, 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 in this invention, and all stable isomers are also within the scope of this invention. Cis and trans geometric isomers of the compounds described in this invention are also within the scope of this invention and can be isolated as mixtures of isomers or as individual isomers. Furthermore, rotation-restricted isomers and mixtures thereof, such as two aromatic or heteroaromatic ring systems formed by the bonding of an aromatic or heteroaromatic ring to another aromatic or heteroaromatic ring, which may produce rotational restriction, are also included within the scope of this invention. For example, when Cy is a phenyl group and has two substituents attached to an adjacent carbon atom, one of which is attached to a carbon atom of pyridine, the rotation of the phenyl group may be hindered. In some cases, the rotation barrier is high enough to separate different hindered isomers.

[0389] The compounds of this invention also include tautomers. Tautomers arise from the exchange of single bonds with adjacent double bonds and the accompanying migration of protons. Tautomers include proton-transfer tautomers having the same chemical formula and total charge. Exemplary proton-transfer tautomers include keto-enol tautomers, amide-imino tautomers, lactam-lactide tautomers, amide-imino tautomers, and enamine-imino tautomers, in which protons in the cyclic structure can interleave at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; certain hydroxyl-substituted compounds can exist as tautomers, as shown below: Tautomers can be in equilibrium, or they can be fixed in space by appropriate substitutions to form a form.

[0390] In some cases, the compounds described in this invention may exist in the form of rotational isomers. The description of the compounds of this invention is intended to cover any single rotational isomer, and any mixture of rotational isomers in any proportion, and does not represent any particular rotational isomer. The description of a particular rotational isomer means that the described rotational isomer substantially free of other rotational isomers.

[0391] This invention further includes isotopic labels of the compounds or intermediates described herein. "Isotope" refers to atoms having the same number of atoms but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0392] As used herein, unless otherwise specified, the term “selectively substituted” means either unsubstituted or substituted.

[0393] As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms are substituted, independently and separately, by the same or different substituents. Exemplary substituents include, but are not limited to, D, halogen, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and 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 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 eOR 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, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with a substituent selected from: D, halogen, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 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(ORe )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 .

[0394] In some embodiments, the compounds or salts thereof described in this invention are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation may include, for example, compositions rich in the compounds of this invention. Substantialtive isolation may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of this invention or salts thereof. Methods for separating the compounds and their salts are conventional in the art.

[0395] This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds described herein, wherein the parent compound is modified by conversion with an existing acid or base to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues such as amines; and basic salts or organic basic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of this invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. Typically, the salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), which are incorporated herein by reference in their entirety.

[0396] The term “pharmaceutically acceptable” in this document refers to those compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and have a reasonable benefit / risk ratio.

[0397] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, and that are added to or otherwise used as a medium, carrier, or diluent to facilitate the administration of a pharmaceutical agent. Exemplary excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0398] "Solvate" refers to a compound represented by Formula I that is physically bonded to one or more solvent molecules.

[0399] "Subject" includes people. The terms "person," "patient," and "subject" are used interchangeably in this document.

[0400] In one implementation, “treating” any disease or disorder means improving the disease or disorder (i.e., preventing or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another implementation, “treating” means improving at least one bodily parameter that the subject may not be able to discern. In yet another implementation, “treating” means modulating the disease or disorder at a physical level (e.g., stabilization of discernible symptoms), a physiological level (e.g., stabilization of bodily parameters), or both. In yet another implementation, “treating” means delaying the onset of the disease or disorder.

[0401] The terms “compounds of the present invention” and equivalent expressions are intended to cover the compounds of formula (I) described herein, as well as their respective subgenuses, and, where the context permits, include stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds of formula (I), as well as pharmaceutically acceptable salts.

[0402] As used herein, the term "isotope variant" refers to a compound that contains an isotopic proportion greater than that naturally occurring at one or more atoms in the atoms constituting the compound. For example, an "isotope variant" of a compound may be radiolabeled, i.e., containing one or more radioactive isotopes, or may be made of non-radioactive isotopes such as, for example, deuterium (…). 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15N), etc. It should be understood that in compounds that have undergone such isotopic substitution, if present, the following atoms can be changed such that, for example, any hydrogen atom can be... 2 H / D, any carbon can be 13 C, or any nitrogen, can be 15 N, and the presence and location of such atoms can be determined within the capabilities of those skilled in the art.

[0403] It should also be understood that compounds having the same molecular formula but different atomic bonding properties or sequences or spatial arrangements are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers", such as diastereomers, enantiomers, and rotational isomers. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be a single (R)- or (S)-stereoisomer or a mixture thereof at each asymmetric center. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all its racemic or other stereoisomers and mixtures. When a structure contains one chiral center but does not show the specific stereochemistry of that center, the structure comprises two enantiomers, individually or as a mixture of enantiomers. When a structure contains more than one chiral center but does not show the specific stereochemistry of that center, the structure comprises all enantiomers and diastereomers, individually or as a mixture. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0404] Pharmaceutical Composition

[0405] The present invention also provides pharmaceutical compositions comprising: a compound of formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, and a pharmaceutically acceptable excipient.

[0406] The pharmaceutical composition may be in a form suitable for oral administration (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), may be for injection (e.g., aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar drug carriers), may be for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), may be for inhalation (e.g., fine powders or liquid aerosols), may be for inhalation (e.g., fine powders), or may be for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0407] Pharmaceutically acceptable excipients may be those described below: carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or extenders, granulators, coatings, controlled-release agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, masking agents, stabilizers, or any other conventional excipients available for pharmaceutical compositions.

[0408] Pharmaceutically acceptable carriers can be, for example, solid, liquid, or gaseous. Exemplary solid carriers include lactose, kaolin, 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. Any convenient pharmaceutical medium can be used when preparing compositions for oral dosage forms. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents can be used to form oral liquid formulations, such as suspensions, elixirs, and solutions; carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants can be used to form oral solid dosage forms, such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage forms when using solid pharmaceutical carriers due to their ease of administration. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0409] Suitable dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, sheets, or patches, such as buccal patches.

[0410] Therefore, the tablet composition may contain a unit dose of the active compound and an inert diluent or carrier, such as sugars or sugar alcohols, for example, lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents 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. The tablet may also contain standard ingredients such as binders and granulators, such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethyl cellulose), 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 tablet may optionally be mixed with one or more excipients or adjuvants 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 powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets are formed from a mixture of a wetted powdered compound and an inert liquid diluent using suitable equipment. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each capsule or pouch preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, formulations for oral human use may contain about 0.5 mg to about 5 g of the active ingredient, mixed with a suitable and convenient amount of a carrier, the amount of which may vary between about 5% and about 95% of the total composition. Unit dosage forms typically contain about 1 mg to about 2 g of the active ingredient, typically in doses of 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0411] The 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 suitable surfactants, such as hydroxypropyl cellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0412] The pharmaceutical compositions of the present invention suitable for injection comprise sterile aqueous solutions or dispersions. Alternatively, the compositions may be in the form of sterile powders for ad hoc preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be an effective fluid for easy injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, they should preferably be preserved to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0413] The pharmaceutical compositions of the present invention can be in forms suitable for topical use, such as aerosols, creams, ointments, lotions, powders, etc. Furthermore, the compositions can be in forms suitable for use with transdermal devices. These formulations can be prepared using compounds of Formula I of the present invention or pharmaceutically acceptable salts thereof via conventional processing methods. Exemplarily, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5 wt% to about 10 wt% of the compound to produce a cream or ointment with a desired consistency.

[0414] The pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture is formed into 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, followed by cooling and molding in a mold.

[0415] The composition can be obtained using conventional pharmaceutical excipients well known in the art through routine procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0416] An effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent the proliferative diseases mentioned in this invention, slow their progression and / or alleviate symptoms associated with the diseases.

[0417] The amount of active ingredient 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, formulations for oral administration in humans typically contain, for example, 0.1 mg to 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, along with a suitable and convenient amount of excipients, the amount of which may vary from about 5% to about 98% of the total composition weight.

[0418] The dosage of the compound indicated by formula (I) for therapeutic or preventative purposes varies, according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0419] Therefore, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0420] In addition to the carrier components described above, the pharmaceutical formulations may, as appropriate, contain one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other excipients may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing compounds of Formula I or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0421] Generally, a dosage level of approximately 0.01 mg / kg to approximately 150 mg / kg body weight per day can be used to treat the above-mentioned conditions, or approximately 0.5 mg to approximately 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 approximately 0.01 to 50 mg of the compound per kilogram of body weight per day, or approximately 0.5 mg to approximately 3.5 g per patient per day.

[0422] However, it should be understood that lower or higher doses may be required than those described above. The specific dosage level and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, drug combination, severity and duration of the specific disease being treated, the subject's predisposition to the disease, and the judgment of the attending physician.

[0423] These and other aspects will become apparent from the following description of the invention.

[0424] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0425] Administration method

[0426] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such compound may be administered to a subject by any convenient method of administration, whether systemic / peripheral or local (i.e. at the site of desired action).

[0427] Methods of administration include, but are not limited to: oral (e.g., by ingestion); sublingual; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, for example, by aerosols, for example, by mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrathoracic; implantation in a depot or reservoir, for example, subcutaneous or intramuscular.

[0428] How to use

[0429] The method typically involves administering a therapeutically effective amount of the compound of the invention to a subject. The therapeutically effective amount of the combination of target compounds may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the nature of the disease, such as the subject's weight and age, the severity of the disease, the route of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells, such as reduced proliferation or downregulation of target proteins. The specific dose will vary depending on the specific compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0430] As used herein, the term "IC" 50 "IC" refers to the half-maximal inhibitory concentration (50%) of an inhibitor in inhibiting a biological activity or biochemical function. This quantitative measure indicates how much of a specific inhibitor is required to inhibit half of a given biological process (or a component of that process, i.e., an enzyme, cell, cell receptor, or microorganism). In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC or IC50). 50 ).

[0431] In some embodiments, the test method uses, for example, an IC40 assay. 50 A PolQ inhibitor with a value approximately or less than a predetermined value. In some embodiments, the PolQ inhibitor has the following IC value for PolQ inhibition. 50Values: Approximately 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 Smaller, 180nM or smaller, 190nM or smaller, 200nM or smaller, 225nM or smaller, 250nM or smaller, 275nM or smaller, 300nM or smaller, 325nM or smaller, 350nM or smaller, 375nM or smaller, 400nM or smaller, 425nM or smaller, 450nM or smaller, 475nM or smaller, 500nM or smaller, 550nM or smaller, 600nM or smaller 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μ M or smaller, 5 μM or smaller, 10 μM or smaller, 15 μM or smaller, 20 μM or smaller, 25 μM or smaller, 30 μM or smaller, 40 μM or smaller, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or smaller (or a value within the range defined by any two of the above numbers and containing any two of the above numbers).

[0432] In some embodiments, the PolQ inhibitor of the present invention selectively inhibits PolQ with the following IC 50 Value: IC50 value relative to Polα, Polβ, Polγ, Polη, Polν, Polδ, Polε and other DNA polymerases 50 The s value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times (or a value within the range defined by any two of the above numbers and containing any two of the above numbers).

[0433] In some embodiments, the PolQ inhibitor of the present invention selectively inhibits PolQ with the following IC 50Values: Less than approximately 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 (or a value within the range defined by any two of the above numbers and containing any two of the above numbers).

[0434] The tested method can be used to treat diseases associated with PolQ. Any disease directly or indirectly caused by abnormal PolQ activity or expression levels is a potential candidate.

[0435] The compounds of the present invention can be used to treat and / or prevent diseases in patients, wherein the diseases are characterized by PolQ overexpression.

[0436] The term "PolQ overexpression" refers to an increased expression or activity of the PolQ enzyme in diseased cells, such as cancer cells, relative to the expression or activity of the PolQ enzyme in control cells (e.g., non-pathological cells of the same type). In some embodiments, the PolQ overexpression level is at least 2, 3, 4, or 5 times that of the PolQ expression level in control cells; the PolQ overexpression may be at least 2, 3, 4, 5, 6, 10, 20, or 50 times that of the PolQ expression level in control cells.

[0437] The compounds of the present invention are used to treat or prevent diseases in patients characterized by an increased dependence on MMEJ DSB repair.

[0438] The compounds of the present invention can be used to treat or prevent diseases in patients characterized by HR deficiency, deletion or reduction 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.

[0439] In some implementations, the method is used to treat or prevent HR-deficient breast cancer.

[0440] In some implementations, the method is used to treat or prevent HR-deficient ovarian cancer.

[0441] In some implementations, the method is used to treat or prevent HR-deficient prostate cancer.

[0442] In some implementations, the method is used to treat or prevent HR-deficient pancreatic cancer.

[0443] The compounds of this invention are used to treat or prevent cancer patients with a deficiency of the 53BP1 / Shieldin complex.

[0444] The compounds of the present invention are used to treat or prevent cancer, which has been treated with or has not been treated with PARPi drugs, or which is resistant to PARPi treatment.

[0445] The compounds of the present invention are used to treat or prevent patients with cancer characterized by NHEJ deficiency, reduced or absent expression of NHEJ-related genes, including but not limited to 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5, and XRCC6.

[0446] The compounds of the present invention, and pharmaceutical compositions comprising them, may be administered alone or in combination with medical therapies to treat any of the said diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, whole-body radioisotopes).

[0447] In other respects, the compounds and pharmaceutical compositions thereof described in this invention may be administered alone or in combination with one or more other pharmaceutical agents to treat any of the said diseases.

[0448] In other methods, the compounds and pharmaceutical compositions thereof described in this invention may be administered in combination with agonists of nuclear receptor drugs.

[0449] In other methods, the compounds and pharmaceutical compositions thereof described in this invention may be administered in combination with antagonists of nuclear receptor drugs.

[0450] In other methods, the compounds and pharmaceutical compositions thereof described in this invention may be administered in combination with antiproliferative agents.

