IRAK4 targeted degradation agent compound, and use thereof

Abstract

The present disclosure relates to a IRAK4 degradation agent compound, and specifically provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound has the substituents and structural features described in the present application. The application also discloses a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt of the composition, and a pharmaceutical use of the compound or the pharmaceutically acceptable salt thereof.

Description

IRAK4 targeted degrader compounds and applications thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the rights and priority of the following two Chinese invention patent applications, the entire contents of which are hereby incorporated by reference into this document in their entirety: Patent application No. 202311383103.6 filed with the State Intellectual Property Office on October 23, 2023, and patent application No. 202410167580.7 filed with the State Intellectual Property Office on February 5, 2024. Technical Field

[0003] The present disclosure relates to compounds or pharmaceutically acceptable salts thereof as IRAK4 degraders, methods for preparing the same, pharmaceutical compositions containing the same, and uses of the same or pharmaceutically acceptable salts thereof or the pharmaceutical compositions in preventing or treating diseases or conditions mediated by IRAK4. Background Art

[0004] Interleukin-1 receptor kinase 4 (IRAK4) is a serine / threonine protein kinase that is a core regulator of the innate immune response and plays a crucial role in immune system activation. Activation of the IL-1 receptor and Toll-like receptors upon binding to their ligands subsequently recruits the intracellular myeloid differentiation factor MyD88. MyD88, through its N-terminal death domain, further recruits IRAK4. Following autophosphorylation, IRAK4 recruits and activates IRAK1 and IRAK2, forming the MyD88-IRAK4-IRAK1 / 2 complex. This complex then transmits signals downstream to the E3 ubiquitin ligase TNF receptor-associated factor (TRAF6), activating the serine / threonine kinase TAK1. This in turn activates the NF-κB and MAPK signaling pathways, leading to the release of multiple inflammatory cytokines and proliferation-related factors. Studies have shown that overactivation of IRAK4 is associated with numerous autoimmune diseases, such as atopic dermatitis, hidradenitis suppurativa, and rheumatoid arthritis. However, IRAK4 deficiency is not lethal, and in adulthood, the risk of bacterial infection is reduced, comparable to that of healthy individuals.

[0005] Furthermore, IRAK4's scaffolding function can also regulate downstream signaling pathways, independent of its kinase function. Studies have shown that mouse macrophages lacking IRAK4 kinase function can still be induced to activate the NF-κB signaling pathway. Furthermore, IRAK4 kinase inhibitors are unable to block IRAK4-mediated NF-κB signaling in human monocytes, suggesting that this may be related to the insufficient efficacy of IRAK4 kinase inhibitors currently under clinical investigation.

[0006] Proteolysis Targeting Chimeria (PROTAC) is a bifunctional molecule with a small molecule inhibitor that recognizes the target protein at one end through a linker, and an E3 ubiquitin ligase ligand that can recognize the E3 ubiquitin ligase at the other end, thereby forming a ternary complex. After the target protein is ubiquitinated, it is degraded in vivo through the ubiquitin-proteasome pathway. Traditional IRAK4 small molecule inhibitors can only block the kinase activity of IRAK4, while IRAK4 PROTAC can degrade intracellular IRAK4, achieving the biological activity of simultaneously blocking IRAK4 kinase activity and scaffold function, and more effectively inhibiting the release of downstream inflammatory factors mediated by IRAK4. Therefore, it is necessary to develop new IRAK4 PROTAC drugs for the treatment of diseases or conditions related to IRAK4.

[0007] Summary of the Invention

[0008] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009] TL-Linker-DIM

[0010] (I)

[0011] in:

[0012] The DIM is a ligand compound capable of binding to E3 ubiquitin ligase;

[0013] The Linker is a connecting group that covalently binds at least one TL and at least one DIM;

[0014] The TL is a group as shown below:

[0015] in:

[0016] A 1 、A 2 、A 3 、A 4 Independently selected from CH, CR 1 or N; R 1 Selected from deuterium, halogen, CN, -C(O)NR 1a R 1b 、NO2、OH、NH2、C1-C6 alkyl、C3-C6 cycloalkyl、C6-C 10 aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclic group is optionally substituted by one or more R a replace;

[0017] R 1a is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by one or more R 1c replace;

[0018] R 1b Selected from H or C1-C6 alkyl;

[0019] B 1 、B 2 One of them is selected from C-NHR 2 、C-OR 2 or C-CHR 2a R 2b , the other is selected from CH or N;

[0020] R 2 、R 2a 、R 2b are independently selected from H, deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally replaced by one or more R b replace;

[0021] Ring Q is a 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring is optionally substituted with one or more R c replace;

[0022] B 3 、B 4 One of them is C and is connected to ring Q, and the other is selected from CH or N;

[0023] X is selected from S, O or NR 3 ;

[0024] R 3 is selected from H, deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl is optionally replaced by one or more R d replace;

[0025] R a 、R 1c 、R b 、R c 、R dare independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl is optionally replaced by one or more R e replace;

[0026] R e Selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl, C1-C3 alkoxy, CN, COOH, C(O)(C1-C3 alkyl), CONH2, C(O)O(C1-C3 alkyl), S(O)2(C1-C3 alkyl), C3-C6 cycloalkyl or 4-6 membered heterocyclyl.

[0027] In some embodiments, B 1 、B 2 One of them is C-NHR 2 , and the other is selected from CH or N.

[0028] In some embodiments, B 1 C-NHR 2 , B 2 is selected from CH or N.

[0029] In some embodiments, B 1 C-NHR 2 , B 2 is N.

[0030] In some embodiments, B 3 is C and connected to ring Q, B 4 is selected from CH or N.

[0031] In some embodiments, B 3 is C and connected to ring Q, B 4 For CH.

[0032] In some embodiments, B 3 Selected from CH or N, B 4 It is C and connected to ring Q.

[0033] In some embodiments, B 1 C-NHR 2 , B 2 Selected from CH or N, B 3 is C and connected to ring Q, B 4 is selected from CH or N.

[0034] In some embodiments, R 2 、R 2a 、R 2bEach of them is independently selected from H, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by one or more R b replace.

[0035] In some embodiments, B 1 C-NHR 2 , R 2 is selected from H, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by one or more R b replace.

[0036] In some embodiments, B 1 C-NHR 2 , R 2 is selected from H, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R b replace.

[0037] In some embodiments, B 1 C-NHR 2 , R 2 is selected from H, deuterium, OH or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R b replace.

[0038] In some embodiments, B 1 C-NHR 2 , R 2 is selected from 4-7 membered heterocyclic group or C1-C4 alkyl group, wherein the 4-7 membered heterocyclic group or C1-C4 alkyl group is optionally replaced by R b replace.

[0039] In some embodiments, B 1 C-NHR 2 , R 2 Selected from tetrahydropyranyl, oxetanyl or optionally R b Substituted C1-C4 alkyl.

[0040] In some embodiments, B 1 C-NHR 2 , R 2is selected from tetrahydropyranyl, oxetanyl, -CH2CN or isopropyl.

[0041] In some embodiments, B 1 C-NHR 2 , R 2 Selected from Or -CH2CN.

[0042] In some embodiments, B 1 C-NHR 2 , R 2 Selected from C1-C4 alkyl, such as isopropyl.

[0043] In some embodiments, A 1 、A 4 Selected from CH, CR 1 or N, A 2 、A 3 Selected from CH or CR 1 .

[0044] In some embodiments, A 4 Selected from CH, CR 1 or N, A 1 、A 2 、A 3 Selected from CH or CR 1 .

[0045] In some embodiments, A 4 Selected from CH or N, A 2 CR 1 , A 1 、A 3 All are CH.

[0046] In some embodiments, A 4 Selected from CH, A 2 CR 1 , A 1 、A 3 All are CH.

[0047] In some embodiments, A 1 Selected from CH, CR 1 or N, A 2 、A 3 、A 4 Selected from CH or CR 1 .

[0048] In some embodiments, A 1 Selected from CH or N, A 3 CR 1 , A 2 、A 4All are CH.

[0049] In some embodiments, A 1 Selected from CH, A 3 CR 1 , A 2 、A 4 All are CH.

[0050] In some embodiments, R 1 Selected from deuterium, halogen, CN, -C(O)NR 1a R 1b , NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R a replace.

[0051] In some embodiments, R 1 is selected from deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R a replace.

[0052] In some embodiments, R 1 is selected from deuterium, halogen, CN, OH or C1-C4 alkyl, wherein the OH or C1-C4 alkyl is optionally replaced by one or more R a replace.

[0053] In some embodiments, R 1 Selected from CN.

[0054] In some embodiments, R 1a Selected from H or C1-C6 alkyl, the C1-C6 alkyl is optionally replaced by one or more R 1c Replacement; R 1b Selected from H or C1-C6 alkyl.

[0055] In some embodiments, R 1a is selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group is optionally substituted by one or more R 1c Replacement; R 1b Selected from H or C1-C6 alkyl.

[0056] In some embodiments, Ring Q is optionally substituted with one or more R c Substituted 5-6 membered heteroaryl ring.

[0057] In some embodiments, Ring Q is optionally substituted with one or more R c A substituted 5-membered heteroaromatic ring, such as one or more R c Substituted pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl.

[0058] In some embodiments, Ring Q is optionally substituted with one or more R c Substituted: thiadiazolyl, triazolyl, pyrazolyl.

[0059] In some embodiments, Ring Q is optionally substituted with one or more R c Substituted: thiadiazolyl, triazolyl.

[0060] In some embodiments, Ring Q is

[0061] In some embodiments, Ring Q is

[0062] In some embodiments, R 3 is selected from H, deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl is optionally replaced by one or more R d replace.

[0063] In some embodiments, R 3 is selected from H, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R d replace.

[0064] In some embodiments, R 3 Selected from H, deuterium or optionally one or more R d Substituted C1-C4 alkyl.

[0065] In some embodiments, R 3 Selected from H or C1-C4 alkyl.

[0066] In some embodiments, X is selected from S, O, or NH.

[0067] In some embodiments, X is selected from NR 3 .

[0068] In some embodiments, X is selected from NH.

[0069] In some embodiments, R a 、R 1c 、R b、R c 、R d are independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R e replace.

[0070] In some embodiments, R a 、R 1c 、R b 、R c 、R d are independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl or 4-8 membered heterocyclic group is optionally replaced by one or more R e replace.

[0071] In some embodiments, R a 、R 1c 、R b 、R c 、R d Each independently selected from deuterium, halogen, OH, CN, NH2, =O or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R e replace.

[0072] In some embodiments, R b For CN.

[0073] In some embodiments, R e Selected from deuterium, halogen, OH, NH2, C1-C3 alkyl, C1-C3 alkoxy, COOH, C(O)(C1-C3 alkyl), CONH2, C(O)O(C1-C3 alkyl), C3-C6 cycloalkyl or 4-6 membered heterocyclyl.

[0074] In some embodiments, R e Selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, COOH, C(O)(C1-C3 alkyl), CONH2 or C(O)O(C1-C3 alkyl).

[0075] In some embodiments, the TL is selected from the structure shown below (TL-1):

[0076] Among them, B 2 、B 4 are independently selected from CH or N, A 1 、A 2 、A 3、A 4 , X, R 2 and Q are as defined above.

[0077] In some embodiments, the TL is selected from the structure shown below (TL-2):

[0078] Among them: B 2 、B 4 are independently selected from CH or N, A 4 is selected from CH or N, n is selected from 0, 1 or 2, R 1 、R 2 , X and ring Q are as defined above.

[0079] In some embodiments, the TL is further selected from the group shown below:

[0080] In some embodiments, the TL is further selected from the group shown below:

[0081] In some embodiments, the TL is selected from the following structures:

[0082] In some embodiments, the TL is

[0083] In some embodiments, the linker is a connecting group that covalently binds a TL and a DIM.

[0084] In some embodiments, the Linker is selected from: A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、

[0085] Where: -L A -、-L B - independently selected from chemical bonds, -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-, -C(O)-, -CR4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -;

[0086] R 1L and R 2L are independently selected from the group consisting of a chemical bond, -C(O)-, alkylene, heteroalkylene, alkenylene, and alkynylene, wherein the alkylene, heteroalkylene, alkenylene, and alkynylene are optionally substituted with a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0087] Q 1 , Q 2 , Q 3 and Q 4 are independently selected from cycloalkylene, heterocyclylene, arylene, heteroarylene or cycloalkenylene, wherein the cycloalkylene, heterocyclylene, arylene, heteroarylene and cycloalkenylene are each independently optionally substituted by a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0088] R 3’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0089] R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0090] R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0091] In some embodiments, the Linker is In some embodiments, the Linker is

[0092] In some embodiments, R 1L and R 2L are independently selected from a bond, -C(O)- or C1-C3 alkylene, said C1-C3 alkylene being optionally substituted by C1-C3 alkyl.

[0093] In some embodiments, Q 1 , Q 2 , Q 3 and Q4 Each is independently selected from C3-C8 cycloalkylene or 5-10 membered heterocyclylene, wherein the C3-C8 cycloalkylene or 5-10 membered heterocyclylene is optionally substituted by a group selected from the following: halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, OH, C1-C3 hydroxyalkyl or NH2.

[0094] In some embodiments, the linker is selected from the following structures: bond, -O-, -C(O)-, -CH2-,

[0095] In some embodiments, the linker is selected from: a bond, -O-, -C(O)-, -CH2-,

[0096] In some embodiments, the Linker is selected from In some embodiments, the Linker is selected from In some embodiments, the Linker is selected from

[0097] In some embodiments, the DIM is selected from ligand compounds capable of binding to a cereblon-type E3 ubiquitin ligase.

[0098] In some embodiments, the DIM is selected from the structure shown in formula (DIM-1) or (DIM-2):

[0099] in:

[0100] Selected from

[0101] Y is a chemical bond, or Y is selected from Y A 、O、NH、NR E 、C(O)O、C(O)NR E '、NR E 'C(O), Y A -NH, Y A-NR E 、Y A -C(O), Y A -C(O)O、Y A -OC(O),Y A -C(O)NR E ' or Y A -NR E 'C(O), wherein the Y A is selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene;

[0102] X' is selected from C(O) or C(R A )2;X A -X B Selected from C(R A )=N or C(R A )2-C(R A )2;

[0103] Every R A independently selected from H or C1-C3 alkyl, said C1-C3 alkyl being optionally replaced by C6-C 10 substituted with aryl or 5-10 membered heteroaryl;

[0104] Every R A 'Independently selected from C1-C3 alkyl;

[0105] Every R B are independently selected from H or C1-C3 alkyl, or two R B Together with the atoms to which it is attached, it forms a C(O), a C3-C6 cycloalkyl, a C3-C6 cycloalkenyl, or a 4-6 membered heterocyclyl;

[0106] R C Selected from H, halogen or C1-C3 alkyl;

[0107] Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy;

[0108] Every R E independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from the group consisting of halogen, N(R a )2、NHC(O)R a 、NHC(O)OR a , OR b, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0109] R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N (R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0110] Every R a Independently selected from H or C1-C6 alkyl;

[0111] R b Selected from H or p-toluenesulfonyl;

[0112] t is selected from 0 or 1;

[0113] m is selected from 0, 1, 2 or 3;

[0114] p is selected from 0, 1 or 2.

[0115] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-3) or (DIM-4):

[0116] Wherein, the rings A, Y, and R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0117] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-5), (DIM-6), (DIM-7) or (DIM-8):

[0118] Wherein, the Y, X', X A -X B 、R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0119] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-9) or (DIM-10):

[0120] Wherein, the Y, X', X A -X B 、R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0121] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11):

[0122] in:

[0123] X C Selected from chemical bonds, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)(NR'2)-, -C(O)-, -C(S)- or

[0124] X D selected from C, N or Si;

[0125] X E is selected from a chemical bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-;

[0126] R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -NR'2, -P(O)(OR')2, -P(O)(NR'2)OR', -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3 or C1-C4 alkyl;

[0127] Every R G Independently selected from H, deuterium, R H , Halogen, CN, -NO2, -OR', -SR', -NR'2, -SiR'3, -S(O)2R', -S(O)2NR'2, -S(O)R', -C(O)R', -C(O)OR', -C(O) NR'2, -C(O)N(R')OR', -C(R')2N(R')C(O)R', -C(R')2N(R')C(O)NR'2, -OC(O)R', -OC(O)NR'2, -OP(O)R '2, -OP(O)(OR')2, -OP(O)(OR')NR'2, -OP(O)(NR'2)2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR '2, -N(R')S(O)2R', -N(R')P(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2 or -N(R')P(O)(NR'2)2;

[0128] Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0129] Ring E, Ring F, and Ring G are independently selected from phenyl, 5-6 membered heteroaryl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or 5-7 membered heterocyclyl, wherein Ring E, Ring F, and Ring G are each optionally further substituted with =O;

[0130] L 1 is selected from a chemical bond, a C1-C3 alkylene group, a C2-C3 alkenylene group or a C2-C3 alkynylene group, wherein any one or two methylene groups in the C1-C3 alkylene group, the C2-C3 alkenylene group or the C2-C3 alkynylene group are optionally replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-;

[0131] Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0132] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0133] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11'):

[0134] wherein X C 、R F 、R G , q, ring E, ring F and ring G are as defined in formula (DIM-11).

[0135] In some embodiments, the DIM is selected from the structure shown in formula (DIM-12):

[0136] wherein: Ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl, wherein said C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl is optionally substituted with ═O; k is selected from 0, 1, 2, 3 or 4; X C 、X D 、X E 、R F 、R G , L 1 and Ring E are as defined in Formula (DIM-11).

[0137] In some embodiments, the DIM is selected from the structure shown in formula (DIM-12'):

[0138] Wherein, the X C 、R F 、R G , k, ring E and ring H are as defined in formula (DIM-12).

[0139] In some embodiments, the DIM is selected from the structure shown in formula (DIM-13):

[0140] Wherein, the X C 、X D 、X E 、R F 、R G , L 1 , Ring E and k are as defined in Formula (DIM-12).

[0141] In some embodiments, the DIM is selected from the structure shown in (DIM-13'):

[0142] Wherein, the X C 、R F 、R G , Ring E and k are as defined in Formula (DIM-13).

[0143] In some embodiments, the DIM is selected from the structure represented by formula (DIM-1), formula (DIM-3), formula (DIM-5), formula (DIM-12), formula (DIM-12'), formula (DIM-13) or formula (DIM-13').

[0144] In some embodiments, the DIM is selected from the structure represented by Formula (DIM-3), Formula (DIM-5), Formula (DIM-12), Formula (DIM-12'), Formula (DIM-13) or Formula (DIM-13').

[0145] In some embodiments, the DIM is selected from the following structures:

[0146] In some embodiments, the DIM is selected from the following structures:

[0147] In some embodiments, the DIM is selected from the following structures:

[0148] In some embodiments, the DIM is selected from the following structures:

[0149] In some embodiments, the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0150] On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound or a specific compound represented by any of the above general formulas of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0151] On the other hand, the present disclosure provides a method for treating a disease mediated by IRAK4 in a mammal, comprising administering a therapeutically effective amount of a compound represented by any of the above general formulas of the present disclosure or a specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0152] On the other hand, the present disclosure provides a method for treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases in mammals, comprising administering a therapeutically effective amount of a compound represented by any of the above general formulas or a specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0153] In another aspect, the present disclosure provides use of a compound or specific compound represented by any of the above general formulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease mediated by IRAK4.

