Amino-containing aza-aromatic ring compound, protac composed thereof and use thereof

Abstract

Provided in the present invention are an amino-containing aza-aromatic ring compound, PROTAC composed thereof and the use thereof. Specifically provided is a compound represented by formula V or a pharmaceutically acceptable salt thereof. The compound provided by the present invention can efficiently degrade a target RIPK2 and efficiently reduce the level of inflammatory factors caused by excessive RIPK2 activity, and has good pharmaceutical prospects.

Description

Amino-containing azaheterocyclic compound, protac formed by the same and application

[0001] This application claims priority to Chinese patent application 202411390245X with a filing date of 2024 / 9 / 30. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to an amino-containing azaheterocyclic compound, a PROTAC formed by the same and application. BACKGROUND

[0003] PROTAC, namely Proteolysis targeting chimera, is different from traditional small molecule inhibitors which usually need to act on the active site of the target protein to inhibit its activity. PROTAC is a bifunctional small molecule, which includes an E3 ubiquitin ligase ligand and a target protein (POI) ligand in its structure. The two are connected by a linker. The target protein and the E3 ubiquitin ligase meet each other, and the target protein is tagged with ubiquitin. With the help of the in vivo "cleaner" ubiquitin-proteasome pathway, the protein is degraded.

[0004] Receptor-interacting protein-2 (RIP2) kinase, also known as CARD3, RICK, CARDIAK or RIPK2, is a TKL family serine / threonine protein kinase involved in innate immune signaling, regulating NOD1 and NOD2-mediated pro-inflammatory signals. Overactive and overexpression of RIPK2 kinase has been shown to be associated with autoimmune diseases. For example, patients with genetic mutations of NOD2 are prone to develop Crohn's disease, Blau syndrome, early-onset sarcoidosis, dermatitis, arthritis and other diseases; while mutations of NOD1 are closely related to asthma, extraintestinal inflammation and other diseases. Small molecule inhibitors of RIPK2 kinase activity block RIPK2-dependent pro-inflammatory signaling, thereby treating inflammatory diseases characterized by excessive increase in RIPK2 kinase activity. At the same time, the amplification of RIPK2 protein increases with the development of cancer in some cancers, indicating that this protein may play a very important role in the development of cancer. According to the DrugBank and CORTELLIS databases, there is no selective RIPK2 inhibitor approved for clinical use, and only 2 drugs are in clinical research, and the highest progress is in clinical phase I.

[0005] It can be seen that it has higher research value to develop RIPK2 inhibitors with high selectivity, novel structure and good drugability, and to create PROTACs with receptor-interacting protein-2 (RIPK2) kinase degradation activity. By developing RIPK2 kinase degraders with good drugability, high selectivity is achieved in the prevention and treatment of diseases related to overactivation or overexpression of RIPK2, so as to improve drug efficacy, reduce toxic side effects, overcome drug resistance, and have high clinical value. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a novel structure of PROTAC with receptor-interacting protein-2 (RIPK2) kinase degradation activity for disease treatment, and for this purpose, the present application provides an amino-containing azaheteroaromatic ring compound, a PROTAC composed of the same and applications. The amino-containing azaheteroaromatic ring compound and the PROTAC composed of the same provided by the present application have good drug efficacy and are suitable for clinical promotion and application.

[0007] The present application solves the above technical problems by the following scheme.

[0008] The present application provides a compound represented by formula V or a pharmaceutically acceptable salt thereof;

[0009] E3 is an E3 ligase ligand (such as CRBN, VHL, IAP small molecule ligand or derivative thereof);

[0010] Linker is L2 is connected to the end of E3;

[0011] L2, L3 and L4 are independently a single bond, NH, S, O, urea, -OCONH-, amide (-CONH-), ester (-COO-), carbonyl (-CO-), -SO-, -SO2-, -NHSO2-, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkylene, C 2-6 alkylene, -O(C 1- 6heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -NH(C 1-6 heteroalkylene)-, -CO-(C 1-6 alkylene)-, -CO-(C 1-6 heteroalkylene), -SO2-(C 1-6 alkylene)-, -SO2-(C 1-6 heteroalkylene), -CONH-(C 1-6 heteroalkylene), -OCO-(C1-6 (heteroalkyl), -COO-(C 1-6 (heteroalkyl) or -(CH2CH2O) i , where i is an integer from 1 to 8;

[0012] Ring D, ring E, and ring F are independently absent (single bond), 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, or C. 6-14 Aryl;

[0013] ii, iii, and iv are independently 0, 1, 2, or 3;

[0014] R D R E and R F Independently deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC 1-6 Heteroalkyl, amino, -NHC 1-6 Heteroalkyl, -SC 1-6 Heteroalkyl, amide, carboxyl, cyano or C 1-6 Ester group;

[0015] It can be a single bond or a double bond independently;

[0016] R 2 -R 2L -R 2b -Y-, where R 2L Connect to the Linker (F end of the ring);

[0017] R 2L It can be a single bond, NH, S, O, amide (-CONH-), urea, carbonyl (-CO-) or -C 1-6 alkylene-;

[0018] R 2b For single bond, -NR 2b-1 -、C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 sub-alkenyl, -COR 2b-4 -or End and R 2L connect;

[0019] R 2b-1 For H, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-12 heteroaryl groups;

[0020] R 2b-3 is a single bond, C 1-6 alkylene, C 2-6 heteroalkylene, substituted by one or more R 2b-3-1 substituted C 1-6 alkylene and substituted by one or more R 2b-3-2 substituted C 2-6 heteroalkylene;

[0021] R 2b-3-1 and R 2b-3-2 are independently H, deuterium, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino;

[0022] R 2b-4 is a single bond, C 1-6 alkylene, C 1-6 alkylene or C 1-6 alkylene;

[0023] z is 0, 1, 2, 3 or 4;

[0024] ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl or C 6-14 aryl;

[0025] L5 is a single bond or carbonyl (-CO-);

[0026] R 2b-5 are independently halogen, deuterium, CN, OH, C 1-6 alkyl, C 1-6 alkyl-CO-R 2b-5-1 , C 1-6 heteroalkyl or -CO-R 2b-5-1 ;

[0027] R 2b-5-1 is OH, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio;

[0028] Y is a single bond, O, -NR Y-1 -, S, C 1-6 alkylene, C 1-6 heteroalkylene, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, C 2-6 alkenylene, -CO-, ureido, ureido R Y-1 -, -COO-, -CONR Y-1 -, -SO2-, -SO-, -SO2NRY-1 -NHS(O)2-, -NHSO-, -SONR Y-1 -NHC(O)-, -NHCOO-, -NHC(O)-NR Y-1 -OC(O)-NR Y-1 -NHC(O)-R Y-1 - or -NHSO2-NR Y-1 -;

[0029] R Y-1 independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-12 membered heteroaryl;

[0030] X1is CH or N;

[0031] X2and X3are independently O, S, NH, N or CH;

[0032] X4, X5and X6are independently CH, C or N;

[0033] and X2, X3, X4, X5and X6are not simultaneously N;

[0034] k is 0, 1, 2, 3 or 4;

[0035] R 1 independently hydrogen, deuterium, halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, OR a , SR a , -NR b R c , -COOR a , -CONR b R c , -NHCONR b R c , SO2R a , SOR a , SO2NR b R c or -NHS(O)2R a ;

[0036] R a , R b and R c independently H, C 1-6 alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-14 aryl or 5-12 membered heteroaryl; or, R b , R c and the atom to which they are attached form a 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl, said 3-10 membered heterocycloalkyl and said 5-12 membered heteroaryl being optionally substituted with one or more R a-1 substituents;

[0037] R a-1 is independently deuterium, halogen, hydroxyl, CN, or C 1-6 alkyl;

[0038] Ring A is

[0039] X7is S, N, carbonyl CH2, or CH;

[0040] X8is CH, NH, CH2, or N;

[0041] X9is O, S, N, NH, -NR g -, -CH=CH-, -CH=N-, CH, CR h , or CH2;

[0042] X 10 is CH, N, or C;

[0043] X 11 is N or CH;

[0044] X 12 is CH or N;

[0045] X 13 is N or CH;

[0046] X 14 is -CONH-, NH, or CH2;

[0047] X 15 is CH or N;

[0048] X 16 is CH or N;

[0049] and X 10 , X 11 , X 12 , X 15 , and X 16 are not simultaneously N;

[0050] n is 0, 1, 2, or 3;

[0051] R 3 is independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C1-6 Alkyl or with one or more R 3-1 Replacement C 1-6 alkyl;

[0052] R 3-1 Independently halogen, deuterium, or hydroxyl;

[0053] R g and R h Independently for C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-12 heteroaryl, -COR i -CONHR i -COC 1-6 Alkyl-R i -SR i -NR j R k -COOR i -CONR j R k -NHCONR j R k -SO2R i -SOR i -SO2NR j R k or -NHS(O)2R i ;

[0054] R i R j and R k Independently for H and C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 heteroaryl, with one or more R i-1 Substituted 3-10 membered cycloalkyl, with one or more R i-2 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R i-3 Replacement C 6-14 aryl or aryl with one or more R i-4 Substituted 5-12 heteroaryl groups; or, R j R k The atom bonded to it forms a 3-10-membered heterocyclic alkyl group or a 5-12-membered heteroaryl group, wherein the 3-10-membered heterocyclic alkyl group and the 5-12-membered heteroaryl group are optionally bonded by one or more R groups. i-5 replace;

[0055] R i-1 Ri-2 R i-3 R i-4 and R i-5 are independently deuterium, halogen, hydroxyl, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 1-6 alkyl;

[0056] any of the above C 2-6 heteroalkyl, 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl, C 1- 6 heteroalkylene is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0057] In a certain aspect, in the compounds, or the pharmaceutically acceptable salts thereof, certain groups have the following definitions, and the definitions of the groups not mentioned are described in any aspect of the present application (hereinafter referred to as “in a certain aspect”).

[0058] In a certain aspect, in the compounds of Formula V, or the pharmaceutically acceptable salts thereof,

[0059] E3 is an E3 ligase ligand (e.g., CRBN, VHL, IAP small molecule ligand, or derivative thereof);

[0060] Linker is L2 is attached to the end of E3;

[0061] L2, L3 and L4 are independently a single bond, NH, S, O, urea, -OCONH-, amide (-CONH-), ester (-COO-), carbonyl (-CO-), -SO-, -SO2-, -NHSO2-, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, C 2-6 alkynylene, -O(C 1- 6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -NH(C 1-6 heteroalkylene)-, -CO-(C 1-6 alkylene)-, -CO-(C 1-6 heteroalkylene), -SO2-(C 1-6 alkylene)-, -SO2-(C 1-6 heteroalkylene), -CONH-(C 1-6 heteroalkylene), -OCO-(C 1-6 heteroalkylene), -COO-(C1-6 heteroalkylene) or -(CH2CH2O) i , i is an integer from 1-8;

[0062] Ring D, Ring E, and Ring F are independently absent (a single bond), 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, or C 6-14 aryl;

[0063] ii, iii, and iv are independently 0, 1, 2, or 3;

[0064] R D , R E , and R F are independently deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 heteroalkyl, -OC 1-6 heteroalkyl, amino, -NHC 1-6 heteroalkyl, -SC 1-6 heteroalkyl, amido, carboxyl, cyano, or C 1-6 ester;

[0065] are independently a single bond or a double bond;

[0066] R 2 is -R 2L -; 2b -Y- wherein R 2L is connected to the end of Ring F;

[0067] R 2L is a single bond, NH, S, O, amido (-CONH-), urea, carbonyl (-CO-), or -C 1-6 alkylene-;

[0068] R 2b is a single bond, -NR 2b-1 -, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, -COR 2b-4 - or is connected to R 2L ;

[0069] R 2b-1 is H, C 1-6 alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-12 membered heteroaryl;

[0070] R 2b-3 is a single bond, C1-6 alkylene, C 2-6 heteroalkylene, substituted by one or more R 2b-3-1 substituted C 1-6 alkylene and substituted by one or more R 2b-3-2 substituted C 2-6 heteroalkylene;

[0071] R 2b-3-1 and R 2b-3-2 are independently H, deuterium, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino;

[0072] R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkyleneamino or C 1-6 alkylenethio;

[0073] z is 0, 1, 2, 3 or 4;

[0074] ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl or C 6-14 aryl;

[0075] L5 is a single bond or carbonyl (-CO-);

