IRAK4 degradation agent compound and application thereof

Abstract

The present disclosure relates to IRAK4 degradation agent compounds, and specifically provides compounds of formula (I) or pharmaceutically acceptable salts thereof, the compounds having substituents and structural characteristics described herein. Also described are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of said compound or a pharmaceutically acceptable salt thereof in medicine.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following two Chinese invention patent applications, the entire contents of which are hereby incorporated by reference into this application:

[0003] Patent application No. 202310958428.6 filed with the State Intellectual Property Office on July 31, 2023, and

[0004] Patent application No. 202311564915.0 submitted to the State Intellectual Property Office on November 21, 2023. Technical Field

[0005] 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 in preventing or treating diseases or conditions mediated by IRAK4. Background Art

[0006] Interleukin-1 receptor kinase 4 (IRAK4) is a serine / serine 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.

[0007] 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.

[0008] 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. Summary of the Invention

[0009] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0010] TL-Linker-DIM

[0011] (I)

[0012] in:

[0013] The DIM is a ligand compound capable of binding to E3 ubiquitin ligase;

[0014] The Linker is a connecting group that covalently binds at least one TL and at least one DIM;

[0015] The TL is a group as shown below:

[0016]

[0017] in:

[0018] is selected from a single bond or a double bond,

[0019] when When it is a single bond, U is C=O and V is NR 1 , R 1 Selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 1 a replace;

[0020] when When it is a double bond, U is selected from CR 2 or N, V ​​is CR 3 or N, R 2 、R 3 are independently selected from H, deuterium, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2a Replace; or, R 2 、R 3 Together with the atoms it is connected to form C5-C 10 Cycloalkenyl, 4-8 membered heterocyclic group or 5-10 membered heteroaryl, the C5-C 10 Cycloalkenyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with one or more R 3a replace;

[0021] Z is selected from CR 6 or N;

[0022] W1 and W2 are independently selected from CH2, NH, O or S, wherein CH2 or NH is optionally substituted by a group selected from deuterium, halogen, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl;

[0023] Q1 and Q2 are independently selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group, C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN or CONH2, the C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or CONH2 is optionally replaced by one or more R 4a replace;

[0024] R 4 、R 5 and R 6are independently selected from H, deuterium, halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy is optionally replaced by R b replace;

[0025] R 1a 、R 2a 、R 3a 、R 4a are independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more R c replace;

[0026] R b 、R c are independently selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl, CN, COOH, C(O)(C1-C3 alkyl), CONH2 or COO(C1-C3 alkyl).

[0027] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a are independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by one or more R c Replacement; R c Selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl, CN, COOH, C(O)(C1-C3 alkyl), CONH2 or COO(C1-C3 alkyl).

[0028] In some embodiments, R 1 is selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by one or more R 1a replace.

[0029] In some embodiments, R 1 Selected from optionally one or more R 1a Substituted C1-C6 alkyl.

[0030] In some embodiments, R 1a is 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 c replace.

[0031] In some embodiments, R 1a Selected from halogen such as F.

[0032] In some embodiments, R 1 Selected from methyl or

[0033] In some embodiments, R 2 、R 3 are independently selected from H, deuterium, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2a replace.

[0034] In some embodiments, R 2 、R 3 independently selected from C1-C6 alkoxy, C3-C6 cycloalkyloxy, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy, C3-C6 cycloalkyloxy, C6-C 10 aryloxy, 5-10 membered heteroaryloxy or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkoxy, C3-C6 cycloalkyloxy, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy, C3-C6 cycloalkyloxy, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2a replace.

[0035] In some embodiments, R 2 、R 3Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, the C1-C6 alkyl or C1-C6 alkoxy optionally substituted by one or more R 2a replace.

[0036] In some embodiments, R 2 、R 3 Each independently selected from methyl or methoxy, said methyl or methoxy optionally replaced by one or more R 2a replace.

[0037] In some embodiments, R 2 、R 3 independently selected from one another, optionally with one or more R 2a Substituted C1-C6 alkoxy.

[0038] In some embodiments, R 2 、R 3 Together with the atoms it is connected to form C5-C 10 Cycloalkenyl, 4-8 membered heterocyclic group or 5-10 membered heteroaryl, the C5-C 10 Cycloalkenyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with one or more R 3a replace.

[0039] In some embodiments, R 2 、R 3 Together with the atoms to which it is attached, it forms a C5-C6 cycloalkenyl, a 4-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the C5-C6 cycloalkenyl, the 4-6 membered heterocyclyl or the 5-6 membered heteroaryl is optionally substituted by one or more R 3a replace.

[0040] In some embodiments, is a double bond, U is CR 2 or N, V ​​is CR 3 or N.

[0041] In some embodiments, is a double bond, U is CR 2 , V is N; or, U is N, V ​​is CR 3 .

[0042] In some embodiments, is a double bond, U is CR 2 , V is N.

[0043] In some embodiments, is a double bond, U is N, and V is CR 3 .

[0044] In some embodiments, Z is N.

[0045] In some embodiments, W1 and W2 are independently selected from NH or O, wherein the NH is optionally substituted with a group selected from halogen, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl.

[0046] In some embodiments, W1 is selected from NH or O.

[0047] In some embodiments, W1 is selected from NH.

[0048] In some embodiments, W1 is selected from O.

[0049] In some embodiments, W2 is selected from NH optionally substituted with a group selected from halogen, OH, NH2, C1-C3 alkyl, or C1-C3 haloalkyl.

[0050] In some embodiments, W2 is selected from NH.

[0051] In some embodiments, Q1 and Q2 are independently selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, C6-C 10 Aryl, C1-C6 alkyl, CN or CONH2, the C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group, C6-C 10 Aryl, C1-C6 alkyl or CONH2 is optionally replaced by one or more R 4a replace.

[0052] In some embodiments, Q1 and Q2 are independently selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl or C6-C 10 Aryl, the C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group or C6-C 10 The aryl group is optionally substituted with one or more R 4a replace.

[0053] In some embodiments, Q1 and Q2 are independently selected from C3-C6 cycloalkyl or 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl or 5-6 membered heteroaryl is optionally replaced by one or more R 4a replace.

[0054] In some embodiments, Q1 is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclyl or C1-C6 alkyl, wherein the C3-C6 cycloalkyl, 4-8 membered heterocyclyl or C1-C6 alkyl is optionally substituted by one or more R 4a replace.

[0055] In some embodiments, Q1 is selected from the group consisting of 4a Substituted C3-C6 cycloalkyl.

[0056] In some embodiments, Q1 is selected from the group consisting of 4a Substituted: cyclopropyl, oxetanyl or methyl.

[0057] In some embodiments, Q1 is selected from the group consisting of 4a Substituted cyclopropyl.

[0058] In some embodiments, Q1 is

[0059] In some embodiments, Q2 is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclyl, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclyl is optionally replaced by one or more R 4a replace.

[0060] In some embodiments, Q2 is selected from the group consisting of 4a Substituted 5-6 membered heteroaryl.

[0061] In some embodiments, Q2 is selected from the group consisting of 4a Substituted pyrazolyl.

[0062] In some embodiments, Q2 is selected from the group consisting of 4a Substituted pyrazolyl, R 4a Selected from cyclohexyl, piperidinyl,

[0063]

[0064] In some embodiments, R 4 、R 5 and R 6 are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R b replace.

[0065] In some embodiments, R 4 、R 5 are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy or NH2, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R b replace.

[0066] In some embodiments, R b is selected from halogen, OH, NH2, =O, C1-C3 alkyl or CN.

[0067] In some embodiments, R 4、R 5 Both are H.

[0068] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a are independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by one or more R c replace.

[0069] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a are independently selected from deuterium, halogen, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more R c replace.

[0070] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a Each of them is independently selected from deuterium, halogen, OH, CN, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more R c replace.

[0071] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a Independently selected from CN, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more R c replace.

[0072] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a Each independently selected from CN, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more Rc replace.

[0073] In some embodiments, R 4a Selected from CN or optionally replaced by one or more R c Substituted groups: methyl, cyclohexyl, piperidinyl,

[0074] In some embodiments, R 4a Selected from CN or optionally replaced by one or more R c Substituted groups: methyl, cyclohexyl, piperidinyl,

[0075] In some embodiments, R 4a Selected from optionally one or more R c Substituted groups: methyl, cyclohexyl, piperidinyl,

[0076] In some embodiments, R c Selected from C1-C3 alkyl, C(O)(C1-C3 alkyl) or COO(C1-C3 alkyl).

[0077] In some embodiments, R c Selected from methyl, ethyl or C(O)CH3.

[0078] In some embodiments, the TL is selected from the structure shown below (TL-1):

[0079]

[0080] Wherein: W1 is selected from NH or O, Q 2 is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 4a Replacement, R 1 、R 4 、R 5 , Q1 and R 4a As defined above.

[0081] In some embodiments, the TL is selected from the structure shown below (TL-2):

[0082]

[0083] Wherein: W1 is selected from NH or O, Q 2 is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 4a Substituted, U is selected from CR 2or N, V ​​is CR 3 or N, R 2 、R 3 are independently selected from H, deuterium, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2a Replacement, R 4 、R 5 ,Q1,R 2a and R 4a As defined above.

[0084] In some embodiments, the TL is connected to a Linker via Q1 or Q2.

[0085] In some embodiments, the TL is connected to a Linker via Q2.

[0086] In some embodiments, the TL is further selected from the group shown below:

[0087]

[0088] In some embodiments, the TL is further selected from the group shown below:

[0089]

[0090] In some embodiments, the TL is selected from the following structures:

[0091] In some embodiments, the linker is a connecting group that covalently binds a TL and a DIM.

[0092] In some embodiments, the Linker is selected from the group consisting of: A -、-LB -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、

[0093] 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)-, -CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -;

[0094] 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;

[0095] Q 1 , Q 2 , Q 3 and Q 4 are independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl and cycloalkenyl 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;

[0096] R 3’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0097] 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;

[0098] R6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0099] In some embodiments, the linker is selected from the following structures: bond, -O-, -C(O)-, -CH2-,

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] In some embodiments, the linker is selected from: a bond, -O-, -C(O)-, -CH2-,

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] In some embodiments, the Linker is selected from

[0121] In some embodiments, the DIM is selected from ligand compounds capable of binding to a cereblon-type E3 ubiquitin ligase.

[0122] In some embodiments, the DIM is selected from the structure shown in formula (DIM-1) or (DIM-2):

[0123]

[0124] in:

[0125] Selected from

[0126] 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;

[0127] 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;

[0128] 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;

[0129] Every R A 'Independently selected from C1-C3 alkyl;

[0130] Every R B are independently selected from H or C1-C3 alkyl, or two R BTogether 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;

[0131] R C Selected from H, halogen or C1-C3 alkyl;

[0132] Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy;

[0133] 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;

[0134] 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;

[0135] Every R a Independently selected from H or C1-C6 alkyl;

[0136] R b Selected from H or p-toluenesulfonyl;

[0137] t is selected from 0 or 1;

[0138] m is selected from 0, 1, 2 or 3;

[0139] p is selected from 0, 1 or 2.

[0140] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-3) or (DIM-4):

[0141]

[0142] Wherein, the rings A, Y, and R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0143] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-5), (DIM-6), (DIM-7) or (DIM-8):

[0144]

[0145] Among them, the Y, X, X A -X B 、R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0146] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-9) or (DIM-10):

[0147]

[0148] Among them, the Y, X, X A -X B 、R A 、R A '、R B 、R C 、R D , m and p are as defined above.

[0149] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11):

[0150]

[0151] in:

[0152] 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)-

[0153]

[0154] X D selected from C, N or Si;

[0155] X E is selected from a chemical bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-;

[0156] 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;

[0157] 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', -NP(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2 or -N(R')P(O)(NR'2)2;

[0158] Every RH Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0159] Ring E, Ring F, and 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 with ═O;

[0160] 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-;

[0161] 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;

[0162] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0163] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11'):

[0164]

[0165] wherein X C 、R F 、R G , q, ring E, ring F and ring G are as defined in formula (DIM-11).

[0166] In some embodiments, the DIM is selected from the structure shown in formula (DIM-12):

[0167]

[0168] 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 1and Ring E are as defined in Formula (DIM-11).

[0169] In some embodiments, the DIM is selected from the structure shown in formula (DIM-12'):

[0170]

[0171] Among them, the X C 、R F 、R G , k, ring E and ring H are as defined in formula (DIM-12).

[0172] In some embodiments, the DIM is selected from the structure shown in formula (DIM-13):

[0173]

[0174] Among them, the X C 、X D 、X E 、R F 、R G , L 1 , Ring E and k are as defined in formula (DIM-12). In some embodiments, the DIM is selected from the structure shown in (DIM-13'):

[0175]

[0176] Among them, the X C 、R F 、R G , Ring E and k are as defined in Formula (DIM-13).

[0177] In some embodiments, the DIM is selected from the following structures:

[0178]

[0179]

[0180] In some embodiments, the compound of formula (I) of the present disclosure is selected from the following compounds:

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound represented by any of the above general formulas of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0190] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0191] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0192] In another aspect, the present disclosure provides the use of a 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 an IRAK4-mediated disease.

[0193] On the other hand, the present disclosure provides the use of a 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 tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.

[0194] In another aspect, the present disclosure provides the use of a compound represented by any of the above general formulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating IRAK4-mediated diseases.

[0195] On the other hand, the present disclosure provides the use of a compound represented by any of the above general formulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.

[0196] In another aspect, the present disclosure provides a compound of any of the above general formulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating IRAK4-mediated diseases.

[0197] In another aspect, the present disclosure provides a compound of any of the above general formulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.

[0198] In some embodiments, the IRAK4-mediated disease is selected from a tumor, an inflammatory disease, a neurodegenerative disease, or an autoimmune disease.

[0199] Definitions and Explanations of Terms

[0200] 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.

[0201] In this document, a carbon atom marked with "*" represents a chiral carbon atom, which means that its absolute configuration is one of (S)-configuration and (R)-configuration.

[0202] In this article Indicates the connection site. of when When not connected to a fixed ring or atom, it means that it can be connected to a group after losing the hydrogen atom at any position in the molecule enclosed by "[]" (including hydrogen atoms directly connected to ring atoms, hydrogen atoms on non-hydrogen substituents of ring atoms, and hydrogen atoms in further substituents on substituents), for example middle The connection position includes but is not limited to Q 1 and Q 1 Substituents on Q 2 and Q 2 Substituents on, etc.

[0203] 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.).

[0204] 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.

[0205] 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.

[0206] Unless otherwise specified, wedge keys and virtual wedge keys To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0207] 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.

[0208] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] The term "substituted" means that a specific atom or group can be replaced by a specified other 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.

[0214] 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.

[0215] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0216] 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.

[0217] 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 ”.

[0218] 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.

[0219] 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, Methylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; 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 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 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".

[0220] 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.

[0221] The term "haloalkyl" refers to a group obtained by further replacing the alkyl group with a halogen, such as "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 the alkyl group with an OH group.

[0222] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene 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.

[0223] 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-", wherein 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".

[0224] 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.

[0225] 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.

[0226] 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."

[0227] The term "alkynyl" refers to a straight 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).

[0228] 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".

[0229] 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".

[0230] The term "cycloalkyloxy" can be understood as "cycloalkyl-O-". For example, "C3-C6 cycloalkyloxy" can be understood as "C3-C6 cycloalkyl-O-".

[0231] 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 5-9 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 5-7 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 3-6 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".

[0232] 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 to 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms) 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 "5-14 membered heterocyclyl" refers to a heterocyclyl group having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and wherein the ring atoms contain 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. "5-14 membered heterocyclyl" may include "6-14 membered heterocyclyl", "6-11 membered heterocyclyl", "6-10 membered heterocyclyl", "6-8 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 thereof contain 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned. "4-10 membered heterocyclyl" includes "4-7 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 heterocyclyl include but are not limited to The heterocyclic group is 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 groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl.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.

[0233] The term "heterocyclyloxy" may be understood as "heterocyclyl-O-".

[0234] 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 1-5 heteroatoms or heteroatom groups (i.e., heteroatom-containing atomic groups). 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-, which usually 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.

[0235] The term "heterocycloalkyloxy" may be understood as "heterocycloalkyl-O-".

[0236] 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.

[0237] The term "aryloxy" may be understood as "aryl-O-".

[0238] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic properties, containing at least one, preferably 1-4, ring atoms selected from N, O, and S, with the remaining ring atoms being carbon atoms. Heteroaryl is preferably a 5- to 10-membered, more preferably a 5- or 6-membered heteroaryl. 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, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, 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".

[0239] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "hydroxy" refers to an -OH group. The term "cyano" refers to a -CN group. The term "amino" refers to an -NH2 group. The term "nitro" refers to a -NO2 group.

[0240] 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 own knowledge and this disclosure.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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".

[0246] 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 as 2 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0254] 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.

[0255] 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

[0256] 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.

[0257] 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.

[0258] All reagents used in this disclosure were commercially available and used without further purification.

[0259] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios. Unless otherwise specified, % refers to wt%.

[0260] 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 determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, 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.

[0261] Explanation of terms or abbreviations:

[0262] t-Bu: tert-butyl; t-BuOK: potassium tert-butoxide; TEA: triethylamine; THF: tetrahydrofuran; Me: methyl; MeOH: methanol; EtOH: ethanol; iPrOH: isopropanol; DCM: dichloromethane; DCE: dichloroethane; DMF: N,N-dimethylformamide; DIEA / DIPEA: N,N-diisopropylethylamine; ACN: acetonitrile; Et2O: diethyl ether; HATU: O-(7-nitrobenzophenone) (1-(triazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate; Boc: tert-butyloxycarbonyl; NaBH(OAc)3: sodium triacetoxyborohydride; AcOH: acetic acid; EA / EtOAc: ethyl acetate; TFA: trifluoroacetic acid; PPh3: triphenylphosphine; Pd(PPh3)2Cl2: bis(triphenylphosphine palladium dichloride); Pd / C: palladium on carbon; Pd(dppf)Cl2: 1,1-bis(diphenylphosphine) Phospho-)ferrocenepalladium chloride; Py: pyridine; Ms: methanesulfonyl; MsCl: methanesulfonyl chloride; MsOH: methanesulfonic acid; Tf2O: trifluoromethanesulfonic anhydride; dioxane: 1,4-dioxane; toluene / PhMe: toluene; DMSO: dimethyl sulfoxide; STAB: sodium triacetoxyborohydride; m-CPBA: m-chloroperbenzoic acid; DMK / acetone: 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; Trisphosgene: triphosgene; TsOH: p-toluenesulfonic acid; DIAD: diisopropylazo-1,2-dicarboxylate; Ruphos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium; Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; LiHMDS: lithium bis(trimethylsilyl)amide; 4A MS: 4A molecular sieve; Pd-PEPPSI-Ipent-Cl: dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); BnBr: benzyl bromide; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; JohnPhos: 2-(di-tert-butylphosphino)biphenyl; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; TAA: tert-amyl alcohol; XantPhos: dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Ephos: dicyclohexyl(3-ethylpropoxy-2′,4′,6′-triisopropyl-[1,1′-diphenyl]-2-yl)phosphine;Ephos Pd-G4: (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2'-methylamino-1,1'-biphenyl-2-yl) palladium; Xphos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] methanesulfonate palladium; BAST: bis(2-methoxyethyl)aminosulfur trifluoride; Solutol HS15: polyethylene glycol (15)-hydroxystearate; HP-CD: hydroxypropyl cyclodextrin; NMP: N-methylpyrrolidone; PCC: pyridinium chlorochromate.

[0263] 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.

[0264] Intermediate A: Synthesis of 6-methyl-4-[(1-methylcyclopropyl)amino]-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-5-one

[0265]

[0266] Step 1: Synthesis of 4-methyl-6-[(1-methylcyclopropyl)amino]-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (A-2)

[0267] Dissolve 4-chloro-6-methyl-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (A-1, 4 g, 16.21 mmol) in dichloromethane (60 mL). Add 1-methylcyclopropylamine hydrochloride (1.93 g, 17.97 mmol) and triethylamine (4.92 g, 48.64 mmol, 6.78 mL). Stir the mixture at room temperature for 24 hours. Monitor the reaction by LC-MS. After complete reaction, concentrate under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to yield the title compound (4.1 g).

[0268] MS m / z(ESI):282.1[M+H] +

[0269] 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 4.33 (q, J = 7.1Hz, 2H), 2.57 (s, 6H), 1.46 (s, 3H), 1.39 (t, J = 7.1Hz, 3H), 0.80 (t, J = 3.4Hz, 2H), 0.71 (t, J = 3.5Hz, 2H).

[0270] Step 2: Synthesis of 6-methyl-4-[(1-methylcyclopropyl)amino]-2-methylthio-pyrido[4,3-d]pyrimidin-5-one (A-3)

[0271] Ethyl 4-methyl-6-[(1-methylcyclopropyl)amino]-2-methylthio-pyrimidine-5-carboxylate (A-2, 2.31 g, 8.22 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of tert-butoxybis(dimethylamino)methane (4.30 g, 24.69 mmol, 5.10 mL). The mixture was stirred at 110°C for 1 h. The reaction was monitored by LC-MS. After the starting material reacted completely, the solvent was removed by concentration under reduced pressure. The residue was transferred to a pressure-resistant reaction flask, ethanol (50 mL) and methylamine (20 mL, 33% ethanol solution) were added, and the mixture was stirred at 90°C for 6 h. The reaction was monitored by LC-MS. After the starting material reacted completely, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford the title compound (1.6 g).

[0272] MS m / z(ESI):277.1[M+H] +

[0273] Step 3: Synthesis of 6-methyl-4-[(1-methylcyclopropyl)amino]-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-5-one (Intermediate A)

[0274] 6-Methyl-4-[(1-methylcyclopropyl)amino]-2-methylthio-pyrido[4,3-d]pyrimidin-5-one (A-3, 1 g, 3.62 mmol) was dissolved in dichloromethane (30 mL). m-Chloroperbenzoic acid (882 mg, 4.34 mmol, 85%) was then added to the reaction system. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the starting material reacted completely, the solvent was removed by concentration under reduced pressure to obtain the crude title compound (930 mg), which was used directly in the subsequent reaction without further purification.

[0275] MS m / z(ESI):293.1[M+H] +

[0276] Intermediate B: Synthesis of 6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one

[0277]

[0278] Step 1: Synthesis of tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (B-2)

[0279] 4-Nitro-1H-pyrazole (B-1, 1.0 g, 8.84 mol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (2.44 g, 17.69 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (4.94 g, 17.69 mmol) were added, and the mixture was stirred at 80°C for 12 h. The reaction was monitored by LC-MS. After the starting material reacted completely, the system was cooled to room temperature. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL). After drying over anhydrous sodium sulfate, the filtrate was filtered and concentrated under reduced pressure to obtain the title compound (1.9 g), which was used directly in the subsequent reaction without further purification.

[0280] MS m / z(ESI):297.1[M+H] +

[0281] Step 2: Synthesis of tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (B-3)

[0282] Dissolve tert-butyl 4-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (B-2, 1.8 g, 6.07 mmol) in ethanol (20 mL). Add palladium on carbon (20% palladium content, 738 mg). Stir at 60°C under a hydrogen atmosphere for 12 h. Monitor the reaction by LC-MS. After complete reaction, filter the reaction mixture through celite, and concentrate the filtrate under reduced pressure to obtain the crude title compound (1.6 g).

[0283] MS m / z(ESI):=267.2[M+H] +

[0284] Step 3: Synthesis of tert-butyl 4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (B-4)

[0285] Dissolve tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (B-3, 911 mg, 3.42 mmol) in toluene (20 mL). Add 6-methyl-4-[(1-methylcyclopropyl)amino]-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-5-one (Intermediate A, 1.0 g, 3.42 mmol). Stir the mixture at 100°C for 12 h. Monitor the reaction by LC-MS. After complete reaction, concentrate the mixture under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (1.0 g).

[0286] MS m / z(ESI):495.3[M+H] +

[0287] Step 4: Synthesis of 6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (Intermediate B)

[0288] Dissolve tert-butyl 4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (B-4, 40 mg, 0.08 mmol) in methanol (1 mL). Add dioxane hydrochloride solution (0.2 mL, 4 M). The mixture is stirred at room temperature for 4 h. The reaction is monitored by LC-MS. After completion of the reaction, the solvent is removed under reduced pressure to obtain the title compound (15 mg).

[0289] MS m / z(ESI):395.2[M+H] +

[0290] Intermediate C: Synthesis of 4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexanecarboxaldehyde

[0291]

[0292] Step 1: Synthesis of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanol (C-2)

[0293] Dissolve 4-(Hydroxymethyl)cyclohexanol (C-1, 3 g, 23.04 mmol) and imidazole (4.71 g, 69.13 mmol) in dichloromethane (30 mL). Finally, add tert-butylchlorodimethylsilane (5.21 g, 34.57 mmol). Monitor the reaction by TLC. After completion, extract the reaction solution with dichloromethane and water. The combined organic phases are washed with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (1.5 g).

[0294] 1 H NMR (400MHz, DMSO-d6) δ4.49-4.19(m,1H),3.40-3.34(m,2H),1.89-1.46(m,4H),1.42-1.01(m,5H),0.86-0.84(m,9H),0.02-0.01(m,6H).

[0295] Step 2: Synthesis of [4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]methanesulfonate (C-3)

[0296] 4-[[tert-Butyl(dimethyl)silyl]oxymethyl]cyclohexanol (C-2, 200 mg, 818.18 μmol) was added to dichloromethane (2 mL), followed by methanesulfonyl chloride (141 mg, 1.23 mmol). Triethylamine (248 mg, 2.45 mmol, 342.35 μL) was added dropwise to the reaction mixture and allowed to react at room temperature. The reaction was monitored by TLC. Upon completion, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (166 mg).

[0297] 1 H NMR(400MHz,DMSO-d6)δ4.53-3.96(m,1H),3.43-3.34(m,2H),3.16-3.10(m,3H),2.08-1 .87(m,2H),1.77-1.40(m,4H),1.28-0.98(m,2H),0.87-0.80(m,9H),0.03~-0.03(m,6H).

[0298] Step 3: Synthesis of tert-butyldimethyl-[[4-(4-nitropyrazol-1-yl)cyclohexyl]methoxy]silane (C-4)

[0299] [4-[[tert-Butyl(dimethyl)silyl]oxymethyl]cyclohexyl]methanesulfonate (C-3, 1.26 g, 3.91 mmol) and 4-nitro-1H-pyrazole (442 mg, 3.91 mmol) were added to N,N-dimethylformamide (1.5 mL), followed by potassium carbonate (1.62 g, 11.72 mmol). The reaction was allowed to react at 80°C. The reaction was monitored by TLC. After completion, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (726 mg).

[0300] 1H NMR(400MHz,DMSO-d6)δ8.95-8.88(m,1H),8.26-8.22(m,1H),4.37-4.15(m,1H),3.55-3.40(m,2H),2.15-2 .02(m,2H),1.87-1.64(m,3H),1.60-1.45(m,3H),1.15-1.05(m,1H),0.89-0.82(m,9H),0.03-0.01(m,6H).

[0301] Step 4: Synthesis of 1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-amine (C-5)

[0302] Add tert-Butyldimethyl-[[4-(4-nitropyrazol-1-yl)cyclohexyl]methoxy]silane (C-4, 630 mg, 1.86 mmol) to tetrahydrofuran (8 mL), followed by palladium on carbon (68 mg, 10% palladium content). The mixture was allowed to react overnight at room temperature under a hydrogen atmosphere (1 MPa). The reaction was monitored by LC-MS. After completion, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent to afford the title compound (599 mg).

