Thiadiazolone derivatives, compositions thereof, and applications

Abstract

The present invention relates to a thiadiazolon derivative represented by formula (I), a pharmaceutical composition thereof, a method for producing it, and its use as a therapeutic agent. TIFF2026516662000199.tif26111

Description

[Technical Field]

[0001] This invention claims the benefits of International Application No. PCT / CN2023 / 087991 filed on April 13, 2023, International Application No. PCT / CN2023 / 101401 filed on June 20, 2023, and International Application No. PCT / CN2023 / 120470 filed on September 21, 2023, the contents of which are incorporated collectively by reference into this invention.

[0002] This invention relates to thiadiazolone, a PolQ inhibitor, and its pharmaceutical compositions. The invention also relates to methods for producing thiadiazolone derivatives and their applications for treating PolQ-mediated diseases, such as cancers with DNA repair deficiencies. [Background technology]

[0003] The DNA damage repair process is crucial for genome maintenance and cellular activity. Double-strand breaks (DSBs) can be repaired by one of three main pathways: homologous recombination (HR), non-homologous end joining (NHEJ), and substituted non-homologous end joining (alt-NHEJ). Substituted non-homologous end joining (alt-NHEJ), also known as microhomology-mediated end joining (MMEJ), is usually considered a "backup" DSB repair pathway when NHEJ or HR is damaged (Truong et al., PNAS 2013, 110(19), 7720-7725).

[0004] Abnormal DNA damage response (DDR) often makes cancer cells sensitive to certain types of DNA damage. Therefore, deficiencies in DDR may be developed as cancer-targeted therapies. DNA repair deficiencies have been demonstrated and are effective 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 MWet al., Lancet (2010); 376(9737): 245-51).

[0005] Extensive genetic, cell biology, and biochemical studies have shown that the 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).

[0006] 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 enables 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 proteins from ssDNA ends and stimulates annealing. The anti-recombinase activity of PolQ promotes the alt-NHEJ pathway. Furthermore, the helicase domain of PolQ contributes to microhomology-mediated strand annealing (Chan SH et al., PLoS Genet. (2010); 6:el001005, and Kawamura K et al., Int. J. Cancer (2004); 109: 9-16). If the ssDNA overhang contains >2 bp of microhomology, PolQ can utilize this annealing activity to promote end joining in the alt-NHEJ pathway (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 by the binding of Rad51 units, followed by ATP enzyme-mediated substitution of Rad51 from DSB damage sites. After annealing, the polymerase domain extends the ssDNA terminus and fills the remaining gap.

[0007] PolQ is expressed relatively low in normal cells, but is significantly overexpressed in HRD ovarian cancer, uterine cancer, and breast cancer subpopulations, and PolQ overexpression is associated with poor prognosis (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 HR, NHEJ, or ATM-deficient cancer cells 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 of BRCA1 or BRCA2 mutations, which underlies the emergence of cisplatin and PARPi drug resistance in tumors (Zatreanu D. et al, Nature Communications (2021) 12:3636). Thus, PolQ is an attractive target for synthetic lethal therapies for cancers with DNA repair deficiencies. The present invention provides a series of compounds with pharmaceutically active properties. [Overview of the project]

[0008] The present invention relates to the compound represented by formula (I). [ka] The present invention provides pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, atropisomers, isotopic derivatives, prodrugs, or deuterium compounds thereof, the definitions of each of the above variables being as defined in the present invention.

[0009] The present invention further provides pharmaceutical compositions comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, and at least one pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present invention is a method for inhibiting PolQ, The present invention provides a method comprising contacting PolQ with a compound represented by formula (I) above, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug, or deuterium compound thereof.

[0011] In another embodiment, the present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug, or deuterium compound thereof.

[0012] Details of one or more embodiments are described below. Other features, purposes, and advantages will become apparent from the specification and claims. [Modes for carrying out the invention]

[0013] The present invention can be better understood by referring to the following description, which includes the definitions and examples below. Some features of the compositions and methods of the present invention described in different contexts may be provided in combination in a single embodiment. Alternatively, for the sake of brevity, various features of the compositions and methods of the present invention described in the context of a single embodiment may be provided individually or in any subcombination.

[0014] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein, and that the terms used in the present invention are merely for the purpose of describing specific embodiments and do not limit the scope of the present invention.

[0015] The present invention relates in particular to a compound represented by formula (I)

Chemical formula

[0016] In some embodiments, ring A is C3-C 14 Cycloalkyl groups, 4-14 member heterocycloalkyl groups, C6-C 14 It is an aryl group or a 5-14 membered heteroaryl group.

[0017] In some embodiments, ring A is C3-C 14 It is a cycloalkyl group.

[0018] In some embodiments, ring A is a saturated C3-C 14 Cycloalkyl groups or partially saturated C3-C 14 It is a cycloalkyl group.

[0019] In some embodiments, ring A is a 4- to 14-membered heterocycloalkyl group.

[0020] In some embodiments, ring A is a saturated 4-14 member heterocycloalkyl group or a partially saturated 4-14 member heterocycloalkyl group.

[0021] In some embodiments, ring A is C6-C 14 It is an aryl group. In some embodiments, ring A is C6-C 10 It is an aryl group.

[0022] In some embodiments, ring A is a phenyl group, a naphthyl group, an anthracenyl group, or a phenantrenyl group. In some embodiments, ring A is a phenyl group.

[0023] In some embodiments, ring A is a 5- to 14-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0024] In some embodiments, ring A is a 5- to 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- to 10-membered heteroaryl group having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring A is a 5- to 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. In some embodiments, ring A is a pyridyl group.

[0025] In some embodiments, ring A is a phenyl group or a 6-membered heteroaryl group having one or two heteroatoms independently selected from N.

[0026] In some embodiments, ring A is a pyrrolyl group, furanyl group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, tetrazolyl group, pyrazolyl group, triazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, indolyl group, isoindolyl group, indolidinyl group, benzofuranyl group, isobenzofuranyl group, benzo[b]thienyl group, benzo[c]thienyl group, indazolyl group, benzo[d]imidazolyl group, pyro [3,2-b]pyridyl group, pyrrolo[3,2-c]pyridyl group, pyrrolo[2,3-c]pyridyl group, pyrrolo[2,3-b]pyridyl group, pyrrolo[3,4-b]pyridyl group, pyrrolo[3,4-c]pyridyl group, benzo[d]isoxazolyl group, benzo[d]oxazolyl group, flo[3,2-b]pyridyl group, flo[3,2-c]pyridyl group, flo[2,3-c]pyridyl group, flo[2,3-b]pyridyl group, benzo[c]isoxazolyl group, flo[3,4-b]pyridyl group, flo[3,4-c ]pyridyl group, benzo[d]isothiazolyl group, benzo[d]thiazolyl group, thieno[3,2-b]pyridyl group, thieno[3,4-c]pyridyl group, benzo[d][1,2,3]triazolyl group, pyrazolo[4,3-b]pyridyl group, pyrazolo[4,3-c]pyridyl group, pyrazolo[3,4-c]pyridyl group, pyrazolo[3,4-b]pyridyl group, imidazo[4,5-b]pyridyl group, imidazo[4,5-c]pyridyl group, imidazo[4,5-b]pyridyl group , pyrrolo[3,2-c]pyridazinyl group, pyrrolo[3,2-d]pyrimidinyl group, pyrrolo[2,3-b]pyridazinyl group, pyrrolo[2,3-d]pyridazinyl group, pyrrolo[2,3-d]pyrimidinyl group, pyrrolo[2,3-c]pyridazinyl group, pyrrolo[3,4-c]pyridazinyl group, pyrrolo[3,4-d]pyrimidinyl group, pyrrolo[3,4-b]pyridazinyl group, pyrrolo[3,4-d]pyridazinyl group, pyrrolo[3,4-d]pyrimidinyl group, or 6H-pyrrolo[3,4-c]pyridazinyl group.

[0027] In some embodiments, ring A is a phenyl group or a pyridyl group. In some embodiments, ring A is a phenyl group or pyridine-4-yl.

[0028] In some embodiments, [ka] teeth, [ka] It has a structure, and among them, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 These are N or CR, respectively, independently. 1 They are selected from among them.

[0029] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 One of them is N.

[0030] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 Two of them are N.

[0031] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 All of them are CR 1 They are selected from among them.

[0032] In some embodiments, the above [ka] teeth, [ka] It has the structure of [the object].

[0033] In some embodiments, the above [ka] teeth, [ka] It has the structure described above. In some embodiments, [ka] teeth, [ka] It has the structure described above. In some embodiments, [ka] teeth, [ka] It has the structure described above. In some embodiments, [ka] teeth, [ka] It has the structure of [the object].

[0034] In some embodiments, the above [ka] teeth, [ka] It has the structure of [the object].

[0035] In some embodiments, the above [ka] teeth, [ka] It has the structure of [the object].

[0036] In some embodiments, ring B is a partially saturated 5-14 member heterocycloalkyl group, C6-C 14 It is an aryl group or a 5-14 membered heteroaryl group.

[0037] In some embodiments, ring B is a partially saturated 5- to 14-membered heterocycloalkyl group.

[0038] In some embodiments, ring B is C6-C 14 It is an aryl group. In some embodiments, ring B is C6-C 10 It is an aryl group. In some embodiments, ring B is a phenyl group, a naphthyl group, an anthracenyl group, or a phenantrenyl group. In some embodiments, ring B is a phenyl group.

[0039] In some embodiments, ring B is a 5- to 14-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 5- to 10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 5- to 6-membered heteroaryl group having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 5- to 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 5- to 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from N.

[0040] In some embodiments, ring B is a pyrrolyl group, furanyl group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, tetrazolyl group, pyrazolyl group, triazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, indolyl group, isoindolyl group, indolidinyl group, benzofuranyl group, isobenzofuranyl group, benzo[b]thienyl group, benzo[c]thienyl group, indazolyl group, benzo[d]imidazolyl group, pyro [3,2-b]pyridyl group, pyrrolo[3,2-c]pyridyl group, pyrrolo[2,3-c]pyridyl group, pyrrolo[2,3-b]pyridyl group, pyrrolo[3,4-b]pyridyl group, pyrrolo[3,4-c]pyridyl group, benzo[d]isoxazolyl group, benzo[d]oxazolyl group, flo[3,2-b]pyridyl group, flo[3,2-c]pyridyl group, flo[2,3-c]pyridyl group, flo[2,3-b]pyridyl group, benzo[c]isoxazolyl group, flo[3,4-b]pyridyl group, flo[3,4-c ]pyridyl group, benzo[d]isothiazolyl group, benzo[d]thiazolyl group, thieno[3,2-b]pyridyl group, thieno[3,4-c]pyridyl group, benzo[d][1,2,3]triazolyl group, pyrazolo[4,3-b]pyridyl group, pyrazolo[4,3-c]pyridyl group, pyrazolo[3,4-c]pyridyl group, pyrazolo[3,4-b]pyridyl group, imidazo[4,5-b]pyridyl group, imidazo[4,5-c]pyridyl group, imidazo[4,5-b]pyridyl group , pyrrolo[3,2-c]pyridazinyl group, pyrrolo[3,2-d]pyrimidinyl group, pyrrolo[2,3-b]pyridazinyl group, pyrrolo[2,3-d]pyridazinyl group, pyrrolo[2,3-d]pyrimidinyl group, pyrrolo[2,3-c]pyridazinyl group, pyrrolo[3,4-c]pyridazinyl group, pyrrolo[3,4-d]pyrimidinyl group, pyrrolo[3,4-b]pyridazinyl group, pyrrolo[3,4-d]pyridazinyl group, pyrrolo[3,4-d]pyrimidinyl group, or 6H-pyrrolo[3,4-c]pyridazinyl group.

[0041] In some embodiments, ring B is a 5- or 6-membered heteroaryl group. In some embodiments, ring A is an imidazolyl group, a pyridyl group, or a pyridadinyl group. In some embodiments, ring A is an imidazolyl group or a pyridyl group.

[0042] In some embodiments, the above [ka] teeth, [ka] Having a structure, Among these, the symbol * indicates connection to ring A, and the symbol ** indicates connection to C=O. X 1 , X 2 , X 3 , X 4 These are N or CR, respectively, independently. 2 Selected from, X 5 , NR 1 It is either O or S.

[0043] In some embodiments, the above [ka] teeth, [ka] It has the structure of X 1 , X 2 , X 3 , X 4 One of them is N, and of those, X 1 , X 2 , X 3 , and X 4 This is as defined in the present invention. In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N, and the other three are each independently CR2 Selected from among, R 2 This is as defined in the present invention. In some embodiments, X 1 , X 2 , X 3 , and X 4 Any two of them are N, and the other two are CR independently. 2 Selected from among, R 2 This is as defined in the present invention. In some embodiments, X 1 , X 2 , X 3 , and X 4 Each of them independently performs CR 2 Selected from among, R 2 This is as defined in the present invention.

[0044] In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, R 2 , X 1 , and X 4 This is as defined in the present invention.

[0045] In some embodiments, the above [ka] teeth, [ka] It has a structure, of which X 1 , X 2 , and X 3 This is as defined in the present invention. In some embodiments, X 1 , X 2 , and X 3 One of them is N, and the other two are CR, each independently. 2 Selected from among, R2 This is as defined in the present invention. In some embodiments, X 1 , X 2 , and X 3 Any two of them are N, and the other one is CR 2 And among them, R 2 This is as defined in the present invention. In some embodiments, X 1 , X 2 , and X 3 Each of them independently performs CR 2 Selected from among, R 2 This is as defined in the present invention.

[0046] In some embodiments, the above [ka] teeth, [ka] It has a structure, of which each X 1 , X 3 , and X 5 This is as defined in the present invention. In some embodiments, each X 1 , X 3 Each of them independently performs CR 2 Selected from X 5 is NR 2 , O or S, of which each R 2 This is as defined in the present invention. In some embodiments, X 1 is N, and X 3 CR 2 X 5 is NR 2 , O or S, of which each R 2 This is as defined in the present invention. In some embodiments, X 1 CR 2 X 3 is N, and X 5 is NR 2 , O or S, of which each R 2 This is as defined in the present invention. In some embodiments, X1 is N, and X 3 is N, and X 5 is NR 2 , O or S, of which R 2 This is as defined in the present invention.

[0047] In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention.

[0048] In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention.

[0049] In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention.

[0050] In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention. In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention. In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention. In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention. In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention. In some embodiments, the above [ka] teeth, [ka] It has a structure, and among them, each R 2 This is as defined in the present invention.

[0051] In some embodiments, the above [ka] teeth, [ka] It has the structure of [the object].

[0052] In some embodiments, m is 0.

[0053] In some embodiments, m is 1.

[0054] In some embodiments, m is 2.

[0055] In some embodiments, m is 3.

[0056] In some embodiments, m is 4.

[0057] In some embodiments, m is 5.

[0058] In some embodiments, n is 0.

[0059] In some embodiments, n is 1.

[0060] In some embodiments, n is 2.

[0061] In some embodiments, n is 3.

[0062] In some embodiments, n is 4.

[0063] In some embodiments, n is 5.

[0064] In some embodiments, each R 1 These are, independently, H, D, halogen, -CN, -NO2, -N3, -SF5, oxo, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C6 cycloalkyl group, 4-6 member heterocycloalkyl group, phenyl group or 5-6 member heteroaryl group, -NR C R D , -OR A , -SR A , -NR C Ure 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 Ure F , -OP(O)OR E Ure F Selected from these, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C6 cycloalkyl group, 4-6 member heterocycloalkyl group, phenyl group, or 5-6 member heteroaryl group is optionally selected as R 1A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0065] In some embodiments, each R 1 Each of these is independently selected from H, D, halogen, -CN, -NO2, -N3, -SF5, and oxo.

[0066] In some embodiments, each R 1 Each is independently selected from H. In some embodiments, each R 1 Each of them is independently selected from D.

[0067] In some embodiments, each R 1 Each is independently selected from halogens. In some embodiments, each R 1 Each is independently selected from -F, -Cl, -Br, and -I. In some embodiments, each R 1 is -F. In some embodiments, each R 1 is -Cl. In some embodiments, each R 1 is Br. In some embodiments, each R 1 It is -I.

[0068] In some embodiments, each R 1 Each is independently selected from -CN. In some embodiments, each R 1 Each is independently selected from -NO2. In some embodiments, each R 1 Each is independently selected from -N3. In some embodiments, each R 1 Each is independently selected from -SF5. In some embodiments, each R 1 Each is independently selected from the oxo.

[0069] In some embodiments, each R 1 Each of them is independently NR C R D Selected from. In some embodiments, for example, each R 1Each of these is independently selected from -NH2, -NHCH3, -NHCH(CH3)2, -NHCH3, -N(CH3)2, and -N(CH2CH3)2.

[0070] In some embodiments, each R 1 Each of these is an OR A Selected from. In some embodiments, for example, each R 1 Each is independently selected from -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CN, -OCH2CONH2, and -OCH2CH2OCH3. In some embodiments, each R 1 Each is independently selected from -OCH3. In some embodiments, each R 1 Each is independently selected from -OCH2CH3. In some embodiments, each R 1 Each is independently selected from -OCH(CH3)2. In some embodiments, each R 1 Each is independently selected from -OCF3. In some embodiments, each R 1 Each is independently selected from -OCHF2. In some embodiments, each R 1 Each is independently selected from -OCH2F. In some embodiments, each R 1 Each is independently selected from -OCF3. In some embodiments, each R 1 Each is independently selected from -OCH2CH2F. In some embodiments, each R 1 Each is independently selected from -OCH2CHF2. In some embodiments, each R 1 Each is independently selected from -OCH2CF3. In some embodiments, each R 1 Each is independently selected from -OCH2CN. In some embodiments, each R 1 Each of these is independently selected from -OCH2CONH2.

[0071] In some embodiments, each R 1 These are each independently -SR A Selected from. In some embodiments, each R 1 Each is independently selected from -SCH3. In some embodiments, each R 1 Each of these is independently selected from -SCH2CH3.

[0072] In some embodiments, each R 1 These are each independently -C(O)R B Selected from. In some embodiments, each R 1 These are independently -CHO, -C(O)CH3, and -C(O)CH2CH3, [ka] Selected from. In some embodiments, each R 1 These are each independently -C(O)NR C R D Selected from. In some embodiments, each R 1 These are -CONH2, -CONHCH3, and -CON(CH3)2, respectively, independently. [ka] Selected from. In some embodiments, each R 1 These are each independently -C(O)OR A Selected from. In some embodiments, each R 1 Each is independently selected from -COOH. In some embodiments, each R 1 These are each independently -OC(O)R B They are selected from among them.

[0073] In some embodiments, each R 1 These are each independently -NR C C(O)R B They are selected from among them.

[0074] In some embodiments, each R 1These are each independently -S(O)R B Selected from. In some embodiments, for example, each R 1 These are -S(O)CH3 and -S(O)CH2CH3, respectively, independently. [ka] Selected from. In some embodiments, each R 1 These are each independently -S(O)2R B Selected from. In some embodiments, for example, each R 1 These are -S(O)2CH3, -S(O)2CH2CH3, and [ka] They are selected from among them.

[0075] In some embodiments, each R 1 These are each independently -S(O)NR C R D Selected from. In some embodiments, for example, each R 1 These are independently selected from -S(O)2NH2, -S(O)2NHCH3, and -S(O)2N(CH3)2.

[0076] In some embodiments, each R 1 These are each independently -NR C S(O)2R D Selected from. In some embodiments, each R 1 Each is independently selected from -NHS(O)2CH3. In some embodiments, each R 1 These are each independently -S(O)2NR C R D Selected from. In some embodiments, each R 1 These are each independently -NR C S(O)2NR C R D Selected from. In some embodiments, each R 1 These are each independently -NR C S(O)(=NRB )R B They are selected from among them.

[0077] In some embodiments, each R 1 Each of these is independently -SiR G R H R I Selected from. In some embodiments, each R 1 Each of these is independently -B(OR C )(OR D ) are selected from. In some embodiments, each R 1 These are each independently -P(O)R E R F Selected from. In some embodiments, each R 1 Each is independently selected from -P(O)(CH3)2. In some embodiments, each R 1 Each of these is independently -P(O)OR E Ure F Selected from. In some embodiments, each R 1 These are each independently -OP(O)OR E Ure F They are selected from among them.

[0078] In some embodiments, each R 1 Each of them is independently C 1- Selected from C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C6 cycloalkyl groups, 4-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups, among which the above C 1- C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C6 cycloalkyl groups, 4-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups are optionally selected for R 1A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0079] In some embodiments, each R 1 Each of them is independently C 1- Selected from C6 alkyl groups, and R is optionally selected 1AIt is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0080] In some embodiments, each R 1 Each 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, -CH2C(O)NH2, and benzyl group.

[0081] In some embodiments, each R 1 Each is independently selected from the C2-C6 alkenyl group, and R is optionally selected. 1A They are substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from R. In some embodiments, for example, each R 1 These are independently selected from -CH=CH2 and -CH=CHCH3, respectively.

[0082] In some embodiments, each R 1 Each is independently selected from the C2-C6 alkynyl groups, and R is optionally selected. 1A They are substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from R. In some embodiments, for example, each R 1 These are each independently selected from -C≡CH, -C≡CCH3, -C≡CD, and -C≡CCD3.