[0076] R 2b-5 are independently halogen, deuterium, CN, OH, C 1-6 alkyl, C 1-6 alkyl-CO-R 2b-5-1 , C 1-6 heteroalkyl or -CO-R 2b-5-1 ;

[0077] R 2b-5-1 is OH, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio;

[0078] Y is a single bond, O, -NR Y-1 -, S, C 1-6 alkylene, C 1-6 heteroalkylene, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, C 2-6 alkenylene, -CO-, ureido, ureido R Y-1 -, -COO-, -CONR Y-1 -, -SO2-, -SO-, -SO2NR Y-1 -, -NHS(O)2-, -NHSO-, -SONRY-1 -NHC(O)-, -NHCOO-, -NHC(O)-NR Y-1 -OC(O)-NR Y-1 -NHC(O)-R Y-1 - or -NHSO2-NR Y-1 -;

[0079] R Y-1 independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, or 5-12 membered heteroaryl;

[0080] X1is CH or N;

[0081] X2and X3are independently O, S, NH, N, or CH;

[0082] X4, X5, and X6are independently CH, C, or N;

[0083] and X2, X3, X4, X5, and X6are not simultaneously N;

[0084] k is 0, 1, 2, 3, or 4;

[0085] R 1 is independently hydrogen, deuterium, halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, OR a , SR a , -NR b R c , -COOR a , -CONR b R c , -NHCONR b R c , SO2R a , SOR a , SO2NR b R c , or -NHS(O)2R a ;

[0086] R a , R b , and R c are independently H, C 1-6 alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, or 5-12 membered heteroaryl; or, R bR c The atom bonded to it forms a 3-10-membered heterocyclic alkyl group or a 5-12-membered heteroaryl group, wherein the 3-10-membered heterocyclic alkyl group and the 5-12-membered heteroaryl group are optionally bonded by one or more R groups. a-1 replace;

[0087] R a-1 Independently deuterium, halogen, hydroxyl, CN or C 1-6 alkyl;

[0088] Ring A is

[0089] X7 represents S, N, and carbonyl groups. CH2 or CH;

[0090] X8 can be CH, NH, CH2, or N;

[0091] X9 represents O, S, N, NH, and -NR. g -, -CH=CH-, -CH=N-, CH, CR h Or CH2;

[0092] X 10 It can be CH, N, or C;

[0093] X 11 For N or CH;

[0094] X 12 For CH or N;

[0095] X 13 For N or CH;

[0096] X 14 It can be -CONH-, NH or CH2;

[0097] X 15 For CH or N;

[0098] X 16 For CH or N;

[0099] And X 10 X 11 X 12 X 15 and X 16 Not both N;

[0100] n is 0, 1, 2, or 3;

[0101] R 3 Independently, it is H, deuterium, halogen, cyano, C 1-6 Heteroalkyl, C 1-6 Alkyl or with one or more R 3-1 Replacement C1-6 alkyl;

[0102] R 3-1 Independently halogen, deuterium, or hydroxyl;

[0103] R g and R h Independently for C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-12 heteroaryl, -COR i -CONHR i -COC 1-6 Alkyl-R i -SR i -NR j R k -COOR i -CONR j R k -NHCONR j R k -SO2R i -SOR i -SO2NR j R k or -NHS(O)2R i ;

[0104] R i R j and R k Independently for H and C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 heteroaryl, with one or more R i-1 Substituted 3-10 membered cycloalkyl, with one or more R i-2 Substituted 3-10 membered heterocyclic alkyl groups, with one or more R i-3 Replacement C 6-14 aryl or aryl with one or more R i-4 Substituted 5-12 heteroaryl groups; or, R j R k The atom bonded to it forms a 3-10-membered heterocyclic alkyl group or a 5-12-membered heteroaryl group, wherein the 3-10-membered heterocyclic alkyl group and the 5-12-membered heteroaryl group are optionally bonded by one or more R groups. i-5 replace;

[0105] R i-1 R i-2 R i-3 R i-4 and Ri-5 independently hydrogen, deuterium, halogen, hydroxyl, CN, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl;

[0106] any of the above C 1-6 alkyl, C 2-6 alkyl, C 1- the heteroatoms in the 6-heteroalkylene group are independently selected from one or more of N, O, S, and P, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0107] In one aspect, the E3 ligase ligand (E3-) is

[0108] A1is N or CH;

[0109] A2is CH2or a single bond;

[0110] L1is a single bond, NH, CONH, or O;

[0111] Ring B is a 5-12 membered heteroaryl or C 6-10 aryl;

[0112] m is 0, 1, 2, 3, or 4;

[0113] R 4 independently halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, or oxo (C=O, oxo substitution on a non-aromatic ring);

[0114] the heteroatoms in the 5-12 membered heteroaryl are independently selected from one, two, three, or four of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0115] Preferably, the 5-12 membered heteroaryl is a monocyclic or fused ring, the heteroatoms are independently selected from one, two, three, or four of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0116] Preferably, when L1is NH, CONH, or O, Ring B is a monocyclic ring.

[0117] In one aspect, the E3 ligase ligand (E3-) is

[0118] A1is N or CH;​

[0119] A2 is CH2 or a single bond;

[0120] A3 is -CH2- or -CO-;

[0121] A4 and A5 are -CH- or N.

[0122] In one aspect, the compound or pharmaceutically acceptable salt thereof; In one aspect, the compound or pharmaceutically acceptable salt thereof;

[0123] In one aspect, the compound or pharmaceutically acceptable salt thereof; In one aspect, the compound or pharmaceutically acceptable salt thereof;

[0124] independently a single or double bond;

[0125] A1 is N or CH;

[0126] A2 is CH2 or a single bond;

[0127] A6 is S, N, -CO-, CH2 or CH;

[0128] A7 is CH, CH2, NH or N;

[0129] A8 is O, S, N, NH, -CH=CH-, -CH=N-, CH or CH2.

[0130] In one aspect, the E3 ligase ligand (E3-) described above is

[0131] R 5 , R 6 , R 7 , R 8 and R 9 are independently H, D, halogen, hydroxyl, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or oxo;

[0132] Preferably, R 5 , R 6 , R 7 and R 8 are independently H, hydroxyl, or C 1-6 alkyl;

[0133] Preferably, R 9 is H, D, or C 1-6 alkyl.

[0134] In one aspect, the compound or pharmaceutically acceptable salt thereof;

[0135] E3, as described in any of the aspects of the application;

[0136] independently a single bond or a double bond;

[0137] R 2 is a single bond, 2L -R 2b -Y- wherein R 2L is connected to the end of ring F;

[0138] R 2L is a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or -C 1-6 alkylene;

[0139] Y is a single bond;

[0140] R 2b is a single bond, -COR 2b-4 - or

[0141] R 2b-3 is a single bond or C 1-6 alkylene;

[0142] R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkylenethio, or C 1-6 alkylenamino;

[0143] z is 0, 1, 2, 3, or 4;

[0144] ring C is a 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, or C 6-14 aryl;

[0145] L5 is a single bond or carbonyl (-CO-);

[0146] R 2b-5 independently C 1-6 alkyl;

[0147] X1 is CH or N;

[0148] X2 and X3 are independently O, S, NH, N, or CH;

[0149] X4, X5, and X6 are independently C or N;

[0150] k is 0, 1, 2, or 3;

[0151] R 1 independently hydrogen or C 1-6 alkyl;

[0152] Ring A is

[0153] X7is N, carbonyl or CH;

[0154] X8is CH, NH or N;

[0155] X9is O, S, N, NH, -CH=CH-, -CH=N-, CH or CH2;

[0156] X 10 is N or C;

[0157] X 11 is N or CH;

[0158] X 12 is CH or N;

[0159] X 13 is N or CH;

[0160] X 14 is -CONH-, NH or CH2;

[0161] X 15 is CH or N;

[0162] X 16 is CH or N;

[0163] n is 0, 1, 2 or 3;

[0164] R 3 independently H or C 1-6 alkyl;

[0165] the heteroatoms in any of the above 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl are independently selected from one or more of N, O and S, the number of heteroatoms being 1, 2, 3 or 4.

[0166] In one aspect, the compound, or a pharmaceutically acceptable salt thereof, is

[0167] the E3 ligase ligand (E3-) is

[0168] A1is N or CH;

[0169] A2is CH2or a single bond;

[0170] L1is a single bond, NH, CONH or O;

[0171] Ring B is 5-12 membered heteroaryl or C6-10 aryl, wherein the 5-12 membered heteroaryl has 1, 2, 3, or 4 heteroatoms independently selected from S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0172] m is 0, 1, 2, 3, or 4;

[0173] R 4 independently halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or oxo (C=0, oxo substitution on non-aromatic ring);

[0174] is wherein L2is attached to ring B;

[0175] L2and L3are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), or -OCONH-(C 1-6 alkylene);

[0176] ii and iii are independently 0, 1, 2, or 3;

[0177] ring D is 3-12 membered heterocycloalkyl or 3-12 cycloalkyl, wherein in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0178] ring E is 3-12 membered heterocycloalkyl or 3-12 cycloalkyl, wherein in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0179] R D and R E are independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0180] are independently a single bond or a double bond;

[0181] R 2 -R 2L -R 2b -Y-, where R 2L Connect to end F of the ring;

[0182] R 2L It can be a single bond, NH, S, O, amide group (-CONH-), carbonyl group (-CO-) or -C 1-6 Alkylene;

[0183] Y represents a single bond;

[0184] R 2b For single bond, -COR 2b-4 -or

[0185] R 2b-3 For single bond or C 1-6 Alkylene;

[0186] R 2b-4 For single bond, C 1-6 alkeneoxy, C 1-6 alkyl thio or C 1-6 alkylamino;

[0187] z can be 0, 1, 2, 3, or 4;

[0188] The ring C is a 5-12-membered heteroaryl, 5-8-membered cycloalkenyl, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, or C 6-14 Aryl group, wherein the heteroatoms in the 3-10 membered heterocyclic alkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; and the heteroatoms in the 5-12 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0189] L5 is a single bond or a carbonyl group (-CO-);

[0190] R 2b-5 Independently for C 1-6 alkyl;

[0191] X1 is CH or N;

[0192] X2 and X3 are independently O, S, NH, N or CH;

[0193] X4, X5, and X6 are independently C or N;

[0194] k can be 0, 1, 2, or 3;

[0195] R 1 Independently hydrogen or C 1-6alkyl;

[0196] Ring A is

[0197] X7is N, carbonyl or CH;

[0198] X8is CH, NH, or N;

[0199] X9is O, S, N, NH, -CH=CH-, -CH=N-, CH, or CH2;

[0200] X 10 is N or C;

[0201] X 11 is N or CH;

[0202] X 12 is CH or N;

[0203] X 13 is N or CH;

[0204] X 14 is -CONH-, NH, or CH2;

[0205] X 15 is CH or N;

[0206] X 16 is CH or N;

[0207] n is 0, 1, 2, or 3;

[0208] R 3 is independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl, or C 3-1 alkyl substituted with one or more R 1-6 alkyl;

[0209] R 3-1 is independently halogen, deuterium, or hydroxyl.