[0303] MS m / z(ESI):310.3[M+H] +

[0304] 1 H NMR(400MHz,DMSO-d6)δ7.08-7.01(m,1H),6.89-6.86(m,1H),4.04-3.95(m,1H),3.89-3.70(m,2H),3.51-3 .40(m,2H),2.01-1.90(m,2H),1.74-1.60(m,3H),1.59-1.39(m,4H),0.87-0.85(m,9H),0.05-0.02(m,6H).

[0305] Step 5: Synthesis of 2-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]amino]-6-methyl-4-[(1-methylcyclopropyl)amino]pyrido[4,3-d]pyrimidin-5-one (C-6)

[0306] 1-[4-[[tert-Butyl(dimethyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-amine (C-5, 92.75 mg, 299.65 μmol) and 6-methyl-4-[(1-methylcyclopropyl)amino]-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-5-one (Intermediate A, 84 mg, 272.41 μmol) were added to toluene (0.5 mL) and reacted at 100°C for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (111 mg).

[0307] MS m / z(ESI):538.4[M+H] +

[0308] Step 6: Synthesis of 2-[[1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]amino]-6-methyl-4-[(1-methylcyclopropyl)amino]pyrido[4,3-d]pyrimidin-5-one (C-7)

[0309] 2-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]amino]-6-methyl-4-[(1-methylcyclopropyl)amino]

[0310] Pyrido[4,3-d]pyrimidin-5-one (C-6, 104 mg, 193.39 μmol) was added to a mixture of dichloromethane (1 mL) and dioxane hydrochloride (1 mL) and allowed to react at room temperature. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the title compound (90 mg).

[0311] MS m / z(ESI):=424.3[M+H] +

[0312] Step 7: Synthesis of 4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexanecarbaldehyde (Intermediate C)

[0313] 2-[[1-[4-(Hydroxymethyl)cyclohexyl]pyrazol-4-yl]amino]-6-methyl-4-[(1-methylcyclopropyl)amino]pyrido[4,3-d]pyrimidin-5-one (C-6, 30 mg, 70.84 μmol) was dissolved in dichloromethane (3 mL), and Dess-Martin reagent (45.16 mg, 106.25 μmol) was added. The mixture was stirred at 25°C for 2 h. After the reaction was complete, the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and sodium sulfite, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain the title compound (29 mg).

[0314] MS m / z(ESI):=422.2[M+H] + .

[0315] Intermediate D: Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)acetic acid

[0316]

[0317] Referring to steps 1 to 3 of Example 3, except that intermediate 3a was replaced by tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate, intermediate D was prepared in the same manner.

[0318] MS m / z(ESI):=387.1[M+H] + .

[0319] Intermediate E: Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetic acid

[0320]

[0321] Referring to steps 1 to 3 of Example 3, except that intermediate 3a was replaced by tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate, intermediate E was prepared in the same manner.

[0322] MS m / z(ESI):=419.8[M+H] + .

[0323] Intermediate F: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxaldehyde

[0324]

[0325] Step 1: Synthesis of 5-bromo-2-(4-(dimethoxymethyl)piperidin-1-yl)pyridine (F-1)

[0326] 5-Bromo-2-fluoropyridine (1a, 2.2 g, 12.50 mmol) and 4-(dimethoxymethyl)piperidine (2.59 g, 16.25 mmol) were dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (4.85 g, 37.50 mmol) was added and allowed to react at 100°C overnight. After sufficient reaction, the mixture was extracted with ethyl acetate (10 mL × 3) and water (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The mixture was then isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (1.72 g).

[0327] MS m / z(ESI):315.00[M+H] +

[0328] Step 2: Synthesis of 2,6-bis(benzyloxy)-6'-(4-(dimethoxymethyl)piperidin-1-yl)-3,3'-bipyridine (F-2)

[0329] 5-Bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]pyridine (F-1, 1.56 g, 4.95 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.48 g, 5.94 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (359 mg, 494.92 μmol) and potassium phosphate (3.15 g, 14.85 mmol) were dissolved in a mixed solution (4:1) of 1,4-dioxane (30 mL) and water (7.5 mL) and reacted at 100 °C under nitrogen protection overnight. After the reaction was completed as monitored by LC-MS, the solvent was removed by concentration under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL × 3) and water (10 mL). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and then purified by liquid chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (2 mg).

[0330] MS m / z(ESI):526.20[M+H] +

[0331] Step 3: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (F-3)

[0332] 2,6-Bis(benzyloxy)-6'-(4-(dimethoxymethyl)piperidin-1-yl)-3,3'-bipyridine (F-2, 1 g, 1.90 mmol) was dissolved in methanol (1 mL), and palladium on carbon (115 mg, 951.23 μmol) was added. The mixture was reacted overnight at 50°C under a hydrogen atmosphere (0.1 MPa). After completion of the reaction as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (137 mg).

[0333] MS m / z(ESI):348.80[M+H] +

[0334] Step 4: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde (Intermediate F)

[0335] Dissolve 3-[6-[4-(dimethoxymethyl)piperidin-1-yl]pyridin-3-yl]piperidine-2,6-dione (F-3, 40 mg, 115.14 μmol) in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL). Add hydrochloric acid (2N, 575.69 μL) and react at 60°C for 2 hours. After completion of the reaction as monitored by LC-MS, add deionized water (10 mL) and lyophilize to obtain the title compound (30 mg).

[0336] MS m / z(ESI):302.20[M+H] + .

[0337] Intermediate G: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidine-4-carboxylic acid

[0338]

[0339] Step 1: Synthesis of tert-butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidine-4-carboxylate (G-2)

[0340] Dissolve 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbaldehyde (G-1, 200 mg, 698.72 μmol) and tert-butyl piperidine-4-carboxylate (258.89 mg, 1.40 mmol) in tetrahydrofuran (2 mL). Add acetic acid to acidify the reaction system (pH = 6). Stir at room temperature for 5 minutes. Add sodium triacetoxyborohydride (444.26 mg, 2.10 mmol) and allow to react overnight at room temperature. After completion of the reaction as monitored by LC-MS, concentrate under reduced pressure to remove the solvent. Purify the mixture by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (356 mg).

[0341] MS m / z(ESI):456.40[M+H] +

[0342] Step 2: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidine-4-carboxylic acid (Intermediate G)

[0343] Tert-butyl 1-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]methyl]piperidine-4-carboxylate (G-2, 342 mg, 750.82 μmol) was dissolved in a mixture of trifluoroacetic acid (3 mL) and dichloromethane (3 mL) and allowed to react at room temperature for 1.5 hours. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated under reduced pressure to remove the solvent, and appropriate amounts of acetonitrile and deionized water were added, followed by lyophilization to afford the title compound (305 mg).

[0344] MS m / z(ESI):400.00[M+H] +

[0345] Intermediate H: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidine-4-carboxaldehyde

[0346]

[0347] Step 1: Synthesis of 5-((4-(dimethoxymethyl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (H-1)

[0348] Dissolve 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbaldehyde (G-1, 200 mg, 698.72 μmol) and 4-(dimethoxymethyl)piperidine (222 mg, 1.40 mmol) in tetrahydrofuran (10 mL). Add acetic acid (42 mg, 698.72 μmol) and sodium triacetoxyborohydride (444 mg, 2.10 mmol). Stir the mixture at 25°C for 16 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (160 mg).

[0349] MS m / z(ESI):430.10[M+H] +

[0350] Step 2: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidine-4-carbaldehyde (Intermediate H)

[0351] 5-((4-(dimethoxymethyl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (H-1, 66 mg, 153.68 μmol) was dissolved in a mixture of tetrahydrofuran (0.5 mL) and water (0.1 mL). Hydrochloric acid (2 M, 768.40 μL) was added and the mixture was reacted at 60°C for 2 hours. After LCMS showed completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent to obtain the title compound (55 mg).

[0352] MS m / z(ESI):384.10[M+H] +

[0353] Intermediate I: Synthesis of 1-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid

[0354]

[0355] Step 1: Synthesis of tert-butyl 1-[(5-bromopyridin-2-yl)methyl]piperidine-4-carboxylate (I-2)

[0356] 5-Bromopyridine-2-carboxaldehyde (I-1, 2 g, 10.75 mmol) and tert-butyl piperidine-4-carboxylate (2.19 g, 11.83 mmol) were dissolved in tetrahydrofuran (20 mL), and acetic acid (645 mg, 10.75 mmol) and sodium triacetoxyborohydride (6.84 g, 32.26 mmol) were added. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (3 g).

[0357] MS m / z(ESI):355.1,357.1[M+H] +

[0358] Step 2: Synthesis of tert-butyl 1-[[5-(2,6-dibenzyloxypyridin-3-yl)pyridin-2-yl]methyl]piperidine-4-carboxylate (I-3)

[0359] 1-[(5-bromo-2-pyridyl)methyl]piperidine-4-carboxylic acid tert-butyl ester (I-2, 3.8 g, 10.70 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.36 g, 12.84 mmol) were dissolved in dioxane (50 mL) and water (10 mL), and potassium phosphate (4.54 g, 21.39 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (776 mg, 1.07 mmol) were added thereto. The mixture was replaced three times under a nitrogen atmosphere and stirred at 80 ° C for 12 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with brine, dried and concentrated to give a crude product, and the residue was purified by silica gel chromatography to give the title compound (3 g).

[0360] MS m / z(ESI):566.1[M+H] +

[0361] Step 3: Synthesis of tert-butyl 1-[[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]methyl]piperidine-4-carboxylate (I-4)

[0362] To a solution of tert-butyl 1-[[5-(2,6-dibenzyloxypyridin-3-yl)pyridin-2-yl]methyl]piperidine-4-carboxylate (I-3, 1 g, 1.77 mmol) in ethyl acetate (100 mL) was added palladium on carbon (1 g, 10% palladium content). The reaction mixture was stirred at 50°C under hydrogen (15 psi) for 12 hours. The mixture was filtered and concentrated to give a residue, which was purified by preparative liquid chromatography to give the title compound (160 mg).

[0363] MS m / z(ESI):388.2[M+H] +

[0364] Step 4: Synthesis of 1-[[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]methyl]piperidine-4-carboxylic acid (Intermediate I)

[0365] Tert-butyl 1-[[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]methyl]piperidine-4-carboxylate (I-4, 80 mg, 206.47 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride (0.5 mL, 4 N) was added. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to dryness to give the title compound (130 mg).

[0366] MS m / z(ESI):332.1[M+H] +

[0367] Intermediate J: Synthesis of 1-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxaldehyde

[0368]

[0369] Intermediate J was prepared by following steps 1 to 4 of intermediate I, except that tert-butyl piperidine-4-carboxylate was replaced with 4-(dimethoxymethyl)piperidine.

[0370] MS m / z(ESI):316.1[M+H] +

[0371] Intermediate K: Synthesis of 3-(6-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)piperidine-2,6-dione

[0372]

[0373] Referring to steps 1 to 5 of Example 1, except that tert-butyl piperidine-4-carboxylate was replaced with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate, intermediate K was prepared in the same manner.

[0374] Intermediate L: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione

[0375]

[0376] Step 1: Synthesis of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (L-2)

[0377] 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (L-1, 637 mg, 2.31 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (523 mg, 2.31 mmol), and diisopropylethylamine (895 mg, 6.93 mmol) were dissolved in dimethyl sulfoxide (5 mL) and stirred at 100°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and filtered. The filter cake was collected and separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 100 / 5) to obtain the title compound (460 mg).

[0378] MS m / z(ESI):383.1[M-Boc+H] +

[0379] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (Intermediate L)

[0380] Dissolve tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (L-2, 460 mg, 0.95 mmol) in dichloromethane (5 mL). Add trifluoroacetic acid (1 mL) to the mixture and stir at room temperature for 30 minutes. Monitor the reaction by LC-MS. After completion, concentrate the solution under reduced pressure to remove the solvent and obtain the crude title compound (368 mg), which is used directly in the subsequent reaction without further purification.

[0381] MS m / z(ESI):383.1[M+H] +

[0382] Intermediate M: Synthesis of 2-(2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetic acid

[0383] Referring to step 2 to step 3 of Example 3, except that intermediate 3b is replaced by intermediate K, intermediate M is prepared in the same manner.

[0384] MS m / z(ESI):=373.1[M+H] +

[0385] Synthesis of Intermediate N: 2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetic acid

[0386]

[0387] Referring to step 2 to step 3 of Example 3, except that intermediate 3b is replaced by intermediate L, intermediate N is prepared in the same manner.

[0388] MS m / z(ESI):=441.1[M+H] +

[0389] Intermediate O: Synthesis of 3-(6-(3,9-diazaspiro[5.5]undec-3-yl)pyridin-3-yl)piperidine-2,6-dione

[0390]

[0391] Referring to steps 1 to 5 of Example 1, except that tert-butyl piperidine-4-carboxylate was replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, the intermediate O was prepared in the same manner.

[0392] MS m / z(ESI):343.2[M+H] +

[0393] Intermediate P: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecane-3-yl)isoindoline-1,3-dione

[0394]

[0395] Referring to the synthesis method of intermediate L, intermediate P was prepared by replacing tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0396] MS m / z(ESI):411.2[M+H] +

[0397] Intermediate Q: Synthesis of (4-(4-amino-1H-pyrazol-1-yl)cyclohexyl)methanol

[0398]

[0399] Step 1: Synthesis of methyl 4-[[methylsulfonyl]oxy]cyclohexane-1-carboxylate (Q-2)

[0400] Methyl 4-hydroxycyclohexane-1-carboxylate (Q-1, 20 g, 126.4 mmol) was dissolved in dichloromethane (200 mL), and triethylamine (26.5 mL, 189.6 mmol) was added. The mixture was stirred at 0°C, and then methylsulfonyl chloride (12.7 mL, 164.4 mmol) was slowly added. After stirring for two hours, 200 mL of saturated sodium bicarbonate solution was added for washing, and then the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (29.0 g), which was directly used for the next step without purification.

[0401] Step 2: Synthesis of methyl 4-[4-nitro-1H-pyrazol-1-yl]cyclohexane-1-carboxylate (Q-3)

[0402] Methyl 4-[[methylsulfonyl]oxy]cyclohexane-1-carboxylate (Q-2, 29 g, 122.7 mmol) was dissolved in N,N-dimethylformamide (200 mL), and cesium carbonate (41.37 g, 127.0 mmol) was added, followed by 4-nitropyrazole (9.57 g, 84.64 mmol), and the mixture was stirred at 100°C. After LC-MS showed the reaction was complete, 200 mL of water 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 separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (18.2 g).

[0403] MS m / z(ESI):254.1[M+H] +

[0404] Step 3: Synthesis of 4-[4-amino-1H-pyrazol-1-yl]cyclohexan-1-ol (Intermediate Q)

[0405] Methyl 4-[4-nitro-1H-pyrazol-1-yl]cyclohexane-1-carboxylate (Q-3, 2.0 g, 7.9 mmol) was dissolved in tetrahydrofuran (200 mL) and stirred at 0°C. Lithium aluminum hydride (1.5 g, 38.5 mmol) was then slowly added. After stirring at 0°C for 30 minutes, the reaction mixture was slowly warmed to 50°C. After LC-MS indicated the reaction was complete, water (1.5 mL) was added to quench the reaction, followed by the addition of 10% sodium hydroxide solution (4.5 mL). The mixture was then 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 afford the title compound (750 mg).

[0406] MS m / z(ESI):196.9[M+H] +

[0407] Synthesis of intermediate R: [4-[4-[[6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]carboxaldehyde

[0408]

[0409] Step 1: Synthesis of 6-chloropyrido[3,2-d]pyrimidine-2,4-diol (R-2)

[0410] 4-(3-Amino-6-chloropyridine-2-carboxamide) (R-1, 5 g, 29.14 mmol) was dissolved in 1,4-dioxane (100 mL), and triphosgene (3.46 g, 11.66 mmol) was added. The reaction was heated to 100°C for 3 hours. The reaction was then cooled to room temperature, and the solid was filtered and washed twice with ethyl acetate to obtain the title compound (5.3 g).

[0411] MS m / z(ESI):198.0[M+H] +

[0412] Step 2: Synthesis of 2,4,6-trichloropyrido[3,2-d]pyrimidine (R-3)

[0413] A mixture of 6-chloropyrido[3,2-d]pyrimidine-2,4-diol (R-2, 1 g, 5.06 mmol) and N,N-diisopropylethylamine (1.48 g, 11.48 mmol, 2 mL) and phosphorus oxychloride (10 mL) was heated at reflux overnight. The phosphorus oxychloride was removed in vacuo, and the residue was dissolved in dichloromethane. The organic phase was quenched with ice water, the organic layer was dried and concentrated, and the residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate gradient elution to 10 / 1) to give the title compound (900 mg).

[0414] MS m / z(ESI):234.0[M+H] +

[0415] Step 3: Synthesis of 2,6-dichloro-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidine (R-4)

[0416] 1-Methylcyclopropanol (110 mg, 1.54 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide (61 mg, 1.54 mmol, 60% purity) was added. After 15 minutes, 2,4,6-trichloropyrido[3,2-d]pyrimidine (R-3, 300 mg, 1.28 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate gradient elution to 1 / 1) to give the title compound (170 mg).

[0417] MS m / z(ESI):270.0[M+H] +

[0418] Step 4: Synthesis of [4-[4-[[6-chloro-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methanol (R-5)

[0419] 2,6-Dichloro-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidine (R-4, 900 mg, 3.33 mmol) was dissolved in isopropanol (20 mL), and [4-(4-aminopyrazol-1-yl)cyclohexyl]methanol (Intermediate Q, 715 mg, 3.67 mmol) and p-toluenesulfonic acid (288 mg, 1.67 mmol) were added. The mixture was stirred at 80 ° C for 16 hours. The mixture was filtered and concentrated to dryness. The residue was flash chromatographed on silica gel (petroleum ether / ethyl acetate gradient elution to 1 / 1) to give the title compound (500 mg).

[0420] MS m / z(ESI):429.1[M+H] +

[0421] Step 5: Synthesis of [4-[4-[[6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methanol (R-6)

[0422] [4-[4-[[6-chloro-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methanol (R-5, 90 mg, 209.83 μmol) and methylboronic acid (63 mg, 1.05 mmol) were dissolved in dioxane (2.5 mL) and water (0.5 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (34 mg, 41.97 μmol) and potassium carbonate (178 mg, 839.33 μmol) were added. The mixture was purged three times under a nitrogen atmosphere and stirred at 100°C under a nitrogen atmosphere for 12 hours. The mixture was diluted with ethyl acetate, washed with brine, dried, and concentrated to give the crude product. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate gradient elution to 1 / 1) to give the title compound (50 mg).

[0423] MS m / z(ESI):409.2[M+H] +

[0424] Step 6: Synthesis of 4-[4-[[6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexanecarbaldehyde (Intermediate R)

[0425] [4-[4-[[6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methanol (R-6, 10 mg, 24.48 μmol) was dissolved in dichloromethane (2 mL), and Dess-Martin periodinane (16 mg, 37.73 μmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and sodium sulfite, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (8 mg).

[0426] MS m / z(ESI):407.2[M+H] +

[0427] Intermediate S: Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

[0428]

[0429] Referring to the synthesis method of intermediate L, intermediate S was prepared by replacing tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate with 1-(2,2-dimethoxyethyl)piperazine.

[0430] MS m / z(ESI):403.1[M+H+18]+

[0431] Intermediate T: Synthesis of 2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetic acid

[0432]

[0433] Step 1: Synthesis of ethyl 2-(4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)acetate (T-2)

[0434] Ethyl 2-(4-hydroxycyclohexyl)acetate (T-1, 900 mg, 4.83 mmol) and 4-nitro-1H-pyrazole (546 mg, 4.83 mmol) were dissolved in tetrahydrofuran (10 mL). Triphenylphosphine (2.53 g, 9.66 mmol) was added and the mixture was cooled to 0°C under argon. Diisopropylazo-1,2-dicarboxylate (1.95 g, 9.66 mmol) was added dropwise. The mixture was allowed to react at room temperature overnight. 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 (gradient elution with ethyl acetate / petroleum ether = 0-30%) to obtain the title compound (730 mg).

[0435] MS m / z(ESI):282.1[M+H] +

[0436] Step 2: Synthesis of ethyl 2-(4-(4-amino-1H-pyrazol-1-yl)cyclohexyl)acetate (T-3)

[0437] Ethyl 2-(4-(4-nitro-1H-pyrazol-1-yl)cyclohexyl)acetate (T-2, 730 mg, 2.60 mmol) was dissolved in methanol (10 mL). Palladium on carbon (10 wt%, 100 mg) was added and the mixture was allowed to react overnight at room temperature under a hydrogen atmosphere (1 atm). LC-MS analysis indicated the reaction was complete. The reaction solution was filtered, and 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 obtain the title compound (630 mg).

[0438] MS m / z(ESI):252.1[M+H] +

[0439] Step 3: Synthesis of ethyl 2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetate (T-4)

[0440] Ethyl 2-(4-(4-amino-1H-pyrazol-1-yl)cyclohexyl)acetate (T-3, 430 mg, 1.71 mmol) and 6-methyl-4-((1-methylcyclopropyl)amino)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-5(6H)-one (Intermediate A, 500 mg, 1.71 mmol) were dissolved in toluene (10 mL) and the mixture was heated to 100°C for 3 h. LC-MS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to obtain the title compound (608 mg).

[0441] MS m / z(ESI):480.2[M+H] +

[0442] Step 4: Synthesis of 2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetic acid (Intermediate T)

[0443] Ethyl 2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetate (T-4, 600 mg, 1.25 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and water (2 mL). Lithium hydroxide monohydrate (263 mg, 6.26 mmol) was added, and the temperature was raised to 60°C and allowed to react overnight. LC-MS analysis indicated completion of the reaction. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was diluted with water (8 mL) and adjusted to pH 4 with dilute hydrochloric acid (3 M). The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude title compound (560 mg).

[0444] MS m / z(ESI):452.2[M+H] +

[0445] Intermediate U: Synthesis of 3-(6-(piperidin-4-yl)pyridin-3-yl)piperidine-2,6-dione

[0446]

[0447] Step 1: Synthesis of tert-butyl 5-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (U-2)

[0448] 5-Bromo-2-iodopyridine (U-1, 1.00 g, 3.52 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.20 g, 3.87 mmol) were dissolved in 1,4-dioxane (10 mL), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (258 mg, 352 μmol) and potassium carbonate (974 mg, 7.04 mmol) were added. The mixture was heated to 80 °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 ethyl acetate (20 mL), and washed with saturated brine (15 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 = 0-30% gradient elution) to give the title compound (772 mg).

[0449] MS m / z(ESI):283.0,285,0[M+H-tBu] +

[0450] Step 2: Synthesis of tert-butyl 2,6-bis(benzyloxy)-3',6"-dihydro-[3,3':6',4"-tripyridine]-1" (2"H)-carboxylate (U-3)

[0451] Tert-butyl 5-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (U-2, 550 mg, 1.62 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (744 mg, 1.78 mmol) were dissolved in 1,4-dioxane (5 mL). [1,1-Bis(diphenylphosphino)ferrocene]palladium dichloride (119 mg, 162 μmol) and potassium carbonate (448 mg, 3.24 mmol) were added to the mixture. 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 (20 mL), and filtered. The filtrate was washed with saturated brine (15 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 = 0-50% gradient elution) to give the title compound (186 mg).

[0452] MS m / z(ESI):550.2[M+H] +

[0453] Step 3: Synthesis of tert-butyl 4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-1-carboxylate (U-4)

[0454] Tert-butyl 2,6-bis(benzyloxy)-3',6"-dihydro-[3,3':6',4"-tripyridine]-1"(2"H)-carboxylate (U-3, 180 mg, 327 μmol) was dissolved in methanol (5 mL). Palladium on carbon (10 wt%, 100 mg) was added and the mixture was allowed to react overnight at room temperature under a hydrogen atmosphere (0.1 MPa). LC-MS analysis indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (120 mg).

[0455] MS m / z(ESI):374.2[M+H] +

[0456] Step 4: Synthesis of 3-(6-(piperidin-4-yl)pyridin-3-yl)piperidine-2,6-dione (Intermediate U)

[0457] Dissolve tert-butyl 4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-1-carboxylate (U-4, 110 mg, 295 μmol) in 1,4-dioxane (2 mL). Add 4 M dioxane hydrochloride solution (1 mL) and react at room temperature for 6 hours. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude title compound (81 mg).

[0458] MS m / z(ESI):274.1[M+H] +

[0459] Intermediate V: Synthesis of 2-((1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one

[0460]

[0461] Step 1: Synthesis of tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (V-2)

[0462] Dissolve tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (V-1, 5.00 g, 20.72 mmol) and triethylamine (4.2 g, 41.44 mmol) in dichloromethane (50 mL). Add methylsulfonyl chloride (2.61 g, 22.79 mmol) under ice-cooling. Allow to react overnight at room temperature. LC-MS indicated the reaction was relatively complete. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to yield the title compound (6.4 g).

[0463] Step 2: Synthesis of tert-butyl 2-(4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (V-3)

[0464] Dissolve tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (V-2, 2.0 g, 6.26 mmol) and 4-nitropyrazole (849.61 mg, 7.51 mmol) in N,N-dimethylformamide (20 mL). Add cesium carbonate (2.45 g, 7.51 mmol). Heat to 100°C and stir for 16 hours. LC-MS indicated completion of the reaction. The reaction solution was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with water (50 mL x 2) and saturated brine (50 mL). The organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford the title compound (1.65 g).

[0465] MS m / z(ESI):281.1[M-56+H] +

[0466] Step 3: Synthesis of tert-butyl 2-(4-amino-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (V-4)

[0467] Dissolve tert-butyl 2-(4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (V-3, 600 mg, 1.78 mmol) in a mixture of methanol (4 mL) and tetrahydrofuran (4 mL). Add palladium on carbon (60 mg). Stir the mixture at room temperature under a hydrogen atmosphere (1 MPa) for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was filtered and washed with ethyl acetate. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford the title compound (500 mg).

[0468] MS m / z(ESI):307.2[M+H] +

[0469] Step 4: Synthesis of tert-butyl 2-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (V-5)

[0470] 6-Methyl-4-((1-methylcyclopropyl)amino)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-5(6H)-one (Intermediate A, 105 mg, 359.15 μmol) and tert-butyl 2-(4-amino-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (V-4, 121.05 mg, 395.07 μmol) were dissolved in toluene (1 mL) and the mixture was heated to 110°C for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (188 mg).

[0471] MS m / z(ESI):535.2[M+H] +

[0472] Step 5: Synthesis of 2-((1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one (Intermediate V)

[0473] Tert-butyl 2-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (V-5, 180 mg, 336.67 μmol) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (0.25 mL) and stirring at room temperature for 2 h. LC-MS indicated the reaction was complete. The reaction solution was concentrated and evaporated to dryness. The residue was neutralized with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to afford the title compound (116 mg).

[0474] MS m / z(ESI):435.2[M+H] +

[0475] Intermediate W: Synthesis of 1-(2-chloro-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0476]

[0477] Step 1: Synthesis of 3-((2-chloro-5-(methoxycarbonyl)phenyl)amino)propionic acid (W-2)

[0478] Under nitrogen, methyl 3-amino-4-chlorobenzoate (W-1, 40 g, 215.51 mmol) was dissolved in acrylic acid (62.12 g, 862.04 mmol). The reaction mixture was stirred at 100°C for 16 hours. LCMS indicated completion of the reaction. Ethyl acetate (200 mL x 3) and water (200 mL) were added for extraction. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (gradient 0-20% tetrahydrofuran / petroleum ether) to obtain the title compound (33 g).