[0154] On the other hand, the present disclosure provides the use of a compound represented by any of the above general formulas or a specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.

[0155] In another aspect, the present disclosure provides the use of a compound or specific compound represented by any of the above general formulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease mediated by IRAK4.

[0156] On the other hand, the present disclosure provides the use of the compound represented by any of the above general formulas or specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.

[0157] In another aspect, the present disclosure provides compounds of any of the above general formulas or specific compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases mediated by IRAK4.

[0158] In another aspect, the present disclosure provides compounds of any of the above general formulas or specific compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating tumors, inflammatory diseases, neurodegenerative diseases, or autoimmune diseases.

[0159] In some embodiments, the disease mediated by IRAK4 is selected from a tumor, an inflammatory disease, a neurodegenerative disease, or an autoimmune disease.

[0160] Any embodiment of any aspect of the present disclosure may be combined with other embodiments, provided that no contradiction occurs. In addition, in any embodiment of any aspect of the present disclosure, any technical feature may be applicable to the technical feature in other embodiments, provided that no contradiction occurs.

[0161] Definitions and Explanations of Terms

[0162] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the Examples, may be combined and coupled with each other in any manner. A particular term should not be considered undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0163] In this article Indicates the attachment site.

[0164] The term "capable of binding" means capable of measurably binding to a target (eg, a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine ​​of an E3 ubiquitin ligase, etc.).

[0165] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. E3 ubiquitin ligases, alone or in complex with E2 ubiquitin ligases, are responsible for transferring ubiquitin to target proteins. Typically, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to the first; a third ubiquitin is attached to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which the ubiquitin ligase only adds a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can instead change their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating matters, E3 ubiquitin ligases can target different lysines on ubiquitin to create chains.

[0166] The term "target protein" refers to proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, a target protein refers to a protein or polypeptide that binds to a compound of the present disclosure and can be degraded.

[0167] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0168] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0169] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the definition of compounds of the present disclosure and mixtures thereof. Substituents such as alkyl groups may have additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of these isomers and mixtures thereof involved in the substituents are also within the definition of compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0170] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

[0171] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0172] The term "optionally substituted" means that the group may be substituted or not substituted. Unless otherwise specified, the type and amount of the substituents may be any based on chemical practicability.

[0173] The term "substituted" means that a specific atom or group can be replaced by another specified atom or group. For example, the CH2 in -CH2CH2CH2- can be replaced by O, S or NH to obtain -CH2OCH2-, -OCH2CH2-, -CH2SCH2-, -SCH2CH2-, -CH2NHCH2- or -NHCH2CH2-, etc.

[0174] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options; for the group N (C1-C6 alkyl) 2, when the C1-C6 alkyl is R b When substituted, the two C1-C6 alkyl groups have independent R b options.

[0175] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0176] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0177] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1 ”.

[0178] In this article, C m -C n It means having mn or an integer number of carbon atoms in the range of m to n. For example, "C1-C 10" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms. Similarly, m-membered to n-membered means that the number of ring atoms is m to n, for example, 5-14 membered ring includes 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring, and also includes any range from n to m, for example, 5-14 membered ring includes 6-14 membered ring, 6-11 membered ring, 5-10 membered ring, 6-10 membered ring, 6-8 membered ring, etc.

[0179] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl The term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C4 alkyl" may further include "C1-C3 alkyl".

[0180] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by a heteroatom selected from NH, O and S, or one or more -CH- are replaced by N; wherein the alkyl group is as defined above.

[0181] The term "haloalkyl" refers to a group obtained by further replacing an alkyl group with a halogen, such as a "C1-C6 haloalkyl" refers to a C1-C6 alkyl group further replaced with a halogen. The term "hydroxyalkyl" refers to a group obtained by further replacing an alkyl group with an OH group.

[0182] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene, -CH(CH3)-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. The term "C1-C6 alkylene" is understood to mean an alkylene group having 1 to 6 carbon atoms. The term "C1-C3 alkylene" is understood to mean an alkylene group having 1 to 3 carbon atoms. Preferably, "C1-C6 alkylene" may include "C1-C3 alkylene". The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- groups are substituted by a heteroatom selected from N, O and S; wherein the alkylene group is as defined above.

[0183] The term "alkoxy" refers to a monovalent group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, which can be understood as "alkyloxy" or "alkyl-O-", where the definition of alkyl is as described above. 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0184] The term "haloalkoxy" refers to a group obtained by further substituted alkoxy with halogen, such as "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy further substituted with halogen.

[0185] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is a straight or branched chain containing 2 to 20 carbon atoms and has at least one double bond. 10 The term "alkenyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and the term "C2-C6 alkenyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms. 10 "Alkenyl" is preferably "C2-C6 alkenyl" or "C2-C4 alkenyl", "C2-C6 alkenyl" is further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It should be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0186] The term "alkenylene" refers to a residue derived from two carbon atoms, either identical or distinct, of a parent alkene, wherein alkenyl is as defined above. The term "C2-C6 alkenylene" is understood to include alkenylene groups having from 2 to 6 carbon atoms. The term "C2-C3 alkenylene" is understood to include alkenylene groups having from 2 to 3 carbon atoms. Preferably, "C2-C6 alkenylene" includes "C2-C3 alkenylene."

[0187] The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, containing 2 to 20 carbon atoms and having at least one triple bond. 10 “Alkynyl” is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The term “C2-C6 alkynyl” is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms. Examples of “C2-C6 alkynyl” include, but are not limited to, ethynyl (-C≡CH3), propynyl (-C≡CCH3, -CH2C≡CH3), but-1-ynyl, but-2-ynyl or but-3-ynyl. “C2-C 10"Alkynyl" may include "C2-C6 alkynyl" or "C2-C3 alkynyl", and "C2-C6 alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3) or prop-2-ynyl (propargyl).

[0188] The term "alkynylene" refers to a radical having two hydrogen atoms derived from the same carbon atom or two different carbon atoms of a parent alkyne, wherein the definition of alkynyl is as shown above. The term "C2-C6 alkynylene" is understood to mean an alkynylene having 2 to 6 carbon atoms. The term "C2-C3 alkynylene" is understood to mean an alkynylene having 2 or 3 carbon atoms. Preferably, "C2-C6 alkynylene" includes "C2-C3 alkynylene".

[0189] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 The term "cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms. The term "C3-C8 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 8 carbon atoms. The term "C3-C6 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 6 carbon atoms, specific examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C5-C9 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 8 carbon atoms. The term "C5-C7 cycloalkyl" is understood to mean a saturated monovalent monocyclic, cyclic, spiro or bridged ring having 5 to 9 carbon atoms. The term "C5-C7 cycloalkyl" is understood to mean a saturated monovalent monocyclic, cyclic, spiro or bridged ring having 5 to 7 carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 The term "cycloalkyl" may include "C3-C8 cycloalkyl", "C3-C6 cycloalkyl", "C5-C9 cycloalkyl" or "C5-C7 cycloalkyl", the term "C3-C8 cycloalkyl" may include "C3-C6 cycloalkyl" or "C5-C7 cycloalkyl", the term "C5-C9 cycloalkyl" may include "C5-C7 cycloalkyl".

[0190] The term "cycloalkyloxy" can be understood as "cycloalkyl-O-". For example, "C3-C6 cycloalkyloxy" can be understood as "C3-C6 cycloalkyl-O-".

[0191] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl. The term "C5-C 10 The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5-10 carbon atoms. The term "C5-C9 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5, 6, 7, 8 or 9 carbon atoms. The term "C5-C7 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5, 6 or 7 carbon atoms. The term "C3-C6 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 3, 4, 5 or 6 carbon atoms. The term "C5-C 10 The term "cycloalkenyl" may include "C5-C9 cycloalkenyl" or "C5-C7 cycloalkenyl", and the term "C5-C9 cycloalkenyl" may include "C5-C7 cycloalkenyl".

[0192] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic group that is not aromatic as a whole) monovalent monocyclic, fused, spiro or bridged ring group containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in the ring atoms, wherein the "heteroatoms or heteroatomic groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)- and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH- or -NHC(=O)NH-, etc., which usually contain 3 to 20 ring atoms. The term "4-14 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. "4-14 membered heterocyclyl" may include "6-14 membered heterocyclyl", "6-11 membered heterocyclyl", "6-10 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocyclyl", "4-8 membered heterocyclyl", "4-7 membered heterocyclyl", "4-6 membered heterocyclyl", "5-10 membered heterocyclyl", "5-9 membered heterocyclyl", "5-8 membered heterocyclyl" or "5-7 membered heterocyclyl". The term "5-10 membered heterocyclyl" may include "5-9 membered heterocyclyl", "5-8 membered heterocyclyl", "5-7 membered heterocyclyl", "6-10 membered heterocyclyl" or "6-8 membered heterocyclyl". The term "4-10 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and the ring atoms contain 1-5 heteroatoms or heteroatom groups independently selected from the above. "4-10 membered heterocyclyl" includes "4-8 membered heterocyclyl", "4-7 membered heterocyclyl" or "4-6 membered heterocyclyl", wherein specific examples of 4 membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; specific examples of 5 membered heterocyclyl include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; Specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolinyl and the like. The “4-10 membered heterocyclyl” may include the ranges of “5-10 membered heterocyclyl”, “5-9 membered heterocyclyl”, “5-8 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-10 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-8 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, and the like; and the “4-7 membered heterocyclyl” may further include the ranges of “4-6 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocycloalkyl”, “5-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, and the like. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0193] The term "heterocyclyloxy" may be understood as "heterocyclyl-O-".

[0194] The term "heterocycloalkyl" refers to a fully saturated monovalent cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (i.e., an atom group containing heteroatoms), wherein the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)- and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH- or -NHC(=O)NH-, etc., which generally contain 3 to 20 ring atoms. The term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. “3-10 membered heterocycloalkyl” includes “3-8 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include but are not limited to azepanyl, oxetanyl or thiepanyl.

[0195] The term "heterocycloalkyloxy" may be understood as "heterocycloalkyl-O-".

[0196] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10"Aryl" is understood to be a monovalent aromatic all-carbon monocyclic or bicyclic group having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example naphthyl.

[0197] The term "aryloxy" may be understood as "aryl-O-".

[0198] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic properties, which contains at least one, preferably 1, 2, 3 or 4, ring atoms selected from N, O, S, with the remaining ring atoms being carbon atoms. The heteroaryl group is preferably a 5-10 membered, more preferably a 5- or 6-membered heteroaryl group. The term "5- to 10-membered heteroaryl" is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. The term "6 membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. The term "5-10 membered heteroaryl" may include "5-6 membered heteroaryl" or "6 membered heteroaryl", and the term "5-6 membered heteroaryl" may include "6 membered heteroaryl".

[0199] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0200] The term "hydroxy" refers to an -OH group.

[0201] The term "cyano" refers to a -CN group.

[0202] The term "amino" refers to a -NH2 group.

[0203] The term "nitro" refers to a -NO2 group.

[0204] The term "therapeutically effective amount" means an amount of a Compound of the Disclosure that: (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a Compound of the Disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0205] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0206] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0207] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0208] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0209] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0210] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0211] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0212] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0213] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0214] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0215] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0216] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0217] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0218] The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound, but as a general guide, a suitable daily dosage of the compound of formula (I) described herein is 0.01 mg / kg to 1000 mg / kg.

[0219] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure. DETAILED DESCRIPTION

[0220] The present disclosure is described in detail below by way of specific embodiments, but this does not imply any adverse limitations on the present disclosure. Various specific embodiments of the present disclosure have been described herein in detail, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0221] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0222] All reagents used in this disclosure were commercially available and used without further purification.

[0223] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios. Unless otherwise specified, % refers to wt%.

[0224] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, D2O, CF3COOD, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0225] Explanation of terms or abbreviations:

[0226] t-Bu: tert-butyl; t-BuOK: potassium tert-butoxide; t-BuNO2: tert-butyl nitrite; TEA: triethylamine; THF: tetrahydrofuran; Me: methyl; MeOH: methanol; MeI: iodomethane; EtOH: ethanol; iPrNH2: isopropylamine; DCM: dichloromethane; DCE: dichloroethane; DMF: N,N-dimethylformamide; DIEA: N,N-diisopropylethylamine; NMP: N-methylpyrrolidone; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate; Boc: tert-butyloxycarbonyl; Bn: benzyl; NaBH(OAc)3: sodium triacetoxyborohydride; AcOH: acetic acid; EA / EtOAc: ethyl acetate; TFA: trifluoroacetic acid; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride; Pd(dppf)Cl2: 1,1-bis(diphenylphosphino)ferrocenepalladium chloride; Pd2(dba3): tris(dibenzylideneacetone)dipalladium; Pd(O Ac)2: palladium acetate; NaOAc: sodium acetate; Py: pyridine; Ms: methanesulfonyl; MsCl: methanesulfonyl chloride; MsOH: methanesulfonic acid; Tf2O: trifluoromethanesulfonic anhydride; dioxane: 1,4-dioxane; toluene / PhMe: toluene; acetone: acetone; DMSO: dimethyl sulfoxide; STAB: sodium triacetoxyborohydride; m-CPBA: m-chloroperbenzoic acid; DMK: acetone; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; M: mole / liter; TBS: tert-butyldimethylsilyl; TBSCl: tert-butylchlorodimethylsilane; IMZ: imidazole; DMP: Dess-Martin periodinane; MPa: megapascal; Bn: benzyl; PMB: p-methoxybenzyl; DMP: Dess-Martin periodinane; RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate; RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; JohnPhos: 2-(di-tert-butylphosphino)biphenyl; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TAA: tert-amyl alcohol; MW: microwave; Cu(Tc): cuprous thiophene-2-carboxylate; BPin: 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; Pd-PEPPSI-Ipent-Cl: dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); JohnPhos: 2-(di-tert-butylphosphino)biphenyl; NMI: 1-methylimidazole; PivOH: trimethylacetic acid; Xphos-Pd-G3: methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); NIS: N-iodosuccinimide; ACN: acetonitrile; IBX: 2-iodoacylbenzoic acid; NADPH: reduced nicotinamide adenine dinucleotide phosphate; HEPES: 4-hydroxyethylpiperazineethanesulfonic acid; NMDG: N-methyl-D-glucamine.

[0227] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0228] Intermediate A: Synthesis of 4-(isopropylamino)-3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile

[0229] Step 1: Synthesis of 5-bromo-2-chloro-N-isopropyl-3-nitropyridin-4-amine (A-2)

[0230] 5-Bromo-2,4-dichloro-3-nitropyridine (A-1, 4.00 g, 14.71 mmol) was dissolved in N,N-dimethylformamide (20 mL). Triethylamine (2.98 g, 29.42 mmol) and isopropylamine (869.64 mg, 14.71 mmol) were added and the mixture was allowed to react at room temperature for 3 h. LC-MS analysis indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL) and then washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution with ethyl acetate / petroleum ether = 0-30%) to obtain the title compound (3.44 g).

[0231] MS m / z(ESI):294.0,296.0[M+H] + .

[0232] Step 2: Synthesis of 4-(5-bromo-4-(isopropylamino)-3-nitropyridin-2-yl)-3-fluorobenzonitrile (A-3)

[0233] 5-Bromo-2-chloro-N-isopropyl-3-nitropyridin-4-amine (A-2, 3.44 g, 11.68 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2.89 g, 11.68 mmol) were dissolved in a mixture of 1,4-dioxane (30 mL) and water (3 mL). Tetrakis(triphenylphosphine)palladium (1.35 g, 1.17 mmol) and sodium bicarbonate (1.96 g, 23.36 mmol) were added, and the mixture was heated to 100°C under argon and allowed to react overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20% gradient elution) to give the title compound (1.66 g).

[0234] MS m / z(ESI):379.0,381.1[M+H] + .

[0235] Step 3: Synthesis of 4-(3-amino-5-bromo-4-(isopropylamino)pyridin-2-yl)-3-fluorobenzonitrile (A-4)

[0236] 4-(5-Bromo-4-(isopropylamino)-3-nitropyridin-2-yl)-3-fluorobenzonitrile (A-3, 1.66 g, 4.38 mmol) was dissolved in a mixture of ethanol (50 mL) and water (5 mL). Ammonium chloride (2.34 g, 43.78 mmol) and reduced iron powder (1.22 g, 21.89 mmol) were added, and the mixture was heated to 60°C and allowed to react overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and filtered. The filtrate was washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution with ethyl acetate / petroleum ether = 0-30%) to obtain the title compound (1.06 g).

[0237] MS m / z(ESI):349.0,351.0[M+H] + .

[0238] Step 4: Synthesis of 3-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (A-5)

[0239] 4-(3-Amino-5-bromo-4-(isopropylamino)pyridin-2-yl)-3-fluorobenzonitrile (A-4, 1.06 g, 3.04 mmol) was dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (2.97 g, 9.11 mmol) was added, and the mixture was heated to 100°C for 6 h. LC-MS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution with ethyl acetate / petroleum ether = 0-30%) to obtain the title compound (361 mg).

[0240] MS m / z(ESI):329.0,331.0[M+H] + .

[0241] Step 5: Synthesis of tert-butyl 4-(5-(7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (A-6)

[0242] 3-Bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (A-5, 100 mg, 304 μmol) and tert-butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (164 mg, 608 μmol) were dissolved in 1,4-dioxane (3 mL). Palladium acetate (7 mg, 30 μmol), cuprous iodide (12 mg, 61 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 61 μmol) and cesium carbonate (297 mg, 911 μmol) were added and the mixture was heated to 100°C under argon protection and reacted overnight. LC-MS detection showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with dichloromethane (10 mL), and washed with saturated brine (10 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to give the title compound (31 mg).

[0243] MS m / z(ESI):519.2[M+H] + .

[0244] Step 6: Synthesis of 4-(isopropylamino)-3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (Intermediate A)

[0245] Tert-butyl 4-(5-(7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (A-6, 26 mg, 50 μmol) was dissolved in 1,4-dioxane (1 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was added and the reaction continued at room temperature for 1 hour. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude title compound (30 mg).

[0246] MS m / z(ESI):419.2[M+H] + .

[0247] Intermediate B: Synthesis of 4-(isopropylamino)-3-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-5H-pyrido[3,2-b]indole-7-carbonitrile

[0248] Step 1: Synthesis of 4-[5-[2-[tert-butyl(dimethyl)silyl]ethynyl]-4-(isopropylamino)-3-nitro-pyridin-2-yl]-3-fluoro-benzonitrile (B-1)

[0249] 4-(5-Bromo-4-(isopropylamino)-3-nitropyridin-2-yl)-3-fluorobenzonitrile (A-3, 750 mg, 1.98 mmol) was dissolved in 1,4-dioxane (10 mL). tert-Butylethynyldimethylsilane (555 mg, 3.96 mmol), cuprous iodide (75.3 mg, 0.39 mmol), and cesium carbonate (1.29 g, 3.96 mmol) were added. The mixture was heated to 100°C under argon and allowed to react overnight. LC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate (20 mL) and then washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution with ethyl acetate / petroleum ether = 0-10%) to obtain the title compound (670 mg).