[0210] In one aspect, the compound, or a pharmaceutically acceptable salt thereof, is

[0211] the E3 ligase ligand (E3-) is

[0212] A1is CH;

[0213] A2is CH2;

[0214] L1is a single bond or NH;

[0215] Ring B is a 5-12 membered heteroaryl or C 6-10aryl, wherein the 5-12 membered heteroaryl has 1, 2, 3, or 4 heteroatoms independently selected from S, N, O, and P, and the number of heteroatoms is 1, 2, 3, or 4;

[0216] m is 0, 1, 2, 3, or 4;

[0217] R 4 independently halogen, cyano, hydroxyl, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or oxo (C=0, oxo substitution on a non-aromatic ring);

[0218] is wherein L2is attached to Ring B;

[0219] L2and L3are independently a single bond, NH, or -C 1-6 alkylene-;

[0220] ii and iii are independently 0, 1, 2, or 3;

[0221] Ring D is 3-12 membered heterocycloalkyl (preferably 5-6 membered heterocycloalkyl), wherein the 3-12 membered heterocycloalkyl has 1, 2, or 3 heteroatoms independently selected from S, N, and O, and the number of heteroatoms is 1, 2, 3, or 4;

[0222] Ring E is 3-12 membered heterocycloalkyl (preferably 5-6 membered heterocycloalkyl), wherein the 3-12 membered heterocycloalkyl has 1, 2, or 3 heteroatoms independently selected from S, N, and O, and the number of heteroatoms is 1, 2, 3, or 4;

[0223] R D and R E are independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0224] are independently a single bond or a double bond;

[0225] R 2 is -R 2L -R 2b -Y-, wherein R 2L is attached to Linker;

[0226] R 2L is a carbonyl group;

[0227] Y is a single bond;

[0228] R 2b is

[0229] z is 0, 1, 2, 3, or 4;

[0230] Ring C is a 5-12 membered heteroaryl (5-6 membered heteroaryl), wherein the 5-12 membered heteroaryl has heteroatoms independently selected from one or more of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4;

[0231] L5is a single bond;

[0232] R 2b-5 is independently C 1-6 alkyl;

[0233] X1is CH;

[0234] X2and X3are independently O, S, or CH;

[0235] X4, X5, and X6are independently C;

[0236] k is 0, 1, 2, or 3;

[0237] R 1 is independently hydrogen or C 1-6 alkyl;

[0238] Ring A is

[0239] X7is N or CH;

[0240] X8is CH;

[0241] X9is S, N, or -CH=N-;

[0242] X 10 is N or C;

[0243] X 11 is CH;

[0244] X 12 is CH;

[0245] X 15 is CH;

[0246] X 16 is CH;

[0247] n is 0, 1, 2, or 3;

[0248] R 3 is independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl, or C 3-1 alkyl substituted with one or more R 1-6 alkyl;

[0249] R 3-1 independently halogen, deuterium, or hydroxyl.

[0250] In one aspect, the compound, or a pharmaceutically acceptable salt thereof, is

[0251] the E3 ligase ligand (E3-) is

[0252] A1is CH;

[0253] A2is CH2;

[0254] L1is a single bond or NH;

[0255] Ring B is a 5-12 membered heteroaryl or C 6-10 aryl, wherein the 5-12 membered heteroaryl has heteroatoms independently selected from 1, 2, 3, or 4 of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0256] m is 1 or 2;

[0257] R 4 independently halogen or oxo, wherein the oxo is substituted on a non-aromatic ring;

[0258] is wherein L2is attached to Ring B;

[0259] L2and L3are independently a single bond, NH, or -C 1-6 alkylene-;

[0260] ii and iii are independently 0 or 1; R D and R E independently halogen or hydroxyl;

[0261] Ring D is a 3-12 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl), wherein the 3-12 membered heterocycloalkyl has heteroatoms independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0262] Ring E is a 3-12 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl), wherein the 3-12 membered heterocycloalkyl has heteroatoms independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0263] are independently a single bond or a double bond;

[0264] R 2 is -R 2L-R 2b -Y-, wherein R 2L is connected to Linker;

[0265] R 2L is carbonyl;

[0266] Y is a single bond;

[0267] R 2b is

[0268] z is 1;

[0269] Ring C is a 5-12 membered heteroaryl (5-6 membered heteroaryl), wherein the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4;

[0270] L5 is a single bond;

[0271] R 2b-5 is independently C 1-6 alkyl;

[0272] X1 is CH;

[0273] X2 is independently O or S;

[0274] X3 is CH;

[0275] X4, X5, and X6 are independently C;

[0276] k is 0;

[0277] Ring A is

[0278] X7 is N or CH;

[0279] X8 is CH;

[0280] X9 is S, N, or -CH=N-;

[0281] X 10 is N or C;

[0282] X 11 is CH;

[0283] X 12 is CH;

[0284] X 15 is CH;

[0285] X 16 is CH;

[0286] n is 0, 1, 2, or 3;

[0287] R3 independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or substituted C 3-1 alkyl or substituted C 1-6 alkyl;

[0288] R 3-1 independently halogen, deuterium, or hydroxyl.

[0289] In one aspect, in the E3 ligase ligand, is

[0290] In one aspect, in the E3 ligase ligand, in ring B, the 5-12 membered heteroaryl is a 5-6 membered monocyclic heteroaryl (e.g., pyridinyl or pyrimidinyl) or a 9-12 membered fused heteroaryl, the heteroatoms can be one or both of N or O, the number of heteroatoms can be one or two, for example, the 5-12 membered heteroaryl is Preferably, in the E3 ligase ligand, ring B is substituted with 0, 1, 2, 3, or 4 R 4 substituted with 0, 1, 2, 3, or 4 R

[0291] In one aspect, in the E3 ligase ligand, in ring B, the C 6-10 aryl is phenyl or naphthyl, for example, phenyl.

[0292] In one aspect, in the E3 ligase ligand, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , the halogen is independently fluorine, chlorine, or bromine, for example, fluorine or chlorine.

[0293] In one aspect, in the E3 ligase ligand, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , the C 1-6 alkylamino is independently -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-i-propyl, -NH-n-butyl, -NH-i-butyl, -NH-sec-butyl, or -NH-t-butyl.

[0294] In one aspect, in the E3 ligase ligand, R 4 , R 5 , R6 7 8 9 1-6

[0295] In one aspect, in the E3 ligase ligand, R 4 5 6 7 8 9 1-6

[0296] In one aspect, in the E3 ligase ligand, R 4 5 6 7 8 9 1-6

[0297] In one aspect, in L2, L3, L4, Y, R 2L 2b 2b-3 1-6

[0298] In one aspect, in L2, L3, L4, Y, and R 2b 1-6 1-6 3-4 1-6 1-6 1-6

[0299] ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​In a certain scheme, L2, L3, L4, Y, and R 2b In, the C 2-6 The alkenyl group contains one, two, or three carbon-carbon double bonds, preferably the C... 2-6 The alkenyl group is a C2-C3 alkenyl group, such as vinylidene or propeneidene.

[0300] In a certain scheme, among L2, L3, L4, and Y, the C 2-6 The acetylenic group contains one, two, or three carbon-carbon triple bonds, preferably the C group. 2-6 The ynyl group is a C2-C3 ynyl group, such as ethynyl or propynyl.

[0301] In one embodiment, the 5-12-membered heteroaryl group in rings D, E, and F is independently a 5-6-membered monocyclic heteroaryl group (e.g., pyridinyl or pyrimidinyl) or a 9-12-membered fused heteroaryl group, and the heteroatom can be one or both of N or O, and the number of heteroatoms can be 1 or 2.

[0302] In one embodiment, the 5-8 membered cycloalkenyl groups in rings D, E, and F are independently 5-6 membered monocyclic cycloalkenyl groups, preferably containing one or two carbon-carbon double bonds, and the heteroatoms can be N, O, or S.

[0303] In one embodiment, the 3-12 membered cycloalkyl group in rings D, E, and F can be a monocyclic, fused, spirocyclic, or bridged 3-12 membered cycloalkyl group, such as a 3-6 membered monocyclic cycloalkyl group, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl.

[0304] In one embodiment, the 3-12 membered heterocyclic alkyl group in rings D, E, and F can be a monocyclic, fused, spirocyclic, or bridged 3-12 membered heterocyclic alkyl group, and the heteroatom can be one or two of N, S, or O, preferably a 3-6 membered monocyclic heterocyclic alkyl group (e.g. ) or 7-12 fused or spirocyclic heterocyclic alkyl groups (e.g. ).

[0305] In a certain scheme, rings D, E, F, and R Y-1 In, the C 6-14 The aryl group is either phenyl or naphthyl.

[0306] In one of the schemes, R D R E R F R 2b-51 R Y-1 R 1 R a-1 R 3 R 3-1 R i-1 R i-2R i-3 R i-4 and R i-5 In this context, the halogen is independently fluorine, chlorine, or bromine.

[0307] In one of the schemes, R D R E R F R 2b-1 R 2b-3-1 R 2b-3-2 R 2b-5 R 2b-5-1 R Y-1 R 1 R i-1 R i-2 R i-3 R i-4 and R i-5 In, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0308] In one of the schemes, R D R E R F R 2b-1 R 2b-5 R Y-1 R 1 In, the C 1-6 The heteroatom in the heteroalkyl group is one or two of N, O, and S, and the number of heteroatoms is independently one or two. The C 1-6 Heteroalkyl, for example, C 3-4 Heteroalkyl groups may be -CH2NHCH2-, -CH2OCH2-, -CH2SCH2-, -CH(CH3)NH-, or -CH2N(CH3)-, preferably C. 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino.

[0309] In one of the schemes, R 2b-3 In, the C 2-6 The heteroatoms in the heteroalkylene group are one or two of N, O, and S, and the number of heteroatoms is independently one or two. The C 2-6 Heteroalkyl, for example, C 3-4 Heteroalkyl groups may be -CH2NHCH2-, -CH2OCH2-, -CH2SCH2-, -CH(CH3)NH-, or -CH2N(CH3)-, preferably C. 2-6 Alkoxy, C 2-6 alkylthio or C 2-6 Alkylamino.

[0310] In one aspect, R D , R E , R F , R 2b-3-1 , R 2b-3-2 , R 2b-5 , R 2b-5-1 , R Y-1 , R i-1 , R i-2 , R i-3 , R i-4 , and R i-5 , the C 1-6 alkoxy is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-i-propyl, -O-n-butyl, -O-i-butyl, -O-s-butyl, or -O-t-butyl.

[0311] In one aspect, R D , R E , R F , R 2b-3-1 , R 2b-3-2 , R 2b-5 , R 2b-5-1 , R Y-1 , R i-1 , R i-2 , R i-3 , R i-4 , and R i-5 , the C 1-6 alkylthio is independently -S-methyl, -S-ethyl, -S-n-propyl, -S-i-propyl, -S-n-butyl, -S-i-butyl, -S-s-butyl, or -S-t-butyl.

[0312] In one aspect, R D , R E , R F , R 2b-3-1 , R 2b-3-2 , R 2b-5 , R 2b-5-1 , R Y-1 , R i-1 , R i-2 , R i-3 , R i-4 , and R i-5 , the C 1-6 alkylamino is independently -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-i-propyl, -NH-n-butyl, -NH-i-butyl, -NH-s-butyl, or -NH-t-butyl.

[0313] In one aspect, R D , R E , and R F , the C 1-6Ester groups are independently -COO-C 1-4 Alkyl, for example -COO-methyl, -COO-ethyl, -COO-n-propyl, -COO-i-propyl or -COO-n-butyl.

[0314] In one aspect, R 2b-1 , R Y-1 , R a , R b , R c , R g , R h , R i , R j and R k In one aspect, the 3-10 membered cycloalkyl group can be a monocyclic, fused, spiro or bridged 3-10 membered cycloalkyl group, for example a 3-6 membered monocyclic cycloalkyl group, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclobutyl.

[0315] In one aspect, R 2b-1 , R Y-1 , R a , R b , R c , R g , R h , R i , R j and R k In one aspect, the 3-10 membered heterocycloalkyl group can be a monocyclic, fused, spiro or bridged 3-10 membered heterocycloalkyl group, the heteroatom(s) can be one or two of N, S or O, preferably a 3-6 membered monocyclic heterocycloalkyl group.

[0316] In one aspect, R 2b-1 , R Y-1 , R a , R b , R c , R g , R h , R i , R j and R k In one aspect, the 5-12 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group (for example pyridyl or pyrimidyl) or a 9-12 membered fused heteroaryl group, the heteroatom(s) can be one or two of N or O, the number of heteroatoms can be one or two.

[0317] In one aspect, ring C, R a , R b , R c , R i , R j and R k In one aspect, the C 6-14 aryl group is phenyl or naphthyl.

[0318] In one of the schemes, R 2b-1 R g and R h In, the C 6-10 The aryl group is either phenyl or naphthyl.

[0319] In one of the schemes, R 2b-4 In, the C 1-6 The alkene oxide is methyleneoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0320] In one of the schemes, R 2b-4 In, the C 1-6 The alkylthionyl group is methylthionyl, ethylthionyl, n-propylthionyl, isopropylthionyl, n-butylthionyl, isobutylthionyl, sec-butylthionyl, or tert-butylthionyl.

[0321] In one of the schemes, R 2b-4 In, the C 1-6 The alkylamino group is methyleneamino (-NHCH2-), ethylamino (-NHCH2CH2-), n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or tert-butylamino.

[0322] In one embodiment, the 5-12 membered heteroaryl group in ring C is independently a 5-6 membered monocyclic heteroaryl group or a 9-12 membered fused heteroaryl group. The heteroatom can be one or both of N and O, and the number of heteroatoms can be one or two, for example...

[0323] In one embodiment, the 5-8 membered cycloalkenyl group in ring C is independently a 5-6 membered monocyclic cycloalkenyl group, preferably containing one or two carbon-carbon double bonds, and the heteroatom can be N, O or S.