[0083] In some embodiments, each R 1 Each is independently selected from C3-C6 cycloalkyl groups, and R is optionally selected. 1A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, each R 1Each of these groups is independently selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and each ring is optionally R 1A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0084] In some embodiments, each R 1 Each is independently selected from a 4-6 membered heterocycloalkyl group having one or two heteroatoms independently selected from N, O, S, and B, and of which the heteroatoms are optionally selected from one or more oxos (e.g., S(O) or S(O)2) and optionally selected from R 1A They may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them.

[0085] In some embodiments, each R 1 Each of these groups is independently selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, or thiomorpholinyl dioxide, and each ring is optionally R 1A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 1 teeth, [ka] That is the case.

[0086] In some embodiments, each R 1 Each is independently selected from the phenyl group, and R is optionally selected. 1A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R. In some embodiments, one of R 1 It is a phenyl group.

[0087] In some embodiments, each R 1Each is independently selected from a 5-6 member heteroaryl group, and R is optionally selected. 1A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, each R 1 Each of these groups is independently selected from pyrrolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, and pyrazinyl groups, and each substituent is optionally R 1A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 1 teeth [ka] That is the case.

[0088] In some embodiments, each R 1 These are (i) H, D, halogen, or -OR, respectively, independently. A , or (ii) selected from C1-C6 alkyl groups and C2-C6 alkynyl groups, each substituent optionally R 1A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of the following, of which R A and R 1A This is as defined in the present invention. In some embodiments, each R 1 These are (i) H, D, halogen, or -OR, respectively, independently. A , or (ii) selected from C1-C6 alkyl groups, R 1A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of the following, of which R A and R 1A This is as defined in the present invention. In some embodiments, each R 1 Each is independently selected from H, -F, -Cl, -CH3, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, or -C≡CH. In some embodiments, each R 1 Each of these is independently selected from H, -F, -Cl, -CH3, -CF3, or -OCH3.

[0089] In some embodiments, one of R 1 is -F. In some embodiments, one of R 1 is -Cl, -CH3, or -CF3. In some embodiments, one of them R 1 It is -OCH3.

[0090] In some embodiments, three of the R 1 It is not H. In some embodiments, three of them R 1 It's not H, but one of the three R's. 1 is -F, and the second of the three R 1 is -Cl, -CH3, or -CF3, and the third of the three R 1 is -OCH3. In some embodiments, three of the R 1 It's not H, but one of the three R's. 1 is -F, and the second of the three R 1 is -Cl, and the third of the three R 1 It is -OCH3.

[0091] In some embodiments, two R 1 These, together with the atoms linked to them, form oxo, C3-C7 cycloalkyl groups, or 4-7 member heterocycloalkyl groups, of which the above C3-C7 cycloalkyl groups or 4-7 member heterocycloalkyl groups are optionally R 1A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0092] In some embodiments, two R 1 These atoms, along with the atoms they bond to, form an oxo molecule.

[0093] In some embodiments, two R 1 C 3- Forms a C7 cycloalkyl group, and optionally R 1AIt is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0094] In some embodiments, two R 1 These, together with the atoms linked to them, form a 4-7 member heterocycloalkyl group, and optionally R 1A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0095] In some embodiments, each R 1A These are D, halogen, -CN, -NO2, -N3, oxo, and -OR, respectively, independently. a , -NR c R d Selected from C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C6 cycloalkyl groups, and 4-6 member heterocycloalkyl groups, of which the above C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C6 cycloalkyl groups, or 4-6 member heterocycloalkyl groups may optionally be D, halogen, -CN, -OH, -NH2, oxo, or -NR. c R d , -OR a , -SR a The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0096] In some embodiments, each R 1A These are D, halogen, -CN, -NO2, -N3, oxo, and -OR, respectively, independently. a , -NR c R d Selected from. In some embodiments, each R 1A Each is independently selected from D. In some embodiments, each R 1A Each is independently selected from halogens (e.g., -F, -Cl, -Br, -I). In some embodiments, each R 1A Each is independently selected from -CN. In some embodiments, each R 1AEach is independently selected from -NO2. In some embodiments, each R 1A Each is independently selected from -N3. In some embodiments, each R 1A Each is independently selected from the oxo. In some embodiments, each R 1A Each of these is independently -OR a (For example, selected from -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3). In some embodiments, each R 1A These are each independently -NR c R d (For example, selected from -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2OH, -N(CH3)CH2CH2OH).

[0097] In some embodiments, each R 1A Each of these is independently selected from C1-C6 alkyl groups, and can be optionally selected from D, halogen, -CN, -OH, -NH2, oxo, and -NR. c R d , -OR a , -SR a It is substituted with a substituent selected from the following.

[0098] In some embodiments, each R 1A Each of these is independently selected from C2-C6 alkenyl groups, and can be optionally selected from D, halogen, -CN, -OH, -NH2, oxo, and -NR. c R d , -OR a , -SR a It is substituted with a substituent selected from the following.

[0099] In some embodiments, each R 1A Each of these is independently selected from C2-C6 alkynyl groups, and can be optionally selected from D, halogen, -CN, -OH, -NH2, oxo, and -NR. c R d , -OR a , -SR a It is substituted with a substituent selected from the following.

[0100] In some embodiments, each R 1A Each of these is independently selected from C3-C6 cycloalkyl groups (e.g., C3 cycloalkyl group, C4 cycloalkyl group, C5 cycloalkyl group, C6 cycloalkyl group), and optionally D, halogen, -CN, -OH, -NH2, oxo, -NR c R d , -OR a , -SR a , C1-C6 alkyl groups, C 1- It is substituted with a substituent selected from C6 haloalkyl groups.

[0101] In some embodiments, each R 1A Each is independently selected from 4-6 member heterocycloalkyl groups, and optionally D, halogen, -CN, -OH, -NH2, oxo, -NR c R d , -OR a , -SR a The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0102] In some embodiments, each R 2 These are, independently, H, D, -CN, -NO2, -N3, oxo, -SF5, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, -NR C R D , -OR A , -SR A , -NR C Ure 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 Ure F , -OP(O)OR E Ure F Selected from among, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl groups and 5-10 membered heteroaryl groups are optionally R 2A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0103] In some embodiments, each R 2 Each is independently selected from H, D, -CN, -NO2, -N3, oxo, -SF5, and halogen. In some embodiments, each R 2 Each is independently selected from H. In some embodiments, each R 2 Each is independently selected from D. In some embodiments, each R 2 Each is independently selected from -CN. In some embodiments, each R 2 Each is independently selected from -NO2. In some embodiments, each R 2 Each is independently selected from -N3. In some embodiments, each R 2 Each of these is independently selected from -SF5.

[0104] In some embodiments, each R 2 Each is independently selected from halogens. In some embodiments, each R 2 Each is independently selected from -F, -Cl, -Br, or -I. In some embodiments, each R 2 Each is independently selected from -F. In some embodiments, each R 2 Each is independently selected from -Cl. In some embodiments, each R 2 Each is independently selected from -Br. In some embodiments, each R 2 Each is independently selected from -I.

[0105] In some embodiments, each R 2 These are each independently -NR C R D Selected from. In some embodiments, each R 2 Each of these is independently selected from -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -NHCH2CH2CH3, -N(CH2CH2CH3)2, -NHCH(CH3)2, and -NHCH2CH2OH.

[0106] In some embodiments, each R 2 Each of these is independently -OR A Selected from. In some embodiments, each R 2 These are independently -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, [ka] They are selected from among them.

[0107] In some embodiments, each R 2 These are each independently -SR A Selected from. In some embodiments, each R 2 Each is independently selected from -SMe.

[0108] In some embodiments, each R 2 is independently -NR C OR A selected from. In some embodiments, R 2 is -C(O)R B In some embodiments, R 2 is -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2,

Chemical formula

[0109] In some embodiments, each R 2 is independently -C(O)R B selected from.

[0110] In some embodiments, each R 2 is independently -C(O)NR C R D selected from. In some embodiments, R 2 is -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2.

[0111] In some embodiments, each R 2 is independently -C(O)OR A selected from. In some embodiments, each R 2 is independently -OC(O)R B selected from.

[0112] In some embodiments, each R 2 is independently -NR C C(O)R B selected from. In some embodiments, R 2 is -NHC(O)CH3, -NCH3C(O)CH3,

Chemical formula

[0113] In some embodiments, each R 2 is independently selected from -S(O)R B . In some embodiments, each R 2 is independently selected from -S(O)2R B . In some embodiments, each R 2 is independently selected from -S(O)NR C R D . In some embodiments, each R 2 is independently selected from -NR C S(O)2R D . In some embodiments, each R 2 is independently selected from -S(O)2NR C R D . In some embodiments, each R 2 is independently selected from -NR C S(O)2NR C R D . In some embodiments, each R 2 is independently selected from -NR C S(O)(=NR B )R B . In some embodiments, each R 2 is independently selected from -SiR G R H R I . In some embodiments, each R 2 is independently selected from -B(OR C )(OR D ). In some embodiments, each R 2 is independently selected from -P(O)R E R F . In some embodiments, each R 2 is independently selected from -P(O)OR E OR F . In some embodiments, each R 2 is independently selected from -OP(O)OR E OR FThey are selected from among them.

[0114] In some embodiments, each R 2 Each is independently selected from C1-C6 alkyl groups, and R is optionally selected. 2A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, for example, R 2 These include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CD3, -CH2OH, -CH2OMe, -CH2CN, [ka] This includes, but is not limited to, R 2 This is a methyl group or CD3.

[0115] In some embodiments, each R 2 Each is independently selected from the C2-C6 alkenyl group, and R is optionally selected. 2A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0116] In some embodiments, each R 2 Each is independently selected from the C2-C6 alkynyl groups, and R is optionally selected. 2A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, R 2 teeth [ka] That is the case.

[0117] In some embodiments, each R 2 Each of them is independently C3-C 10 Selected from cycloalkyl groups, R is optionally selected. 2A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0118] In some embodiments, each R 2 These are each independently saturated C3-C 10 Cycloalkyl groups or partially saturated C3-C 10 Selected from cycloalkyl groups, each substituent is optionally R 2A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0119] In some embodiments, each R 2 Each of these groups is independently selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and each substituent is optionally R 2A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 2 teeth, [ka] That is the case.

[0120] In some embodiments, each R 2 Each is independently selected from 4-10 member heterocycloalkyl groups, and R is optionally selected. 2A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0121] In some embodiments, each R 2 Each is independently selected from saturated 4-10 member heterocycloalkyl groups or partially saturated 4-10 member heterocycloalkyl groups, and each substituent is optionally R 2A It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given molecules.

[0122] In some embodiments, each R 2 Each of these groups is independently selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, and pyrazolidinyl groups, and each substituent is optionally R 2Ais substituted with 1, 2, 3, 4 or 5 substituents independently selected from each other. In some embodiments, one of the Rs 2 is

Chemical formula

[0123] In some embodiments, each R 2 is independently selected from C6-C 10 aryl groups and is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from each other from R 2A In some embodiments, each R 2 is independently selected from phenyl groups and naphthyl groups, and each substituent is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from each other from R 2A as follows.

[0124] In some embodiments, each R 2 is independently selected from 5- to 10-membered heteroaryl groups and is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from each other from R 2A as follows.

[0125] In some embodiments, each R 2These are, independently, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, tetrazolyl group, pyrazolyl group, triazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, indolyl group, isoindolyl group, indolidinyl group, benzofuranyl group, isobenzofuranyl group, benzo[b]thienyl group, benzo[c]thienyl group, indazolyl group, benzo[d]imidazolyl group, and pyrrolol[3,2-b]py Lysyl group, pyrrolo[3,2-c]pyridyl group, pyrrolo[2,3-c]pyridyl group, pyrrolo[2,3-b]pyridyl group, pyrrolo[3,4-b]pyridyl group, pyrrolo[3,4-c]pyridyl group, benzo[d]isoxazolyl group, benzo[d]oxazolyl group, flo[3,2-b]pyridyl group, flo[3,2-c]pyridyl group, flo[2,3-c]pyridyl group, flo[2,3-b]pyridyl group, benzo[c]isoxazolyl group, flo[3,4-b]pyridyl group, flo[3,4-c]pyridyl group, benzo[ d] isothiazolyl group, benzo[d]thiazolyl group, thieno[3,2-b]pyridyl group, thieno[3,4-c]pyridyl group, benzo[d][1,2,3]triazolyl group, pyrazolo[4,3-b]pyridyl group, pyrazolo[4,3-c]pyridyl group, pyrazolo[3,4-c]pyridyl group, pyrazolo[3,4-b]pyridyl group, imidazo[4,5-b]pyridyl group, imidazo[4,5-c]pyridyl group, imidazo[4,5-b]pyridyl group, pyrrolo[3,2-c]pyridyl group The substituent is selected from dadinyl group, pyrrolo[3,2-d]pyrimidinyl group, pyrrolo[2,3-b]pyridinyl group, pyrrolo[2,3-d]pyridazinyl group, pyrrolo[2,3-d]pyrimidinyl group, pyrrolo[2,3-c]pyridazinyl group, pyrrolo[3,4-c]pyridazinyl group, pyrrolo[3,4-d]pyrimidinyl group, pyrrolo[3,4-b]pyridazinyl group, pyrrolo[3,4-d]pyridazinyl group, pyrrolo[3,4-d]pyrimidinyl group, or 6H-pyrrolo[3,4-c]pyrimidazinyl group, and each substituent is optionally R 2A It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R. In some embodiments, one of R 2 teeth [ka] That is the case.

[0126] In some embodiments, each R 2 Each of these is independently selected from (i) H, D, -CN, or halogen, or (ii) C1-C6 alkyl or 5-10 member heteroaryl group, and each substituent is optionally R 2A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of the following, of which R 2A This is as defined in the present invention. In some embodiments, each R 2 Each of these is independently selected from (i) H, D, or -CN, or (ii) C1-C6 alkyl or 5-membered heteroaryl group, and each substituent is optionally R 2A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of the following, of which R 2A This is as defined in the present invention. In some embodiments, each R 2 Each is independently selected from H, D, -CN, a methyl group, or a 1-methylpyrazolyl group. In some embodiments, each R 2 Each of these is independently selected from either an H group or a methyl group.

[0127] In some embodiments, one of R 2 (i)-CN or halogen, or (ii)C1-C6 alkyl group or 5-10 member heteroaryl group, and each substituent is optionally R 2A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of the following, of which R 2A This is as defined in the present invention. In some embodiments, one of R 2 is -CN, a methyl group, or a 1-methylpyrazolyl group. In some embodiments, one of these R 2 This is a methyl group.

[0128] In some embodiments, one of R 2(i)-CN or halogen, or (ii)C1-C6 alkyl group or 5-10 member heteroaryl group, and each substituent is optionally R 2A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of the following, of which R 2A This is as defined in the present invention, and other R 2 H is H. In some embodiments, one of R is H. 2 is -CN, a methyl group, or a 1-methylpyrazolyl group, and other R 2 H is H. In some embodiments, one of R is H. 2 It is a methyl group, and other R 2 H is H.

[0129] In some embodiments, two R 2 These, together with the atoms linked to them, form oxo, C3-C7 cycloalkyl groups, and 4-7 member heterocycloalkyl groups, of which the above C3-C7 cycloalkyl groups and 4-7 member heterocycloalkyl groups are optionally R 2A They are substituted with one, two, three, or four substituents independently selected from each of them.

[0130] In some embodiments, two R 2 These atoms, along with the atoms they bond to, form an oxo molecule.

[0131] In some embodiments, two R 2 These, together with the atoms linked to them, form a C3-C7 cycloalkyl group, and optionally R 2A They are substituted with one, two, three, or four substituents independently selected from each of them.

[0132] In some embodiments, two R 2 These, together with the atoms linked to them, form a 4-7 member heterocycloalkyl group, and optionally R 2A They are substituted with one, two, three, or four substituents independently selected from each of them.

[0133] In some embodiments, each R2A These are, independently, D, halogen, -CN, -OH, -NH2, -NO2, -SF5, oxo, C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, and C3-C 6シ chloroalkyl groups, 4-6 member heterocycloalkyl groups, phenyl groups, 5-6 member heteroaryl groups, -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 Selected from these, among which the above C1-C4 alkyl groups, C2-C4 alkenyl groups, C2-C4 alkynyl groups, C3-C6 cycloalkyl groups, and 4-6 member heterocycloalkyl groups are optionally D, halogen, -CN, -OH, -NH2, oxo, and -NR. c1 R d1 , -OR a1 , -SR a1 The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0134] In some embodiments, each R 2A Each of these is independently selected from D, halogen, -CN, -OH, -NH2, -NO2, -SF5, and oxo.

[0135] In some embodiments, each R 2A Each of these is independently selected from C1-C4 alkyl groups, and can be optionally selected from D, halogen, -CN, -OH, -NH2, oxo, and -NR. c1 R d1 , -OR a1 , -SR a1 , are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups. In some embodiments, each R 2A Each 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, and -CH2CH2CH2CN.

[0136] In some embodiments, each R 2A Each of these is independently selected from C2-C4 alkenyl groups, and can be optionally selected from D, halogen, -CN, -OH, -NH2, oxo, and -NR. c1 R d1 , -OR a1 , -SR a1 The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0137] In some embodiments, each R 2A Each of these is independently selected from C2-C4 alkynyl groups, and can be optionally selected from D, halogen, -CN, -OH, -NH2, oxo, and -NR. c1 R d1 , -OR a1 , -SR a1The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0138] In some embodiments, each R 2A Each of these is independently selected from C3-C6 cycloalkyl groups, and optionally D, halogen, -CN, -OH, -NH2, oxo, -NR c1 R d1 , -OR a1 , -SR a1 The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0139] In some embodiments, each R 2A Each of these is independently selected from 4-6 member heterocycloalkyl groups, and optionally D, halogen, -CN, -OH, -NH2, oxo, -NR c1 R d1 , -OR a1 , -SR a1 The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0140] In some embodiments, each R 2A Each of these is independently selected from the phenyl group, and optionally D, halogen, -CN, -OH, -NH2, oxo, -NR c1 R d1 , -OR a1 , -SR a1 The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0141] In some embodiments, each R 2A Each of these is independently selected from 5-6 membered heteroaryl groups, and can be optionally D, halogen, -CN, -OH, -NH2, oxo, or -NR. c1 R d1 , -OR a1 , -SR a1 The substituents are substituted with substituents selected from C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0142] In some embodiments, each R 2A These are each independently -NR c R d Selected from. In some embodiments, each R 2A Each of these is independently -OR a Selected from. In some embodiments, each R 2A These are each independently -SR a They are selected from among them.

[0143] In some embodiments, each R 2A These are each independently -C(O)R b Selected from. In some embodiments, each R 2A These are each independently -C(O)NR c R d Selected from. In some embodiments, each R 2A These are each independently -C(O)OR a Selected from. In some embodiments, each R 2A These are each independently -OC(O)R b Selected from. In some embodiments, each R 2A These are each independently -OC(O)NR c R d They are selected from among them.

[0144] In some embodiments, each R 2A These are each independently -NR c C(O)R b Selected from. In some embodiments, each R 2A These are each independently -NR c C(O)NR c R d Selected from. In some embodiments, each R 2A These are each independently -NR c C(O)OR a They are selected from among them.

[0145] In some embodiments, each R 2A These are -S(O)(=NR) independently of each other. b )R bSelected from. In some embodiments, each R 2A These are each independently -S(O)R b Selected from. In some embodiments, each R 2A These are each independently -S(O)NR c R d Selected from. In some embodiments, each R 2A These are each independently -S(O)2R b Selected from. In some embodiments, each R 2A These are each independently -NR c S(O)2R d Selected from. In some embodiments, each R 2A These are each independently -S(O)2NR c R d Selected from. In some embodiments, each R 2A These are each independently -NR c S(O)2NR c R d Selected from. In some embodiments, each R 2A These are each independently -NR c S(O)(=NR b )R b They are selected from among them.

[0146] In some embodiments, R 3 is C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 14 Cycloalkyl groups, 4-14 member heterocycloalkyl groups, C6-C 10 The aryl group is a 5- to 14-membered heteroaryl group, of which the above C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 14 Cycloalkyl groups, 4-14 member heterocycloalkyl groups, C6-C 10 Aryl groups and 5-14 membered heteroaryl groups can be optionally selected as R 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0147] In some embodiments, R 3 is C1-C 10 It is an alkyl group, and R is optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from. In some embodiments, R 3 is a C1-C8 alkyl group, and R is optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from. In some embodiments, R 3 is a C1-C6 alkyl group, and R is optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0148] In some embodiments, R 3 is C2-C 10 It is an alkenyl group, and R is optionally selected 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0149] In some embodiments, R 3 is C2-C 10 It is an alkynyl group, and R is optionally selected 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0150] In some embodiments, R 3 is C3-C 14 It is a cycloalkyl group, and R is optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0151] In some embodiments, R 3 R is a 4-14 member heterocycloalkyl group, and R is optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0152] In some embodiments, R 3 is C6-C 14It is an aryl group, and R is optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from. In some embodiments, R 3 These are a phenyl group, a naphthyl group, an anthracenyl group, and a phenantrenyl group, and each substituent is optionally R 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0153] In some embodiments, R 3 It is a 5-14 member heteroaryl group, and R can be optionally selected. 4 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0154] In some embodiments, R 3 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2 CH(OH)CH2CH3, -CH2CH2CH(CH3)OH, -CH2CH2C(CH3)2OH, -CH2CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2COOH, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, [ka] That is the case.