[0479] Step 2: Synthesis of methyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (W-3)

[0480] 3-((2-chloro-5-(methoxycarbonyl)phenyl)amino)propionic acid (W-2, 33 g, 128.07 mmol) was dissolved in acetic acid (330 mL), and urea (53.84 g, 896.50 mmol) was added. The reaction mixture was stirred at 110°C under nitrogen for 16 hours. LCMS showed the formation of the product. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the acid, and then extracted with ethyl acetate (200 mL × 3) and water (200 mL). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by beating with tert-methyl ether (150 mL) to obtain the title compound (15.3 g).

[0481] Step 3: Synthesis of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (W-4)

[0482] Methyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (W-3, 15.3 g, 54.12 mmol) was dissolved in dioxane (60 mL) and hydrochloric acid (6 M, 75 mL) was added. The reaction mixture was stirred at 90°C under nitrogen for 66 hours. LCMS indicated the formation of the product. After the reaction, ethyl acetate (60 mL x 3) and water (120 mL) were added for extraction. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by slurrying with tert-methyl ether (60 mL) to obtain the title compound (11 g).

[0483] Step 4: Synthesis of perfluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (W-5)

[0484] Under nitrogen, 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (W-4, 1 g, 3.72 mmol) was dissolved in N,N-dimethylformamide (20 mL). Pentafluorophenyl trifluoroacetate (2.61 g, 9.31 mmol) and N,N-diisopropylethylamine (1.92 g, 14.89 mmol, 2.59 mL) were slowly added. The reaction mixture was stirred at 25°C for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was dissolved in water (40 mL) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (gradient 0-24% tetrahydrofuran / petroleum ether) to obtain the title compound (1.65 g).

[0485] MS m / z(ESI):435.1[M+H] +

[0486] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.37(d,J=2.1Hz,1H),8.18(dd,J=2.1,8.5Hz,1H),7.90 (d,J=8.4Hz,1H),3.88-3.79(m,1H),3.74-3.64(m,1H),3.58-3.46(m,1H),3.09-2.98(m,1H).

[0487] Step 5: Synthesis of tert-butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (W-6)

[0488] Under nitrogen, perfluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (W-5, 600 mg, 1.38 mmol) was dissolved in dimethyl sulfoxide (10 mL). Piperazine-1-carboxylic acid tert-butyl ester (514.15 mg, 2.76 mmol) and N,N-diisopropylethylamine (535.17 mg, 4.14 mmol) were slowly added. The reaction mixture was stirred at 25°C for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was dissolved in water (40 mL) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (gradient 0-2% methanol / dichloromethane) to obtain the title compound (353 mg).

[0489] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.66(dd,J=2.3,8.2Hz,1H),7.60(s,1H),7.47-7.40(m,1H),3.83-3.72(m,1H),3.62(br dd,J=6.5,11.3Hz,3H),3.50-3.36(m,6H),2.75(br s,2H),1.41(s,9H).

[0490] Step 6: Synthesis of 1-(2-chloro-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate W)

[0491] Under nitrogen, tert-butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (W-6, 190 mg, 434.89 μmol) was dissolved in HCl / 1,4-dioxane (4 mL). The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated to obtain the title compound (179 mg).

[0492] MS m / z(ESI):337.1[M+H] +

[0493] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.44(br s,1H),7.71-7.63(m,2H),7.49(dd,J=2.0,8.2Hz,1H),3.76(br dd,J=6.1,13.1Hz,2H),3.68-3.63(m,2H),3.61(br s,2H),3.15(br s,4H),2.79-2.72(m,2H).

[0494] Intermediate X: Synthesis of 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0495]

[0496] Intermediate X was prepared by following steps 5 to 6 of intermediate W, except that tert-butyl piperazine-1-carboxylate was replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0497] MS m / z(ESI):405.2[M+H] +

[0498] 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.80(br s,1H),7.66(d,J=8.2Hz,1H),7.56(d,J=2.0Hz,1H),7.40(dd,J=2.0,8.2Hz,1H),3.80-3.71(m,1H),3.68-3.58(m,3H),3.31(br d,J=2.6Hz,2H),3.03(br d,J=1.2Hz,4H),2.79-2.72(m,2H),1.66(br s,4H),1.57-1.41(m,4H)

[0499] Intermediate Y: Synthesis of 3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0500]

[0501] Step 1: Synthesis of tert-butyl 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Y-1)

[0502] Under nitrogen protection, 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (6e, 270 mg, 798.45 μmol) was dissolved in toluene (9 mL), and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (216.84 mg, 958.14 μmol), (2-dicyclohexylphosphino-2',6'-dicarboxylate) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate were added to the reaction solution. The reaction mixture was stirred at 100°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was adjusted to pH 7 with formic acid, filtered, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (gradient 0-50% tetrahydrofuran / petroleum ether) to obtain the title compound (300 mg).

[0503] MS m / z(ESI):384.3[M+H-100] +

[0504] 1H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 6.96 (t, J = 8.0Hz, 1H), 6.80-6.60 (m, 2H), 5.33 (br dd,J=5.2,12.7Hz,1H),3.59(d,J=18.0Hz,7H),3.33-3.30(m,3H),2.98-2.81(m,1H),2.72-2.52(m,4H),1.78-1.65(m,4H),1.41(s,9H).

[0505] Step 2: Synthesis of 3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate Y)

[0506] Tert-butyl 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Y-1, 260 mg, 537.68 μmol) was dissolved in trifluoroethanol (5 mL). Ethyl tetrafluoroborate (348.27 mg, 1.08 mmol, 50% purity) was added and the reaction was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was filtered and the filter cake dried to afford the title compound (210 mg).

[0507] MS m / z(ESI):384.2[M+H] +

[0508] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.34(br s,1H),7.09-6.89(m,1H),6.76(d,J=7.9Hz,1H),6.68(d,J=8.1Hz,1H),5.33(br dd,J=5.3,12.8Hz,1H),3.67(s,4H),3.58(s,3H),3.09(br s,4H),2.96-2.81(m,1H),2.76-2.57(m,2H),1.99-1.92(m,5H).

[0509] Intermediate Z: 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

[0510]

[0511] 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 (Z-2)

[0512] Under nitrogen, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Z-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, and concentrated to afford the title compound (20 mg).

[0513] 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 Z)

[0514] 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Z-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. LCMS showed that the product was the primary product. 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).

[0515] MS m / z(ESI):371.00[M+H] +

[0516] Intermediate AA: Synthesis of 3-(4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione

[0517]

[0518] Step 1: Synthesis of 1-(benzyloxy)-4-bromobenzene (AA-2)

[0519] 4-Bromophenol (AA-1, 4.00 g, 23.12 mmol), benzyl bromide (4.745 g, 27.92 mmol), and potassium carbonate (6.381 g, 46.24 mmol) were dissolved in N,N-dimethylformamide (40 mL) at room temperature. The temperature was raised to 45°C, and the reaction mixture was stirred at 45°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with methyl tert-butyl ether (40 mL x 2). The organic phase was washed with saturated brine (30 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 = 20 / 1) to obtain the title compound (6.084 g).

[0520] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.4Hz, 1H), 6.22 (d, J = 8.4Hz, 1H), 4.40 (s, 2H), 3.47-3.34 (m, 1H), 1.21 (d, J = 6.8Hz, 6H).

[0521] Step 2: Synthesis of tert-butyl 4-(4-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (AA-3)

[0522] At room temperature, 1-(benzyloxy)-4-bromobenzene (AA-2, 6.084 g, 23.12 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.507 g, 24.28 mmol), potassium carbonate (6.381 g, 46.24 mmol), and tetrakis(triphenylphosphine)palladium (1.069 g, 0.04 mmol) were dissolved in 1,4-dioxane / water (60 mL / 15 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C. The reaction mixture was stirred at 90°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (60 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 obtained residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound (4.902 g).

[0523] MS m / z(ESI):310.2[M-tBu+H] +

[0524] Step 3: Synthesis of tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (AA-4)

[0525] Tert-butyl 4-(4-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (AA-3, 3.77 g, 10.32 mmol) was dissolved in anhydrous methanol / dichloromethane (30 mL / 24 mL) at room temperature. Palladium on carbon (1.0 g) was then added, and the atmosphere was replaced with hydrogen. The reaction mixture was stirred at 26°C for 12 hours. The reaction mixture was filtered through a pad of celite, and the filter cake was rinsed with methanol (30 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (2.8 g).

[0526] MS m / z(ESI):222.1[M-tBu+H] +

[0527] Step 4: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-1-carboxylate (AA-5)

[0528] At room temperature, tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (AA-4, 2.778 g, 10.02 mmol) was dissolved in N,N-dimethylformamide (50 mL). The temperature was lowered to 0°C, and sodium hydroxide (1.203 g, 60% purity, 30.07 mmol) was added portionwise. The reaction mixture was stirred at 26°C for 1 hour. The reaction mixture was then lowered to 0°C, and 3-bromopiperidine-2,6-dione 6 (5.742 g, 30.07 mmol) was added. The reaction mixture was stirred at 26°C for 6 hours. After completion of the reaction, saturated aqueous ammonium chloride (50 mL) was added to quench the sodium hydroxide, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (728 mg).

[0529] MS m / z(ESI):289.1[M-tBu+H] +

[0530] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.15(d,J=8.4Hz,2H),6.93(d,J=8.8Hz,2H),5.16-5.12(m,1H),4.06(d ,J=11.6Hz,2H),2.82-2.57(m,5H),2.19-2.09(m,2H),1.72(d,J=12.4Hz,2H),1.49-1.43(m,2H),1.41(s,9H).

[0531] Step 5: Synthesis of 3-(4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione (Intermediate AA)

[0532] Dissolve tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-1-carboxylate (AA-5, 25 mg, 64.36 μmol) in a mixture of dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) and react at room temperature for 3 hours. LCMS showed predominantly the product. Concentrate under reduced pressure to remove the solvent to afford the title compound (26 mg).

[0533] MS m / z(ESI):289.20[M+H] +

[0534] Intermediate AB: Synthesis of 2-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one

[0535]

[0536] Referring to the synthesis method of intermediate V, except that intermediate V-1 is replaced by tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, intermediate AB is prepared in the same manner.

[0537] MS m / z(ESI):407.1[M+H] +

[0538] 1 H NMR(400MHz,D2O)δ7.97(s,1H),7.81-7.74(m,2H),6.33-4.39(m,1H),4.67-4.71(s,1H),4.25(s,2 H),4.14(s,2H),3.42(s,3H),2.83-2.90(m,2H),2.65-2.75(m,2H),1.39(s,3H),0.86-0.76(m,4H).

[0539] Intermediate AD: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindoline-1,3-dione

[0540]

[0541] Referring to the synthesis method of intermediate L, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate was replaced with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate, and intermediate AD was prepared in the same manner.

[0542] MS m / z(ESI):383.1[M+H] +

[0543] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.30(s,1H),7.67-7.65(m,1H),7.36(d,J=2.0Hz,1H),7.25(dd,J1=2.0Hz,J2=8.4Hz,1H),5.06(dd,J1=5.2 Hz,J2=12.8Hz,1H),3.73(t,J=6.0Hz,4H),3.46(t,J=5.2Hz,4H),2.93-2 .83(m,1H),2.60-2.53(m,2H),2.04-1.98(m,1H),1.85(t,J=5.2Hz,4H).

[0544] Intermediate AE: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(2,8-diazaspiro[4.5]decane-7-yl)isoindoline-1,3-dione

[0545]

[0546] Referring to the synthesis method of intermediate L, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate was replaced with tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate, and intermediate AE was prepared in the same manner.

[0547] MS m / z(ESI):397.1[M+H] +

[0548] Intermediate AF: Synthesis of 2-(2,6-dioxapiperidin-3-yl)-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione

[0549]

[0550] Referring to the synthesis method of intermediate L, intermediate L-1 was replaced by 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione, and intermediate AF was prepared in the same manner.

[0551] Intermediate AJ: Synthesis of 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione

[0552]

[0553] Step 1: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (AJ-2)

[0554] tert-Butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (AJ-1, 1 g, 3.59 mmol) was added to tetrahydrofuran (30 mL). Sodium hydride (215.56 mg, 5.39 mmol) was added under ice-cooling and stirred for 15 minutes. 3-Bromopiperidine-2,6-dione (689.83 mg, 3.59 mmol) was added and stirred at room temperature overnight. LCMS indicated that the reaction was complete. The reaction solution was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (610 mg) was obtained by separation and purification via silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1).

[0555] MS m / z(ESI):389.5[M+H] +

[0556] Step 2: Synthesis of 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione (Intermediate AJ)

[0557] Dissolve tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (610 mg, 1.57 mmol) in dichloromethane (10 mL). Add 5 mL of trifluoroacetic acid (178.59 mg, 1.57 mmol) and stir at room temperature overnight. LCMS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford the crude title compound (410 mg), which was carried on to the next step without purification.

[0558] MS m / z(ESI):290.1[M+H] +

[0559] Intermediate AK: Synthesis of 3-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenoxy)piperidine-2,6-dione

[0560]

[0561] Referring to the synthesis method of intermediate AN, the 4-(dimethoxymethyl)piperidine was replaced with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate, and intermediate AK was prepared in the same manner.

[0562] MS m / z(ESI):330.80[M+H] +

[0563] Intermediate AL: Synthesis of 3-((5-(piperazin-1-yl)pyridin-2-yl)oxy)piperidine-2,6-dione

[0564]

[0565] Step 1: Synthesis of 3-((5-iodopyridin-2-yl)oxy)piperidine-2,6-dione (AL-2)

[0566] Dissolve 5-iodopyridin-2-ol (AL-1,5 g, 22.62 mmol) in tetrahydrofuran (50 mL). Add sodium hydride (1.36 g, 33.94 mmol) under ice-cooling. Stir for 15 minutes, then add 3-bromopiperidine-2,6-dione (5.65 g, 29.41 mmol). Heat to 60°C and allow to react overnight. LCMS monitoring indicated the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL x 3), and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford the title compound (1.16 g).

[0567] MS m / z(ESI):332.5[M+H] +

[0568] Step 2: Synthesis of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)oxy)pyridin-3-yl)piperazine-1-carboxylate (AL-3)

[0569] Tert-butyl piperazine-1-carboxylate (841.26 mg, 4.52 mmol), 3-((5-iodopyridin-2-yl)oxy)piperidine-2,6-dione (AL-2, 500 mg, 1.51 mmol), potassium tert-butoxide (506.84 mg, 4.52 mmol), and dichloro(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene)(3-chloropyridinyl)palladium(II) (119.19 mg, 150.56 μmol) were dissolved in N,N-dimethylformamide (20 mL) and heated to 100°C overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (10 mL × 3), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The title compound was obtained (120 mg) by separation and purification by silica gel column chromatography (dichloromethane / methanol = 30 / 1).

[0570] MS m / z(ESI):391.2[M+H] +

[0571] Step 3: Synthesis of 3-((5-(piperazin-1-yl)pyridin-2-yl)oxy)piperidine-2,6-dione (Intermediate AL)

[0572] Dissolve tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)oxy)pyridin-3-yl)piperazine-1-carboxylate (AL-3, 56 mg, 143 μmol) in 1,4-dioxane (5 mL). Add 4 M hydrogen chloride-1,4-dioxane solution (2 mL) and allow to react 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 crude title compound (50 mg).

[0573] MS m / z(ESI):291.1[M+H] +

[0574] Intermediate AM: Synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione

[0575]

[0576] Step 1: Synthesis of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate (AM-2)

[0577] Dissolve tert-butyl 4-(5-hydroxypyridin-2-yl)piperazine-1-carboxylate (AM-1, 515 mg, 1.84 mmol) in tetrahydrofuran (8 mL). Add sodium hydroxide (147 mg, 3.69 mmol, 60% purity). Stir for 10 minutes. Add 3-bromopiperidine-2,6-dione (531 mg, 2.77 mmol). Stir at 60°C for 6 hours. LCMS showed the product was primarily obtained. Extract with ethyl acetate (10 mL x 3) and water (20 mL), wash with saturated brine, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). Concentrate under reduced pressure to remove the solvent to obtain the title compound (302 mg).

[0578] MS m / z(ESI):391.40[M+H] +

[0579] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.96-7.94(m,1H),7.39-7.34(m,1H),6.85-6.80(m,1H),5.05- 4.98(m,1H),3.43-3.39(m,4H),3.37-3.34(m,4H),2.71-2.58(m,2H),2.25-2.04(m,2H),1.42(s,9H).

[0580] Step 2: Synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione (Intermediate AM)

[0581] Dissolve tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate (AM-2, 459 mg, 1.18 mmol) in a mixture of dichloromethane (3 mL) and trifluoroacetic acid (0.6 mL) and allow to react at room temperature for 3 hours. The solvent was then concentrated under reduced pressure to yield the title compound (327 mg).

[0582] MS m / z(ESI):291.10[M+H] +

[0583] Intermediate AN: Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carboxaldehyde

[0584]

[0585] Step 1: Synthesis of 1-(4-benzyloxyphenyl)-4-(dimethoxymethyl)piperidine (AN-2)

[0586] 1-(Benzyloxy)-4-iodobenzene (AN-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, 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 (2.14 g).

[0587] MS m / z(ESI):342.2[M+H] +

[0588] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)phenol (AN-3)

[0589] 1-(4-Benzyloxyphenyl)-4-(dimethoxymethyl)piperidine (AN-2, 1.99 g, 5.83 mmol) was dissolved in ethyl acetate (40 mL), and palladium on carbon (1.99 g, 16.39 mmol) was added. The mixture was allowed to react overnight at 60°C 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).

[0590] MS m / z(ESI):252.2[M+H] +

[0591] Step 3: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (AN-4)

[0592] Dissolve 4-(4-(dimethoxymethyl)piperidin-1-yl)phenol (AN-3, 1.38 g, 5.49 mmol) in tetrahydrofuran (20 mL). Add sodium hydride (329.46 mg, 8.24 mmol, 60% purity) under ice-cooling. Stir for 15 minutes, then add 3-bromopiperidine-2,6-dione (1.37 g, 7.14 mmol). Stir and react at room temperature overnight. After LC-MS indicated completion of the reaction, 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 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).

[0593] MS m / z(ESI):363.1[M+H] +

[0594] 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).

[0595] Step 4: Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbaldehyde (Intermediate AN)

[0596] Dissolve 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (AN-4, 50 mg, 0.138 mmol) in acetone (1 mL) at room temperature. Add aqueous hydrochloric acid (2 mL, 1 N) dropwise at room temperature, heat 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.

[0597] Intermediate AO: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidine-4-carboxaldehyde

[0598]

[0599] Step 1: Synthesis of 7-bromo-3-iodo-1H-indazole (AO-2)

[0600] 7-Bromo-1H-indazole (AO-1,5 g, 25.51 mmol) was dissolved in N,N-dimethylformamide (60 mL) at room temperature, and potassium hydroxide (2.15 g, 38.27 mmol) and iodine (9.72 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).

[0601] MS m / z(ESI):322.9[M+H] +

[0602] Step 2: Synthesis of 7-bromo-3-iodo-1-methyl-1H-indazole (AO-3)

[0603] 7-Bromo-3-iodo-1H-indazole (AO-2, 8 g, 24.845 mmol) was dissolved in THF (150 mL) at room temperature and potassium tert-butoxide (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 THF (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. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (5.4 g).

[0604] MS m / z(ESI):336.9[M+H] +

[0605] Step 3: Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (AO-4)

[0606] 7-Bromo-3-iodo-1-methyl-1H-indazole (AO-3, 3 g, 8.93 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.09 g, 9.82 mmol), potassium carbonate (2.46 g, 17.86 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 and the temperature was raised to 90°C. The reaction mixture was stirred at 90°C 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, 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).

[0607] MS m / z(ESI):500.1[M+H] +

[0608] Step 4: Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (AO-5)

[0609] At room temperature, 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (AO-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 (2 40.97 mg, 0.516 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (452.02 g, 0.516 mmol) were dissolved in 1,4-dioxane (40 mL). The atmosphere was replaced with nitrogen, and the temperature was raised to 100°C. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution 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 = 3 / 1) to give the title compound (1.16 g).

[0610] MS m / z(ESI):579.4[M+H] +

[0611] Step 5: Synthesis of 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (AO-6)

[0612] 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (AO-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 26°C for 16 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (590 mg).

[0613] MS m / z(ESI):401.1[M+H] +

[0614] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.37-7.35(m,1H),7.00-6.98(m,2H),4.34-4.30(m,1H),4.23(s,3H),4.15(d,J=4.8Hz,1H), 3.30(s,6H),3.23(d,J=10.0Hz,2H),2.70-2.56(m,4H),2.36-2.27(m,1H),2.20-2.12(m,1H),1.79-1.69(m,3H),1.55-1.45(m,2H).

[0615] Step 6: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidine-4-carbaldehyde (Intermediate AO)

[0616] Dissolve 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (AO-6, 25 mg, 63 μmol) in tetrahydrofuran (4 mL). Add hydrogen chloride-water solution (2 M, 2 mL) and react at 60°C overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude title compound (20 mg).

[0617] MS m / z(ESI):355.1[M+H] +

[0618] Intermediate AP: Synthesis of 1-(2-chloro-5-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0619]

[0620] Step 1: Synthesis of 3-((2-chloro-5-iodophenyl)amino)propionic acid (AP-1)

[0621] Dissolve 2-chloro-5-iodoaniline (AP-1, 5.0 g, 19.7 mmol) in acetic acid (50 mL). Add acrylic acid (4.3 g, 59.2 mmol) and heat to 100°C overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude title compound (7.1 g), which was carried on to the next step without purification.

[0622] MS m / z(ESI):325.9[M+H] +

[0623] Step 2: Synthesis of 1-(2-chloro-5-iodophenyl)dihydropyrimidine-2,4(1H,3H)-dione (AP-3)

[0624] Crude 3-((2-chloro-5-iodophenyl)amino)propionic acid (AP-2, 7.1 g) was dissolved in acetic acid (30 mL). Urea (25.8 g, 430.1 mmol) was added, and the mixture was heated to 110°C and reacted for 48 h. LC-MS analysis indicated that the reaction was no longer proceeding. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove some of the acetic acid. The solution was then diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to obtain the title compound (1.65 g).

[0625] MS m / z(ESI):350.9[M+H] +

[0626] Step 3: Synthesis of tert-butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate (AP-4)

[0627] 1-(2-Chloro-5-iodophenyl)dihydropyrimidine-2,4(1H,3H)-dione (AP-3, 1.0 g, 2.9 mmol) and tert-butyl piperazine-1-carboxylate (638 mg, 3.4 mmol) were dissolved in N,N-dimethylformamide (10 mL). Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (226 mg, 285 μmol) and cesium carbonate (2.3 g, 7.1 mmol) were added. The mixture was heated to 70°C under argon and allowed to react overnight. LC-MS analysis indicated that the reaction was no longer proceeding. The reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and washed with saturated ammonium chloride solution (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 (241 mg).

[0628] MS m / z(ESI):353.1[M+H-tBu] +

[0629] Step 4: Synthesis of 1-(2-chloro-5-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate AP)

[0630] Tert-butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate (AP-4, 240 mg, 587 μmol) was dissolved in 1,4-dioxane (5 mL). A 4 M hydrogen chloride-dioxane solution (2 mL) was added and the mixture was allowed to react at room temperature for 5 h. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude title compound (182 mg), which was used directly in the next step without purification.

[0631] MS m / z(ESI):309.1[M+H] +

[0632] Intermediate AQ: Synthesis of 1-(2-methyl-5-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0633]

[0634] Referring to the synthesis method of intermediate AP, intermediate AP-1 was replaced by 5-iodo-2-methylaniline, and intermediate AQ was prepared in the same manner.

[0635] Intermediate AR: Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde

[0636]

[0637] Step 1: Synthesis of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propionic acid (AR-2)

[0638] To a stirred solution of 6-bromo-1-methyl-1H-indazol-3-amine (AR-1, 10.00 g, 44.248 mmol) in glacial acetic acid (6.29 g, 104.87 mmol) and water (30 mL) at room temperature was added acrylic acid (3.189 g, 44.248 mmol). The mixture was stirred at 105°C under nitrogen for 20 hours. The resulting residue was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (4.2 g).

[0639] MS m / z(ESI):298.14[M+H] +

[0640] Step 2: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (AR-3)

[0641] At room temperature, 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (AR-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).

[0642] MS m / z(ESI):323.15[M+H] +

[0643] Step 3: Synthesis of 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (AR-4)

[0644] At room temperature, 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (AR-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).

[0645] MS m / z(ESI):402.1[M+H] +

[0646] 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).

[0647] Step 4: Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (Intermediate AR)

[0648] Dissolve 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (AR-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.

[0649] Intermediate AS: Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonane-7-carbaldehyde

[0650]

[0651] Step 1: Synthesis of (2-azaspiro[3.5]nonan-7-yl)methanol (AS-2)

[0652] Dissolve tert-butyl 7-(hydroxymethyl)-2-azaspiro[3.5]nonane-2-carboxylate (AS-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. Concentrate the solvent in vacuo to obtain the crude title compound, which is used directly in the next reaction.

[0653] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (AS-3)

[0654] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (L-1, 864.6 mg, 3.13 mmol), (2-azaspiro[3.5]nonan-7-yl)methanol (AS-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).

[0655] MS m / z(ESI):412.2[M+H] +

[0656] Step 3: Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonane-7-carbaldehyde (Intermediate AS)

[0657] Under ice, 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (AS-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).

[0658] MS m / z(ESI):410.1[M+H] +

[0659] 1H 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).

[0660] Intermediate AT: Synthesis of 2-((1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-(1-methylcyclopropylamino)pyridin[4,3-d]pyrimidin-5(6H)-one

[0661]

[0662] Step 1: Synthesis of tert-butyl 5-(4-nitro-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-2)

[0663] Dissolve tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-1, 2.8 g, 13.13 mmol) and 4-nitro-1H-pyrazole (Compound B-1, 1.48 g, 13.1 mmol) in tetrahydrofuran (20 mL). Add triphenylphosphine (8.41 g, 26.26 mmol). Slowly add diisopropyl azodicarboxylate (3.98 g, 19.69 mmol) at room temperature and stir. After LC-MS indicates the reaction is complete, add 20 mL of water and extract with ethyl acetate (20 mL x 3). The organic phases are combined and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (3.9 g).

[0664] MS m / z(ESI):309.4[M+H] +

[0665] Step 2: Synthesis of tert-butyl 5-(4-amino-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-3)

[0666] Dissolve tert-butyl 5-(4-nitro-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-2, 3.9 g, 12.65 mmol) in ethyl acetate (20 mL). Add palladium on carbon (3.9 g, 32.11 mmol). Allow to react overnight at room temperature under a hydrogen atmosphere. LC-MS indicates completion of the reaction. The reaction mixture is diluted with ethyl acetate (60 mL) and filtered. The filter cake is rinsed with methanol (20 mL), and the filtrate is concentrated to afford the crude title compound (4.35 g), which is used directly in subsequent reactions without further purification.

[0667] MS m / z(ESI):279.1[M+H] +

[0668] Step 3: Synthesis of tert-butyl 5-(4-((6-methyl-4-(1-methylcyclopropylamino)-5-oxo-5,6-dihydropyrido[4,3-D]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-4)

[0669] tert-Butyl 5-(4-amino-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-3, 200 mg, 718.52 μmol) and 6-methyl-4-((1-methylcyclopropyl)amino)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-5(6H)-one (Intermediate A, 210 mg, 718.52 μmol) were dissolved in dimethyl sulfoxide (5 mL) and toluene (5 mL) and stirred at 100°C overnight. After LC-MS indicated completion of the reaction, the reaction solution was extracted with ethyl acetate (30 mL × 3) and saturated aqueous sodium chloride (50 mL). The organic phase was collected, 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 afford the title compound (176 mg).