[0250] MS m / z(ESI):439.2[M+H] + .

[0251] Step 2: Synthesis of 4-[3-amino-5-[2-[tert-butyl(dimethyl)silyl]ethynyl]-4-(isopropylamino)-pyridin-2-yl]-3-fluoro-benzonitrile (B-2)

[0252] Dissolve 4-[5-[2-[tert-Butyl(dimethyl)silyl]ethynyl]-4-(isopropylamino)-3-nitro-pyridin-2-yl]-3-fluoro-benzonitrile (B-1, 500 mg, 1.14 mmol) in a mixture of ethanol (10 mL) and water (4 mL). Add ammonium chloride (610 mg, 11.4 mmol) and reduced iron powder (318 mg, 5.7 mmol). Heat to 60°C and react overnight. LC-MS analysis indicates completion of the reaction. Cool the reaction mixture to room temperature, filter, and remove the filtrate by vortexing. Extract the mixture with ethyl acetate (20 mL) and water (20 mL). The organic phase is washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to dryness under reduced pressure to obtain the title compound (460 mg).

[0253] MS m / z(ESI):409.2[M+H] + .

[0254] Step 3: Synthesis of 3-ethynyl-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (B-3)

[0255] 4-[3-Amino-5-[2-[tert-butyl(dimethyl)silyl]ethynyl]-4-(isopropylamino)-pyridin-2-yl]-3-fluoro-benzonitrile (B-2, 160 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (383 mg, 1.17 mmol) was added, and the mixture was heated to 100°C for 12 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), and filtered. The filtrate was washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution with ethyl acetate / petroleum ether = 0-50%) to obtain the title compound (14.0 mg).

[0256] MS m / z(ESI):275.1[M+H] + .

[0257] Step 4: Synthesis of tert-butyl 4-[4-[7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl]-1H-1,2,3-triazol-1-yl]piperidine-1-carboxylate (B-4)

[0258] 3-Ethynyl-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (B-3, 8.0 mg, 29 μmol) and tert-butyl 4-azidopiperidine-1-carboxylate (6.6 mg, 29 μmol) were dissolved in tetrahydrofuran (0.5 mL). Cuprous thiophene-2-carboxylate (0.55 mg, 2.9 μmol) was added and the mixture was allowed to react overnight at room temperature under argon. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to obtain the title compound (4.0 mg).

[0259] MS m / z(ESI):501.3[M+H] + .

[0260] Step 5: Synthesis of 4-(isopropylamino)-3-[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]-5H-pyrido[3,2-b]indole-7-carbonitrile (Intermediate B)

[0261] tert-Butyl 4-[4-[7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl]-1H-1,2,3-triazol-triazol-1-yl]piperidine-1-carboxylate (B-4, 4.0 mg, 7.9 μmol) was dissolved in ethyl acetate (0.5 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (0.02 mL) was added and the reaction was continued at room temperature for 2 h. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the title compound (3.5 mg).

[0262] MS m / z(ESI):401.2[M+H] + ;

[0263] 1 H NMR(400MHz,D2O)δ8.51(s,1H),8.05(s,1H),7.82-7.80(m,1H),7.70(s,1H),7.20-7.18(m,1H),5.01-4.99(m,1H) ,4.21-4.18(m,1H),3.67-3.63(m,2H),3.33-3.27(m,2H),2.58-2.55(m,2H),2.43-2.37(m,2H),1.38-1.36(m,6H).

[0264] Intermediate C: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxaldehyde

[0265] Step 1: Synthesis of 2,6-bis(benzyloxy)-6'-fluoro-3,3'-bipyridine (C-2)

[0266] 2-Fluoro-5-iodopyridine (C-1, 3 g, 13.5 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (8.46 g, 20.3 mmol) were dissolved in 1,4-dioxane (80 mL). Water (20 mL) was then added, along with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (495 mg, 0.68 mmol) and cesium carbonate (6.60 g, 20.27 mmol). The mixture was stirred at 90°C. After LC-MS indicated the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (3.5 g).

[0267] MS m / z[ESI]:387.10[M+H] + .

[0268] Step 2: Synthesis of 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (C-3)

[0269] Dissolve 2,6-bis(benzyloxy)-6'-fluoro-3,3'-bipyridine (C-2, 3.5 g, 9.06 mmol) in ethyl acetate (100 mL), add palladium on carbon (2.0 g), and stir under a hydrogen atmosphere. Stir the reaction at 50°C for 12 h. After LC-MS showed the reaction was complete, filter and concentrate the filtrate under reduced pressure to obtain the crude title compound (1.8 g), which was carried on to the next step without purification.

[0270] MS m / z[ESI]:209.1[M+H] + .

[0271] Step 3: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (C-4)

[0272] 3-(6-Fluoropyridin-3-yl)piperidine-2,6-dione (C-3, 450 mg, 2.16 mmol) and 4-(dimethoxymethyl)piperidine (1.03 mg, 6.48 mmol) were dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (558.70 mg, 4.32 mmol) was added. The mixture was heated to 120°C and microwaved for 2.5 h. After LC-MS indicated completion of the reaction, 100 mL of ethyl acetate was added for dilution. The organic phase was washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to afford the title compound (340 mg).

[0273] MS m / z(ESI):348.2[M+H] + .

[0274] Step 4: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde (Intermediate C)

[0275] Dissolve 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (C-4, 40 mg, 115.14 μmol) in tetrahydrofuran (2 mL). Add dilute hydrochloric acid (2N, 575 μL). Heat to 60°C and react for 2 h. After completion of the reaction, lyophilize the reaction solution to obtain the title compound (40.0 mg).

[0276] MS m / z(ESI):302.1[M+H] + .

[0277] Intermediate D: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0278] Dissolve 5-(4-(dimethoxymethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C-1, 30 mg, 0.072 mmol) in acetone (1 mL) at room temperature. Add aqueous hydrochloric acid (2 mL, 1 N) dropwise at room temperature, raise the temperature to 80°C, and stir for 1 hour. Monitor the reaction for completion by TLC. Dilute with saturated aqueous sodium bicarbonate (20 mL) and extract with dichloromethane (15 mL x 3). Combine the organic phases and concentrate in vacuo to obtain the crude title compound, which is used directly in the next step.

[0279] MS m / z(ESI):370.1[M+H] + .

[0280] Intermediate E: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0281] Step 1: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (E-2)

[0282] At room temperature, 3-(6-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (E-1, 800 mg, 2.48 mmol) and 4-(dimethoxymethyl)piperidine (394.19 mg, 2.48 mmol) were dissolved in dioxane (10 mL), and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (145.57 mg, 173.30 μmol) and cesium carbonate (2.42 g, 7.43 mmol) were added. The atmosphere was replaced with N2, the temperature was raised to 100°C, and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the mixture was diluted with dichloromethane, 5% acetic acid solution was added to adjust the pH to 6-7, and the mixture was extracted with dichloromethane. The organic phase was dried over saturated brine and anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (dichloromethane: methanol = 15:1) to obtain the title compound (468.4 mg).

[0283] MS m / z(ESI):402.1[M+H] +

[0284] Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate E)

[0285] Dissolve 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (E-2, 37 mg, 0.092 mmol) in acetone (1 mL) at room temperature. Add aqueous hydrochloric acid (2 mL, 1 N) dropwise at room temperature, raise the temperature to 80°C, and stir for 1 hour. Monitor the reaction for completion using a microplate reader. Dilute with saturated aqueous sodium bicarbonate (20 mL) and extract with dichloromethane (15 mL x 3). Combine the organic phases and concentrate in vacuo to yield the crude title compound (33 mg), which is used directly in the next step.

[0286] Intermediate F: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0287] Referring to the synthesis method of intermediate E, intermediate E-1 was replaced with 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione, and intermediate F was prepared by the same method.

[0288] Intermediate G: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxaldehyde

[0289] Step 1: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (G-2)

[0290] Under nitrogen, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (G-1, 500 mg, 1.48 mmol) and 4-(dimethoxymethyl)piperidine (470.86 mg, 2.96 mmol) were dissolved in dioxane (6 mL). Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) (144 mg, 147.86 μmol) and cesium carbonate (2.41 g, 7.39 mmol) were added. The reaction was stirred at 100°C for 6 hours. LCMS indicated the reaction was complete. The mixture was extracted with ethyl acetate (10 mL) and water (10 mL x 2). The organic phases were combined, dried, filtered, and the filtrate concentrated to afford the title compound (20 mg).

[0291] Step 2: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbaldehyde (Intermediate G)

[0292] 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (G-2, 18 mg, 43.22 μmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (0.4 mL). Hydrochloric acid (2 M, 216.10 μL) was added and the mixture was reacted at 60°C for 3 hours. The solvent was removed by concentration under reduced pressure, and the mixture was lyophilized by adding appropriate amounts of acetonitrile and water to afford the title compound (15 mg).

[0293] MS m / z(ESI):371.00[M+H] +

[0294] Intermediate H: Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonane-7-carbaldehyde

[0295] Step 1: Synthesis of (2-azaspiro[3.5]nonan-7-yl)methanol (H-2)

[0296] Dissolve tert-butyl 7-(hydroxymethyl)-2-azaspiro[3.5]nonane-2-carboxylate (H-1, 800 mg, 3.13 mmol) in dichloromethane (4 mL) at room temperature. Add dioxane hydrochloride (2 mL, 4 N) dropwise at room temperature and stir for 2 hours. The reaction mixture is concentrated in vacuo to remove the solvent, affording the crude title compound, which is used directly in the next reaction.

[0297] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (H-3)

[0298] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (864.6 mg, 3.13 mmol), (2-azaspiro[3.5]nonan-7-yl)methanol (H-2, crude product, 3.13 mmol), and diisopropylethylamine (2.02 g, 15.65 mmol) were dissolved in dimethyl sulfoxide (5 mL). The temperature was raised to 100°C, and the reaction mixture was stirred at 100°C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (100 mL), filtered, and the filter cake was collected and separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 100 / 2) to obtain the title compound (1.20 g).

[0299] MS m / z(ESI):412.2[M+H] +

[0300] Step 3: Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonane-7-carbaldehyde (Intermediate H)

[0301] Under ice, 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (H-3, 500.0 mg, 1.22 mmol) was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (776.2 mg, 1.83 mmol) was slowly added. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 2 hours. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 100 / 2) to obtain the title compound (450.0 mg).

[0302] MS m / z(ESI):410.1[M+H] +

[0303] 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 9.59 (s, 1H), 7.63 (d, J = 8.4Hz, 1H), 6.76 (d, J=2.0Hz, 1H), 6.63 (dd, J1=2.0Hz, J2=8.0Hz, 1H), 5.05 (dd, J1=5.6Hz, J2=1 2.8Hz,1H),3.72(s,4H),2.93-2.83(m,1H),2.60-2.47(m,2H),2.35-2.29(m,1 H),2.03-1.97(m,1H),1.91-1.80(m,4H),1.63-1.47(m,2H),1.43-1.34(m,2H).

[0304] Intermediate I: Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carboxaldehyde

[0305] Step 1: Synthesis of 1-(4-benzyloxyphenyl)-4-(dimethoxymethyl)piperidine (I-2)

[0306] 1-(Benzyloxy)-4-iodobenzene (I-1, 3 g, 9.67 mmol), 4-(dimethoxymethyl)piperidine (4.62 g, 29.02 mmol), 2-(di-tert-butylphosphino)biphenyl (577.31 mg, 1.93 mmol), potassium tert-butoxide (3.26 g, 29.02 mmol), and tris(dibenzylideneacetone)dipalladium (885.81 mg, 967.34 μmol) were dissolved in tert-amyl alcohol (40 mL) and stirred at 100°C overnight. After LC-MS indicated the reaction was complete, saturated aqueous ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (2.14 g).

[0307] MS m / z(ESI):342.2[M+H] +

[0308] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)phenol (I-3)

[0309] 1-(4-Benzyloxyphenyl)-4-(dimethoxymethyl)piperidine (I-2, 1.99 g, 5.83 mmol) was dissolved in ethyl acetate (40 mL), and 10% palladium on carbon (55% wt H2O, 400 mg) was added. The mixture was reacted at 60°C overnight under a hydrogen atmosphere. After LC-MS indicated completion of the reaction, the reaction solution was diluted with ethyl acetate (60 mL) and filtered through celite. The filter cake was rinsed with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford the title compound (1.43 g).

[0310] MS m / z(ESI):252.2[M+H] +

[0311] Step 3: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (I-4)

[0312] 4-(4-(Dimethoxymethyl)piperidin-1-yl)phenol (I-3, 1.38 g, 5.49 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (329.46 mg, 8.24 mmol, 60% purity) was added under ice-cooling. After stirring for 15 minutes, 3-bromopiperidine-2,6-dione (1.37 g, 7.14 mmol) was added and the mixture was stirred at room temperature overnight. After LC-MS indicated the reaction was complete, the reaction solution was added dropwise to saturated aqueous ammonium chloride (40 mL) to quench any residual sodium hydride. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to afford the title compound (1.62 g).

[0313] MS m / z(ESI):363.1[M+H] +

[0314] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),6.94-6.83(m,4H),5.02-4.97(m,1H),4.09(d,J=6.7Hz,1H),3.58-3.49(m, 2H),3.28(s,6H),2.73-2.64(m,1H),2.56-2.51(m,4H),2.23-2.03(m,2H),1.75-1.67(m,2H),1.41-1.23(m,2H).

[0315] Step 4: Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbaldehyde (Intermediate I)

[0316] Dissolve 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (50 mg, 0.138 mmol) in acetone (1 mL) at room temperature. Add aqueous hydrochloric acid (2 mL, 1 N) dropwise at room temperature, raise the temperature to 80°C, and stir for 1 hour. Monitor the reaction for completion by TLC. Dilute with saturated aqueous sodium bicarbonate (20 mL) and extract with dichloromethane (15 mL x 3). Combine the organic phases and concentrate in vacuo to obtain the crude title compound, which is used directly in the next step.

[0317] Intermediate L: Synthesis of 4-(isopropylamino)-3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)benzofuro[3,2-b]pyridine-7-carbonitrile

[0318] Step 1: Synthesis of 4-bromo-3-((2-chloro-4-nitropyridin-3-yl)oxy)benzonitrile (L-2)

[0319] 4-Bromo-3-hydroxybenzonitrile (L-1, 10 g, 50.50 mmol) was dissolved in tetrahydrofuran (100 mL). Sodium hydroxide (4.04 g, 101.00 mmol, 60% purity) was added under ice-cooling and stirred for 30 minutes. 2-Chloro-3-fluoro-4-nitro-pyridine (8.92 g, 50.50 mmol) was then added and stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction solution was diluted with ethyl acetate (10 mL x 3), washed with saturated brine (30 mL), and the organic phase was dried, concentrated to dryness, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (15.38 g).

[0320] MS m / z(ESI):355.9[M+H] +

[0321] Step 2: Synthesis of 3-((4-amino-2-chloropyridin-3-yl)oxy)-4-bromobenzonitrile (L-3)

[0322] 4-Bromo-3-((2-chloro-4-nitropyridin-3-yl)oxy)benzonitrile (L-2, 15.59 g, 43.97 mmol) was dissolved in ethanol (15 mL) and water (6 mL). Iron powder (12.28 g, 219.86 mmol) and ammonium chloride (23.52 g, 439.72 mmol) were added, and the mixture was stirred at 60°C overnight. After completion of the reaction, the reaction mixture was filtered through celite, extracted with ethyl acetate (30 mL × 3) and water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane / methanol = 20 / 1) afforded the title compound (5.61 g).

[0323] MS m / z(ESI):325.9[M+H] +

[0324] Step 3: Synthesis of 3-((4-amino-2-chloropyridin-3-yl)oxy)-4-(trimethylstannyl)benzonitrile (L-4)

[0325] 3-((4-Amino-2-chloropyridin-3-yl)oxy)-4-bromobenzonitrile (L-3, 1.36 g, 4.19 mmol) was dissolved in 1,4-dioxane (30 mL), and tetrakistriphenylphosphine palladium (484.21 mg, 419.03 μmol) and hexamethyltin (1.51 g, 4.61 mmol) were added. The mixture was reacted at 100°C overnight under argon. LC-MS analysis indicated the reaction was complete. The reaction solution was added to saturated aqueous sodium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (1.5 g).

[0326] MS m / z(ESI):410.0[M+H] +

[0327] Step 4: Synthesis of 4-aminobenzofuro[3,2-b]pyridine-7-carbonitrile (L-5)

[0328] 3-((4-Amino-2-chloropyridin-3-yl)oxy)-4-(trimethyltinyl)benzonitrile (L-4, 1.4 g, 3.43 mmol) was dissolved in 1,4-dioxane (50 mL), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (580.23 mg, 685.49 μmol) was added. The mixture was reacted at 100°C overnight under argon. LC-MS analysis indicated the reaction was complete. The reaction mixture was added to saturated aqueous sodium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (423 mg).

[0329] MS m / z(ESI):210.0[M+H] +

[0330] Step 5: Synthesis of 4-aminobenzofuro[3,2-b]pyridine-7-carbonitrile (L-6)

[0331] 4-Aminobenzofuro[3,2-b]pyridine-7-carbonitrile (L-5, 370 mg, 1.77 mmol) was dissolved in acetonitrile (10 mL), and acetic acid (106 mg, 1.77 mmol) and N-iodosuccinimide (796 mg, 3.54 mmol) were added. The mixture was stirred at 70°C for 12 hours. The solvent was removed by concentration under reduced pressure, and ethyl acetate (5 mL × 3) and water (10 mL) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (439 mg).

[0332] MS m / z(ESI):336.1[M+H] +

[0333] Step 6: Synthesis of 3-iodo-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (L-7)

[0334] 4-Aminobenzofuro[3,2-b]pyridine-7-carbonitrile (L-6, 503 mg, 1.50 mmol) was dissolved in N,N-dimethylformamide (6 mL). Sodium hydroxide (180 mg, 4.50 mmol, 60% purity) was added to the solution at 0°C. After the reaction solution warmed to room temperature, a solution of 2-iodopropane (766 mg, 4.51 mmol) in N,N-dimethylformamide was added dropwise at 80°C. The reaction was allowed to react for 6 hours. LCMS showed the product was primarily obtained. The reaction solution was cooled to room temperature and quenched with crushed ice. The product was extracted with dichloromethane (2 × 20 mL) and water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (71 mg).

[0335] MS m / z(ESI):378.18[M+H] +

[0336] Step 7: Synthesis of tert-butyl 4-(5-(7-cyano-4-(isopropylamino)benzofuro[3,2-b]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (L-8)

[0337] Under a nitrogen atmosphere, 3-iodo-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (L-7, 60 mg, 159.08 μmol) and tert-butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (43 mg, 159.08 μmol) were dissolved in dioxane (0.5 mL). Cesium carbonate (207 mg, 636.30 μmol), cuprous iodide (6 mg, 31.82 μmol), palladium acetate (7 mg, 31.18 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 63.95 μmol), and trimethylacetic acid (5 mg, 48.96 μmol) were added. The mixture was heated to 100°C and stirred for 12 hours. LCMS showed that the product was the main product. The solvent was removed by concentration under reduced pressure, and the residue was extracted with ethyl acetate (5 mL×3) and water (20 mL). The residue was purified by thin layer chromatography (dichloromethane / methanol=10 / 1) twice to give the title compound (26 mg).