[0155] In some embodiments, each R 4 Each is independently selected from H, D, halogen, -CN, -NO2, -N3, and oxo. In some embodiments, each R 4 Each is independently selected from H. In some embodiments, each R 4 Each is independently selected from D. In some embodiments, each R 4Each is independently selected from halogens (e.g., -F, -Cl, -Br, or -I). In some embodiments, each R 4 Each is independently selected from -CN. In some embodiments, each R 4 Each is independently selected from -NO2. In some embodiments, each R 4 Each of these is independently selected from -N3.

[0156] In some embodiments, one of R 4 -NR C R D In some embodiments, one of the R 4 These are -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, and -N(CH2CH3)2.

[0157] In some embodiments, one of R 4 は-OR A In some embodiments, one of the R 4 -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCF2CF3, -OCH2CH2OH, -OCH2CH2OCH3, -OTBS, -OTMS, [ka] That is the case.

[0158] In some embodiments, one of R 4 Ha-SR A In some embodiments, one of the R 4 -NR C Ure A That is the case.

[0159] In some embodiments, one of R 4 is C(O)R B In some embodiments, one of the R4 -C(O)CH3, -C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)2, [ka] Each ring is optionally 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 ) is substituted with 1, 2, 3, 4, or 5 substituents independently selected from ).

[0160] In some embodiments, one of R 4 -C(O)NR C R D In some embodiments, one of the R 4 -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, [ka] That is the case.

[0161] In some embodiments, one of R 4 is -C(O)OR A In some embodiments, one of the R 4 These are -C(O)OH, -C(O)OCH3, and -C(O)OCH2CH3.

[0162] In some embodiments, one of R 4 -OC(O)R B In some embodiments, one of the R 4 -OC(O)NR C R D That is the case.

[0163] In some embodiments, one of R 4 -NR C C(O)R B In some embodiments, one of the R 4 -NR C C(O)NR C R D In some embodiments, one of the R 4 -NR C C(O)OR A That is the case.

[0164] In some embodiments, one of R 4 -S(O)R B In some embodiments, one of the R 4 -S(O)2R B In some embodiments, one of the R 4 -S(O)NR C R D In some embodiments, one of the R 4 -NR C S(O)2R D In some embodiments, one of the R 4 -S(O)2NR C R DIn some embodiments, one of the R 4 -NR C S(O)2NR C R D In some embodiments, one of the R 4 -NR C S(O)(=NR B )R B That is the case.

[0165] In some embodiments, one of R 4 -SiR G R H R I In some embodiments, one of the R 4 is -B(OR C )(OR D ) is. In some embodiments, one of R 4 -P(O)R E R F That is the case.

[0166] In some embodiments, each R 4 Each is independently selected from C1-C6 alkyl groups, and R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from R. In some embodiments, each R 4 Each of these is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, and -C(CH3)3, and each substituent is arbitrarily selected from R 5 They are substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given set.

[0167] In some embodiments, each R 4 Each is independently selected from the C2-C6 alkenyl group, and R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from R. In some embodiments, each R 4Each of these is independently selected from -CH=CH2, -CH=CHCH3, and -CH2CH=CH2, and each substituent is arbitrarily selected from R 5 They are substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given set.

[0168] In some embodiments, each R 4 Each is independently selected from the C2-C6 alkynyl groups, and R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from R. In some embodiments, each R 4 Each of these is independently selected from -C≡CH and -C≡CCH3, and each substituent is arbitrarily selected from R 5 They are substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given set.

[0169] In some embodiments, each R 4 These are each independently C6-C 10 Selected from aryl groups, R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from R. In some embodiments, each R 4 Each of these groups is independently selected from a phenyl group and a naphthyl group, and each substituent is optionally R 5 They are substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the given set.

[0170] In some embodiments, each R 4 Each of them is independently C3-C 10 Selected from cycloalkyl groups, R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 4 Each of these groups is independently selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and each substituent is optionally R 5 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R4 These are, independently, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. [ka] They are selected from among them.

[0171] In some embodiments, each R 4 Each is independently selected from 5-10 membered heteroaryl groups, and R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 4 The substituents are pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, and indolyl groups, and each substituent is optionally R 5 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 4 teeth, [ka] That is the case.

[0172] In some embodiments, each R 4 Each is independently selected from 4-10 member heterocycloalkyl groups, and R is optionally selected. 5 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 4 The substituents are azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, piperidinyl group, dioxanyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, piperazinyl group, morpholinyl group, azepanyl group, diazocanyl group, and 1,4-diazepanyl group, and each substituent is optionally R 5It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each of them. In some embodiments, one of the R 4 teeth, [ka] That is the case.

[0173] In some embodiments, two R 4 These atoms, along with the atoms they bond to, form an oxo molecule.

[0174] In some embodiments, two R 4 These, together with the atoms linked to them, form C3-C6 cycloalkyl groups and 4-6 member heterocycloalkyl groups, and each ring is optionally R 5 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0175] In some embodiments, two R 4 along with the atoms that are linked to them [ka] It forms.

[0176] In some embodiments, each R 5 Each is independently selected from D, -CN, halogen, -NO2, -SF5, and oxo. In some embodiments, each R 5 Each is independently selected from D. In some embodiments, each R 5 Each is independently selected from -CN. In some embodiments, each R 5 Each is independently selected from halogens (e.g., -F, -Cl, -Br, or -I). In some embodiments, each R 5 Each is independently selected from -NO2. In some embodiments, each R 5 Each is independently selected from -SF5. In some embodiments, each R 5 Each is independently selected from the oxo.

[0177] In some embodiments, each R 5 Each of these is independently selected from selectively substituted C1-C6 alkyl groups.

[0178] In some embodiments, each R 5 Each of these is independently selected from the selectively substituted C2-C6 alkenyl groups.

[0179] In some embodiments, each R 5 Each of these is independently selected from the selectively substituted C2-C6 alkynyl groups.

[0180] In some embodiments, each R 5 Each of these is independently selected from selectively substituted C3-C6 cycloalkyl groups.

[0181] In some embodiments, each R 5 Each of these is independently selected from selectively substituted 4- to 6-membered heterocycloalkyl groups.

[0182] In some embodiments, each R 5 Each of these is independently -OR a Selected from. In some embodiments, each R 5 These are each independently -SR a They are selected from among them.

[0183] In some embodiments, each R 5 These are each independently -C(O)R b Selected from. In some embodiments, each R 5 These are each independently -C(O)NR c R d Selected from. In some embodiments, each R 5 These are each independently -C(O)OR a Selected from. In some embodiments, each R 5 These are each independently -OC(O)R b Selected from. In some embodiments, each R 5These are each independently -OC(O)NR c R d They are selected from among them.

[0184] In some embodiments, each R 5 These are each independently -NR c R d Selected from. In some embodiments, one of R 5 is -NH2, -NH(CH3), or -N(CH3)2. In some embodiments, each R 5 These are each independently -NR c C(O)R b Selected from. In some embodiments, each R 5 These are each independently -NR c C(O)NR c R d Selected from. In some embodiments, each R 5 These are each independently -NR c C(O)OR a They are selected from among them.

[0185] In some embodiments, each R 5 These are -S(O)(=NR) independently of each other. b )R b Selected from. In some embodiments, each R 5 These are each independently -S(O)R b Selected from. In some embodiments, each R 5 These are each independently -S(O)NR c R d Selected from. In some embodiments, each R 5 These are each independently -S(O)2R b Selected from. In some embodiments, each R 5 These are each independently -NR c S(O)2R d Selected from. In some embodiments, each R 5 These are each independently -S(O)2NR c R d Selected from. In some embodiments, each R 5These are each independently -NR c S(O)2NR c R d Selected from. In some embodiments, each R 5 These are each independently -NR c S(O)(=NR b )R b They are selected from among them.

[0186] In some embodiments, each R A Each is independently selected from H. In some embodiments, each R A Each of them is independently selected from D.

[0187] In some embodiments, each R A These are, independently, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, can optionally be 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 Ure f , -OP(O)OR e Ure 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 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the given molecule.

[0188] In some embodiments, one of R A -SiRG R H R I In some embodiments, one of the R A Ha-TMS, [ka] That is the case.

[0189] In some embodiments, each R Bは Each is independently selected from H. In some embodiments, each R Bは Each is independently selected from D.

[0190] In some embodiments, each R Bは Each is independently a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, can optionally be 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 ) is substituted with 1, 2, 3, 4, or 5 substituents independently selected from ).

[0191] In some embodiments, R C and R D Each is independently selected from H. In some embodiments, R C and R D Each of them is independently selected from D.

[0192] In some embodiments, R C and R D These are, independently, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, can optionally be 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 ) is substituted with 1, 2, 3, 4, or 5 substituents independently selected from ).

[0193] In some embodiments, R C and R D These atoms, together with the N atoms linked to them, form a 4- to 7-membered heterocycloalkyl group and are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -OH, oxo, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 cyanoalkyl group, -OC1-C4 alkyl group, or -OC1-C4 haloalkyl group.

[0194] In some embodiments, each R a Each is independently selected from H. In some embodiments, each R a Each of them is independently selected from D.

[0195] In some embodiments, each R a These are, independently, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, halogen, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, C1-C4 alkyl group, -OC1-C4 alkyl group, C1-C4 haloalkyl group, or -OC1-C4 haloalkyl group.

[0196] In some embodiments, each R a1 Each is independently selected from H. In some embodiments, each R a1 Each of them is independently selected from D.

[0197] In some embodiments, each R a1These are, independently, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 A cycloalkyl-C1-C6 alkyl group, or a 4-10 member heterocycloalkyl-C1-C6 alkyl group, is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, halogen, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, C1-C4 alkyl group, -OC1-C4 alkyl group, C1-C4 haloalkyl group, or -OC1-C4 haloalkyl group.

[0198] In some embodiments, each R b R is independently selected from H. In some embodiments, each R b It is selected independently from D.

[0199] In some embodiments, each R b These are independently C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, or 4-10 membered heterocycloalkyl-C1-C6 alkyl groups, can optionally include D, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, and C6-C 10 Aryl group, C3-C 10 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups.

[0200] In some embodiments, each R b1 R is independently selected from H. In some embodiments, each R b1 It is selected independently from D.

[0201] In some embodiments, each R b1 These are independently C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10Selected from cycloalkyl-C1-C6 alkyl groups or 4-10 member heterocycloalkyl-C1-C6 alkyl groups, of which the above C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, or 4-10 membered heterocycloalkyl-C1-C6 alkyl groups, can optionally include D, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, and C6-C 10 Aryl group, C3-C 10 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups.

[0202] In some embodiments, R c and R d Each is independently selected from H. In some embodiments, R c and R d Each of them is independently selected from D.

[0203] In some embodiments, R c and R d These are, independently, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10Cycloalkyl-C1-C6 alkyl groups, 4-10 member heterocycloalkyl-C1-C6 alkyl groups, C6-C 10 Aryl-C3-C 10 Cycloalkyl groups, C6-C 10 Aryl-4 to 10-membered heterocycloalkyl groups, C6-C 10 Aryl-5~10 member heteroaryl group, bis(C6-C 10 Aryl group), 5-10 member heteroaryl-C3-C 10 Cycloalkyl group, 5-10 member heteroaryl group - 4-10 member heterocycloalkyl group, 5-10 member heteroaryl group - C6-C 10 Selected from aryl groups or bis (5-10 membered heteroaryl groups), among which the above C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, 4-10 member heterocycloalkyl-C1-C6 alkyl groups, C6-C 10 Aryl-C3-C 10 Cycloalkyl groups, C6-C 10 Aryl-4 to 10-membered heterocycloalkyl groups, C6-C 10 Aryl-5~10 member heteroaryl group, bis(C6-C 10 Aryl group), 5-10 member heteroaryl-C3-C 10 Cycloalkyl group, 5-10 member heteroaryl group - 4-10 member heterocycloalkyl group, 5-10 member heteroaryl group - C6-C 10 The aryl group or bis(5-10 membered heteroaryl group) can be optionally D, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, C1-C4 hydroxyalkyl group, C1-C4 cyanoalkyl group, C6-C 10Aryl group, 5-10 membered heteroaryl group, -C(O)OR a1 , -C(O)R b1 -S(O)2R b1 The molecule is substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C4alkyl-O-C1-C4alkyl groups and C1-C4alkyl-O-C1-C4alkyl-O- groups.

[0204] In some embodiments, R c and R d These, together with the N atoms linked to them, form 4-7 member heterocycloalkyl groups, and optionally, D, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, C1-C4 hydroxyalkyl group, C1-C4 cyanoalkyl group, C6-C 10 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from an aryl group, a 5- to 10-membered heteroaryl group, a C1-C4 alkoxy-C1-C4 alkyl group, or a C1-C4 alkoxy-C1-C4 alkoxy group.

[0205] In some embodiments, R c1 and R d1 Each is independently selected from H. In some embodiments, R c1 and R d1 Each of them is independently selected from D.

[0206] In some embodiments, R c1 and R d1 These are, independently, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10Cycloalkyl-C1-C6 alkyl groups, 4-10 member heterocycloalkyl-C1-C6 alkyl groups, C6-C 10 Aryl-C3-C 10 Cycloalkyl groups, C6-C 10 Aryl-4 to 10-membered heterocycloalkyl groups, C6-C 10 Aryl-5~10 member heteroaryl group, bis(C6-C 10 Aryl group), 5-10 member heteroaryl-C3-C 10 Cycloalkyl group, 5-10 member heteroaryl group - 4-10 member heterocycloalkyl group, 5-10 member heteroaryl group - C6-C 10 Selected from aryl groups or bis (5-10 membered heteroaryl groups), among which the above C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, C6-C 10 Aryl-C1-C6 alkyl group, 5-10 member heteroaryl-C1-C6 alkyl group, C3-C 10 Cycloalkyl-C1-C6 alkyl groups, 4-10 member heterocycloalkyl-C1-C6 alkyl groups, C6-C 10 Aryl-C3-C 10 Cycloalkyl groups, C6-C 10 Aryl-4 to 10-membered heterocycloalkyl groups, C6-C 10 Aryl-5~10 member heteroaryl group, bis(C6-C 10 Aryl group), 5-10 member heteroaryl-C3-C 10 Cycloalkyl group, 5-10 member heteroaryl group - 4-10 member heterocycloalkyl group, 5-10 member heteroaryl group - C6-C 10 The aryl group or bis(5-10 membered heteroaryl group) can be optionally D, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, C1-C4 hydroxyalkyl group, C1-C4 cyanoalkyl group, C6-C 10Aryl group, 5-10 membered heteroaryl group, C(O)OR a1 , C(O)R b1 S(O)2R b1 The molecule is substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C4alkyl-O-C1-C4alkyl groups and C1-C4alkyl-O-C1-C4alkyl-O- groups.

[0207] In some embodiments, R c1 and R d1 These, together with the N atoms linked to them, form 4-7 member heterocycloalkyl groups, and optionally, D, -OH, -CN, -NH2, -NH(C1-C4 alkyl group), -N(C1-C4 alkyl group)2, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, C1-C4 hydroxyalkyl group, C1-C4 cyanoalkyl group, C6-C 10 It is substituted with 1, 2, 3, 4, or 5 substituents independently selected from an aryl group, a 5- to 10-membered heteroaryl group, a C1-C4 alkoxy-C1-C4 alkyl group, or a C1-C4 alkoxy-C1-C4 alkoxy group.

[0208] In some embodiments, each R E These are selected independently from H and D.

[0209] In some embodiments, each R E These are, independently, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkenyl group, a (C1-C4 alkoxy)-C1-C4 alkyl group, a C2-C4 alkynyl group, and a C6-C 10 Aryl group, 5-10 membered heteroaryl group, C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl-C1-C4 alkyl groups, C3-C 10 Selected from cycloalkyl-C1-C4 alkyl groups, 5-10 member heteroaryl-C1-C4 alkyl groups, or 4-10 member heterocycloalkyl-C1-C4 alkyl groups.

[0210] In some embodiments, each R F These are selected independently from H and D.

[0211] In some embodiments, each R F These are, independently, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and a C6-C 10 Aryl group, 5-10 membered heteroaryl group, C3-C 10 Selected from cycloalkyl groups or 4- to 10-membered heterocycloalkyl groups.

[0212] In some embodiments, each R e These are selected independently from H and D.

[0213] In some embodiments, each R e These are, independently, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkenyl group, a (C1-C4 alkoxy)-C1-C4 alkyl group, a C2-C4 alkynyl group, and a C6-C 10 Aryl group, 5-10 membered heteroaryl group, C3-C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C6-C 10 Aryl-C1-C4 alkyl groups, C3-C 10 Selected from cycloalkyl-C1-C4 alkyl groups, 5-10 member heteroaryl-C1-C4 alkyl groups, or 4-10 member heterocycloalkyl-C1-C4 alkyl groups.

[0214] In some embodiments, each R f These are selected independently from H and D.

[0215] In some embodiments, each R f These are, independently, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and a C6-C 10 Aryl group, 5-10 membered heteroaryl group, C3-C 10 Selected from cycloalkyl groups or 4- to 10-membered heterocycloalkyl groups.

[0216] In some embodiments, R G , R H and R I Each is independently selected from a selectively substituted C1-C4 alkyl group or a selectively substituted phenyl group.

[0217] In some embodiments, R G R is a selectively substituted C1-C4 alkyl group (e.g., C1 alkyl group, C2 alkyl group, C3 alkyl group, C4 alkyl group) or a phenyl group. In some embodiments, R G These are methyl groups, ethyl groups, propyl groups (e.g., n-propyl groups, i-propyl groups), butyl groups (n-butyl groups, i-butyl groups, t-butyl groups), or phenyl groups.

[0218] In some embodiments, R H R is a selectively substituted C1-C4 alkyl group (e.g., C1 alkyl group, C2 alkyl group, C3 alkyl group, C4 alkyl group) or a phenyl group. In some embodiments, R H These are methyl groups, ethyl groups, propyl groups (e.g., n-propyl groups, i-propyl groups), or butyl groups (n-butyl groups, i-butyl groups, t-butyl groups), or phenyl groups.

[0219] In some embodiments, R I R is a selectively substituted C1-C4 alkyl group (e.g., C1 alkyl group, C2 alkyl group, C3 alkyl group, C4 alkyl group) or a phenyl group. In some embodiments, R I These are methyl groups, ethyl groups, propyl groups (e.g., n-propyl groups, i-propyl groups), or butyl groups (n-butyl groups, i-butyl groups, t-butyl groups), or phenyl groups.

[0220] In some embodiments, the compound represented by formula (I) is represented by formula (IIa), (IIb), or (IIc), [ka] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, X 1 , X 2 , X 3 , X 4 These are N or CR, respectively, independently. 2 Selected from, Eventually, R 1 , R 2 , R 3 And m are as defined in formula (I) of the present invention.

[0221] In some embodiments, the compound represented by formula (I) is represented by formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg), [ka] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, Eventually, R 1 , R 2 , R 3 And m are as defined in formula (I) of the present invention.

[0222] In some embodiments, the compound represented by formula (I) is represented by formulas (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), or (IVg), [ka] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, Y 3 is N or CR 1 And, Eventually, R 1 , R 2 , R 3 And m are as defined in formula (I) of the present invention.

[0223] In some embodiments, the compound represented by formula (I) above is [Table 1] TIFF2026516662000077.tif234157 or a pharmaceutically acceptable salt thereof.

[0224] The present invention further provides a pharmaceutical composition comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0225] The present invention further provides a method for treating or preventing PolQ overexpression cancer, comprising administering a therapeutically effective amount of the compound described in the present invention, or a pharmaceutical composition containing the compound described in the present invention, to the patient.

[0226] The present invention further provides a method for treating or preventing cancer, wherein the characteristic of the cancer is increased dependence on MMEJ-DSB repair, and the method comprises administering a therapeutically effective amount of a compound described in the present invention, or a pharmaceutical composition containing a compound described in the present invention, to the patient.

[0227] The present invention further provides a method for treating or preventing cancer, wherein the cancer is characterized by HR deficiency, decreased or deleted expression of HR-related genes, and the method comprises administering a therapeutically effective amount of a compound described in the present invention, or a pharmaceutical composition containing a compound described in the present invention, to the patient.

[0228] The present invention further provides a method for treating or preventing cancer, wherein the cancer is characterized by a deficiency of the 53BP1 / Shieldin complex, and the method comprises administering to a patient a therapeutically effective amount of the compound described in the present invention, or a pharmaceutical composition containing the compound described in the present invention.

[0229] The present invention further provides a method for treating or preventing cancer, wherein the cancer is either treated with or not treated with a PARPi drug, is drug-resistant to PARPi treatment, and comprises administering to the patient a therapeutically effective amount of a compound described in the present invention, or a pharmaceutical composition containing a compound described in the present invention.

[0230] The present invention further provides a method for treating or preventing cancer, wherein the cancer is characterized by NHEJ deficiency, decreased or deleted expression of NHEJ-related genes, and the method comprises administering a therapeutically effective amount of a compound described in the present invention, or a pharmaceutical composition containing a compound described in the present invention, to the patient.

[0231] The present invention further provides applications of the compounds described in the present invention or the pharmaceutical compositions described above in the manufacture of drugs for treating PolQ overexpression disorders.

[0232] The present invention further provides applications of the above-mentioned compound or pharmaceutical composition in the manufacture of drugs for treating diseases that increase dependence on MMEJ-DSB repair.

[0233] The present invention further provides applications of the above compound or pharmaceutical composition in the manufacture of drugs for treating cancer, wherein the characteristics of the cancer are HR deficiency, decreased or deleted expression of HR-related genes.