[0670] MS m / z(ESI):507.2[M+H]+

[0671] Step 4: Synthesis of 2-((1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-(1-methylcyclopropylamino)pyridin[4,3-d]pyrimidin-5(6H)-one (Intermediate AT)

[0672] Tert-butyl 5-(4-((6-methyl-4-(1-methylcyclopropylamino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (AT-4, 176 mg, 347.6 μmol) was dissolved in 1,4-dioxane (5 mL). A 4 M solution of hydrochloric acid in 1,4-dioxane (1 mL) was added and the mixture was stirred at room temperature for 8 h. After LC-MS indicated completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, followed by addition of water (3 mL) and acetonitrile (4 mL) and lyophilization to afford the title compound (139 mg).

[0673] MS m / z(ESI):407.4[M+H] +

[0674] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,2H),9.27(s,1H),8.77(s,1H),8.21(s,1H) ,8.02(d,J=7.3Hz,1H),7.90(s,1H),6.47(d,J=8.0Hz,1H),4.93-4.86(m,1H ),4.10(s,1H),2.96(d,J=24.0Hz,3H),2.47-2.28(m,2H),2.05-1.95(m,1H) ,1.84(d,J=11.4Hz,1H),1.51(s,2H),1.35-1.18(m,3H),1.01-0.77(m,4H).

[0675] Intermediate AU: Synthesis of 3-(4-(piperidin-3-yl)phenoxy)piperidine-2,6-dione

[0676]

[0677] Intermediate AU was prepared by referring to the synthesis method of intermediate AA, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was replaced by 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[0678] MS m / z(ESI):289.1[M+H] +

[0679] Intermediate AV: Synthesis of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetic acid

[0680]

[0681] Referring to the synthesis method of intermediate L, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate was replaced with tert-butyl 2-(piperidin-4-yl)acetate, and intermediate AV was prepared in the same manner.

[0682] MS m / z(ESI):400.0[M+H] +

[0683] 1 H NMR (400MHz, DMSO-d6) δ12.03 (s, 1H), 11.06 (s, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.30 (d, J=2.0Hz,1H),7.22(dd,J1=8.8Hz,J2=2.0Hz,1H),5.05(dd,J1=12.8Hz,J2=5.2Hz,1H ),4.03(d,J=13.2Hz,2H),2.97(t,J=12.0Hz,2H),2.91-2.84(m,1H),2.56-2.51(m, 1H),2.18(d,J=8.0Hz,2H),2.04-1.92(m,2H),1.77-1.73(m,2H),1.28-1.18(m,3H).

[0684] Intermediate AW: Synthesis of 1-(4-(2,7-diazaspiro[3.5]non-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0685]

[0686] Step 1: Synthesis of tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (AW-2)

[0687] At room temperature, 1-bromo-4-iodobenzene (AW-1, 1.0 g, 3.5 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (790 mg, 3.5 mmol), sodium tert-butoxide (670 mg, 7.0 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (260 mg, 0.35 mmol) were dissolved in toluene (10 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 80°C. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 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 concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (710 mg).

[0688] MS m / z(ESI):325.1[M-56+H] +

[0689] Step 2: Synthesis of tert-butyl 2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (AW-3)

[0690] At room temperature, the compound tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (AW-2, 800 mg, 2.1 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 10.5 mmol), cesium carbonate (2.06 g, 6.3 mmol), dicyclohexyl(3-ethylpropoxy-2′,4′,6′-triisopropyl-[1,1′-diphenyl]-2-yl)phosphine (56 mg, 0.11 mmol) and (methanesulfonic acid {dicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-diphenyl]-2-yl)phosphine} (2'-Methylamino-1,1'-biphenyl-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium (97 mg, 0.11 mmol) was dissolved in 1,4-dioxane (20 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 100°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 (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 (dichloromethane / methanol = 20 / 1) to obtain the title compound (110 mg).

[0691] MS m / z(ESI):315.1[M-100+H] +

[0692] 1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.10(d,J=8.8Hz,2H),6.38(d,J=9.2Hz,2H),3.65 (t,J=6.8Hz,2H),3.34(s,4H),2.66(t,J=6.4Hz,2H),1.68(t,J=5.6Hz,4H),1.39(s,9H).

[0693] Step 3: Synthesis of 1-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate AW)

[0694] Dissolve tert-butyl 2-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (AW-3, 30 mg, 72.38 μmol) in dichloromethane, add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude title compound, which was directly carried to the next step.

[0695] MS m / z(ESI):315.1[M+H] +

[0696] Intermediate AY: Synthesis of 3-(6-(2,8-diazaspiro[4.5]dec-8-yl)pyridin-3-yl)piperidine-2,6-dione

[0697]

[0698] Referring to steps 1 to 5 of Example 1, except that tert-butyl piperidine-4-carboxylate was replaced with tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate, the intermediate AY was prepared in the same manner.

[0699] MS m / z(ESI):329.3[M+H] +

[0700] Intermediate AZ: Synthesis of 3-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)piperidine-2,6-dione

[0701]

[0702] Referring to steps 1 to 5 of Example 1, except that tert-butyl piperidine-4-carboxylate was replaced with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate, the intermediate AZ was prepared in the same manner.

[0703] MS m / z(ESI):315.1[M+H] +

[0704] Intermediate BA: Synthesis of 6-methyl-4-(1-methylcyclopropyloxy)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one (Intermediate BA)

[0705]

[0706] Step 1: Synthesis of ethyl 4-methyl-6-(1-methylcyclopropyloxy)-2-(methylthio)pyrimidine-5-carboxylate (BA-1)

[0707] 1-Methylcyclopropanol (584.53 mg, 8.11 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (194.56 mg, 4.86 mmol, 60% purity) was added under ice-cooling. The mixture was stirred at 0°C for 30 minutes. Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (A-1, 1.00 g, 4.05 mmol) was then added to the solution. The mixture was warmed to room temperature and stirred for 2 hours. After LC-MS indicated the reaction was complete, the mixture was diluted with 100 mL of ethyl acetate. The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford the title compound (1.03 g).

[0708] MS m / z(ESI):283.1[M+H] +

[0709] Step 2: Synthesis of 4-methyl-6-(1-methylcyclopropyloxy)-2-(methylthio)pyrimidine-5-carboxylic acid (BA-2)

[0710] Dissolve ethyl 4-methyl-6-(1-methylcyclopropyloxy)-2-(methylthio)pyrimidine-5-carboxylate (BA-1, 1.00 g, 3.54 mmol) in ethanol (7.5 mL), add sodium hydroxide (1 M, 7.08 mL), and react at room temperature overnight. After completion of the reaction, adjust the pH to 5 with dilute hydrochloric acid, and concentrate under reduced pressure to remove the solvent. The residue is dissolved in a mixture of dichloromethane and methanol (20 mL x 3), and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent to obtain the crude title compound (1.17 g).

[0711] MS m / z(ESI):255.1[M+H] +

[0712] Step 3: Synthesis of N,4-dimethyl-6-(1-methylcyclopropyloxy)-2-(methylthio)pyrimidine-5-carboxamide (BA-3)

[0713] 4-Methyl-6-(1-methylcyclopropyloxy)-2-(methylthio)pyrimidine-5-carboxylic acid (BA-2, 1.10 g, 4.33 mmol) was dissolved in N,N-dimethylformamide (15 mL). N,N-diisopropylethylamine (1.12 g, 8.65 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.47 g, 6.49 mmol) were added. The mixture was allowed to react at room temperature for 10 min. Methylamine (2.04 g, 21.63 mmol, 33% wt solution in ethanol) was then added and the reaction continued at room temperature for 1 h. LC-MS indicated the reaction was relatively complete. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford the title compound (960 mg).

[0714] MS m / z(ESI):268.1[M+H] +

[0715] Step 4: Synthesis of 6-methyl-4-(1-methylcyclopropyloxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (BA-4)

[0716] N,4-Dimethyl-6-(1-methylcyclopropyloxy)-2-(methylthio)pyrimidine-5-carboxamide (BA-3, 450 mg, 1.68 mmol) and tert-butoxybis(dimethylamino)methane (880.06 mg, 5.05 mmol) were dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 110°C for 2 h. Tetrahydrofuran (5 mL) and hydrochloric acid (4 M, 2.10 mL) were then added and stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The reaction solution was poured into saturated sodium bicarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to afford the title compound (290 mg).

[0717] MS m / z(ESI):278.1[M+H] +

[0718] Step 5: Synthesis of 6-methyl-4-(1-methylcyclopropyloxy)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-5(6H)-one (BA-5)

[0719] Dissolve 6-methyl-4-(1-methylcyclopropyloxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (BA-4, 275 mg, 0.99 mmol) in dichloromethane (5 mL). Add m-chloroperbenzoic acid (241.5 mg, 1.39 mmol) and stir at room temperature for 2 hours. LC-MS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, yielding the crude title compound, which was used directly in the next reaction.

[0720] MS m / z(ESI):294.1[M+H] +

[0721] Step 6: Synthesis of tert-butyl 4-(4-((6-methyl-4-(1-methylcyclopropyloxy)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (BA-6)

[0722] Dissolve 6-methyl-4-(1-methylcyclopropyloxy)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-5(6H)-one (BA-5, 290 mg, 988.61 μmol) and tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (B-3, 263.31 mg, 988.61 μmol) in toluene (4 mL) and heat to 100°C for 2 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (594 mg).

[0723] MS m / z(ESI):496.3[M+H] +

[0724] Step 7: Synthesis of 6-methyl-4-(1-methylcyclopropyloxy)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one (Intermediate BA)

[0725] Tert-butyl 4-(4-((6-methyl-4-(1-methylcyclopropyloxy)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (BA-6, 470 mg, 948.40 μmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (0.72 mL) and stirring at room temperature for 2 h. LC-MS indicated the reaction was complete. The reaction solution was concentrated and evaporated to dryness. The residue was neutralized with saturated sodium bicarbonate solution. The aqueous phase was lyophilized and then dissolved in a mixture of dichloromethane and methanol (20 mL x 3). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to afford the title compound (350 mg).

[0726] MS m / z(ESI):396.1[M+H] +

[0727] 1 H NMR(400MHz,DMSO-d6)δ9.98-9.49(m,1H),8.22-7.93(m,1H),7.84-7.49(m,2H),6.42-5.99(m,1H),4.29-4.1 3(m,1H),3.09(d,J=12.7Hz,2H),2.73-2.61(m,2H),2.03-1.94(m,2H),1.91-1.66(m,5H),1.07-0.74(m,4H).

[0728] Intermediate BB: Synthesis of 2-[[1-[1-oxa-8-azaspiro[4,5]dec-3-yl]-1H-pyrazol-4-yl]amino]-6-methyl-4-[[1-methylcyclopropyl]amino]pyrido[4,3-d]pyrimidin-5[6H]-one

[0729]

[0730] Referring to the synthesis method of intermediate AT, the raw material AT-1 was replaced with tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, and intermediate BB was prepared in the same manner.

[0731] MS m / z(ESI):451.3[M+H] +

[0732] Intermediate BC: Synthesis of 3-(4-((R)-2-methylpiperazin-1-yl)phenoxy)piperidine-2,6-dione

[0733]

[0734] Step 1: Synthesis of tert-butyl (R)-4-(4-(benzyloxy)phenyl)-3-methylpiperazine-1-carboxylate (BC-2)

[0735] Dissolve 1-(Benzyloxy)-4-bromobenzene (BC-1,5 g, 19.00 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (5.71 g, 28.50 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.59 g, 1.90 mmol), and cesium carbonate (18.57 g, 57.01 mmol) in dioxane (100 mL). The atmosphere was replaced with nitrogen three times and stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether gradient 0-10%) to obtain the title compound (4.49 g).

[0736] MS m / z(ESI):383.1[M+H] +

[0737] 1 H NMR (400MHz, CDCl3) δ7.54-7.28(m,5H),7.03-6.82(m,4H),5.05(s,2H),3.45(br s,5H),3.12-2.86(m,2H),1.51(s,9H),0.93(d,J=6.1Hz,3H).

[0738] Step 2: Synthesis of (R)-tert-butyl 4-(4-hydroxyphenyl)-3-methylpiperazine-1-carboxylate (BC-3)

[0739] Under argon, tert-butyl (R)-4-(4-(benzyloxy)phenyl)-3-methylpiperazine-1-carboxylate (BC-2, 4.49 g, 11.74 mmol) was dissolved in methanol (100 mL). Wet palladium hydroxide (1 g) and wet palladium on carbon (1 g) were added. The atmosphere was replaced with hydrogen three times. The reaction was stirred at 25°C under a hydrogen atmosphere (50 psi) for 16 hours. TLC indicated the reaction was complete. The reaction solution was filtered and concentrated to obtain the title compound (3.4 g).

[0740] MS m / z(ESI):293.1[M+H] +

[0741] 1H NMR (400MHz, CDCl3) δ6.89 (br d, J=8.6Hz, 2H), 6.84-6.74 (m, 2H), 6.27 (br s,1H),3.76-3.20(m,5H),3.06-2.96(m,1H),2.94-2.83(m,1H),1.51(s,9H),0.89(br d,J=5.7Hz,3H).

[0742] Step 3: Synthesis of tert-butyl (3R)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3-methylpiperazine-1-carboxylate (BC-4)

[0743] Dissolve (R)-tert-Butyl 4-(4-hydroxyphenyl)-3-methylpiperazine-1-carboxylate (BC-3, 1.00 g, 3.42 mmol) in N,N-dimethylformamide (20 mL). Slowly add sodium hydride (342.00 mg, 8.55 mmol, 60% purity). The reaction mixture is stirred at 0°C for 30 minutes. Then, slowly add 3-bromopiperidine-2,6-dione (985.10 mg, 5.13 mmol). Stirring at 0°C for 1 hour is continued. LCMS indicates completion of the reaction. The reaction mixture is quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase is washed three times with saturated brine (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product is obtained. The crude product is purified by flash silica gel column chromatography (tetrahydrofuran / petroleum ether gradient 0-50%) to obtain the title compound (600 mg).

[0744] MS m / z(ESI):404.4[M+H] +

[0745] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.02-6.80(m,4H),5.04(dd,J=4.8,10.3Hz,1H),3.86-3.59(m,2H),3.49(br s,1H),3.36(br s,1H),3.28-3.07(m,1H),3.05-2.95(m,1H),2.93-2.84(m,1H),2.75-2.54(m,2H),2.24-2.03(m,2H),1.42(s,9H),0.82(d,J=6.2Hz,3H).

[0746] Step 4: Synthesis of 3-(4-((R)-2-methylpiperazin-1-yl)phenoxy)piperidine-2,6-dione (Intermediate BC)

[0747] Tert-butyl (3R)-4-[4-[(2,6-dioxopiperidin-3-yl)oxy]phenyl]-3-methylpiperazine-1-carboxylate (50 mg, 123.92 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated to dryness to give the title compound (56 mg).

[0748] MS m / z(ESI):304.2[M+H] +

[0749] Intermediate BG: Synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione

[0750]

[0751] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (BG-2)

[0752] Dissolve 4-bromo-3-fluorophenol (BG-1,2 g, 10.47 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.86 g, 15.71 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (768.29 mg, 1.05 mmol), and potassium carbonate (4.34 g, 31.41 mmol) in dioxane (50 mL). The atmosphere was replaced with nitrogen three times and stirred at 100°C under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether gradient 0-20%) to obtain the title compound (2.1 g).

[0753] MS m / z(ESI):316.3[M+Na] +

[0754] 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),7.13-7.03(m,1H),6.70-6.55(m,2H),5.84(br s,1H),4.07(br d,J=2.9Hz,2H),3.62(t,J=5.6Hz,2H),2.48(br s,2H),1.53(s,9H).

[0755] Step 2: Synthesis of tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (BG-3)

[0756] Under argon, tert-butyl 4-(2-fluoro-4-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (BG-2, 2.1 g, 7.16 mmol) was dissolved in tetrahydrofuran (50 mL). Wet palladium hydroxide (400 mg) and wet palladium on carbon (400 mg) were added. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at 25°C under a hydrogen atmosphere (50 psi) for 16 hours. TLC indicated the reaction was complete. The reaction solution was filtered and concentrated to obtain the title compound (2.04 g).

[0757] MS m / z(ESI):318.2[M+Na] +

[0758] 1 H NMR (400MHz, CDCl3) δ7.08-6.96(m,1H),6.66-6.55(m,2H),6.39(br s,1H),4.37-4.14(m,2H),3.00-2.69(m,3H),1.78(br d,J=13.2Hz,2H),1.66-1.56(m,2H),1.51(s,9H).

[0759] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidine-1-carboxylate (BG-4)

[0760] Dissolve tert-butyl 4-(2-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (BG-3, 1 g, 3.39 mmol) in N,N-dimethylformamide (20 mL). Slowly add sodium hydride (338.58 mg, 8.46 mmol, 60% purity). The reaction mixture is stirred at 0°C for 30 minutes. Then, slowly add 3-bromopiperidine-2,6-dione (975.17 mg, 5.08 mmol). Stirring at 0°C for 1 hour is continued. LCMS indicates completion of the reaction. The reaction mixture is quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase is washed three times with saturated brine (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product is obtained. The crude product is purified by flash silica gel column chromatography (tetrahydrofuran / petroleum ether gradient 0-40%) to obtain the desired product (537 mg).

[0761] MS m / z(ESI):429.3[M+Na] +

[0762] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.22(t,J=8.8Hz,1H),6.96-6.74(m,2H),5.22(dd,J=5.3,11.0Hz,1H),4.05(br dd,J=7.3,14.5Hz,2H),2.92-2.55(m,5H),2.26-2.08(m,2H),1.69(br d,J=12.1Hz,2H),1.61-1.48(m,2H),1.42(s,9H).

[0763] Step 4: Synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione (Intermediate BG)

[0764] Dissolve tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidine-1-carboxylate (BG-4, 50 mg, 123.02 μmol) in dichloromethane (1 mL). Add trifluoroacetic acid (140.26 mg, 1.23 mmol, 94.20 μL) and allow to react for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and lyophilized with water to obtain the crude title compound (36 mg).

[0765] MS m / z(ESI):307.2[M+H] +

[0766] Intermediate BH: Synthesis of 3-(4-(3-fluoropiperidin-4-yl)phenoxy)piperidine-2,6-dione

[0767]

[0768] Step 1: Synthesis of tert-butyl 4-(4-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (BH-1)

[0769] 1-(Benzyloxy)-4-bromobenzene (BC-1,8 g, 30.40 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (14.10 g, 45.60 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium (2.57 g, 3.04 mmol), and sodium carbonate (12.91 g, 121.78 mmol) were dissolved in dioxane (160 mL) / water (40 mL), replaced with nitrogen three times, and stirred at 80 ° C under nitrogen protection for 16 hours. After the reaction, the mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (gradient 0-5% ethyl acetate / petroleum ether) to obtain the title compound (7.1 g).

[0770] MS m / z(ESI):310.3[M-56+H] +

[0771] 1 H NMR (400MHz, DMSO-d6) δ7.51-7.29(m,7H),6.98(d,J=8.8Hz,2H),6.05(br s,1H),5.11(s,2H),3.97(br s,2H),3.52(br t,J=5.6Hz,2H),2.43(br d,J=1.5Hz,2H),1.43(s,9H).

[0772] Step 2: Synthesis of tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (BH-2)

[0773] Dissolve tert-butyl 4-(4-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (BH-1, 6 g, 16.42 mmol) in tetrahydrofuran (50 mL). The atmosphere was replaced with nitrogen three times, and borane solution in tetrahydrofuran (1 M, 32.83 mL) was slowly added dropwise. The mixture was stirred at 25°C under nitrogen for 3 hours. The reaction mixture was cooled to 0°C, and sodium hydroxide solution (3 M, 10.94 mL), hydrogen peroxide (4.65 g, 41.04 mmol, 4.19 mL, 30% purity), and ethanol (6 mL) were slowly added dropwise in that order. The reaction mixture was stirred at 60°C for 16 hours. After the reaction, the reaction mixture was quenched with saturated sodium sulfite (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (gradient 0-20% ethyl acetate / petroleum ether) to give the title compound (5.95 g).

[0774] MS m / z(ESI):406.1[M+Na] +

[0775] 1 H NMR (400MHz, CDCl3) δ7.51-7.30(m,5H),7.20(d,J=8.6Hz,2H),6.99(d,J=8.6Hz,2H),5.08(s,2H),4.43(br d,J=10.6Hz,1H),4.30-4.11(m,1H),3.64(dt,J=5.0,10.1Hz,1H),2.77(br t,J=12.3Hz,1H),2.64(br t,J=11.3Hz,1H),2.55-2.43(m,1H),1.84(br d,J=3.3Hz,1H),1.71(s,2H),1.51(s,9H).

[0776] Step 3: Synthesis of tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (BH-3)

[0777] Dissolve tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (BH-2, 5.95 g, 15.52 mmol) in dichloromethane (100 mL). Add bis(2-methoxyethyl)aminosulfur trifluoride (6.87 g, 31.03 mmol, 5.72 mL) at -78°C. Stir the reaction mixture at 25°C for 16 hours. After completion, pour the reaction mixture into 100 mL of ice water to quench the mixture. Extract the mixture with dichloromethane (50 mL x 2). The organic phase is washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product is purified by flash silica gel column chromatography (gradient 0-10% ethyl acetate / petroleum ether) to obtain the title compound (3.37 g).

[0778] MS m / z(ESI):408.3[M+Na] +

[0779] 1 H NMR (400MHz, CDCl3) δ7.51-7.29(m,5H),7.22(d,J=8.6Hz,2H),6.99(d,J=8.8Hz,2H),5.08(s,2H),4.86-4 .63(m,1H),4.38-4.00(m,2H),3.05-2.75(m,3H),2.26-2.12(m,1H),1.88-1.70(m,1H),1.56-1.44(m,9H).

[0780] Step 4: Synthesis of tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (BH-4)

[0781] Under argon, tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (BH-3, 3.37 g, 8.74 mmol) was dissolved in tetrahydrofuran (50 mL). Wet palladium hydroxide (1 g) and wet palladium on carbon (1 g) were added. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at 25°C under a 50 psi hydrogen atmosphere for 16 hours. TLC indicated completion of the reaction. The reaction solution was filtered and concentrated to obtain the title compound (2.57 g).

[0782] MS m / z(ESI):318.0[M+Na] +

[0783] 1H NMR(400MHz,CDCl3)δ7.12(br d,J=7.9Hz,2H),6.83(d,J=8.4Hz,2H),4.83-4.60(m,1H),4.29-4.01(m,2H) ,3.09-2.74(m,3H),2.23-2.09(m,1H),1.84-1.72(m,1H),1.54-1.46(m,9H).

[0784] Step 5: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3-fluoropiperidine-1-carboxylate (BH-5)

[0785] Dissolve tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (BH-4, 300 mg, 1.02 mmol) in N,N-dimethylformamide (10 mL). Slowly add sodium hydride (101.57 mg, 2.54 mmol, 60% purity). The reaction mixture is stirred at 0°C for 30 minutes. Then, slowly add 3-bromopiperidine-2,6-dione (292.55 mg, 1.52 mmol). Stirring at 0°C for 1 hour is continued. LCMS indicates completion of the reaction. The reaction mixture is quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase is washed three times with saturated brine (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product is obtained. The crude product is purified by flash silica gel column chromatography (gradient 0-50% tetrahydrofuran / petroleum ether) to obtain the title compound (250 mg).

[0786] MS m / z(ESI):429.3[M+Na] +

[0787] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.26(d,J=8.6Hz,2H),6.99(d,J=8.6Hz,2H),5.20(dd,J=5.3,10.8Hz,1H),5.01-4.76(m,1H),4.10-3.97(m,1 H),3.88(brdd,J=2.4,5.9Hz,1H),2.95-2.88(m,2H),2.74-2.69(m,2H),2 .65-2.57(m,1H),2.28-2.05(m,3H),1.63-1.51(m,1H),1.50-1.27(m,9H).

[0788] Step 6: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3-fluoropiperidine-1-carboxylate (Intermediate BH)

[0789] Dissolve tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3-fluoropiperidine-1-carboxylate (BH-5, 230 mg, 565.88 μmol) in 2M dioxane hydrochloride (10 mL). Stir the reaction at 25°C for 16 hours. LCMS indicated completion of the reaction. Concentrate the reaction mixture to obtain the desired product (190 mg).

[0790] MS m / z(ESI):307.3[M+H] +

[0791] 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 9.08 (m, 1H), 7.28 (d, J = 8.8Hz, 2H), 7. 02(d,J=8.8Hz,2H),5.23(dd,J=5.3,10.8Hz,1H),5.06-4.80(m,1H),3.43(br s,2H),3.29(br d,J=6.2Hz,1H),3.17-3.10(m,2H),2.74-2.68(m,1H),2.66-2.57(m,1H),2.37-2.26(m,1H),2.23-2.10(m,2H),2.05-1.92(m,1H).

[0792] Intermediate BI: Synthesis of 4-(4-((5-methoxy-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexane-1-carbaldehyde

[0793]

[0794] Step 1: Synthesis of ethyl (E)-4-(2-(dimethylamino)vinyl)-6-((1-methylcyclopropyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (BI-1)

[0795] Ethyl 4-methyl-6-((1-methylcyclopropyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (A-2, 725 mg, 2.58 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (1.35 g, 7.73 mmol) were dissolved in N,N-dimethylformamide (16 mL) and stirred at 130°C for 8 h. After LC-MS indicated the reaction was complete, the reaction solution was distilled under reduced pressure to obtain the crude title compound (1.26 g), which was used directly in the subsequent reaction without further purification.

[0796] MS m / z(ESI):337.1[M+H] +

[0797] Step 2: Synthesis of 4-((1-methylcyclopropyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (BI-2)

[0798] Ethyl (E)-4-(2-(dimethylamino)vinyl)-6-((1-methylcyclopropyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (BI-1, 1.26 g, crude) was dissolved in ammonia methanol (25 mL) and stirred at 60°C for 8 h. After LC-MS indicated completion of the reaction, the reaction solution was extracted with ethyl acetate (30 mL × 3) and saturated aqueous sodium chloride (30 mL), and the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (305 mg).

[0799] MS m / z(ESI):263.1[M+H] +

[0800] Step 3: Synthesis of 5-chloro-N-(1-methylcyclopropyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine (BI-3)

[0801] 4-((1-Methylcyclopropyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (BI-2, 305 mg, 1.16 mmol) was dissolved in phosphorus oxychloride (10 mL) and stirred at 100°C overnight. After LC-MS indicated completion of the reaction, the reaction solution was concentrated by distillation under reduced pressure and then diluted with a small amount of acetonitrile. The reaction solution was added dropwise to ice water to quench the residual phosphorus oxychloride. The mixture was then extracted with dichloromethane (30 mL x 3) and saturated aqueous sodium chloride (30 mL). The organic phase was collected, 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 = 1 / 1) to obtain the title compound (217 mg).

[0802] MS m / z(ESI):281.0[M+H] +

[0803] Step 4: Synthesis of 5-methoxy-N-(1-methylcyclopropyl)-2-(methylthio)pyridin[4,3-d]pyrimidin-4-amine (BI-4)

[0804] 5-Chloro-N-(1-methylcyclopropyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine (BI-3, 206 mg, 736 μmol) was dissolved in methanol (5 mL), followed by the addition of sodium methoxide-methanol solution (5.4 M, 273 μL). The mixture was stirred at room temperature overnight. After LC-MS indicated completion of the reaction, the reaction solution was extracted with ethyl acetate (10 mL × 3) and saturated aqueous sodium chloride (10 mL). The organic phase was collected, 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 (174 mg).