[0451] Combination therapy

[0452] The compounds of this 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, radiation therapy, targeted therapy (e.g., growth factor inhibitors, kinase inhibitors, cyclin-dependent kinase inhibitors, etc.), other DDR modulators (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.

[0453] 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, radiation therapy, or chemotherapy. Exemplary radiation therapies include gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes. Exemplary suitable chemotherapeutic agents include one or more antitumor agents from the following categories: other antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate agents, such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as bleomycin, doxorubicin, doxorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin, and scintillans); antimitotic agents (e.g., vinblastine alkaloids such as vincristine, vinblastine, vinorelbine, and vinorelbine, and antitumor drugs such as paclitaxel and doxorubicin and polo kinase inhibitors); topoisomerase inhibitors ( Examples include podophyllotoxins such as etoposide and teniposide, acridine, topotecan, and camptothecin; cell growth inhibitors such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifen, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilumet, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (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 c-Src kinase family inhibitors (AZD0530, dasatinib, and bosutinib), and metalloproteinase family inhibitors (e.g., marimasitol, a family of urokinase plasminogen activator receptor function or heparinase antibodies).

[0454] 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, Vol. 54, ppl1-29); such inhibitors also include tyrosine kinase inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, and CI). 1033), ERB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin-derived growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib; serine / threonine kinase inhibitors (e.g., Ras / Raf inhibitors sorafenib, telbifabib, and lonafabib); cell proliferation inhibitors via MEK and / or AKT kinases; c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, and 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). Examples include VEGF receptor tyrosine kinase inhibitors such as vandetanib, vataranib, sunitinib, axitinib, pazopanib, and AZD2171; compounds disclosed in international patent applications WO97 / 22596, WO97 / 30035, WO97 / 32856, and WO98 / 13354; and compounds acting through other mechanisms (e.g., linolamine, integrin avβ3 function inhibitors, and angiostatin); vascular damaging agents such as cobustatin A4 and those disclosed in international patent application WO99 / Compounds disclosed in WO02166, WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; endothelin receptor antagonists, such as zippertentan or atrasentan; PARP inhibitors such as olaparib, rucaparib, niraparib, tapolazoparib, veliparib, and pamiparib; PARP1 selective inhibitors such as AZD9547, AZD5305, AG-14361 and NMS-P118;Other DNA damage repair modulators include DNA-PK inhibitors (e.g., LY294002, NU7026, NU7441, IC86621, IC87102, IC87361, OK-1035, SU11752, vanillin, NK314, IC486241, BVAN08, M3814, AZD7648, VX-984, doxycycline), ATM inhibitors (e.g., caffeine, wortmannin, CP-466722, KU-55933, KU-60019, and KU-559403), and 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 inhibitors (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, isohydroxamic acid, and cyclic tetrapeptides, succinyl aniline isohydroxamic acid (SAHA), trogostatin 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 ( Examples include RP6306, USP1 inhibitors (e.g., KSQ-4279), and PARG inhibitors (e.g., IDE161); antisense therapies, such as therapies targeting the above targets, such as ISIS2503, an anti-ras antisense; gene therapy methods, including methods such as replacing abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-guided enzyme prodrug therapy) methods, such as methods using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug-resistant gene therapy;And immunotherapy methods, including, for example, in vitro and in vivo methods to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines like interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; methods to reduce T cell dysfunction; methods using transfected immune cells such as cytokine-transfected dendritic cells; methods using cytokine-transfected tumor cell lines; methods using anti-idiotype antibodies; and methods using immune checkpoint inhibitors such as CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, and OX4. 0, 41BB, VISTA, CD96, TGF, 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, etc.

[0455] synthesis

[0456] The compounds described in this 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.

[0457] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is one that does not substantially react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out; for example, the temperature range can be from the freezing temperature of the solvent to its boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Those skilled in the art can select a solvent suitable for a particular reaction step based on the specific reaction steps described above.

[0458] The preparation of the compounds of the present invention may involve the above-described protection and deprotection of various chemical groups. The need for the above-described protection and deprotection, and the selection of suitable protecting groups, can be readily determined by those skilled in the art. The disclosed chemical protecting groups are as follows, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Ed. (Wiley, 2019); Petrussion et al., "Protecting Groups in Carbohydrate Chemistry" J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed. (Wiley, 2014).

[0459] The reaction can be monitored using 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., ultraviolet-visible light), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0460] As used in this invention, “ambient temperature,” “room temperature,” and “rt” generally refer to temperature in the art, such as reaction temperature, which refers to the temperature of the space where the reaction is performed, for example, about 20°C to about 30°C.

[0461] The compounds of the present invention can be prepared according to various preparation routes known in the literature. The following methods provide general guidance related to the preparation of the compounds described in the present invention. Those skilled in the art will understand that the preparation methods in the following methods 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 as follows.

[0462] The following examples are provided to illustrate some of the concepts described herein. While these examples are intended to provide embodiments, they should not be construed as limiting the more general embodiments described herein.

[0463] abbreviations

[0464]

[0465]

[0466]

[0467] Synthesis scheme

[0468] A series of heterocyclic amide derivatives of Formula I can be prepared according to the method described in Scheme 1. Carboxylic acids 1-4 react with substituted amines 1-6 under standard amide coupling conditions (e.g., in the presence of an activating agent such as BOP, PyBOP, HATU, HBTU, EDCI, or T3P and a base such as Hunig's base, Et3N, pyridine, or DMAP) to give Formula I. Furthermore, carboxylic acids 1-4 react with chlorinating agents such as oxaloyl chloride, thionyl chloride, POCl3, or TCFH to give the corresponding acyl chlorides 1-5, which then react with suitable amines 1-6 to give the corresponding amide derivatives of Formula I.

[0469] Carboxylic acid ester derivative 1-1, wherein W 1 A halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) with compounds 1-2 wherein M 1 Suzuki coupling of boric acid or borate esters under standard Suzuki coupling conditions (e.g., in the presence of a palladium catalyst, such as Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, and a base, such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3) yields carboxylic acid esters 1-3. Furthermore, carboxylic acid ester derivative 1-1, wherein W 1 A halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf, OMs, or OPO(OR)2) with formula 1-2, where M 1 Stille coupling of ZnBr, SnMe3, or SnBu3 under standard Stille coupling conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)3, Pd(PPh3)4, or Pd(PPh3)2Cl2, and an additive such as CuCl or LiCl) yields carboxylic acid esters 1-3. Saponification of carboxylic acid esters 1-3 in the presence of a base such as LiOH, NaOH, KOH, or Me3SnOH yields the corresponding carboxylic acid derivatives 1-4.

[0470] Option 1

[0471]

[0472] A series of bicyclic intermediates of formulas 2-3 and 2-5, used for the preparation of amide heterocyclic amide derivatives of formula I, can be prepared according to the method of scheme 2. Compound 2-1, wherein W 2 Compound 2-3 can be prepared by reacting a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) with a suitable amine derivative 2-2 in the presence of a base, such as Hunig's base. Compound 2-1, wherein W 2 HXR is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) with a suitable alcohol or thiol derivative. A Compound 2-5 can be prepared by reacting compound 2-4 (where X is O or S) with a base such as KOH, NaH, NaHMDS, KHMDS, or n-BuLi. Furthermore, compound 2-1 can be reacted with a suitable alcohol or thiol derivative 2-4 under Ullmann coupling conditions (e.g., CuI, K3PO4 and ligands such as proline derivatives, BINAP, etc.) or under Buchwald-Hartwig coupling conditions (e.g., Pd2(dba)3, Bippyphos, RockPhos, FcP). t Coupling Bu2 with a base, such as t-BuOK, K3PO4, Cs2CO3, or K2CO3, yields compounds 2-5.

[0473] Option 2

[0474]

[0475] A series of bicyclic intermediates of formulas 3-3, 3-5, 3-7, 3-8, and 3-9, used for the preparation of heterocyclic amide derivatives of formula I, can be prepared according to the method described in scheme 3. Bicyclic compound 3-1, wherein W 2 Halogens (Br or Cl) or pseudohalogens (e.g., OTf or OMs) with (R 4 ) t -Cy-M 2 3-2 (Cy is C3-C) 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 heteroaryl, M 2 Suzuki coupling of boric acid or borate esters (with t = 0, 1, 2, 3, 4, or 5) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as Pd(dppf)Cl2, and a base, such as K3PO4) yields the corresponding intermediate 3-3. Furthermore, compound 3-1 can be coupled with a suitable compound 3-2 (e.g., M...) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as Pd(dppf)Cl2, and a base, such as K3PO4) to give the corresponding intermediate 3-3. 2Coupling of Sn(Me)3, Sn(Bu)3, ZnCl or BrZn under standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as Pd(Ph3P)4) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as Pd(Ph3P)4 or Pd(dppf)Cl2) yields intermediate 3-3.

[0476] Similarly, compound 3-1 is associated with suitable double-bonded compounds 3-4 (e.g., M... 3 For Sn(Me)3, Sn(Bu)3, ZnCl, or BrZn, where s is 1, 2, 3, 4, or 5, coupling can be performed under standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as Pd(Ph3P)4) or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as Pd(Ph3P)4 or Pd(dppf)Cl2), or with 3-4 where M 3 Boric acid or boronic ester, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as Pd(dppf)Cl2, and a base such as K3PO4), or with olefin derivatives 3-4, wherein M 3 H can be coupled under standard Heck coupling conditions (e.g., in the presence of a palladium catalyst, such as Pd(OAc)2, a base, such as TEA, and a ligand such as tris(2-methoxyphenyl)phosphine) to give olefin intermediates 3-5. Compound 3-1 coupled with a suitable terminal alkyne derivative 3-6 (e.g., s is 1, 2, 3, 4, or 5) under standard Sonogashira coupling conditions (e.g., Pd(PPh3)2Cl2, CuI, a base, such as TEA, and DIPEA) to give alkynyl derivative 3-7. Coupling of said olefin compound 3-5 and alkynyl derivative 3-7 in the presence of a palladium catalyst, such as Pd / C or Pd(OH)2 / C, yields the corresponding compounds 3-8 and 3-9.

[0477] Option 3

[0478]

[0479] A series of bicyclic intermediates, represented by formulas 4-3, 4-6, 4-8, 4-13, and 4-16, can be prepared according to the method described in Scheme 4. Aromatic amine derivative 4-1 reacts with potassium thiocyanate under acidic conditions, such as HCl or H₂SO₄, to yield the target compound represented by formula 4-3. Furthermore, formula 4-3 can also be prepared via a two-step cyclization reaction. Aromatic amine derivative 4-1 reacts with potassium thiocyanate and benzoyl chloride under alkaline conditions, such as NaOMe, tBuOK, or NaOH, to yield the target compound represented by formula 4-3.

[0480] Similarly, a series of bicyclic intermediates shown in formulas 4-6, 4-8, 4-13 and 4-16 were prepared by a two-step cyclization reaction with potassium thiocyanate or with benzoyl isothiocyanate, in a manner similar to that in Scheme 4.

[0481] Option 4

[0482]

[0483]

[0484] A series of bicyclic intermediates of Formula 5-4 can be prepared according to the method described in Scheme 5. The reaction of pyridine-4-amine derivative 5-1 with ethoxycarbonyl isothiocyanate yields thiourea derivative 5-2, which, upon reaction with Br2 or NBS, can be further converted to the corresponding bromide 5-3. The brominated pyrimidine derivative 5-3 undergoes a cyclization reaction under alkaline conditions, such as in the presence of NaOMe, tBuOK, or NaOH, to yield the compound shown in Formula 5-4.

[0485] Option 5

[0486]

[0487] A series of intermediates shown in Formulas 6-8 can be prepared according to the method described in Scheme 6. Aldehydes 6-1 (wherein W) 6 (Br or -SCH3) with suitable acetic acid 6-2 R 6 Condensation under standard conditions, such as in the presence of a base like piperidine, yields α-unsaturated acid 6-3. Furthermore, aldehyde 6-1 reacts with compound 6-4, where R... s and R t Independently selected C1-C6 alkyl groups undergo a Horner-Wadsworth-Emmons reaction under standard conditions (e.g., in the presence of a base such as NaH, BuLi, NaHMDS, or LiHMDS) to yield α-unsaturated esters 6-5, which, under standard conditions (e.g., in the presence of a base such as NaOH or LiOH, or an acid such as HCl or H2SO4), can be hydrolyzed to α-unsaturated acids 6-3.

[0488] The -unsaturated acid 6-3 undergoes a Curtius rearrangement and a corresponding cyclization reaction under standard conditions (e.g., in the presence of diphenylphosphohydrazine and a base such as Et3N or Hunig's base) to give pyridinone 6-6. Furthermore, the -unsaturated acid 6-3 reacts with isobutyl chloroformate, and then with sodium azide and isobutyl chloroformate, to give -unsaturated acyl azide 6-7. Acyl azide 6-7 undergoes a Curtius rearrangement, followed by an electrophilic cyclization reaction under elevated temperature to give pyridinone 6-6. The pyridinone 6-6 reacts with a suitable reagent W... 5 -R 3 W 5 Alkylation of halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) under basic conditions (e.g., in the presence of a base such as TEA or Hunig's base) yields intermediates shown in formulas 6-8. Furthermore, pyridones 6-6 react with W... 5 -R 3 W 5 Boric acid or borate ester and R 3 Aryl or heteroaryl groups can be coupled with Chan-Lam under standard Chan-Lam conditions (e.g., in the presence of a copper catalyst such as Cu(OAc)2 and a base such as pyridine) to yield 6-8.

[0489] The aldehyde intermediates shown in 6-12, 6-17, and 6-18 can be prepared according to the method described in Scheme 6. The acid precursor 6-10 is amide-coupled with N,O-dimethylhydroxylamine under standard amide coupling conditions (e.g., in the presence of an amide coupling agent such as BOP, PyBOP, HATU, HBTU, or EDCI, and a base such as TEA, Hunig's base, or pyridine) to give Weinreb amide 6-11. Weinreb amide 6-11 can be reduced with DIBAL-H in a THF solution at -78°C or reacted with Schwartz's reagent (Cp₂Zr(H)Cl) in a THF solution at rt to give aldehyde 6-12. Furthermore, halogen compound 6-13 (W 4 Aldehydes 6-12 can be obtained by reacting Br or I with Grignard reagents such as i-PrMgBr or strong metal reagents such as BuLi, followed by reaction with formylation reagents such as DMF, N-methoxy-N-methylformamide or N-formylmorpholine.