[0234] The present invention further provides applications of the above compound or pharmaceutical composition in the manufacture of a drug for treating cancer, wherein the cancer is characterized by a deficiency of the 53BP1 / Shieldin complex.

[0235] The present invention provides applications of the above compound or pharmaceutical composition in the manufacture of a drug for treating cancer, further providing applications in which the cancer is treated with or not treated with a PARPi drug and is drug-resistant to PARPi treatment.

[0236] The present invention further provides applications of the above compound or pharmaceutical composition in the manufacture of drugs for treating cancer, wherein the cancer is characterized by NHEJ deficiency, decreased or deleted expression of NHEJ-related genes.

[0237] definition Unless otherwise specified, the following terms have the meanings set forth below. Other terms are defined elsewhere in this specification.

[0238] Unless otherwise specified in the context, the singular forms “1(a),” “an,” and “the” as used herein include multiple subjects. It should also be noted that claims can be drafted to exclude any optional element. Accordingly, this description aims to provide a prior basis relating to the use of such exclusive terms, such as “only,” “only,” etc., in reference to claim elements or “negative” restrictions.

[0239] In different parts of this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both forward and reverse forms of the linking substituent. For example, -NR(CR'R'')- includes -NR(CR'R'')- and -(CR'R'')NR-, and the purpose is to disclose each form separately. Where a structure requires a linking group, the Markousch variables listed for that group are understood as linking groups. For example, if a structure requires a linking group and the Markousch group definition for that variable lists "alkyl group" or "aryl group," it should be understood that "alkyl group" or "aryl group" represents a linked alkylene group or arylene group, respectively.

[0240] The term "substituted" means that one atom or group of atoms replaces a hydrogen atom and is linked to another group as a "substituent." Unless otherwise specified, the term "substitution" refers to any number of substitutions, such as mono-, di-, tri-, tetra-, or penta-substitutions, where such substitutions are permitted. Substituents are independently selected and may be substituted at any chemically possible position. It should be understood that substitutions at a particular atom are limited by its 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, for example, oxo, can substitute two hydrogen atoms.

[0241] The term "Cn-Cm" represents a range including the above endpoints, where n and m are integers representing the number of carbon atoms. For example, the term "C1-C6 alkyl group" specifically refers to methyl, ethyl, C3, C4, C5, and C6 alkyl groups. "C0 alkyl group" refers to a covalent bond or H.

[0242] The compounds of the present invention are stable. As used herein, “stable” means that the compound is sufficiently stable during the process of separation from the reaction mixture to a useful purity, and preferably, that the compound can be prepared into an effective therapeutic agent.

[0243] It should also be understood that, for clarity, some features of the present invention described in the context of a single embodiment may be provided in combination with a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment may be provided individually or in any suitable subcombination.

[0244] As used herein, unless otherwise specified, the term “alkyl group” refers to a linear or branched saturated hydrocarbon group, either by itself or as part of another substituent. 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, for example, C 1-2 Alkyl alkyl group, C 1-3 Alkyl alkyl group, C 1-4 Alkyl alkyl group, C 1-5 Alkyl alkyl group, C 1-6 Alkyl alkyl group, C 1-7 Alkyl alkyl group, C 1-8 Alkyl alkyl group, C 1-9 Alkyl alkyl group, C 1-10 Alkyl alkyl group, C 2-3 Alkyl alkyl group, C 2-4 Alkyl alkyl group, C 2-5 Alkyl alkyl group, C 2-6 Alkyl alkyl group, C 3-4 Alkyl alkyl group, C 3-5 Alkyl alkyl group, C 3-6 Alkyl alkyl group, C 4-5 Alkyl alkyl group, C 4-6 Alkyl alkyl group, C 5-6 It is an alkyl group. Similarly, C 1-8 , C 1-8 Alkyl groups are defined as groups arranged in a linear or branched chain and having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, and tert-butyl), pentyl (e.g., n-pentyl, isopentyl, and neopentyl), hexyl, heptyl, and octyl groups.

[0245] As used herein, unless otherwise specified, “alkenyl group” refers to an alkyl group having one or more carbon-carbon double bonds. Exemplary alkenyl groups include, but are not limited to, vinyl groups and propenyl groups. An alkenyl group may contain any number of carbon atoms, for example, C2-3 Alkenyl group, C 2-4 Alkenyl group, C 2-5 Alkenyl group, C 2-6 Alkenyl group, C 2-7 Alkenyl group, C 2-8 Alkenyl group, C 2-9 Alkenyl group, C 2-10 Alkenyl group, C 3-4 Alkenyl group, C 3-5 Alkenyl group, C 3-6 Alkenyl group, C 4-5 Alkenyl group, C 4-6 Alkenyl group and C 5-6 The group is an alkenyl group. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl groups. The one or more carbon-carbon double bonds may be located in the chain (e.g., 2-butene) or at the terminal (e.g., 1-butene).

[0246] As used herein, unless otherwise specified, “alkynyl group” refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl and propynyl groups. An alkynyl group may contain any number of carbon atoms, for example, C 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 5-6 This is an alkynyl group. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl groups. The one or more carbon-carbon triple bonds may be located in the chain (e.g., 2-butyne) or at the terminal (e.g., 1-butyne).

[0247] As used herein, unless otherwise specified, “haloalkyl group” refers to an alkyl group having one or more halogen substituents. Exemplary haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0248] As used herein, unless otherwise specified, “aryl group” refers to an unsubstituted or substituted monocyclic or polycyclic (e.g., having two, three, or four fused rings) aromatic hydrocarbon. 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, anthracenyl, phenantrenyl, indanyl, and indenyl groups.

[0249] As used herein, unless otherwise specified, “cycloalkyl group” refers to an unsubstituted or substituted non-aromatic carbon ring, and includes cyclized alkyl groups, alkenyl groups, and alkynyl groups. Cycloalkyl groups include monocyclic- or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including fused rings, spiro rings, and crosslinking rings (e.g., crosslinking ring bicycloalkyl groups). In some embodiments, cycloalkyl groups 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. Cycloalkyl groups may further have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. Cycloalkyl groups may optionally be substituted with oxo or thio (e.g., -C(O)- or -C(S)-). The definition of a cycloalkyl group further includes a group having one or more aromatic rings condensed with (i.e., having a common bond with) the cycloalkyl group, such as benzo derivatives of cyclopentyl, cyclopentenyl, and cyclohexyl groups. A cycloalkyl group having one or more condensed aromatic rings can be linked via an aromatic ring moiety or a non-aromatic ring moiety. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form, for example, oxo or thio substituents. In some embodiments, the cycloalkyl group is selected from C3-C7 monocyclic cycloalkyl groups. In some embodiments, the cycloalkyl group is C 4- C 10The cycloalkyl group is selected from a spiro ring or a crosslinked ring cycloalkyl group. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norbornyl, norbornyl, cubenyl, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, and spiro[3.3]heptyl groups. In some embodiments, the cycloalkyl group is selected from a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In some embodiments, the cycloalkyl group is a non-aromatic hydrocarbon group containing a ring, with 3 to 12 carbon atoms ("C3-C"). 12 It has a cycloalkyl group, preferably having 3 to 6 carbon atoms ("C3-C6"). Examples of cycloalkyl groups include, for example, a cyclopropyl group (C3, 3-membered), a cyclobutyl group (C4, 4-membered), a cyclopropylmethyl group (C4), a cyclopentyl group (C5), a cyclohexyl group (C6), a 1-methylcyclopropyl group (C4), a 2-methylcyclopentyl group (C4), and an adamantyl group (C 10 ) and others.

[0250] The term "spirocycloalkyl group," when used alone or as part of a substituent, refers to a non-aromatic cyclic hydrocarbon group containing two cycloalkyl groups, of which typically the two cycloalkyl groups share one carbon atom.

[0251] As used herein, unless otherwise specified, “heteroaryl group” refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member, e.g., boron, sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having two, three, or four 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, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, prinyl, carbazolyl, benzimidazolyl, and indolinyl groups. In some embodiments, the heteroaryl groups have 1 to about 20 carbon atoms, and in some further embodiments, they have 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0252] As used herein, unless otherwise specified, “heterocycloalkyl group” means an unsubstituted or substituted monocyclic (saturated or partially unsaturated) or polycyclic heterocyclic group having at least one non-aromatic ring (saturated or partially unsaturated), of which one or more ring-forming carbon atoms may be substituted with heteroatoms selected from N, O, S, Si, and B, and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted with one or more oxo or thio atoms (e.g., C(O), S(O), C(S), or S(O)2). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyl groups include monocyclic and polycyclic 3-10 member, 4-10 member, 3-7 member, 4-7 member, and 5-6 member heterocycloalkyl groups. The heterocycloalkyl group further comprises a spiro ring and a crosslinking ring (for example, a 5-10 membered crosslinking ring biheterocycloalkyl group in which one or more of the ring-forming carbon atoms are substituted with heteroatoms independently selected from N, O, S, Si, and B). The heterocycloalkyl group can be linked via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0-3 double bonds. In some embodiments, the heterocycloalkyl group contains 0-2 double bonds.

[0253] The above heterocycloalkyl group further includes a group having one or more aromatic rings fused to the above non-aromatic heterocycle (i.e., having a common bond with the heterocycloalkyl group), such as piperidine, morpholine, or benzo or thieno derivatives of azepane. The heterocycloalkyl group containing the fused aromatic ring can be linked via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring. In some embodiments, the above heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the above heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the above heterocycloalkyl group is a monocyclic 4 to 6-membered heterocycloalkyl group having one or two heteroatoms independently selected from N, O, S, and B, and simultaneously having one or more ring atoms substituted with oxo.

[0254] Exemplary heterocycloalkyl groups include pyrrolidine-2-one, 1,3-isoxazolidine-2-one, pyranyl group, tetrahydropyranyl group, oxetanyl group, azetidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, piperidinyl group, pyrrolidinyl group, isoxazolidinyl group, isothiazolidinyl group, pyrazolidinyl group, oxazolidinyl group, thiazolidinyl group, and imidazolidinyl group. , azepanyl group, benzazapentenyl group, 1,2,3,4-tetrahydroisoquinolyl group, azabicyclo[3.1.0]hexyl group, diazabicyclo[3.1.0]hexyl group, oxabicyclo[2.1.1]hexyl group, azabicyclo[2.2.1]heptyl group, diazabicyclo[2.2.1]heptyl group, azabicyclo[3.1.1]heptyl group, diazabicyclo[3.2.1]heptyl group, azabicyclo[3. 2.1]octyl group, oxabicyclo[2.2.2]octyl group, azabicyclo[2.2.2]octyl group, diazabicyclo[2.2.2]octyl group, azaadamantyl group, diazadamantyl group, oxadamantyl group, azaspiro[3.3]heptyl group, azaspiro[3.3]heptyl group, oxa-azaspiro[3.3]heptyl group, azaspiro[3.4]octyl group, diazaspiro[3.4]octyl group, oxa-azaspiro[3.4]octyl group, o This includes, but is not limited to, xa-azaspiro[3,5]nonyl group, azaspiro[2,5]octyl group, diazaspiro[2,5]octyl group, azaspiro[4,4]nonyl group, diazaspiro[4,4]nonyl group, oxa-azaspiro[4,4]nonyl group, azaspiro[4,5]decyl group, diazaspiro[4,5]decyl group, diazaspiro[4,4]nonyl group, oxa-diazaspiro[4,4]nonyl group, octahydropyrrolo[3,4-c]pyrrolyl group, etc.

[0255] In some embodiments, a heterocycloalkyl 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 heterocycloalkyl group can be linked via any heteroatom or carbon atom, provided that it has a stable structure that can be produced. Exemplary heterocycloalkyl groups include, but are not limited to, azepanyl, azilidinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperadinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxylanyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and piperadinyl groups.

[0256] In some embodiments, the term “spiroheterocycloalkyl group,” when used alone or as part of a substituent, refers to a non-aromatic ring comprising two rings, where at least one ring is selected from a heterocycloalkyl group and the two rings share one carbon atom.

[0257] As used herein, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0258] As used herein, unless otherwise specified, “alkoxy group” refers to an -O-alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy groups.

[0259] As used herein, unless otherwise specified, “hydroxyalkyl group” refers to an alkyl group substituted with an OH group.

[0260] As used herein, unless otherwise specified, “cyanoalkyl group” refers to an alkyl group substituted with CN.

[0261] As used herein, unless otherwise specified, “alkoxyalkyl group” refers to an alkyl group substituted with an alkoxy group.

[0262] As used herein, unless otherwise specified, “haloalkoxy group” refers to an -O-(haloalkyl group).

[0263] As used herein, unless otherwise specified, “arylalkyl group” refers to an alkyl group substituted with an aryl group, and “cycloalkyl group” refers to an alkyl group substituted with a cycloalkyl group. An exemplary arylalkyl group is the benzyl group.

[0264] As used herein, unless otherwise specified, “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group, and “heterocycloalkylalkyl” refers to an alkyl group substituted with a heterocycloalkyl group.

[0265] As used herein, unless otherwise specified, “oxo” refers to an oxygen substituent (i.e., =O) linked via a double bond.

[0266] As used herein, unless otherwise specified, the term “optionally substituted” above means either non-substituted or substituted.

[0267] As used herein, unless otherwise specified, the term “substituted” above means that one or more hydrogen atoms are substituted with substituents independently selected from the same or different substituents.

[0268] The compounds described in this invention may be asymmetric (for example, having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this invention. Compounds containing asymmetrically substituted carbon atoms described in this invention can be obtained by separation as optical isomers or racemates. How to produce optically active products from optically active starting materials is known in the art, for example, by separation of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, such as C=N double bonds, may 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 separated into mixtures of isomers or individual isomers. Furthermore, atropisomers and mixtures thereof, such as two aromatic ring or heteroaromatic ring systems formed by the bonding of one aromatic ring or heteroaromatic ring to another aromatic ring or heteroaromatic ring, are included within the scope of this invention, limited to being rotatable. For example, if Cy is a phenyl group and has two substituents linked to adjacent carbon atoms, and one of these carbon atoms is linked to a pyridine carbon atom, the rotation of the phenyl group may be inhibited. In some cases, the rotational barrier is high enough to separate different atropisomers.

[0269] The compounds described in the present invention further include tautomers. Tautomerism is achieved by the exchange of a single bond with an adjacent double bond and the resulting transfer of a proton. Tautomers include proton-transfer tautomers having the same chemical formula and total charge. Exemplary proton-transfer tautomers include keto-enol tautomerism, amide-imido acid tautomerism, lactam-lactide tautomerism, amide-imido acid tautomerism, and enamine-imido tautomerism, in which the proton can tautomerize at two or more positions in the heterocyclic system in the cyclic structure, for example, 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles, and some hydroxy-substituted compounds may exist as tautomers. [ka] These are shown in the following. The tautomers may be in equilibrium, or they may form a single form by fixing the space through appropriate substitution.

[0270] In some cases, the compounds described in the present invention may exist in the form of rotational isomers. The descriptions of the compounds of the present invention are intended to include any single rotational isomer and any mixture of rotational isomers in any ratio, and do not represent any particular rotational isomer. A description of a particular rotational isomer means that it refers to the rotational isomer described above and does not include any other rotational isomers.

[0271] The present invention further comprises isotope-labeled compounds of the compounds or intermediates described in the present invention. "Isotope" refers to an atom having the same number of atoms but a different molecular weight. For example, isotopes of hydrogen include protium and deuterium.

[0272] As used herein, unless otherwise specified, the term “selective substitution” means non-substitution or substitution.

[0273] As used herein, unless otherwise specified, the term “substituted” means that one or more hydrogen atoms are substituted with substituents independently selected from the same or different substituents. Exemplary substituents include D, halogen, oxo, C1-C6 alkyl, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl, and C1-C6 alkyl-NR. c R d -(CH2CH2O) o C1-C6 alkyl groups (where o is 1-10), C 2-6 Alkenil-NR c R d , C 2-6 Alkinyl-NR c R d ,-OC 2-6 Alkyl-NR c R d -CN, -NO2, -N3, -OR a , -SR a, -C(O)R b -C(O)NR c R d -CH2C(O)NR c R d , -C(O)OR a -OC(O)R b -OC(O)NR c R d , -NR c R d , -NR c C(O)R b , -NR c C(O)NR c R d , -NR c C(O)OR a -C(=NR c )NR c R d , -NR c C(=NR c )NR c R d , -P(R f )2, -P(OR e )2, -P(O)R e R f ,-P(O)OR e Ure 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 The aryl group, heteroaryl group, spirocycloalkyl group, spiroheterocycloalkyl group, cycloalkyl group, or heterocycloalkyl group is included, but is not limited to these, and among them, the aryl group, heteroaryl group, spirocycloalkyl group, spiroheterocycloalkyl group, cycloalkyl group, or heterocycloalkyl group may be optionally D, halogen, oxo, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 haloalkyl group, or C1-C6 alkyl-NR c R d , C 2-6 Alkenil-NRc R d , C 2-6 Alkinyl-NR c R d , OC 2-6 Alkyl-NR c R d -CN, -NO2, -N3, -OR a , -SR a , -C(O)R b -C(O)NR c R d -CH2C(O)NR c R d , -C(O)OR a -OC(O)R b -OC(O)NR c R d , -NR c R d , -NR c C(O)R b , -NR c C(O)NR c R d , -NR c C(O)OR a -C(=NR c )NR c R d , -NR c C(=NR c )NR c R d , -P(R f )2, -P(OR e )2, -P(O)R e R f ,-P(O)OR e Ure 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 It is substituted with a substituent selected from the following.

[0274] In some embodiments, the compounds or salts thereof described in the present invention are substantially separated. "Substantially separated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation may include, for example, a composition rich in the compounds of the present invention. Substantially separated may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds or salts thereof of the present invention. Methods for separating the compounds and their salts are common in the art.

[0275] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of the compound described herein, of which the parent compound is modified by converting it to its salt form with an existing acid or base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and base or organic base salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from a non-toxic inorganic or organic acid. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, the salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof, generally preferred in non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts is given in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each incorporated herein by reference as a whole.

[0276] The term "pharmaceutically acceptable" as used herein means a compound, substance, composition and / or dosage form that, within reasonable medical judgment, does not cause excessive toxicity, irritation, allergic reactions or other problems or complications, and has a reasonable benefit-to-hazard ratio for contact with human and animal tissues.

[0277] "Pharmacologically acceptable excipients" refer to substances that, when added to a pharmacological composition or used in other ways as a medium, carrier, or diluent, facilitate the administration of a drug and are compatible with it, non-toxic, biologically resistant, and suitable for other biological administration to a subject, such as inert substances. Exemplary excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0278] A "solvate" refers to the physical bond between a compound represented by formula I and one or more solvent molecules.

[0279] "Subject" includes human beings. The terms "human being," "patient," and "subject" may be used interchangeably in this specification.

[0280] In one embodiment, “treating or treating” any disease or disorder means improving the disease or disorder (i.e., preventing or reducing the progression of the disease or at least one clinical symptom of its clinical symptoms). In another embodiment, “treatment” means improving at least one physical parameter that the subject may not be aware of. In yet another embodiment, “treatment” means regulating the disease or disorder at the physical level (e.g., stabilization of symptoms), the physiological level (e.g., stabilization of physical parameters), or both levels. In yet another embodiment, “treatment” means delaying the onset of the disease or disorder.

[0281] The “compounds of the present invention” and equivalent expressions are intended to cover the compounds represented by formula (I) as described herein, and their respective subgenera, and, where permitted in the context, such expressions include stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) and pharmaceutically acceptable salts of the compounds represented by formula (I).

[0282] As used herein, the term “isotope variant” refers to a compound having an isotopic ratio greater than the natural abundance of one or more atoms among 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, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15 Non-radioactive isotopes such as N) can be used. What needs to be understood is that in compounds in which such isotope substitutions have been made, if present, for example, any hydrogen 2 It may also be H / D, and any carbon 13 It may be C, or any nitrogen 15 It may be N, and the presence and position of such an atom can be determined within the capabilities of a person skilled in the art.

[0283] It should also be understood that compounds having the same molecular formula but differing in the bonding properties or order of atoms or the spatial arrangement of atoms are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers," and examples include diastereomers, enantiomers, and rotational isomers. The compounds of the present invention may have one or more chiral centers, and therefore such compounds may, at each chiral center, be a single (R)- or (S)-stereoisomer or a mixture thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include its racemic or all other stereoisomers and mixtures. If a structure has one chiral center but the specific stereochemistry of that center is not shown, the structure includes two enantiomers, either individually or as a mixture of enantiomers. If a structure has one or more chiral centers but the specific stereochemistry of those centers is not shown, the structure includes all enantiomers and diastereomers, either individually or as a mixture. Methods for measuring stereochemistry and separating stereoisomers are well known in the field.

[0284] Pharmaceutical composition The present invention further provides a pharmaceutical composition comprising a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, and a pharmaceutically acceptable excipient.

[0285] The pharmaceutical composition may be in a form suitable for oral administration (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for injectable use (e.g., water or oily suspensions, or emulsions, sesame oil, corn oil, cottonseed oil or peanut oil, and elixirs, mannitol, glucose or sterile aqueous solutions, and similar drug carriers), for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), for inhalation use (e.g., fine powders or liquid aerosols), for inhalation administration (e.g., fine powders), or for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or suppositories for rectal administration).