[0805] MS m / z(ESI):277.1[M+H] +

[0806] Step 5: Synthesis of 5-methoxy-N-(1-methylcyclopropyl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-amine (BI-5)

[0807] The starting material 5-methoxy-N-(1-methylcyclopropyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine (BI-4, 60 mg, 217.11 μmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (52.89 mg, 306.48 μmol) was added. The mixture was stirred for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude title compound, which was directly used for the next reaction.

[0808] MS m / z(ESI):293.1[M+H] +

[0809] Step 6: Synthesis of (4-(4-((5-methoxy-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)-methanol (BI-6)

[0810] [4-(4-Aminopyrazol-1-yl)cyclohexyl]methanol (Intermediate Q, 40.07 mg, 205.23 μmol) and 5-methoxy-N-(1-methylcyclopropyl)-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-4-amine (BI-5, 60 mg, 205.23 μmol) were dissolved in toluene (5 mL) and heated to 100°C with stirring overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (56 mg).

[0811] MS m / z(ESI):424.3[M+H] +

[0812] Step 7: Synthesis of 4-(4-((5-methoxy-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexane-1-carbaldehyde (Intermediate BI)

[0813] (4-(4-((5-methoxy-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)-methanol (BI-6, 56 mg) was dissolved in tetrahydrofuran (206.50 μL), and dilute hydrochloric acid (2 M, 2.07 mL) was added. The mixture was heated to 55°C and stirred for 2 hours. LCMS showed that the reaction was complete. The mixture was extracted with ethyl acetate (5 mL*3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give a crude product of the title compound (50 mg).

[0814] Intermediate BJ: Synthesis of 3-(4-(3,3-difluoropiperidin-4-yl)phenoxy)piperidine-2,6-dione

[0815]

[0816] Step 1: Synthesis of tert-butyl 4-(4-(benzyloxy)phenyl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (BJ-2)

[0817] 2-(4-(Benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BJ-1, 2.53 g, 8.16 mmol), tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (2.75 g, 7.49 mmol), sodium bicarbonate (1.26 g, 15.00 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (548 mg, 0.75 mmol) were dissolved in 1,4-dioxane / water (24 mL / 6 mL) at room temperature. The reaction system was purged with nitrogen three times, and the reaction mixture was stirred at 45°C for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic phases were 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 give the title compound (2.81 g).

[0818] MS m / z(ESI):346.2[M-tBu+H] +

[0819] Step 2: Synthesis of tert-butyl 3,3-difluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (BJ-3)

[0820] At room temperature, tert-butyl 4-(4-(benzyloxy)phenyl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (BJ-2, ​​2.81 g, 7.00 mmol) was dissolved in tetrahydrofuran (28 mL). Palladium on carbon (679 mg, 10% palladium content) was then added. The reaction system was purged with hydrogen three times, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. After completion of the reaction, the reaction solution was filtered through celite, the filter cake was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was the title compound (1.94 g).

[0821] MS m / z(ESI):258.2[M-tBu+H] +

[0822] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3,3-difluoropiperidine-1-carboxylate (BJ-4)

[0823] At room temperature, tert-butyl 3,3-difluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (BJ-3, 1.94 g, 6.19 mmol) was dissolved in N,N-dimethylformamide (20 mL). The temperature was lowered to 0°C, and sodium hydroxide (743 mg, 18.57 mmol, purity: 60%) was added portionwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0°C, and 3-bromopiperidine-2,6-dione (3.56 g, 18.5 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, saturated aqueous ammonium chloride (50 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (30 mL), 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 = 1 / 1) to obtain the title compound (300.4 mg).

[0824] MS m / z(ESI):369.1[M-tBu+H] +

[0825] 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.21(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,2H),5.21-5.18( m,1H),4.22-4.08(m,2H),3.29-3.21(m,2H),2.97-2.57(m,3H),2.22-1.78(m,4H),1.42(s,9H).

[0826] Step 4: Synthesis of 3-[4-[3,3-difluoropiperidin-4-yl]phenoxy]piperidine-2,6-dione (Intermediate BJ)

[0827] Tert-butyl 4-[4-[[2,6-dioxopiperidin-3-yl]oxy]phenyl]-3,3-difluoropiperidine-1-carboxylate (BJ-4, 30 mg, 70.68 μmol) was dissolved in dichloromethane (1 mL), followed by the addition of trifluoroacetic acid (40.3 mg, 0.35 mmol). The reaction was stirred at room temperature overnight. After LCMS monitoring indicated complete consumption of the starting material, the mixture was concentrated under reduced pressure to afford the crude title compound (20 mg), which was used directly in subsequent reactions without further purification.

[0828] MS m / z[ESI]:325.1[M+H] +

[0829] Intermediate BL: Synthesis of 6-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]-5-oxo-4a,5,6,8a-tetrahydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]spiro[3.3]heptane-2-carbaldehyde

[0830]

[0831] Step 1: Synthesis of methyl 6-[4-nitro-1H-pyrazol-1-yl]spiro[3.3]heptane-2-carboxylate (BL-2)

[0832] Methyl 6-hydroxyspiro[3.3]heptane-2-carboxylate (BL-1, 300 mg, 1.76 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of triphenylphosphine (924.61 mg, 3.53 mmol) and 4-nitropyrazole (239.16 mg, 2.11 mmol). The mixture was stirred at room temperature, and diisopropyl azodicarboxylate (712.81 mg, 3.53 mmol) was slowly added dropwise. After LCMS indicated the reaction was complete, the solvent was evaporated, and the product was purified by flash column chromatography (PE:EA = 10:1) to give the crude title compound (455 mg).

[0833] Step 2: Synthesis of [6-[4-amino-1H-pyrazol-1-yl]spiro[3.3]hept-2-yl]methanol (BL-3)

[0834] Methyl 6-[4-nitro-1H-pyrazol-1-yl]spiro[3.3]heptane-2-carboxylate (BL-2, 260 mg, 980.1 μmol) was dissolved in tetrahydrofuran (10 mL). The reaction was transferred to 0°C and lithium aluminum hydride powder (185.98 mg, 4.90 mmol) was slowly added. The reaction was maintained at 0°C for 20 minutes, then transferred to 50°C and stirred for 2 hours. After LCMS monitoring, water (0.2 mL) was added, stirred for 5 minutes, and then 15% aqueous sodium hydroxide solution (0.6 mL) was added. After stirring for 10 minutes, water (0.2 mL) was added, and anhydrous sodium sulfate (4 g) was added to the reaction system. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was collected and dried. The residue was purified by flash column chromatography (DCM:MeOH = 20:1) to obtain the title compound (200 mg).

[0835] MS m / z[ESI]:208.1[M+H] +

[0836] Step 3: Synthesis of 2-((1-(6-(hydroxymethyl)spiro[3.3]hept-2-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one (BL-4)

[0837] [6-[4-Amino-1H-pyrazol-1-yl]spiro[3.3]hept-2-yl]methanol (BL-3, 200 mg, 964.88 μmol) was dissolved in toluene (10 mL). 6-Methyl-4-[[1-methylcyclopropyl]amino]-2-[methylsulfinyl]-6,8a-dihydropyrido[4,3-d]pyrimidin-5[4aH]-one (Intermediate A, 200 mg, 679.42 μmol) was then added, and the reaction was stirred at 100°C for 3 h. The reaction was monitored for completion by LCMS. The solvent was evaporated, and the residue was purified by flash column chromatography (DCM:MeOH = 20:1) to provide the title compound (120 mg).

[0838] MS m / z[ESI]:436.2[M+H] +

[0839] Step 4: Synthesis of 6-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]-5-oxo-4a,5,6,8a-tetrahydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]spiro[3.3]heptane-2-carbaldehyde (Intermediate BL)

[0840] 2-((1-(6-(Hydroxymethyl)spiro[3.3]hept-2-yl)-1H-pyrazol-4-yl)amino)-6-methyl-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one (BL-4, 100 mg, 229.61 μmol) was dissolved in dichloromethane (5 mL). Pyridine chlorochromate (98.99 mg, 459.24 μmol) was then added, and the reaction was stirred at room temperature overnight. The reaction was monitored for completion by LCMS. The solvent was dried, and the residue was purified by flash column chromatography (DCM:MeOH=20:1) to give the title compound (75 mg).

[0841] MS m / z[ESI]:434.2[M+H] +

[0842] Synthesis of Intermediate BN: 1-[5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl]-4-fluoropiperidine-4-carboxaldehyde

[0843]

[0844] Step 1: Synthesis of [4-fluoro-1-[5-iodopyridin-2-yl]piperidin-4-yl]methanol (BN-2)

[0845] (4-Fluoro-4-piperidinyl]methanol (BN-1, 715 mg, 5.37 mmol) and 2-fluoro-5-iodopyridine (798.19 mg, 3.58 mmol) were dissolved in dimethyl sulfoxide (5 mL). Triethylamine (1.09 g, 10.77 mmol, 1.50 mL) was added and the mixture was heated to 60°C for 2 hours. LCMS monitoring showed the reaction was complete. The reaction solution was extracted with appropriate amount of water and ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (837 mg).

[0846] MS m / z[ESI]:337.1[M+H] +

[0847] Step 2: Synthesis of [1-[2',6'-bis[benzyloxy]-[3,3'-bipyridyl]-6-yl]-4-fluoropiperidin-4-yl]methanol (BN-3)

[0848] 2,6-Bis[benzyloxy]-3-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]pyridine (1.19 g, 2.85 mmol), [4-fluoro-1-[5-iodopyridin-2-yl]piperidin-4-yl]methanol (BN-2, 800 mg, 2.38 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (174.14 mg, 237.99 μmol), and potassium carbonate (657.84 mg, 4.76 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The mixture was heated to 100°C under a nitrogen atmosphere for 5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure and extracted with appropriate amounts of water and dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (960 mg).

[0849] MS m / z[ESI]:500.2[M+H] +

[0850] Step 3: Synthesis of 3-[6-[4-fluoro-4-[hydroxymethyl]piperidin-1-yl]pyridin-3-yl]piperidine-2,6-dione (BN-4)

[0851] Dissolve [1-[2',6'-bis[benzyloxy]-[3,3'-bipyridyl]-6-yl]-4-fluoropiperidin-4-yl]methanol (BN-3, 900 mg, 1.80 mmol) in tetrahydrofuran (15 mL) and ethanol (15 mL), add palladium hydroxide on carbon (253.00 mg, palladium content 10%) and palladium on carbon (191.55 mg, palladium content 10%), and heat to 50°C under a hydrogen atmosphere to react overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain the title compound (260 mg).

[0852] MS m / z[ESI]:322.2[M+H] +

[0853] Step 4: Synthesis of 1-[5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl]-4-fluoropiperidine-4-carbaldehyde (Intermediate BN)

[0854] 3-[6-[4-Fluoro-4-[hydroxymethyl]piperidin-1-yl]pyridin-3-yl]piperidine-2,6-dione (BN-4, 30 mg, 93.36 μmol) was dissolved in dichloromethane (1 mL), and Dess-Martin reagent (59.40 mg, 140.05 μmol) was added. The reaction was allowed to react at room temperature for 3 hours. LCMS monitoring indicated that the reaction was complete. The reaction solution was added to a saturated aqueous sodium sulfite solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (13 mg).

[0855] MS m / z[ESI]:320.1[M+H] +

[0856] Intermediate BO: Synthesis of 4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]cyclohexane-1-carboxylic acid

[0857]

[0858] Dissolve 6-methyl-4-[[1-methylcyclopropyl]amino]-2-[methylsulfinyl]pyrido[4,3-d]pyrimidin-5[6H]-one (Intermediate A, 167.66 mg, 573.47 μmol) and 4-[4-amino-1H-pyrazol-1-yl]cyclohexane-1-carboxylic acid (BO-1, 120 mg, 573.48 μmol) in toluene (5 mL) and heat to 100°C with stirring for 3-5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford the title compound (40 mg).

[0859] MS m / z[ESI]:438.2[M+H] +

[0860] Synthesis of Intermediate BP: 1-[5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl]-4-hydroxypiperidine-4-carboxaldehyde

[0861]

[0862] Referring to the synthesis method of intermediate BN, BN-1 was replaced with 4-(hydroxymethyl)piperidin-4-ol, and the intermediate BP was prepared in the same manner.

[0863] Intermediate BQ: Synthesis of N-[2,6-dioxopiperidin-3-yl]-2-fluoro-4-[[R]-2-methylpiperazin-1-yl]benzamide

[0864]

[0865] Step 1: Synthesis of (R)-4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (BQ-2) Methyl 4-bromo-2-fluorobenzoate (BQ-1, 2.1 g, 9.01 mmol) and (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.71 g, 13.53 mmol) were dissolved in dioxane (40 mL) at room temperature, and cesium carbonate (8.81 g, 2 The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 2). 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 obtain the crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (2.8 g).

[0866] Step 2: Synthesis of (R)-4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-2-fluorobenzoic acid (BQ-3)

[0867] At room temperature, tert-butyl (R)-4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3-methylpiperazine-1-carboxylate (BQ-2, 1.00 g, 2.84 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL), and lithium hydroxide monohydrate (297 mg, 7.08 mmol) was added. The mixture was reacted 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 (796 mg).

[0868] Step 3: Synthesis of tert-butyl (3R)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3-methylpiperazine-1-carboxylate (BQ-4)

[0869] At room temperature, (R)-4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-2-fluorobenzoic acid (BQ-3, 796 mg, 2.35 mmol) and 3-aminopiperidine-2,6-dione (464 mg, 3.62 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (607 mg, 4.70 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.07 g, 2.82 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 (400 mg).

[0870] MS m / z[ESI]:449.2[M+H] +

[0871] Step 4: Synthesis of N-[2,6-dioxopiperidin-3-yl]-2-fluoro-4-[[R]-2-methylpiperazin-1-yl]benzamide (Intermediate BQ)

[0872] Dissolve tert-butyl (3R)-4-[4-[[2,6-dioxopiperidin-3-yl]carbamoyl]-3-fluorophenyl]-3-methylpiperazine-1-carboxylate (BQ-4, 30 mg, 66.89 μmol) in dichloromethane (1 mL). Add trifluoroacetic acid (152.54 mg, 1.34 mmol) and stir at room temperature overnight. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to afford the crude title compound (24 mg), which was carried on to the next step without purification.

[0873] MS m / z[ESI]:349.2[M+H] +

[0874] Intermediate BR: Synthesis of 6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one

[0875]

[0876] Step 1: Synthesis of 6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-2-methylthio-pyrido[4,3-d]pyrimidin-5-one (BR-1)

[0877] Ethyl 4-methyl-6-[(1-methylcyclopropyl)amino]-2-methylthio-pyrimidine-5-carboxylate (A-2, 3 g, 10.66 mmol) was added to a reaction flask and dissolved in N,N-dimethylformamide (30 mL). Tert-butoxybis(dimethylamino)methane (5.57 g, 31.99 mmol) was then added and stirred at 110°C for 1 hour. LC-MS analysis revealed the disappearance of the starting material, and the DMF solvent was removed by vortexing to yield a yellow viscous liquid. This liquid was transferred to a pressure-resistant reaction flask, and EtOH (50 mL) and 2,2-difluoroethylamine (2.53 g, 31.21 mmol) were added. The mixture was then stirred at 90°C for 6 hours. After completion of the reaction by LC-MS, the solvent was removed by vortexing. The product was then purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to yield the title compound (2.1 g).

[0878] MS m / z[ESI]:327.1[M+H] +

[0879] Step 2: Synthesis of 6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-5-one (BR-2)

[0880] 6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-one (BR-1, 100 mg, 306.41 μmol) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (63.61 mg, 367.69 μmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated to dryness to obtain the crude title compound (100 mg).

[0881] MS m / z(ESI):342.6[M+H] +

[0882] Step 3: Synthesis of tert-butyl 4-[4-[[6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (BR-3)

[0883] 6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-5-one (BR-2, 800 mg, 2.34 mmol) was dissolved in toluene (20 mL), and tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (404 mg, 1.52 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (780 mg).

[0884] MS m / z(ESI):545.2[M+H] +

[0885] Step 4: Synthesis of 6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (Intermediate BR)

[0886] Tert-butyl 4-[4-[[6-(2,2-difluoroethyl)-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (BR-3, 300 mg, 550.87 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25° C. for 16 hours. The mixture was concentrated to dryness to give the title compound (200 mg).

[0887] MS m / z(ESI):445.2[M+H] +

[0888] 1 H NMR(400MHz, DMSO-d6)δ10.72(s,1H),10.13(s,1H),8.11(s,1H),7.94–7.83(m,1H),7.73(s,1H),6.50–6.17(m, 2H),4.59–4.33(m,3H),3.49–3.38(m,2H),3.16–3.03(m,2H),2.23–2.00(m,4H),1.54(s,3H),0.96–0.74(m,4H).

[0889] Intermediate BS: Synthesis of 2-((1-(2-azaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-yl)amino)-6-(2,2-difluoroethyl)-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one

[0890]

[0891] Referring to the synthesis method of intermediate V, the difference is that intermediate V-1 is replaced by 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, and intermediate A is replaced by intermediate BR-2. Intermediate BS is prepared in the same way.

[0892] Example 1: Synthesis of 3-[6-[4-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methyl]piperazin-1-yl]pyridin-3-yl]piperidine-2,6-dione (Compound 1)

[0893]

[0894] Step 1: Synthesis of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1b)

[0895] 5-Bromo-2-fluoropyridine (1a, 1.03 g, 5.85 mmol) and tert-butyl piperazine-1-carboxylate (1.09 g, 5.85 mmol) were dissolved in dimethyl sulfoxide (20 mL). Potassium carbonate (1.62 g, 11.71 mmol) was added, and the mixture was heated to 120°C with stirring for 2 h. After LC-MS showed completion of the reaction, 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 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 separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (1.24 g).

[0896] MS m / z(ESI):342.1,344.1[M+H] +

[0897] Step 2: Synthesis of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (1d)

[0898] Tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1b, 500 mg, 1.46 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1c, 1.86 g, 7.31 mmol), and potassium acetate (430 mg, 4.38 mmol) were dissolved in toluene (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (212 mg, 292.20 μmol) was added, and the mixture was heated to 100°C under nitrogen for 5 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (560 mg), which was carried on to the next step without further purification.

[0899] Step 3: Synthesis of tert-butyl 4-[5-(2,6-dibenzyloxypyridin-3-yl)pyridin-2-yl]piperazine-1-carboxylate (1f)

[0900] Dissolve tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (1d, 400 mg, 1.03 mmol), 2,6-dibenzyloxy-3-bromopyridine (1e, 457 mg, 1.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (75 mg, 102.75 μmol), and potassium phosphate (654 mg, 3.08 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen, heat to 100°C and react overnight. LC-MS indicated the reaction was relatively complete. The solvent was removed by concentration under reduced pressure, and the concentrate was diluted with 10 mL of water. Extract with dichloromethane (10 mL×3), combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give the title compound (340 mg).

[0901] MS m / z(ESI):553.3[M+H] +

[0902] Step 4: Synthesis of tert-butyl 4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperazine-1-carboxylate (1 g)

[0903] Dissolve tert-butyl 4-[5-(2,6-dibenzyloxypyridin-3-yl)pyridin-2-yl]piperazine-1-carboxylate (1f, 200 mg, 361.88 μmol) in ethyl acetate (5 mL). Add palladium on carbon (43.95 mg, 361.88 μmol). Stir and react at 50°C under a hydrogen atmosphere (1 MPa) for 16 h. LC-MS indicated completion of the reaction. The reaction solution was filtered and washed with ethyl acetate. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to afford the title compound (75 mg).

[0904] MS m / z(ESI):375.3[M+H] +

[0905] Step 5: Synthesis of 3-(6-piperazin-1-yl-pyridin-3-yl)piperidine-2,6-dione (1h)

[0906] Dissolve tert-butyl 4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperazine-1-carboxylate (1 g, 60 mg, 160.24 μmol) in dichloromethane (5 mL), then add trifluoroacetic acid (2.5 mL) and stir at room temperature for 2 h. LC-MS indicated the reaction was complete. The reaction solution was concentrated and evaporated to dryness. An appropriate amount of water and acetonitrile were added and lyophilized to afford the crude title compound (120 mg), which was used directly in the subsequent reaction without further purification.

[0907] MS m / z(ESI):275.1[M+H] +

[0908] Step 6: Synthesis of 3-[6-[4-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methyl]piperazin-1-yl]pyridin-3-yl]piperidine-2,6-dione (Compound 1)

[0909] 4-[4-[[6-Methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexanecarbaldehyde (Intermediate C, 25 mg, 59.31 μmol) and 3-(6-piperazin-1-ylpyridin-3-yl)piperidine-2,6-dione (1h, 25 mg, 59.31 μmol) were dissolved in N,N-dimethylformamide (1 mL). Triethylamine (12 mg, 118.63 μmol) was added first, followed by acetic acid (3 mg, 59.31 μmol) and sodium triacetoxyborohydride (38 mg, 177.94 μmol). The mixture was stirred at room temperature for 16 h, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative thin layer chromatography to give the title compound (3.7 mg).

[0910] MS m / z(ESI):680.3[M+H] +

[0911] 1 H NMR(400MHz,CD3OD)δ9.89-9.70(m,1H),8.12-8.00(m,1H),7.92-7.84(m,1H),7.72-7.59(m,1H), 7.46-7.33(m,2H),6.77-6.70(m,1H),6.19-6.07(m,1H),4.14-4.05(m,1H),3.72-3.66(m,1H),3. 47-3.40(m,4H),3.36(s,3H),2.69-2.57(m,2H),2.52-2.41(m,4H),2.33-2.28(m,1H),2.20-2.16 (m,1H),2.12-2.01(m,3H),1.99-1.80(m,3H),1.67-1.58(m,3H),1.48(s,4H),0.79-0.75(m,4H).

[0912] Example 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]methyl]piperidin-1-yl]isoindole-1,3-dione (Compound 2)

[0913]

[0914] Step 1: Synthesis of 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carboxaldehyde (2b)

[0915] 5-[4-(Dimethoxymethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (2a, 50 mg, 120.35 μmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (0.75 mL). Hydrochloric acid (2N, 601.77 μL) was added and the mixture was heated to 50°C for 2 h. LC-MS indicated the reaction was complete. Water (5 mL) was added to the system, and extraction was performed with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (44 mg).

[0916] MS m / z(ESI):370.1[M+H] +

[0917] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]methyl]piperidin-1-yl]isoindole-1,3-dione (Compound 2)

[0918] 6-Methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (Intermediate B, 21 mg, 54.15 μmol) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-carbaldehyde (2b, 20 mg, 54.15 μmol) were added to tetrahydrofuran (2 mL). One drop of acetic acid was added, and the mixture was heated to 60°C and stirred for 2 h. Then, sodium triacetoxyborohydride (23 mg, 108.29 μmol) was added and the reaction continued overnight. LC-MS indicated the reaction was complete. The solvent was removed by concentration under reduced pressure, and the title compound (12 mg) was obtained by purification via preparative liquid chromatography.

[0919] MS m / z(ESI):748.3[M+H] +

[0920] 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.89(s,1H),9.52(s,1H),8.13(s,1H),7.68-7.54(m,3H),7.32(s,1H),7.20-7.26(m,1H),6.05-6.1(m ,1H),5.02-5.12(m,1H),4.00-4.11(m,3H),3.04-2.78(m,5H),2.31-1 .68(m,13H),1.50-1.56(m,2H),1.20-1.30(m,4H),0.80-0.90(m,3H).

[0921] Example 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]-2-oxo-ethyl]piperazin-1-yl]isoindoline-1,3-dione (Compound 3)

[0922]

[0923] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (3b)

[0924] Tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazine-1-carboxylate (3a, 100 mg, 226.01 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (26 mg, 226.01 μmol, 1 mL) was added to the mixture and stirred at room temperature for 30 min. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the crude title compound (140 mg), which was used directly in the subsequent reaction without further purification.

[0925] MS m / z(ESI):343[M+H] +

[0926] Step 2: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetate (3c)

[0927] 2-(2,6-Dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione (3b, 130 mg, 379.73 μmol) was dissolved in acetone (2 mL) and stirred until homogeneous. Tert-butyl bromoformate (96 mg, 493.65 μmol) was added, and the mixture was heated to 60°C and stirred for 2 h. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain the title compound (105 mg).

[0928] MS m / z(ESI):457[M+H] +

[0929] Step 3: Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetic acid (3d)

[0930] Tert-butyl 2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]acetate (3c, 105 mg, 230.02 μmol) was dissolved in dichloromethane (5 mL) and stirred until homogeneous. Trifluoroacetic acid (1 mL) was added and stirred at room temperature for 30 min. The reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the crude title compound (140 mg), which was used directly in the subsequent reaction without further purification.

[0931] MS m / z(ESI):401.0[M+H] +

[0932] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyridinyl][4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]-2-oxo-ethyl]piperazin-1-yl]isoindoline-1,3-dione (Compound 3)

[0933] To the reaction flask were added 2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]acetic acid (3d, 40 mg, 79.92 μmol), N,N-dimethylformamide (3 mL), 6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrrolidone (3 mL). Idino[4,3-d]pyrimidin-5-one (Intermediate B, 38.27 mg, 79.92 μmol), N,N-diisopropylethylamine (20.66 mg, 159.85 μmol, 27.84 μL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30.15 mg, 79.92 μmol) were stirred at room temperature for 6 hours. The reaction was monitored by LC-MS. After the reaction was complete, water (10 mL) was added to the reaction solution, which was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to remove the solvent. The crude product was isolated and purified by silica gel preparative thin-layer chromatography to afford the title compound (4 mg).

[0934] MS m / z(ESI):777.3[M+H] +

[0935] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.87(s,1H),9.52(s,1H),8.08(s,1H),7.68(d,J=8.5Hz,1H),7.62-7 .60(m,2H),7.36(s,1H),7.26(d,J=8.6Hz,1H),6.09(d,J=7.5Hz,1H),5.07(dd,J=12.9,5.5Hz,1H),4.41(d ,J=15.7Hz,2H),4.18(d,J=13.3Hz,1H),3.46(s,3H),3.37(s,3H),3.19-3.14(m,2H),2.89(s,2H),2.78-2. 73(m,1H),2.58(s,4H),2.05(s,3H),1.86(s,1H),1.69(s,1H),1.50(s,2H),1.24(s,2H),0.82-0.80(m,4H).

[0936] Example 4: Synthesis of 1-[4-[4-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]methyl]piperidin-1-yl]phenyl]hexahydropyrimidine-2,4-dione (Compound 4)

[0937]

[0938] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (4b)

[0939] 1-[4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (4a, 30 mg, 86.35 μmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL). Hydrochloric acid (2N, 431.77 μL) was added and the mixture was heated to 50°C for 2 h. LC-MS confirmed the completion of the reaction. Water (5 mL) was added to the reaction solution, which was then extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to afford the crude title compound (20 mg).

[0940] MS m / z(ESI):302.1[M+H] +

[0941] Step 2: Synthesis of 1-[4-[4-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]methyl]piperidin-1-yl]phenyl]hexahydropyrimidine-2,4-dione (Compound 4)

[0942] 6-Methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (Intermediate B, 7 mg, 17 μmol) and 1-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]piperidine-4-carbaldehyde (4b, 5 mg, 17 μmol) were added to tetrahydrofuran (0.5 mL). One drop of acetic acid was added, and the mixture was heated to 60°C and stirred for 2 hours. The mixture was cooled to room temperature and sodium triacetoxyborohydride (7 mg, 33 μmol) was added. The reaction was continued for 2 hours. LC-MS indicated the reaction was complete. The mixture was extracted with ethyl acetate and water. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford the title compound (1.62 mg).