[0490] Furthermore, amide 6-14 undergoes a cyclization reaction with aldehyde 6-15 to yield thiazole aldehyde 6-17. 6-14 undergoes a cyclization reaction with dialdehyde 6-16 to yield thiazole 6-18.

[0491] Option 6

[0492]

[0493] The intermediates shown in Formula 7-7 can be prepared according to the method described in Scheme 7. Carboxylic acid 7-1 (W 4 Esterification of ester 7-2 with a suitable alcohol such as MeOH or EtOH (H, Br, or I) yields the corresponding ester 7-2. Ester 7-2 is lithiated with a strong base such as butyllithium, followed by the addition of a formylation agent such as DMF, N-methoxy-N-methylformamide 7-3 (R 6 =H) or N-formylmorpholine can yield aldehyde 7-4. Aldehyde 7-4 reacts with hydrazine to directly give pyridazinone 7-5. Pyridazinone 7-5 reacts with a suitable reagent W 5 -R 3 7-6, where W 5 Alkylation of halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) under basic conditions (e.g., in the presence of a base such as TEA or Hunig's base) yields the intermediate shown in Formula 7-7. Furthermore, pyridazinones 7-5 with W 5 -R 3 7-6, where W 5 Boric acid or borate ester and R 3 Aryl or heteroaryl groups can be coupled with Chan-Lam under standard Chan-Lam conditions (e.g., in the presence of a copper catalyst such as Cu(OAc)2 and a base such as pyridine) to obtain 7-7.

[0494] Option 7

[0495]

[0496] A series of intermediate aldehyde-carboxylic acid esters 8-3 can be prepared according to the method in Scheme 8. Halogen-ester derivatives 8-1, wherein W... 4 Halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) can be converted into the corresponding cyano derivatives 8-2. The cyano group of 8-2 can be hydrogenated with a Ni catalyst or reduced in the presence of a reducing agent such as AlH(Bu-i)2 or SnCl2 to give the aldehyde compound 8-3.

[0497] Furthermore, halogen ester 8-1 can be converted to the corresponding ethylene ester derivative 8-4 by reacting with ethylene borate ester under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as Pd(dppf)Cl2, and a base, such as K3PO4) or with tributylvinyltin or vinyl zinc chloride under standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as Pd(Ph3P)4) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst, such as Pd(Ph3P)4 or Pd(dppf)Cl2). The alkenyl group of ester 8-4 can be oxidized with ozone or with NaIO4 / OsO4 to obtain 8-3, wherein W 4 It is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs).

[0498] Option 8

[0499]

[0500] A series of intermediates shown in Formula 9-9 can be prepared according to the method described in Scheme 9. Compound 9-1 can be converted into the corresponding amide 9-2. The amide 9-2 reacts with the trialkyl orthoformate 9-3 in the presence of an acid such as p-TsOH or HCl to give the target product, bicyclic pyrimidinone 9-4. Furthermore, the amino ester 9-5 reacts with the cyano derivative 9-6 or the ethyl alkyl-iminoformate 9-7 in the presence of an acid (e.g., dry HCl, TsOH, or H2SO4) to give bicyclic pyrimidinone 9-4. The bicyclic pyrimidinone 9-4 reacts with a suitable reagent W 5 -R 3 9-5, where W 5 Alkylation of halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) under basic conditions (e.g., in the presence of a base such as TEA or Hunig's base) yields the intermediates shown in Formula 9-6. Furthermore, bicyclic pyrimidinones 9-4 with W... 5 -R 3 9-8, where W 5 Boric acid or borate ester and R 3 Aryl or heteroaryl groups can be coupled with Chan-Lam under standard Chan-Lam conditions (e.g., in the presence of a copper catalyst such as Cu(OAc)2 and a base such as pyridine) to obtain 9-8.

[0501] Option 9

[0502]

[0503] A series of aminocarboxylic acid intermediates of formula 10-6 can be prepared according to the method described in Scheme 10. Acylated ethyl 2-amino-2-cyanoacetate 10-1 with a suitable acid anhydride 10-2 or acyl chloride 10-3 in the presence of a suitable base such as Et3N, Hunig's base, or pyridine yields an acylated 2-amino-2-cyanoacetic acid derivative 10-4. Cyclization of the acylated amino derivative 10-4 with Lawesson's reagent in a suitable solvent such as THF, toluene, or pyridine yields a 5-amino-2-alkylthiazol-4-carboxylic acid ester 10-5. Ester hydrolysis of compound 10-5 under standard conditions (e.g., in the presence of a suitable base such as LiOH, KOH, or NaOH) yields 5-amino-2-alkylthiazol-4-carboxylic acid 10-6.

[0504] Option 10

[0505]

[0506] A series of intermediates shown in Formula 11-5 can be prepared according to the method described in Scheme 11. The reaction of 11-1 with a solution of bromoacetic acid in the presence of KSCN yields the bicyclic aminothiazole shown in Formula 11-2. The demethylation reaction of 11-2 with a DCM solution of BBr3 yields compound 11-3. Compound 11-3 is then reacted with a suitable reagent W... 5 -R 3 11-4, where W 5 Alkylation of halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) under basic conditions (e.g., in the presence of a base such as TEA or Hunig's base) yields compounds shown in formulas 11-5. Furthermore, compounds 11-3 react with W... 5 -R 3 11-4, where W 5 Boric acid or borate ester and R 3 Chan-Lam coupling of aryl or heteroaryl groups under standard Chan-Lam conditions (e.g., in the presence of a copper catalyst such as Cu(OAc)2 and a base such as pyridine) yields 11-5.

[0507] Option 11

[0508]

[0509] Similarly, a series of intermediates shown in Formula 12-5 can be prepared according to the method described in Scheme 12. The reaction of 12-1 with a solution of bromoacetic acid in the presence of potassium thiocyanate (KSCN) yields bicyclic aminothiazole 12-2. The demethylation of 12-2 with a solution of BBr3 in DCM yields compound 12-3. Compound 12-3 reacts with a suitable halogenated derivative 12-4, wherein W... 5 Alkylation of halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) under basic conditions (e.g., in the presence of a base such as TEA, Hunig's base, Cs₂CO₃, NaH, or NaHMDS) yields compounds shown in Formula 12-5. Furthermore, compounds 12-3 react with W... 5 -R 3 12-4, where W 5 Boric acid or borate ester and R 3 Chan-Lam coupling of aryl or heteroaryl groups under standard Chan-Lam conditions (e.g., in the presence of a copper catalyst such as Cu(OAc)2 and a base such as pyridine) yields 12-5.

[0510] Option 12

[0511]

[0512] A series of bicyclic intermediates of formulas 13-4 and 13-7 can be prepared according to the method described in Scheme 13. Tert-butyl (5-amino-1,3,4-thiadiazol-2-yl)carbamate 13-1 undergoes a cyclization reaction with α-bromoketone 13-2 or α-bromoaldehyde 13-5 derivatives in the presence of a base, such as K₂CO₃ or NaOH, to respectively obtain protected bicyclic intermediates 13-3 or 13-6. Removal of the Boc protecting group under acidic conditions, such as TFA or HCl, yields the bicyclic intermediates of formulas 13-4 and 13-7.

[0513] Option 13

[0514]

[0515] A series of bicyclic intermediates of formula 14-4 can be prepared according to the method described in scheme 14. The protected 5-amino-1,3,4-thiadiazole derivative 14-1 is halogenated in the presence of a halogenating agent such as NIS or NBS and a free radical initiator such as AIBN or BPO to give the iodinated or brominated derivative 14-2 (wherein W... 7(Br or I) reacts with ammonium formate under acidic conditions, such as HCl, to convert it into bicyclic intermediate 14-3. Bicyclic intermediate 14-3 is then deprotected under acidic conditions, such as TFA or HCl, to yield the product shown in Formula 14-4.

[0516] Option 14

[0517]

[0518] A series of bicyclic intermediates of formula 15-4 can be prepared according to the method described in scheme 15. 2,5-Dibromothiazo[5,4-d]thiazole 15-1 and W 2 -R 3 15-2, where W 2 Boric acid or boronic esters can be Suzuki coupled under standard Suzuki coupling conditions (e.g., in the presence of a palladium catalyst, such as Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, and a base, such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3) to give compound 15-3. Compound 15-3 can be catalytically aminated with LiHMDS under standard Buchwald coupling conditions (e.g., in the presence of a palladium catalyst and a ligand, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3, or XantPhos Pd G3) to give the compound shown in formula 15-4.

[0519] Option 15

[0520]

[0521] A series of bicyclic intermediates of Formula 16-4 can be prepared according to the method described in Scheme 16. The amino-pyrazole derivative 16-1 is reacted with ethoxycarbonyl isothiocyanate to give thiourea derivative 16-2. Thiourea derivative 16-2 is brominated with Br2 or NBS to give bromo-pyrazole derivative 16-3. Bromo-pyrazole derivative 16-3 is reacted under alkaline conditions, such as NaOMe, t-BuOK, or NaOH, to give the bicyclic intermediate of Formula 16-4.

[0522] Option 16

[0523]

[0524] A series of bicyclic intermediates of Formula 17-3 can be prepared according to the method described in Scheme 17. The 2-aminothiazole derivative 17-1 is reacted with ethoxycarbonyl isothiocyanate to give thiourea derivative 17-2. The thiourea derivative 17-2 is then cyclized with NH₂OH under alkaline conditions, such as TEA or DABCO, to give the bicyclic intermediate of Formula 17-3.

[0525] Option 17

[0526]

[0527] A series of bicyclic intermediates of formula 18-4 can be prepared according to the method described in scheme 18. Thiazole-4(5H)-one derivative 18-2 can be prepared via R... 3 -CN 18-1 is reacted with mercaptoacetic acid to prepare 18-2, using HOAc as a solvent. The thiazol-4(5H)-one derivative 18-2 is brominated with NBS or Br2 to give the 5-bromothiazol-4(5H)-one derivative 18-3. The 5-bromothiazol-4(5H)-one derivative 18-3 is reacted with thiourea under acidic conditions, such as HOAc or H2SO4, to give the bicyclic intermediate shown in Formula 18-4.

[0528] Option 18

[0529] Example

[0530] Example 1: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-methoxythiazo[5,4-b]pyridin-2-yl)-6-methylnicotinamide

[0531]

[0532] Method A:

[0533] To a mixture of 5-methoxythiazo[5,4-b]pyridine-2-amine (181 mg, 1 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (296 mg, 1 mmol, Int-A) in DMF (2 mL), NMI (400 mg, 5 mmol) and TCFH (336 mg, 1.2 mmol) were added. The reaction mixture was stirred overnight at 50 °C and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with ACN / water (30–55%), to give the target compound (150 mg) as a white solid. LCMS calculated value C 21 H 17 ClFN4O3S[M+H] +m / z = 459.1; Measured value: 459.1.

[0534] Method B:

[0535] To a mixture of 5-methoxythiazo[5,4-b]pyridine-2-amine (181 mg, 1 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (296 mg, 1 mmol, Int-A) in DMF (2 mL), DIEA (260 mg, 2 mmol) and HATU (456 mg, 1.2 mmol) were added. The reaction mixture was stirred overnight at 70 °C, and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with ACN / water (30–65%, containing 0.5% TFA) to give the target compound (56 mg) as a white solid. LCMS calculated value C 21 H 17 ClFN4O3S[M+H] + m / z = 459.1; Measured value: 459.1.

[0536] The compounds listed in Table 1 were prepared using Int-A (a carboxylic acid derivative) and suitable intermediates (Int-X, as a derivative) or commercial reagents (CAM, an amine derivative) as starting materials, following a method similar to that in Example 1.

[0537] Table 1. Preparation Examples (Ex)

[0538]

[0539]

[0540] Example 15: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)benzothiazol-2-yl)-6-methylnicotinamide

[0541]

[0542] Step 1: 5-(2-methoxyethoxy)benzo[d]thiazol-2-amine

[0543]

[0544] A mixture of 2-aminobenzo[d]thiazolyl-5-ol (200 mg, 1.2 mmol), 1-bromo-2-methoxyethane (251 mg, 1.8 mmol), Cs₂CO₃ (1.18 g, 3.6 mmol), and 1,4-dioxane (10 mL) was stirred at 100 °C for 16 hours under vacuum and purged three times with nitrogen. The reaction mixture was diluted with 20 mL of H₂O and extracted with EA (20 mL × 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 silica gel column chromatography, eluting with PE / EA (50-100%) to give the target compound (87 mg) as a yellow solid. LCMS calculated value: C₁₀H₁₃N₂O₂S[M+H] + m / z = 225.1; Measured value: 225.1.

[0545] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)benzo[d]thiazolyl-2-yl)-6-methylnicotinamide

[0546] To a mixture of 5-(2-methoxyethoxy)benzo[d]thiazol-2-amine (45 mg, 0.2 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (60 mg, 0.2 mmol, Int-A) in DMF (1 mL), NMI (84 mmg, 1.0 mmol) and TCFH (82 mg, 0.3 mmol) were added. The reaction mixture was stirred overnight at 40 °C and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (30–50%), to give the target compound (64.5 mg) as a white solid. LCMS calculated value: C 24 H 22 ClFN3O4S[M+H] + m / z = 502.1; Measured value: 502.1.

[0547] Example 16: (3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-(2-methoxyethoxy)benzo[d]thiazolyl-2-yl)-6-methylnicotinamide

[0548]

[0549] This compound was prepared by a method similar to steps 1-2 in Example 15, except that 2-aminobenzo[d]thiazol-6-ol was used instead of 2-aminobenzo[d]thiazol-5-ol in step 1. LCMS calculated value: C 24 H 22 ClFN3O4S[M+H] +m / z = 502.1; Measured value: 502.1.