[0324] In one embodiment, the 3-10 membered cycloalkyl group in ring C can be a monocyclic, fused, spirocyclic, or bridged 3-10 membered cycloalkyl group, such as a 3-6 membered monocyclic cycloalkyl group, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl.

[0325] In one embodiment, the 3-10 membered heterocyclic alkyl group in ring C is a monocyclic, fused, spirocyclic, or bridged 3-10 membered heterocyclic alkyl group, and the heteroatom can be one or two of N, S, or O, preferably a 3-6 membered monocyclic heterocyclic alkyl group, for example...

[0326] In one of the schemes, R Y-1 In, the C 2-6 The alkenyl group contains one, two, or three carbon-carbon double bonds, preferably the C... 2-6 The alkenyl group is a C2-C3 alkenyl group, such as vinyl or propenyl.

[0327] In one aspect, R Y-1 In one aspect, the C 2-6 Alkynyl contains one, two or three carbon-carbon triple bonds, preferably the C 2-6 Alkynyl is C2-C3alkynyl, for example ethynyl or propynyl.

[0328] In one aspect, R a , R b , R c , R a-1 , R 3 , R g , R h , R i , R j and R k In one aspect, the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

[0329] In one aspect, R a , R b , R c , R g , R h , R i , R j and R k In one aspect, the C 1-6 The heteroatoms in heteroalkyl are one or two of N, O and S, the number of heteroatoms is independently one or two, and the C 1-6 Heteroalkylene is for example C 3-4 Heteroalkyl is for example -CH2NHCH2-, -CH2OCH2-, -CH2SCH2-, -CH(CH3)NH- or -CH2N(CH3)-, preferably C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino.

[0330] In one aspect, in ring A, is

[0331] In one aspect, in ring A, is

[0332] In one aspect, in ring A, is

[0333] In one aspect, R 2L is a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or -1-6 alkylene, for example R 2L is a single bond, O, carbonyl (-CO-), or -C 1-6 alkylene.

[0334] In one aspect, is not a single bond.

[0335] In one aspect, Y is a single bond.

[0336] In one aspect, R 2b is a single bond, -COR 2b-4 - or

[0337] In one aspect, -R 2L -R 2b In -Y-, -R 2b is -Y- is a single bond, L5 is a single bond or carbonyl, R 2L is a single bond, NH, or C 1-6 alkylene.

[0338] In one aspect, -R 2L -R 2b In -Y-, -R 2b is -Y- and R 2b-3 is a single bond, R 2L is a single bond, O, or C 1-6 alkylene.

[0339] In one aspect, -R 2L -R 2b In -Y-, -R 2L is -Y- is a single bond, R 2L is a single bond, R 2b-3 is a single bond or C 1- 6alkylene.

[0340] In one aspect, R 2b-4 is a single bond.

[0341] In one aspect, z is 0 or 1.

[0342] In one aspect, ring C is a 5-12 membered heteroaryl or a 3-10 membered heterocycloalkyl.

[0343] In one aspect, R 2b-5 is independently C 1-6 alkyl or -CO-R 2b-5-1 , for example C 1-6 alkyl.

[0344] In certain embodiments, k is 0 or 1.

[0345] In certain embodiments, R 1 is independently hydrogen or C 1-6 alkyl, for example C 1-6 alkyl.

[0346] In certain embodiments, X8is CH or NH.

[0347] In certain embodiments, X9is S, N, -CH=CH- or -CH=N-.

[0348] In certain embodiments, X 11 and X 13 is CH.

[0349] In certain embodiments, n is 0.

[0350] In certain embodiments, R 3 is independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3- 1 substituted C 1-6 alkyl, preferably R 3 is independently H, deuterium, halogen, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3-1 substituted C 1-6 alkyl.

[0351] In certain embodiments, A1is CH.

[0352] In certain embodiments, A2is CH2.

[0353] In certain embodiments, L1is a single bond or NH.

[0354] In certain embodiments, ring B is a 5-12 membered heteroaryl or C 6-10 aryl (preferably a 6 or 9 membered heteroaryl or phenyl), wherein the heteroatoms in the heteroaryl are independently selected from 1, 2, 3 or 4 of S, N, O and P, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0355] In certain embodiments, m is 1 or 2.

[0356] In certain embodiments, R 4 is independently halogen or oxo, the oxo substituent being on a non-aromatic ring.

[0357] In certain embodiments, ii and iii are independently 0 or 1.

[0358] In certain embodiments, RD and R E independently halogen or hydroxyl.

[0359] In one aspect, L2and L3are independently a single bond, NH, or -C 1-6 alkylene.

[0360] In one aspect, ring D is a 3-12 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl), wherein the 3-12 membered heterocycloalkyl has 1, 2, or 3 heteroatoms independently selected from S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0361] In one aspect, ring E is a 3-12 membered heterocycloalkyl (preferably a 5-6 membered heterocycloalkyl), wherein the 3-12 membered heterocycloalkyl has 1, 2, or 3 heteroatoms independently selected from S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0362] In one aspect, R 2L is carbonyl.

[0363] In one aspect, Y is a single bond.

[0364] In one aspect, R 2b is

[0365] In one aspect, z is 1.

[0366] In one aspect, ring C is a 5-12 membered heteroaryl (preferably a 5-6 membered heteroaryl, for example ).

[0367] In one aspect, L5is a single bond.

[0368] In one aspect, R 2b-5 is independently C 1-6 alkyl (e.g., methyl).

[0369] In one aspect, X1is CH.

[0370] In one aspect, X2and X3are independently O, S, or CH, preferably X2is O or S; and X3is CH.

[0371] In one aspect, X4, X5, and X6are independently C.

[0372] In one aspect, k is 0, 1, 2, or 3, for example 0.

[0373] In one aspect, R 1independently hydrogen or C 1-6 alkyl.

[0374] In one aspect, ring A is

[0375] In one aspect, X7is N or CH.

[0376] In one aspect, X8is CH.

[0377] In one aspect, X9is S, N or -CH=N-.

[0378] In one aspect, X 10 is N or C.

[0379] In one aspect, X 11 is CH.

[0380] In one aspect, X 12 is CH.

[0381] In one aspect, X 15 is CH.

[0382] In one aspect, X 16 is CH.

[0383] In one aspect, n is 0, 1, 2 or 3.

[0384] In one aspect, R 3 is independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3- 1 substituted C 1-6 alkyl.

[0385] In one aspect, R 3-1 is independently halogen, deuterium or hydroxyl. In one aspect, ring A is optionally substituted with 0, 1, 2 or 3 R 3 denotes the direction of attachment to X4.

[0386] In one aspect, R 3 is independently hydrogen or C 1-6 alkyl, for example C 1-6 alkyl.

[0387] In one aspect, is -L2-L3-L4-, L2is attached to ring B.

[0388] ​In one aspect, L2, L3, and L4are independently a single bond, NH, O, amido (-CONH-), ester (-COO-), carbonyl (-CO-), C 1-6 alkylene, -NH(C 1-6 alkylene)-, or -(CH2CH2O) i i is an integer from 1 to 8.

[0389] In one aspect, L2, L3, and L4are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), -COO-(C 1-6 alkylene), or -(CH2CH2O) i i is an integer from 1 to 8.

[0390] Preferably, L2is independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or C 1-6 alkylene; L3and L4are C 1-6 alkylene, or -(CH2CH2O) i i is an integer from 1 to 8.

[0391] In one aspect, L2is a single bond, NH, O, S, -O(C 1-6 alkylene)-, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 heteroalkylene)-, -NH(C 1-6 alkylene)-, amido, or carbonyl;

[0392] L3is a single bond, C 1-6 alkylene, C 1-6 heteroalkylene, amido, or carbonyl;

[0393] L4is a single bond, NH, amido, carbonyl, or -CO-(C 1-6 alkylene)-;

[0394] Ring E is a 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl;

[0395] iii is independently 0, 1, 2, or 3;

[0396] R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0397] said 3-12 membered heterocycloalkyl, C 1-6 in the heteroalkylene, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0398] Preferably, ring E is a 3-12 membered heterocycloalkyl,

[0399] L2is NH or -NH(C 1-6 alkylene)-;

[0400] L3is a single bond, C 1-6 alkylene, or carbonyl;

[0401] L4is a single bond;

[0402] iii are independently 0, 1, 2, or 3;

[0403] R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl.

[0404] In one aspect, L2and L3are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1- 6alkylene)-, -CONH-(C 1-6 alkylene), or -OCONH-(C 1-6 alkylene);

[0405] ii and iii are independently 0, 1, 2, or 3;

[0406] ring D is a 3-12 membered heterocycloalkyl or a 3-12 membered cycloalkyl;

[0407] ring E is a 3-12 membered heterocycloalkyl or a 3-12 membered cycloalkyl;

[0408] R D and R E are independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0409] In the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0410] Preferably,

[0411] Ring D is a 3-12 membered heterocycloalkyl;

[0412] Ring E is a 3-12 membered heterocycloalkyl

[0413] L2and L3are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or -C 1-6 alkylene-;

[0414] ii and iii are independently 0, 1, 2, or 3;

[0415] R D and R E are independently deuterium, halogen, hydroxyl, or C 1-6 alkyl.

[0416] In one aspect, L2, L3, and L4are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), or -OCONH-(C 1-6 alkylene);

[0417] ii, iii, and iv are independently 0, 1, 2, or 3;

[0418] Ring D is a 3-12 membered heterocycloalkyl or a 3-12 membered cycloalkyl;

[0419] Ring E is a 3-12 membered heterocycloalkyl or a 3-12 membered cycloalkyl;

[0420] Ring F is a 3-12 membered heterocycloalkyl or a 3-12 membered cycloalkyl;

[0421] R D , R E , R F are independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0422] In the 3-12 membered heterocycloalkyl group, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0423] Preferably, ring D is a 3-12 membered heterocycloalkyl group;

[0424] Ring E is a 3-12 membered heterocycloalkyl group;

[0425] Ring F is a 3-12 membered heterocycloalkyl group;

[0426] ii, iii, and iv are independently 0, 1, 2, or 3;

[0427] R D , R E , R F is independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0428] L2, L3, and L4 are independently a single bond or -C 1-6 alkylene-.

[0429] In one aspect, ring D, ring E, and ring F are independently a 3-12 membered heterocycloalkyl group, for example,

[0430] In one aspect, is

[0431] In one aspect, is any one of the following structures:

[0432] In one aspect, is

[0433] In one aspect, the is any one of the following structures:

[0434] In one aspect, the compound of Formula V is a compound of Formula V-1;

[0435] A2, L1, ring B, m, R 4 , R 2 , X1, X2, X3, X4, X5, X6, k, R 1 , ring A, n, R 3 as described in any one of the present application;

[0436] L2is a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C

[0437] L2, L3and L4are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1- 6alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), -COO-(C 1-6 alkylene) or -(CH2CH2O) i , i is an integer from 1 to 8;

[0438] Preferably,

[0439] L2is a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or C 1-6 alkylene;

[0440] L3and L4are C 1-6 alkylene or -(CH2CH2O) i , i is an integer from 1 to 8.

[0441] In a certain aspect, L2is a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or C wherein is connected to ring B.

[0442] In a certain aspect, the compound of Formula V-1 is:

[0443] In a certain aspect, the compound of Formula V is the compound of Formula V-2;

[0444] A2, A1, L1, ring B, m, R 4 , R 2 , X1, X2, X3, X4, X5, X6, k, R 1 , ring A, n, R 3 as described in any of the present application;

[0445] For L2is a single bond, NH, O, S, -O(C

[0446] L2is a single bond, NH, O, S, -O(C 1-6 alkylene)-, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -S(C 1- 6alkylene)-, -NH(C 1-6 heteroalkylene)-, -NH(C 1-6 alkylene)-, amido, or carbonyl;

[0447] L3is a single bond, C 1-6 alkylene, C 1-6 heteroalkylene, amido, or carbonyl;

[0448] L4is a single bond, NH, amido, carbonyl, or -CO-(C 1-6 alkylene)-;

[0449] Ring E is a 3-12 membered heterocycloalkyl or a 3-12 membered cycloalkyl;

[0450] iii is independently 0, 1, 2, or 3;

[0451] R E is independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0452] In the 3-12 membered heterocycloalkyl, C 1-6 heteroalkylene, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0453] Preferably,

[0454] Ring E is a 3-12 membered heterocycloalkyl, L2is NH or -NH(C 1-6 alkylene)-, L3is a single bond, C 1-6 alkylene, or carbonyl, and L4is a single bond.