[0943] MS m / z(ESI):680.2[M+H] +

[0944] 1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.07(s,1H),7.68(s,1H),7.43–7.38(m,1H),7.13– 7.08(m,2H),6.95–6.90(m,2H),6.05-6.15(m,1H),4.40-4.49(m,3H),4.07-4.15(m,1H), 3.75–3.67(m,2H),3.66–3.59(m,2H),3.37(s,3H),3.16–3.10(m,2H),2.72–2.60(m,4H), 2.44–2.31(m,4H),2.10–2.02(m,4H),1.86(s,3H),1.78-1.85(m,2H),0.65-0.80(m,4H).

[0945] Example 5: Synthesis of 3-[6-[4-[2-[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]-2-oxo-ethyl]piperazin-1-yl]pyridin-3-yl]piperidine-2,6-dione (Compound 5)

[0946]

[0947] Step 1: Synthesis of tert-butyl 2-(4-(5-iodopyridin-2-yl)piperazin-1-yl)acetate (5c)

[0948] Dissolve 2-fluoro-5-iodopyridine (5a, 2.0 g, 8.97 mmol) and tert-butyl 2-(piperazin-1-yl)acetate (5b, 1.98 g, 9.87 mmol) in dimethyl sulfoxide (20 mL). Add N,N-diisopropylethylamine (2.32 g, 17.94 mmol) and heat to 80°C overnight. LC-MS analysis indicated the reaction was complete. After cooling the reaction solution to room temperature, ethyl acetate (30 mL) was added for dilution. The mixture was then washed with saturated brine (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (2.5 g).

[0949] MS m / z(ESI):404.0[M+H] +

[0950] Step 2: Synthesis of tert-butyl 2-(4-(2',6'-bis(benzyloxy)-[3,3'-bipyridyl]-6-yl)piperazin-1-yl)acetate (5e)

[0951] Tert-butyl 2-(4-(5-iodopyridin-2-yl)piperazin-1-yl)acetate (5c, 2.2 g, 5.46 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5d, 2.5 g, 6.00 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (396 mg, 545.6 μmol) and potassium carbonate (1.51 g, 10.9 mmol) were added, and the mixture was heated to 100°C under argon protection and reacted overnight. The reaction was monitored by LC-MS. After completion of the reaction, the system was cooled to room temperature, ethyl acetate (10 mL) was added to dilute and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system = 2 / 1) to give the title compound (2.03 g).

[0952] MS m / z(ESI):567.2[M+H] +

[0953] Step 3: Synthesis of tert-butyl 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate (5f)

[0954] Dissolve tert-butyl 2-(4-(2',6'-bis(benzyloxy)-[3,3'-bipyridyl]-6-yl)piperazin-1-yl)acetate (5e, 2.0 g, 3.53 mmol) in ethyl acetate (20 mL). Add palladium on carbon (10% palladium content, 2 g) under a hydrogen atmosphere and allow to react overnight at room temperature. LC-MS analysis indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound (790 mg).

[0955] MS m / z(ESI):389.2[M+H] +

[0956] Step 4: Synthesis of 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (5 g)

[0957] Dissolve tert-butyl 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate (5f, 560 mg, 1.44 mmol) in dichloromethane (5 mL). Add trifluoroacetic acid (1 mL) and continue the reaction at room temperature for 3 h. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to afford the crude title compound (700 mg), which was carried on to the next step without further purification.

[0958] MS m / z(ESI):333.1[M+H] +

[0959] Step 5: Synthesis of 3-[6-[4-[2-[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]-2-oxo-ethyl]piperazin-1-yl]pyridin-3-yl]piperidine-2,6-dione (Compound 5)

[0960] 2-[4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperazin-1-yl]acetic acid (5 g, 40 mg, 120.35 μmol) was added to N,N-dimethylformamide (1 mL), followed by the addition of 1-methylimidazole (30 mg, 361.06 μmol, 40.86 μL) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (51 mg, 180.53 μmol) and stirring for 5 min. 6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (Intermediate B, 47 mg, 120.35 μmol) was then added and the reaction was allowed to proceed at room temperature for 2 h. LC-MS showed that the reaction was basically complete. The product was extracted with ethyl acetate (1 mL) and water (1 mL). The organic phases were combined and washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (20 mg).

[0961] MS m / z(ESI):709.3[M+H] +

[0962] 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.87(s,1H),9.52(s,1H),8.08(s,1H),7.96(s,1H),7.67- 7.53(m,2H),7.45-7.35(m,1H),6.85-6.76(m,1H),6.13-6.05(m,1H),4.48–4.36(m,2H),4.24-4. 17(m,1H),3.80-3.72(m,1H),3.52-3.43(m,2H),3.41-3.34(m,3H),3.30-3.05(m,4H),2.83-2.58 (m,4H),2.23-1.93(m,5H),1.91-1.60(m,4H),1.50(s,3H),1.27-1.22(m,1H),0.91-0.68(m,4H).

[0963] Example 6: Synthesis of 3-[3-methyl-4-[3-[[1-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methyl]piperidin-4-yl]oxy]prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 6)

[0964]

[0965] Step 1: Synthesis of [1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]trifluoromethanesulfonate (6b)

[0966] At 0 ° C, trifluoromethanesulfonic anhydride (8.55 g, 30.33 μmol) was added dropwise to a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (6a, 5.4 g, 21.66 μmol) and pyridine (3.43 g, 43.33 μmol, 3.49 mL) in dichloromethane (30 mL). The mixture was stirred at 0 ° C under nitrogen for 1.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 1) to give the title compound (5.5 g).

[0967] Step 2: Synthesis of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (6d)

[0968] To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (6c, 0.9 g, 3.96 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (888 mg, 7.93 mmol). The reaction mixture was stirred at 0°C for 0.5 h. Subsequently, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (6b, 3.02 g, 7.93 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting reaction mixture was stirred at 20°C under nitrogen for 0.5 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative column to give the title compound (1.76 g).

[0969] MS m / z(ESI):458.0 / 460.0[M+H] +

[0970] Step 3: Synthesis of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (6e)

[0971] 3-(4-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (6d, 780 mg, 1.70 μmol) was dissolved in 1,2-dichloroethane (10 mL), methanesulfonic acid (5 mL) was added, and the mixture was stirred at 100 ° C for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure and ice water (20 mL) was added to the residue, and a large amount of precipitate was formed in the system. The mixture was filtered and the filter cake was collected and dried under vacuum to give the title compound (400 mg).

[0972] MS m / z(ESI):338.0 / 340.0[M+H] +

[0973] Step 4: Synthesis of tert-butyl 4-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyloxy]piperidine-1-carboxylate (6 g)

[0974] 3-(4-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (6e, 400 mg, 1.18 mmol), tert-butyl 4-prop-2-ynyloxypiperidine-1-carboxylate (6f, 283 mg, 1.18 mmol), cesium fluoride (719 mg, 4.73 μmol), cuprous iodide (23 mg, 118.29 μmol), bistriphenylphosphine palladium dichloride (83 mg, 118.29 μmol), and molecular sieves (80 mg) were dissolved in N,N-dimethylformamide (10 mL). Under nitrogen, the mixture was stirred at 80°C for 8 h. After completion of the reaction, the reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was separated and purified by preparative liquid chromatography to obtain the title compound (140 mg).

[0975] MS m / z(ESI):441.1[M+H-56] +

[0976] Step 5: Synthesis of 3-[3-methyl-2-oxo-4-[3-(piperidin-4-yloxy)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione (6h)

[0977] Dissolve tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyloxy]piperidine-1-carboxylate (6 g, 230 mg, 463.19 μmol) in dichloromethane (10 mL). Add trifluoroacetic acid (4 mL), and stir the mixture at 25°C for 16 hours. After completion of the reaction, filter the reaction mixture, and concentrate under reduced pressure to remove the solvent. The residue is separated and purified by preparative liquid chromatography to obtain the title compound (100 mg).

[0978] MS m / z(ESI):397.1[M+H] +

[0979] Step 6: Synthesis of 3-[3-methyl-4-[3-[[1-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methyl]piperidin-4-yl]oxy]prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 6)

[0980] 4-[4-[[6-Methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexanecarbaldehyde (Intermediate C, 30 mg, 71.18 μmol) and 3-[3-methyl-2-oxo-4-[3-(4-piperidinyloxy)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione (6h, 38 mg, 56.94 μmol) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (7 mg, 71.18 μmol, 9.93 μL), acetic acid (4 mg, 71.18 μmol), and sodium triacetoxyborohydride (45 mg, 213.53 μmol) were added sequentially. The mixture was stirred at 25°C for 16 h. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase column chromatography to give the title compound (1.04 mg).

[0981] MS m / z(ESI):802.4[M+H] +

[0982] 1 H NMR(400MHz,CD3OD)δ9.80(s,1H),8.07-7.98(m,1H),7.91-7.80(m,1H),7.71-7.61(m,1H),7.42-7.37(m,1H),7.35-7 .24(m,1H),7.09-7.02(m,2H),6.99-6.94(m,1H),6.18-6.09(m,1H),5.28-5.20(m,2H),4.47-4.41(m,4H),4.16-4.06 (m,1H),3.73-3.63(m,4H),3.55-3.52(m,2H),3.42-3.31(m,3H),2.95-2.85(m,2H),2.75-2.68(m,2H),2.56-2.49(m, 2H),2.11-2.06(m,2H),1.97-1.90(m,4H),1.74-1.69(m,2H),1.66-1.55(m,4H),1.55-1.42(m,3H),0.83-0.69(m,4H).

[0983] Example 7: Synthesis of 3-(6-(4-(2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 7)

[0984]

[0985] To the reaction flask were added 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)acetic acid (Intermediate D, 15 mg, 38.82 μmol), N,N-dimethylformamide (3 mL), 6-methyl-4-((1-methylcyclopropyl)amino)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrido[4,3-d]pyrimidin-5-one (Intermediate B, 16.7 mg, 42.4 μmol), N,N-diisopropylethylamine (15.05 mg, 116.46 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14.65 mg, 38.82 μmol) in sequence and stirred at room temperature for 6 h. The reaction was monitored by LC-MS and showed completion. The solvent was evaporated and the residue was purified by HPLC [using decreasingly polar mixtures of water (containing 0.5% formic acid) and acetonitrile as eluents; acetonitrile gradient ratio 30%-60%, elution time 6.5 minutes] to give the title compound (2 mg).

[0986] MS m / z(ESI):382.4[(M+2H) / 2] +

[0987] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.87(s,1H),9.51(s,1H),8.08(s,1H),7.64–7.56(m,2H),7. 54–7.47(m,1H),7.10–7.03(m,2H),6.12–6.06(m,1H),5.08–5.01(m,1H),4.52–4.25(m,4H),4.24– 4.16(m,2H),3.21–3.13(m,2H),2.97–2.69(m,3H),2.62–2.55(m,4H),2.39–2.31(m,1H),2.11–2.0 2(m,2H),1.99–1.92(m,1H),1.91–1.61(m,3H),1.49(s,3H),1.34–1.00(m,4H),0.88–0.76(m,6H).

[0988] Example 8: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)isoindole-1,3-dione (Compound 8)

[0989]

[0990] Referring to the synthesis method of Example 7, intermediate D was replaced by intermediate E, and compound 8 was prepared in the same manner.

[0991] MS m / z(ESI):398.2[(M+2H) / 2] +

[0992] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.87(s,1H),9.52(s,1H),8.09(s,1H),7.76–7.70(m,1H),7.65–7. 58(m,2H),7.49–7.43(m,1H),6.14–6.04(m,1H),5.14–5.05(m,1H),4.49–4.35(m,2H),4.22–4.13(m,1H) ,3.59–3.54(m,2H),3.37–3.36(m,3H),3.28–3.25(m,2H),2.92–2.76(m,2H),2.64–2.60(m,3H),2.09–1. 99(m,3H),1.53–1.48(m,3H),1.34–1.27(m,2H),1.16–1.05(m,2H),0.86–0.85(m,4H),0.84–0.83(m,4H).

[0993] Example 9: Synthesis of 3-(6-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 9)

[0994]

[0995] 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carbaldehyde (Intermediate F, 40 mg, 132.74 μmol) and 6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(piperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one (Intermediate B, 52.36 mg, 132.75 μmol) were added to N,N-dimethylformamide (1 mL), and triethylamine was added to make the solution alkaline (pH = 8). After stirring for 2 minutes, acetic acid was added to make the reaction system acidic (pH = 6). After stirring for 30 minutes, sodium triacetoxyborohydride (84 mg, 398.22 μmol) was added and the reaction was allowed to react at room temperature overnight. After the reaction was completed as monitored by LC-MS, the product was extracted with ethyl acetate (10 mL×3) and water (10 mL). The aqueous phase was collected and concentrated under reduced pressure to remove the solvent. The product was purified by preparative thin-layer chromatography (dichloromethane / methanol=10 / 1) and lyophilized to give the title compound (22 mg).

[0996] MS m / z(ESI):680.30[M+H] +

[0997] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.89(s,1H),9.52(s,1H),8.14(s,1H),7.97-7.91(m,1H),7.67-7.59(m,1H),7. 58-7.53(m,1H),7.37-7.32(m,1H),6.81-6.75(m,1H),6.12–6.03(m,1H),4.32-4.21(m,2H),4.13-4.00(m,2H),3.76- 3.68(m,1H),3.38(s,3H),3.19-3.12(m,2H),2.97-2.88(m,2H),2.82-2.61(m,4H),2.20-2.16(m,2H),2.10-2.04(m,2 H),2.02–1.95(m,3H),1.93-1.87(m,2H),1.81-1.70(m,3H),1.56-1.50(m,2H),1.28-1.21(m,2H),0.88-0.80(m,3H).

[0998] Example 10: Synthesis of 1-(6-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-3-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 10)

[0999]

[1000] Referring to the synthesis method of Example 9, the intermediate F was replaced by 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carboxaldehyde, and compound 10 was prepared in the same manner.

[1001] MS m / z(ESI):681.30[M+H] +

[1002] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.01-9.75(m,1H),9.63-9.18(m,1H),8.24-8.07(m,2H),7.76 -7.60(m,2H),7.57-7.49(m,1H),6.92-6.87(m,1H),6.20-6.13(m,1H),4.38-4.30(m,2H),4.18-4.10( m,1H),3.78-3.73(m,2H),3.44(s,3H),3.03-2.95(m,2H),2.90-2.82(m,2H),2.81-2.70(m,3H),2.26- 2.22(m,2H),2.18-2.02(m,5H),1.87-1.77(m,3H),1.59(s,3H),1.18-1.11(m,2H),0.95-0.87(m,4H).

[1003] Example 11: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carbonyl)piperidin-1-yl)methyl)isoindoline-1,3-dione (Compound 11)

[1004]

[1005] Referring to the synthesis method of Example 7, intermediate D was replaced by intermediate G, and compound 11 was prepared in the same manner.

[1006] MS m / z(ESI):776.60[M+H] +

[1007] 1 H NMR(400MHz,DMSO-d6)δ11.21-11.09(m,1H),10.24-10.03(m,1H),9.81-9.56( m,1H),8.31-7.97(m,4H),7.88-7.57(m,2H),6.23(s,1H),5.29-5.11(m,1H),4 .80-4.24(m,5H),4.15-3.98(m,1H),3.41(s,3H),3.29-3.13(m,2H),3.07-2.8 3(m,3H),2.82-2.52(m,4H),2.35-1.55(m,9H),1.49(s,3H),0.93-0.69(m,4H).

[1008] Example 12: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)isoindoline-1,3-dione (Compound 12)

[1009]

[1010] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate H, and compound 12 was prepared in the same manner.

[1011] MS m / z(ESI):762.40[M+H] +

[1012] 1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.93-9.68(m,1H),9.53-9.06(m,1H),8.18-8.02(m,1H),7.90-7.7 7(m,3H),7.66-7.52(m,2H),6.34-5.99(m,1H),5.21-5.08(m,1H),4.13-3.99(m,1H),3.64(s,2H),3.37( s,3H),2.91-2.84(m,3H),2.84-2.75(m,2H),2.67-2.53(m,2H),2.23-2.12(m,2H),2.08-1.95(m,7H),1. 89-1.74(m,2H),1.74-1.61(m,2H),1.51(s,3H),1.30-1.20(m,1H),1.19-1.08(m,2H),0.89-0.73(m,4H).

[1013] Example 13: Synthesis of 3-[6-[[4-[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidine-1-carbonyl]piperidin-1-yl]methyl]pyridin-3-yl]piperidine-2,6-dione (Compound 13)

[1014]

[1015] Referring to the synthesis method of Example 7, intermediate D was replaced by intermediate I, and compound 13 was prepared in the same manner.

[1016] MS m / z(ESI):708.2[M+H] +

[1017] 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.87(s,1H),9.50(s,1H),8.42-8.29(m,1H),8.1 0(s,1H),7.68-7.56(m,3H),7.44-7.38(m,1H),6.14-6.05(m,1H),4.55-4.32(m,3H),4. 10-4.02(m,1H),3.96-3.89(m,1H),3.57(s,3H),3.27-3.15(m,2H),2.88-2.81(m,2H),2 .76-2.64(m,3H),2.31-1.98(m,8H),1.69-1.55(m,5H),1.49(s,3H),0.90-0.77(m,4H).

[1018] Example 14: Synthesis of 3-[6-[[4-[[4-[[6-methyl-4-[(1-methylcyclopropyl)amino]-5-oxo-pyrido[4,3-d]pyrimidin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]methyl]piperidin-1-yl]methyl]pyridin-3-yl]piperidine-2,6-dione (Compound 14)

[1019]

[1020] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate J, and compound 14 was prepared in the same manner.

[1021] MS m / z(ESI):694.2[M+H] +

[1022] 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.88(s,1H),9.49(s,1H),8.38-8.30(m,1H),8.16-8.07(m,1H),7.68-7 .52(m,3H),7.44-7.35(m,1H),6.15-6.04(m,1H),4.11-4.00(m,1H),3.96-3.88(m,1H),3.59-3.50(m,2H),3. 37(s,3H),2.94-2.78(m,4H),2.72-2.65(m,1H),2.59-2.53(m,1H),2.29-2.21(m,1H),2.19-2.13(m,2H),2.1 0-1.92(m,7H),1.92-1.80(m,2H),1.71-1.62(m,2H),1.55-1.45(m,4H),1.20-1.08(m,2H),0.89-0.72(m,4H).

[1023] Example 15: Synthesis of 3-(6-(7-(2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 15)

[1024]

[1025] Referring to the synthesis method of Example 7, intermediate D was replaced by intermediate M, and compound 15 was prepared in the same manner.

[1026] MS m / z(ESI):749.7[M+H] +

[1027] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.89(s,1H),9.55–9.50(m,1H),8.24–8.20(m,2H),8.09(s,1H),7 .91–7.86(m,1H),7.63–7.58(m,2H),7.38–7.33(m,1H),6.37–6.32(m,1H),6.11–6.07(m,1H),4.45–4.3 7(m,2H),4.23–4.16(m,1H),3.63(s,3H),3.04–3.00(m,2H),2.69–2.61(m,2H),2.40–2.36(m,2H),2.19 –2.06(m,4H),1.78–1.71(m,4H),1.52–1.50(m,3H),1.47(s,3H),1.16–1.12(m,4H),0.84–0.83(m,6H).

[1028] Example 16: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(2-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (Compound 16)

[1029]

[1030] Referring to the synthetic method of Example 7, intermediate D was replaced by intermediate N, and compound 16 was prepared in the same manner.

[1031] MS m / z(ESI):817.3[M+H] +

[1032] 1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.50(s,1H),9.16(s,1H),8.05-8.15(m,1H),7.67–7.59(m,2H),6.7 5-6.78(m,1H),6.63-6.67(m,1H),6.16-6.14(m,1H),5.00-5.11(m,2H),4.49–4.35(m,3H),4.15-4.25(m ,2H),3.70-3.81(m,4H),3.98-3.05(m,1H),2.89–2.72(m,2H),2.35-2.45(m,3H),2.13–1.98(m,3H),1.7 7(s,3H),1.46-1.55(m,3H),1.31-1.37(m,2H),1.20-1.27(m,4H),1.13-1.18(m,2H),0.78-0.88(m,4H).

[1033] Example 17: Synthesis of 3-(6-(7-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 17)

[1034]

[1035] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate K, and compound 17 was prepared in the same manner.

[1036] MS m / z(ESI):720.40[M+H] +

[1037] 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.94-9.67(m,1H),9.52-9.07(m,1H),8.18-8.00(m,1H),7.94-7.86(m,1H),7.69-7.49(m,2H),7.38-7. 31(m,1H),6.38-6.29(m,1H),6.14-6.02(m,1H),4.20-3.97(m,1H),3.7 5-3.68(m,1H),3.65-3.58(m,4H),3.37(s,3H),2.77-2.60(m,2H),2.39 -2.25(m,4H),2.23-2.09(m,4H),2.09-1.93(m,4H),1.89-1.78(m,3H) ,1.56-1.43(m,5H),1.24(s,3H),1.10-1.01(m,1H),0.89-0.74(m,4H).

[1038] Example 18: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (Compound 18)

[1039]

[1040] Referring to the synthetic method of Example 9, compound 18 was prepared in the same manner except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate L.

[1041] MS m / z(ESI):788.3[M+H] +

[1042] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.97-9.64(m,1H),9.57-9.05(m,1H),8.13-7.94(m,1H),7.72- 7.49(m,3H),7.32-7.13(m,1H),6.83-6.74(m,1H),6.68-6.59(m,1H),6.17-6.00(m,1H),5.09-4.97(m ,1H),3.75(s,3H),3.37(s,3H),2.92-2.82(m,1H),2.66-2.54(m,2H),2.17-1.98(m,4H),1.97-1.86( m,3H),1.83-1.72(m,4H),1.58-1.43(m,4H),1.37-1.16(m,8H),1.16-1.00(m,2H),0.91-0.77(m,3H).

[1043] Example 19: Synthesis of 3-[6-[9-[[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]cyclohexyl]methyl]-3,9-diazaspiro[5.5]undec-3-yl]pyridin-3-yl]piperidine-2,6-dione (Compound 19)

[1044]

[1045] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate O, and compound 19 was prepared in the same manner.

[1046] MS m / z(ESI):748.3[M+H] +

[1047] 1 H NMR (400MHz, DMSO-d6) δ10.82-10.17(s,1H),9.39-9.13(m,4H),8.12-7.91(m,1H),7.85–7.66(m,1H),7.54-7.15(m,1H),725-6.90(m ,1H),6.7-6.25(m,1H),5.35-5.30(m,1H),3.55(s,4H),3.04-2.97(s,2H),2.38–1.39(m,23H),1.25-1.23(m,10H),0.92-0.82(m,3H).

[1048] Example 20: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(9-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)isoindoline-1,3-dione (Compound 20)

[1049]

[1050] Referring to the synthetic method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate P, and compound 20 was prepared in the same manner.

[1051] MS m / z(ESI):816.3[M+H] +

[1052] 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.95-9.81(m,1H),9.57-9.39(m,1H),8.16-8.04(m ,1H),7.68-7.51(m,3H),7.33-7.18(m,2H),6.16-6.03(m,1H),5.08-5.01(m,1H),4.27-3 .95(m,2H),3.52-3.43(m,6H),3.37(s,3H),2.94-2.82(m,1H),2.62-2.54(m,2H),2.38-2 .28(m,4H),2.25-2.11(m,2H),2.07-1.77(m,6H),1.57-1.46(m,12H),0.88-0.75(m,4H).

[1053] Example 21: Synthesis of 3-[6-[7-[[4-[[6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl]amino]pyrazol-1-yl]cyclohexyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]pyridin-3-yl]piperidine-2,6-dione (Compound 21)

[1054]

[1055] Referring to the synthetic method of Example 9, intermediate B was replaced by intermediate R, and intermediate F was replaced by intermediate K, and compound 21 was prepared in the same manner.

[1056] MS m / z(ESI):705.3[M+H] +

[1057] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.54-9.32(m,1H),8.27-8.07(m,1H),7.89(s,1H) ),7.87-7.73(m,1H),7.69-7.60(m,1H),7.59-7.53(m,1H),7.39-7.32(m,1H),6.39-6.3 1(m,1H),4.24-4.14(m,1H),3.75-3.69(m,1H),3.69-3.56(m,4H),2.54(s,3H),2.23-1. 91(m,8H),1.88-1.70(m,10H),1.68-1.41(m,6H),1.11-1.04(m,2H),0.90-0.76(m,4H).

[1058] Example 22: Synthesis of 2-[2,6-dioxopiperidin-3-yl]-5-[4-[2-[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]piperidin-1-yl]ethyl]piperazin-1-yl]isoindoline-1,3-dione (Compound 22)

[1059]

[1060] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate S, and compound 22 was prepared in the same manner.

[1061] MS m / z(ESI):763.3[M+H] +

[1062] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.88(s,1H),9.51(s,1H),8.13(s,1H),7.72-7.53( m,1H),7.45-7.11(m,2H),6.64(s,1H),6.19-6.03(m,1H),5.44-5.28(m,1H),5.20-4.98(m ,1H),3.51(s,1H),3.44(s,2H),3.37(s,2H),3.20-2.76(m,3H),2.64-2.54(m,2H),2.38- 2.08(m,2H),2.07-1.93(m,3H),1.62-1.41(m,3H),1.34-1.01(m,14H),0.91-0.69(m,3H).

[1063] Example 23: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(1-(2-(4-((6-methyl-4-(((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetyl)piperidin-4-yl)isoindole-1,3-dione (Compound 23)

[1064]

[1065] Referring to the synthetic method of Example 7, intermediate B was replaced by intermediate T, and intermediate D was replaced by 2-(2,6-dioxo-piperidin-3-yl)-5-(piperidin-4-yl)-1H-isoindole-1,3(2H)-dione, and compound 23 was prepared in the same manner.

[1066] MS m / z(ESI):775.2[M+H] +

[1067] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.90(s,1H),9.50(s,1H),8.14(s,1H),7.88-7.80(m,2H),7.81-7.73(m,1H) ,7.64-7.54(m,2H),6.09(d,J=7.5Hz,1H),5.18-5.09(m,1H),4.60(d,J=12.9Hz,1H),4.21-4.10(m,1H),4.09-4.0 0(m,1H),3.37(s,3H),3.17-3.06(m,1H),3.08-2.98(m,1H),2.96-2.82(m,1H),2.65-2.52(m,3H),2.40-2.33(m,2 H),2.15-2.00(m,4H),1.86-1.81(m,5H),1.66-1.61(m,2H),1.53(s,3H),1.51-1.45(m,3H),0.83(d,J=8.6Hz,4H).

[1068] Example 24: Synthesis of 3-(6-(1-(2-(4-(4-(6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetyl)piperidin-4-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 24)

[1069]

[1070] Referring to the synthesis method of Example 7, intermediate B was replaced by intermediate T, and intermediate D was replaced by intermediate U, and compound 23 was prepared in the same manner.

[1071] MS m / z(ESI):707.3[M+H] +

[1072] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.90(s,1H),9.51(s,1H),8.36(d,J=2.3Hz,1H),8.14(s,1H),7.65-7.54(m,3H),7.2 6(d,J=8.1Hz,1H),6.09(d,J=7.4Hz,1H),4.55(d,J=12.8Hz,1H),4.20-4.09(m,2H),4.01(d,J=13.6Hz,1H),3.94-3.85(m, 1H),3.37(s,4H),3.18-3.06(m,1H),3.00-2.87(m,1H),2.77-2.57(m,2H),2.59-2.52(m,1H),2.39-2.32(m,2H),2.33-2.1 7(m,1H),2.14-1.98(m,3H),1.88-1.80(m,4H),1.69-1.59(m,1H),1.56-1.43(m,6H),1.26-1.21(m,1H),0.88-0.68(m,4H).