[0286] pharmaceutically acceptable excipients may include carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or bulking agents, granulators, coatings, release regulators, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavorings, sweeteners, taste masking agents, stabilizers, or any other common excipients usable in pharmaceutical compositions.

[0287] Pharmaceutically acceptable carriers may be, for example, solids, liquids, or gases. Exemplary solid carriers include lactose, clay, sucrose, talc powder, 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 gas. When preparing oral dosage forms, any convenient drug medium may be used. For example, water, glycols, oils, alcohols, flavorings, preservatives, and colorants can be used to form oral liquid preparations such as suspensions, elixirs, and solutions. For example, starch, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrant carriers may be used to form oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage forms when using solid drug carriers because they are easy to administer. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0288] Drug dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard shell or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, sheets, or patches, such as cheek patches.

[0289] Accordingly, the tablet composition may contain a unit dose of the active compound, as well as an inert diluent or carrier, for example, sugars or sugar alcohols, such as lactose, sucrose, sorbitol, or mannitol, and / or non-sugar 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 further contain standard components such as binders and granulators such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parahydroxybenzoic acid esters), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and foaming agents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and will not be described in detail here. The above tablets may be obtained by mixing with one or more auxiliary components or auxiliaries as optional and manufacturing by compression or molding. Compressed tablets can be molded by compression using appropriate equipment, and the active ingredient may be mixed with a binder, lubricant, inert diluent, surfactant or dispersant as optional in a free-flowing form such as powder or granules. A mixture of a wet powder compound for molded tablets and an inert liquid diluent may be molded using appropriate equipment. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, a human oral formulation may contain about 0.5 mg to about 5 g of the active ingredient, which is mixed with a suitable and convenient amount of carrier which can vary between about 5% and about 95% of the total composition. Each dosage form typically contains approximately 1 mg to 2 g of the active ingredient, and is usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0290] The pharmaceutical composition of the present invention, suitable for parenteral administration, may be prepared as a solution or suspension of the active compound in water. It may also contain a suitable surfactant such as hydroxypropylcellulose. The dispersion may also be prepared in a mixture of glycerin, liquid polyethylene glycol, and its oil. It may also contain a preservative to prevent harmful growth of microorganisms.

[0291] The pharmaceutical compositions of the present invention suitable for injection comprise a sterile aqueous solution or dispersion. The composition may also be in the form of a sterile powder for immediate preparation of such a sterile injectable solution or dispersion. In all cases, the final injectable form must be sterile and a fluid effective for facilitating injection. The pharmaceutical composition must be stable under manufacturing and storage conditions. Therefore, it is preferable to store it in a manner that prevents 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., glycerin, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0292] The pharmaceutical compositions of the present invention may be in forms suitable for topical use, such as aerosols, creams, ointments, lotions, and powders. The compositions may also be in forms applicable to transdermal devices. These formulations may be manufactured by conventional processing methods using the compound represented by Formula I of the present invention or a pharmaceutically acceptable salt thereof. Exemplarily, a cream or ointment may be produced 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.

[0293] The pharmaceutical composition of the present invention may be in a form suitable for rectal administration, where the carrier is solid. Preferably, the mixture forms a suppository of a unit dose. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be obtained by mixing the composition with a softened or molten carrier, followed by cooling and molding in a mold.

[0294] The composition may be obtained by conventional procedures using common medicinal excipients well known in the art. Accordingly, a composition for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0295] An effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used to treat or prevent, slow the progression of, and / or alleviate symptoms associated with the proliferative diseases referred to in this invention.

[0296] The amount of the active ingredient used to produce a single dosage form in combination with one or more excipients varies depending on the individual being treated and the specific route of administration. For example, formulations for oral administration to humans typically contain, for example, 0.1 mg to 1000 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and an appropriate and convenient amount of excipients, the amount of which can vary between about 5% and about 98% of the total composition weight.

[0297] The dosage of the compound represented by formula (I) used for therapeutic or preventive purposes varies depending on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration, based on known medical principles.

[0298] Accordingly, the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier and a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound represented by formula I or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0299] The above-mentioned pharmaceutical preparation may optionally contain, in addition to the above-mentioned carrier component, one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, and preservatives (including antioxidants). It may also contain other auxiliary agents to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compound shown in Formula I or a pharmaceutically acceptable salt thereof may be prepared in the form of a powder or liquid concentrate.

[0300] Generally, a dose level of approximately 0.01 mg / kg to 150 mg / kg of body weight per day may be used to treat the above-mentioned diseases, or approximately 0.5 mg to 7 g per patient. 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 daily, or approximately 0.5 mg to 3.5 g per patient daily.

[0301] However, it should be understood that lower or higher doses than those mentioned above may be required. The specific dose level and treatment regimen for any particular subject depends on several factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, timing of administration, route of administration, excretion rate, drug combinations, severity and course of the specific disease being treated, the subject's tendency toward the disease, and the attending physician's judgment.

[0302] These and other points will become clear from the following description of the present invention.

[0303] The following describes non-limiting and exemplary pharmaceutical compositions and methods for producing the same.

[0304] Method of administration The compounds shown in formula (I) above, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing these compounds may be administered to the subject by any convenient method of administration, whether systemic / circumferential or topical (i.e., the desired site of action).

[0305] Methods of administration include, but are not limited to, oral (e.g., by ingestion), oral, sublingual, transdermal (e.g., by patches, ointments, etc.), transmucosal (e.g., by patches, ointments, etc.), intranasal (e.g., by nasal sprays), ocular (e.g., by eye drops), pulmonary (e.g., by inhalation or blowing therapy, e.g., by aerosols, e.g., by mouth or nose), rectal (e.g., by suppositories or enteral preparations), vaginal (e.g., by pessaries), parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intravertebral, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrathoracic), and implantation in a depot or reservoir, including, but not limited to, subcutaneous or intramuscular.

[0306] How to use The above method typically involves administering a therapeutically effective dose of the compound of the present invention to a target. The therapeutically effective dose of the combination of target compounds will vary depending on the expected application (in vitro or in vivo) or the target and disease symptoms, such as the target's weight and age, the severity of the disease symptoms, and the method of administration, which can be readily determined by those skilled in the art. The term also applies to doses that induce a specific response in target cells, such as a decrease in the proliferation or downregulation of the activity of the target protein. The specific dose will vary depending on the specific compound selected, the administration plan followed, whether or not 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.

[0307] The test method may be used for the treatment of PolQ-related diseases. Any disease directly or indirectly caused by abnormal activity or expression levels of PolQ may be a potential disease.

[0308] The compounds of the present invention are used to treat and / or prevent a patient's disease, which is characterized by the overexpression of PolQ.

[0309] The term "PolQ overexpression" refers to an increase in the expression or activity of the PolQ enzyme in diseased cells, such as cancer cells, compared to the expression or activity of the PolQ enzyme in control cells (e.g., non-lesional cells of the same type). In some embodiments, the PolQ overexpression level may be at least 2 times, at least 3 times, at least 4 times, or at least 5 times the PolQ expression level of control cells, and may be at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 10 times, at least 20 times, or at least 50 times the PolQ expression level of control cells. Exemplary PolQ overexpressing cancers include, but are not limited to, ovarian cancer, breast cancer, cervical cancer, uterine cancer, pancreatic cancer, lung cancer, colorectal cancer, gastric cancer, bladder cancer, and prostate cancer.

[0310] The compounds of the present invention are used to treat or prevent a patient's disease, characterized by increased dependence on MMEJ DSB repair.

[0311] 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, and include, but are 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.

[0312] In some embodiments, the above method is used to treat or prevent HR-deletion breast cancer.

[0313] In some embodiments, the above method is used to treat or prevent HR-deletion ovarian cancer.

[0314] In some embodiments, the above method is used to treat or prevent HR-deletion prostate cancer.

[0315] In some embodiments, the above method is used to treat or prevent HR-deletion pancreatic cancer.

[0316] The compounds of the present invention are used to treat or prevent cancer in patients with a deficiency of the 53BP1 / Shieldin complex.

[0317] The compounds of the present invention are used to treat or prevent cancer, wherein the cancer is either treated with or not treated with PARPi drugs and is drug-resistant to PARPi treatment.

[0318] The compounds of the present invention are used to treat or prevent cancer in patients, the cancer being characterized by NHEJ deficiency, decreased or deleted expression of NHEJ-related genes, and include, but are not limited to, 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5, and XRCC6.

[0319] The compounds of the present invention and pharmaceutical compositions containing them can be administered alone or in combination with medical therapies to treat any of the above-mentioned diseases. Medical therapies include, for example, surgery and radiotherapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachiotherapy, whole-body radioisotopes).

[0320] In other embodiments, the compounds and pharmaceutical compositions described in the present invention may be administered alone or in combination with one or more other agents to treat any of the above-mentioned diseases.

[0321] In other ways, the compounds and pharmaceutical compositions described in the present invention can be administered in combination with nuclear receptor agonists.

[0322] In other ways, the compounds and pharmaceutical compositions described in the present invention can be administered in combination with antagonists of nuclear receptor drugs.

[0323] In other ways, the compounds and pharmaceutical compositions described in the present invention can be administered in combination with antiproliferative agents.

[0324] synthesis The compounds and salts thereof described in the present invention may be produced using known organic synthesis techniques and can be synthesized according to any one of various possible synthetic routes, such as the scheme described below.

[0325] The above reaction for producing the compounds of the present invention can be carried out in a suitable solvent, which can be easily selected by an expert in the field of organic synthesis. The suitable solvent does not necessarily have to react with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out; for example, the temperature range may be from the freezing temperature of the solvent to the boiling temperature of the solvent. The predetermined reaction may be carried out in one solvent or a mixture of one or more solvents. Based on the specific reaction steps described above, a person skilled in the art can select a solvent suitable for the specific reaction step.

[0326] The preparation of the compounds of the present invention can involve the above-mentioned protection and deprotection of various chemical groups. The need for the above-mentioned protection and deprotection, and the selection of the appropriate protecting group, can be easily determined by those skilled in the art. Disclosed chemical protecting groups include, for example, Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith el ah, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Ed. (Wiley, 2019); Peturssion 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).

[0327] The reaction can be monitored based on any suitable method known in the field. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., ultraviolet-visible light), mass spectrometry, or chromatography such as high-performance liquid chromatography (HPLC) or thin-layer chromatography.

[0328] The terms "ambient temperature," "room temperature," and "rt" used in this invention generally refer to temperatures such as reaction temperatures in this field, and to the temperature of the space during the reaction operation, for example, a temperature of about 20°C to about 30°C.

[0329] The compounds of the present invention can be produced according to various production routes known in the literature. The following plan provides general guidance on the production of the compounds described in the present invention. Those skilled in the art should understand that various compounds of the present invention can be produced by modifying or optimizing the production methods in the following plan using general knowledge of organic chemistry. An exemplary synthesis method for producing the compounds of the present invention is as follows.

[0330] The above concepts described in the present invention will be illustrated by providing the following examples. While the above examples are provided as examples, they should not be considered to limit the more general examples described herein.

[0331] Abbreviation [Table 2] TIFF2026516662000080.tif20150

[0332] Synthesis scheme The heterocyclic amide derivatives represented by the series of formulas (I) could be prepared according to the method described in Plan 1. Formula (I) was obtained by reacting carboxylic acid 1-1 with substituted 5-amino-1,3,4-thiadiazole-2(3H)-one derivatives 1-2 under standard coupling conditions (for example, in the presence of an active reagent, e.g., BOP, PyBOP, HATU, HBTU, EDCI, or T3P, and a base, e.g., Hug's base, Et3N, pyridine, or DMAP). Alternatively, carboxylic acid 1-1 could be reacted with the above-mentioned chloride reagents, such as oxalyl chloride, thionyl chloride, POCl3, or TCFH, to obtain the chlorides 1-3 of the corresponding acids, which were then reacted with suitable amines 1-2 under basic conditions, such as Hug's base, Et3N, pyridine, or DMAP, to obtain the compounds represented by the corresponding formula (I).

[0333] Plan 1 [ka] The carboxylic acid derivatives represented by the series of formulas 2-4 could be prepared according to the method of Plan 2. Carboxylic acid ester 2-3 could be obtained by coupling a suitable carboxylic acid ester derivative 2-1 (wherein 1)W is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs), or 2)W is boric acid or a boric acid ester) and a suitable formula 2-2 (wherein 1)M is boric acid or a boric acid ester, or 2)M is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs)) under standard Suzuki coupling conditions (e.g., in the presence of a palladium catalyst, e.g., Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4 and a base, e.g., t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3).

[0334] Alternatively, carboxylic acid ester 2-3 could be obtained by Still coupling compound 2-2 (wherein W is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf, OMs, or OPO(OR)2, and each R is independently selected from a methyl group, an ethyl group, a propyl group, or CH2CF3)) with compound 2-2 (wherein M is ZnBr, SnMe3, or SnBu3) under standard Still coupling conditions (e.g., in the presence of a palladium catalyst, e.g., Pd2(dba)3, Pd(PPh3)4, or Pd(PPh3)2Cl2 and an additive such as CuCl or LiCl).

[0335] Carboxylic acid esters 2-3 were saponified in the presence of a base such as LiOH, NaOH, KOH, or Me3SnOH to obtain the corresponding carboxylic acid derivatives 2-4.

[0336] Plan 2 [ka] Similarly, the heterocyclic acid derivatives represented by the series of formulas 3-5 could be prepared according to the method of Plan 3. Suitable compound 3-1 and suitable compound 3-3 were CC-coupled according to the Suzuki coupling or Stille coupling described in Plan 2 to obtain ester compound 3-4. Compound 3-4 was saponified in the presence of a base such as LiOH, NaOH, KOH, or Me3SnOH to obtain the corresponding acid 3-5.

[0337] Alternatively, a suitable carboxylic acid 3-2 and a suitable compound 3-3 could be coupled under standard Suzuki coupling conditions or Stille coupling conditions according to the method described in Plan 2 to directly provide the corresponding acid 3-5.

[0338] Plan 3 [ka] The heterocyclic amide derivatives represented by the series of formulas (IIa) could be prepared according to the method of Plan 4. Amide derivative 4-3 could be obtained using carboxylic acid 4-1 and a suitable 5-amino-1,3,4-thiadiazole-2(3H)-one derivative 4-2, according to a method similar to Plan 1. The amide derivative 4-3 (wherein W is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs)) and compound 4-5 (wherein M is boric acid, boric acid ester, trimethyltin group, or tributyltin group) were coupled under standard Suzuki coupling conditions or Stille 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 obtain the compound shown in formula (IIa).

[0339] Alternatively, the amide derivative 4-3 (wherein W is boric acid, boric acid ester, trimethyltin group, or tributyltin group) and compound 4-5 (wherein M is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs)) were coupled under standard Suzuki coupling conditions or Stille 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 obtain the compound shown in formula (IIa).

[0340] Plan 4 [ka] The series of substituted 5-amino-1,3,4-thiadiazole-2(3H)-one derivatives shown in formula 5-4 could be prepared according to the method of Plan 5. Hydrazinethioformamide 5-1 and R 3 -W 1 5-2 (of which, W 1 The above hydrazinethioformamide derivative 5-3 could be obtained by alkylating a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) in the presence of a base such as K2CO3, Cs2CO3, TEA, or Hug's base. Alternatively, hydrazinethioformamide derivative 5-3 is R 3 -W 1 5-2 (of which, W 1 The hydrazinethioformamide derivative 5-3 (which is -CHO) could be obtained by reducing it under standard reducing ammonia conditions (for example, in the presence of a reducing agent such as NaBH(OAc)3 or NaBH3CN). The hydrazinethioformamide derivative 5-3 was reacted in the presence of a condensing agent such as CDI, 4-nitrophenyl chloroformate or triphosgene, and a base (for example, K2CO3 or TEA) to obtain the 5-amino-1,3,4-thiadiazole-2(3H)-one derivative 5-4.

[0341] Plan 5 [ka] The series of substituted 5-amino-1,3,4-thiadiazole-2(3H)-one derivatives shown in formulas 6-8 could be prepared according to the method of Plan 6. 5-bromo-1,3,4-thiadiazole-2-amine 6-2 and alcohol R A OH6-1 was subjected to a substitution reaction in a suitable solvent such as THF, DMF, or DMSO in the presence of a base such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, Na2CO3, NaH, NaHMDS, or LDA to obtain the 1,3,4-thiadiazole-2-amine derivative 6-5.

[0342] Alternatively, the 1,3,4-thiadiazole-2-amine derivative 6-5 was prepared from dithiocarbonate 6-3, which could be obtained by reacting alcohol 6-1 with CS2 and iodomethane in the presence of a THF solution of a base such as NaH, t-BuOK, t-BuONa, or NaHMDS. Compound 6-4 was obtained by hydrolysis of dithiocarbonate 6-3 with a hydrazine hydroxide solution, and compound 6-4 was further produced by reacting this with BrCN in the presence of a base such as Hug's base or TEA to generate the 1,3,4-thiadiazole-2-amine derivative 6-5. The 1,3,4-thiadiazole-2-amine derivative 6-5 was dealkylated in the presence of an acid such as HBr, HCl, H2SO4, BCl3, or BBr3 to obtain 5-amino-1,3,4-thiadiazole-2(3H)-one 6-6. 5-amino-1,3,4-thiadiazole-2(3H)-one 6-6 and R 3 -W 2 (Eventually, W 2 The 5-amino-1,3,4-thiadiazole-2(3H)-one derivatives shown in formulas 6-8 were obtained by N-alkylation reaction with a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such as NaH, NaHMDS, t-BuOK, or t-BuONa.

[0343] Plan 6 [ka] Alternatively, 5-amino-1,3,4-thiadiazole-2(3H)-one, shown in formula 7-3, could be prepared according to the method of plan 7. Hydrazinethioformamide 7-1 could be reacted with a reagent such as CDI, 4-nitrophenyl chloroformate, or triphosgene in the presence of a base (e.g., K2CO3 or TEA) to obtain 5-amino-1,3,4-thiadiazole-2(3H)-one 7-3. Alternatively, 1,3,4-thiadiazole-2,5-diamine 7-2 could be reacted with an aqueous H2SO4 solution of a nitrite (e.g., NaNO2 or isoamyl nitrite) in the presence of a catalyst such as CuSO4, CuO, or Cu(NO3)2 to obtain the target product 5-amino-1,3,4-thiadiazole-2(3H)-one, shown in formula 7-3.

[0344] Plan 7 [ka] Int-1:4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid [ka] Step 1: (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid [ka] At -70°C in an N2 atmosphere, 1-chloro-2-fluoro-4-methoxybenzene (2.0 g, 12.5 mmol) was added to a 20 mL solution of dry THF to which LDA (2.0 M THF solution, 12.5 mL) was added. The mixture was stirred at -70°C for 1 hour, and then triisopropyl propylboronate (4.70 g, 25.0 mmol) was added at -70°C. The resulting mixture was stirred at -70°C for 2 hours and quenched at 0°C with saturated NH4Cl (50 mL). The aqueous phase was adjusted to a pH of approximately 2-3 with HCl solution (1.0 M) and extracted with siRNA (40 mL x 5). 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 flash chromatography and eluted with alkylethanol (0-10%) to obtain (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (1.6 g), a white solid.

[0345] Step 2: Methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate [ka] A mixture of 1,4-dioxane (24 mL) and H2O (3 mL) containing methyl 4-chloro-6-methylnicotinate (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) was degassed, packed with nitrogen gas, purged three times, and 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 flash chromatography and eluted with ethyl acetate / PE (0-20%) to obtain the target compound (2.8 g), which was a yellow solid. LCMS calculated value C 15 H 14 FClNO3[M+H] + :m / z=310.1, measured value 310.0.

[0346] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid [ka] 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate methyl (70 mg, 0.23 mmol) in a solution of MeOH (2 mL) and H2O (2 mL) is mixed with LiOH . H2O (28 mg, 1.0 mmol) was added. Next, the mixture was stirred overnight under rt. The reaction mixture was diluted with water, the pH was adjusted to approximately 3-4 with HCl solution (2 M), and extracted with DCM (20 mL x 5). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (50 mg), a yellow oily substance, which was used directly in the next step without further purification. LCMS calculated value C 14 H 12 FClNO3[M+H] + :m / z=296.0, measured value 296.0.

[0347] Int-2:4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid [ka] Step 1: 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A mixture of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (9.7 g, 40 mmol), bis(pinacolato)diborone (12.7 g, 50 mmol), KOAc (9.8 g, 100 mmol), and Pd(dppf)Cl2 (0.87 g, 1.2 mmol) in 1,4-dioxane (120 mL) was degassed, packed with nitrogen gas, and purged three times. The reaction mixture was stirred at 100°C for 16 hours and concentrated under reduced pressure. The residue was diluted with SiO2 (150 mL) and washed with water and saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in PE (100 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure to obtain the target compound (11.5 g, 99% yield), a yellow oily substance. TLC R f = 0.4 (EtOAc / PE = 1 / 50,UV 254 nm).