[0455] In an aspect, For wherein is connected to Ring B.

[0456] In an aspect, the compound of Formula V-2 is any one of the following compounds:

[0457] In one aspect, the compound of Formula V is a compound of Formula V-3:

[0458] A2, A1, L1, ring B, m, R 4 , X1, X2, X3, X4, X5, X6, k, R 2 , X1, X2, X3, X4, X5, X6, k, R 1 , ring A, n, R 3 as described in any one of the present invention;

[0459] as described in any one of the present invention; wherein L2is attached to ring B;

[0460] L2and L3are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), or -OCONH-(C 1-6 alkylene);

[0461] ii and iii are independently 0, 1, 2, or 3;

[0462] ring D is a 3-12 membered heterocycloalkyl or a 3-12 cycloalkyl;

[0463] ring E is a 3-12 membered heterocycloalkyl or a 3-12 cycloalkyl;

[0464] R D and R E are independently deuterium, halogen, hydroxyl, or C 1-6 alkyl;

[0465] in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from one, two, or three of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0466] preferably,

[0467] ring D is a 3-12 membered heterocycloalkyl;

[0468] ring E is a 3-12 membered heterocycloalkyl

[0469] L2and L3are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or -C1-6 Alkylene-.

[0470] In one scheme, in the compound shown in Formula V and the compound shown in Formula V-3, A1 and A2 are CH.

[0471] In one scheme, in the compounds shown in Formula V and Formula V-3, when A1 is CH, ring B is phenyl or a 6-membered heteroaryl group.

[0472] In one scheme, in the compound shown in formula V and the compound shown in formula V-3, R 2 -R 2L -R 2b -Y-,-R 2L And -Y- is a single bond, R 2b for

[0473] In one scheme, the compounds shown in Formula V and Formula V-3 have 5-12 heteroaryl rings.

[0474] In one scheme, in the compound shown in formula V and the compound shown in formula V-3, R 2b-3 It is a single key.

[0475] In one scheme, in the compound shown in formula V and the compound shown in formula V-3, R 2b-5 C 1-6 alkyl.

[0476] In one embodiment, in the compounds shown in Formula V and Formula V-3, the... for

[0477] In one embodiment, ring B is a 9-10 membered fused-ring heterocyclic alkyl group, wherein the heteroatoms are independently selected from one, two, or three of S, N, and O, and the number of heteroatoms is independently one, two, three, or four. For example, ring B is...

[0478] In one scheme, ring B is C. 10-14 cycloaryl, the C 10-14 fused aryl groups can be formed by two aromatic rings, aromatic rings or non-aromatic rings forming a fused ring.

[0479] In one embodiment, ring B is a 6-membered heteroaromatic ring (e.g., pyridyl) or a benzene ring containing 0-2 nitrogen atoms, for example... For any of the following structures

[0480] In one embodiment, in rings D, E, and F, the 3-12 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group, wherein the heteroatom is independently selected from N, and the number of heteroatoms is independently 1 or 2.

[0481] In one aspect, in ring D, ring E, ring F, the 3-12 membered heteroalkyl is a 4-6 membered cycloalkyl, for example, cyclobutyl, cyclopentyl, or cyclohexyl.

[0482] In one aspect, L2and L3are not simultaneously a single bond.

[0483] In one aspect, in ring A, the 5-12 membered heteroaryl is a fused ring, wherein the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0484] In one aspect, In one aspect, wherein is connected to ring B.

[0485] In one aspect, the compound of Formula V-3 is any one of the following compounds:

[0486] In one aspect, the compound of Formula V is a compound of Formula V-4:

[0487] A2, A1, L1, ring B, m, R 4 , R 2 , X1, X2, X3, X4, X5, X6, k, R 1 , ring A, n, R 3 as described in any one of the present disclosure;

[0488] Linker In one aspect, L2is connected to ring B.

[0489] L2, L3, and L4are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1- 6alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6alkylene)-, -CONH-(C 1-6 alkylene) or -OCONH-(C 1-6 alkylene);

[0490] ii, iii and iv are independently 0, 1, 2 or 3;

[0491] Ring D is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl;

[0492] Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl;

[0493] Ring F is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl;

[0494] R D , R E , R F are independently deuterium, halogen, hydroxyl or C 1-6 alkyl;

[0495] In the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0496] Preferably,

[0497] Ring D is 3-12 membered heterocycloalkyl;

[0498] Ring E is 3-12 membered heterocycloalkyl;

[0499] Ring F is 3-12 membered heterocycloalkyl;

[0500] ii, iii and iv are independently 0, 1, 2 or 3;

[0501] R D , R E , R F are independently deuterium, halogen, hydroxyl or C 1-6 alkyl;

[0502] L2, L3 and L4 are independently single bond or -C 1-6 alkylene-.

[0503] In one aspect, the compound of Formula V is a compound of Formula V-5:

[0504] R 5 , R 6 , R 9 , R 7 , R 8 , R 2X1, X2, X3, X4, X5, X6, k, R 1 ring A, n, R 3 as described in any one of the present invention;

[0505] -L2-L3-L4- (the ring D, ring E and ring F are not present), L4is connected with R 2 at the end.

[0506] L2, L3and L4are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -O(C 1- 6alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), -COO-(C 1-6 alkylene) or -(CH2CH2O) i i is an integer from 1 to 8;

[0507] Preferably,

[0508] L2is independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-) or C 1-6 alkylene;

[0509] L3and L4are C 1-6 alkylene or -NH(C 1-6 alkylene)-.

[0510] In a certain aspect, wherein is connected with R 2 at the end.

[0511] In a certain aspect, the compound of Formula V-5 is any one of the following compounds:

[0512] In a certain aspect, the compound of Formula V is any one of the compounds synthesized in Examples 1-85.

[0513] The present invention provides a pharmaceutical composition comprising the compound of Formula V or a pharmaceutically acceptable salt thereof described above and a pharmaceutically acceptable excipient.

[0514] ​The present application provides the use of the above-mentioned compound represented by Formula V or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, which comprises:

[0515] (1) as a receptor-interacting protein-2 degrader;

[0516] (2) for preparing a medicament for treating or preventing a receptor-interacting protein-2 mediated disease or disorder.

[0517] For example, the receptor-interacting protein-2 mediated disease or disorder is a disease associated with inflammation and immune response, preferably a disease associated with abnormal activation of NOD signaling pathway, which can be effectively regulated by a RIPK2 kinase inhibitor or degrader. For example, inflammatory bowel disease (IBD) (e.g., Crohn's disease or ulcerative colitis), rheumatoid arthritis (RA), inflammatory disease (e.g., sepsis), inflammatory skin disease, cancer, autoimmune disease (e.g., multiple sclerosis (MS), systemic lupus erythematosus), metabolic disease (e.g., type 2 diabetes), allergic disease (e.g., asthma and allergic rhinitis), atherosclerosis or cardiovascular disease, or irritable bowel syndrome (IBS).

[0518] The present application provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof;

[0519] wherein, X1, X2, X3, X4, k, R 1 , Y, R 2b , ring A, n and R 3 as described in any one of the present application;

[0520] R 2a is hydrogen, halogen, CN, hydroxyl, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio;

[0521] ring A is

[0522] Preferably, the compound represented by Formula I satisfies any one of the following conditions:

[0523] (1) when X2 is S, X7, X8 and X9 are -N=CH-S-, R 2b is L5 is a carbonyl group;

[0524] (2) when X2 is S, X7, X8 and X9 are -N=CH-O-, R 2b is Ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, or naphthyl;

[0525] (3) when X2 is S, X9 is NH, X7 is S, N, carbonyl or CH2.

[0526] In one aspect, the compound of Formula I is one wherein X2 is O, NH, N, NR 1 or CR 1 .

[0527] In one aspect, the compound of Formula I is one wherein X7 is carbonyl, and X8 is NH.

[0528] In one aspect, the compound of Formula I is one wherein X7 is N, and X9 is O or S; or X8, X9, and X 10 contain one, two, or three N.

[0529] In one aspect, the compound of Formula I is one wherein X 15 and / or X 16 is N.

[0530] In one aspect, the compound of Formula I is one wherein ring A is

[0531] In one aspect, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is one wherein

[0532] wherein, is independently a single or double bond;

[0533] X1 is CH or N;

[0534] X2 is O, S, NH, N, or CH;

[0535] X3 is CH, N, or NH;

[0536] X4 is C or N;

[0537] k is 0, 1, 2, or 3;

[0538] R 1 is independently hydrogen or C 1-6 alkyl;

[0539] R 2a is hydrogen, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino;

[0540] Y is a single bond;

[0541] R 2b is a single bond, -COR 2b-4 - or

[0542] R 2b-3 is a single bond, C 1-6 alkylene or C 2b-3-1 alkylene substituted with 1, 2 or 3 R 1-6 ;

[0543] R 2b-3-1 is H, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio;

[0544] R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkyleneamino or C 1-6 alkylenethio;

[0545] z is 0, 1, 2, 3 or 4;

[0546] ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl or C 6-14 aryl; in said 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; in said 3-10 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0547] L5 is a single bond or carbonyl; R 2b-5 is independently deuterium, halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy or C 1-6 alkylamino;

[0548] ring A is

[0549] X7 is N, carbonyl or CH;

[0550] X8 is CH, NH or N;

[0551] X9 is O, S, N, NH, -CH=CH-, -CH=N-, CH or CH2;

[0552] X 10 is N or C;

[0553] X11 is N or CH;

[0554] X 12 is CH or N;

[0555] X 13 is N or CH;

[0556] X 14 is -CONH-, NH or CH2;

[0557] X 15 is CH or N;

[0558] X 16 is CH or N;

[0559] and X 10 , X 11 , X 12 , X 15 and X 16 are not simultaneously N;

[0560] n is 0, 1, 2 or 3;

[0561] R 3 is independently H, deuterium, hydroxyl, halogen or C 1-6 alkyl. (Preferably, R 3 is independently H, deuterium, halogen or C 1-6 alkyl).

[0562] In one aspect, the compound of Formula I is

[0563] wherein, is independently a single or double bond;

[0564] X1is CH or N;

[0565] X2is O, S, NH, N or CH;

[0566] X3is CH, N or NH;

[0567] X4is C or N;

[0568] k is 0 or 1;

[0569] R 1 is C 1-6 alkyl;

[0570] R 2a is hydrogen, hydroxyl, halogen or C 1-6 alkoxy;

[0571] Y is a single bond;

[0572] R 2b is a single bond, -COR 2b-4 - or R 2b-3 is C 1-6 alkylene;

[0573] R 2b-3-1 is C 1-6 alkoxy;

[0574] R 2b-4 is a single bond;

[0575] L5 is a single bond or carbonyl;

[0576] z is 0, 1 or 2;

[0577] ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl or 3-10 membered heterocycloalkyl; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; in the 3-10 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0578] R 2b-5 is independently C 1-6 alkyl;

[0579] ring A is

[0580] X7 is S, N, carbonyl or CH;

[0581] X8 is CH, NH or N;

[0582] X9 is O, S, N, NH, -CH=CH- or -CH=N-;

[0583] X 10 is N or C;

[0584] X 11 is N or CH;

[0585] X 12 is CH or N;

[0586] X 15 is CH or N;

[0587] X 16 is CH or N;

[0588] n is 0.

[0589] In one aspect, the compound of formula I, X2 is O or S; X3 is CH, and X4 is C.

[0590] In one embodiment, in the compound represented by Formula I, X2 is NH or NCH3, and X3 is N.

[0591] In one of the schemes, for (Ring A passes through X) 11 (Connected to X4) The end is connected to X4.

[0592] In a certain scheme, X7 is N, X8 is CH, X9 is O or S, X 10 Let C and X be the values ​​of C and X respectively. 11 For CH, X 15 For CH, X 16 For CH, X 12 For CH.

[0593] In a certain scheme, X7 is N, X8 is CH, X9 is N, X 10 Let N, X 11 For CH, X 15 For CH, X 16 For CH, X 12 For CH.

[0594] In one scheme, X7 is a carbonyl group, X8 is NH, X9 is -CH=CH-, and X... 10 Let C and X be the values ​​of C and X respectively. 11 For CH, X 15 For CH, X 16 For CH, X 12 For CH.