[1073] Example 25: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Compound 25)

[1074]

[1075] Referring to the synthetic method of Example 9, compound 25 was prepared by the same method except that intermediate B was replaced by intermediate V and intermediate F was replaced by intermediate 2b.

[1076] MS m / z(ESI):788.4[M+H] +

[1077] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.88(s,1H),9.49(s,1H),8.15-8.06(m,1H),7.74-7.52(m ,3H),7.30(s,1H),7.22(d,J=8.7Hz,1H),6.09(d,J=7.5Hz,1H),5.13-5.00(m,1H),4.89-4.74(m, 1H),4.03(d,J=12.9Hz,2H),3.38(s,3H),3.02-2.82(m,3H),2.70-2.53(m,3H),2.41-1.94(m,11H ),1.90-1.72(m,3H),1.71-1.44(m,6H),1.19-1.03(m,2H),0.90-0.79(m,3H),0.79-0.64(m,1H).

[1078] Example 26: Synthesis of 3-(6-(4-((2-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 26)

[1079]

[1080] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate V, and compound 26 was prepared in the same manner.

[1081] MS m / z(ESI):720.4[M+H] +

[1082] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.88(s,1H),9.49(s,1H),8.09(s,1H),8.00-7.85(m,1H), 7.75-7.54(m,2H),7.44-7.28(m,1H),6.78(d,J=8.8Hz,1H),6.09(d,J=7.5Hz,1H),4.94-4.69(m, 1H),4.25(d,J=13.0Hz,2H),3.80-3.67(m,1H),3.38(s,3H),2.82-2.72(m,2H),2.40-2.24(m,5H) ,2.20-2.06(m,5H),2.02-1.93(m,2H),1.81-1.45(m,12H),1.13-1.00(m,2H),0.88-0.76(m,4H).

[1083] Example 27: Synthesis of 1-(2-chloro-5-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 27)

[1084]

[1085] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate W, and compound 27 was prepared in the same manner.

[1086] MS m / z(ESI):742.30[M+H] +

[1087] 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.94-9.84(m,1H),9.51(s,1H),8.14-8.02(m,1H),7.68 -7.63(m,1H),7.63-7.59(m,1H),7.59-7.56(m,1H),7.45-7.38(m,1H),6.14-6.04(m,1H),4.22 -3.97(m,1H),3.82-3.73(m,1H),3.68-3.59(m,2H),3.37(s,3H),2.80-2.70(m,2H),2.45-2.30(m,3H),2.28-2.12(m,2H),2.10 -1.96(m,2H),1.94-1.76(m,3H),1.71-1.58(m,2H),1.57-1.45(m,5H),1.30-1.20(m,3H),1.16-0.97(m,2H),0.89-0.77(m,4H).

[1088] Example 28: Synthesis of 1-(2-chloro-5-(9-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 28)

[1089]

[1090] Referring to the synthesis method of Example 9, compound 28 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate X.

[1091] MS m / z(ESI):405.7[(M+2H) / 2] +

[1092] 1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),10.0-9.93(m,1H),9.60-9.52(m,1H),8.15-8.10( m,1H),7.73-7.60(m,4H),7.50-7.42(m,1H),6.20-6.10(m,1H),3.85-3.73(m,1H),3.73- 3.63(m,3H),3.47-3.43(m,4H),2.85-2.78(m,2H),2.14-2.05(m,3H),1.98-1.90(m,2H), 1.60-1.53(m,8H),1.42-1.40(m,1H),1.30(s,9H),1.15-1.07(m,2H),0.95-0.85(m,5H).

[1093] Example 29: Synthesis of 3-(3-methyl-4-(7-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 29)

[1094]

[1095] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate Y, and compound 29 was prepared in the same manner.

[1096] MS m / z(ESI):789.3[M+H] +

[1097] 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.88(s,1H),9.43(s,1H),8.06(s,1H),7.75–7.51(m,2H),7.06–6 .92(m,1H),6.83–6.63(m,2H),5.40–5.24(m,2H),4.12–3.96(m,2H),3.64–3.53(m,3H),3.43–3.32(m,1 1H),2.95–2.81(m,1H),2.74–2.54(m,1H),2.40–2.25(m,2H),2.11–1.95(m,2H),1.93–1.86(m,1H),1.8 3–1.72(m,1H),1.56–1.43(m,2H),1.34(s,1H),1.31–1.14(m,5H),1.13–0.98(m,2H),0.90–0.53(m,5H).

[1098] Example 30: Synthesis of 3-(3-methyl-5-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 30)

[1099]

[1100] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate Z, and compound 30 was prepared in the same manner.

[1101] MS m / z(ESI):749.40[M+H] +

[1102] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.01-9.94(m,1H),8.13-8.05(m,1H),7.72-7.67(m,1H),7. 37-7.19(m,2H),6.99-6.93(m,1H),6.90-6.85(m,1H),6.73-6.63(m,2H),5.34-5.26(m,1H),4.60- 4.40(m,2H),3.76-3.58(m,6H),3.21-3.03(m,4H),2.98-2.85(m,3H),2.75-2.59(m,4H),2.29-2.2 2(m,2H),2.04-1.95(m,2H),1.93-1.80(m,4H),1.56-1.44(m,3H),1.38(s,3H),0.90-0.70(m,4H).

[1103] Example 31: Synthesis of 3-[[4-[1-[[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin]-2-yl]amino]-1H-pyrazol-1-yl]cyclohexyl]methyl]piperidin-4-yl]phenyl]amino]piperidine-2,6-dione (Compound 31)

[1104]

[1105] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by 3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione, and compound 31 was prepared in the same manner.

[1106] MS m / z(ESI):693.3[M+H] +

[1107] 1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.97-9.68(m,1H),9.57-9.35(m,1H),8.23-8.00(m,1H),7.73-7.51(m, 2H),7.03-6.87(m,2H),6.76-6.52(m,2H),6.17-6.00(m,1H),5.73-5.60(m,1H),5.42-5.24(m,1H),4.33-4.1 9(m,1H),4.11-3.97(m,1H),3.51(s,2H),3.37(s,3H),3.02-2.92(m,2H),2.79-2.68(m,1H),2.64-2.54(m,1H ),2.37-2.16(m,2H),2.14-1.97(m,4H),1.91(s,3H),1.75-1.43(m,3H),1.41-1.00(m,8H),0.92-0.72(m,4H).

[1108] Example 32: Synthesis of 3-[4-[1-[[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]cyclohexyl]methyl]piperidin-4-yl]phenoxy]piperidine-2,6-dione (Compound 32)

[1109]

[1110] Referring to the synthetic method of Example 9, compound 32 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AA.

[1111] MS m / z(ESI):694.3[M+H] +

[1112] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.99-9.62(m,1H),9.62-9.07(m,1H),8.20-8.02(m,1H),7 .74-7.50(m,2H),7.29-7.07(m,2H),7.04-6.87(m,2H),6.39-5.93(m,1H),5.21-5.09(m,1H),4.2 0-3.99(m,1H),3.51(s,3H),3.05-2.93(m,2H),2.74-2.57(m,2H),2.48-2.42(m,1H),2.24-2.04( m,5H),1.91(s,3H),1.79-1.46(m,10H),1.34-1.18(m,3H),1.13-1.01(m,1H),0.94-0.68(m,4H).

[1113] Example 33: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((6-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Compound 33)

[1114]

[1115] Referring to the synthesis method of Example 9, compound 33 was prepared by the same method except that intermediate B was replaced by intermediate AB and intermediate F was replaced by intermediate 2b.

[1116] MS m / z(ESI):380.3[(M+2H) / 2] +

[1117] 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.87(s,1H),9.52(s,1H),8.18-8.07(m,1H),7.69 -7.58(m,3H),7.33-7.28(m,1H),7.25-7.20(m,1H),6.09(m,J=7.5Hz,1H),5.11-5.03(m ,1H),4.77-4.65(q,1H),4.08-3.98(m,3H),3.65-3.50(s,4H),3.01-2.85(m,4H),2.70- 2.60(m,4H),2.27(s,1H),2.09-1.95(m,2H),1.77-1.70(m,2H),1.55-1.47(s,3H),1.28 -1.14(m,5H),0.91-0.75(m,5H).

[1118] Example 34: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(2-(4-((6-methyl-4-(((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindole-1,3-dione (Compound 34)

[1119]

[1120] Referring to the synthesis method of Example 7, intermediate B was replaced by intermediate T, and intermediate D was replaced by intermediate L, and compound 34 was prepared in the same manner.

[1121] MS m / z(ESI):816.3[M+H] +

[1122] 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),9.91(s,1H),9.50(s,1H),8.14(s,1H),7.68-7.54(m,3H),6.77(d,J=2.1H z,1H),6.68-6.61(m,1H),6.09(d,J=7.5Hz,1H),5.10-5.00(m,1H),4.21-4.09(m,1H),3.80(s,3H),3.45(s,5H) ,2.95-2.81(m,1H),2.63-2.52(m,1H),2.33(d,J=6.9Hz,2H),2.14-1.96(m,5H),1.83(s,2H),1.76(s,2H),1.69 (s,2H),1.68-1.57(m,1H),1.53(s,2H),1.48(s,4H),1.24(d,J=5.9Hz,2H),0.83(d,J=11.0Hz,4H),0.71(s,1H).

[1123] Example 35: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(9-(2-(4-((6-methyl-4-(((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)acetyl)-3,9-diazaspiro[5.5]undec-3-yl)isoindole-1,3-dione (Compound 35)

[1124]

[1125] Referring to the synthesis method of Example 7, intermediate B was replaced by intermediate T, and intermediate D was replaced by intermediate P, and compound 35 was prepared in the same manner.

[1126] MS m / z(ESI):844.4[M+H] +

[1127] 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.93(s,1H),9.55(s,1H),8.14(s,1H),7.68-7.59(m,2H),7.57(s ,1H),7.31(d,J=2.3Hz,1H),7.26-7.18(m,1H),6.11(d,J=7.4Hz,1H),5.11-5.01(m,1H),4.20-4.09(m, 1H),3.51-3.43(m,7H),3.38(s,3H),2.96-2.81(m,1H),2.64-2.51(m,2H),2.36-2.28(m,2H),2.11-1.9 6(m,5H),1.86-1.77(m,2H),1.68-1.59(m,1H),1.63-1.51(m,7H),1.49-1.36(m,7H),0.87-0.69(m,4H).

[1128] Example 36: Synthesis of 3-(1-methyl-7-(3-((1-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyridinyl[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (Compound 36)

[1129]

[1130] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AC (prepared according to patent WO2023131167), and compound 36 was prepared in the same manner.

[1131] MS m / z(ESI):786.3[M+H] +

[1132] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),10.01-9.70(m,1H),9.55-9.09(m,1H),8.25-8.00(m ,1H),7.84-7.72(m,1H),7.72-7.46(m,2H),7.31-7.06(m,1H),6.18-6.06(m,1H),5.45-5.2 3(m,1H),4.62-4.49(m,1H),4.47-4.37(m,1H),4.29(s,2H),4.22-3.97(m,1H),3.58(s,1H) ,3.37(s,4H),2.79-2.58(m,3H),2.46-1.16(m,23H),1.11-0.96(m,1H),0.94-0.63(m,4H).

[1133] Example 37: Synthesis of 3-[4-[1-[[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]cyclohexyl]methyl]piperidin-4-yl]phenoxy]piperidine-2,6-dione (Compound 37)

[1134]

[1135] Referring to the synthesis method of Example 9, compound 37 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AD.

[1136] MS m / z(ESI):788.3[M+H] +

[1137] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.96-9.63(m,1H),9.57-9.08(m,1H),8. 12-8.02(m,1H),7.69-7.53(m,3H),7.36-7.30(m,1H),7.28-7.21(m,1H),6.16- 6.00(m,1H),5.12-5.02(m,1H),4.21-3.93(m,2H),2.94-2.82(m,2H),2.63-2. 53(m,3H),2.06-1.38(m,22H),1.28-1.03(m,5H),0.85(dd,J=12.3,7.3Hz,4H).

[1138] Example 38: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]dec-8-yl)isoindoline-1,3-dione (Compound 38)

[1139]

[1140] Referring to the synthesis method of Example 9, compound 38 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AE.

[1141] MS m / z(ESI):401.3[(M+2H) / 2] +

[1142] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.91–9.85(m,1H),9.51–9.45(m,1H),8.08–8.02(m,1H),7.67–7.57(m,3 H),7.35–7.29(m,1H),7.26–7.21(m,1H),6.12–6.05(m,1H),5.09–5.03(m,1H),4.09–4.00(m,1H),3.55–3.48(m ,2H),3.47–3.41(m,2H),3.37(s,3H),2.97–2.80(m,2H),2.62–2.55(m,2H),2.39–2.31(m,2H),2.28–2.15(m,2 H),2.08–1.97(m,4H),1.96–1.88(m,2H),1.66–1.56(m,6H),1.51(s,3H),1.18–0.99(m,3H),0.87–0.80(m,6H).

[1143] Example 39: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(7-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (Compound 39)

[1144]

[1145] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AF, and compound 39 was prepared in the same manner.

[1146] MS m / z(ESI):788.3[M+H] +

[1147] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.92-9.85(m,1H),9.53-9.45(m,1H),8.15-8.06 (m,1H),7.63-7.52(m,3H),7.12-7.08(m,1H),6.80-6.75(m,1H),6.13-6.05(m,1H),5.0 7–5.00(m,1H),3.91(s,3H),3.37(s,4H),2.63-2.58(m,2H),2.35-2.25(m,2H),2.03-1 .97(m,3H),1.88-1.73(m,3H),1.55-1.50(s,3H),1.30-1.24(m,8H),0.87-0.80(m,9H).

[1148] Example 40: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(7-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (Compound 40)

[1149]

[1150] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AG (prepared with reference to patent WO2020211822), and compound 40 was prepared in the same manner.

[1151] MS m / z(ESI):387.3[(M+2H) / 2] +

[1152] 1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.90-9.82(m,1H),9.47(s,1H),8.15-8.03(m,1H),7.67- 7.48(m,3H),6.96(m,1H),6.90-6.85(m,1H),6.13-6.03(m,1H),5.10-5.01(m,1H),4.03-3.95( m,1H),3.73-3.63(m,3H),3.37(s,4H),3.03-2.93(m,2H),2.91-2.81(m,2H),2.27-2.23(m,1H) ,2.08-1.95(m,4H),1.91-1.86(m,1H),1.52-1.47(m,3H),1.26-1.22(m,6H),0.88-0.80(m,8H).

[1153] Example 41: Synthesis of 3-(6-(7-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyridin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound 41)

[1154]

[1155] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AH (prepared according to patent WO2023009719), and compound 41 was prepared in the same manner.

[1156] MS m / z(ESI):774.40[M+H] +

[1157] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.87-9.77(m,1H),9.46-9.39(m,1H),8.10-7.97(m,1H),7.56-7.45(m,2H),7.33-7.27( m,1H),6.64-6.59(m,2H),6.05-5.99(m,1H),5.04-4.97(m,1H),4.27-4.21(m,1H),4.16-4.05(m,2H),3.56-3.48(m,5H),3.33- 3.30(m,6H),2.89-2.78(m,1H),2.57-2.48(m,1H),2.29-2.20(m,4H),2.16-2.10(m,1H),2.07-2.01(m,1H),1.95-1.88(m,2H), 1.86-1.82(m,1H),1.71-1.66(m,4H),1.59-1.50(m,2H),1.46(s,3H),1.20-1.14(m,1H),1.04-0.91(m,1H),0.81-0.70(m,4H).

[1158] Example 42: Synthesis of 3-(5-(7-((4-(4-(4-(6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 42)

[1159]

[1160] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AI (prepared with reference to patent WO2018102725), and compound 42 was prepared in the same manner.

[1161] MS m / z(ESI):774.40[M+H] +

[1162] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.82(d,J=11.4Hz,1H),9.44(d,J=5.8Hz,1H),8.03-7.97(m,1H) ,7.55(d,J=7.4Hz,1H),7.42(d,J=8.3Hz,1H),6.78-6.67(m,1H),6.49-6.40(m,2H),6.03(d,J=7.5Hz,1 H),5.02-4.91(m,1H),4.26-4.19(m,1H),4.10(d,J=5.0Hz,1H),3.58(s,6H),3.44(s,8H),2.54(s,1H) ,2.35-2.23(m,4H),2.14-2.09(m,1H),2.01-1.84(m,8H),1.75(s,3H),1.64-1.53(m,4H),1.45(s,3H).

[1163] Example 43: Synthesis of 3-(4-(4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione (Compound 43)

[1164]

[1165] Referring to the synthesis method of Example 9, compound 43 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediates AJ.

[1166] MS m / z(ESI):695.3[M+H] +

[1167] 1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.95-9.86(m,1H),9.55-9.45(m,1H),8.15-8.05(m,,1H),7. 67-7.53(m,2H),6.93-6.85(m,4H),6.15-6.05(m,1H),5.06-4.96(m,4.9Hz,1H),3.03(m,3H),2.70- 2.65(m,1H),2.20-2.15(m,J=9.6,6.0Hz,2H),1.99(s,1H),1.54-1.52(m,3H),1.48(s,2H),1.40(s, 1H),1.26-1.24(m,3H),1.16-1.13(m,2H),0.96-0.94(m,1H),0.87-0.86(m,7H),0.85-0.84(m,8H).

[1168] Example 44: Synthesis of 3-(4-(2-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenoxy)piperidine-2,6-dione (Compound 44)

[1169]

[1170] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AK, and compound 44 was prepared in the same manner.

[1171] MS m / z(ESI):735.30[M+H] +

[1172] 1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.93-9.82(m,1H),9.53-9.45(m,1H),8.13-8.02(m,1H ),7.63-7.55(m,2H),6.91-6.85(m,4H),6.12-6.05(m,1H),5.04-4.97(m,1H),4.10-3.98(m,1 H),3.04-2.90(m,5H),2.74-2.55(m,4H),2.22-2.10(m,2H),2.11-1.96(m,4H),1.88-1.80(m, 5H),1.68-1.58(m,2H),1.52(s,3H),1.27-1.21(m,4H),1.20-1.04(m,4H),0.86-0.79(m,4H).

[1173] Example 45: Synthesis of 3-((5-(4-((4-(4-(6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)pyridin-2-yl)oxy)piperidine-2,6-dione (Compound 45)

[1174]

[1175] Referring to the synthesis method of Example 9, compound 45 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AL.

[1176] MS m / z(ESI):696.3[M+H] +

[1177] 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.89(d,J=12.4Hz,1H),9.49(s,1H),8.07(s,1H),7.73(d,J =3.0Hz,1H),7.64-7.51(m,2H),7.51-7.43(m,1H),6.81-6.73(m,1H),6.09(d,J=7.4Hz,1H),5.83- 5.74(m,1H),4.06(d,J=12.4Hz,1H),3.09-3.04(m,4H),2.87-2.73(m,1H),2.63-2.51(m,3H),2.3 1-2.22(m,1H),2.22-2.02(m,7H),2.07-1.87(m,8H),1.75-1.57(m,3H),1.61(s,3H),1.52(s,3H).

[1178] Example 46: Synthesis of 3-((6-(4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin)-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione (Compound 46)

[1179]

[1180] Referring to the synthetic method of Example 9, compound 46 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AM.

[1181] MS m / z(ESI):696.3[M+H] +

[1182] 1 H NMR(400MHz,DMSO-d6)δ9.92-9.68(m,1H),9.52-9.10(m,1H),8.16-8.02(m,1H),7.96- 7.89(m,1H),7.69-7.50(m,2H),7.37-7.30(m,1H),6.83-6.76(m,1H),6.17-5.99(m,1H ),5.05-4.96(m,1H),4.19-4.01(m,1H),2.68-2.59(m,2H),2.48-2.39(m,4H),2.30-1. 86(m,10H),1.85-1.42(m,9H),1.28-1.21(m,2H),1.19-0.99(m,2H),0.90-0.78(m,4H).

[1183] Example 47: Synthesis of 3-(4-(4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (Compound 47)

[1184]

[1185] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate AN, and compound 47 was prepared in the same manner.

[1186] MS m / z(ESI):695.3[M+H] +

[1187] 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.89(s,1H),9.51(s,1H),8.14(s,1H),7.74–7.51(m,2H),7.3 2–7.12(m,1H),7.00–6.78(m,3H),6.20–6.03(m,1H),5.36–5.30(m,1H),5.06–4.93(m,1H),4.14–4. 03(m,1H),3.55–3.48(m,3H),2.99–2.90(m,1H),2.62–2.55(m,2H),2.25–2.17(m,2H),2.05–1.96(m ,2H),1.82–1.75(m,1H),1.65–1.61(m,1H),1.56–1.46(m,3H),1.29–1.17(m,9H),0.89–0.77(m,6H).

[1188] Example 48: Synthesis of 3-(4-(4-((6-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (Compound 48)

[1189]

[1190] Referring to the synthesis method of Example 9, compound 48 was prepared by the same method except that intermediate B was replaced by intermediate AB and intermediate F was replaced by intermediate AN.

[1191] MS m / z(ESI):354.2[(M+2H) / 2] +

[1192] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.95(s,1H),10.42(s,1H),8.12(s,1H),8.04–7.96(m, 1H),7.88–7.61(m,2H),7.12(s,2H),6.52–6.36(m,1H),5.39–5.17(m,1H),4.92–4.66(m,1H),4 .35–4.10(m,3H),3.50–3.43(m,6H),2.96–2.86(m,1H),2.74–2.62(m,4H),2.27–2.11(m,3H), 2.09–1.91(m,4H),1.87–1.77(m,1H),1.54–1.45(m,2H),1.25–1.20(m,4H),0.98–0.78(m,6H).

[1193] Example 49: Synthesis of 3-(1-methyl-7-(4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyridin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (Compound 49)

[1194]

[1195] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate AO, and compound 49 was prepared in the same manner.

[1196] MS m / z(ESI):733.3[M+H] +

[1197] 1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.89(s,1H),9.56(s,1H),8.09(s,1H),7.73-7.60 (m,2H),7.42-7.36(m,1H),7.03(d,J=4.9Hz,2H),6.10(d,J=7.6Hz,1H),4.37-4.31(m,1 H),4.26(s,3H),3.67(s,1H),3.51(s,1H),3.38(s,7H),3.17(d,J=4.0Hz,2H),2.81-2.5 9(m,6H),2.40-2.30(m,3H),2.05-1.95(m,4H),1.59-1.44(m,7H),1.35(d,J=2.4Hz,3H).

[1198] Example 50: Synthesis of 1-(2-chloro-5-(4-((4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 50)

[1199]

[1200] Referring to the synthetic method of Example 9, compound 50 was prepared in the same manner except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AP.

[1201] MS m / z(ESI):714.3[M+H] +

[1202] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),9.93-9.86(m,1H),9.49(s,1H),8.06(s,1H),7.65-7. 56(m,2H),7.34(s,1H),7.06(s,1H),6.93(s,1H),6.09(d,J=7.6Hz,1H),4.06(s,1H),3.71- 3.55(m,1H),3.51(s,2H),3.16(s,5H),2.75-2.69(m,2H),2.09-2.04(m,2H),1.94-1.89(m, 2H),1.69-1.64(m,5H),1.52(s,4H),1.24(d,J=5.5Hz,4H),1.09(s,2H),0.88-0.80(m,4H).

[1203] Example 51: Synthesis of 1-(2-methyl-5-(4-((4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 51)

[1204]

[1205] Referring to the synthesis method of Example 9, compound 51 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AQ.

[1206] MS m / z(ESI):693.8[M+H] +

[1207] 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.95-9.86(m,1H),9.49(s,1H),8.19-8.01(m,1H), 7.64-7.49(m,2H),7.24-7.04(m,2H),6.89-6.75(m,2H),6.17-6.05(m,1H),5.37-5.26(m ,1H),4.23-4.00(m,2H),3.73(s,1H),3.51(s,2H),3.10(s,3H),2.77-2.65(m,2H),2.38- 2.13(m,3H),2.14-1.76(m,5H),1.73-1.43(m,4H),1.34-1.16(m,8H),0.95-0.70(m,3H).

[1208] Example 52: Synthesis of 1-(1-methyl-6-(4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 52)

[1209]

[1210] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate AR, and compound 52 was prepared in the same manner.

[1211] MS m / z(ESI):734.4[M+H] +

[1212] 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.99-9.73(m,2H),9.65-9.45(m,1H),8.18-8.05(m,1H),7.76-7 .58(m,2H),7.54-7.38(m,1H),7.00-6.78(m,2H),6.18-5.98(m,1H),4.56-4.38(m,1H),3.92-3.81(m,5 H),3.76-3.62(m,1H),3.38(s,2H),3.12-3.03(m,2H),2.82-2.71(m,3H),2.42-2.17(m,4H),2.10-2.03 (m,1H),1.99-1.87(m,2H),1.58-1.46(m,3H),1.43-1.33(m,2H),1.28-1.14(m,5H),0.90-0.73(m,4H).

[1213] Example 53: Synthesis of 3-(4-(4-((2-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (Compound 53)

[1214]

[1215] Referring to the synthetic method of Example 9, compound 53 was prepared by the same method except that intermediate B was replaced by intermediate V and intermediate F was replaced by intermediate AN.

[1216] MS m / z(ESI):735.40[M+H] +

[1217] 1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.88(s,1H),9.51(s,1H),8.17–8.01(m,1H),7.69–7 .54(m,2H),6.97–6.77(m,4H),6.15–6.04(m,1H),5.06–4.93(m,1H),4.88–4.70(m,1H),3. 61–3.44(m,2H),3.37(s,3H),2.60–2.54(m,2H),2.36–2.27(m,3H),2.21–2.10(m,4H),1.8 1–1.55(m,7H),1.55–1.46(m,4H),1.31–1.18(m,5H),0.98–0.92(m,1H),0.90–0.80(m,6H).

[1218] Example 54: Synthesis of 3-(6-(7-((4-(4-((5-methoxy-4-((1-methylcyclopropyl)amino))pyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 54)

[1219]

[1220] Referring to the synthesis method of Example 9, compound 54 was prepared by the same method except that intermediate B was replaced by intermediate BI and intermediate F was replaced by intermediate K.

[1221] MS m / z(ESI):360.3[(M+2H) / 2] +

[1222] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.41(s,1H),8.19-8.02(m,2H),7.96-7.88(m,1H),7.59(s,1H),7.42-7.32(m,1H ),7.25-7.13(m,1H),6.75-6.63(m,1H),6.44-6.28(m,1H),5.75(s,1H),4.05-3.93(m,2H),3.77-3.68(m,2H),3.67-3. 59(m,2H),3.40-3.36(m,5H),2.71-2.62(m,1H),2.35-2.24(m,2H),2.12-2.02(m,2H),2.00-1.91(m,1H),1.77-1.69(m ,2H),1.59-1.45(m,2H),1.36-1.30(m,1H),1.29-1.18(m,4H),1.15-0.99(m,2H),0.96-0.91(m,1H),0.90-0.73(m,6H).

[1223] Example 55: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(4-(4-((6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (Compound 55)

[1224]

[1225] Referring to the synthetic method of Example 9, intermediate F was replaced by intermediate AS, and compound 55 was prepared in the same manner.