[0550] Example 17: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-ethoxybenzo[d]thiazolyl)-6-methylnicotinamide

[0551]

[0552] This compound was prepared by a method similar to steps 1-2 of Example 15, except that iodoethane was used instead of 1-bromo-2-methoxyethane in step 1. LCMS calculated value: C 23 H 20 ClFN3O3S[M+H] + m / z = 472.1; Measured value: 472.1

[0553] Example 18: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-ethoxybenzo[d]thiazolyl)-6-methylnicotinamide

[0554]

[0555] This compound was prepared by a method similar to steps 1-2 in Example 15, except that in step 1, iodoethane and 2-aminobenzo[d]thiazol-4-ol were used instead of 1-bromo-2-methoxyethane and 2-aminobenzothiazol-5-ol. LCMS calculated value C 23 H 20 ClFN3O3S[M+H] + m / z = 472.1; Measured value: 472.1.

[0556] Example 19: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(7-(2-methoxyethoxy)benzo[d]thiazolyl)-6-methylnicotinamide

[0557]

[0558] Step 1: (7-bromobenzo[d]thiazolyl)tert-butyl carbamate

[0559]

[0560] To a mixture of 7-bromobenzo[d]thiazol-2-amine (0.9 g, 4.0 mmol), DMAP (122 mg, 1.0 mmol), and TEA (410 mg, 4.0 mmol) in THF (10 mL), Boc₂O (1.31 g, 6.0 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (20–30%), to give the target compound (1.0 g) as a pale yellow solid. LCMS calculated value C 12 H 14 BrN2O2S[M+H] + m / z = 329.0; Measured value: 329.1

[0561] Step 2: (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzo[d]thiazolyl)tert-butyl carbamate

[0562]

[0563] A mixture of (7-bromobenzo[d]thiazolyl)carbamate tert-butyl ester (1.0 g, 3 mmol), bis(1,1-diphenyl-2,2-dimethoxy)borane (1.27 g, 5 mmol), KOAc (1.0 g, 10 mmol), and Pd(dppf)Cl2 (220 mg, 0.3 mmol) and 1,4-dioxane (20 mL) was prepared under vacuum and purged three times with nitrogen. The reaction mixture was stirred overnight at 100 °C. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL), filtered through a short silica gel column, and concentrated under reduced pressure to give the target compound (1.0 g) as a brown oil. LCMS calculation of C 18 H 26 BN₂O₄S[M+H] + m / z = 377.2; measured value: 377.1.

[0564] Step 3: tert-butyl 7-hydroxybenzo[d]thiazolyl-2-yl)carbamate

[0565]

[0566] Hydrogen peroxide (1.0 mL, 33%) was added to a mixture of (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)benzo[d]thiazolyl)carbamate tert-butyl ester (1.0 g, 2.67 mmol), NaOH (0.42 g, 10.6 mmol), THF (40 mL), and water (10 mL) in an ice-water bath. The reaction mixture was stirred at 0 °C for 4 hours, then concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (20-30%), to give the target compound (0.34 g) as a yellow oil. LCMS calculated value C 12 H 15 N₂O₃S[M+H] + m / z = 267.1; Measured value: 267.1.

[0567] Step 5: 2-Aminobenzo[d]thiazolyl-7-ol

[0568]

[0569] A solution of 0.34 g of tert-butyl (7-hydroxybenzo[d]thiazo-2-yl)carbamate in DCM (1 mL) was mixed with HCl solution (1 mL, 4.0 M, 1,4-dioxane solution) and stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to give the target compound (0.2 g) as a yellow solid. LCMS calculated value: C7H7N2OS[M+H] + m / z = 167.0; Measured value: 167.0.

[0570] Step 6: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(7-(2-methoxyethoxy)benzo[d]thiazolyl)-6-methylnicotinamide

[0571] This compound was prepared using a method similar to steps 1-2 of Example 15, except that in step 1, 2-aminobenzo[d]thiazol-7-ol was used instead of 2-aminobenzo[d]thiazol-5-ol. LCMS calculated value: C 24 H 22 ClFN3O4S[M+H] + m / z = 502.1; Measured value: 502.1.

[0572] Example 20: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(7-ethoxybenzo[d]thiazolyl)-6-methylnicotinamide

[0573]

[0574] This compound was prepared in a manner similar to steps 1-2 of Example 15, except that in step 1, 2-aminobenzo[d]thiazol-7-ol (Step 5 of Example 19) and iodoethane were used instead of 2-aminobenzo[d]thiazol-5-ol and 1-bromo-2-methoxyethane. LCMS calculated value C 23 H 20 ClFN3O3S[M+H] + m / z = 472.1; Measured value: 472.1.

[0575] Example 21: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-(2-hydroxyethoxy)benzo[d]thiazolyl-2-yl)-6-methylnicotinamide

[0576]

[0577] Step 1: 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]thiazol-2-amine

[0578]

[0579] To a DMF (30 mL) solution of 2-aminobenzo[d]thiazolyl-6-ol (2.0 g, 12 mmol), Cs₂CO₃ (11.8 g, 36.1 mmol) and tert-butyl(2-iodoethoxy)dimethylsilane (3.44 g, 12 mmol) were added. The reaction mixture was stirred at 60 °C for 5 hours. The reaction mixture was diluted with water (50 mL). The precipitate was collected by filtration to give the target compound (2.5 g) as a white solid. LCMS calculated C 15 H 25 N₂O₂SSi[M+H] + m / z = 325.1; Measured value: 325.1.

[0580] Step 2: N-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]thiazolyl-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0581]

[0582] To a mixture of 6-(2-((tert-butyldimethylsiloxy)oxy)ethoxy)benzo[d]thiazol-2-amine (66 mg, 0.2 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (60 mg, 0.2 mmol, Int-A) DMF (1 mL), NMI (84 mg, 0.3 mmol) and TCFH (82 mg, 1 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (40-50%), to give the target compound (40 mg) as a white solid. LCMS calculated value C 29 H 34 ClFN3O4SSi[M+H] + m / z = 602.2; Measured value: 602.2.

[0583] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-(2-hydroxyethoxy)benzo[d]thiazolyl-2-yl)-6-methylnicotinamide

[0584] To a solution of N-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzo[d]thiazo-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (40 mg, 0.67 mmol) in THF (2 mL), TBAF solution (1.3 mL, 1.0 M THF) was added. The reaction mixture was stirred at rt for 2 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc / PE (80-90%), to give the target compound (19 mg) as a white solid. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 12.8 (s, 1H), 8.88 (s, 1H), 7.66 (d, J = 9.0Hz, 1H), 7.63–7.55 (m, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.06 (d, J = 9.0Hz, 1H), 6.93 (d, J = 9.0Hz, 1H), 4.89 (t, J = 6.0Hz, 1H), 4.03 (t, J = 5.4Hz, 2H), 3.74 (q, J = 5.4Hz, 2H), 3.57 (s, 3H), 2.59 (s, 3H). LCMS calculated C 23 H 20 ClFN3O4S[M+H] + m / z = 488.1; measured value: 488.0.

[0585] Example 22: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-((R)-2-hydroxypropoxy)benzo[d]thiazolyl)-6-methylnicotinamide

[0586]

[0587] Step 1: (R)-1-((2-aminobenzo[d]thiazolyl)oxy)prop-2-ol

[0588]

[0589] To a solution of 2-aminobenzo[d]thiazolyl-6-ol (330 mg, 2.0 mmol) in MeCN (4 mL) and water (0.5 mL), K₂CO₃ (560 mg, 4.0 mmol) and (R)-2-methoxyethylene oxide (580 mg, 10 mmol) were added. The reaction mixture was stirred at 85 °C for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (15-25%), to give the target compound (160 mg) as a white solid. LCMS calculated value C 10 H 13 N₂O₂S[M+H] + m / z = 225.1; measured value: 225.0.

[0590] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-((R)-2-hydroxypropoxy)benzo[d]thiazolyl)-6-methylnicotinamide

[0591] To a mixture of (R)-1-((2-aminobenzo[d]thiazolyl)oxy)prop-2-ol (45 mg, 0.2 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (60 mg, 0.2 mmol, Int-A) in DMF (1 mL), NMI (84 mg, 0.3 mmol) and TCFH (82 mg, 1 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (45–55%), to give the target compound (6.8 mg) as a white solid. LCMS calculated C 24 H 22 ClFN3O4S[M+H] + m / z = 502.1; Measured value: 502.1.

[0592] Example 23: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-((S)-2-hydroxypropoxy)benzo[d]thiazolyl)-6-methylnicotinamide

[0593]

[0594] This compound was prepared using a method similar to steps 1-2 of Example 22, except that in step 1, (S)-2-methoxyethylene oxide was used instead of (R)-2-methoxyethylene oxide. LCMS calculated value: C 24 H 22 ClFN3O4S[M+H] + m / z = 502.1; Measured value: 502.1.

[0595] Example 24: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)thiazo[4,5-b]pyridin-2-yl)-6-methylnicotinamide

[0596]

[0597] Step 1: N-((6-chloro-3-iodopyridin-2-yl)aminothioformyl)benzamide

[0598]

[0599] Benzoyl isothiocyanate (0.95 g, 5.85 mmol) was added to a solution of 6-chloro-3-iodopyridin-2-amine (1 g, 3.9 mmol) in acetone (15 mL) at rt. The reaction mixture was stirred at 70 °C for 16 h. The mixture was then quenched with water and extracted with ethyl acetate (60 mL). The organic phase was washed with water and saturated brine. The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product (1.0 g) as a yellow solid. LCMS calculated value C 13 H 10 ClN3OS[M+H] + m / z = 417.8; measured value: 417.9.

[0600] Step 2: N-(5-chlorothiazo[4,5-b]pyridin-2-yl)benzamide

[0601]

[0602] To a solution of N-((6-chloro-3-iodopyridin-2-yl)aminothiocarbamoyl)benzamide (1.0 g, 2.4 mmol) and L-proline (60 mg, 0.48 mmol) in 1,4-dioxane (10 mL), CuI (90 mg, 0.4 mmol) and K₂CO₃ (0.5 g, 3.6 mmol) were added. The reaction mixture was stirred overnight at 80 °C. The reaction mixture was quenched with an aqueous solution of ammonium chloride (10 mL). The precipitate was collected by filtration to give the target compound (560 mg) as a brown solid. LCMS calculated C 13 H9ClN3OS[M+H] + m / z = 290.0; measured value: 290.1.

[0603] Step 3: N-(5-(2-methoxyethoxy)thiazo[4,5-b]pyridin-2-yl)benzamide

[0604]

[0605] To a solution of N-(5-chlorothiazo[4,5-b]pyridin-2-yl)benzamide (290 mg, 1.0 mmol) in 2-methoxyethanol (4 mL) in an ice-water bath, NaH (160 mg, 4 mmol, 60% mineral oil dispersion) was added. The reaction mixture was stirred overnight at 70 °C, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (40 mL) and washed with water. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (40-60%), to give the target compound (50 mg) as a yellow solid. LCMS calculated value C 16 H 16 N3O3S[M+H] + m / z = 330.1; Measured value: 330.1.

[0606] Step 4: 5-(2-methoxyethoxy)thiazo[4,5-b]pyridine-2-amine

[0607]

[0608] A 70% aqueous solution (0.5 mL, 70%) of N-(5-(2-methoxyethoxy)thiazo[4,5-b]pyridin-2-yl)benzamide (50 mg, 0.15 mmol) in H₂SO₄ was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water (10 mL), the pH was adjusted to approximately 12 with solid NaOH, and then concentrated under reduced pressure. The residue was purified by chromatography on a C18 column, eluting with acetonitrile / water (40-60%), to give the target compound (15 mg) as a yellow solid. LCMS calculated value C9H12 N3O2S[M+H] + m / z = 226.1; Measured value: 226.1.

[0609] Step 5: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)thiazo[4,5-b]pyridin-2-yl)-6-methylnicotinamide

[0610] To a mixture of 5-(2-methoxyethoxy)thiazo[4,5-b]pyridine-2-amine (15 mg, 0.067 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (30 mg, 0.1 mmol, Int-A) in DMF (1 mL), NMI (32 mg, 0.4 mmol) and TCFH (42 mg, 0.15 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (30-45% containing 0.5% trifluoroacetic acid) to give the target compound (8.6 mg) as a white solid. LCMS calculated value C 23 H 21 ClFN4O4S[M+H] + m / z = 503.1; Measured value: 503.1.

[0611] Example 25: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)thiazo[5,4-b]pyridin-2-yl)-6-methylnicotinamide

[0612]

[0613] Step 1: 5-Bromo-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-b]pyridine

[0614]

[0615] This compound was prepared using a method similar to step 1 of Int-1, except that 6-bromothiazo[5,4-b]pyridin-2-amine was substituted for 5-bromothiazo[4,5-b]pyrazin-2-amine. LCMS calculated C2 12 H 11 BrN3S[M+H] + m / z = 308.0; Measured value: 307.9. Step 2: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-5-(2-methoxyethoxy)thiazo[5,4-b]pyridine

[0616]

[0617] To a solution of 5-bromo-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-b]pyridine (154 mg, 0.5 mmol) in 2-methoxyethanol (4 mL), NaH (80 mg, 2 mmol, 60% mineral oil dispersion) was added. The reaction mixture was stirred overnight at 70 °C, and then concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (50 mL) and washed with water and saturated brine. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (30-60%), to give the target compound (60 mg) as a yellow solid. LCMS calculated value C 15 H 18 N3O2S[M+H] + m / z = 304.1; Measured value: 304.1.