[0595] In one of the schemes, for -YR 2b -R 2a For H, halogen, or -COR 2b-4 -R 2a .

[0596] In one scheme, ring C is a 5-12 cyclic aromatic heterocycle (e.g. C 6-14 Aromatic rings, 3-10 membered cycloalkyl groups, or 3-10 membered heterocycloalkyl groups, such as -YR 2b -R 2a for

[0597] In one of the schemes, for

[0598] In one of the schemes, for

[0599] In one aspect, R 1 is methyl.

[0600] In one aspect, is I, H,

[0601] In one aspect, the compound of Formula I is any one of the following:

[0602] The present application provides a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0603] The present application provides the use of the compound of Formula I or a pharmaceutically acceptable salt thereof, the above pharmaceutical composition, the use comprising:

[0604] (1) as a receptor-interacting protein-2 inhibitor;

[0605] (2) for the manufacture of a medicament for treating or preventing a disease or disorder mediated by receptor-interacting protein-2;

[0606] In the compound of Formula I or a pharmaceutically acceptable salt thereof,

[0607] wherein, X1, X2, X3, X4, k, R 1 , Y, R 2b , ring A, n and R 3 as described in any aspect of the present application;

[0608] R 2a is hydrogen, halogen, CN, hydroxyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio;

[0609] Preferably, the compound of Formula I or a pharmaceutically acceptable salt thereof is as described in any aspect of the present application.

[0610] For example, the receptor interacting protein-2 mediated disease or disorder is a disease associated with inflammation and immune responses, preferably a disease associated with abnormal activation of the NOD signaling pathway, which can be effectively modulated by a RIPK2 kinase inhibitor or degrader. For example, inflammatory bowel disease (IBD) (e.g., Crohn’s disease or ulcerative colitis), rheumatoid arthritis (RA), inflammatory diseases (e.g., sepsis), inflammatory skin diseases, cancer, autoimmune diseases (e.g., multiple sclerosis (MS), systemic lupus erythematosus), metabolic diseases (e.g., type 2 diabetes), allergic diseases (e.g., asthma and allergic rhinitis), atherosclerosis or cardiovascular diseases, or irritable bowel syndrome (IBS).

[0611] Terminology:

[0612] Unless otherwise indicated, the terms used in the present application have the following definitions, and the definitions of terms not mentioned below are as generally understood by a person of ordinary skill in the art to which the present application pertains.

[0613] As understood by a person of ordinary skill in the art, the means that the corresponding group is connected to other fragments, groups in the compound through the site. When allowed, there can be multiple sites for substitution.

[0614] The term “a group B substituted with multiple groups A” means that one or more hydrogen atoms in group B are independently replaced with group A or B is unsubstituted. When multiple A groups are present simultaneously, their definitions are independent of and unaffected by each other, unless otherwise specified. For example, “a C1-C6alkyl substituted with 3 halogens” means that C1-C6alkyl can be substituted with 3 halogens, and the definitions of the 3 halogens are independent of and unaffected by each other, including but not limited to: trifluoromethyl, difluoromethyl, , and the like.

[0615] The term is a double bond or a single bond.

[0616] In the present application, means a group substituted with n R substituents, unless otherwise specified, wherein R replaces H in the above-mentioned groups to form a stable structure, for example, , R 1 is a substituent, and when R 1 is present, R 1 replaces one or more H in the ring.

[0617] As understood by a person of ordinary skill in the art, means a substituted ring The central H atom (two) forms a link chain.

[0618] The term "plurality" means 2 and more, for example 2, 3, 4, 5.

[0619] The term "pharmaceutically acceptable" means relatively non-toxic, safe, suitable for patient use.

[0620] The term "pharmaceutically acceptable salt" means a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the compounds with a sufficient amount of the desired pharmaceutically acceptable base in a suitable inert solvent. Where the compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the compounds with a sufficient amount of the desired pharmaceutically acceptable acid in a suitable inert solvent. See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0621] The "-" in a group means that the group is attached to the rest of the molecule at that point. For example, CH3-C(=O)- means acetyl.

[0622] The term "halogen" means fluorine, chlorine, bromine, or iodine. Halogen substitution in the present invention includes, but is not limited to, substitution with one halogen, substitution with two halogens, substitution with three halogens, and typically multiple substitution occurs on one carbon atom.

[0623] The term "oxo" means =O, an oxygen atom replacing two hydrogens on the same carbon atom, i.e., a carbonyl group replacing a methylene group.

[0624] The term "alkyl" means a straight or branched chain, saturated, monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0625] The term "alkylene" means an alkyl group in which two bonds are replaced, the alkyl group being defined above.

[0626] The term "alkoxy" means the group R X -O-, R X is defined as the term "alkyl". Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, and the like.

[0627] The term "alkylene" refers to an alkyl group in which two bonds are replaced, the definition of alkyl being as above.

[0628] The term "alkylthio" refers to the group R X -S-, R X The definition of R is as the term "alkyl". Alkylthio includes, but is not limited to, methylthio, ethylthio, n-propylthio, i-propylthio, and the like.

[0629] The term "alkylene" refers to an alkyl group in which two bonds are replaced, the definition of alkyl being as above.

[0630] The term "alkylamino" refers to the group R X -NH-, R X The definition of R is as the term "alkyl". Alkylthio includes, but is not limited to, methylthio, ethylthio, n-propylthio, i-propylthio, and the like.

[0631] The term "alkylene" refers to an alkyl group in which two bonds are replaced, the definition of alkyl being as above.

[0632] The term "heteroalkyl" refers to a straight or branched chain, 1 or more heteroatoms (e.g., 1, 2, or 3) selected from the group of N, O, and S (e.g., 1, 2, or 3) having the indicated number of carbon atoms (e.g., C1-C6). Heteroalkyl is preferably alkyl, alkoxyl, alkylthio, or alkylamino.

[0633] The term "heteroalkylene" refers to a heteroalkyl group in which two bonds are replaced, the definition of heteroalkyl being as above.

[0634] The term "ester" refers to the group -COOR X , R X The definition of R is as the term "alkyl".

[0635] The term "alkenyl" refers to a straight or branched chain, unsaturated, monovalent hydrocarbon group having the indicated number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds. Alkenyl includes, but is not limited to, ethenyl, , and the like.

[0636] The term "alkenylene" refers to an alkenyl group in which two bonds are replaced, the definition of alkenyl being as above.

[0637] The term "alkynyl" refers to a straight or branched chain, unsaturated, monovalent hydrocarbon group having the indicated number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 triple bonds. Alkynyl includes, but is not limited to, ethynyl, , and the like.

[0638] The term "alkynylene" refers to an alkynyl group in which two bonds are taken by a substituent, the definition of alkynyl being as above.

[0639] As used herein and unless otherwise indicated, the term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C3-C6). Cycloalkyl groups include, but are not limited to: 10 14 10

[0640] As used herein and unless otherwise indicated, the term "cycloalkenyl" refers to a "cycloalkyl" group having one or more carbon-carbon double bonds, the definition of "cycloalkyl" being as above. For example:

[0641] As used herein and unless otherwise indicated, the term "aryl" refers to a cyclic, unsaturated hydrocarbon radical having the indicated number of carbon atoms (e.g., C6-C10or C6-C12), which is monocyclic or polycyclic (e.g., 2 or 3), which is fused where polycyclic, sharing two atoms and one bond between rings, and which is aromatic (at least one ring per aryl group). Aryl groups include, but are not limited to: phenyl, naphthyl, and the like.

[0642] As used herein and unless otherwise indicated, the term "heterocycloalkyl" refers to a monocyclic, bridged, spirocyclic, fused, heterocyclic radical having the indicated number of ring atoms (e.g., 3-10 membered, 3-12 membered, or 4-10 membered), the indicated number of heteroatoms (e.g., 1, 2, or 3), and the indicated type of heteroatoms (one or more of N, O, and S). Heterocycloalkyl groups can be saturated or unsaturated. Heterocycloalkyl groups are attached to the remainder of the molecule by a carbon atom or a heteroatom. Monocyclic heterocycloalkyl groups include, but are not limited to: Sprio cycloalkyl groups include, but are not limited to: Fused heterocycloalkyl groups include

[0643] ​​​​As used herein and unless otherwise indicated, the term "heteroaryl" means a cyclic, unsaturated, monovalent radical of specified number of ring atoms (e.g., 5-12 membered, 5-10 membered, or 5-6 membered), specified number of heteroatoms (e.g., 1, 2, or 3), specified types of heteroatoms (one or more of N, O, and S), monocyclic or polycyclic, sharing two atoms and one bond between monocyclic rings, and at least one ring having aromaticity. Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or a heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring having a heteroatom or a ring not having a heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring having aromaticity or a ring not having aromaticity. Heteroaryl groups include, but are not limited to, the following:

[0644] In certain embodiments, treating or being treated refers to improvement, prevention or reversal of a disease or disorder or at least one discernible symptom thereof. In other embodiments, treating or being treated refers to improvement, prevention or reversal of at least one measurable physical parameter of a disease or disorder being treated, which can not be discernible in the mammal. In yet another embodiment, treating or being treated refers to slowing the progression of a disease or disorder, or stabilization, either physically, e.g., discernible symptoms, or physiologically, e.g., measurable parameters, or both. In other embodiments, treating or being treated refers to delaying the onset of a disease or disorder.

[0645] In certain embodiments, the compounds of the present disclosure can be administered as a prophylactic measure. As used herein, "preventing" or "being prevented" refers to reducing the risk of acquiring a given disease or disorder. In a preferred mode of the embodiments, a specified compound is administered to a subject as a prophylactic measure, e.g., a subject with a family history or predisposition for cancer or an autoimmune disease.

[0646] Without deviating from the common general knowledge in the art, the above-mentioned preferred conditions can be combined in any way, i.e. to obtain each preferred embodiment of the present application.

[0647] The reagents and starting materials used in the present application are commercially available.

[0648] The positive progress effect of the present application is that the compounds of the present application have one or more of the following advantages:

[0649] (1) The amino-containing azaheteroaromatic ring compound provided by the present application has good inhibitory effect on RIPK2.

[0650] (2) The PROTAC degrader can efficiently degrade the target RIPK2 and efficiently eliminate the level of inflammatory factors caused by excessive activity of RIPK2. ​

[0651] (3) The PROTAC degrader has good degradation selectivity for RIPK2.

[0652] (4) The aza-heteroaromatic ring compound containing an amino group provided by the present application has improved solubility and good prospects for drug development.

[0653] (4) The PROTAC aza-heteroaromatic ring compound containing an amino group provided by the present application has high activity inhibition for medium-high expression of RIPK2 in various human and mouse cells, or high selectivity and high efficiency degradation, and significantly down-regulates the high expression of inflammatory factors induced in cells. The representative compound also has a significant effect on degrading RIPK2 protein and down-regulating inflammatory factors in patient samples. DETAILED DESCRIPTION

[0654] The present application will be further described by way of examples below, but the present application is not limited to the scope of the examples described. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the product.

[0655] List of abbreviations:

[0656] Petroleum ether: petroleum ether

[0657] Ethyl acetate: ethyl acetate

[0658] Sodium sulfate: sodium sulfate

[0659] Potassium phosphate: K3PO4

[0660] Dioxane: dioxane

[0661] Bis(diphenylphosphino)ferrocene palladium dichloride: Pd(dppf)Cl2

[0662] Lithium hydroxide: lithium hydroxide monohydrate

[0663] Hydrogen chloride: HCl

[0664] Methanol: MeOH

[0665] Dichloromethane: DCM

[0666] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCI

[0667] N,N-diisopropylethylamine: DIEA

[0668] 1-hydroxybenzotriazole: HOBT

[0669] Trifluoroacetic acid: TFA

[0670] Cesium carbonate: Cs2CO3

[0671] N,N-dimethylformamide: DMF

[0672] N-methylpyrrolidone: NMP

[0673] tetrahydrofuran: THF

[0674] acetonitrile: acetonitrile

[0675] formic acid: formic acid

[0676] sodium sulfite: Na2SO3

[0677] nitrogen-iodobutyramide: NIS.