[0338] MS m / z(ESI):520.6[M+H] +

[0339] Step 8: Synthesis of 4-(isopropylamino)-3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)benzofuro[3,2-b]pyridine-7-carbonitrile (Intermediate L)

[0340] Dissolve tert-butyl 4-[5-[7-cyano-4-(isopropylamino)benzofuro[3,2-b]pyridin-3-yl]-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (L-8, 20 mg, 38.49 μmol) in a mixture of dichloromethane (3 mL) and trifluoroacetic acid (0.6 mL) and stir at room temperature for 2 hours. LCMS showed predominantly the product. Concentrate to remove the solvent to afford the title compound (16 mg).

[0341] MS m / z(ESI):420.10[M+H] +

[0342] Intermediate M: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde

[0343] Step 1: Synthesis of 6-bromo-3-iodo-1-methyl-1H-indazole (M-2)

[0344] Compound 6-bromo-3-iodo-1H-indazole (M-1, 5.0 g, 15.5 mmol) and potassium hydroxide (2.17 g, 38.71 mmol) were dissolved in acetone (30 mL). The temperature was lowered to 0°C, and methyl iodide (3.30 g, 23.22 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filter cake was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (3.15 g).

[0345] MS m / z(ESI):336.9[M+H] +

[0346] Step 2: Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (M-3)

[0347] At room temperature, 6-bromo-3-iodo-1-methyl-1H-indazole (M-2, 3.15 g, 9.35 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.48 g, 8.35 mmol), cesium carbonate (5.44 g, 16.69 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.18 g, 0.25 mmol) were dissolved in tetrahydrofuran / water (90 mL / 15 mL). Under nitrogen, the temperature was raised to 80°C, and the reaction mixture was stirred at 80°C for 14 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (2.9 g).

[0348] Step 3: Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (M-4)

[0349] At room temperature, compound 3-(2,6-di(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (M-3, 2.9 g, 5.81 mmol), 4-(dimethoxymethyl)piperidine (1.87 g, 11.77 mmol), cesium carbonate (5.75 g, 17.64 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.27 g, 0.59 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (0.49 g, 0.59 mmol) were dissolved in toluene (40 mL). Under nitrogen protection, the temperature was raised to 100°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (2.07 g).

[0350] MS m / z(ESI):579.4[M+H] +

[0351] Step 4: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (M-5)

[0352] 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (M-4, 717 mg, 1.24 mmol) was dissolved in tetrahydrofuran / anhydrous ethanol (7 mL / 7 mL) at room temperature. Palladium on carbon (70 mg) and palladium hydroxide (70 mg) were then added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (0.1 MPa) for 12 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (471 mg).

[0353] MS m / z(ESI):401.1[M+H] +

[0354] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),7.47(d,J=8.8Hz,1H),6.90(dd,J=1.2Hz,9.2Hz,1H),6.82(s,1H),4.26-4.24(m,1H),4.10(d,J=6.4 Hz,1H),3.88(s,3H),3.80(d,J=12.4Hz,2H),3.28(s,6H),2.71-2.59(m,4H),2.30-2.14(m,2H),1.73(d,J=10.4Hz,3H),1.38-1.36(m,2H).

[0355] Step 5: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (Intermediate M)

[0356] Dissolve 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (M-5, 40 mg, 0.100 mmol) in acetone (1 mL) at room temperature. Add aqueous hydrochloric acid (2 mL, 1 N) dropwise at room temperature, raise the temperature to 80°C, and stir for 1 hour. Monitor the reaction for completion by TLC. Dilute with saturated aqueous sodium bicarbonate (20 mL) and extract with dichloromethane (15 mL x 3). Combine the organic phases and concentrate in vacuo to obtain the crude title compound, which is used directly in the next step.

[0357] Synthesis of Intermediate N: 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidine-4-carboxaldehyde

[0358] Step 1: Synthesis of 7-bromo-3-iodo-1H-indazole (N-2)

[0359] 7-Bromo-1H-indazole (N-1,5 g, 25.38 mmol) was dissolved in N,N-dimethylformamide (60 mL) at room temperature. Potassium hydroxide (2.15 g, 38.27 mmol) and iodine (9.71 g, 38.27 mmol) were added at 0°C. The reaction solution was stirred at room temperature for 16 h, quenched with water (100 mL), and then quenched with saturated aqueous sodium sulfite solution (100 mL) and stirred for 15 min. The reaction mixture was filtered and the filter was washed with water to obtain the title compound (8 g).

[0360] MS m / z(ESI):322.9[M+H] +

[0361] Step 2: Synthesis of 7-bromo-3-iodo-1-methyl-1H-indazole (N-3)

[0362] 7-Bromo-3-iodo-1H-indazole (N-2,8 g, 24.8 mmol) was dissolved in THF (150 mL) at room temperature, and a 1M solution of potassium tert-butoxide in THF (49.70 mL, 49.70 mmol) was added dropwise at 0°C for 1 hour. A solution of iodomethane (6.35 g, 44.72 mmol) in tetrahydrofuran (50 mL) was added dropwise at 0°C. After addition, the reaction mixture was stirred at 15°C for 14 hours. The reaction solution was filtered and concentrated, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (5.4 g).

[0363] MS m / z(ESI):336.9[M+H] +

[0364] Step 3: Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (N-4)

[0365] 7-Bromo-3-iodo-1-methyl-1H-indazole (N-3,3 g, 8.9 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.09 g, 9.8 mmol), potassium carbonate (2.46 g, 17.8 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (653.68 mg, 0.893 mmol) were dissolved in 1,4-dioxane / water (30 mL / 3 mL) at room temperature. The atmosphere was replaced with nitrogen, the temperature was raised to 90°C, and the mixture was stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), separated, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (2.58 g).

[0366] MS m / z(ESI):500.1[M+H] +

[0367] Step 4: Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (N-5)

[0368] At room temperature, 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (N-4, 2.58 g, 5.16 mmol), 4-(dimethoxymethyl)piperidine (1.64 g, 10.32 mmol), cesium carbonate (5.05 g, 15.48 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (241 mg, 0.516 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (452 ​​mg, 0.540 mmol) were dissolved in 1,4-dioxane (40 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 100°C, and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), separated, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (1.16 g).

[0369] MS m / z(ESI):579.4[M+H] +

[0370] Step 5: Synthesis of 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (N-6)

[0371] 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (N-5, 980 mg, 1.69 mmol) was dissolved in tetrahydrofuran / anhydrous ethanol (7 mL / 7 mL) at room temperature. Palladium on carbon (90 mg) and palladium hydroxide (90 mg) were then added. The atmosphere was replaced with hydrogen, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound (590 mg).

[0372] MS m / z(ESI):401.1[M+H] +

[0373] Step 6: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidine-4-carbaldehyde (Intermediate N)

[0374] Dissolve 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (N-6, 37 mg, 0.092 mmol) in acetone (1 mL) at room temperature. Add aqueous hydrochloric acid (2 mL, 1 N) dropwise at room temperature, raise the temperature to 80°C, and stir for 1 hour. Monitor the reaction for completion by TLC. Dilute with saturated aqueous sodium bicarbonate (20 mL) and extract with dichloromethane (15 mL x 3). Combine the organic phases and concentrate in vacuo to obtain the crude title compound, which is used directly in the next step.

[0375] Synthesis of Intermediate O:N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide

[0376] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate (O-2)

[0377] At room temperature, methyl 4-bromo-2-fluorobenzoate (O-1, 2.0 g, 8.58 mmol) and 4-(dimethoxymethyl)piperidine (2.05 g, 12.87 mmol) were dissolved in 1,4-dioxane (30 mL). Cesium carbonate (5.58 g, 17.16 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (401 mg, 0.86 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (719 mg, 0.86 mmol) were added. The reaction system was purged with nitrogen three times and the reaction mixture was stirred at 100 ° C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (1.44 g).

[0378] MS m / z(ESI):312.1[M+H] +

[0379] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid (O-3)

[0380] Methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate (O-2, 1.44 g, 4.63 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL) at room temperature, and lithium hydroxide monohydrate (486 mg, 11.58 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, the mixture was diluted with water (20 mL), and the pH was adjusted to approximately 3-4 with 2N aqueous hydrochloric acid. Solids precipitated and were filtered. The filter cake was washed with water to obtain a crude product. The crude product was dissolved in ethyl acetate (20 mL), washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.30 g).

[0381] MS m / z(ESI):298.1[M+H] +

[0382] Step 3: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (O-4)

[0383] At room temperature, 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid (O-3, 1.30 g, 4.37 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (862 mg, 5.24 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (1.69 g, 13.11 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.99 g, 5.24 mmol) were added. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound (1.30 g).

[0384] MS m / z(ESI):408.2[M+H] +

[0385] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (Intermediate O)

[0386] At room temperature, 4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (O-4, 700 mg, 1.72 mmol) was dissolved in acetone (9 mL). Aqueous hydrochloric acid (3 mL, 2N) was added, and the mixture was heated to 80°C and stirred for 1 hour. After the reaction, the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate was added to adjust the pH to 7-8, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (520 mg).

[0387] MS m / z(ESI):362.1[M+H] +

[0388] Intermediate P: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid

[0389] Step 1: Synthesis of tert-butyl 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylate (P-1)

[0390] Dissolve 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (C-3, 200 mg, 960.67 μmol) in dimethyl sulfoxide (1 mL), add tert-butyl piperidine-4-carboxylate (534 mg, 2.88 mmol) and N,N-diisopropylethylamine (248 mg, 1.92 mmol, 334.65 μL), and microwave the mixture at 120°C for 2 h. LCMS showed the product was the primary product. Ethyl acetate (5 mL) and water were added to the reaction mixture, which was then extracted with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1). The solvent was then concentrated under reduced pressure to afford the title compound (217 mg).

[0391] MS m / z(ESI):374.10[M+H] +

[0392] Step 2: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (Intermediate P)

[0393] Dissolve tert-butyl 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylate (P-1, 171 mg, 457.90 μmol) in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (1 mL) and allow to react at room temperature for 2 hours. Monitor the reaction by LCMS. After completion, concentrate the solution under reduced pressure to remove the solvent and obtain the title compound (145 mg).

[0394] MS m / z(ESI):318.10[M+H] +

[0395] Intermediate Q: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxaldehyde

[0396] Referring to the synthesis method of intermediate G, intermediate G-1 was replaced with 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, and intermediate Q was prepared by the same method.

[0397] Synthesis of Intermediate R: 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde

[0398] Step 1: Synthesis of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (R-2)

[0399] To a stirred solution of 6-bromo-1-methyl-1H-indazol-3-amine (R-1, 10.00 g, 44.248 mmol) in glacial acetic acid (6.29 g, 104.87 mmol) and water (30 mL) was added acrylic acid (3.189 g, 44.248 mmol) at room temperature. The mixture was stirred at 105°C under nitrogen for 20 h. The resulting residue was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (4.2 g).

[0400] MS m / z(ESI):298.14[M+H] +

[0401] Step 2: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R-3)

[0402] At room temperature, 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (R-2, 4.2 g, 14.14 mmol) and urea (4.24 g, 70.71 mmol) were dissolved in glacial acetic acid (50.0 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 140°C. The reaction mixture was stirred at 140°C for 16 hours. After the mixture was cooled to room temperature, concentrated hydrochloric acid (10.0 mL) was added and the reaction mixture was heated to 140°C again with stirring for 30 minutes. After completion of the reaction, the residue was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (1.3 g).

[0403] MS m / z(ESI):323.15[M+H] +

[0404] Step 3: Synthesis of 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R-4)

[0405] At room temperature, 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R-3, 500 mg, 1.548 mmol), 4-(dimethoxymethyl)piperidine (492.26 mg, 3.096 mmol), cesium carbonate (1.51 g, 4.644 mmol) and [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (78.03 mg, 0.093 mmol) were dissolved in 1,4-dioxane (10 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 100°C, and the reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with dichloromethane (30 mL). AcOH (2 mL, 2N) was added dropwise to adjust the pH to 6. The mixture was diluted with water and separated. The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain the title compound (430 mg).

[0406] MS m / z(ESI):402.1[M+H] +

[0407] 1H NMR(400MHz, DMSO-d6)δ10.50(s,1H),7.45(d,J=8.8Hz,1H),6.93-6.83(m,2H),4.10(d,J=6.4Hz,1H),3.90 -3.87(m,5H),3.80(d,J=12.4Hz,2H),3.28(s,6H),2.74-2.71(m,4H),1.76-1.73(m,3H),1.40-1.38(m,2H).

[0408] Step 4: Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (Intermediate R)

[0409] Dissolve 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (R-4, 30 mg, 74.73 μmol) in tetrahydrofuran (1 mL). Add dilute hydrochloric acid (2 M, 373.64 μL) and heat to 60°C for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure and lyophilized with water to obtain the crude title compound (25 mg), which was directly used in the next step.

[0410] Intermediate S: Synthesis of 3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-5H-pyrido[3,2-b]indole-7-carbonitrile

[0411] Step 1: Synthesis of 5-bromo-2-chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine (S-1)

[0412] Dissolve 5-bromo-2,4-dichloro-3-nitropyridine (2 g, 7.36 mmol) in N,N-dimethylformamide (10 mL), add tetrahydropyran-4-amine (744.04 mg, 7.36 mmol) and triethylamine (1.12 g, 11.03 mmol, 1.54 mL), and stir at room temperature for 3 hours. Monitor the reaction by LCMS. After completion, add the reaction solution to an appropriate amount of water and extract with ethyl acetate (20 mL x 3). The organic phase is washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (2.08 g).

[0413] MS m / z(ESI):336.0 / 338.0[M+H] +

[0414] Step 2: Synthesis of 4-(5-bromo-3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-3-fluorobenzonitrile (S-2)

[0415] Dissolve 5-bromo-2-chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine (1.8 g, 5.35 mmol) in 1,4-dioxane (20 mL). Add tetrakistriphenylphosphine palladium (618.00 mg, 534.81 μmol) and 3-fluoro-4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]benzonitrile (1.32 g, 5.35 mmol). Stir at room temperature for 12 hours. LCMS monitoring indicated a relatively complete reaction. The reaction mixture was extracted with appropriate amounts of water and dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford the title compound (800 mg).

[0416] MS m / z(ESI):421.0 / 423.0[M+H] +

[0417] Step 3: Synthesis of tert-butyl 4-(5-(6-(4-cyano-2-fluorophenyl)-5-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (S-3)

[0418] Under nitrogen atmosphere, 4-(5-bromo-3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-3-fluorobenzonitrile (700 mg, 1.66 mmol) was dissolved in 1,4-dioxane (5 mL), and tert-butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (449.28 mg, 1.66 mmol) and trimethylacetic acid (50. The mixture was added with 1,4-dimethyl-1,4-diphenyl-2-oxo-1,4-dimethyl-1,4-dioxo ...

[0419] MS m / z(ESI):611.2[M+H] +

[0420] Step 4: Synthesis of tert-butyl 4-(5-(5-amino-6-(4-cyano-2-fluorophenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (S-4)

[0421] Tert-butyl 4-(5-(6-(4-cyano-2-fluorophenyl)-5-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (120 mg, 196.51 μmol) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). 10% palladium on carbon (55% wt H2O, 24 mg) was added and heated to 50°C under a hydrogen atmosphere for overnight reaction. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to yield (44 mg).

[0422] MS m / z(ESI):581.3[M+H] +

[0423] Step 5: Synthesis of tert-butyl 4-(5-(7-cyano-4-((tetrahydro-2H-pyran-4-yl)amino)-5H-pyrido[3,2-b]indol-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (S-5)

[0424] Tert-butyl 4-(5-(5-amino-6-(4-cyano-2-fluorophenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (44 mg, 75.77 μmol) and cesium carbonate (123.44 mg, 378.87 μmol) were dissolved in N,N-dimethylformamide (1 mL) and the temperature was raised to 100°C for overnight reaction. LCMS monitoring showed that the reaction was complete. An appropriate amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phase was washed three times with saturated brine, concentrated under reduced pressure, and purified by thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain (3.3 mg).

[0425] MS m / z(ESI):561.3[M+H] +

[0426] Step 6: Synthesis of 3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Intermediate S)

[0427] Dissolve tert-butyl 4-[5-[7-cyano-4-[tetrahydropyran-4-ylamino]-5H-pyrido[3,2-b]indol-3-yl]-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (3.3 mg, 5.89 μmol) in methanol (1.99 mL) and add a solution of hydrochloric acid (4 M, 29.43 μL) in 1,4-dioxane. The mixture is allowed to react at room temperature for 3 hours. LCMS monitoring indicates a reaction. The precipitated solid in the reaction solution is filtered and collected to give the title compound (1.3 mg).

[0428] MS m / z(ESI):461.1[M+H] +

[0429] Intermediate T: Synthesis of 3-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile

[0430] Step 1: Synthesis of tert-butyl 3-(1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-2)

[0431] Dissolve 2-bromo-1,3,4-thiadiazole (2 g, 12.12 mmol) in N,N-dimethylformamide (20 mL), add tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-1, 2.83 g, 13.33 mmol) and N,N-diisopropylethylamine (3.13 g, 24.24 mmol, 4.22 mL), raise the temperature to 100°C, and stir for 12 hours. LCMS monitoring indicates completion of the reaction. Add an appropriate amount of water to the reaction solution and extract with ethyl acetate (30 mL x 3). The organic phase is washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford the title compound (3 g).

[0432] MS m / z(ESI):297.1[M+H] +

[0433] Step 2: Synthesis of tert-butyl 3-(5-(6-(4-cyano-2-fluorophenyl)-4-isopropylamino-5-nitropyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-3)

[0434] Under nitrogen atmosphere, 4-(5-bromo-4-isopropylamino-3-nitropyridin-2-yl)-3-fluorobenzonitrile (A-3, 1.02 g, 2.69 mmol) was dissolved in 1,4-dioxane (30 mL), and tert-butyl 3-(1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-2, 1.2 g, 4.05 mmol) and pivalic acid ( The mixture was added with 1,4-diphenylphosphine-9,9-dimethylxanthene (82.70 mg, 809.75 μmol), cuprous iodide (102.81 mg, 539.83 μmol), palladium acetate (121.20 mg, 539.83 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (624.71 mg, 1.08 mmol), and cesium carbonate (2.64 g, 8.10 mmol). The mixture was heated to 100°C and stirred for 12 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered through celite, and the filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (700 mg).

[0435] MS m / z(ESI):595.2[M+H] +

[0436] Step 3: Synthesis of tert-butyl 3-(5-(5-amino-6-(4-cyano-2-fluorophenyl)-4-isopropylaminopyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-4)

[0437] Tert-butyl 3-(5-(6-(4-cyano-2-fluorophenyl)-4-isopropylamino-5-nitropyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-3, 700 mg, 1.18 mmol) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). 10% palladium on carbon (55% wt H2O, 140 mg) was added and the mixture was heated to 50°C under a hydrogen atmosphere for 3-5 hours. LCMS monitoring showed that the reaction solution was filtered through celite, and the collected filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (505 mg).