[0348] Step 2: 3-Fluoro-4-(trifluoromethyl)phenol [ka] In an ice bath, a mixture of cold 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.5 g, 40 mmol), NaOH (6.4 g, 160 mmol), THF (400 mL), and water (20 mL) was mixed with H2O2 (16 mL, 33%). The reaction mixture was stirred at 0°C for 4 hours and then concentrated under reduced pressure. The residue was diluted with PE (300 mL) and filtered. The filtrate was washed with water (100 mL) and saturated saline (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (7.0 g, 97% yield), a yellow oily substance. LCMS calculation value: C7H3F4O[MH] - :m / z=179.0, measured value 179.0. TLC R f =0.45(EtOAc / PE=1 / 25,UV 254 nm)

[0349] Step 3: 2-fluoro-4-methoxy-1-(trifluoromethyl)benzene [ka] MeI (8.5 g, 60 mmol) was added to a mixture of 3-fluoro-4-(trifluoromethyl)phenol (7.0 g, 38.9 mmol) and K2CO3 (13.8 g, 100 mmol) in MeCN (40 mL). The reaction mixture was stirred at 40°C for 4 hours, then concentrated under reduced pressure. The residue was diluted with PE (200 mL) and filtered. The filtrate was washed with water and saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column flash chromatography and eluted with HCl / PE (0-5%) to obtain the target compound (4.2 g, yield 56%) as a colorless oil. TLC R f = 0.55 (EtOAc / PE = 1 / 25,UV 254 nm)

[0350] Step 4: (2-Fluoro-6-Methoxy-3-(trifluoromethyl)phenyl)boronic acid [ka] At -60°C, n-BuLi (10 mL, 2.5 M hexane solution) was added to a solution of 2-fluoro-4-methoxy-1-(trifluoromethyl)benzene (3.9 g, 20 mmol) in THF (40 mL). After stirring for 1 hour, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.6 g, 25 mmol) was added at -60°C. The reaction mixture was stirred in rt for 1 hour. At 0°C, the reaction mixture was quenched with HCl solution (2.0 M, 20 mL), then stirred for 30 minutes, and extracted with ELISA (40 mL x 5). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2.0 g, 42%), a yellow oily substance, which did not require further purification.

[0351] Step 5: 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinate methyl [ka] The compound was prepared according to a method similar to step 2 of Int-1, using (2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)boronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid as the starting material, and the target product, which is a yellow solid, was obtained. LCMS calculated value C 16 H 14 F4NO3[M+H] + :m / z=344.1, measured value 344.1.

[0352] Step 6: 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid The compound was prepared according to a method similar to step 3 of Int-1, using methyl 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinate as a starting material, to obtain the target product, which is a white solid. LCMS calculated value C 15 H 12 F4NO3[M+H] + :m / z=330.1, measured value 330.1.

[0353] Example 1: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(2-methoxyethyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (100 mg, 0.85 mmol) was added to a 1 mL solution of DMF to which NaH (40 mg, 1.0 mmol, 60% suspended in mineral oil) was added. The reaction mixture was stirred at 25°C for 1 hour. 1-iodo-2-methoxyethane (167 mg, 0.9 mmol) was added to the mixture, and the mixture was stirred overnight at 90°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (0-5%) to obtain the target compound (37 mg) as a white solid. LCMS calculated value: C5H 10 N3O2S[M+H] + :m / z=176.0, measured value 176.0.

[0354] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide To a mixture of 5-amino-3-(2-methoxyethyl)-1,3,4-thiadiazole-2(3H)-one (37 mg, 0.21 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (62 mg, 0.21 mmol, Int-1) in DMF (0.5 mL), NMI (87 mg, 1.1 mmol) and TCFH (77 mg, 0.28 mmol) were added. The reaction mixture was stirred overnight at 50°C. The mixture was concentrated under reduced pressure and then purified by prep-HPLC on a C18 column. Elution with MeCN / water (20-59%) yielded the target compound (17.7 mg) as a white solid. LCMS calculated value C 19 H 19 ClFN4O4S[M+H] + :m / z=453.1, measured value 453.1.

[0355] Example 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide [ka] The compound was prepared according to a method similar to steps 1-2 of Example 1, except that in step 1, 1-iodo-2-methoxyethane was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonic acid. LCMS calculated value C 18 H 14 ClF4N4O3S[M+H] + :m / z=477.0, measured value 477.0.

[0356] Example 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] The compound was prepared according to a method similar to steps 1-2 of Example 1, except that in step 1, 1-iodo-2-methoxyethane was replaced with iodoethane. LCMS calculated value C 18 H 17 ClFN4O3S[M+H] + :m / z=423.1, measured value 423.1.

[0357] Example 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-methoxypropyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka]

[0358] The compound was prepared according to a method similar to steps 1-2 of Example 1, except that in step 1, 1-iodo-3-methoxypropane was used to replace 1-iodo-2-methoxyethane. LCMS calculated value C 20 H 21 ClFN4O4S[M+H] +:m / z=467.1, measured value 467.1.

[0359] Example 5: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-methoxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] The compound was prepared according to a method similar to steps 1-2 of Example 1, except that in step 1, 1-bromo-4-methoxybutane was substituted for 1-iodo-2-methoxyethane. LCMS calculated value C 21 H 23 ClFN4O4S[M+H] + :m / z=481.1, measured value 481.1.

[0360] Example 6: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (60 mg, 1.5 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and tert-butyl(2-iodoethoxy)dimethylsilane (290 mg, 1.0 mmol) was added. The mixture was stirred overnight at 90°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (30-55%) to obtain the target compound (65 mg) as a white solid. LCMS calculated value C 10 H 22 N3O2SSi[M+H] + :m / z=276.1, measured value 276.0.

[0361] Step 2: N-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide [ka] To a mixture of 5-amino-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3,4-thiadiazole-2(3H)-one (55 mg, 0.2 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (61 mg, 0.20 mmol, Int-1) in MeCN (0.5 mL), NMI (87 mg, 1.1 mmol) and TCFH (75 mg, 0.26 mmol) were added. The reaction mixture was stirred overnight at 40°C. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (40-59%) to obtain the target compound (24.2 mg) as a white solid. LCMS calculated value C 24 H 31 ClFN4O4SSi[M+H] + :m / z=553.1, measured value 553.1.

[0362] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide To a solution of N-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (24.2 mg, 0.044 mmol) in THF (0.5 mL), TBAF (0.1 mL, 0.1 mmol, 1.0 M THF solution) was added. The reaction mixture was stirred overnight in rt and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (10-40%) to obtain the target compound (4.0 mg) as a white solid. LCMS calculated value C 18 H 17 ClFN4O4S[M+H] + :m / z=439.1, measured value 439.1.

[0363] Example 7: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-hydroxypropyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (60 mg, 1.5 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then (3-bromopropoxy)(tert-butyl)dimethylsilane (252 mg, 1.0 mmol) was added. The mixture was stirred overnight at 90°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (30-55%) to obtain the target compound (100 mg) as a white solid. LCMS calculated value C 11 H 24 N3O2SSi[M+H] + :m / z=290.1, measured value 290.1.

[0364] Step 2: N-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide [ka] To a mixture of 5-amino-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3,4-thiadiazole-2(3H)-one (58 mg, 0.2 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (61 mg, 0.2 mmol, Int-1) in MeCN (0.5 mL), NMI (87 mg, 1.1 mmol) and TCFH (75 mg, 0.26 mmol) were added. The reaction mixture was stirred overnight at 40°C. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (40-59%) to obtain the target compound (56 mg) as a white solid. LCMS calculated value C 25 H 33 ClFN4O4SSi[M+H] + :m / z=567.2, measured value 567.2.

[0365] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-hydroxypropyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide To a solution of N-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (56 mg, 0.1 mmol) in THF (0.5 mL), TBAF (0.3 mL, 0.3 mmol, 1.0 M THF solution) was added. The reaction mixture was stirred overnight under rt and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (10-40%) to obtain the target compound (9.4 mg) as a white solid. 1 H NMR (600 MHz,DMSO-d6) δ 12.57 (s,1H),8.81 (s,1H),7.60 (t,J =9.0 Hz,1H),7.38 (s,1H),6.96 (d,J =9.0 Hz,1H),4.56 (s,1H),3.90-3.78 (m,2H),3.64 (s,3H),3.48-3.40 (m,2H),2.51 (s,3H),1.84-1.75 (m,2H). LCMS calculated value C 19 H 19 ClFN4O4S[M+H] + :m / z=453.1, measured value 453.1.

[0366] Example 8: 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)acetic acid [ka] Step 1: 2-(5-amino-2-oxo-1,3,4-thiadiazole-3(2H)-yl)methyl acetate [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (700 mg, 6.0 mmol) was added to a 10 mL solution of DMF (10 mL) with NaH (264 mg, 6.6 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then 2-methyl bromoacetate (1.1 mg, 7.2 mmol) was added. The mixture was stirred overnight at 90°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (10-30%) to obtain the target compound (540 mg) as a white solid. LCMS calculation value: C5H8N3O3S[M+H] + :m / z=190.0, measured value 190.0.

[0367] Step 2: 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)methyl acetate [ka] A mixture of methyl 2-(5-amino-2-oxo-1,3,4-thiadiazole-3(2H)-yl)acetate (540 mg, 2.84 mmol), 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (888 mg, 3.0 mmol, Int-1), NMI (1.0 g, 12 mmol), and TCFH (841 mg, 3.0 mmol) in DMF (8 mL) was stirred overnight at 40°C. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (20-45%) to obtain the target compound (370 mg) as a white solid. LCMS calculated value C 19 H 17 ClFN4O5S[M+H] + :m / z=467.1, measured value 467.1.

[0368] Step 3: 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)acetic acid 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)methyl acetate (47 mg, 0.1 mmol) in a solution of THF (0.5 mL) and H2O (0.5 mL) with LiOH . H2O (17 mg, 0.4 mmol) was added. The reaction mixture was stirred overnight in rt and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (10%~25%, containing 0.1% TFA) to obtain the target compound (20.8 mg) as a white solid. LCMS calculated value C 18 H 15 ClFN4O5S[M+H] + :m / z=453.0, measured value 453.0.

[0369] Example 9: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2-oxoethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] HATU (76 mg, 0.2 mmol) was added to a mixture of (R)-N,N-dimethylpyrrolidine-3-amine (23 mg, 0.2 mmol), 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)acetic acid (46 mg, 0.1 mmol, Example 8), and DIEA (40 mg, 0.3 mmol) in DMF (5 mL). The mixture was stirred overnight at 50°C. The reaction mixture was quenched with water at 0°C and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (10%~30%, containing 0.05% TFA) to obtain the target compound (11.6 mg), which was a white solid. LCMS calculated value C 24 H 27 ClFN6O4S[M+H] + :m / z=549.1, measured value 549.1.

[0370] Example 10: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-((S)-3-(dimethylamino)pyrrolidine-1-yl)-2-oxoethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] The compound was prepared according to a method similar to that of Example 9, with (S)-N,N-dimethylpyrrolidine-3-amine replacing (R)-N,N-dimethylpyrrolidine-3-amine. LCMS calculated value C 24 H 27 ClFN6O4S[M+H] + :m / z=549.1, measured value 549.1.

[0371] Example 11: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-cyanoethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 3-(5-amino-2-oxo-1,3,4-thiadiazole-3(2H)-yl)propionitrile [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (100 mg, 0.85 mmol) was added to a 1 mL solution of DMF to which NaH (40 mg, 1.0 mmol, 60% suspended in mineral oil) was added. The reaction mixture was stirred at 25°C for 1 hour. 3-bromopropionitrile (120 mg, 0.9 mmol) was added to the mixture, and the mixture was stirred at rt for 36 hours. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (20-35%) to obtain the target compound (78 mg) as a white solid. LCMS calculated value: C5H7N4OS[M+H] + :m / z=171.0, measured value 171.0.

[0372] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-cyanoethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide To a mixture of 3-(5-amino-2-oxo-1,3,4-thiadiazole-3(2H)-yl)propanenitrile (68 mg, 0.4 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (120 mg, 0.4 mmol, Int-1) in DMF (1 mL), NMI (124 mg, 1.6 mmol) and TCFH (170 mg, 0.6 mmol) were added. The reaction mixture was stirred overnight at 40°C. The mixture was concentrated under reduced pressure and then purified by prep-HPLC on a C18 column. Elution with MeCN / water (30-55%) yielded the target compound (53 mg) as a white solid. LCMS calculated value C 19 H 16 ClFN5O3S[M+H] + :m / z=448.1, measured value 448.1.

[0373] Example 12: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-cyanopropyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] The compound was prepared according to a method similar to steps 1-2 of Example 11, except that in step 1, 3-bromopropionitrile was replaced with 4-bromobutyronitrile. LCMS calculated value C 20 H 18 ClFN5O3S[M+H] + :m / z=462.1, measured value 462.1.

[0374] Example 13: 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-N-(4-(3-hydroxypropyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] The compound was prepared according to a method similar to steps 2-3 of Example 7, using 5-amino-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 7) and Int-2 as starting materials. LCMS calculated value C 20 H 19 F4N4O4S[M+H] + :m / z=487.1, measured value 487.1.

[0375] Example 14: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF to which NaH (60 mg, 1.5 mmol, 60% suspended in mineral oil) was added. The reaction mixture was stirred at 25°C for 1 hour, and then (4-bromobutoxy)(tert-butyl)dimethylsilane (270 mg, 1.0 mmol) was added. The mixture was stirred overnight at 90°C, quenched with water at 0°C, and diluted with RINKAN (30 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column flash chromatography and eluted with EA / PE (50-80%) to obtain the target compound (160 mg), a yellow oily substance. LCMS calculated value C 12 H 26 N3O2SSi[M+H] + :m / z=304.1, measured value 304.0.

[0376] Step 2: N-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide [ka] To a mixture of 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (91 mg, 0.3 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (60 mg, 0.2 mmol, Int-1) in DMF (1 mL), NMI (62 mg, 0.8 mmol) and TCFH (70 mg, 0.25 mmol) were added. The reaction mixture was stirred overnight under rt and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (40-60%) to obtain the target compound (102 mg) as a white solid. LCMS calculated value C 26 H 35 ClFN4O4SSi[M+H] + :m / z=581.2, measured value 581.2.

[0377] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide To a solution of N-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (102 mg, 0.17 mmol) in THF (0.5 mL), TBAF (0.5 mL, 0.5 mmol, in a 1.0 M THF solution) was added. The reaction mixture was stirred overnight under rt and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (10-40%) to obtain the target compound (34 mg) as a white solid. 1H NMR (600 MHz,DMSO-d6) δ 9.09 (s,1H),7.46 (t,J =9.0 Hz,1H),7.00 (s,1H),6.90 (d,J =9.0 Hz,1H),4.91 (t,J =5.4 Hz,1H),3.70-3.60 (m,5H),3.40 (t,J =5.4 Hz,2H),2.51 (s,3H),1.66-1.60 (m,2H),1.40-1.30 (m,2H). LCMS calculated value C 20 H 21 ClFN4O4S[M+H] + :m / z=467.1, measured value 467.1.

[0378] Example 15: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-hydroxy-3-methylbutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(3-hydroxy-3-methylbutyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (80 mg, 2.0 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then 4-bromo-2-methylbutan-2-ol (203 mg, 1.0 mmol) was added. The mixture was stirred overnight at 40°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (20-35%) to obtain the target compound (100 mg) as a white solid. LCMS calculated value: C7H 14 N3O2S[M+H] + :m / z=204.1, measured value 204.0.

[0379] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-hydroxy-3-methylbutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide The compound was prepared according to a method similar to step 2 of Example 14, using 5-amino-3-(3-hydroxy-3-methylbutyl)-1,3,4-thiadiazole-2(3H)-one and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) as starting materials. LCMS calculated value C 21 H 23 ClFN4O4S[M+H] + :m / z=481.1, measured value 481.1.

[0380] Example 16: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(3-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (60 mg, 1.5 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then 2-(2-bromoethyl)-2-methyl-1,3-dioxolane (194 mg, 1.0 mmol) was added. The mixture was stirred overnight at 40°C, quenched with water at 0°C, and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (40-45%) to obtain the target compound (90 mg) as a white solid. LCMS calculated value: C8H 14N3O3S[M+H] + :m / z=232.1, measured value 232.1.

[0381] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(4-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide [ka] The compound was prepared according to a method similar to step 2 of Example 14, using 5-amino-3-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-1,3,4-thiadiazole-2(3H)-one and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) as starting materials. LCMS calculated value C 22 H 23 ClFN4O5S[M+H] + :m / z=509.1, measured value 509.0.

[0382] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-oxo-4-(3-oxobutyl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide [ka] A solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(4-(2-(2-methyl-1,3-dioxan-2-yl)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide (50 mg, 0.1 mmol) in THF (1 mL) and HCl (1 mL, 4.0 M) was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the target compound (46 mg), which was a yellow solid, was collected. LCMS calculated value C 20 H 19 ClFN4O4S[M+H] + :m / z=465.1, measured value 465.1.

[0383] Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-oxo-4-(3-oxobutyl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-oxo-4-(3-oxobutyl)-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide (47 mg, 0.1 mmol) in MeOH (1 mL), NaBH4 (19 mg, 0.5 mmol) was added. The reaction mixture was stirred under rt for 1 hour, and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column and eluted with MeCN / water (30-55%) to obtain the target compound (34 mg) as a white solid. LCMS calculated value C 20 H 21 ClFN4O4S[M+H] + :m / z=467.1, measured value 467.1.

[0384] Example 17: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-((3-hydroxycyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-((3-hydroxycyclobutyl)methyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (80 mg, 2.0 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then 3-(bromomethyl)cyclobutan-1-ol (164 mg, 1.0 mmol) was added. The mixture was stirred overnight at 40°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (20-35%) to obtain the target compound (70 mg) as a white solid. LCMS calculated value: C7H 12 N3O2S[M+H] + :m / z=202.1, measured value 202.1.

[0385] Step 2: 3-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)methyl)cyclobutyl-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate [ka] 5-amino-3-((3-hydroxycyclobutyl)methyl)-1,3,4-thiadiazole-2(3H)-one (40 mg, 0.2 mmol), 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (150 mg, 0.5 mmol, Int-1), and pyridine (80 mg, 2.0 mmol) were mixed in DCM (3 mL) and POCl3 (153 mg, 1.0 mmol) was added. The reaction mixture was stirred in rt for 1 hour and diluted with MeOH (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / H2O (70-90%) to obtain the target compound (52 mg) as a white solid. LCMS calculated value C 35 H 30 Cl2F2N5O6S[M+H] + :m / z=756.1, measured value 756.3.

[0386] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-((3-hydroxycyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide 3-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)methyl)cyclobutyl-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate (52 mg, 0.07 mmol) in a solution of THF (0.5 mL) and water (0.5 mL) with LiOH . H2O (10 mg, 0.25 mmol) was added. The mixture was stirred overnight under rt. The reaction mixture was quenched with TFA (0.1 mL) and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / H2O (10-20%, containing 0.1% TFA) to obtain the target compound (24.5 mg) as a white solid. LCMS calculated value C 21 H 21 ClFN4O4S[M+H] + :m / z=479.1, measured value 479.1.

[0387] Example 18: N-(4-(2-(1H-pyrazole-1-yl)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 3-(2-(1H-pyrazole-1-yl)ethyl)-5-amino-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (60 mg, 1.5 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then 1-(2-chloroethyl)-1H-pyrazole (130 mg, 1.0 mmol) was added. The mixture was stirred overnight at 40°C, quenched with water at 0°C, and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (15-20%) to obtain the target compound (90 mg), a yellow oily substance. LCMS calculation value: C7H 10 N5OS[M+H] + :m / z=212.1, measured value 212.0.

[0388] Step 2: N-(4-(2-(1H-pyrazole-1-yl)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide The compound was prepared according to a method similar to step 2 of Example 14, using 3-(2-(1H-pyrazole-1-yl)ethyl)-5-amino-1,3,4-thiadiazole-2(3H)-one and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) as starting materials. LCMS calculated value C 21 H 19 ClFN6O3S[M+H] + :m / z=489.1, measured value 489.1.

[0389] Example 19: N-(4-(2-(1H-imidazole-1-yl)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 3-(2-(1H-imidazole-1-yl)ethyl)-5-amino-1,3,4-thiadiazole-2(3H)-one [ka] The compound was prepared according to a method similar to Step 1 of Example 18, using 5-amino-1,3,4-thiadiazole-2(3H)-one and 1-(2-chloroethyl)-1H-imidazole as raw materials to obtain the target compound, which is a yellow oily substance. LCMS calculation value: C7H 10 N5OS[M+H] + :m / z=212.1, measured value 212.0.

[0390] Step 2: N-(4-(2-(1H-imidazole-1-yl)ethyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide The compound was prepared according to a method similar to step 2 of Example 14, using 3-(2-(1H-imidazole-1-yl)ethyl)-5-amino-1,3,4-thiadiazole-2(3H)-one and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) as starting materials. LCMS calculated value C 21 H 19 ClFN6O3S[M+H] + :m / z=489.1, measured value 489.1.

[0391] Example 20: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-hydroxypropyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(2-hydroxypropyl)-1,3,4-thiadiazole-2(3H)-one [ka] At 0°C, 5-amino-1,3,4-thiadiazole-2(3H)-one (120 mg, 1.0 mmol) was added to a 1 mL solution of DMF with NaH (80 mg, 2.0 mmol, 60% suspended in mineral oil). The reaction mixture was stirred at 25°C for 1 hour, and then 1-bromopropan-2-ol (140 mg, 1.0 mmol) was added. The mixture was stirred overnight at 40°C. At 0°C, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (10-15%) to obtain the target compound (50 mg) as a white solid. LCMS calculated value: C5H 10 N3O2S[M+H] + :m / z=176.0, measured value 176.0.