[0618] Step 3: 5-(2-methoxyethoxy)thiazo[5,4-b]pyridine-2-amine

[0619]

[0620] A solution of 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-5-(2-methoxyethoxy)thiazo[5,4-b]pyridine (60 mg, 0.2 mmol) in TFA (1 mL) and water (1 mL) was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (25-40%), to give the target compound (23 mg) as a yellow oil. LCMS calculated C9H 12 N3O2S[M+H] + m / z = 226.1; Measured value: 226.1. Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)thiazo[5,4-b]pyridin-2-yl)-6-methylnicotinamide

[0621] To a mixture of 5-(2-methoxyethoxy)thiazo[5,4-b]pyridine-2-amine (23 mg, 0.1 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (30 mg, 0.1 mmol, Int-A) in DMF (1 mL), NMI (32 mg, 0.4 mmol) and TCFH (42 mg, 0.15 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (30-45% containing 0.5% trifluoroacetic acid) to give the target compound (10 mg) as a white solid. LCMS calculated value C23 H 21 ClFN4O4S[M+H] + m / z = 503.1; Measured value: 503.1.

[0622] Example 26: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-(2-methoxyethoxy)thiazo[4,5-c]pyridin-2-yl)-6-methylnicotinamide

[0623]

[0624] Step 1: 6-Chlorothiazolo[4,5-c]pyridine-2-amine

[0625]

[0626] This compound was prepared using a method similar to step 1 of Int-3, with 4,6-dichloropyridin-3-amine used instead of 2,4-dichloropyrimidin-5-amine. LCMS calculated value: C6H5ClFN3S[M+H] + m / z = 186.0; measured value: 186.1.

[0627] Step 2: 6-Chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-c]pyridine

[0628]

[0629] This compound was prepared using a method similar to step 1 of Int-1, except that 6-bromothiazo[4,5-b]pyrazin-2-amine was used instead of 6-chlorothiazo[4,5-b]pyrazin-2-amine in step 1. LCMS calculated value: [M+H] + m / z = 264.0; Measured value: 264.0.

[0630] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-(2-methoxyethoxy)thiazo[4,5-c]pyridin-2-yl)-6-methylnicotinamide

[0631] This compound was prepared in a manner similar to steps 2-4 of Example 25, except that in step 2, 5-bromo-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-c]pyridine was used instead of 6-chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-b]pyridine (Step 1 of Example 25). LCMS calculated value: C 23 H 21 ClFN4O4S[M+H] + m / z = 503.1; Measured value: 503.1.

[0632] Example 27: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-((2-methoxyethyl)thio)thiazo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide

[0633]

[0634] Step 1: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-b]pyrazine-6-thiol

[0635]

[0636] To a DMF (3 mL) solution of 6-bromo-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-b]pyrazine (310 mg, 1.0 mmol, Int-1 step 1), NaSH (230 mg, 4.0 mmol) was added. The reaction mixture was stirred overnight at 70 °C. The resulting mixture was diluted with ethyl acetate (40 mL) and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound (260 mg) as a brown oil. LCMS calculated value C 11 H 11 N4S2[M+H] + m / z = 263.0; Measured value: 263.0.

[0637] Step 2: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6-((2-methoxyethyl)thio)thiazo[4,5-b]pyrazine

[0638]

[0639] To a mixture of 2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-b]pyrazin-6-thiol (260 mg, 1.0 mmol) and Cs₂CO₃ (0.65 g, 2 mmol) in DMF (5 mL), 1-bromo-2-methoxyethane (280 mg, 2 mmol) was added. The reaction mixture was stirred at 50 °C for 2 hours. The resulting mixture was diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (30-60%), to give the target compound (170 mg) as a yellow oil. LCMS calculated value: C 14 H 17 N4OS2[M+H] + m / z = 321.1; Measured value: 321.1.

[0640] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-((2-methoxyethyl)thio)thiazo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide

[0641] This compound was prepared in a manner similar to steps 3-4 of Example 25, in which step 3 was replaced by 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6-((2-methoxyethyl)thio)thiazo[4,5-b]pyrazine (Step 2 of Example 25). LCMS calculated value: C 22 H 20 ClFN5O3S2[M+H] + m / z = 520.1; Measured value: 520.1.

[0642] Example 28: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-ethoxythiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0643]

[0644] Step 1: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0645]

[0646] To a mixture of 5-chlorothiazo[5,4-d]pyrimidin-2-amine (2.05 g, 11 mmol, Int-3, step 1) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (2.97 g, 10 mmol, Int-A) in MeCN (40 mL), NMI (3.2 g, 40 mmol) and TCFH (4.2 mg, 15 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (70–100%), to give the target compound (3.0 g) as a white solid. LCMS calculated value C 19 H 13 Cl2FN5O2S[M+H] + m / z = 464.0; measured value: 464.1.

[0647] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-ethoxythiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0648] Cesium carbonate (1.6 g, 5 mmol) was added to a 20 mL ethanol solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (230 mg, 0.5 mmol). The reaction mixture was stirred at 80 °C for 48 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a C18 column, eluting with acetonitrile / water (35-55%), to give the target compound (37.4 mg) as a white solid. LCMS calculated value: C 21 H 18 ClFN5O3S[M+H] + m / z = 474.1; Measured value: 474.1.

[0649] Example 29: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)thiazo[5,4-d]pyrimidin-2-yl)nicotinamide

[0650]

[0651] This compound was prepared using a method similar to step 2 of Example 28, with 2,2,2-trifluoroethanol used instead of ethanol as the solvent. LCMS calculated value: C 21 H 15 ClF4N5O3S[M+H] + m / z = 528.0; measured value: 528.1.

[0652] Example 30: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-hydroxyethoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0653]

[0654] This compound was prepared using a method similar to step 2 of Example 28, with ethylene glycol used instead of ethanol as the solvent. LCMS calculated value: C 21 H 18 ClFN5O4S[M+H] + m / z = 490.1; Measured value: 490.1.

[0655] Example 31: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-ethoxyethoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0656]

[0657] This compound was prepared using a method similar to step 2 of Example 28, but with 2-ethoxyethanol used instead of ethanol as the solvent. LCMS calculated value: C 23 H 22 ClFN5O4S[M+H] + m / z = 518.1; Measured value: 518.1.

[0658] Example 32: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-hydroxy-2-methylpropoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0659]

[0660] This compound was prepared using a method similar to step 2 of Example 28, with 2-methylpropane-1,2-diol used instead of ethanol as the solvent. LCMS calculated value: C 23 H 22 ClFN5O4S[M+H] + m / z = 518.1; Measured value: 518.1.

[0661] Example 33: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((S)-1-hydroxypropyl-2-yl)oxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide and

[0662] Example 34: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((S)-2-hydroxypropoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0663]

[0664] Cesium carbonate (0.65 g, 2 mmol) was added to a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (230 mg, 0.5 mmol, Example 28, Step 1) in (S)-1,2-propanediol (10 mL). The reaction mixture was stirred at 80 °C for 48 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (prep-HPLC) and eluted with acetonitrile / water to give peak 1 (earlier eluted fraction, Rt = 19.3 min, 15.9 mg) as a white solid, which was named 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((S)-1-hydroxypropoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (Example 33); peak 2 (later eluted fraction, Rt = 20.0 min, 6.0 mg) as a white solid, which was named 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((S)-2-hydroxypropoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (Example 34). Preparative high-performance liquid chromatography (HPLC) conditions: Column: Ultimate XB-C18 column, 30 x 150 mm, 5 μm; Mobile phase: acetonitrile / water (containing 0.5% ammonium bicarbonate) (35%); Flow rate: 50 mL / min; Flow time: 25 min. Calculated LCMS value C 22 H 20 ClFN5O4S[M+H] + m / z = 504.1; Measured value: 504.1.

[0665] Example 35: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((R)-1-hydroxypropyl-2-yl)oxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide and

[0666] Example 36: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((R)-2-hydroxypropoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0667]

[0668] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (230 mg, 0.5 mmol, Example 28, step 1) in (R)-1,2-propanediol (10 mL), Cs₂CO₃ (0.65 g, 2 mmol) was added. The reaction mixture was stirred at 80 °C for 48 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (prep-HPLC) and eluted with acetonitrile / water to give peak 1 (the earlier eluted fraction, Rt = 19.3 min, 16.7 mg), a white solid, which was named 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((((R)-1-hydroxypropoxy-2-yl)oxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (Example 33); peak 2 (the later eluted fraction, Rt = 20.0 min, 8.6 mg), a white solid, which was named 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((R)-2-hydroxypropoxy)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (Example 34). Preparative high-performance liquid chromatography (HPLC) conditions: Column: Ultimate XB-C18 column, 30 x 150 mm, 5 μm; Mobile phase: acetonitrile / water (containing 0.5% ammonium bicarbonate) (35%); Flow rate: 50 mL / min; Flow time: 25 min. Calculated LCMS value C 22 H 20 ClFN5O4S[M+H] + m / z = 504.1; Measured value: 504.1.

[0669] Example 37: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-hydroxyethyl)-4-oxo-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-6-methylnicotinamide

[0670]

[0671] Step 1: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6,7-dihydrothiazo[5,4-c]pyridin-4(5H)-one

[0672]

[0673] This compound was prepared using a method similar to step 1 of Int-1, with 6-bromothiazo[4,5-b]pyrazin-2-amine replaced by 2-amino-6,7-dihydrothiazo[5,4-c]pyridin-4(5H)-one. C0 was calculated by liquid chromatography-mass spectrometry. 12 H 14N3OS[M+H] + m / z = 248.1; Measured value: 248.1.

[0674] Step 2: 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6,7-dihydrothiazo[5,4-c]pyridin-4(5H)-one

[0675]

[0676] To a DMF (4 mL) solution of 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6,7-dihydrothiazo[5,4-c]pyridin-4(5H)-one (250 mg, 1.0 mmol) cooled in an ice-water bath, NaH (80 mg, 2 mmol, 60% mineral oil dispersion) and tert-butyl(2-iodoethoxy)dimethylsilane (290 mg, 1 mmol) were added. The reaction mixture was stirred overnight at room temperature, then quenched with ice water at 0 °C, and extracted with ethyl acetate (50 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether 15-30%, to give the target compound (270 mg) as a yellow oil. LCMS calculated C 20 H 32 N3O2SSi[M+H] + m / z = 406.2; Measured value: 406.2.

[0677] Step 3: 2-Amino-5-(2-hydroxyethyl)-6,7-dihydrothiazo[5,4-c]pyridine-4(5H)-one

[0678]

[0679] 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6,7-dihydrothiazo[5,4-c]pyridin-4(5H)-one (270 mg, 0.67 mmol) was stirred overnight at 60 °C in TFA (1 mL) and aqueous solution (0.5 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (10-30%), to give the target compound (110 mg) as a yellow oil. LCMS calculated C8H 12 N3O2S[M+H] + m / z = 214.1; Measured value: 214.1.

[0680] Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-hydroxyethyl)-4-oxo-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-6-methylnicotinamide

[0681] To a mixture of 2-amino-5-(2-hydroxyethyl)-6,7-dihydrothiazo[5,4-c]pyridin-4(5H)-one (110 mg, 0.5 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (150 mg, 0.5 mmol, Int-A) in MeCN (5 mL), NMI (165 mg, 2 mmol) and TCFH (220 mg, 0.8 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (10–30%), to give the target compound (200 mg) as a white solid. LCMS calculated value C 22 H 21 ClFN4O4S[M+H] + m / z = 491.1; Measured value: 491.1.

[0682] Example 38: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(4-hydroxypiperidin-1-yl)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0683]

[0684] To a mixture of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide (100 mg, 0.22 mmol, Example 28, step 1) and piperidine-4-ol (100 mg, 1 mmol) in DMF (2 mL), DIEA (260 mg, 2 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours, and then concentrated under reduced pressure. The residue was purified by chromatography on a C18 column, eluting with acetonitrile / water (containing 0.5% trifluoroacetic acid, 20-35%), to give the target compound (37.4 mg) as a white solid. LCMS calculated value C 24 H 23 ClFN6O3S[M+H] + m / z = 529.1; Measured value: 529.1.

[0685] Example 39: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(4-methylpiperazin-1-yl)thiazo[5,4-d]pyrimidin-2-yl)nicotinamide

[0686]

[0687] This compound was prepared using a method similar to that in Example 38, with 1-methylpiperazine used instead of piperidine-4-ol. LCMS calculated value: C 24 H 24 ClFN7O2S[M+H] + m / z = 528.1; Measured value: 528.1.

[0688] Example 40: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-morpholinylthiazo[5,4-d]pyrimidin-2-yl)nicotinamide

[0689]

[0690] This compound was prepared using a method similar to that in Example 38, with morpholine used instead of piperidine-4-ol. LCMS calculated value: C 23 H 21 ClFN6O3S[M+H] + m / z = 515.1; Measured value: 515.1.

[0691] Example 41: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-hydroxyethyl)thio)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0692]

[0693] Step 1: 5-Chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-d]pyrimidine

[0694]

[0695] This compound was prepared by a method similar to step 1 of Int-1, except that 6-bromothiazo[4,5-b]pyrazin-2-amine was replaced with 5-chlorothiazo[5,4-d]pyrimidin-2-amine (step 1 of Int-3). LCMS calculated value C 11 H 10 ClN4S[M+H] + m / z = 265.0; Measured value: 265.0.

[0696] Step 2: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-d]pyrimidine-5-thiol

[0697]

[0698] To a DMF (10 mL) solution of 5-chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-d]pyrimidine (530 mg, 2.0 mmol), NaSH (460 mg, 8.0 mmol) was added. The reaction mixture was stirred overnight at 70 °C. The resulting mixture was diluted with ethyl acetate (60 mL) and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (10-40%), to give the target compound (400 mg) as a brown oil. LCMS calculated value C 11 H 11 N4S2[M+H] + m / z = 263.0; Measured value: 263.0.

[0699] Step 3: 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-d]pyrimidine

[0700]

[0701] To a mixture of 2 mL of DMF containing 2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[5,4-d]pyrimidine-5-thiol (104 mg, 0.25 mmol) and Cs₂CO₃ (325 mg, 1 mmol), tert-butyl(2-iodoethoxy)dimethylsilane (145 mg, 0.5 mmol) was added. The reaction mixture was stirred at 50 °C for 2 hours. The resulting mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with ethyl acetate / petroleum ether (5-25%), to give the target compound (120 mg) as a yellow oil. LCMS calculated value C 19 H 29 N4OS2Si[M+H] + m / z = 421.2; measured value: 421.1.