[0678] PROTAC preparation examples

[0679] UP05 intermediate

[0680] Under nitrogen protection, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (5 g, 21.45 mmol) was dissolved in dioxane (50 mL), pinacol diboronic acid (10.9 g, 42.9 mmol), KOAc (5.3 g, 53.63 mmol) and Pd(dtbpf)Cl2(2.8 g, 4.29 mmol) were added, and stirred at 80 °C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (400 mL) was added, and ethyl acetate (250 mL*3 times) was used for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:4) to obtain (3-ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl boronic acid (2.5 g, yield: 58.9%, yellow oil). LCMS: (ESI, m / z): [M+H] + = 199.1

[0681] Under nitrogen protection, 3-bromo-4-chlorothieno[3,2-c]pyridine (25 g, 100.6 mmol) was dissolved in dioxane (250 mL), and ammonia water (250 mL) was added, and stirred at 120 °C for 24 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:2) to obtain 3-bromothieno[3,2-c]pyridin-4-amine (13.5 g, yield: 58.6%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 229.1

[0682] Under nitrogen atmosphere, 3-bromo-thieno[3,2-c]pyridin-4-amine (10 g, 43.65 mmol) was dissolved in DMF (100 mL), NIS (19.6 g, 87.3 mmol) was added, stirred at 50 °C for 5 hours under nitrogen atmosphere. The reaction was completed and cooled to room temperature, aqueous sodium sulfite solution (800 mL, 5%) was added, extracted with ethyl acetate (500 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1:3) to obtain 3-bromo-7-iodo-thieno[3,2-c]pyridin-4-amine (12.5 g, yield: 80.7%, brown solid). LCMS: (ESI, m / z): [M+H] + = 356.8

[0683] Under nitrogen atmosphere, 3-bromo-7-iodo-thieno[3,2-c]pyridin-4-amine (12.5 g, 35 mmol) was dissolved in dioxane (130 mL), (3-ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl boronic acid (7.67 g, 39 mmol), K3PO4 (18.69 g, 88 mmol) and Pd(dtbpf)Cl2 (4.58 g, 7 mmol) were added, stirred at 90 °C for 4 hours under nitrogen atmosphere. The reaction was completed and cooled to room temperature, water (1 L) was added, extracted with ethyl acetate (650 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1:1) to obtain ethyl 5-(4-amino-3-bromo-thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (10.3 g, yield: 76.7%, brown solid). LCMS: (ESI, m / z): [M+H] + = 383.0

[0684] Ethyl 5-(4-amino-3-bromothieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylate (10 g, 26 mmol) was dissolved in dioxane (100 mL) under nitrogen protection, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (7.53 g, 29 mmol), K3PO4 (13.92 g, 66 mmol) and Pd(dtbpf)Cl2 (3.42 g, 5 mmol) were added, stirred at 100 °C under nitrogen protection for 4 hours. The reaction was completed and cooled to room temperature, added water (800 mL), extracted with ethyl acetate (500 mL*3 times), combined organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to obtain ethyl 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (7.6 g, yield: 66.5%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 436.1

[0685] Ethyl 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (7.6 g, 17 mmol) was dissolved in a mixture solution of water (40 mL) and THF (40 mL) under nitrogen protection, added lithium hydroxide monohydrate (1.26 g, 52 mmol), stirred at room temperature under nitrogen protection for 1 hour. The reaction solution was concentrated under reduced pressure to a volume of 40 mL, then 3M aqueous hydrochloric acid was added dropwise to PH = 6, and filtered. The filter cake was dried to obtain 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (51 mg, yield: 71.7%, white solid).

[0686] LCMS: (ESI, m / z): [M+H] + = 408.1

[0687] 1 H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 9.54 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.07 (s, 1H), 7.00 (br, 2H) 3.92 (s, 3H)

[0688] Example 1

[0689] Under nitrogen protection, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2 g, 7.24 mmol) was dissolved in NMP (20 mL), and tert-butyl 4-amino-[1,4'-bipiperidin]-1'-carboxylate (2.3 g, 7.97 mmol) and DIEA (2.3 g, 18.1 mmol) were added. The mixture was stirred at 120 °C for 4 h under nitrogen protection. The reaction was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*3 times). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1:20) to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.2 g, yield: 56.3%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 540.3

[0690] Under nitrogen protection, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.2 g, 4.08 mmol) was dissolved in DCM (22 mL), and TFA (5.5 mL) was added. The mixture was stirred at room temperature for 2 h under nitrogen protection. After the reaction solution was concentrated and dried in vacuum, 4-([1,4'-bipiperidin]-4-ylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.7 g, yield: 94.9%, yellow oil) was obtained. LCMS: (ESI, m / z): [M+H] + = 440.2

[0691] Under nitrogen atmosphere, 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.12 mmol) was dissolved in DMF (0.8 mL), 4-([1,4'-bipiperidin]-4-ylamino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (56.6 mg, 0.13 mmol), EDCI (35.3 mg, 0.18 mmol), DIEA (47.5 mg, 0.37 mmol) and HOBT (24.8 mg, 0.18 mmol) were added, stirred at room temperature for 18 hours under nitrogen atmosphere. The reaction was completed and cooled to room temperature, added water (10 mL), extracted with ethyl acetate (4 mL*3 times), combined organic phase, dried over anhydrous sodium sulfate, concentrated. The crude product was purified by Flash (C18 column chromatography, 10%-50% acetonitrile / 5‰ TFA in water; gradient 10 minutes, UV 254 nm) to give 4-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (22.5 mg, yield: 22.1%, white solid). LCMS: (ESI, m / z): [M+H] + = 828.3. 1 H NMR (600 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.53 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.63-7.57 (m, 2H), 7.18 (d, J = 11.8 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.83 (s, 1H), 6.26 (d, J = 7.9 Hz, 1H), 5.71 (s, 2H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.78 (d, J = 12.5 Hz, 1H), 4.57 (d, J = 12.5 Hz, 1H), 3.87 (s, 3H), 3.58 (d, J = 8.0 Hz, 1H), 3.19-3.16 (m, 1H), 2.89-2.84 (m, 4H), 2.62-2.57 (m, 3H), 2.43-2.40 (m, 2H), 2.05-1.95 (m, 3H), 1.85 (s, 2H), 1.50-1.45 (m, 4H).

[0692] Example 2

[0693] Under nitrogen protection, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2 g, 7.24 mmol) was dissolved in NMP (20 mL), and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (2.3 g, 7.97 mmol) and DIEA (2.3 g, 18.1 mmol) were added. The mixture was stirred at 120 °C for 4 h under nitrogen protection. The reaction was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*3 times). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1:20) to give tert-butyl 4-(((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (2.3 g, yield: 58.9%, green solid).

[0694] LCMS: (ESI, m / z): [M+H] + = 540.3

[0695] Under nitrogen protection, tert-butyl 4-(((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (2.3 g, 4.26 mmol) was dissolved in DCM (23 mL), and TFA (5.8 mL) was added. The mixture was stirred at room temperature for 4 h under nitrogen protection. After the reaction solution was concentrated and dried in vacuum, 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (1.98 g, yield: 105.7%, white solid) was obtained.

[0696] LCMS: (ESI, m / z): [M+H] + = 440.3

[0697] Under nitrogen, 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (51 mg, 0.13 mmol) was dissolved in DMF (0.8 mL), and 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-yl)piperazin-1-yl)isoindoline-1,3-dione (57.8 mg, 0.13 mmol), EDCI (36 mg, 0.19 mmol), DIEA (48.4 mg, 0.38 mmol), and HOBT (25.3 mg, 0.19 mmol) were added. The reaction was stirred at room temperature under nitrogen for 18 h. The reaction was purified directly by flash purification (C18 column chromatography, 10-40% acetonitrile / water; gradient 10 min, UV 254 nm) to give 4-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (18 mg, yield: 17.3%, white solid). LCMS: (ESI, m / z): [M+H] + = 829.3. 1 H NMR (600 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.74 (s, 1H), 9.54 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.78 (t, J = 9.5 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.46 (dd, J = 24.2, 7.8 Hz, 2H), 7.20 (s, 1H), 6.93 (s, 1H), 5.12 (dd, J = 12.8, 5.5 Hz, 1H), 4.73 (d, J = 11.8 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 3.94 - 3.81 (m, 5H), 3.71 (s, 2H), 3.42 - 3.23 (m, 5H), 3.19 (s, 2H), 2.98 - 2.81 (m, 2H), 2.66 - 2.52 (m, 2H), 2.25 (s, 1H), 2.14 - 2.02 (m, 1H), 1.89 (dd, J = 32.2, 10.4 Hz, 2H), 1.37 - 1.17 (m, 2H).

[0698] Example 3

[0699] Tert-butyl 3-(piperazin-l-ylmethyl)azetidine-l-carboxylate (270 mg, 1.06 mmol) was dissolved in DMF (2.7 mL) under nitrogen, 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (392 mg, 1.16 mmol) and DIEA (409.9 mg, 3.17 mmol) were added, stirred at 90 °C for 5 hours under nitrogen. The reaction was completed and cooled to room temperature, added water (30 mL), extracted with ethyl acetate (20 mL*3 times), combined organic phase, dried over anhydrous sodium sulfate, concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1:20) to obtain tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)methyl)azetidine-l-carboxylate (244 mg, yield: 45.1%, green solid).

[0700] LCMS: (ESI, m / z): [M+H] + = 512.1

[0701] Tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)methyl)azetidine-l-carboxylate (204 mg, 0.4 mmol) was dissolved in DCM (2 mL) under nitrogen, added TFA (0.5 mL), stirred at room temperature for 4 hours under nitrogen. The reaction was concentrated and dried in vacuum to obtain 5-(4-(azetidin-3-ylmethyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (160 mg, yield: 97.5%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 412.1

[0702] Under nitrogen, 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (40 mg, 0.1 mmol) was dissolved in DMF (0.8 mL), and 5-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (42.4 mg, 0.1 mmol), EDCI (28.3 mg, 0.15 mmol), DIEA (38 mg, 0.29 mmol), and HOBT (19.9 mg, 0.15 mmol) were added. The reaction was stirred at 50 °C under nitrogen for 2 h. The reaction was cooled to room temperature and purified by flash purification (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 5-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione (3.1 mg, yield: 3.9%, white solid). LCMS: (ESI, m / z): [M+H] + = 801.2

[0703] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.07 (s, 0.5H, TFA salt), 9.54 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.24 (dd, J = 4.3, 1.3 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 13.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.82 (s, 1.5H), 5.11 (dd, J = 12.9, 5.3 Hz, 1H), 4.74 (t, J = 9.1 Hz, 1H), 4.41 (dd, J = 9.9, 5.5 Hz, 1H), 4.33 - 4.16 (m, 3H), 3.92 - 3.85 (m, 5H), 3.72 - 3.43 (m, 3H), 3.34 (s, 2H), 3.35 - 3.11 (m, 3H), 3.02 (s, 1H), 2.96 - 2.83 (m, 1H), 2.66 - 2.54 (m, 1H), 2.11 - 1.98 (m, 1H).

[0704] Example 4

[0705] Under nitrogen protection, 1-bromo-2-fluoro-4-nitrobenzene (2 g, 9.09 mmol) was dissolved in dioxane (20 mL), and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1- carboxylate (5.2 g, 18.18 mmol), Cs2CO3(7.4 g, 22.73 mmol), XPhos G3Pd (3.1 g, 3.64 mmol) and Pd2(dba)3(1.7 g, 1.82 mmol) were added. The reaction was stirred at 100 °C for 3 hours under nitrogen protection. The reaction was cooled to room temperature, water (160 mL) was added, and the organic phase was extracted with ethyl acetate (100 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1:1) to obtain tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1- carboxylate (1.9 g, yield: 49.5%, white solid). LCMS: (ESI, m / z): [M+H] + = 423.2

[0706] Under nitrogen protection, tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate (1.9 g, 4.5 mmol) was dissolved in MeOH (19 mL), and 10% Pd / C (2 g, 55% water content) was added. The reaction was stirred at room temperature for 2 hours under nitrogen protection. The reaction liquid was filtered, and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated and dried under vacuum to obtain tert-butyl 4-((4-(4-amino-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1- carboxylate (1.7 g, yield: 96.3%, yellow oil). LCMS: (ESI, m / z): [M+H] + = 393.2

[0707] Tert-butyl 4-((4-(4-amino-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1- carboxylate (500 mg, 1.27 mmol) was dissolved in DMF (5 mL) under nitrogen, 3- bromopiperidine-2,6-dione (269 mg, 1.4 mmol) and DIEA (493.9 mg, 3.82 mmol) were added, and stirring was performed at 100 °C under nitrogen for 5 hours. After the reaction was completed, the solution was cooled to room temperature, water (40 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3 times). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1:9) to obtain tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate (210 mg, yield: 32.7%, purple solid). LCMS: (ESI, m / z): [M+H] + = 504.3

[0708] Tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate (210 mg, 0.42 mmol) was dissolved in DCM (2.1 mL) under nitrogen, TFA (0.5 mL) was added, and stirring was performed at room temperature under nitrogen for 2 hours. After the reaction solution was concentrated and dried in vacuum, 3-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (160 mg, yield: 95.1%, brown oil) was obtained. LCMS: (ESI, m / z): [M+H] + = 404.2

[0709] Under nitrogen, 3-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione (90 mg, 0.22 mmol) was dissolved in DMF (0.9 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (95.4 mg, 0.23 mmol), EDCI (64.2 mg, 0.33 mmol), DIEA (86.3 mg, 0.67 mmol), and HOBT (45.2 mg, 0.33 mmol) were added. The reaction was stirred at 50 °C under nitrogen for 2 h. The reaction was purified directly by Flash (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-((4-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (27 mg, yield: 15.3%, white solid). LCMS: (ESI, m / z): [M+H] + = 793.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.57 - 9.44 (m, 2H), 8.38 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.64 (dd, J = 8.2, 1.6 Hz, 1H), 7.27 (s, 2H), 6.94 - 6.88 (m, 2H), 6.56 (dd, J = 15.0, 2.4 Hz, 1H), 6.51 - 6.42 (m, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 11.4 Hz, 1H), 4.29 (dd, J = 11.5, 4.8 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 3.28 - 3.22 (m, 5H), 3.14 (s, 2H), 3.06 (t, J = 11.3 Hz, 2H), 2.84 (d, J = 11.0 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.63 - 2.56 (m, 1H), 2.21 (s, 1H), 2.14 - 2.04 (m, 1H), 1.95 - 1.79 (m, 3H), 1.34 - 1.16 (m, 2H).