[0392] Step 2: 1-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)propan-2-yl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate [ka] 5-amino-3-(2-hydroxypropyl)-1,3,4-thiadiazole-2(3H)-one (35 mg, 0.2 mmol), 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (150 mg, 0.5 mmol, Int-1), and pyridine (80 mg, 2.0 mmol) were mixed in DCM (3 mL), to which POCl3 (153 mg, 1.0 mmol) was added. The reaction mixture was stirred in rt for 1 hour and diluted with MeOH (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, and the target compound (38 mg), which was a white solid, was eluted with MeCN / H2O (70-90%). LCMS calculated value C 33 H 28 Cl2F2N5O6S[M+H] + m / z = 730.1, measured value 730.2.

[0393] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-((3-hydroxycyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide 1-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-2-oxo-1,3,4-thiadiazole-3(2H)-yl)propan-2-yl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate (36.5 mg, 0.05 mmol) in a solution of THF (0.5 mL) and water (0.5 mL), LiOH . H2O (10 mg, 0.25 mmol) was added. The mixture was stirred overnight under rt. The reaction mixture was quenched with TFA (0.1 mL) and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / H2O (10%~20%, containing 0.1% TFA) to obtain the target compound (7.2 mg) as a white solid. LCMS calculated value C 19 H 19 ClFN4O4S[M+H] + :m / z=453.1, measured value 453.1.

[0394] Example 21: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 5-amino-3-(2-hydroxybutyl)-1,3,4-thiadiazole-2(3H)-one [ka] The compound was prepared according to a method similar to that of Step 1 of Example 20, by substituting 1-bromobutan-2-ol for 1-bromopropan-2-ol to obtain the target compound, which is a colorless oil. LCMS calculated value: C6H12 N3O2S[M+H] + :m / z=190.1, measured value 190.0.

[0395] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(2-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 21, using 5-amino-3-(2-hydroxybutyl)-1,3,4-thiadiazole-2(3H)-one and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) as starting materials. LCMS calculated value C 20 H 21 ClFN4O4S[M+H] + :m / z=467.1, measured value 467.1.

[0396] Example 22: 3-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)isonicotinamide [ka] Step 1: Methyl 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinate [ka] A mixture of methyl 3-chloroisonicotinate (1.0 g, 6 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (0.94 g, 5 mmol, Int-1 step 1), K2CO3 (1.66 g, 12 mmol), and Pd(dppf)Cl2 (0.34 g, 0.5 mmol) in 1,4-dioxane (24 mL) and H2O (3 mL) was degassed, packed with nitrogen gas, purged three times, and then stirred overnight at 80°C. 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 flash chromatography and eluted with ethyl acetate / PE (60-70%) to obtain the target compound (0.9 g), which was a yellow solid. LCMS calculated value C 14 H 12 ClFNO3[M+H] + :m / z=296.0, measured value 296.0.

[0397] Step 2: 3-(3-chloro-2-fluoro-6-methoxyphenyl) isonicotinic acid [ka] A solution of methyl 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinate (0.9 g, 3.0 mmol) in THF (4 mL) and H2O (4 mL) is prepared with LiOH . H2O (380 mg, 9.0 mmol) was added. After stirring overnight under rt, the reaction mixture was diluted with water, the pH was adjusted to approximately 2-3 with aqueous HCl (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (10-15%) to obtain the target compound (0.78 g), which was a white solid. LCMS calculated value C 13 H 10 ClFNO3[M+H] + :m / z=282.0, measured value 282.0.

[0398] Step 3: 3-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)isonicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 19 H 19 ClFN4O4S[M+H] + :m / z=453.1, measured value 453.1.

[0399] Example 23: N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-formamide [ka] Step 1: 1-(2-methoxyphenyl)-1H-imidazole-5-formate ethyl [ka] A mixture of ethyl glyoxylate (3.32 g, 50% toluene solution), o-anisidine (2.0 g, 16.2 mmol), and Na2SO4 (13.8 g, 97.4 mmol) in toluene (20 mL) was degassed, N2 was packed into the mixture, the mixture was substituted three times, and then stirred at 110°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The above residue, a mixture of K2CO3 (1.48 g, 10.7 mmol), and TosMIC (1.59 g, 8.1 mmol) in EtOH (20 mL) was degassed, N2 was packed into the mixture, the mixture was substituted three times, and then stirred at 50°C for 12 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with SiO2 (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ¼ / PE (10-50%) to obtain the target compound (1.1 g) as a brown solid. LCMS calculated value C 13 H 15 N2O3[M+H] + :m / z=247.1, measured value 247.1.

[0400] Step 2: 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid [ka] 1-(2-methoxyphenyl)-1H-imidazole-5-ethyl formate (500 mg, 2.0 mmol) and LiOH . A mixture of H2O (170 mg, 4.1 mmol) in MeOH (5 mL) and H2O (4 mL) was stirred overnight in rt. The resulting mixture was diluted with water (20 mL), the pH was adjusted to approximately 4-5 with aqueous HCl (2 M), and extracted with DCM (20 mL x 3). The combined organic phase was washed with water and saturated saline, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (200 mg), which was a yellow solid. LCMS calculated value C 11 H 11 N2O3[M+H] + :m / z=219.1, measured value 219.1.

[0401] Step 3: N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-formamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 17 H 20 N5O4S[M+H] + :m / z=390.1, measured value 390.1.

[0402] Example 24: N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide [ka] Step 1: 4-(2-methoxyphenyl)-6-methylnicotinic acid [ka] The compound was prepared according to a method similar to steps 1-2 of Example 22, in which step 1, methyl 4-chloro-6-methylnicotinate and (2-methoxyphenyl)boronic acid were used as raw materials to obtain the target compound (3.3 g), which is a yellow solid. LCMS calculated value C 14 H 14 NO3 [M+H] + :m / z=244.1, measured value 244.0.

[0403] Step 2: N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 4-(2-methoxyphenyl)-6-methylnicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 20 H 23 N4O4S[M+H] + :m / z=415.1, measured value 415.1.

[0404] Example 25: 4-(5-chloro-2-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid [ka] The compound was prepared according to a method similar to steps 1-2 of Example 22, except that in step 1, (5-chloro-2-methoxyphenyl)boronic acid was used as the starting material instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid. LCMS calculated value C 14 H 13 ClNO3[M+H] + :m / z=278.1, measured value 278.0.

[0405] Step 2: 4-(5-chloro-2-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 20 H 22 ClN4O4S[M+H] + :m / z=449.1, measured value 449.1.

[0406] Example 26: 6-Cyano-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-2-(2-methoxyphenyl)nicotinamide [ka] Step 1: 2-Chloro-3-(methoxycarbonyl)pyridine 1-oxide [ka] At 0°C, 3.0 g of methyl 2-chloronicotinate (3.0 g, 17.5 mmol) and 3.7 g of trifluoroacetic anhydride (17.5 mmol) were mixed in 12 mL of DCM, to which urea peroxide (3.3 g, 35.0 mmol) was added dropwise. The mixture was stirred overnight under rt. The mixture was added to 30 mL of cold saturated Na₂CO₃ solution and adjusted to pH 8-9. The mixture was extracted with 3 x 20 mL DCM. The combined organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (2.0 g), a white solid. LC-MS calculated value: C₂H₂ClNO₃[M+H] + m / z = 188.0, measured value 187.9.

[0407] Step 2: Methyl 2-chloro-6-cyanonicotinate [ka] 2-chloro-3-(methoxycarbonyl)pyridine 1-oxide (2.0 g, 10.7 mmol) and TMSCN (1.59 g, 16 mmol) were dissolved in DCM (30 mL) and acetyl chloride (1.67 g, 21.3 mmol) was added. The resulting mixture was stirred overnight under rt and quenched with saturated Na2CO3 solution (40 mL). 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 silica gel column flash chromatography and eluted with RINKAN (5-35%) to obtain the target compound (1.5 g), a white solid. LCMS calculated value: C8H7ClN2O2[M+H] + :m / z=197.0, measured value 196.9.

[0408] Step 3: Methyl 6-cyano-2-(2-methoxyphenyl)nicotinate [ka] The compound was prepared according to a method similar to Step 1 of Example 22, using methyl 2-chloro-6-cyanonicotinate and (2-methoxyphenyl)boronic acid as raw materials. LCMS calculated value C 15 H 13 N2O3[M+H] + :m / z=269.1, measured value 269.0.

[0409] Step 4: 6-Cyano-2-(2-methoxyphenyl)nicotinic acid [ka] Methyl 6-cyano-2-(2-methoxyphenyl)nicotinate (200 mg, 0.75 mmol) and LiOH .A mixture of H2O (47 mg, 1.12 mmol) in THF (3 mL) and H2O (3 mL) was stirred overnight under rt. The pH of the mixture was adjusted to approximately 2-3 with HCl aqueous solution (2 M), filtered, and the filtrate was concentrated under reduced pressure. The residue was polished with CH3CN (50 mL) and MeOH (10 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (100 mg), which was a yellow solid. LCMS calculated value C 14 H 11 N2O3[M+H] + :m / z=255.1, measured value 255.1.

[0410] Step 5: 6-Cyano-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-2-(2-methoxyphenyl)nicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 6-cyano-2-(2-methoxyphenyl)nicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 20 H 20 N5O4S[M+H] + :m / z=426.1, measured value 426.1.

[0411] Example 27: 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-2) and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 21 H 21 F4N4O4S[M+H] + :m / z=501.1, measured value 501.1.

[0412] Example 28: 4-(2-fluoro-6-methoxy-3-methylphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide [ka] Step 1: 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid [ka] The compound was prepared according to a method similar to steps 1-2 of Example 22, in which 2-fluoro-6-methoxy-3-methylphenylboronic acid and methyl 4-chloro-6-methylnicotinate were used as raw materials in step 1. LCMS calculated value C 15 H 15 FNO3[M+H] + :m / z=276.1, measured value 276.1.

[0413] Step 2: 4-(2-fluoro-6-methoxy-3-methylphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-methylnicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 21 H 24 FClN4O4S[M+H] + :m / z=447.1, measured value 447.1.

[0414] Example 29: 2'-Chloro-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formamide [ka] Step 1: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formate methyl [ka] The compound was prepared according to a method similar to that of Step 1 of Example 22, using methyl 4-chloro-6-methylnicotinate and (2-chloro-5-methoxypyridine-4-yl)boronic acid as starting materials to obtain the target compound, which is a yellow solid. LCMS calculated value C 14 H 14 ClN2O3[M+H] + :m / z=293.1, measured value 293.1.

[0415] Step 2: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formic acid [ka] A solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formate (0.3 g, 1.0 mmol) in THF (2 mL) and H2O (2 mL) is prepared with LiOH .H2O (0.13 g, 3.0 mmol) was added. The mixture was stirred overnight under rt, the reaction mixture was diluted with water, the pH was adjusted to approximately 2-3 with aqueous HCl (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (10-15%) to obtain the target compound, which was a yellow oily substance. LCMS calculated value C 13 H 12 ClN2O3[M+H] + :m / z=279.1, measured value 279.1.

[0416] Step 3: 2'-Chloro-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 19 H 21 ClN5O4S[M+H] + :m / z=450.1, measured value 450.1.

[0417] Example 30: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-(1-methyl-1H-pyrazole-3-yl)nicotinamide [ka] Step 1: Methyl 6-chloro-4-(3-chloro-2-fluoro-6-methoxyphenyl)nicotinate [ka] The compound was prepared according to a method similar to Step 1 of Example 22, using methyl 4,6-dichloronicotinate and (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (Int-1 Step 1) as starting materials to obtain the target compound, which is a yellow solid. LCMS calculated value C 14 H 11 Cl2FNO3[M+H] + :m / z=330.0, measured value 330.0.

[0418] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazole-3-yl)methyl nicotinate [ka] A mixture of 1,4-dioxane (4 mL) and H2O (0.4 mL) containing methyl 6-chloro-4-(3-chloro-2-fluoro-6-methoxyphenyl)nicotinate (0.3 g, 1 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.42 g, 2 mmol), K2CO3 (0.41 g, 3 mmol), and Pd(dppf)Cl2 (73 mg, 0.1 mmol) was degassed, packed with nitrogen gas, purged three times, and then stirred overnight at 80°C. 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 flash chromatography and eluted with MeOH / DCM (0-7%) to obtain the target compound (120 mg), which was a yellow solid. LCMS calculated value C 18 H 16 ClFN3O3[M+H] + :m / z=376.1, measured value 376.1.

[0419] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazole-3-yl)nicotinic acid [ka] 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazole-3-yl) methyl nicotinate (120 mg, 0.32 mmol) in a solution of THF (2 mL) and H2O (2 mL) is mixed with LiOH . H2O (42 mg, 1.0 mmol) was added. The mixture was stirred overnight under rt, the reaction mixture was diluted with water, the pH was adjusted to approximately 2-3 with aqueous HCl (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with MeCN / water (0-10%) to obtain the target compound (100 mg) as a white solid. LCMS calculated value C 17 H 14 ClFN3O3[M+H] + :m / z=362.1, measured value 362.1.

[0420] Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)-6-(1-methyl-1H-pyrazole-3-yl)nicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazole-3-yl)nicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as raw materials. LCMS calculated value C 23 H 23 FClN6O4S[M+H] + :m / z=533.1, measured value 533.1.

[0421] Example 31: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyano-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide [ka] Step 1: Methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinate [ka] A mixture of methyl 4-chloro-6-cyanonicotinate (0.4 g, 2.0 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (0.49 g, 2.4 mmol, Int-1 step 1), Na2CO3 (0.64 g, 6 mmol), and Pd(dppf)Cl2 (146 mg, 0.25 mmol) in 1,4-dioxane (20 mL) and H2O (5 mL) was degassed, packed with N2, substituted three times, and then stirred overnight at 80°C. The resulting mixture was diluted with water (20 mL) and extracted with siRNA (20 mL × 3). The combined organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column flash chromatography and eluted with siRNA / PE (30-50%) to obtain the target compound (0.44 g), a pale yellow solid. LCMS calculated value C 15 H 10 ClFN2O3[M+H] + :m / z=320.0, measured value 320.0.

[0422] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinic acid [ka] 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinate methyl (0.42 g, 1.31 mmol) and LiOH . A mixture of H2O (168 mg, 4 mmol) in THF (3 mL) and H2O (3 mL) was stirred overnight in rt. The reaction mixture was diluted with water, the pH was adjusted to approximately 3-4 with aqueous HCl (2 M), and extracted with DCM (20 mL x 5). The combined organic phase was washed with saturated saline solution, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (210 mg) which was a yellow oily substance. LCMS calculated value C 14H9ClFN2O3[M+H] + :m / z=307.0, measured value 307.0.

[0423] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyano-N-(4-(4-hydroxybutyl)-5-oxo-4,5-dihydro-1,3,4-thiadiazole-2-yl)nicotinamide The compound was prepared according to a method similar to steps 2-3 of Example 14, in step 2, using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinic acid and 5-amino-3-(4-((tert-butyldimethylsilyl)oxy)butyl)-1,3,4-thiadiazole-2(3H)-one (step 1 of Example 14) as starting materials. LCMS calculated value C 20 H 18 FClN5O4S[M+H] + :m / z=478.1, measured value 478.1.

[0424] Example A: Biological Test The ability of the compounds disclosed herein to inhibit PolQ(1-899)ATP enzyme activity was measured using the following test method.

[0425] PolQ ATP enzyme activity was measured using the ADP-Glo ​​assay method. For the inhibition test, the compound was added to a 384-well plate in a 10-point dilution. 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), excluding the low control well (20 μL of test buffer added to the low control well). The plate was then incubated at room temperature for 30 minutes. Equivolute (20 μL) of 100 μM ATP and 150 nM test buffer containing 50 thymine bases in ssDNA was added to all test wells. The plate was incubated at room temperature for 60 minutes before adding the ADP Glo detection reagent. After incubation for 60 minutes, 5 μL of the reaction mixture was transferred to another 384-well plate, 5 μL of ADP Glo was added, and it was incubated for another 60 minutes. Next, 10 μL of enzyme detection reagent was added, and it was incubated for another 60 minutes. The luminescence values ​​were read using Envision. The formula for calculating the inhibition percentage was as follows:

[0426] %Inhibition=(Signal Max -Signal Compound ) / (Signal Max -Signal Min ) × 100%, Of these, "Max" was the high-concentration control (DMSO), and "Min" was the enzyme-free control.

[0427] I C 50 The values ​​were calculated using the following formula by 4-parameter logic curve fitting.

[0428] Y=LowerBound+((UpperBound- LowerBound) / (1+((IC 50 / x)^Hill))).

[0429] I C 50The values ​​were determined by fitting the data to four standard parameters using the GraphPad Prism software Hill Slope. 50 *≦10 nM, 10 nM<**≦100 nM, 100 nM<***≦500 nM,****>500 nM. The experimental results for the compounds are shown in Table 1.

[0430] Table 1. PolQ ATP enzyme test [Table 3]