[0438] m / z:ES + [M+H] + =565.3

[0439] Step 4: Synthesis of tert-butyl 3-(5-(7-cyano-4-isopropylamino-5H-pyrido[3,2-b]indol-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-5)

[0440] Tert-butyl 3-(5-(5-amino-6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-4, 75 mg, 132.82 μmol) and cesium carbonate (216 mg, 662.94 μmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at 100°C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (30 mg).

[0441] MS m / z(ESI):545.20[M+H] +

[0442] Step 5: Synthesis of 3-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Intermediate T)

[0443] Tert-butyl 3-(5-(7-cyano-4-isopropylamino-5H-pyrido[3,2-b]indol-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (T-5, 30 mg, 55.08 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 ° C for 16 hours. The mixture was filtered and concentrated to dryness to give the title compound (40 mg).

[0444] MS m / z(ESI):445.10[M+H] + .

[0445] Intermediate V: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-hydroxypiperidine-4-carboxaldehyde

[0446] Step 1: Synthesis of 3-(6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (V-1)

[0447] 3-(6-Fluoropyridin-3-yl)piperidine-2,6-dione (C-3, 450 mg, 2.16 mmol) and 4-(hydroxymethyl)piperidin-4-ol (1.03 mg, 7.85 mmol) were dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (558.70 mg, 4.32 mmol) was added. The mixture was heated to 120°C and microwaved for 2.5 h. After LC-MS indicated completion of the reaction, 100 mL of ethyl acetate was added for dilution. The organic phase was washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to afford the title compound (320 mg).

[0448] Step 2: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-hydroxypiperidine-4-carbaldehyde (Intermediate V)

[0449] At room temperature, 3-(6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (V-1, 32 mg, 0.10 mmol) was dissolved in dimethyl sulfoxide (1 mL), and 2-iodoacylbenzoic acid (56 mg, 0.20 mmol) was slowly added with stirring. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (22 mg).

[0450] Example 1: Synthesis of 3-(5-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 1)

[0451] The crude product of 4-(isopropylamino)-3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (Intermediate A, 15 mg) and 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde (Intermediate C, 15 mg, 50 μmol) were dissolved in N,N-dimethylformamide (1 mL). Sodium acetate (9 mg, 107 μmol) was added and the mixture was allowed to react at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (15 mg, 71 μmol) was added and the reaction was continued overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was added dropwise to saturated sodium bicarbonate solution (4 mL). A solid precipitated and was filtered. The filter cake was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to obtain the title compound (2 mg).

[0452] MS m / z(ESI):704.3[M+H] + ;

[0453] 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),10.73(s,1H),8.89(d,J=9.0Hz,1H),8.43(s,1H),8.25(d,J=8.1Hz,1H),8. 05(s,1H),7.94(d,J=2.5Hz,1H),7.59-7.52(m,1H),7.40-7.32(m,1H),6.78(d,J=8.9Hz,1H),4.61-4.50(m,1H), 4.26(d,J=12.9Hz,2H),3.77-3.67(m,1H),3.60-3.53(m,3H),2.80(t,J=12.3Hz,2H),2.74-2.60(m,1H),2.58-2. 50(m,5H),2.24(d,J=6.8Hz,2H),2.23-2.09(m,1H),2.04-1.94(m,1H),1.84-1.76(m,6H),1.33(d,J=6.2Hz,6H).

[0454] Example 2: Synthesis of 3-(5-(4-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 2)

[0455] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate D, and compound 2 was prepared in the same manner.

[0456] MS m / z(ESI):772.3[M+H] + ;

[0457] 1H NMR (400MHz, DMSO-d6) δ11.44(s,1H),11.07(s,1H),8.94(d,J=8.9Hz,1H),8.44(s,1H),8.26(d,J=8.1Hz,1H),8.05(t,J=1.0H z,1H),7.66(d,J=8.5Hz,1H),7.58(dd,J=8.1,1.4Hz,1H),7.32(d,J=2.3Hz,1H),7.24(d,J=9.0Hz,1H),5.07(dd,J=12.9,5.4Hz ,1H),4.59-4.47(m,1H),4.06(d,J=13.1Hz,2H),3.57(s,4H),2.97(q,J=14.8,13.6Hz,2H),2.92-2.82(m,1H),2.60(d,J=2.0Hz ,1H),2.57-2.51(m,6H),2.23(d,J=6.7Hz,2H),2.07-1.96(m,1H),1.93-1.79(m,3H),1.52-1.41(m,1H),1.33(d,J=6.1Hz,6H).

[0458] Example 3: Synthesis of 3-(1-(1-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 3)

[0459] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and compound 3 was prepared in the same manner.

[0460] MS m / z(ESI):686.3[M+H] + ;

[0461] 1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.79(s,1H),8.93(s,1H),8.66(s,1H),8.30–8.24(m,1H),8.19– 8.12(m,1H),8.02(s,1H),7.98–7.93(m,1H),7.59–7.53(m,1H),7.39–7.34(m,1H),6.82–6.77(m,1H),4 .63–4.56(m,1H),4.49–4.33(m,2H),4.32–4.23(m,2H),3.77–3.67(m,2H),3.03–2.98(m,1H),2.85–2.6 0(m,4H),2.26–2.08(m,7H),2.01–1.95(m,1H),1.83–1.76(m,2H),1.29–1.24(m,6H),1.19–1.05(m,4H).

[0462] Example 4: Synthesis of 3-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 4)

[0463] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate D, and compound 4 was prepared in the same manner.

[0464] MS m / z(ESI):754.3[M+H] + ;

[0465] 1H NMR (400MHz, DMSO-d6) δ11.34(s,1H),11.06(s,1H),8.93(s,1H),8.66(s,1H),8.30–8.21(m,1H),8.20–8.08( m,1H),8.06–7.98(m,1H),7.70–7.62(m,1H),7.59–7.51(m,1H),7.35–7.28(m,1H),7.28–7.20(m,1H),5.12–5. 01(m,1H),4.66–4.55(m,1H),4.47–4.35(m,1H),4.13–3.99(m,2H),3.05–2.91(m,4H),2.91–2.83(m,1H),2.6 2–2.54(m,2H),2.27–2.21(m,2H),2.21–1.97(m,7H),1.92–1.79(m,3H),1.31–1.24(m,6H),1.22–1.12(m,2H).

[0466] Example 5: Synthesis of 3-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 5)

[0467] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate E, and compound 5 was prepared in the same manner.

[0468] MS m / z(ESI):740.4[M+H] +

[0469] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.18(s,1H),9.11(s,1H),8.90(s,1H),8.65(s,1H ),8.26(s,1H),7.74–7.65(m,1H),7.45–7.38(m,1H),7.32–7.26(m,1H),7.20(s,2H),5.12 –5.07(m,1H),4.38–4.18(m,2H),3.84–3.77(m,3H),3.08(s,2H),2.82–2.78(m,2H),2.60 –2.56(m,3H),1.99–1.93(m,3H),1.43–1.41(m,8H),1.24–1.23(m,6H),0.86–0.83(m,4H).

[0470] Example 6: Synthesis of 3-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 6)

[0471] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate F, and compound 6 was prepared in the same manner.

[0472] MS m / z(ESI):740.4[M+H] +

[0473] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),11.01-10.90(m,1H),8.95-8.86(m,1H),8.68-8.62(m,1H),8.29-8 .23(m,1H),8.18-8.07(m,1H),8.05-8.00(m,1H),7.58-7.48(m,2H),7.08-7.01(m,2H),5.08-5.00(m,1H) ,4.64-4.56(m,1H),4.46-4.36(m,1H),4.36-4.16(m,3H),3.93-3.86(m,2H),3.04-2.96(m,2H),2.96-2. 76(m,4H),2.27-2.22(m,2H),2.21-2.08(m,6H),1.85-1.80(m,2H),1.29-1.26(m,6H),1.26-1.21(m,4H).

[0474] Example 7: Synthesis of 3-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido(3,2-b)indole-7-carbonitrile (Compound 7)

[0475] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate G, and compound 7 was prepared in the same manner.

[0476] MS m / z(ESI):755.3[M+H] +

[0477] 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),11.06(s,1H),8.94(s,1H),8.66(s,1H),8.29–8.22(m,1H),8.19–8.13(m,1H),8.05–8 .00(m,1H),7.58–7.53(m,1H),6.95–6.90(m,1H),6.85–6.82(m,1H),6.67–6.61(m,1H),5.32–5.26(m,1H),4.65–4.57(m,1H) ,4.45–4.39(m,1H),3.64–3.57(m,2H),3.05–2.98(m,2H),2.68–2.62(m,3H),2.28–2.24(m,2H),2.19–2.12(m,5H),2.09–2. 06(m,1H),2.02–1.96(m,2H),1.87–1.80(m,2H),1.72–1.63(m,2H),1.29–1.26(m,6H),1.25–1.23(m,3H),0.87–0.80(m,2H).

[0478] Example 8: Synthesis of 3-(1-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]non-7-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 8)

[0479] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate H, and compound 8 was prepared in the same manner.

[0480] MS m / z(ESI):794.4[M+H] +

[0481] 1H NMR (400MHz, DMSO-d6) δ11.35(s,1H),11.06(s,1H),8.94-8.89(m,1H),8.68-8.64(m,1H),8.29-8.23(m,1H),8.19-8. 11(m,1H),8.03-7.99(m,1H),7.66-7.61(m,1H),7.57-7.53(m,1H),6.78-6.74(m,1H),6.66-6.61(m,1H),5.09-5.01( m,1H),4.67-4.55(m,1H),4.47-4.36(m,1H),3.77-3.68(m,4H),3.06-2.84(m,3H),2.64-2.53(m,2H),2.28-2.09(m,7 H),1.95-1.88(m,2H),1.78-1.72(m,2H),1.58-1.47(m,3H),1.29-1.26(m,6H),1.25-1.21(m,2H),1.04-0.91(m,2H).

[0482] Example 9: Synthesis of 3-(1-(1-((1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 9)

[0483] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate I, and compound 9 was prepared in the same manner.

[0484] MS m / z(ESI):701.30[M+H] +

[0485] 1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.82(s,1H),8.86(s,1H),8.59(s,1H),8.21-8.16(m,1H ),8.12-8.06(m,1H),7.98-7.94(m,1H),7.52-7.45(m,1H),6.87-6.77(m,4H),4.97-4.90(m,1H) ,4.58-4.48(m,1H),4.40-4.29(m,1H),3.50-3.42(m,2H),2.98-2.89(m,2H),2.66-2.46(m,5H) ,2.21-2.15(m,2H),2.14-2.00(m,8H),1.80-1.70(m,2H),1.22-1.19(m,6H),1.18-1.10(m,2H).

[0486] Example 10: Synthesis of 3-(5-(4-((1-(5-(2,4-dioxohexahydropyrimidin-1-yl)-pyridin-2-yl)-piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 10)

[0487] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate J (prepared according to patent WO2023023255A1), and compound 10 was prepared in the same manner.

[0488] MS m / z(ESI):705.2[M+H] +

[0489] 1H NMR(400MHz,DMSO-d6)δ11.53–11.40(m,1H),10.34(s,1H),8.97–8.90(m,1H),8.43(s,1H),8.29–8 .22(m,1H),8.09–8.00(m,2H),7.60–7.53(m,1H),7.50–7.44(m,1H),6.87–6.80(m,1H),4.60–4.51 (m,1H),4.32–4.24(m,2H),3.71–3.66(m,2H),3.62–3.47(m,4H),2.86–2.77(m,2H),2.73–2.66(m, 3H),2.26–2.19(m,2H),1.87–1.72(m,4H),1.36–1.31(m,6H),1.11–1.05(m,2H),0.79–0.73(m,2H).

[0490] Example 11: Synthesis of 3-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido(3,2-b)indole-7-carbonitrile (Compound 11)

[0491] Referring to the synthesis method of Example 1, intermediate C was replaced with intermediate K (prepared according to patent WO2022099117A1), and compound 11 was prepared in the same manner.

[0492] MS m / z(ESI):772.3(M+H) +

[0493] 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),11.10(s,1H),8.98–8.92(m,1H),8.44(s,1H),8.28–8.23(m,1H),8.05( s,1H),7.72–7.65(m,1H),7.60–7.55(m,1H),7.36–7.31(m,2H),5.14–5.05(m,1H),4.59–4.51(m,1H),3.74–3. 68(m,2H),3.58–3.54(m,3H),2.92–2.87(m,2H),2.57–2.53(m,4H),2.30–2.26(m,2H),2.06–1.99(m,1H),1.8 8–1.83(m,2H),1.40–1.39(m,1H),1.34–1.32(m,6H),1.24–1.22(m,2H),0.97–0.93(m,1H),0.86–0.82(m,3H).

[0494] Example 12: Synthesis of 3-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 12)

[0495] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate G, and compound 12 was prepared in the same manner.

[0496] MS m / z(ESI):773.3[M+H] +

[0497] 1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),11.09(s,1H),9.02(s,1H),8.49(s,1H),8.33–8.25(m,1H),8.08(s ,1H),7.65–7.57(m,1H),6.99–6.92(m,1H),6.86(s,1H),6.70–6.63(m,1H),5.35–5.25(m,2H),4.64–4.51 (m,1H),4.12(s,1H),3.75–3.58(m,6H),3.33–3.30(m,5H),2.96–2.83(m,2H),2.72–2.68(m,3H),2.65–2. 59(m,2H),2.22–2.14(m,1H),2.04–1.96(m,2H),1.89–1.82(m,2H),1.37–1.32(m,6H),1.25–1.21(m,1H).

[0498] Example 13: Synthesis of 3-(5-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylaminobenzofuro[3,2-b]pyridine-7-carbonitrile (Compound 13)

[0499] Referring to the synthetic method of Example 1, intermediate A was replaced by intermediate L, and compound 13 was prepared in the same manner.

[0500] MS m / z(ESI):705.3[M+H] +

[0501] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.35(s,1H),8.69-8.61(m,1H),8.54-8.48(m, 1H),8.45-8.36(m,1H),7.97-7.93(m,1H),7.35-7.32(m,1H),7.11-7.06(m,1H),4.8 4-4.71(m,1H),4.40-4.28(m,2H),4.13-4.07(m,2H),3.99-3.88(m,4H),2.76-2.62( m,2H),2.23-2.14(m,3H),2.04-1.98(m,10H),1.42-1.40(m,6H),1.36-1.35(m,2H).

[0502] Example 14: Synthesis of 3-(5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 14)

[0503] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate M, and compound 14 was prepared in the same manner.

[0504] MS m / z(ESI):757.3[M+H] +

[0505] 1 H NMR(400MHz,DMSO-d6)δ11.62–11.40(m,1H),10.86(s,1H),8.97–8.87(m,1H),8.40(s,1H),8.3 0–8.19(m,1H),8.04(s,1H),7.53–7.46(m,2H),6.94–6.89(m,1H),6.86–6.82(m,1H),4.78–4.68 (m,1H),4.28–4.24(m,1H),3.89(s,3H),3.83–3.77(m,2H),3.61–3.54(m,4H),2.80–2.60(m,5H) ,2.59–2.53(m,4H),2.36–2.23(m,3H),2.20–2.13(m,1H),1.91–1.72(m,4H),1.36–1.30(m,6H).

[0506] Example 15: Synthesis of 3-(5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 15)

[0507] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate N, and compound 15 was prepared in the same manner.

[0508] MS m / z(ESI):757.2[M+H] +

[0509] 1H NMR (400MHz, DMSO-d6) δ11.46(s,1H),10.88(s,1H),9.00–8.86(m,1H),8.44(s,1H),8.30–8. 21(m,1H),8.05(s,1H),7.62–7.53(m,1H),7.47–7.32(m,2H),7.09–6.94(m,3H),4.59–4.49( m,1H),4.36–4.31(m,1H),4.28–4.22(m,4H),3.67–3.53(m,4H),2.79–2.55(m,3H),2.32(s,3 H),2.24–2.13(m,2H),2.08(s,3H),1.94–1.86(m,2H),1.41–1.30(m,6H),0.93–0.81(m,3H).

[0510] Example 16: Synthesis of 3-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 16)

[0511] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate E, and compound 16 was prepared in the same manner.

[0512] MS m / z(ESI):758.3[M+H] +

[0513] 1H NMR (400MHz, DMSO-d6) δ11.65–11.28(m,1H),10.97(s,1H),8.98–8.87(m,1H),8.41(s,1H),8.28–8.19(m,1H),8.04( s,1H),7.57–7.48(m,1H),7.44–7.39(m,1H),7.28–7.24(m,1H),7.18–7.14(m,1H),5.12–5.06(m,1H),4.74–4.59(m, 1H),4.37–4.17(m,3H),3.81–3.72(m,2H),3.59–3.53(m,3H),3.18–3.15(m,1H),2.97–2.85(m,2H),2.77–2.69(m,2H) ),2.42–2.30(m,2H),2.30–2.20(m,2H),2.03–1.95(m,2H),1.87–1.72(m,4H),1.51–1.41(m,2H),1.35–1.30(m,6H).

[0514] Example 17: Synthesis of 3-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 17)

[0515] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate O, and compound 17 was prepared in the same manner.

[0516] MS m / z(ESI):764.3[M+H] +

[0517] 1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.83(s,1H),8.97-8.90(m,1H),8.4 7-8.42(m,1H),8.28-8.23(m,1H),8.07-8.03(m,1H),8.03-7.95(m,1H),7. 67-7.54(m,2H),6.85-6.69(m,2H),4.78-4.68(m,1H),4.58-4.46(m,1H),3 .92-3.85(m,2H),3.62-3.52(m,4H),2.90-2.81(m,2H),2.58-2.52(m,3H), 2.28-2.20(m,2H),2.21-1.96(m,3H),1.87-1.75(m,3H),1.38-1.29(m,6H),1.29-1.07(m,4H).

[0518] Example 18: Synthesis of 3-(5-(4-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 18)

[0519] 4-(Isopropylamino)-3-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (Intermediate A, 153 mg, 365.54 μmol) was dissolved in N,N-dimethylformamide (2 mL), 1-methylimidazole (75 mg, 913.85 μmol) was added to make it alkaline, and N,N,N',N' was added. 1-Tetramethylchloroformamidine hexafluorophosphate (215 mg, 767.63 μmol) was stirred at room temperature for 1 hour. 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (Intermediate P, 116 mg, 365.57 μmol) was dissolved in N,N-dimethylformamide and then made basic with 1-methylimidazole. The reaction was allowed to react at room temperature for 1 hour, monitored by LCMS. Preparative liquid chromatography (YMC C18, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of water (containing 0.5% ammonium bicarbonate) and acetonitrile (50%-80% acetonitrile)) afforded the title compound (92 mg).