[1226] MS m / z(ESI):788.4[M+H] +

[1227] 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.92-9.85(m,1H),9.59-9.49(m,1H),8.17-8.03(m,1H) ,7.74-7.57(m,3H),6.80-6.74(m,1H),6.66-6.62(m,1H),6.14-6.06(m,1H),5.10-5.01(m,1H) ,3.80-3.67(m,4H),3.39-3.37(m,5H),2.95-2.83(m,2H),2.64-2.54(m,2H),2.05-1.98(m,2H) ,1.96-1.91(m,2H),1.83-1.64(m,4H),1.53(s,3H),1.28-1.20(m,6H),1.11-0.90(m,4H),0.88 -0.82(m,4H).

[1228] Example 56: Synthesis of 3-(4-(4-(5-(4-(6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-yl)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (Compound 56)

[1229]

[1230] Referring to the synthetic method of Example 9, compound 56 was prepared by the same method except that intermediate B was replaced by intermediate AT and intermediate F was replaced by intermediate AN.

[1231] MS m / z(ESI):707.3[M+H] +

[1232] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.89(d,J=10.0Hz,1H),9.62(s,1H),8.18(d,J=18.9Hz,1H),7.72(d,J=17.9Hz,2H),7.63 (d,J=7.5Hz,1H),6.89(s,4H),6.10(d,J=7.4Hz,1H),5.05-4.96(m,1H),4.85-4.73(m,1H),4.27-4.18(m,1H),4.16-4.08(m,1H) ,3.58-3.49(m,2H),3.38(s,3H),3.15-3.03(m,2H),2.92-2.85(m,1H),2.82-2.75(m,1H),2.74-2.52(m,3H),2.22-2.12(m,1H), 2.11-2.05(m,1H),2.05-1.95(m,1H),1.86(s,1H),1.84-1.72(m,2H),1.74-1.60(m,2H),1.52(s,4H),1.34(s,3H),1.17(s,3H).

[1233] Example 57: Synthesis of 3-(4-(1-((4-(4-(6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-3-yl)phenoxy)piperidine-2,6-dione (Compound 57)

[1234]

[1235] Referring to the synthetic method of Example 9, compound 57 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AU.

[1236] MS m / z(ESI):694.3[M+H] +

[1237] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.92-9.85(m,1H),9.52-9.45(m,1H),8.17-8.03(m,1H),7.64-7.50(m,2H) ,7.21-7.14(m,3H),6.98-6.91(m,3H),6.09(d,J=7.5Hz,1H),5.20-5.11(m,1H),4.20-4.09(m,1H),4.06-3.98(m, 1H),3.37(s,4H),2.90-2.81(m,4H),2.78-2.54(m,3H),2.25-2.02(m,3H),1.94-1.86(m,2H),1.84-1.76(m,1H),1 .75-1.68(m,1H),1.67-1.58(m,1H),1.51(s,4H),1.36-1.22(m,1H),1.24(s,2H),1.09(s,1H),0.88-0.73(m,4H).

[1238] Example 58: Synthesis of 2-[2,6-dioxopiperidin-3-yl]-5-[4-[2-[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]piperidin-1-yl]-2-oxoethyl]piperidin-1-yl]isoindoline-1,3-dione (Compound 58)

[1239]

[1240] Referring to the synthesis method of Example 7, intermediate D was replaced by intermediate AV, and compound 58 was prepared in the same manner.

[1241] MS m / z[ESI]:776.3[M+H] +

[1242] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.88(s,1H),9.51(s,1H),8.10(s,1H),7.75-7.5 4(m,3H),7.39-7.17(m,2H),6.19-6.04(m,1H),5.13-5.02(m,1H),4.57-4.33(m,3H),4. 11-3.97(m,3H),3.38(s,4H),3.28-3.10(m,1H),3.05-2.95(m,1H),2.92-2.55(m,4H),2 .37-2.27(m,1H),2.26-1.59(m,7H),1.51(s,3H),1.41-1.14(m,4H),0.95-0.65(m,3H).

[1243] Example 59: Synthesis of 1-(4-(7-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 59)

[1244]

[1245] Referring to the synthesis method of Example 9, compound 59 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AW.

[1246] MS m / z(ESI):360.4[(M+2H) / 2] +

[1247] 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),10.00-9.80(m,1H),9.56-9.44(m,1H),8.18-7.97( m,1H),7.69-7.55(m,2H),7.14-7.05(m,2H),6.49-6.36(m,2H),6.13-6.04(m,1H),3.69- 3.63(m,2H),3.56(s,2H),3.40-3.36(m,7H),2.71-2.64(m,2H),2.12-2.04(m,2H),1.86- 1.76(m,3H),1.73-1.60(m,3H),1.57-1.47(m,4H),1.30-1.20(m,6H),0.90-0.77(m,6H).

[1248] Example 60: Synthesis of 3-(3-methyl-5-(1-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 60)

[1249]

[1250] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AX (prepared according to patent WO2023283610), and compound 60 was prepared in the same manner.

[1251] MS m / z(ESI):748.3[M+H] +

[1252] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.94–9.85(m,1H),9.53–9.46(m,1H),8.15–8.04(m,1H),7.67– 7.56(m,2H),7.10(s,1H),7.05–6.98(m,1H),6.97–6.89(m,1H),6.15–6.06(m,1H),5.40–5.27(m,1H), 4.20–3.95(m,1H),3.37(s,3H),2.94–2.85(m,1H),2.76–2.56(m,3H),2.12–1.90(m,6H),1.86–1.63( m,6H),1.55–1.43(m,4H),1.35–1.31(m,1H),1.30–1.20(m,5H),1.15–1.03(m,2H),0.90–0.65(m,6H).

[1253] Example 61: Synthesis of 3-(6-(2-((4-(4-(6-methyl-4-((1-methylcyclopropyl)amino)-5-oxo-5,6-dihydropyridin-[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 61)

[1254]

[1255] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate AY, and compound 61 was prepared in the same manner.

[1256] MS m / z(ESI):734.3[M+H] +

[1257] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.89(d,J=10.6Hz,1H),9.50(s,1H),8.05(s ,1H),7.94(s,1H),7.64-7.56(m,2H),7.37(d,J=8.6Hz,1H),6.82(s,1H),6.09(d, J=7.5Hz,1H),4.06(s,1H),3.78-3.68(m,1H),3.52(s,3H),3.37(s,5H),2.69-2.6 6(m,1H),2.35-2.32(m,1H),2.21-1.90(m,11H),1.52(s,7H),1.27-1.20(m,11H).

[1258] Example 62: Synthesis of 3-(6-(2-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 62)

[1259]

[1260] Referring to the synthesis method of Example 9, compound 62 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate AZ.

[1261] MS m / z(ESI):720.3[M+H] +

[1262] 1H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.87(s,1H),9.48(s,1H),8.82(s,1H),7.93(d,J=2.5Hz,1H),7. 56(s,1H),7.38-7.34(m,2H),6.79(s,1H),6.09(d,J=7.7Hz,1H),5.34-5.31(m,4H),4.66(s,1H),3.82( s,1H),3.75-3.68(m,3H),3.51(s,4H),3.00-2.96(m,3H),2.94(s,1H),2.79(s,1H),2.76-2.71(m,2H), 2.68-2.64(m,2H),2.56(s,6H),2.34-2.32(m,1H),2.12(s,2H),2.07(s,1H),2.03(s,4H),1.76(s,3H).

[1263] Example 63: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-((4-(4-((6-methyl-4-(1-methylcyclopropyloxy)-5-oxo-5,6-dihydropyridine)[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-2-azaspiro[3.5]nonane-2-yl)isoindoline-1,3-dione (Compound 63)

[1264]

[1265] Referring to the synthesis method of Example 9, compound 63 was prepared by the same method except that intermediate B was replaced by intermediate BA and intermediate F was replaced by intermediate AS.

[1266] MS m / z(ESI):789.4[M+H] +

[1267] 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.92-9.54(m,1H),8.18-7.94(m,1H),7.76-7.5 9(m,3H),6.79-6.75(m,1H),6.68-6.61(m,1H),6.37-6.04(m,1H),5.09-5.01(m,1H), 3.77-3.67(m,4H),3.04-2.81(m,2H),2.66-2.53(m,2H),2.06-1.87(m,7H),1.81-1.6 4(m,6H),1.59-1.43(m,3H),1.28-1.17(m,6H),1.05-0.91(m,4H),0.90-0.73(m,4H).

[1268] Example 64: Synthesis of 3-(4-(4-((4-(4-((6-methyl-4-(1-methylcyclopropyloxy)-5-oxo-5,6-dihydropyridin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (Compound 64)

[1269]

[1270] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate BA, and intermediate F was replaced by intermediate AN, and compound 64 was prepared in the same manner.

[1271] MS m / z(ESI):696.3[M+H] +

[1272] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.85(s,1H),9.58(s,1H),8.07(s,1H),8. 00(s,2H),7.68(s,1H),7.51-7.46(m,1H),7.28(s,1H),6.32(d,J=7.3Hz,1H),6 .10(s,1H),5.35-5.31(m,1H),5.04-4.98(m,1H),4.71-4.65(m,3H),4.40-4.35 (m,1H),4.11(s,2H),3.66(s,6H),3.59(s,3H),2.99-2.86(m,8H),1.35(s,9H).

[1273] Example 65: Synthesis of 3-(4-(1-((4-(4-((6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazol-1)-yl)cyclohexyl)methyl)piperidin-4-yl)phenoxy)piperidine-2,6-dione (Compound 65)

[1274]

[1275] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate R, and intermediate F was replaced by intermediate AA, and compound 65 was prepared in the same manner.

[1276] MS m / z(ESI):679.40[M+H] +

[1277] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.48-9.23(m,2H),7.89-7.76(m,1H),7.71-7.63 (m,1H),7.59-7.53(m,1H),7.28-7.13(m,2H),7.08-6.92(m,2H),5.23-5.13(m,1H),4.2 7-4.08(m,2H),3.76-3.56(m,7H),3.14-2.92(m,2H),2.89-2.66(m,4H),2.22-2.07(m, 4H),2.05-1.89(m,4H),1.75(s,3H),1.39-1.15(m,4H),1.13-0.99(m,2H),0.86(s,3H).

[1278] Example 66: Synthesis of 3-(6-(4-((3-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (Compound 66)

[1279]

[1280] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate BB, and compound 66 was prepared in the same manner.

[1281] MS m / z(ESI):736.3[M+H] +

[1282] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.89(s,1H),9.60-9.18(m,1H),8.15(s,1H),7.99-7.84(m,1H) ,7.80-7.53(m,1H),7.49-7.19(m,2H),6.84-6.66(m,1H),6.35-6.00(m,1H),5.12-4.88(m,1H),4.33- 4.20(m,2H),4.14-4.05(m,1H),4.01-3.92(m,1H),3.76-3.68(m,1H),2.83-2.63(m,4H),2.47-2.24( m,4H),2.21-1.94(m,5H),1.92-1.63(m,8H),1.56-1.43(m,3H),1.33-1.21(m,4H),1.10-0.78(m,4H).

[1283] Example 67: Synthesis of 3-(4-(4-((3-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-oxa-8-azaspiro[4.5]dec-8-yl)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (Compound 67)

[1284]

[1285] Referring to the synthesis method of Example 9, compound 67 was prepared by the same method except that intermediate B was replaced by intermediate BB and intermediate F was replaced by intermediate AN.

[1286] MS m / z(ESI):751.3[M+H] +

[1287] 1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.92–9.68(m,1H),9.54–9.15(m,1H),8.19–8.11(m,1H),7.67–7 .56(m,2H),6.90–6.82(m,4H),6.29–6.02(m,1H),5.05–4.96(m,2H),4.17–4.06(m,1H),3.99–3.91(m,1 H),3.53–3.48(m,2H),3.39–3.37(m,4H),2.73–2.55(m,4H),2.36–2.29(m,2H),2.20–1.97(m,6H),1.80 –1.74(m,2H),1.71–1.61(m,4H),1.52(s,3H),1.36–1.28(m,2H),1.20–1.13(m,2H),0.89–0.81(m,4H).

[1288] Example 68: Synthesis of 1-(6-(4-((2-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 68)

[1289]

[1290] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate V, and intermediate F was replaced by 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carboxaldehyde, and compound 68 was prepared in the same manner.

[1291] MS m / z(ESI):721.4[M+H] +

[1292] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.88(s,1H),9.49(s,1H),8.10(s,1H),8.03(d,J=2.8Hz,1H),7.61(s,2H ),7.50-7.42(m,1H),6.82(d,J=9.1Hz,1H),6.09(d,J=7.5Hz,1H),4.83-4.74(m,1H),4.25(d,J=13.0Hz,2H),3 .73-3.65(m,2H),3.37(s,6H),2.84-2.73(m,2H),2.74-2.65(m,2H),2.34-2.29(m,5H),2.26-2.21(m,1H),2.1 4-2.08(m,4H),2.05-1.95(m,1H),1.78-1.70(m,3H),1.69-1.64(m,2H),1.60-1.50(m,4H),1.26-1.21(m,3H).

[1293] Example 69: Synthesis of 3-(4-((R)-3-methyl-4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyridinyl[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione (Compound 69)

[1294]

[1295] Referring to the synthetic method of Example 9, intermediate B was replaced by intermediate C, and intermediate F was replaced by intermediate BD (prepared with reference to intermediate BC), and compound 69 was prepared in the same manner.

[1296] MS m / z(ESI):709.3[M+H] +

[1297] 1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.97-9.83(m,1H),9.50(s,1H),8.18-8.02(m,1 H),7.67-7.53(m,2H),6.96-6.83(m,4H),6.15-6.05(m,1H),5.07-4.95(m,1H),4.27- 3.93(m,2H),2.91(s,1H),2.82-2.59(m,4H),2.45(s,2H),2.32-1.96(m,6H),1.90-1. 78(m,2H),1.72-1.43(m,7H),1.36-1.16(m,5H),1.10-0.97(m,3H),0.88-0.80(m,3H).

[1298] Example 70: Synthesis of 3-(4-((S)-3-methyl-4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyridinyl[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione (Compound 70)

[1299]

[1300] Referring to the synthesis method of Example 9, the intermediate B was replaced by intermediate C, and the intermediate F was replaced by intermediate BE (referring to the synthesis method of intermediate BC, Replace with Compound 70 was prepared by the same method.

[1301] MS m / z(ESI):709.3[M+H] +

[1302] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.95(d,J=11.8Hz,1H),9.53(s,1H),8.13(s, 1H),6.97-6.92(m,4H),6.70(s,1H),6.15(d,J=7.3Hz,1H),5.42-5.36(m,1H),5.10- 5.03(m,1H),3.57(s,1H),3.44(s,4H),2.18(s,1H),2.13(s,2H),2.10-2.01(m,8H), 1.82(s,1H),1.58(s,3H),1.41(d,J=3.4Hz,6H),1.11(d,J=5.2Hz,7H),0.91(s,3H).

[1303] Example 71: Synthesis of 3-(4-((S)-2-methyl-4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyridinyl[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione (Compound 71)

[1304]

[1305] Referring to the synthesis method of Example 9, the intermediate B was replaced by intermediate C, and the intermediate F was replaced by intermediate BF (referring to the synthesis method of intermediate BC, Replace with Compound 71 was prepared by the same method.

[1306] MS m / z(ESI):709.4[M+H] +

[1307] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.90(d,J=14.9Hz,1H),9.49(s,1H),8.11(d,J=31.1Hz,1H),7.6 0(d,J=15.0Hz,2H),7.08-6.78(m,4H),6.09(d,J=7.6Hz,1H),5.13-4.93(m,1H),4.13-3.99(m,1H),3. 69(s,2H),3.38(s,3H),3.36(s,6H),3.15-2.86(m,2H),2.77-2.56(m,3H),2.45-2.30(m,1H),2.30-1. 79(m,5H),1.77-1.56(m,3H),1.53(s,3H),1.17-1.01(m,1H),1.02-0.88(m,3H),0.84(d,J=6.9Hz,3H).

[1308] Example 72: Synthesis of 3-(4-((R)-2-methyl-4-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyridinyl[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione (Compound 72)

[1309]

[1310] Referring to the synthesis method of Example 9, compound 72 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate BC.

[1311] MS m / z(ESI):709.3[M+H] +

[1312] 1 H NMR (400MHz, DMSO-d6) δ10.92-10.82(m,1H),9.95-9.81(m,1H),9.55-9.43(m,1H),8.16-8. 04(m,1H),7.66-7.48(m,2H),6.94-6.79(m,3H),6.11-6.03(m,1H),5.05-4.96(m,1H),4.21- 3.96(m,2H),3.75-3.65(m,1H),3.41-3.34(m,2H),3.12-2.84(m,3H),2.73-2.55(m,3H),2.4 2-2.35(m,1H),2.28-1.76(m,10H),1.69-1.43(m,6H),1.15-1.02(m,2H),0.94–0.69(m,7H).

[1313] Example 73: Synthesis of 3-(6-(7-((4-(4-((6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazol-1)-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 73)

[1314]

[1315] Referring to the synthesis method of Example 9, intermediate B was replaced by intermediate R, and intermediate F was replaced by intermediate AH (prepared according to patent WO2023009719), and compound 73 was prepared in the same manner.

[1316] MS m / z(ESI):759.40[M+H] +

[1317] 1H NMR (400MHz, DMSO-d6) δ11.03–10.93(m,1H),9.55–9.32(m,1H),8.29–7.96(m,1H),7.92–7.71(m,1 H),7.67–7.59(m,1H),7.59–7.52(m,1H),7.41–7.34(m,1H),6.73–6.65(m,2H),5.14–5.02(m,1H), 4.36–4.27(m,1H),4.23–4.04(m,2H),3.58(s,4H),2.96–2.84(m,1H),2.54(s,3H),2.43–2.29(m,4 H),2.14–1.95(m,4H),1.86–1.70(m,9H),1.65–1.43(m,4H),1.17–0.97(m,4H),0.91–0.77(m,4H).

[1318] Example 74: Synthesis of 3-(6-(7-((4-(4-((6-methyl-4-(1-methylcyclopropyloxy)pyrido[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazol-1)-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 74)

[1319]

[1320] Referring to the synthesis method of Example 9, compound 74 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate BG.

[1321] MS m / z(ESI):712.30[M+H] +

[1322] 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.12–9.75(m,1H),9.20(s,1H),8.19–8.08(m,1H),7.81–7.58 (m,2H),7.34–7.20(m,1H),7.04–6.87(m,2H),6.31–6.13(m,1H),5.34–5.22(m,1H),4.33–4.12(m,1H) ,3.88–3.57(m,2H),3.45(s,4H),3.23–3.02(m,6H),2.82–2.65(m,2H),2.28–2.13(m,4H),2.01–1.89( m,4H),1.80–1.73(m,1H),1.64–1.55(m,3H),1.33–1.27(m,2H),1.26–1.21(m,3H),0.95–0.86(m,3H).

[1323] Example 75: Synthesis of 3-(4-(3-fluoro-1-((4-(4-((6-methyl-4-((1-methylcyclopropyl)amino))-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)phenoxy)piperidine-2,6-dione (Compound 75)

[1324]

[1325] Referring to the synthesis method of Example 9, compound 75 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate BH.

[1326] MS m / z(ESI):712.3[M+H] +

[1327] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.94-9.86(m,1H),9.54-9.46(m,1H),8.15-8.03(m,1H) ,7.64-7.50(m,2H),7.31-7.22(m,2H),7.02-6.93(m,2H),6.16-6.04(m,1H),5.25-5.14(m,1H) ,4.83-4.72(m,1H),4.70-4.60(m,1H),4.18-4.10(m,1H),4.10-3.98(m,1H),3.45-3.36(m,6H) ,2.96-2.84(m,2H),2.81-2.56(m,4H),2.21-2.10(m,4H),1.92-1.73(m,4H),1.50(s,3H),1.12 -0.95(m,2H),0.88-0.66(m,5H).

[1328] Example 76: Synthesis of 3-[4-[3,3-difluoro-1-[[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyridinyl[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]cyclohexyl]methyl]piperidin-4-yl]phenoxy]piperidine-2,6-dione (Compound 76)

[1329]

[1330] Referring to the synthesis method of Example 9, compound 76 was prepared by the same method except that intermediate B was replaced by intermediate C and intermediate F was replaced by intermediate BJ.

[1331] MS m / z(ESI):730.3[M+H] +

[1332] 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),9.90(s,1H),9.52(s,1H),8.18–7.99(m,1H ),7.74–7.51(m,2H),7.39–7.17(m,2H),7.09–6.87(m,2H),6.18–6.02(m,1H),5. 32–5.10(m,1H),4.28–3.97(m,2H),3.37(s,2H),3.22–2.86(m,3H),2.74–2.52(m ,2H),2.38–2.01(m,7H),1.91–1.47(m,8H),1.33–1.00(m,5H),0.92–0.55(m,4H).

[1333] Example 77: Synthesis of 3-[3-methyl-4-[4-[[4-[4-[[6-methyl-4-[[1-methylcyclopropyl]amino]]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl]amino]-1H-pyrazol-1-yl]piperidin-1-yl]methyl]piperidin-1-yl]-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]piperidine-2,6-dione (Compound 77)

[1334]

[1335] Referring to the synthesis method of Example 9, intermediate F was replaced by intermediate BK (prepared with reference to Example 390 of patent WO2022266258A1), and compound 77 was prepared in the same manner.

[1336] MS m / z(ESI):749.3[M+H] +

[1337] 1 H NMR(400MH...

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: is selected from a single bond or a double bond, when When it is a single bond, U is C=O and V is NR 1 , R 1 is selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 1 a replace; when When it is a double bond, U is selected from CR 2 or N, V ​​is CR 3 or N, R 2 , R 3 are independently selected from H, deuterium, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2 a substitution; or, R 2 , R 3 Together with the atoms it is connected to, it forms C5-C 10 Cycloalkenyl, 4-8 membered heterocyclic group or 5-10 membered heteroaryl, the C5-C 10 Cycloalkenyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with one or more R 3 a replace; Z is selected from CR 6 or N; W1 and W2 are independently selected from CH2, NH, O or S, wherein CH2 or NH is optionally substituted by a group selected from deuterium, halogen, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl; Q1 and Q2 are independently selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group, C6-C 10 aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN or CONH2, the C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or CONH2 is optionally substituted with one or more R 4 a replace; R 4 , R 5 and R 6 are independently selected from H, deuterium, halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy is optionally replaced by R b replace; R 1 a. R 2 a. R 3 a. R 4 a are independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by one or more Rc; R b , Rc are independently selected from deuterium, halogen, OH, NH2, =O, C1-C3 alkyl, CN, COOH, C(O)(C1-C3 alkyl), CONH2 or COO(C1-C3 alkyl).

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by one or more R 1 a substitution, or R 1 Selected from one or more R 1 a substituted C1-C6 alkyl.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R 2 , R 3 are independently selected from H, deuterium, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2a Replace; or, R 2 , R 3 independently selected from C1-C6 alkoxy, C3-C6 cycloalkyloxy, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy, C3-C6 cycloalkyloxy, C6-C 10 aryloxy, 5-10 membered heteroaryloxy or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkoxy, C3-C6 cycloalkyloxy, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy, C3-C6 cycloalkyloxy, C6-C 10 The aryloxy, 5-10 membered heteroaryloxy or 4-8 membered heterocyclyloxy group is optionally substituted with one or more R 2a Replace; or, R 2 , R 3 Each of the above groups is independently selected from C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more R 2a Replace; or, R 2 , R 3 independently selected from one another, optionally with one or more R 2a Substituted C1-C6 alkoxy; or, R 2 , R 3 Together with the atoms it is connected to, it forms C5-C 10 Cycloalkenyl, 4-8 membered heterocyclic group or 5-10 membered heteroaryl, the C5-C 10 Cycloalkenyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with one or more R 3a Replace; or, R 2 , R 3 The atoms to which it is attached together form a C5-C6 cycloalkenyl, a 4-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the C5-C6 cycloalkenyl, the 4-6 membered heterocyclyl or the 5-6 membered heteroaryl is optionally substituted by one or more R 3a replace.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: is a double bond, U is CR 2 or N, V ​​is CR 3 or N; or, is a double bond, U is CR 2 , V is N; or, is a double bond, U is N, and V is CR 3 .

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: Z is N.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: W1 and W2 are independently selected from NH or O, wherein NH is optionally substituted by a group selected from halogen, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl; or, W1 is selected from NH or O; or, W1 is selected from NH; or, W1 is selected from O; or, W2 is selected from NH optionally substituted by a group selected from halogen, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl; or, W2 is selected from NH.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: Q1 and Q2 are independently selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group, C6-C 10 aryl, C1-C6 alkyl, CN or CONH2, the C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group, C6-C 10 Aryl, C1-C6 alkyl or CONH2 is optionally replaced by one or more R 4a or, Q1 and Q2 are independently selected from C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl or C6-C 10 Aryl, the C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group or C6-C 10 The aryl group is optionally substituted with one or more R 4a or, Q1, Q2 are independently selected from C3-C6 cycloalkyl or 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl or 5-6 membered heteroaryl is optionally substituted by one or more R 4a or, Q1 is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclyl or C1-C6 alkyl, wherein the C3-C6 cycloalkyl, 4-8 membered heterocyclyl or C1-C6 alkyl is optionally substituted by one or more R 4a or, Q1 is selected from optionally substituted with one or more R 4a substituted C3-C6 cycloalkyl; or, Q2 is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 4a or, Q2 is selected from optionally substituted with one or more R 4a Substituted 5-6 membered heteroaryl.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: R 4 , R 5 and R 6 are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R b Replace; or, R 4 , R 5 are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy or NH2, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R b replace.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 1a , R 2a , R 3a , R 4a is independently selected from deuterium, halogen, OH, CN, NH2, =O, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by one or more R c Replace; or, R 1a , R 2a , R 3a , R 4a are independently selected from deuterium, halogen, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more R c Replace; or; R 1a , R 2a , R 3a , R 4a Each of the above is independently selected from deuterium, halogen, OH, CN, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more R c Replace; or, R 1a , R 2a , R 3a , R 4a independently selected from CN, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more R c Replace; or, R 1a , R 2a , R 3a , R 4a Each of the above is independently selected from CN, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more R c replace.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: The TL is selected from the structure shown in the following (TL-1): Where: W1 is selected from NH or O, Q 2 is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 4a Replacement, R 1 , R 4 , R 5 , Q1 and R 4a As defined in any one of claims 1 to 9.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: The TL is selected from the structure shown in the following (TL-2): Where: W1 is selected from NH or O, Q 2 is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclic group is optionally substituted by one or more R 4a Substitution, U is selected from CR 2 or N, V ​​is CR 3 or N, R 2 , R 3 are independently selected from H, deuterium, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C6-C 10 Aryl, C6-C 10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 4-8 membered heterocyclyl or 4-8 membered heterocyclyloxy are optionally substituted with one or more R 2a Replacement, R 4 , R 5 ,Q1,R 2a and R 4a As defined in any one of claims 1 to 9.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: The TL is selected from one of the following structures: Alternatively, the TL is selected from one of the following structures:

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: The Linker is a connecting group that covalently binds a TL and a DIM.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: The Linker is selected from: -L A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、 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 Each of the cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl groups is independently selected from the group consisting of 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.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein: The DIM is selected from ligand compounds capable of binding to cereblon type E3 ubiquitin ligase.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, 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 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; 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.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, 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’, -NP(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.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, 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 , X D , X E , R F , R G , L 1 and Ring E is as defined in claim 17.

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein: The DIM is selected from the structure shown in formula (DIM-13): Among them, the X C , X D , X E , R F , R G , L 1 , ring E and k are as defined in claim 18.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: The compound has a structure selected from one of the following:

21. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, and a pharmaceutically acceptable excipient.

22. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 or the pharmaceutical composition according to claim 21 in the preparation of a medicament for preventing or treating an IRAK4-mediated disease.

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