[0431] Although the present invention has been fully explained through the examples, it should be noted that various changes and modifications will be obvious to those skilled in the art. These changes and modifications should be included in the claims appended to the present invention.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug, or deuterium compound thereof, 【Chemistry 1】 Ring A is C 3 -C 14 Cycloalkyl groups, 4-14 member heterocycloalkyl groups, C 6 -C 14 It is an aryl group or a 5-14 membered heteroaryl group. Ring B is a partially saturated 5- to 14-membered heterocycloalkyl group, C 6 -C 14 It is an aryl group or a 5-14 membered heteroaryl group. m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, or 5. Each R 1 is independently H, D, halogen, -CN, -NO 2 , -N 3 , -SF 5 , oxo, C 1- C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 3 -C 6 cycloalkyl group, 4- to 6-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group, -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) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR 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 Selected from among, of which C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 6 Cycloalkyl groups, 4-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups are optionally selected for R 1A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, or Two R's 1 These, along with the atoms linked to them, are oxo, C 3 -C 7 A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group is formed, and of which, the C 3 -C 7 Cycloalkyl groups or 4- to 7-membered heterocycloalkyl groups are optionally selected for R 1A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, Each R 1A is independently D, halogen, CN, -NO 2 2, N 3 2, oxo, OR a 2, NR c R d 2, C(O)NR c R d C 1- C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocycloalkyl group, phenyl group, or 5-6 membered heteroaryl group, and among them, the C 1- C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 3- C 6 cycloalkyl group, 4-6 membered heterocycloalkyl group, phenyl group, or 5-6 membered heteroaryl group is optionally substituted with a substituent selected from D, halogen, -CN, -OH, -NH 2 2, oxo, -NR c R d 2, -OR a 2, -SR a C 1- C 6 alkyl group, C 1- C 6 haloalkyl group Each R 2 These are H, D, -CN, and -NO, respectively, independently. 2 , -N 3 , oxo, -SF 5 , halogen, C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, -NR C R D , -OR A , -SR A , -NR C Ure 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) 2 R B -S(O)NR C R D , -NR C S(O) 2 R D -S(O) 2 NR C R D , -NR C S(O) 2 NR 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 Ure F , -OP(O)OR E Ure F Selected from among, of which C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl groups and 5-10 membered heteroaryl groups are optionally R 2A Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, or Two R's 2 These, along with the atoms linked to them, are oxo, C 3 -C 7 A cycloalkyl group forms a 4- to 7-membered heterocycloalkyl group, and among them, the C 3 -C 7 Cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups are R 2A Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R 2A These are D, halogen, -CN, -OH, and -NH, respectively, independently. 2 , -NO 2 ,-SCIENCE FICTION 5 , oxo, C 1 -C 4 Alkyl alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, C 3 -C 6 Cycloalkyl groups, 4-6 member heterocycloalkyl groups, phenyl groups, 5-6 member heteroaryl groups, -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) 2 R b , -NR c S(O) 2 R d -S(O) 2 NR c R d , -NR c S(O) 2 NR c R d , or -NR c S(O)(=NR b )R b Selected from among, of which C 1 -C 4 Alkyl alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, C 3 -C 6 Cycloalkyl groups, 4-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups can be optionally D, halogens, -CN, -OH, or -NH. 2 , oxo, -NR c1 R d1 , -OR a1 , -SR a1 , C 1- C 6 Alkyl alkyl group, C 1- C 6 Substituting with a substituent selected from haloalkyl groups, R 3 C 1 -C 10 Alkyl alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, C 3 -C 14 Cycloalkyl groups, 4-14 member heterocycloalkyl groups, C 6 -C 14 The group is an aryl group, a 5- to 14-membered heteroaryl group, of which the C 1 -C 10 Alkyl alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, C 3 -C 14 Cycloalkyl groups, 4-14 member heterocycloalkyl groups, C 6 -C 14 Aryl groups and 5- to 14-membered heteroaryl groups are optionally R 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, Each R 4 These are H, D, halogen, -CN, and -NO, respectively, independently. 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , -NR C Ure 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) 2 R B -S(O)NR C R D , -NR C S(O) 2 R D -S(O) 2 NR C R D , -NR C S(O) 2 NR 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 , C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 6 -C 10 Aryl group, C 3 -C 10 Selected from cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups, of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 6 -C 10 Aryl group, C 3 -C 10 Cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups are optionally used in R 5 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, or Two R's 4 These, along with the atoms linked to them, are oxo, C 3 -C 6 They form cycloalkyl groups and 4-6 member heterocycloalkyl groups, and each ring can be optionally R 5 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, Each R 5 These are D, CN, halogen, and NO, respectively, independently. 2 , -N 3 ,SCIENCE FICTION 5 , oxo, selective substitution C 1 -C 6 Alkyl alkyl groups, selective substitution of C 2 -C 6 Alkenyl group, selectively substituted C 2 -C 6 Alkynyl group, selectively substituted C 3 -C 6 Cycloalkyl groups, selectively substituted 4- to 6-membered heterocycloalkyl 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) 2 R b , -NR c S(O) 2 R d -S(O) 2 NR c R d , -NR c S(O) 2 NR c R d , -NR c S(O)(=NR b )R b , -SiR G R H R I , or -B (OR C ) (OR D ) are selected from, of which the selective substituents are D, halogen, CN, OH, C 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, -OC 1 -C 4 alkyl group, -OC 1 -C 4 Selected from haloalkyl groups, Each R A These are H, D, and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl, SiR G R H R I Selected from among, of which C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl groups can be optionally D, -CN, halogen, or C. 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, -C 1 -C 4 alkyl-OH, -C 1 -C 4 Alkyl-CN, -C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl alkyl group, -C 1 -C 4 Alkyl-OC 1 -C 4 Haloalkyl groups, -NO 2 , oxo, -OR a , -SR a ,-SCIENCE FICTION 5 , -NHOR a , -C(O)R b -C(O)NR c R d , -C(O)OR a -OC(O)R b -OC(O)NR c R d , -NR c R d , -NR c C(O)R b , -NR c C(O)NR c R d , -NR c C(O)OR a , -B (OR c ) (OR d ), -C (=NR c )NR c R d , -NR d C (=NR c )NR c R d , -NR d C (=NR c )R b ,-P(O)R e R f , -P(O)OR e Ure f , -OP(O)OR e Ure f -S(O)R b -S(O)NR c R d -S(O) 2 R b , -NR c S(O) 2 R b -S(O) 2 NR c R d , -NR c S(O) 2 NR c R d , or -NR c S(O)(=NR b )R b Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, Each R B These are H, D, and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Selected from alkyl groups, of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl groups can be optionally D, -CN, halogen, oxo, or C. 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, C 1 -C 4 Cyanoalkyl group, C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl alkyl group, C 1 -C 4 Alkyl-OC 1 -C 4 Haloalkyl groups, -SF 5 , -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) 2 R b , -NR c S(O) 2 R b -S(O) 2 NR c R d , -NR c S(O) 2 NR c R d , or -B (OR c ) (OR d ) is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above, R C and R D These are H, D, and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Selected from alkyl groups, of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl groups can be optionally D, CN, halogen, oxo, or C. 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, C 1 -C 4 Cyanoalkyl group, -C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl alkyl group, -C 1 -C 4 Alkyl-OC 1 -C 4 Haloalkyl groups, -SF 5 , -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) 2 R b , -NR c S(O) 2 R b -S(O) 2 NR c R d , -NR c S(O) 2 NR c R d or -B (OR c ) (OR d ) is substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above, Alternatively, R C and R D These, together with the N atoms linked to them, form 4- to 7-membered heterocycloalkyl groups, and can optionally be D, -OH, oxo, -CN, or -NH. 2 , -NH(C 1 -C 4 Alkyl(alkyl group), -N(C) 1 -C 4 (Alkyl group) 2 , halogen, C 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, C 1 -C 4 Cyanoalkyl groups, -OC 1 -C 4 Alkyl alkyl groups, or -OC 1 -C 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from the haloalkyl group, R a and R a1 These are H, D, and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Selected from alkyl groups, of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl groups can be optionally D, halogen, -OH, -CN, or -NH. 2 , -NH(C 1 -C 4 Alkyl(alkyl group), -N(C) 1 -C 4 (Alkyl group) 2 , C 1 -C 4 Alkyl alkyl groups, OC 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl groups, or -OC 1 -C 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from the haloalkyl group, R b and R b1 These are H, D, and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Selected from alkyl groups, of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl groups can be optionally D, OH, CN, or -NH. 2 , -NH(C 1 -C 4 Alkyl(alkyl group), -N(C) 1 -C 4 (Alkyl group) 2 , halogen, C 1 -C 4 Alkyl alkyl group, C 1 -C 4 Alkoxy group, C 1 -C 4 Haloalkyl group, C 1 -C 4 Haloalkoxy group, C 6 -C 10 Aryl group, C 3 -C 10 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from cycloalkyl groups, 5-10 membered heteroaryl groups, and 4-10 membered heterocycloalkyl groups, R c , R d , R c1 , R d1 These are H, D, and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl, 5-10 member heteroaryl-C 1 -C 6 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl, 4-10 member heterocycloalkyl-C 1 -C 6 Alkyl alkyl group, C 6 -C 10 Aryl-C 3 -C 10 Cycloalkyl groups, C 6 -C 10 Aryl-4 to 10-membered heterocycloalkyl groups, C 6 -C 10 Aryl-5 to 10-membered heteroaryl group, bis(C) 6 -C 10 Aryl group), 5-10 member heteroaryl-C 3 -C 10 Cycloalkyl groups, 5-10 member heteroaryl groups - 4-10 member heterocycloalkyl groups, 5-10 member heteroaryl groups - C 6 -C 10 Selected from aryl groups or bis (5-10 membered heteroaryl groups), of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 Cycloalkyl group, 4- to 10-membered heterocycloalkyl group, C 6 -C 10 Aryl group, 5- to 10-membered heteroaryl group, C 6 -C 10 Aryl-C 1 -C 6 Alkyl group, 5- to 10-membered heteroaryl-C 1 -C 6 Alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 6 Alkyl group, 4- to 10-membered heterocycloalkyl-C 1 -C 6 Alkyl group, C 6 -C 10 Aryl-C 3 -C 10 Cycloalkyl group, C 6 -C 10 Aryl-4- to 10-membered heterocycloalkyl group, C 6 -C 10 Aryl-5- to 10-membered heteroaryl group, bis(C 6 -C 10 Aryl group), 5- to 10-membered heteroaryl-C 3 -C 10 Cycloalkyl group, 5- to 10-membered heteroaryl-4- to 10-membered heterocycloalkyl group, 5- to 10-membered heteroaryl-C 6 -C 10 Aryl group, or bis(5- to 10-membered heteroaryl group) is optionally D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl group), -N(C 1 -C 4 Alkyl group) 2 , halogen, C 1 -C 4 Alkyl group, C 1 -C 4 Alkoxy group, C 1 -C 4 Haloalkyl group, C 1 -C 4 Haloalkoxy group, C 1 -C 4 Hydroxyalkyl group, C 1 -C 4 Cyanoalkyl group, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C(O)OR a1 , C(O)R b1 , S(O) 2 R b1 , C 1 -C 4 Alkyl-OC 1 -C 4 Alkyl or C 1 -C 4 Alkyl-OC 1 -C 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl-O-, Alternatively, R c and R d together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, optionally substituted with D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl group), -N(C 1 -C 4 alkyl group) 2 , halogen, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, C 1 -C 4 haloalkyl group, C 1 -C 4 haloalkoxy group, C 1 -C 4 hydroxyalkyl group, C 1 -C 4 cyanoalkyl group, C 6 -C 10 aryl group, 5- to 10-membered heteroaryl group, C 1 -C 4 alkoxy group-C 1 -C 4 alkyl group or C 1 -C 4 alkoxy group-C 1 -C 4 alkoxy group and is independently selected from 1, 2, 3, 4 or 5 substituents, Alternatively, R c1 and R d1 These, together with the N atoms linked to them, form 4- to 7-membered heterocycloalkyl groups, and can optionally be D, -OH, -CN, or -NH 2 , -NH(C 1 -C 4 Alkyl(alkyl group), -N(C) 1 -C 4 (Alkyl group) 2 , halogen, C 1 -C 4 Alkyl alkyl group, C 1 -C 4 Alkoxy group, C 1 -C 4 Haloalkyl group, C 1 -C 4 Haloalkoxy group, C 1 -C 4 Hydroxyalkyl group, C 1 -C 4 Cyanoalkyl group, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 1 -C 4 Alkoxy group -C 1 -C 4 Alkyl alkyl group or C 1 -C 4 Alkoxy group -C 1 -C 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from the alkoxy group, R E and R e These are H, D, and C, respectively, independently. 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, C 2 -C 4 Alkenyl group, (C 1 -C 4 Alkyl)-C 1 -C 4 Alkyl alkyl group, C 2 -C 4 Alkynyl group, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 3 -C 10 Cycloalkyl groups, 4-10 member heterocycloalkyl groups, C 6 -C 10 Aryl-C 1 -C 4 Alkyl alkyl group, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5-10 member heteroaryl-C 1 -C 4 Alkyl alkyl groups, or 4-10 member heterocycloalkyl-C 1 -C 4 Selected from alkyl groups, R F and R f These are H, D, and C, respectively, independently. 1 -C 4 Alkyl alkyl group, C 2 -C 4 Alkenyl group, C 2 -C 4 Alkynyl group, C 6 -C 10 Aryl group, 5-10 membered heteroaryl group, C 3 -C 10 Selected from cycloalkyl groups or 4- to 10-membered heterocycloalkyl groups, R G , R H and R I These are each independently selective substitutions of C 1 -C 4 Selected from alkyl groups or selectively substituted phenyl groups, the selective substituents are D, halogen, CN, OH, and C. 1 -C 4 Alkyl alkyl group, C 1 -C 4 Haloalkyl group, -OC 1 -C 4 alkyl group, -OC 1 -C 4 Characterized by being selected from haloalkyl groups, Compounds represented by formula (I), or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, atropisomers, isotopic derivatives, prodrugs, or deuterium compounds thereof.

2. Ring A is C 6 -C 10 The ring A is an aryl group or a 5- to 10-membered heteroaryl group, preferably a phenyl group or a 6-membered heteroaryl group, more preferably Cy is a phenyl group, a pyridyl group, or a pyrazinyl group, and even more preferably ring A is a phenyl group or pyridine-4-yl. The compound according to claim 1.

3. The aforementioned 【Chemistry 2】 teeth, 【Transformation 3】 It has a structure, and among them, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 These are N or CR, respectively, independently. 1 Selected from, preferably one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 It is N, and of those two Y 1 , Y 2 , Y 3 , Y 4 , Y 5 is N, or Y 1 , Y 2 , Y 3 , Y 4 , Y 5 All of them are CR 1 Preferably, the 【Chemistry 4】 teeth, 【Transformation 5】 Characterized by having a structure The compound according to claim 1 or 2.

4. Each R 1 These are (i) H, D, halogen, or -OR, respectively, independently. A , or (ii) C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Selected from alkynyl groups, each substituent is optionally R 2A It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from The compound according to any one of claims 1 to 3.

5. Each R 1 These are H, -F, -Cl, and -CH, respectively, independently. 3 , -CHF 2 -CF 3 ,-OCH 3 -OCHF 2 , -OCF 3 Characterized by being selected from -C≡CH, The compound according to any one of claims 1 to 4.

6. One R 1 is, -OCH 3 Alternatively, characterized in that -C≡CH, The compound according to any one of claims 1 to 5.

7. One R 1 -F, -Cl, -CH 3 , -CHF 2 -CF 3 ,-OCH 3 -OCHF 2 , or -OCF 3 Characterized by, The compound according to any one of claims 1 to 6.

8. The aforementioned 【Transformation 6】 teeth, 【Transformation 7】 Having a structure, preferably the above 【Transformation 8】 teeth, 【Chemistry 9】 Characterized by having a structure The compound according to any one of claims 1 to 7.

9. Ring B is C 6 -C 10 Ring B is an aryl group or a 5- to 10-membered heteroaryl group, preferably a 6-membered heteroaryl group, a 5-membered heteroaryl group, or C 6 The ring B is an aryl group, and more preferably, the ring B is a pyridyl group, a pyridadinyl group, or an imidazolyl group. The compound according to any one of claims 1 to 8.

10. The aforementioned 【Chemistry 10】 teeth, 【Chemistry 11】 Having a structure, Among these, the symbol * indicates connection to ring A, and the symbol ** indicates connection to C=O. X 1 , X 2 , X 3 , X 4 These are N or CR, respectively, independently. 2 Selected from, X 5 , NR 1 , characterized by being O or S, The compound according to any one of claims 1 to 9.

11. The aforementioned 【Chemistry 12】 teeth, 【Chemistry 13】 Having a structure, preferably the above 【Chemistry 14】 teeth, 【Chemistry 15】 Having a structure, more preferably the 【Chemistry 16】 teeth, 【Chemistry 17】 Having a structure, and more preferably the above [Chemistry 18] teeth, 【Chemistry 19】 Characterized by having a structure The compound according to claim 10.

12. Each R 2 These are (i) H, D, -CN, or halogen, respectively, or (ii) C 1 -C 6 Selected from alkyl groups or 5-10 membered heteroaryl groups, each substituent is optionally R 2A Substituting with 1, 2, 3, 4, or 5 substituents independently selected from R, preferably each R 2 Each is characterized by being independently selected from H, D, -CN, a methyl group, or a 1-methylpyrazolyl group. The compound according to any one of claims 1 to 11.

13. The aforementioned 【Chemistry 20】 teeth, 【Chemistry 21】 Characterized by having a structure The compound according to any one of claims 1 to 12.

14. R 3 is C 1 -C 10 It is an alkyl group, and R is optionally selected. 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, preferably R 3 is C 1 -C 8 It is an alkyl group, and R is optionally selected. 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, more preferably R 3 is C 1 -C 6 It is an alkyl group, and R is optionally selected. 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

15. R 3 は、-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH) 3 ) 2 、-C(CH 3 ) 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CF 2 CH 3 、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH 2 CH(OH)CH 3 、-CH 2 CH(OH)CH 2 CH 3 、-CH 2 CH 2 CH(CH) 3 )OH、-CH 2 CH 2 C(CH) 3 ) 2 OH、-CH 2 CH 2 CH 2 CH 2 OH、-CH 2 CH 2 AND 3 、-CH 2 CH 2 CH 2 AND 3 、-CH 2 COOH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、 【Chemistry 22】 Characterized by, The compound according to any one of claims 1 to 14.

16. R 3 is C 2 -C 10 It is an alkenyl group, and R is optionally selected 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

17. R 3 is C 2 -C 10 It is an alkynyl group, and R is optionally selected 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

18. R 3 is C 3 -C 14 It is a cycloalkyl group, and R is optionally selected. 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

19. R 3 R is a 4- to 14-membered heterocycloalkyl group, and R is optionally selected. 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

20. R 3 is C 6 -C 14 It is an aryl group, and R is optionally selected. 4 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, preferably R 3 The substituents are a phenyl group, a naphthyl group, an anthracenyl group, and a phenantrenyl group, and each substituent can be optionally R 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

21. R 3 It is a 5-14 member heteroaryl group, and R can be selected optionally. 4 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to any one of claims 1 to 13.

22. Each R 4 These are H, D, halogen, -CN, and -NO, respectively, independently. 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , -NR C Ure 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) 2 R B -S(O)NR C R D , -NR C S(O) 2 R D -S(O) 2 NR C R D , -NR C S(O) 2 NR 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 , C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 6 -C 10 Aryl group, C 3 -C 10 Selected from cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups, of which the C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 6 -C 10 Aryl group, C 3 -C 10 Cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups are optionally used in R 5 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from A compound according to any one of claims 1 to 21.

23. Each R 4 These are H, D, halogen, -CN, and -N, respectively, independently. 3 , oxo, -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 , -NR C C(O)R B -S(O)R B -S(O) 2 R B -S(O)NR C R D , -NR C S(O) 2 R D -S(O) 2 NR C R D , C 6 -C 10 Aryl group, C 3 -C 10 Selected from cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups, of which the C 6 -C 10 Aryl group, C 3 -C 10 Cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups are optionally used in R 5 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from The compound according to any one of claims 1 to 22.

24. Each R 4 These are H, D, halogen, -CN, and -N, respectively, independently. 3 , oxo, -NR C R D , -OR A , -SR A , -C(O)R B -C(O)NR C R D , -C(O)OR A , C 6 -C 10 Aryl group, C 3 -C 10 Selected from cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups, of which the C 6 -C 10 Aryl group, C 3 -C 10 Cycloalkyl groups, 5-10 membered heteroaryl groups, or 4-10 membered heterocycloalkyl groups are optionally used in R 5 It is characterized by being substituted with 1, 2, 3, 4, or 5 substituents independently selected from The compound according to any one of claims 1 to 23.

25. Each R 4 is independently H, D, halogen, -CN, -NO 2 , -N 3 , oxo, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCF 2 CF 3 -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -C(O)NH 2 , -C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , 【Chemistry 23】 -C(O)CH 3 、-C(O)CH 2 CH 3 、-C(O)CH 2 CH 2 CH 3 、-C(O)CH(CH 3 ) 2 、-OTMS、 【Chemistry 24】 Characterized by being selected from, A compound according to any one of claims 1 to 24.

26. Each R 4 Each is independently CH 3 CH 2 CH 3 CH 2 CH 2 CH 3 CH (CH 3 ) 2 CH 2 CH 2 CH 2 CH 3 CH 2 CH (CH 3 ) 2 , C (CH 3 ) 3 -CH=CH 2 -CH=CHCH 3 ,-CH 2 CH=CH 2 -C≡CH, -C≡CCH 3 , selected from cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group, 1,2,4-triazolyl group, 1,2,3-triazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, indolyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, piperidinyl group, dioxanyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, piperazinyl group, morpholinyl group, azepanyl group, diazokanyl group, and 1,4-diazepanyl group, each substituent is optionally R 5 Characterized by being substituted with 1, 2, 3, 4, or 5 substituents selected from, The compound according to any one of claims 1 to 25.

27. Two R's 4 It is characterized by forming an oxo together with the atoms that are linked to them, A compound according to any one of claims 1 to 21.

28. Two R's 4 C 3 -C 6 They form cycloalkyl groups and 4-6 member heterocycloalkyl groups, and each ring can be optionally R 5 Substituted with 1, 2, 3, 4, or 5 substituents independently selected from, preferably two R 4 along with the atoms that are linked to them 【Chemistry 25】 A feature that forms A compound according to any one of claims 1 to 21.

29. Each R 5 These are D, CN, halogen, and NO, respectively, independently. 2 ,SCIENCE FICTION 5 , oxo, selective substitution C 1 -C 6 Alkyl alkyl groups, selective substitution of C 2 -C 6 Alkenyl group, selectively substituted C 2 -C 6 Alkynyl group, selectively substituted C 3 -C 6 Cycloalkyl groups, selectively substituted 4-6 member heterocycloalkyl 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) 2 R b , NR c S(O) 2 R d , S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b Characterized by being selected from, A compound according to any one of claims 1 to 28.

30. The compound represented by formula (I) is represented by formula (IIa), (IIb), or (IIc), 【Chemistry 26】 or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, X 1 , X 2 , X 3 , X 4 These are N or CR, respectively, independently. 2 Selected from among, R 1 , R 2 , R 3 And m is characterized as defined in formula (I), The compound according to any one of claims 1 to 29.

31. The compound represented by formula (I) is represented by formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg), 【Chemistry 27】 or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, Eventually, R 1 , R 2 , R 3 And m is characterized as defined in formula (I), A compound according to any one of claims 1 to 30.

32. The compound represented by formula (I) is represented by formulas (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), or (IVg), 【Chemistry 28】 Y 3 is N or CR 1 And, Eventually, R 1 , R 2 , R 3 And m is characterized as defined in formula (I), The compound according to any one of claims 1 to 31.

33. The aforementioned compound, Table 1 or a pharmaceutically acceptable salt thereof, The compound according to any one of claims 1 to 32.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope derivative, prodrug or deuterium compound thereof, and at least one pharmaceutically acceptable excipient.

35. A method for treating or preventing PolQ-overexpressing cancer, A method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutical composition according to claim 34.

36. A method for treating or preventing cancer, The characteristic of the cancer is an increased dependence on MMEJ-DSB repair, and the method comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutical composition according to claim 34.

37. A method for treating or preventing cancer, The characteristics of the cancer are HR deficiency, decreased or deleted expression of HR-related genes, and the method comprises administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 33, or the pharmaceutical composition according to claim 34.

38. A method for treating or preventing cancer, The cancer is characterized by a deficiency of the 53BP1 / Shieldin complex, and the method comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutical composition according to claim 34.

39. A method for treating or preventing cancer, The cancer is either treated with or not treated with a PARPi drug and is drug-resistant to PARPi treatment, and the method comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 34.

40. A method for treating or preventing cancer, The characteristics of the cancer are NHEJ deficiency, decreased or deleted expression of NHEJ-related genes, and the method comprises administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 33, or the pharmaceutical composition according to claim 34.

41. Application of a compound according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 34 in the manufacture of a drug for treating PolQ overexpression disease.

42. Application of a compound according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 34 in the manufacture of a drug for treating a disease that increases dependence on MMEJ-DSB repair.

43. An application of the compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 34 in the manufacture of a drug for treating cancer, The characteristics of the aforementioned cancer are HR deficiency, decreased or deleted expression of HR-related genes, and application.

44. An application of the compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 34 in the manufacture of a drug for treating cancer, The aforementioned cancer is characterized by a deficiency in the 53BP1 / Shieldin complex.

45. An application of the compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 34 in the manufacture of a drug for treating cancer, The aforementioned cancers are either treated with or not treated with PARPi drugs, and have drug resistance to PARPi treatment.

46. An application of the compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 34 in the manufacture of a drug for treating cancer, The aforementioned cancer is characterized by NHEJ deficiency, decreased or deleted expression of NHEJ-related genes, and application.

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