[0702] Step 4: 2-((2-aminothiazo[5,4-d]pyrimidin-5-yl)thio)ethanol-1-ol

[0703]

[0704] A solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(6-(((2-methoxyethyl)thio)thiazo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (120 mg, 0.29 mmol) in TFA (1 mL) and H₂O (0.5 mL) was stirred overnight at 60 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (10-30%), to give the target compound (60 mg) as a yellow oil. LCMS calculated value: C₇H₉N₄OS₂[M+H] + m / z = 229.0; Measured value: 229.0.

[0705] Step 5: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-hydroxyethyl)thio)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0706] To a mixture of 2-((2-aminothiazo[5,4-d]pyrimidin-5-yl)thio)ethyl-1-ol (60 mg, 0.26 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (77 mg, 0.26 mmol, Int-A) in MeCN (5 mL), NMI (82 mg, 1 mmol) and TCFH (112 mg, 0.4 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (20–50%), to give the target compound (32 mg) as a white solid. LCMS calculated value: C 21 H 18 ClFN5O3S2[M+H] + m / z = 506.0; measured value: 506.1.

[0707] Example 42: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-hydroxypropyl)thio)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0708]

[0709] This compound was prepared according to steps 3 and 5 of Example 41, except that in step 3, 1-bromoprop-2-ol was used instead of tert-butyl(2-iodoethoxy)dimethylsilane. LCMS calculated value: C 22 H 20 ClFN5O3S2[M+H] + m / z = 520.1; Measured value: 520.1.

[0710] Example 43: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((3-cyanopropyl)thio)thiazo[5,4-d]pyrimidin-2-yl)-6-methylnicotinamide

[0711]

[0712] This compound was prepared according to a method similar to steps 3 and 5 of Example 41, except that in step 3, 4-bromobutyronitrile was used instead of tert-butyl(2-iodoethoxy)dimethylsilane. LCMS calculated value C 23 H 19 ClFN6O2S2[M+H] + m / z = 529.1; Measured value: 529.1.

[0713] Int-A: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0714]

[0715] Step 1: (3-Chloro-2-fluoro-6-methoxyphenyl)boronic acid

[0716]

[0717] Under a nitrogen atmosphere at -70°C, LDA (2.0 M THF solution, 12.5 mL) was added to a dry tetrahydrofuran (20 mL) solution of 1-chloro-2-fluoro-4-methoxybenzene (2.0 g, 12.5 mmol). After stirring the mixture at -70°C for 1 hour, triisopropylboronic acid ester (4.7 g, 25.0 mmol) was added at -70°C. The resulting mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched at 0°C with a saturated aqueous NH4Cl solution (50 mL). The aqueous layer was adjusted to pH approximately 2-3 with hydrochloric acid (1.0 M) and extracted with ethyl acetate (40 mL × 5). The combined organic layers were washed with saturated brine (40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (0-10%) to give (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (1.6 g) as a grayish-white solid.

[0718] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid methyl ester

[0719]

[0720] A mixture of 4-chloro-6-methylnicotinic acid (3.0 g, 16 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (3.2 g, 16 mmol), K₂CO₃ (4.4 g, 32 mmol), and Pd(dppf)Cl₂ (1.1 g, 1.6 mmol) in 1,4-dioxane (24 mL) and water (3 mL) was evacuated and purged with nitrogen three times. The mixture was stirred at 80 °C for 16 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (0-20%), to give the target compound (2.8 g) as a yellow solid. LCMS calculated value: C 15 H 14 FClNO3[M+H] + m / z = 310.1; Measured value: 310.0. Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0721]

[0722] LiOH was added to a solution of methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate (70 mg, 0.23 mmol) in MeOH (2 mL) and H₂O (2 mL). . H₂O (28 mg, 1.0 mmol). After stirring the mixture overnight at room temperature, the reaction mixture was diluted with water and adjusted to pH 3-4 with 2 M hydrochloric acid solution, followed by extraction with DCM (20 mL × 5). The combined organic layers were washed with saturated brine (15 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product (50 mg), which was a yellow oil and could be used directly in the next reaction without further purification. LCMS calculated value C 14 H 12 FClNO3[M+H] + m / z = 296.0; Measured value: 296.0.

[0723] Int-1: 6-Methoxythiazo[4,5-b]pyrazin-2-amine

[0724]

[0725] Step 1: 6-Bromo-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-b]pyrazine

[0726]

[0727] To a mixture of 6-bromothiazo[4,5-b]pyrazin-2-amine (230 mg, 1.0 mmol) and 2,5-hexanedione (228 mg, 2.0 mmol) in toluene (10 mL), p-toluenesulfonic acid (1 mg) and 4A molecular sieve (200 mg) were added. The reaction mixture was stirred overnight at 100 °C. The mixture was concentrated under reduced pressure, diluted with H₂O, and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the target compound (300 mg) as a yellow oil. LCMS calculated value C 11 H 10 BrN4S[M+H] + m / z = 309.0; measured value: 309.1.

[0728] Step 2: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6-methoxythiazo[4,5-b]pyrazine

[0729]

[0730] To a MeOH solution of 150 mg (0.49 mmol) of 6-bromo-2-(2,5-dimethyl-1H-pyrrolo-1-yl)thiazo[4,5-b]pyrazine in 4 mL of NaH (80 mg, 2 mmol, 60% mineral oil dispersion), the reaction mixture was stirred overnight at 70 °C and then concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (30-65%), to give the target compound (120 mg) as a yellow solid. LCMS calculated value: C 12 H 12 N4OS[M+H] + m / z = 261.1; Measured value: 261.1.

[0731] Step 3: 6-Methoxythiazo[4,5-b]pyrazin-2-amine

[0732] A solution of 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-6-methoxythiazo[4,5-b]pyrazine (120 mg, 0.46 mmol) in TFA (1 mL) and H₂O (1 mL) was stirred at 60 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a C18 column, eluting with acetonitrile / water (10-40%), to give the target compound (15 mg) as a yellow solid. LCMS calculated value: C₆H₇N₄OS[M+H] + m / z = 183.0; Measured value: 183.0.

[0733] Int-2:6-(2-methoxyethoxy)thiazo[4,5-b]pyrazin-2-amine

[0734]

[0735] This compound was prepared using a method similar to steps 2-3 of Int-1, except that in step 2, 2-methoxyethanol-1-ol was used instead of methanol as the solvent. The calculated LCMS value is C8H. 11 N4O2S[M+H] + m / z = 227.0; measured value: 227.1.

[0736] Int-3: 5-(2-methoxyethoxy)thiazo[5,4-d]pyrimidin-2-amine

[0737]

[0738] Step 1: 5-Chlorothiazolo[5,4-d]pyrimidine-2-amine

[0739]

[0740] Potassium thiocyanate (5.93 g, 60 mmol) was added to a solution of 2,4-dichloropyrimidin-5-amine (1 g, 10 mmol) in AcOH (16 mL). The reaction mixture was stirred at 80 °C for 4 hours, and then the pH was adjusted to 7-8 with a saturated aqueous solution of NaHCO3. The precipitate was collected by filtration to give the product (500 mg) as a brown solid. 1 H NMR: (400MHz, DMSO-d) 6 δ 8.53 (s, 1H), 8.30 (s, 2H). LCMS calculated values: C5H4ClN4S[M+H] + m / z = 187.0; Measured value: 187.1

[0741] Step 2: 5-(2-methoxyethoxy)thiazo[5,4-d]pyrimidine-2-amine

[0742] To a solution of 2-methoxyethanol (122 mg, 1.61 mmol) in THF (5 mL), NaH (129 mg, 3.2 mmol, 60% mineral oil dispersion) was added. After stirring at 25 °C for 1 hour, 5-chlorothiazo[5,4-d]pyrimidine-2-amine (200 mg, 1.1 mmol) was added to the mixture, and the mixture was stirred overnight at 60 °C. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified preparatively by thin-layer chromatography using silica gel plates, eluting with MeOH / DCM (5%) to give the target compound (50 mg) as a yellow solid. 1 H NMR: (400MHz, DMSO-d) 6 δ 8.40(s, 1H), 7.83(s, 2H), 4.44–4.30(m, 2H), 3.70–3.58(m, 2H), 3.29(s, 3H). LCMS calculated C8H 11 N4O2S[M+H] + m / z = 227.1; Measured value: 227.1.

[0743] Int-4: 2-(2-((2-aminothiazo[4,5-b]pyrazin-6-yl)(methyl)amino)ethyl)isothiazolidin-1,1-dioxide

[0744]

[0745] Step 1: (2-((3-chloropropyl)sulfonamido)ethyl)(methyl)carbamate tert-butyl ester

[0746]

[0747] At 0 °C, 3-chloropropane-1-sulfonyl chloride (1.11 g, 6.2 mmol) was added to a mixture of (2-aminoethyl)(methyl)carbamate tert-butyl ester (1.0 g, 5.7 mmol) and DIEA (1.0 g, 7.4 mmol) in THF (60 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM (30 mL × 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (0–33%), to give the target compound (1.1 g) as a yellow solid. TLC: Rf = 0.5 (petroleum ether / ethyl acetate = 1:1). 1 H NMR: (400MHz, DMSO-d) 6δ 7.27 (s, 1H), 3.79-3.69 (m, 2H), 3.26-3.19 (m, 2H), 3.16-2.99 (m, 4H), 2.85-2.74 (m, 3H), 2.14-2.03 (m, 2H), 1.43-1.33 (m, 9H). Step 2: (2-(1,1-dioxoisothiazolin-2-yl)ethyl)(methyl)carbamate tert-butyl ester

[0748]

[0749] At 0 °C, NaH (190 mg, 4.7 mmol, 60% mineral oil dispersion) was added to a DMF (20 mL) solution of (500 mg, 1.6 mmol) of (2-((3-chloropropyl)sulfonamide)ethyl)(methyl)carbamate (tert-butyl) ester (500 mg, 1.6 mmol), and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC on a silica gel plate, eluted with petroleum ether / ethyl acetate (50%), to give the target compound (320 mg) as a yellow solid. TLC: Rf = 0.6 (PE / EA = 1:1). 1 H NMR: (400MHz, DMSO-d) 6 )δ3.33-3.28(m,2H),3.26-3.11(m,4H),3.05-2.95(m,2H),2.84-2.74(m,3H),2.20(s,2H),1.43-1.33(m,9H).

[0750] Step 3: 2-(2-(methylamino)ethyl)isothiazolidinyl 1,1-dioxide

[0751]

[0752] To a solution of tert-butyl (2-(1,1-dioxoisothiazolin-2-yl)ethyl)(methyl)carbamate (300 mg, 1.1 mmol) in DCM (2 mL), hydrochloric acid solution (2 mL, 8 mmol, 4 M, 1,4-dioxane solution) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to give the target compound (60 mg) as a yellow solid. LCMS calculated C6H 15 N₂O₂S[M+H] + m / z = 179.1; Measured value: 179.1. 1 HNMR: (400MHz, DMSO-d) 6)δ3.29-3.18(m,6H),3.12-3.03(m,2H),2.63-2.52(m,4H),2.30-2.19(m,2H).

[0753] Step 4: 2-(2-((2-aminothiazo[4,5-b]pyrazin-6-yl)(methyl)amino)ethyl)isothiazoline 1,1-dioxide

[0754] To a mixture of 6-bromothiazo[4,5-b]pyrazin-2-amine (46 mg, 0.2 mmol) and 2-(2-(methylamino)ethyl)isothiazoline 1,1-dioxide (57 mg, 0.4 mmol) in DMF (10 mL), DIEA (130 mg, 1.0 mmol) was added. The reaction mixture was stirred overnight at 90 °C. The resulting mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column (eluting with acetonitrile / water (10-45%)) to give the target compound (20 mg) as a yellow solid. LCMS calculated value C 11 H 17 N6O2S2[M+H] + m / z = 329.1; Measured value: 329.1.

[0755] Int-5: 5,7-bis(2-methoxyethoxy)thiazo[4,5-b]pyridine-2-amine

[0756]

[0757] Step 1: N-(6-chloro-4-methoxypyridin-2-yl)-1,1-diphenylformamidinium

[0758]

[0759] A mixture of 2,6-dichloro-4-methoxypyridine (10 g, 57 mmol), diphenylmethylamine (9.4 g, 51 mmol), BINAP (3.1 g, 5 mmol), Cs₂CO₃ (55 g, 168 mmol), and Pd(OAc)₂ (1.1 g, 5 mmol) in toluene (150 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was diluted with saturated NH₄Cl solution (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with PE / EA (0–10%), to give the target compound (10 g) as a yellow oil. LCMS calculated value C 19 H16 ClN2O[M+H] + m / z = 323.1; measured value: 323.0.

[0760] Step 2: 6-Chloro-4-methoxypyridine-2-amine

[0761]

[0762] A solution of N-(6-chloro-4-methoxypyridin-2-yl)-1,1-diphenylformamidin (10 g, 31 mmol) in HCl (6 M, 50 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H₂O (300 mL) and then extracted with PE (300 mL). The aqueous phase was concentrated under reduced pressure to give the target compound (4 g) as a white solid. LCMS calculated value: C₆H₈ClN₂O[M+H] + m / z = 159.0; measured value: 159.1.

[0763] Step 3: 5-Chloro-7-methoxythiazo[4,5-b]pyridine-2-amine

[0764]

[0765] d. A mixture of 6-chloro-4-methoxypyridine-2-amine (2 g, 12.5 mmol) and potassium thiocyanate (1.8 g, 18.8 mmol) in AcOH (20 mL) was stirred at 60 °C for 30 min. Br2 (12.5 mL, 1.0 M HOAc solution) was added dropwise. The reaction mixture was stirred at 60 °C for 30 min, diluted with saturated NH4Cl solution (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with PE / EA (0-10%), to give the target compound (1 g) as a white solid. 1 H NMR (400MHz, DMSO-d) 6 δ 7.04 (s, 2H), 6.08 (s, 1H), 3.89 (s, 3H). LCMS calculated values: C7H7ClN3OS[M+H] + m / z = 216.0; Measured value: 216.0.