[0520] MS m / z(ESI):718.3[M+H] +

[0521] 1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.80(s,1H),9.01-8.90(m,1H),8.49-8.41(m,1H),8.29-8.23(m,1H),8.0 8-8.02(m,1H),7.99-7.92(m,1H),7.61-7.54(m,1H),7.42-7.35(m,1H),6.86-6.79(m,1H),4.61-4.49(m,1H),4. 35-4.25(m,2H),3.83-3.71(m,3H),3.70-3.59(m,4H),3.59-3.52(m,2H),3.02-2.85(m,3H),2.73-2.62(m,1H),2 .24-2.12(m,1H),2.03-1.95(m,1H),1.77-1.69(m,2H),1.63-1.55(m,2H),1.38-1.31(m,6H),1.28-1.22(m,1H).

[0522] Example 19: Synthesis of 3-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 19)

[0523] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate Q, and compound 19 was prepared in the same manner.

[0524] MS m / z(ESI):773.2[M+H] +

[0525] 1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),11.11(s,1H),8.98-8.92(m,1H),8.49-8.41(m,1H),8.30-8.22(m,1H),8.0 9-8.02(m,1H),7.62-7.55(m,1H),7.03-6.95(m,1H),6.94-6.82(m,2H),5.41-5.31(m,1H),4.59-4.51(m,1H),3. 66-3.54(m,5H),3.18-3.09(m,2H),2.98-2.80(m,2H),2.77-2.63(m,3H),2.59-2.53(m,2H),2.34-2.27(m,2H),2 .09-1.95(m,2H),1.90-1.81(m,2H),1.76-1.63(m,2H),1.38-1.28(m,6H),1.28-1.20(m,3H),0.87-0.81(m,1H).

[0526] Example 20: Synthesis of 3-(5-(4-((1-(3-(2,4-dioxohexahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 20)

[0527] Referring to the synthetic method of Example 1, intermediate C was replaced by intermediate R, and compound 20 was prepared in the same manner.

[0528] MS m / z(ESI):758.2[M+H] +

[0529] 1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.49(s,1H),8.97–8.88(m,1H),8.4 4(s,1H),8.30–8.19(m,1H),8.05(s,1H),7.61–7.53(m,1H),7.49–7.38(m,1 H),6.96–6.87(m,1H),6.85–6.77(m,1H),4.61–4.49(m,1H),3.94–3.86(m, 4H),3.84–3.79(m,2H),3.62–3.53(m,3H),2.84–2.65(m,4H),2.58–2.51(m, 5H),2.35–2.20(m,2H),2.14–1.97(m,1H),1.90–1.72(m,3H),1.36–1.29(m,5H),1.28–1.20(m,2H),0.89–0.76(m,1H).

[0530] Example 21: Synthesis of 3-(5-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 21)

[0531] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate S, and compound 21 was prepared in the same manner.

[0532] MS m / z(ESI):746.2[M+H] +

[0533] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.13–8.84(m,1H),8.45(s,1H),8.32–8.21(m,1H),8.06(s,1H),8. 00–7.90(m,1H),7.54(s,1H),7.40–7.30(m,1H),6.85–6.74(m,1H),6.05–5.91(m,1H),5.37–5.24(m,1H) ,5.04–4.93(m,1H),4.38–4.18(m,2H),3.89–3.68(m,2H),3.65–3.48(m,4H),2.86–2.63(m,4H),2.38–1. 93(m,7H),1.91–1.72(m,3H),1.60–1.43(m,2H),1.32–1.20(m,4H),1.18–1.07(m,2H),0.91–0.78(m,1H).

[0534] Example 22: Synthesis of 3-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 22)

[0535] Referring to the synthetic method of Example 1, intermediate A was replaced by intermediate S, and intermediate C was replaced by intermediate E, and compound 22 was prepared in the same manner.

[0536] MS m / z(ESI):800.3[M+H] +

[0537] 1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.98(s,1H),9.16–8.83(m,1H),8.45(s,1H),8.35–8.20(m,1H),8.06 (s,1H),7.61–7.52(m,1H),7.46–7.38(m,1H),7.30–7.23(m,1H),7.19–7.12(m,1H),5.40–4.96(m,2H),4.57 (s,1H),4.46–4.19(m,2H),3.94–3.73(m,4H),3.65–3.52(m,5H),2.96–2.86(m,1H),2.79–2.65(m,3H),2.64 –2.54(m,4H),2.27–2.23(m,1H),2.09–1.97(m,3H),1.89–1.73(m,3H),1.57–1.45(m,2H),1.29–1.20(m,4H).

[0538] Example 23: Synthesis of 3-(5-(8-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-isopropylamino-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 23)

[0539] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate T, and compound 23 was prepared in the same manner.

[0540] MS m / z(ESI):731.3[M+H] +

[0541] 1H NMR (400MHz, DMSO-d6) δ12.04(s,1H),10.87(s,1H),8.71(s,1H),8.43–8.42(m,1H),8.20( s,1H),7.95–7.94(m,1H),7.72–7.69(m,1H),7.61–7.60(m,1H),7.56–7.53(m,1H),7.10–7. 08(m,1H),4.72–4.64(m,1H),4.32–4.25(m,4H),3.95–3.80(m,5H),3.01–2.95(m,4H),2.6 9–2.56(m,2H),2.28–2.16(m,3H),2.03–1.91(m,5H),1.42–1.40(m,6H),1.35–1.26(m,3H).

[0542] Example 24: Synthesis of 3-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 24)

[0543] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate K, and compound 24 was prepared in the same manner.

[0544] MS m / z(ESI):754.3[M+H] +

[0545] 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),11.09(s,1H),8.94(s,1H),8.66(s,1H),8.25(d,J=8.1Hz,1H),8.15 (d,J=9.4Hz,1H),8.03(s,1H),7.71-7.66(m,1H),7.58-7.54(m,1H),7.37-7.31(m,2H),5.14-5.06(m,1H) ,4.60(s,1H),4.47-4.36(m,1H),3.72(d,J=11.7Hz,2H),3.01(d,J=9.4Hz,2H),2.94-2.81(m,4H),2.28(d ,J=7.0Hz,2H),2.23-1.98(m,8H),1.85(d,J=12.6Hz,2H),1.76(s,1H),1.27(d,J=6.2Hz,6H),1.23(s,2H).

[0546] Example 25: Synthesis of 3-(1-(1-((1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 25)

[0547] Referring to the synthesis method of Example 1, compound 25 was prepared by replacing intermediate A with intermediate B and intermediate C with intermediate J.

[0548] MS m / z(ESI):687.3[M+H] +

[0549] 1H NMR (400MHz, DMSO-d6) δ11.35(s,1H),10.33(s,1H),8.92(s,1H),8.67(s,1H),8.26(d,J=8.0 Hz,1H),8.04(d,J=8.3Hz,2H),7.57(d,J=8.0Hz,1H),7.48(d,J=9.2Hz,1H),7.00-6.80(m,1H ),4.52-4.37(m,1H),4.30(s,2H),3.81-3.58(m,2H),3.10-2.94(m,2H),2.92-2.76(m,3H),2 .78-2.64(m,3H),2.40-2.29(m,2H),2.29-2.02(m,7H),1.91-1.71(m,4H),1.29-1.25(m,6H).

[0550] Example 26: Synthesis of 3-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 26)

[0551] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate B, and intermediate C was replaced by intermediate U, and compound 26 was prepared in the same manner.

[0552] MS m / z(ESI):686.2[M+H] +

[0553] 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),10.25(s,1H),8.93(s,1H),8.66(s,1H),8.26(d,J=8.1H z,1H),8.15(d,J=9.4Hz,1H),8.03(t,J=1.0Hz,1H),7.56(dd,J=8.1,1.4Hz,1H),7.17–7.09(m ,2H),6.97–6.90(m,2H),4.60(s,1H),4.50–4.35(m,1H),3.77–3.64(m,5H),3.03-3.01(m,2H) ,2.68(t,J=5.2Hz,4H),2.21(d,J=38.1Hz,9H),1.82(d,J=12.7Hz,3H),1.27(d,J=6.2Hz,6H).

[0554] Example 27: Synthesis of 3-(5-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (Compound 27)

[0555] Referring to the synthesis method of Example 1, intermediate C was replaced by intermediate V, and compound 27 was prepared in the same manner.

[0556] MS m / z(ESI):720.3[M+H] +

[0557] 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.82(s,1H),9.04–8.78(m,1H),8 .46–8.23(m,1H),8.12–7.92(m,1H),7.70–7.03(m,3H),6.86–6.63(m,1H) ,5.43–5.20(m,1H),4.65–4.27(m,2H),3.96–3.67(m,2H),3.51(s,6H),2. 82–2.62(m,3H),2.44–1.84(m,7H),1.68–1.29(m,8H),0.98–0.75(m,3H).

[0558] Example 28: Synthesis of 3-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (Compound 28)

[0559] Referring to the synthesis method of Example 1, compound 28 was prepared by replacing intermediate A with intermediate L and intermediate C with intermediate E.

[0560] MS m / z(ESI):379.8[(M+2H) / 2] +

[0561] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.19–8.97(m,1H),8.51(s,1H),8.41(s,1H),8.31–8.16(m,1H),7.95–7. 75(m,1H),7.49–7.39(m,1H),7.33–7.22(m,1H),7.22–7.12(m,1H),5.20–5.01(m,1H),4.82–4.63(m,1H),4.39 –4.29(m,1H),4.28–4.14(m,1H),3.83–3.70(m,2H),3.67–3.52(m,3H),3.01–2.81(m,2H),2.81–2.64(m,3H),2 .46–2.30(m,2H),2.29–2.13(dt,J=25.2,7.7Hz,2H),2.04–1.69(m,5H),1.49–1.11(m,9H),0.94–0.76(m,1H).

[0562] Example 29: Synthesis of 3-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (Compound 29)

[0563] Referring to the synthetic method of Example 1, compound 29 was prepared by the same method except that intermediate A was replaced by intermediate L and intermediate C was replaced by intermediate G.

[0564] MS m / z(ESI):774.60[M+H] +

[0565] 1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.12–8.96(m,1H),8.53(s,1H),8.43(s,1H),8.29–8.23(m ,1H),7.92–7.85(m,1H),6.95–6.89(m,1H),6.85–6.79(m,1H),6.66–6.59(m,1H),5.31–5.24(m,1 H),4.77–4.68(m,1H),3.67–3.46(m,6H),2.97–2.80(m,2H),2.74–2.53(m,8H),2.31–2.22(m,2H ),2.06–1.93(m,2H),1.87–1.79(m,2H),1.76–1.60(m,2H),1.44–1.33(m,6H),1.31–1.25(m,2H).

[0566] Example 30: Synthesis of 3-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4)-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (Compound 30)

[0567] Referring to the synthesis method of Example 1, compound 30 was prepared by the same method except that intermediate A was replaced by intermediate L and intermediate C was replaced by intermediate Q.

[0568] MS m / z(ESI):774.40[M+H] +

[0569] 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.11–9.01(m,1H),8.53(s,1H),8.44(s,1H),8.32–8.21(m,1H),7.94–7.83(m,1H),7.04–6.83(m,3H),5.3 9–5.31(m,1H),4.78–4.67(m,1H),3.69–3.52(m,6H),3.18–3.07(m,2H) ,2.95–2.83(m,2H),2.75–2.54(m,8H),2.35–2.26(m,2H),2.04–1.93(m, 2H),1.90–1.80(m,2H),1.77–1.59(m,2H),1.43–1.28(m,6H).

[0570] Example 31: Synthesis of 3-(5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (Compound 31)

[0571] Referring to the synthetic method of Example 1, compound 31 was prepared by replacing intermediate A with intermediate L and intermediate C with intermediate M.

[0572] MS m / z(ESI):379.3[(M+2H) / 2] +

[0573] 1 H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.09–9.03(m,1H),8.58–8.51(m,1H),8.47–8.40(m,1H),8.30–8.23 (m,1H),7.92–7.86(m,1H),7.51–7.43(m,1H),6.95–6.89(m,1H),6.87–6.81(m,1H),4.82–4.64(m,2H),4.2 9–4.22(m,1H),3.94–3.85(m,3H),3.85–3.76(m,2H),3.58(s,3H),2.80–2.70(m,2H),2.66–2.58(m,2H),2 .37–2.22(m,3H),2.20–2.11(m,1H),1.91–1.69(m,4H),1.47–1.35(m,6H),1.23(s,3H),0.89–0.76(m,2H).

[0574] Example 32: Synthesis of 3-(5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (Compound 32)

[0575] Referring to the synthesis method of Example 1, intermediate A was replaced by intermediate L, and intermediate C was replaced by intermediate N, and compound 32 was prepared in the same manner.

[0576] MS m / z(ESI):379.3[(M+2H) / 2] +

[0577] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.08–9.01(m,1H),8.54–8.50(m,1H),8.43–8.40(m,1H) ),8.28–8.22(m,1H),7.91–7.84(m,1H),7.41–7.34(m,1H),7.03–6.99(m,2H),4.79–4.66(m,1 H),4.36–4.30(m,1H),4.27–4.23(m,3H),3.64–3.52(m,4H),3.26(s,2H),2.75–2.61(m,5H),2 .60–2.53(m,4H),2.37–2.27(m,3H),2.22–2.11(m,2H),1.96–1.85(m,3H),1.41–1.35(m,6H).

[0578] Example 33: Synthesis of 3-(5-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)benzofuro[3,2-b]pyridine-7-carbonitrile (Compound 33)

[0579] Referring to the synthesis method of Example 1, compound 33 was prepared by replacing intermediate A with intermediate L and intermediate C with intermediate R.

[0580] MS m / z(ESI):759.3[M+H] +

[0581] 1H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 9.06 (d, J = 8.4Hz, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8. 27(d,J=8.0Hz,1H),7.89(dd,J=8.0,1.3Hz,1H),7.44(d,J=9.0Hz,1H),6.94–6.78(m,2H), 4.79–4.69(m,1H),3.93–3.77(m,6H),3.58(s,3H),2.80–2.69(m,3H),2.55(m,3H),2.26(m ,1H),1.85(d,J=13.2Hz,2H),1.38(d,J=6.4Hz,4H),1.31–1.26(m,6H),1.25–1.24(m,4H).

[0582] Example 34: Synthesis of 4-(4-((4-(5-(7-cyano-4-(isopropylamino)benzofuro[3,2-b]pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (Compound 34)

[0583] Referring to the synthesis method of Example 1, compound 34 was prepared by replacing intermediate A with intermediate L and intermediate C with intermediate O.

[0584] MS m / z(ESI):765.3[M+H] +

[0585] 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.62(s,1H),9.05(d,J=8.5Hz,1H),8.54(s,1H),8.43(s,1H),8.27(d,J =8.0Hz,1H),8.00(d,J=7.3Hz,1H),7.89(d,J=8.0Hz,1H),7.62(s,1H),6.81(d,J=8.9Hz,1H),4.73(d,J=6.8Hz ,1H),3.90(d,J=12.4Hz,3H),3.79(d,J=13.5Hz,1H),3.57(s,3H),3.02(t,J=12.1Hz,2H),2.88–2.75(m,4H),2 .23(d,J=6.7Hz,3H),2.18–1.96(m,4H),1.90(d,J=13.3Hz,2H),1.80(d,J=12.4Hz,2H),1.38(d,J=6.4Hz,6H).

[0586] Biological activity and related properties test examples

[0587] Test Example 1: HiBiT method to detect the degradation effect of compounds on IRAK4 in THP-1-HiBiT-IRAK4 overexpressing cells

[0588] THP-1-HiBiT-IRAK4 cells (manufactured by Shanghai Medicilon) were seeded in 96-well flat-bottom white plates (Corning, Cat. No. 3917) at a seeding density of 60,000 cells / 25 μL / well. Compounds were then added at a concentration gradient of 25 μL / well (final concentration: 5 μM starting concentration, 5-fold dilutions, 8 concentrations total), mixed, and incubated at 37°C in a 5% CO2 incubator for 24 hours. The experimental groups were as follows: sample treatment group (cells + compound gradient), solvent control group (cells + solvent control), and blank control group (medium only). 50 μL of Nano-Glo HiBiT Lytic Detection buffer (Promega, Cat. No. N3040) was added and incubated at room temperature with shaking (350 rpm) for 10 minutes. Fluorescence (RLU) values ​​were read using a microplate reader (PE Envision). The degradation rate of the compound on IRAK4 (%) = (1-(RLU value of the sample treatment group-RLU value of the blank control group) / (RLU value of the solvent control group-RLU value of the blank control group)) × 100%, and the degradation rate of the compound at each concentration and the maximum degradation rate D max Graphpad Prism 9 software was used to perform nonlinear fitting based on compound concentration-degradation rate to obtain the degradation activity curve of the compound and calculate the half degradation concentration (DC50 ). D max The larger the value, the DC 50 The smaller the value, the stronger the degradation activity of the compound. max and DC 50 The values ​​are shown in Table 1.

[0589] Table 1. D of IRAK4 degraders max and DC 50

[0590] Test Example 2 Metabolic Stability Determination of the Disclosed Compounds in Liver Microsomes

[0591] 1. Test materials and instruments

[0592] 1. Source of liver microsomes: human liver microsomes (Corning 452161), CD-1 mouse liver microsomes (Corning 452701)

[0593] 2.Na2HPO4 (Shanghai test 20040618)

[0594] 3. KH2PO4 (Shanghai test 10017608)

[0595] 4.NADPH (Roche diagnostics gmbh 10107824001)

[0596] 5. Tolbutamide (Sigma-aldrich T0891-100G)

[0597] 6. Positive control compound verapamil (Aladdin V303890-100 mg)

[0598] 7.AB5500+ LC / MS

[0599] 2. Test steps

[0600] Preparation of 100 mM phosphate buffer (PBS): Weigh 7.098 g of Na₂HPO₄ and dissolve it in 500 mL of pure water by sonication to prepare Solution A. Weigh 3.400 g of KH₂PO₄ and dissolve it in 250 mL of pure water by sonication to prepare Solution B. Place Solution A on a stirrer and slowly add Solution B until the pH reaches 7.4 to prepare 100 mM PBS buffer.

[0601] 2. Preparation of reaction system

[0602] Prepare the reaction system according to the table below

[0603] Table 2 Reaction system preparation information

[0604] 3. Preincubate the reaction system in a 37°C water bath for 10 minutes. Add 40 μL of 10 mM NADPH solution (dissolved in 100 mM phosphate buffer) to the reaction system for a final NADPH concentration of 1 mM. Replace the NADPH solution with 40 μL of phosphate buffer as a negative control. This negative control is used to eliminate the effects of the chemical stability of the compound itself.

[0605] 4. 4 μL of 100 μM compounds of the present disclosure and the positive control compound verapamil were added to the reaction system to initiate the reaction. The final concentration of the compounds was 1 μM.

[0606] 5. After thorough mixing on a vortex shaker at 0.5, 15, 30, 45, and 60 minutes, remove 50 μL of the incubated sample and terminate the reaction with 4x the volume of glacial acetonitrile containing the internal standard (50 ng / mL tolbutamide). Centrifuge the sample at 4000 rpm for 15 minutes. After centrifugation, transfer 50 μL of the supernatant to the injection plate and mix thoroughly with 150 μL of ultrapure water for LC-MS / MS analysis.

[0607] All data were calculated using Microsoft Excel software. Peak areas were detected by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0608] In vitro half-life (t 1 / 2 ) is calculated by the slope (k):

[0609] in vitro 1 / 2 =0.693 / k

[0610] The t calculated by the above formula is 1 / 2 See Table 3 for values.

[0611] Table 3 Half-life values ​​of the disclosed compounds in liver microsomes

[0612] Test Example 3 Determination of the Potential Inhibitory Effect of the Disclosed Compounds on Voltage-Gated Potassium Ion Channel hERG

[0613] 1. Materials and Reagents

[0614] 1 Experimental materials and instruments

[0615] 1.1 Materials and Instruments

[0616] 2 Cell lines and culture

[0617] HEK293 cell line stably expressing hERG ion channel (Cat. No. K1236) was purchased from Invitrogen. The cell line was cultured in a medium containing 85% DMEM, 10% dialyzed fetal bovine serum, 0.1mM MEM non-essential amino acid solution, 100U / mL penicillin-streptomycin solution, 25mM HEPES, 5μg / mL blasticidin, and 400μg / mL geneticin. When the cell density grew to 40% to 80% of the bottom area of ​​the culture dish, trypsin was used for digestion and passage, and passaged three times a week. Before the experiment, cells were plated at 5×10 5 The cells were cultured at a density of 100 μg / mL in 6 cm culture dishes and induced with 1 μg / mL doxycycline for 48 h. The cells were then digested and seeded on glass slides for subsequent manual patch clamp experiments.

[0618] 3 Preparation of test compounds

[0619] 1) The test compound was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM.

[0620] 2) The stock solution was diluted with DMSO in a 1:3 gradient to form three other intermediate concentration solutions, with concentrations of 3.33 mM, 1.11 mM, and 0.37 mM, respectively.

[0621] 3) Prior to the experiment, the test compound stock solution and intermediate concentration solutions were diluted 1000-fold with NMDG extracellular solution to obtain a series of working solutions with concentrations of 10 μM, 3.33 μM, 1.11 μM, and 0.37 μM. Simultaneously, the 10 mM stock solution was diluted 333.33-fold with NMDG extracellular solution to obtain a 30 μM working solution. The DMSO content in the working solutions was 0.1-0.3% (v / v).

[0622] (Note: The DMSO content in the working solution should be controlled within 1% (volume ratio) to avoid cytotoxicity.)

[0623] 4) After preparing the working solution, visually inspect it for precipitation or turbidity. If so, this may be due to poor solubility of the compound in physiological solutions. Further sonication in a water bath for 30 minutes may be recommended to improve solution clarity.

[0624] 5) Determine the potential inhibitory effect of the test substance on hERG channels at five concentrations of 30 μM, 10 μM, 3.33 μM, 1.11 μM, and 0.37 μM, fit the dose-effect curve, and calculate the IC 50 .

[0625] 2. Experimental Methods

[0626] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank on the microscope stage.

[0627] 2) Using an Olympus IX51, IX71, or IX73 inverted microscope, center the field of view on a suitable cell. Using a ×10 objective lens, locate the tip of the glass electrode and position it in the center of the field of view. Then, use the micromanipulator to lower the electrode while adjusting the coarse focus knob to gradually bring the electrode closer to the cell.

[0628] 3) When approaching the cell, switch to a ×40 objective lens for observation and use the micromanipulator to fine-tune the gear to gradually bring the electrode closer to the cell surface.

[0629] 4) Apply negative pressure to form a seal with a resistance higher than 1 GΩ between the electrode tip and the cell membrane.

[0630] 5) In voltage clamp mode, the instantaneous capacitance current C fast Then, short negative pressures were repeatedly applied to rupture the membrane, ultimately establishing whole-cell recording mode.

[0631] 6) Under the condition of membrane potential clamp at -60mV, the slow capacitive current C slow 、Cell membrane capacitance (C m ) and input membrane resistance (R a ) are compensated separately.

[0632] 7) After the cells stabilize, change the clamping voltage to -90 mV, set the sampling frequency to 20 kHz, and the filtering frequency to 10 kHz. Leakage current detection conditions are: clamping voltage to -80 mV, time duration 500 ms.

[0633] 8) The hERG current measurement method is as follows: a 4.8-second depolarization command voltage is applied to depolarize the membrane potential from -80 mV to +30 mV. Then, a 5.2-second repolarization voltage is applied to reduce the membrane potential to -50 mV to eliminate channel inactivation, thereby observing the hERG tail current. The peak value of the tail current is the magnitude of the hERG current.

[0634] 9) hERG currents used to detect test compounds were recorded for 120 seconds before administration to assess the stability of hERG currents generated by the test cells. Only cells that were stable within the acceptable range of the evaluation criteria were allowed to proceed to subsequent compound testing.

[0635] 10) Determine the inhibitory effect of the test compound on the hERG current: First, the hERG current measured in the extracellular solution containing 0.1% DMSO is used as the detection baseline. After the hERG current remains stable for at least 5 minutes, the solution containing the test compound is perfused around the cells in sequence from low concentration to high concentration. After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cells and record the hERG current synchronously. After the recorded current tends to stabilize, record the last 5 hERG current values, and take the average value as the final current value at a specific concentration. After the compound is tested, add 150nM dofetilide to the same cell to completely inhibit its current as a positive control for the cell. At the same time, the positive compound dofetilide is synchronously detected using the same patch clamp system before and after the end of the test compound experiment to ensure the reliability and sensitivity of the entire detection system.

[0636] 3. Data Analysis

[0637] The data were exported by PatchMaster software and analyzed according to the following steps:

[0638] 1) After perfusing blank solvent or 30μM, 10μM, 3.33μM, 1.11μM and 0.37μM compound working solutions, the average of the five consecutive current values ​​obtained was calculated and used as the "tail current magnitude" 空白 ” and “tail current size 化合物 ”.

[0639] 2) The current suppression percentage is calculated using the following formula.

[0640] 3) The dose-effect curve was fitted using Graphpad Prism 8.0 software and the IC was calculated. 50 value.

[0641] The hERG inhibition of the disclosed compounds is shown in Table 4 below. The test data show that the hERG inhibition activity of the disclosed compounds is poor and the potential safety risk in the future is relatively small.

[0642] Table 4 Inhibitory activity of the disclosed compounds on voltage-gated potassium channel hERG

[0643] Test Example 4 Determination of Plasma Protein Binding Rate of the Disclosed Compounds

[0644] 1. Test materials and instruments

[0645] 1. CD-1 mouse plasma (BioIVT)

[0646] 2. Human plasma (from healthy Asian volunteers from Weifang High-tech Industrial Development Zone People's Hospital (collected at the hospital with ethical approval))

[0647] 3.Na2HPO4 (Sigma S5136-500G)

[0648] 4.NaH2PO4 (Sigma S3139-500G)

[0649] 5.NaCl (Sigma S5886-IKG)

[0650] 6. Positive control compound ketoconazole (Sigma Lot#SLBB5223V)

[0651] 7. Alprazolam (Ceriliant FE12172003)

[0652] 8. Labetalol (NIFDC 100484-201001)

[0653] 9. Ketoprofen (NIFDC 100337-201104)

[0654] 10. Polycarbonate centrifuge tube (BECKMAN, 343778)

[0655] 11. Ultracentrifuge rotor (BECKMAN, MLA-150)

[0656] 12. Optima™ MAX-XP Ultracentrifuge (BECKMAN)

[0657] 2. Test steps

[0658] 1. Prepare DMSO working solutions of the test compound and positive control compound at a concentration of 1 mM.

[0659] 2. Set the water bath, incubator, and ultracentrifuge to 37°C. Pre-incubate the rotor in a 37°C incubator for approximately 30 minutes.

[0660] 3. Thaw frozen plasma (stored at -80°C) in a room temperature water bath. Centrifuge at 3,220 g for 10 minutes to remove clots. Collect the supernatant into a fresh tube. Check and record the pH of the plasma.

[0661] 4. Pre-incubate the plasma in a 37°C water bath for 5 minutes.

[0662] 5. Add 3 μL of 1 mM working solution to 2997 μL of pre-warmed plasma to obtain a spiked plasma sample with a final concentration of 1 μM.

[0663] 6. Transfer 1 mL of spiked plasma sample to two ultracentrifuge tubes (n=2). Balance the ultracentrifuge tubes in a preheated rotor and incubate at 37°C, 5% CO2 for 30 minutes. After incubation, centrifuge the ultracentrifuge tubes at 800,000 g for 3 hours at 37°C.

[0664] 7. Transfer 50 μL of spiked plasma samples to six 0.6 mL tubes. Incubate the samples at 37°C, 5% CO2 for 0, 0.5, and 3.5 hours. At the designated time points, add 50 μL of PBS, mix thoroughly, and then add 400 μL of acetonitrile containing internal standards (IS, 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen) to precipitate the protein. Vortex the samples for 5 minutes and then centrifuge at 20,000 g for 15 minutes. The 0.5 hour sample is a non-centrifuged control sample.

[0665] 8. After ultracentrifugation, remove 50 μL from the center of the ultracentrifuge tube as the post-ultracentrifugation sample. Add 50 μL of blank plasma to this sample. Then, treat the sample identically to the uncentrifuged control sample. Transfer 100 μL of the supernatant to the injection plate and add 100 μL of ultrapure water to mix thoroughly. Prepare for LC-MS / MS analysis.

[0666] 9. Data Analysis: All calculations were performed using Microsoft Excel. The percentage of binding of the test compound and the control compound was calculated as follows:

[0667] Free rate % = (peak area ratio 超速离心后样品 / peak area ratio 非离心对照样品 )×100%

[0668] Binding rate % = 100% - free rate %

[0669] Table 5 Protein binding of the disclosed compounds in CD-1 mouse / human plasma

[0670] Test Example 5 Determination of membrane permeability and transport properties of the disclosed compounds

[0671] The membrane permeability and transport properties of the disclosed compounds were determined using the following test methods.

[0672] 1. Test materials and instruments

[0673] 1. Caco-2 cells (ATCC)

[0674] 2. HEPES (Solarbio 804D049), Penicillin / Streptomycin (Solarbio 20200109) and Trypsin / EDTA (Solarbio), PBS (Solarbio 20200620)

[0675] 3. Fetal bovine serum (FBS) (Sigma WXBD0055V), Lucifer yellow (Sigma MKCJ3738), NaHCO3 (Sigma SLBZ4647)

[0676] 4. Hank's balanced salt solution (HBSS) (Gibco 2085528) and non-essential amino acids (NEAA) (Gibco 2211548), Trypsin / EDTA (Gibco 2120732)

[0677] 5. High glucose DMEM medium (Corning 20319014)

[0678] 6.96-well HTS transwell plate(Corning,3391)

[0679] 7. Resistance tester (Millipore, ERS-2)

[0680] 8. Vision (Nexcelom Bioscience)

[0681] 9. Infinite 200PRO Microplate Reader (Tecan, Infinite M200PRO)

[0682] 10. Positive control compounds: metoprolol (Sinopharm 100084-201403), erythromycin (MCE 84550), and cimetidine (Sinopharm 100158-201406)

[0683] 11. Kanamycin (Merck QR11795)

[0684] 12. Triple Quad™ 5500+ LC / MS (AB Inc)

[0685] 13.CO2 incubator (Thermo 371)

[0686] 14. T-75 culture flask (Thermo 156499)

[0687] 2. Test steps

[0688] 1. Caco-2 cell culture

[0689] 1) Preparation of transport buffer (HBSS containing 25 mM HEPES, pH 7.4): Accurately weigh 5.958 g HEPES and 0.35 g NaHCO₃, dissolve in 900 mL of pure water, then add 100 mL of 10× HBSS, stir well, adjust the pH to 7.4 with sodium hydroxide, and filter.

[0690] 2) Preparation of Caco-2 cell culture medium: FBS, penicillin, streptomycin, kanamycin, and NEAA were added to high-glucose DMEM medium to prepare a cell culture medium containing 10% FBS, 0.1 mg / mL streptomycin, 100 units of penicillin, 0.6 μg / mL kanamycin, and 1×NEAA.

[0691] 3) Culture cells in a T-75 flask in a 37°C, 5% CO2 incubator. Discard the medium when cells reach 80-90% confluence. Rinse the cells with 5 mL of PBS, add 1.5 mL of trypsin / EDTA, and incubate in a 37°C incubator for 5-10 minutes until the cells detach as a quicksand. Neutralize the trypsin / EDTA with Caco-2 cell culture medium.

[0692] 4) Centrifuge the cell suspension at 120 x g for 10 minutes and discard the supernatant.

[0693] 5) Add cell culture medium to resuspend the cells and adjust the density to 6.86×10 5 cells / mL of cell suspension.

[0694] 2. Caco-2 Cell Seeding

[0695] 1) Add 50 μL of culture medium to each well of the Transwell chamber, add 25 mL of Caco-2 cell culture medium to the lower layer, and place in a 37°C, 5% CO2 incubator to preheat for 1 hour.

[0696] 2) Add 50 μL of cell suspension to each well of the preheated Transwell chamber, and the final seeding density is 2.4×10 5 cells / cm 2 .

[0697] 3) Culture for 14-18 days, changing the medium every other day. Change the medium within 48 hours of initial seeding. The medium must be changed the day before the experiment.

[0698] 3. Assessing Monolayer Cell Membrane Integrity:

[0699] 1) After 14 days of culture, cells were confluent and differentiated and ready for transport experiments.

[0700] 2) Use a resistance meter to measure the resistance of the single-layer membrane and record the resistance of each hole.

[0701] 3) After the measurement is completed, re-incubate the Transwell culture plate

[0702] 4) Calculate TEER value:

[0703] TEER value = TEER (Ω) measured value × membrane area (cm 2 )

[0704] The resistance of the cell membrane is less than 230Ω·cm 2 , indicating that the cell monolayer membrane has poor density and cannot be used for the experiment.

[0705] 4. Transport Experiment

[0706] 1) Dilute a 10 mM DMSO stock solution of the disclosed compound or positive control compound with DMSO to obtain a 2 mM stock solution, and then dilute the 2 mM stock solution with transport buffer to obtain a 10 μM working solution of the disclosed compound or positive control compound.

[0707] 2) Remove the Caco-2 cell plate from the incubator, wash the Transwell plate twice with preheated transport buffer, and incubate it in a 37°C incubator for 30 minutes.

[0708] 3) To measure the rate of compound transport from the apical to the basolateral side (A→B), add 108 μL of compound working solution to the top of the Transwell chamber. Immediately, remove 8 μL of sample from the top and transfer it to 72 μL of transport buffer. Add 240 μL of stop solution containing an internal standard to terminate transport, which serves as the initial apical sample. Simultaneously, add 300 μL of transport buffer to the receiving end (basolateral side). This experiment is performed in duplicate.

[0709] 4) To measure the transport rate of the compound from the basolateral to the apical side (B→A), add 308 μL of compound working solution to the receiving end (basolateral side). Immediately, remove 8 μL of sample from the basolateral side and transfer it to 72 μL of transport buffer. Add 240 μL of stop solution containing an internal standard to terminate transport, which serves as the initial basolateral sample. Simultaneously, add 300 μL of transport buffer to the apical side of the Transwell chamber. This experiment is performed in duplicate.

[0710] 5) Place the cell culture plate in a 37°C CO2 incubator and incubate for 2 hours.

[0711] 6) After the transport experiment is complete, transfer 8 μL of sample from the dosing end (i.e., the top end in the A→B direction and the base end in the B→A direction) to 72 μL of transport buffer. Add 240 μL of stop solution containing an internal standard to terminate transport. Transfer 80 μL of sample from the receiving end (i.e., the base end in the A→B direction and the top end in the B→A direction) to 240 μL of stop solution containing an internal standard. Vortex at 1000 rpm for 10 minutes and centrifuge at 3,220 g for 30 minutes. Transfer 100 μL of the supernatant to the sample injection plate and add 100 μL of ultrapure water to mix thoroughly. Prepare for LC-MS / MS analysis.

[0712] 7) After the transport experiment, measure fluorescence. Prepare a 10 mM Lucifer Yellow stock solution in water and dilute to 100 μM with transport buffer. Add 100 μL of Lucifer Yellow solution to the top of the Transwell chamber and 300 μL of transport buffer to the basolateral end. Incubate in a 37°C CO2 incubator for 30 minutes. Transfer 80 μL of the solution from the basolateral end to a 96-well plate and measure cell fluorescence using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm (to assess membrane integrity).

[0713] The fluorescence value of Caco-2 cell monolayer was calculated using the following formula:

[0714] LY Leakage={I acceptor ×0.3 / (I acceptor ×0.3+I donor ×0.1)}×100%

[0715] I acceptor Refers to the fluorescence density on the receiving side (0.3 mL), I donor Refers to the fluorescence density of the drug-administered side (0.1 mL). LY > 1.0% indicates poor monolayer membrane tightness, and the corresponding results will be excluded from the evaluation.

[0716] The peak areas of the compound at the administration side and the receiving side were measured. The apparent permeability coefficient (P app , unit: cm / s) and efflux ratio (ER):

[0717] P app ={V A ×[drug] acceptor / (Area×incubation time×[drug] initial dono}

[0718] V A is the volume of the receiving end solution (A→B is 0.3 mL, B→A is 0.1 mL), Area is the Transwell-96 plate membrane area (0.143 cm2 ); incubation time is the incubation time (unit: s).

[0719] P app(B-A) is the apparent permeability coefficient from the base to the top; P app(A-B) is the apparent permeability from the top to the base.

[0720] The calculated apparent permeability coefficient and efflux ratio of the disclosed compound are shown in Table 6. The test data show that the disclosed compound has good Caco-2 permeability.

[0721] Table 6 Apparent permeability coefficient and efflux ratio of the compounds disclosed herein

[0722] Test Example 6 Inhibitory Effects of the Disclosed Compounds on CYP2C9, CYP2D6, and CYP3A4 Enzyme Activities

[0723] The inhibition of the compounds on the activities of CYP2C9, CYP2D6, and CYP3A4 enzymes was determined using the following test method.

[0724] 1. Test materials and instruments

[0725] 1. Human liver microsomes (Corning 452117)

[0726] 2.Na2HPO4 (Shanghai test 20040618)

[0727] 3. KH2PO4 (Shanghai test 10017608)

[0728] 4.NADPH (Roche diagnostics gmbh 10107824001)

[0729] 5. Positive substrates: diclofenac sodium (Dalian Meilun MB1277), dextromethorphan hydrobromide (Dalian Meilun MB1568), and midazolam (Cerilliant M-908)

[0730] 6. Positive inhibitors sulfaphenazole (Dalian Meilun MB3276), quinidine (Dalian Meilun MB1702) and ketoconazole (Dalian Meilun MB1132)

[0731] 7. Tolbutamide (Sigma-aldrich T0891-100G)

[0732] 8. AB Sciex Triple Quad 5500+ LC / MS

[0733] Second test step

[0734] Preparation of 100 mM phosphate buffer (PBS): Weigh 7.098 g of Na₂HPO₄ and dissolve it in 500 mL of pure water by sonication to prepare Solution A. Weigh 3.400 g of KH₂PO₄ and dissolve it in 250 mL of pure water by sonication to prepare Solution B. Place Solution A on a stirrer and slowly add Solution B until the pH reaches 7.4 to prepare 100 mM PBS buffer.