[0766] Step 4: 5-Chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-methoxythiazo[4,5-b]pyridine

[0767]

[0768] To a mixture of 5-chloro-7-methoxythiazo[4,5-b]pyridine-2-amine (100 mg, 0.47 mmol) and 2,3-butanedione (170 mg, 2.0 mmol) in toluene (10 mL), p-toluenesulfonic acid (1 mg) and 4A molecular sieve (200 mg) were added. The reaction mixture was stirred overnight at 100 °C. The resulting mixture was concentrated under reduced pressure, diluted with H₂O, and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with PE / EA (20-40%), to give the target compound (50 mg) as a yellow oil. LCMS calculated value C 13 H 13 ClN3OS[M+H] + m / z = 294.0; measured value: 294.1.

[0769] Step 5: 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-5,7-bis(2-methoxyethoxy)thiazo[4,5-b]pyridine

[0770]

[0771] To a solution of 5-chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-methoxythiazo[4,5-b]pyridine (50 mg, 0.17 mmol) in 2-methoxyethanol (2 mL), NaH (40 mg, 1 mmol, 60% mineral oil dispersion) was added. The reaction mixture was stirred overnight at 70 °C, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (40 mL) and washed with water. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (30–65%), to give the target compound (30 mg) as a yellow solid. LCMS calculated value C 18 H 25 N3O4S[M+H] + m / z = 378.1; Measured value: 378.1.

[0772] Step 6: 5,7-bis(2-methoxyethoxy)thiazo[4,5-b]pyridine-2-amine

[0773] A solution of 2-(2,5-dimethyl-1H-pyrrolo-1-yl)-5,7-bis(2-methoxyethoxy)thiazo[4,5-b]pyridine (30 mg, 0.8 mmol) in TFA (0.5 mL) and water (0.5 mL) was stirred at 60 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with acetonitrile / water (10-40%), to give the target compound (15 mg) as a yellow solid. LCMS calculated value C 12 H 18 N3O4S[M+H] + m / z = 300.1; Measured value: 300.1. Int-6: 6-methylimidazo[2,1-b][1,3,4]thiadiazole-2-amine

[0774]

[0775] To a solution of 1,3,4-thiadiazole-2,5-diamine (300 mg, 2.6 mmol) in ethanol (6 mL), 1-chloro-2-propanone (1.43 g, 15.5 mmol) was added. The reaction mixture was stirred at 85 °C for 16 hours. The resulting mixture was diluted with H₂O (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC on a silica gel column, eluting with MeOH / DCM (7%), to give the target compound (200 mg) as a white solid. 1 H NMR: (400MHz, DMSO-d) 6 δ 7.36(s, 1H), 7.31(s, 2H), 2.14(s, 3H). LCMS calculated value: C5H7N4S[M+H] + m / z = 155.0; Measured value: 155.0.

[0776] Int 7: 6-Ethylimidazo[2,1-b][1,3,4]thiadiazole-2-amine

[0777]

[0778] This compound was prepared using a method similar to Int-6, with 1-bromo-2-butanone used instead of 1-chloro-2-propanone in step 1. LCMS calculated value: C6H9N4S[M+H] + m / z = 169.0; Measured value: 169.0.

[0779] Int-8: N 6 -(2-Methoxyethyl)-N6-methylthiazo[4,5-b]pyrazine-2,6-diamine

[0780]

[0781] This compound was prepared using a method similar to Int-4, except that in step 4, 2-methoxy-N-methylethyl-1-amine was used instead of 2-(2-(methylamino)ethyl)isothiazolidin-1,1-dioxide. The calculated LCMS value is C9H. 14 N5OS[M+H] + m / z = 240.1; Measured value: 240.1.

[0782] Int-9: 6-ethoxythiazo[4,5-b]pyrazin-2-amine

[0783]

[0784] This compound was prepared using a method similar to steps 2-3 of Int-1, with ethanol used instead of methanol as the solvent in step 2. The calculated LCMS value is C7H9N4OS[M+H]. + m / z = 196.0; Measured value: 196.1.

[0785] Int 10: 2-((2-aminothiazo[4,5-b]pyrazin-6-yl)oxy)ethanol-1-ol

[0786]

[0787] This compound was prepared using a method similar to steps 2-3 of Int-1, in which ethylene glycol was used instead of methanol as the solvent in step 2. The calculated LCMS value is C7H9N4O2S[M+H]. + m / z = 212.0; Measured value: 212.0.

[0788] Example A: Biological Test

[0789] The ability of the disclosed compounds to inhibit PolQ(1-899) ATPase activity was determined using the following test method.

[0790] PolQ ATPase activity was determined using the ADP-Glo ​​assay. A 10-spot dilution of the compound was added to a 384-well plate for the inhibition assay. PolQ (1-899) (1 nM) test buffer (20 mM Tris HCl (pH 8.0), 80 mM KCl, 10 mM MgCl2, 1 mM DTT, 0.01% BSA, 0.01% Tween, 5% glycerol) was transferred to the test wells (20 μL), except for the low control wells (20 μL of test buffer was added to the low control wells). The plate was then incubated at room temperature for 30 minutes. An equal volume (20 μL) of 100 μM ATP and 150 nM ssDNA containing 50 thymine bases was added to all test wells. The plate was incubated at room temperature for 60 minutes before adding the ADP-Glo ​​assay reagent. After incubation for 60 minutes, transfer 5 μL of the reaction mixture to another 384-well plate, add 5 μL of ADP Glo, and incubate for another 60 minutes. Then add 10 μL of enzyme detection reagent and incubate for another 60 minutes. Read the luminescence value using Envision. The percentage of inhibition is calculated using the following formula:

[0791] %Inhibition=(Signal Max -Signal Compound ) / (Signal Max -Signal Min )*100%

[0792] Among them, "Max" is the high control (DMSO) and "Min" is the enzyme-free control.

[0793] IC 50 The value is calculated using a four-parameter logistic curve fitting, using the following formula:

[0794] Y=LowerBound+((UpperBound-LowerBound) / (1+((IC 50 / x)^Hill))).

[0795] IC 50 The values ​​were determined by fitting the data to a standard 4-parameter model using the Hill Slope feature in GraphPad Prism software. 50 : *≤10nM, 10nM<**≤100nM, 100nM<***≤500nM, ****>500nM. The experimental results for the compounds are shown in Table 2.

[0796] Table 2. PolQ ATPase test

[0797]

[0798]

[0799] Although the invention has been fully described by way of examples, it is worth noting that various changes and modifications will be apparent to those skilled in the art. These changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof, characterized in that... : Ring A is C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl or 5-14 heteroaryl groups; Ring B is a partially unsaturated 5-14 membered heterocyclic group, C6-C 14 Aryl or 5-14 heteroaryl groups; The ring C is an 8-14 member heteroaryl group, optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R. 6 Substituents; wherein the 8-14 membered heteroaryl group comprises at least one aromatic ring; m is 1, 2, 3, 4 or 5; n is 1, 2, 3, 4 or 5; Each R 1 Each is independently selected from H, D, halogen, -CN, -NO2, N3, -SF5, oxo, C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl, -NR C R D -OR A -SR A -NR C OR A , -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C C(O)R B , -S(O)R B -S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR C S(O)2NR C R D -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F ; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl are optionally represented by 1, 2, 3, 4, or 5 independently selected from R 1A Substituents; or Two Rs 1 Together with the atoms it is attached to, it forms an oxo group, C 3- C7 cycloalkyl or 4-7 membered heterocyclic group; wherein, the C 3- C7 cycloalkyl or 4-7 membered heterocyclic groups are optionally surrounded by 1, 2, 3, 4 or 5 groups, each independently selected from R 1A Substituents of the substituents; Each R 1A Each is independently selected from D, halogen, CN, -NO2, N3, oxo, OR a NR c R d C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic; wherein, the C 1- C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C 3- The C6 cycloalkyl group or the 4-6 membered heterocyclic group is optionally substituted with a substituent selected from the following: D, halogen, CN, OH, NH2, oxo, NR. c R d OR a SR a C 1- C6 alkyl, C 1- C6 haloalkyl; Each R 2 Each element is independently selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, -NR C R D -OR A -SR A -NR C OR A , -C(O)R B , -C(O)NR C R D -C(O)OR A , -OC(O)R B -NR C C(O)R B , -S(O)R B -S(O)2R B , -S(O)NR C R D -NR C S(O)2R D -S(O)2NR C R D -NR C S(O)2NR C R D -NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F , -P(O)OR E OR F -OP(O)OR E OR F ; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 heteroaryl, optionally denoted by 1, 2, 3, 4 or 5, each independently selected from R 2A Substituents; or Two Rs 2 Together with the atoms to which it is attached, it forms an oxo, C3-C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, 3 or 4 atoms, each independently selected from R 2A Substituents of the substituents; Each R 2A Each of the following is independently selected from D, halogen, CN, OH, NH2, NO2, SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, NR c R d OR a SR 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 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)2R d 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl; R 3 For H, D, halogen, CN, oxo, NO2, SF5, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 heteroaryl, OR A SR A NR C OR A NR C R D C(O)R B C(O)NR C R D NR C C(O)R B NR C C(O)OR A NR C S(O)2R D NR C S(O)2NR C R D S(O)R B S(O)2R B ; wherein, the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 10 aryl, 5-14 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 4 Substituents of the substituents; Each R 4 Each is independently selected from D, halogen, CN, NO2, N3, oxo, and NR. C R D OR A SR A NR C OR 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 C(O)R B NR C C(O)NR C R D NR C C(O)OR A S(O)R B S(O)2R B S(O)NR C R D NR C S(O)2R D S(O)2NR C R D NR C S(O)2NR C R D NR C S(O)(=NR B )R B SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic groups optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R 5 Substituents of the substituents; Each R 5 Independently selected from D, CN, halogen, NO2, SF5, oxo, selectively substituted C1-C6 alkyl, selectively substituted C2-C6 alkenyl, selectively substituted C2-C6 alkynyl, selectively substituted C3-C6 cycloalkyl, selectively substituted 4-6 membered heterocyclic groups, OR a SR 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)2R d S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ; Each R 6 Each element is independently selected from D, halogen, CN, NO2, -N3, oxo, SF5, and NR. C R D OR A SR A SiR G R H R I B(OR) C (OR) D ), -P(O)R E R F C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group is optionally composed of 1, 2, 3, 4, or 5 groups, each independently selected from R 6A Substituents of the substituents; Two Rs 6 Oxyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic groups are formed together on the same carbon atom; wherein, the C3-C7 cycloalkyl, 4-7 membered heterocyclic groups are optionally composed of 1, 2, 3 or 4 independently selected from R 6A Substituents of the substituents; Two adjacent R 6 Together with the atoms to which it is attached, it forms a C3-C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C3-C7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, 3 or 4 atoms, each independently selected from R 6A Substituents of the substituents; Each R 6A Each of the following is independently selected from D, halogen, CN, OH, NH2, NO2, SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, NR c R d OR a SR 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 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)2R d 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally substituted with substituents selected from the following: D, halogen, CN, OH, NH2, oxo, NR c1 R d1 OR a1 SR a1 C 1- C6 alkyl, C 1- C6 haloalkyl; Each R A Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, 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 , 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 ; Each R B Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a C(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)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 B(OR) c (OR) d ); R C and R D Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OR a OC(O)NR c R d NR c R d NR c C(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 B (OR) c (OR) d ); Or R C and R D Together with the N atom to which it is attached, it forms a 4-7 membered heterocyclic group, which may be optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl; R a and R a1 Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 alkyl group is a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C3-C6 alkyl group. 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from the following: D, halogen, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl; R b and R b1 Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic; R c R d R c1 R d1 Each is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 Aryl, or bis(5-10 heteroaryl); wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-heteroaryl, bis(C6-C 10 (Aryl), 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 The aryl group, or bis(5-10 heteroaryl group), is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C(O)OR a1 C(O)R b1 S(O)2R b1 C1-C4 alkyl-O-C1-C4 alkyl or C1-C4 alkyl-O-C1-C4 alkyl-O-; Or R c and R d Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkoxy-C1-C4 alkoxy; Or R c1 and R d1 Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from the following: 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, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkoxy-C1-C4 alkoxy; R E and R e Each of the following is 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 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 heterocyclic-C1-C4 alkyl; R F and R f Each is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl groups, or 4-10 membered heterocyclic groups; R G R H and R I Each is independently selected from selectively substituted C1-C4 alkyl groups or selectively substituted phenyl groups.

2. The compound according to claim 1, characterized in that, Ring A is C6-C 10 Aryl, or 5-10-membered heteroaryl; preferably, ring A is phenyl or 6-membered heteroaryl; more preferably, Cy is phenyl, pyridyl, or pyrazinyl; even more preferably, ring A is phenyl or pyridin-4-yl.

3. The compound according to claim 1 or 2, characterized in that, The It has the following structure: Among them, Z 1 Z 2 Z 3 Z 4 Z 5 Selected independently from N or CR 1 Preferably, Z 1 Z 2 Z 3 Z 4 Z 5 Any one of them is N; Z 1 Z 2 Z 3 Z 4 Z 5 Any two Ns; or Z 1 Z 2 Z 3 Z 4 Z 5 All are CR 1 Preferably, the It has the following structure:

4. The compound according to any one of claims 1-2, characterized in that, Each R 1 Each is independently selected from (i) H, D, halogen, or –OR A ; or (ii) C1-C6 alkyl, C2-C6 alkynyl; each substituent is optionally selected from 1, 2, 3, 4, or 5 independently selected from R 1A Substituents are substituted.

5. The compound according to any one of claims 1-4, characterized in that, Each R 1 Each can be independently selected from H, –F, –Cl, –CH3, –CHF2, –CF3, –OCH3, –OCHF2, –OCF3, or -C≡CH.