[0735] 2. Prepare a 10 mM NADPH solution in 100 mM PBS buffer. Dilute a 10 mM stock solution of the disclosed compounds with DMSO to obtain a 200× concentration of compound working solutions (10000, 3333.3, 1111.1, 370.37, 123.46, 41.15, 13.7, 0 μM). Dilute a positive inhibitor stock solution with DMSO to obtain a 200× concentration of positive inhibitor working solutions (sulfaphenazole, 1000, 300, 100, 30, 10, 3, 0 μM; quinidine / ketoconazole, 100, 30, 10, 3, 1, 0.3, 0 μM). Prepare a 200× concentration of substrate working solutions (1200 μM diclofenac, 400 μM dextromethorphan, and 200 μM midazolam) in water, acetonitrile, or acetonitrile / methanol.

[0736] 3. Mix 2 μL of 20 mg / mL liver microsome solution, 1 μL of substrate working solution, 1 μL of compound working solution, and 176 μL of PBS buffer, and preincubate in a 37°C water bath for 10 minutes. For the positive control, add 1 μL of positive inhibitor working solution instead of compound working solution. Simultaneously, preincubate with 10 mM NADPH solution in a 37°C water bath for 10 minutes. After 10 minutes, add 20 μL of NADPH to each well to initiate the reaction. Incubate at 37°C for 5 minutes (CYP2C9), 20 minutes (CYP2D6), or 5 minutes (CYP3A4). All incubations should be performed in duplicate. After the appropriate incubation time, terminate the reaction by adding 400 μL of ice-cold methanol containing the internal standard (50 ng / mL tolbutamide). Vortex to mix thoroughly and centrifuge at 3220 g at 4°C for 30 minutes. After centrifugation, 50 μL of supernatant was transferred to the sample injection plate, and 100 μL of ultrapure water was added to mix well for LC-MS / MS analysis.

[0737] The IC values ​​of the disclosed compounds against CYP2C9, CYP2D6 and CYP3A4 were calculated using Excel XLfit 5.3.1.3. 50 The values ​​are shown in Table 7. The test data show that the disclosed compounds have no significant inhibitory effect on CYP2C9, CYP2D6, and CYP3A4.

[0738] Table 7 IC values ​​of the compounds disclosed herein for CYP2C9, CYP2D6 and CYP3A450 value

[0739] Test Example 7 Pharmacokinetic Properties of the Disclosed Compounds in Mice

[0740] 1. Test material

[0741] 1. Healthy adult CD-1 male mice were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0742] 2. PEG400 (polyethylene glycol 400), HP-β-CD (hydroxypropyl-β-cyclodextrin), hydrochloric acid, tolbutamide, methanol, acetonitrile, propylene glycol and formic acid were purchased from Merck (USA).

[0743] 3. K2EDTA anticoagulant tubes were purchased from Jiangsu Xinkang Medical Equipment Co., Ltd.

[0744] 2. Test methods

[0745] 1. Drug Preparation: Weigh a certain amount of the disclosed compound and dissolve it in 20% PEG400 + 4% 1M HCl + 76% (20% HP-β-CD) to prepare a 1 mg / mL solution for oral administration. Dilute the oral administration solution with 20% HP-β-CD to 0.2 mg / mL for intravenous administration.

[0746] 2. Administration: Oral gavage group: CD-1 mice were given the drug orally without fasting, at a dose of 10 mg / kg. Intravenous group: CD-1 mice were given the drug orally without fasting, at a dose of 1 mg / kg.

[0747] 3. Animal experiments: After oral or intravenous administration to mice, blood (>20 μL) was collected from the eye socket at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood was added into K2EDTA anticoagulant tubes and centrifuged at 12000 rpm, 4°C, for 5 minutes to separate the plasma, which was then stored at -20°C.

[0748] 4. Determination of the test compound content in mouse plasma after oral administration of different drug concentrations: Thaw the sample at room temperature and vortex for 1 minute. Quantitatively transfer 10 μL to a 2 mL 96-well plate. Add 50 μL of internal standard solution (10 ng / mL tolbutamide in acetonitrile) and 50 μL of precipitant (acetonitrile:methanol 7:3). Vortex (1000 rpm for 3 minutes). Centrifuge (4000 rpm for 15 minutes). Transfer 80 μL of the supernatant to a 2 mL 96-well plate. Add 80 μL of diluent (water) and shake well (1000 rpm for 3 minutes). Quantitative analysis was performed using an LC-MS / MS system (AB Sciex Triple Quad 6500+).

[0749] 5. Data Processing: The pharmacokinetic parameters were calculated using the non-compartmental statistical moment method using Phoenix WinNonlin 8.0 software (Certara, USA). The test results are shown in Tables 8 and 9. The test data indicate that the disclosed compounds have good oral absorption in mice.

[0750] Table 8 Pharmacokinetic parameters of the compound after single oral administration in mice

[0751] Note: NA stands for not applicable.

[0752] Table 9 Pharmacokinetic parameters of the compound after single intravenous administration in mice

[0753] Test Example 8 Pharmacokinetic Properties of the Disclosed Compounds in Rats

[0754] 1. Test material

[0755] 1. Healthy adult SD male rats were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0756] 2. PEG400 (polyethylene glycol 400), HP-β-CD (hydroxypropyl-β-cyclodextrin), hydrochloric acid, tolbutamide, methanol, acetonitrile, propylene glycol and formic acid were purchased from Merck (USA).

[0757] 3. K2EDTA anticoagulant tubes were purchased from Jiangsu Xinkang Medical Equipment Co., Ltd.

[0758] 2. Test methods

[0759] 1. Drug Preparation: Weigh a certain amount of the disclosed compound and dissolve it in 20% PEG400 + 4% 1M HCl + 76% (20% HP-β-CD) to prepare a 1 mg / mL solution for oral administration. Dilute the oral administration solution with 20% HP-β-CD to 0.2 mg / mL for intravenous administration.

[0760] 2. Administration: Oral gavage group: SD rats were fasted and administered with a dose of 10 mg / kg. Intravenous group: SD rats were fasted and administered with a dose of 1 mg / kg.

[0761] 3. Animal experiments: After oral or intravenous administration to rats, 100 μL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood was added to an anticoagulant tube and centrifuged at 12,000 rpm, 4°C, for 5 minutes to separate the plasma, which was then stored at -20°C.

[0762] 4. Determination of the test compound content in rat plasma after oral or intravenous administration of different drug concentrations: Thaw the sample at room temperature and vortex for 1 minute. Quantitatively transfer 10 μL to a 2 mL 96-well plate. Add 50 μL of internal standard solution (10 ng / mL tolbutamide in acetonitrile) and 50 μL of precipitant (acetonitrile:methanol 7:3). Vortex (1000 rpm for 3 minutes). Centrifuge (4000 rpm for 15 minutes). Transfer 80 μL of the supernatant to a 2 mL 96-well plate. Add 80 μL of diluent (water) and shake well (1000 rpm for 3 minutes). Quantitative analysis was performed using an LC-MS / MS system (AB Sciex Triple Quad 6500+).

[0763] 5. Data Processing: The pharmacokinetic parameters were calculated using the non-compartmental statistical moment method using Phoenix WinNonlin 8.0 software (Certara, USA). The test results are shown in Tables 10 and 11. The test data indicate that the disclosed compounds have good oral absorption in rats.

[0764] Table 10 Pharmacokinetic parameters of the compounds after single oral administration in rats

[0765] Table 11 Pharmacokinetic parameters of the compounds after single intravenous administration in rats

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, TL-Linker-DIM (I) in: The DIM is a ligand compound capable of binding to E3 ubiquitin ligase; The Linker is a linking group that covalently binds at least one TL and at least one DIM; The TL is a group as shown below: in: A 1 , A 2 , A 3 , A 4 Independently selected from CH, CR 1 or N; R 1 Selected from deuterium, halogen, CN, -C(O)NR 1a R 1b 、NO2、OH、NH2、C1-C6 alkyl、C3-C6 cycloalkyl、C6-C 10 aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclic group is optionally substituted by one or more R a replace; R 1a is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 1c replace; R 1b Selected from H or C1-C6 alkyl; B 1 , B 2 One of the selected C-NHR 2 、C-OR 2 or C-CHR 2a R 2b , the other is selected from CH or N; R 2 , R 2a , R 2b are independently selected from H, deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by one or more R b replace; Ring Q is a 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring is optionally substituted with one or more R c replace; B 3 , B 4 One of them is C and is connected to ring Q, and the other is selected from CH or N; X is selected from S, O or NR 3 ; R 3 is selected from H, deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 heteroaryl or 4-8 heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 heteroaryl or 4-8 heterocyclyl is optionally replaced by one or more R d replace; R a , R 1c , R b , R c , R d is independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 heteroaryl or 4-8 heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 heteroaryl or 4-8 heterocyclyl is optionally replaced by one or more R e replace; R e Selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl, C1-C3 alkoxy, CN, COOH, C(O)(C1-C3 alkyl), CONH2, C(O)O(C1-C3 alkyl), S(O)2(C1-C3 alkyl), C3-C6 cycloalkyl or 4-6 membered heterocyclyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: B 1 , B 2 One of them is C-NHR 2 , the other is selected from CH or N; or, B 1 C-NHR 2 , B 2 is selected from CH or N; or, B 1 C-NHR 2 , B 2 is N.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: B 3 is C and connected to ring Q, B 4 is selected from CH or N; or, B 3 is C and connected to ring Q, B 4 is CH; or, B 3 Selected from CH or N, B 4 It is C and connected to ring Q.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R 2 , R 2a , R 2b is independently selected from H, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by one or more R b replace.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: B 1 C-NHR 2 , R 2 is selected from H, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by one or more R b Replace; or, B 1 C-NHR 2 , R 2 is selected from H, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R b Replace; or, B 1 C-NHR 2 , R 2 is selected from H, deuterium, OH or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R b Replace; or, B 3 is C and connected to ring Q, B 4 is selected from CH or N; or, B 1 C-NHR 2 , R 2 is selected from tetrahydropyranyl, oxetanyl or optionally R b Substituted C1-C4 alkyl.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: A 1 , A 4 Selected from CH, CR 1 or N, A 2 , A 3 Select from CH or CR 1 Or, A 4 Selected from CH, CR 1 or N, A 1 , A 2 , A 3 Select from CH or CR 1 Or, A 4 Selected from CH or N, A 2 CR 1 , A 1 , A 3 All are CH; or, A 4 Selected from CH, A 2 CR 1 , A 1 , A 3 All are CH; or, A 1 Selected from CH, CR 1 or N, A 2 , A 3 , A 4 Select from CH or CR 1 Or, A 1 Selected from CH or N, A 3 CR 1 , A 2 , A 4 All are CH; or, A 1 Selected from CH, A 3 CR 1 , A 2 , A 4 All are CH.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: R 1 Selected from deuterium, halogen, CN, -C(O)NR 1a R 1b , NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R a Replace; or, R 1 is selected from deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R a Replace; or, R 1 is selected from deuterium, halogen, CN, OH or C1-C4 alkyl, wherein the OH or C1-C4 alkyl is optionally replaced by one or more R a replace.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: R 1a is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R 1c Replacement; R 1b is selected from H or C1-C6 alkyl; or, R 1a is selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group is optionally substituted by one or more R 1c Replacement; R 1b Selected from H or C1-C6 alkyl.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: Ring Q is optionally substituted with one or more R c substituted 5-6 membered heteroaromatic ring; or, ring Q is optionally substituted with one or more R c A substituted 5-membered heteroaromatic ring, such as one or more R c The following groups are substituted: pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl; or, ring Q is optionally substituted with one or more R c Substituted: thiadiazolyl, triazolyl, pyrazolyl.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: R 3 is selected from H, deuterium, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl is optionally replaced by one or more R d Replace; or, R 3 is selected from H, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R d Replace; or, R 3 is selected from H, deuterium or optionally one or more R d Substituted C1-C4 alkyl.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: X is selected from S, O or NH; or, X is selected from NR 3 ; or, X is selected from NH.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: R a , R 1c , R b , R c , R d is independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R e Replace; or, R a , R 1c , R b , R c , R d Each of which is independently selected from deuterium, halogen, OH, CN, NH2, =O or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by one or more R e replace.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R e is selected from deuterium, halogen, OH, NH2, C1-C3 alkyl, C1-C3 alkoxy, COOH, C(O)(C1-C3 alkyl), CONH2, C(O)O(C1-C3 alkyl), C3-C6 cycloalkyl or 4-6 membered heterocyclyl; or, R e Selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, COOH, C(O)(C1-C3 alkyl), CONH2 or C(O)O(C1-C3 alkyl).

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: The TL is selected from the structure shown in the following (TL-1): Among them, B 2 , B 4 are independently selected from CH or N, A 1 , A 2 , A 3 , A 4 ,X,R 2 and Q is as defined in any one of claims 1-13.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: The TL is selected from the structure shown in the following (TL-2): Among them: B 2 , B 4 are independently selected from CH or N, A 4 is selected from CH or N, n is selected from 0, 1 or 2, R 1 , R 2 , X and ring Q are as defined in any one of claims 1-13.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein: The TL is selected from one of the following structures:

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: The Linker is a connecting group that covalently binds a TL and a DIM.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein: The Linker is selected from: -L A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、 or The Linker is selected from Linker or The Linker is Where: -L A -、-L B - independently selected from a chemical bond, -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-, -C(O)-, -CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -; R 1L and R 2L independently selected from a chemical bond, -C(O)-, alkylene, heteroalkylene, alkenylene and alkynylene, wherein the alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted by a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl; Q 1 , Q 2 , Q 3 and Q 4 are independently selected from cycloalkylene, heterocyclylene, arylene, heteroarylene or cycloalkenylene, wherein the cycloalkylene, heterocyclylene, arylene, heteroarylene and cycloalkenylene are each independently optionally substituted by a group selected from the following: halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3’ is selected from the group consisting of H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein: The DIM is selected from ligand compounds capable of binding to cereblon type E3 ubiquitin ligase.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: The DIM is selected from the structure shown in formula (DIM-1) or (DIM-2): in: Selected from Y is a chemical bond, or Y is selected from Y A , O, NH, NR E 、C(O)O、C(O)NR E '、NR E 'C(O),Y A -NH, Y A -NR E , Y A -C(O),Y A -C(O)O、Y A -OC(O),Y A -C(O)NR E ' or Y A -NR E 'C(O), wherein said Y A is selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; X' is selected from C(O) or C(R A )2;X A -X B Selected from C(R A )=NorC(R A )2-C(R A )2; Every R A independently selected from H or C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by C6-C 10 Aryl or 5-10 membered heteroaryl substituted; Every R A 'Independently selected from C1-C3 alkyl; Every R B are independently selected from H or C1-C3 alkyl, or two R B Together with the atoms to which it is attached, it forms C(O), C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-6 membered heterocyclyl; R C Selected from H, halogen or C1-C3 alkyl; Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy; Every R E independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from halogen, N(R a )2. NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N(R a )2. NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Every R a Independently selected from H or C1-C6 alkyl; R b Selected from H or p-toluenesulfonyl; t is selected from 0 or 1; m is selected from 0, 1, 2 or 3; p is selected from 0, 1 or 2.

21. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: The DIM is selected from the structure shown in formula (DIM-11): in: X C Selected from chemical bonds, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)(NR'2)-, -C(O)-, -C(S)- or X D is selected from C, N or Si; X E is selected from a chemical bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-; R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR'-, -SR'-, -S(O)R'-, -S(O)2R'-, -NR'2-, -P(O)(OR')2, -P(O)(NR'2)OR'-, -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3 or C1-C4 alkyl; Each R G is independently selected from H, deuterium, R H , halogen, CN, -NO2, -OR’, -SR’, -NR’2, -SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -C(R’)2N(R’)C(O)R’, -C(R’)2N(R’)C(O)NR’2, -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, -OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, -N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2 or -N(R’)P(O)(NR’2)2; Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl; Ring E, Ring F, Ring G are independently selected from phenyl, 6-membered heteroaryl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7-membered heterocyclyl or 5-6-membered heteroaryl, wherein Ring E, Ring F and Ring G are each optionally further substituted by =O; L 1 Selected from a chemical bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene, wherein any 1 or 2 methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-; Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

22. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: The DIM is selected from the structure shown in formula (DIM-12): Wherein: Ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl, wherein the C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl is optionally substituted by =O; k is selected from 0, 1, 2, 3 or 4; X C Selected from chemical bonds, -CH2-, -CH(CF3)-, -SO2-, -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)(NR'2)-, -C(O)-, -C(S)- or X D is selected from C, N or Si; X E is selected from a chemical bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-; R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -NR'2, -P(O)(OR')2, -P(O)(NR'2)OR', -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3 or C1-C4 alkyl; Each R G is independently selected from H, deuterium, R H , halogen, CN, -NO2, -OR’, -SR’, -NR’2, -SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -C(R’)2N(R’)C(O)R’, -C(R’)2N(R’)C(O)NR’2, -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, -OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, -N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2 or -N(R’)P(O)(NR’2)2; L 1 Selected from a chemical bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene, wherein any 1 or 2 methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-; Ring E is selected from phenyl, 5-6 membered heteroaryl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl or 5-7 membered heterocyclyl, and the ring E is optionally further substituted by =O; Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: The DIM is selected from the structure shown in formula (DIM-13): wherein k is selected from 0, 1, 2, 3 or 4; X C Selected from chemical bonds, -CH2-, -CH(CF3)-, -SO2-, -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)(NR'2)-, -C(O)-, -C(S)- or X D is selected from C, N or Si; X E is selected from a chemical bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-; R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -NR'2, -P(O)(OR')2, -P(O)(NR'2)OR', -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3 or C1-C4 alkyl; Every R G independently selected from H, deuterium, R H 、Halogen、CN、-NO2、-OR'、-SR'、-NR'2、-SiR'3、-S(O)2R'、-S(O)2NR'2、 -S(O)R', -C(O)R', -C(O)OR', -C(O)NR'2, -C(O)N(R')OR', -C(R')2N(R')C(O)R', -C( R')2N(R')C(O)NR'2, -OC(O)R', -OC(O)NR'2, -OP(O)R'2, -OP(O)(OR')2, -OP(O)(OR') NR'2, -OP(O)(NR'2)2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2 R', -N(R')P(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2 or -N(R')P(O)(NR'2)2; L 1 Selected from a chemical bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene, wherein any 1 or 2 methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-; Ring E is selected from phenyl, 5-6 membered heteroaryl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl or 5-7 membered heterocyclyl, and the ring E is optionally further substituted by =O; Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl.

24. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein: The compound has a structure selected from one of the following:

25. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, and a pharmaceutically acceptable excipient.

26. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 or the pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing or treating a disease mediated by IRAK4.

27. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 25 for use in preventing or treating a disease mediated by IRAK4.

28. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 or the pharmaceutical composition according to claim 25 in preventing or treating a disease mediated by IRAK4.

29. A method for treating a disease mediated by IRAK4 in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 25 to a mammal, preferably a human, in need of such treatment.

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