6. The compound according to any one of claims 1-5, characterized in that, One of the R mentioned 1 The groups are –OCH3 or -C≡CH.

7. The compound according to any one of claims 1-6, characterized in that, One of the R 1 The values ​​are –F, –Cl, –CH3, –CHF2, –CF3, –OCH3, –OCHF2, or –OCF3.

8. The compound according to any one of claims 1-7, wherein... It has the following structure: Preferably, the It has the following structure:

9. The compound according to any one of claims 1-8, characterized in that, Cycle B is a partially unsaturated 5-14 membered heterocyclic group.

10. The compound according to any one of claims 1-9, characterized in that, Ring B is C6-C 10 Aryl or 5-10-membered heteroaryl; preferably, ring B is C6 aryl, 5-membered heteroaryl or 6-membered heteroaryl; more preferably, ring B is pyridyl, pyridazinyl or imidazolyl.

11. The compound according to any one of claims 1-10, characterized in that, The It has the following structure: Among them, X 1 For N or CR 2 ;X 2 For N or CR 2 ;X 3 For N or CR 2 ;X 4 For N or CR 2 ;X 1 X 2 X 3 X 4 At most three of them are N; the * is connected to -C(=O)NH-, and the ** is connected to ring A; preferably, the It has the following structure: Wherein, the * is connected to ring A, and the ** is connected to -C(=O)NH-; preferably, the It has the following structure: More preferably, the It has the following structure: Wherein, the * is connected to -C(=O)NH-, and the ** is connected to ring A.

12. The compound according to any one of claims 1-11, characterized in that, Each R 2 Each substituent is independently selected from (i) H, D, –CN, or halogen; or (ii) C1-C6 alkyl or 5-10 heteroaryl, each substituent optionally being composed of 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted; preferably, each R... 2 Each is independently selected from H, D, –CN, methyl, or 1-methylpyrazolyl.

13. The compound according to any one of claims 1-12, characterized in that, The It has the following structure:

14. The compound according to any one of claims 1-13, characterized in that, The ring C is an 8-14 member heteroaryl group, optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R. 6 Substituents are substituted.

15. The compound according to any one of claims 1-14, characterized in that, The ring C is indolyl, isoindolyl, indazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indazole, benzo[d]imidazolyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4]pyridyl -b]pyridyl, pyrrolo[3,4-c]pyridyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, furano[2,3-b]pyridyl, benzo[c]isoxazolyl, furano[3,4-b]pyridyl, furano[3,4-c]pyridyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, thieno[3,2-b]pyridyl, thieno[3,4-c]pyridyl, benzo[d][1,2,3]triazolyl, pyrazolo[4,3-b]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3, [4-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-c]pyridyl, imidazo[4,5-b]pyridyl, 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, thiazo[5,4-b]pyridinyl, thiazo[4,5-b]pyrazinyl, thiazo[5,4-d]pyrimidinyl, thiazo[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]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)-keto, 5,6-dihydro-4H-pyrrolo[3,[4-d]thiazolyl-4-one, benzo[d]thiazolyl, thiazo[4,5-b]pyridyl, thiazo[4,5-c]pyridyl, thiazo[5,4-c]pyridyl, thiazo[4,5-c]pyridazinyl, thiazo[4,5-d]pyrimidinyl, thiazo[5,4-c]pyridazinyl, thiazo[4,5-d]pyridazinyl, thiazo[5,4-e][1,2,4]triazinyl, thiazo[4,5-e][1,2,4]triazinyl, pyrazolo[5,1-b][1,3,4]thiadiazolyl, imidazo[1,5-b][1,2,4]thiadiazolyl, pyrazolo[1,5-b][1,2,4]thiadiazolyl, [1,2,4]triazolo[1,5-b][1, [2,4]thiadiazolyl, [1,2,4]triazolo[4,3-b][1,2,4]thiadiazolyl, spiro[cyclopropyl-1,6'-pyrrolo[3,4-d]thiazolyl]-4'(5'H)-keto, spiro[cyclobutyl-1,6'-pyrrolo[3,4-d]thiazolyl]-4'(5'H)-keto, thiazo[4,5-c]pyridine- 4(5H)-keto, thiazo[5,4-d]pyrimidine-7(6H)-keto, 6,7-dihydrothiazo[4,5-c]pyridine-4(5H)-keto, 5',6'-dihydro-4'H-spiro[cyclopropyl-1,7'-thiazo[4,5-c]pyridine]-4'-keto, 5',6'-dihydro-4'H-spiro[cyclobutyl-1,7'- '-Thiazo[4,5-c]pyridine-4'-keto, thiazo[4,5-c]pyridine-6(5H)-keto, thiazo[4,5-d]pyridazine-4(5H)-keto, thiazo[5,4-c]pyridine-6(5H)-keto, thiazo[4,5-d]pyrimidine-5(6H)-keto, thiazo[5,4-c]pyridine-4'-keto (5H)-keto, thiazo[4,5-d]pyridazine-7(6H)-keto, 4,5-dihydro-6H-pyrrolo[3,4-d]thiazo-6-keto, spiro[cyclopropyl-1,4'-pyrrolo[3,4-d]thiazo]-6'(5'H)-keto, spiro[cyclobutyl-1,4'-pyrrolo[3,4-d]thiazo]-6'(5'H)-keto H)-keto, 6,7-dihydrothiazo[5,4-c]pyridine-4(5H)-keto, 4,7-dihydrothiazo[5,4-c]pyridine-6(5H)-keto, 4,7-dihydrothiazo[4,5-c]pyridine-6(5H)-keto, 6,7-dihydrothiazo[5,4-d]pyrimidine-5(4H)-keto, 4,7-dihydro Thiazolo[5,4-c]pyridine-6(5H)-keto, 4,7-dihydrothiazo[4,5-c]pyridine-6(5H)-keto, 6,7-dihydrothiazo[5,4-d]pyrimidine-5(4H)-keto, 5',6'-dihydro-4'H-spiro[cyclopropyl-1,7'-thiazo[5,4-c]pyridine]-4'-keto, 5',6'-Dihydro-4'H-spiro[cyclobutyl-1,7'-thiazo[5,4-c]pyridine]-4'-keto; each substituent is optionally composed of 1, 2, 3, 4 or 5 independently selected from R, 6 Substituents are substituted.

16. The compound according to any one of claims 1-15, characterized in that, Ring C is in, It can be a single bond or a double bond; Y 1 Y 2 Y 3 Y 4 To indicate whether they are the same or different, each is independently selected from N or CH; Y 5 It can be CH, NH, N or S; Y 6 It can be CH, NH, N or S; Y 7 Y 8 Y 9 Each is independently selected from CH, NH, N, and S; p and q are each independently selected from 0, 1, or 2; The * is connected to -NHC(=O)-, R 3 Connected at any position in ring C, any hydrogen atom in ring C is connected by R. 3 Substitution; one or more hydrogens of the ring C are optionally replaced by 1, 2, 3, 4 or 5 hydrogens, each independently selected from R. 6 Substituents of the substituents; Preferably, ring C is: Wherein, the * is connected to -NHC(=O)-, R 3 Connected at any position on the ring C; the ring C is optionally composed of 1, 2, 3, 4 or 5 independently selected from R. 6 Substituents are substituted.

17. The compound according to any one of claims 1-16, characterized in that, Ring C is Wherein, the * is connected to -NHC(=O)-, and the ** is connected to R. 3 Connected; ring C is optionally composed of 1, 2, 3, 4, or 5 elements independently selected from R. 6 Substituents are substituted.

18. The compound according to any one of claims 1-17, characterized in that, Ring C is Wherein, the * is connected to -NHC(=O)-, and the ** is connected to R. 3 Connected; ring C is optionally composed of 1, 2, 3, 4, or 5 elements independently selected from R. 6 Substituents are substituted.

19. The compound according to any one of claims 1-18, characterized in that, Ring C is Wherein, the * is connected to -NHC(=O)-, and the ** is connected to R. 3 Connected; ring C is optionally selected by 1, 2, 3, 4 or 5 independently chosen from R. 6 Substituents are substituted.

20. The compound according to any one of claims 1-19, characterized in that, R 3 For H, D, halogen, CN, oxo, NO2, SF5, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 heteroaryl, OR A SR A NR C OR A NR C R D C(O)R B C(O)NR C R D NR C C(O)R B NR C C(O)OR A NR C S(O)2R D NR C S(O)2NR C R D S(O)R B S(O)2R B ; wherein, the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl group, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 10 aryl, 5-14 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 independently selected from R 4 Substituents are substituted.

21. The compound according to any one of claims 1-20, characterized in that, H, D, halogen, CN, oxo, NO2, SF5, OR A NR C R D SR A C1-C 10 Alkyl, C3-C 14 Cycloalkyl, or 4-14 membered heterocyclic group; wherein, the C1-C 10 Alkyl, C3-C 14 The cycloalkyl group, or a 4-14 membered heterocyclic group, is optionally surrounded by 1, 2, 3, 4, or 5 groups, each independently selected from R. 4 Substituents are substituted.

22. The compound according to any one of claims 1-21, characterized in that, R 3 for CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CH3, CF2CF3, CF2CH2CH3, CH2CH2OH , CH2CH2CH2OH, CH2CH2OCH3, CH2CH2CH2OCH3, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, OCF2CF3, OCH2CH2 OH, OCH2CH2OCH3, OCH2CH2OCH2CH3, OCH(CH3)CH2OH, OCH2CH(CH3)OH, OCH2C(CH3)2OH, SCH3, SCH2CH2CN, SCH2CH2CH2CN, SCH2CH2OH, SCH2CH2OCH3, SCH2CH(CH3) OH, NH2, NHCH3, N(CH3)2, NHCH2CH3, N(CH2CH3)2, NHCH2CH2CH3, N(CH2CH2CH3)2, NHCH(CH3)2, NHCH2CH2OH, N(CH3)CH2CH2OH, NHCH2CH2OCH3, N(CH3)CH2CH2OCH3, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, dioxahexacycloyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazine, morpholinyl, azacycloheptyl, 1,4-diazacycloheptyl, phenyl, naphthyl, pyrrolyl, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrazinyl, pyridazinyl, indolyl, isindolyl, inazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophene, benzo[c]thiophene, inazolyl; each ring is optionally composed of 1, 2, 3, 4 or 5 rings independently selected from R 4 Substituents are substituted.

23. The compound according to any one of claims 1-22, characterized in that, R 3 is H, D, halogen, CN, oxo, NO2, SF5, CH3, CH2CH3, CH2CH2OH, CH2CH2OCH3, OH, OCH3, OCH2CH3, OCH2CF3, OCF2CF3, OCH2CH2OH, OCH2CH2OCH3, OCH2CH2OCH2CH3, OCH2C(CH3)2OH, NH2, NHCH3, N(CH3)2, NHCH2CH3, N(CH2CH3)2, N(CH3)CH2CH2OCH3, 24. The compound according to any one of claims 1-23, characterized in that, The compounds represented by formula (I) are as shown in formulas (IIa), (IIb), (IIc), (IId) or (IIe): Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof; X 1 For N or CR 2 ; X 2 For N or CR 2 ; X 3 For N or CR 2 ; X 4 For N or CR 2 ; Among them, ring A, ring C, and ring R 1 R 2 R 3 And m is as defined in the present invention (I).

25. The compound according to any one of claims 1-24, characterized in that, The compound represented by formula (I) is as shown in formula (IIIa). As shown in (IIIb), (IIIc), (IIId), (IIIe), or (IIIf): Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof; Among them, ring A, ring C, and ring R 1 R 2 R 3 And m is as defined in the present invention (I).

26. The compound according to any one of claims 1-25, characterized in that, The compounds represented by formula (I) are as shown in formulas (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf): Among them, rings C and R 1 R 2 R 3 And m is as defined in the present invention (I).

27. The compound according to any one of claims 1-26, characterized in that, The compound is: Or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide, or deuterated compound thereof.

28. A pharmaceutical composition comprising: The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, transisomer, isotope derivative, prodrug, N-oxide or deuterated compound, and at least one pharmaceutically acceptable excipient.

29. A method for treating or preventing PolQ overexpression cancer, comprising: The patient is given a therapeutically effective amount of the compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

30. A method for treating or preventing cancer, wherein, The cancer is characterized by an increased dependence on MMEJ-DSB repair, comprising: administering to the patient a therapeutically effective amount of the compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

31. A method for treating or preventing cancer, wherein, The cancer is characterized by HR deficiency, reduced or absent expression of HR-related genes, including: administering to the patient a therapeutically effective amount of the compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

32. A method for treating or preventing cancer, wherein the cancer lacks the 53BP1 / Shieldin complex, comprising: The patient is given a therapeutically effective amount of the compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

33. A method for treating or preventing cancer, said cancer being treated or not treated with PARPi drugs, or being resistant to PARPi treatment, comprising: The patient is given a therapeutically effective amount of the compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

34. A method for treating or preventing cancer, wherein, The cancer is characterized by NHEJ deficiency, reduced or absent expression of NHEJ-related genes, including: administering to the patient a therapeutically effective amount of the compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

35. Use of a compound according to any one of claims 1-27, or a pharmaceutical composition according to claim 28, in the preparation of a medicament for treating PolQ overexpression diseases.

36. The use of any one of the compounds 1-27 according to any one of claims, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for treating diseases dependent on increased MMEJ-DSB repair.

37. The use of a compound according to any one of claims 1-27, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for treating cancer, wherein, The cancer is characterized by HR deficiency, with reduced or absent expression of HR-related genes.

38. The use of a compound according to any one of claims 1-27, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for treating cancer, wherein, The cancer lacks the 53BP1 / Shieldin complex.

39. The use of a compound according to claims 1-27 or any one of them, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for treating cancer, wherein, The cancer may or may not have received PARPi treatment, and it may be resistant to PARPi treatment.

40. The use of a compound according to any one of claims 1-27, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for treating cancer, wherein, The cancer is characterized by NHEJ deficiency, with reduced or absent expression of NHEJ-related genes.

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