[0710] Example 5

[0711] Ethyl 5-(4-amino-3-bromothieno[3,2-c]pyridin-7-yl)-l-methyl-lH-pyrazole-3- carboxylate (150 mg, 0.39 mmol) was dissolved in dioxane (1.5 mL) and water (0.3 mL) under nitrogen, 1-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one (101.8 mg, 0.43 mmol), K3PO4(208.8 mg, 0.98 mmol) and Pd(dtbpf)Cl2(51.2 mg, 0.08 mmol) were added, stirred at 100 °C for 3 h under nitrogen. The reaction was cooled to room temperature, water (12 mL) was added, the organic phase was extracted with ethyl acetate (7.5 mL*3 times), combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1: 1) to give ethyl 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thieno[3,2- c]pyridin-7-yl)-lH-pyrazole-3-carboxylate (57 mg, yield: 36.6%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 410.1

[0712] Ethyl 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thieno[3,2-c]pyridin-7- yl)-lH-pyrazole-3-carboxylate (57 mg, 0.14 mmol) was dissolved in a mixture of water (0.4 mL) and THF (0.4 mL) under nitrogen, lithium hydroxide monohydrate (10.4 mg, 0.43 mmol) was added, stirred at room temperature for 2 h under nitrogen. The reaction was concentrated, the crude product was purified by Flash (C18 column chromatography, 5%-45% acetonitrile / water; gradient 10 min, UV 254 nm), and then lyophilized to give 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thieno[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (36 mg, yield: 65.5%, white solid). LCMS: (ESI, m / z): [M+H] + = 382.1

[0713] Under nitrogen, 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thieno[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (36 mg, 0.09 mmol) was dissolved in DMF (0.8 mL), and 3-((4-([l,4'-bipiperidin]-4-ylamino)-3-fluorophenyl)amino)piperidine- 2,6-dione (40 mg, 0.1 mmol), EDCI (27.2 mg, 0.14 mmol), DIEA (36.5 mg, 0.28 mmol), and HOBT (19.1 mg, 0.14 mmol) were added. The reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was purified by flash (C18 column chromatography, 0% to 40% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-((4-(((l'-(5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thieno[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carbonyl)-[l,4'-bipiperidin]-4-yl)amino)-3- fluorophenyl)amino)piperidine-2,6-dione (25 mg, yield: 34.5%, white solid). LCMS: (ESI, m / z): [M+H] + = 767.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.01 (s, 0.3H, formyl hydrogen), 8.01 (s, 1H), 7.85 - 8.82 (m, 1H), 7.71 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.31 (dt, J = 27.0, 7.2 Hz, 1H), 6.79 (s, 1H), 6.62 (t, J = 9.3 Hz, 1H), 6.50 (d, J = 14.2 Hz, 1H), 6.44 (s, 1H), 6.38 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 6.8 Hz, 1H), 6.09 (s, 2H), 5.43 (d, J = 6.8 Hz, 1H), 4.79 (d, J = 12.2 Hz, 1H), 4.57 (d, J = 9.8 Hz, 1H), 4.16 (s, 1H), 3.83 (s, 3H), 3.49 (s, 3H), 3.13 (s, 2H), 2.97 (d, J = 10.3 Hz, 2H), 2.77 - 2.67 (m, 3H), 2.63 - 2.54 (m, 1H), 2.43 (s, 2H), 2.14 - 2.04 (m, 1H), 1.95 - 1.79 (m, 4H), 1.49 - 1.40 (m, 4H).

[0714] Example 6

[0715] Ethyl 5-(4-amino-3-bromothieno[3,2-c]pyridin-7-yl)-l-methyl-lH-pyrazole-3- carboxylate (150 mg, 0.39 mmol) was dissolved in dioxane (1.5 mL) and water (0.3 mL) under nitrogen, 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5- a]pyridine (106.1 mg, 0.43 mmol), K3PO4 (208.8 mg, 0.98 mmol) and Pd(dtbpf)Cl2 (51.2 mg, 0.08 mmol) were added, stirred at 100 °C for 3 hours under nitrogen. The reaction was cooled to room temperature, water (12 mL) was added, extracted with ethyl acetate (7.5 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1: 1) to give ethyl 5-(3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-aminothieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylate (52 mg, yield: 31.5%, yellow solid). LCMS: (ESI, m / z): [M+H] = 420.1 +

[0716] Ethyl 5-(3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-aminothieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylate (52 mg, 0.12 mmol) was dissolved in a mixture of water (0.4 mL) and THF (0.4 mL) under nitrogen, lithium hydroxide monohydrate (8.9 mg, 0.37 mmol) was added, stirred at room temperature for 2 hours under nitrogen. The reaction was concentrated, the crude product was purified by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-aminothieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylic acid (31 mg, yield: 63.9%, white solid). LCMS: (ESI, m / z): [M+H] = 392.1 +

[0717] ​​Under nitrogen, 5-(3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-aminothieno[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (36 mg, 0.09 mmol) was dissolved in DMF (0.8 mL), and 3-((4-([l,4'-bipiperidin]-4-ylamino)-3- fluorophenyl)amino)piperidine-2,6-dione (39 mg, 0.1 mmol), EDCI (26.5 mg, 0.14 mmol), DIEA (35.6 mg, 0.28 mmol), and HOBT (18.6 mg, 0.14 mmol) were added. The reaction was stirred at room temperature under nitrogen for 2 h. The reaction was purified directly by flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-((4-(((l'-(5-(3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-aminothieno[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carbonyl)-[l,4'-bipiperidin]-4-yl)amino)-3- fluorophenyl)amino)piperidine-2,6-dione (25 mg, 35% yield, white solid). LCMS: (ESI, m / z): [M+H] = 777.3 + = 777.3

[0718] 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.03 (d, J = 6.9 Hz, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.27 (d, J = 6.9 Hz, 1H), 6.80 (s, 1H), 6.61 (t, J = 9.4 Hz, 1H), 6.50 (d, J = 14.2 Hz, 1H), 6.38 (d, J = 8.5 Hz, 1H), 6.04 (s, 2H), 5.41 (d, J = 7.2 Hz, 1H), 4.76 (d, J = 12.9 Hz, 1H), 4.55 (d, J = 13.1 Hz, 1H), 4.16 (s, 1H), 3.85 (s, 3H), 3.13 - 3.06 (m, 3H), 2.86 (d, J = 10.2 Hz, 2H), 2.75 - 2.67 (m, 2H), 2.58 (s, 2H), 2.27 (t, J = 10.4 Hz, 2H), 2.15 - 2.03 (m, 1H), 1.87 - 1.79 (m, 4H), 1.45 - 1.32 (m, 4H).

[0719] Example 7

[0720] Dissolve 26-dioxopiperidinyl isoindolinone (2 g, 7.24 mmol) in NMP (20 mL) under nitrogen protection, add tert-butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 7.97 mmol) and DIEA (2.8 g, 21.72 mmol), stir for 5 hours at 120 °C under nitrogen protection. Cool to room temperature after reaction is completed, add water (200 mL), extract with ethyl acetate (100 mL*3 times), combine the organic phase, dry over anhydrous sodium sulfate, concentrate. Purify the crude product using column chromatography (petroleum ether = 100% - MeOH:DCM = 1:20) to obtain tert-butyl 2-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.2 g, yield: 86.5%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 511.2

[0721] Dissolve tert-butyl 2-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.2 g, 6.27 mmol) in DCM (32 mL) under nitrogen protection, add TFA (8 mL), stir for 3 hours at room temperature under nitrogen protection. Concentrate and dry in vacuum after the reaction solution to obtain 4-(((7-azaspiro[3.5]nonan-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.55 g, yield: 99.1%, green solid). LCMS: (ESI, m / z): [M+H] + = 411.2

[0722] Under nitrogen, 4-(((7-azaspiro[3.5]nonan-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg, 0.12 mmol) was dissolved in DMF (0.8 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (52.1 mg, 0.13 mmol), EDCI (35.1 mg, 0.18 mmol), DIEA (47.1 mg, 0.37 mmol), and HOBT (24.7 mg, 0.18 mmol) were added. The reaction was stirred at 50 °C under nitrogen for 2 h. The reaction was cooled to room temperature and purified directly by flash purification (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 4-(((7-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-7-azaspiro[3.5]nonan-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.3 mg, yield: 21.9%, white solid). LCMS: (ESI, m / z): [M+H] + = 800.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.54 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.66-7.57 (m, 2H), 7.52-7.21 (br, 2H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.93 (s, 1H), 6.53 (s, 1H), 5.06 (dd, J = 12.8, 5.3 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 1H), 3.80 (s, 1H), 3.60-3.53 (m, 2H), 3.40 (s, 2H), 2.94-2.83 (m, 1H), 2.72-2.52 (m, 3H), 2.05-2.04 (m, 1H), 2.02-1.94 (m, 2H), 1.65-1.60 (m, 4H), 1.58-1.55 (m, 2H).

[0723] Example 8

[0724] Under nitrogen atmosphere, 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione (1.2 g, 3.71 mmol) was dissolved in dioxane (12 mL), and tert-butyl 4-amino-[l,4'-bipiperidine]-l'-carboxylate (2.1 g, 7.43 mmol), Cs2CO3(3 g, 9.29 mmol), XPhos G3 Pd (1.3 g, 1.49 mmol) and Pd2(dba)3(680.2 mg, 0.74 mmol) were added. The reaction mixture was stirred at 100 °C for 5 h under nitrogen atmosphere. The reaction was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (60 mL*3 times). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (MeOH:DCM = 1:20) to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)amino)-[l,4'-bipiperidine]-l'-carboxylate (240 mg, yield: 12.3%, green solid). LCMS: (ESI, m / z): [M+H] + = 526.3

[0725] Under nitrogen atmosphere, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)amino)-[l,4'-bipiperidine]-l'-carboxylate (240 mg, 0.46 mmol) was dissolved in DCM (2.4 mL), and TFA (0.6 mL) was added. The reaction mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The reaction mixture was concentrated and purified by flash purification (C18 column chromatography, 0% - 30% acetonitrile / water; gradient 10 min, UV 220 nm), and lyophilized to give 3-(5-([l,4'-bipiperidine]-4-ylamino)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, yield: 77.2%, green solid). LCMS: (ESI, m / z): [M+H] + = 426.2

[0726] Under nitrogen, 3-(5-([1,4'-bipiperidin]-4-ylamino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (0.8 mL), and 5-(4-amino-3- (benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (50.3 mg, 0.12 mmol), EDCI (33.8 mg, 0.18 mmol), DIEA (45.5 mg, 0.35 mmol), and HOBT (23.8 mg, 0.18 mmol) were added. The reaction was stirred at 50 °C under nitrogen for 2 hours. The reaction was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Flash purification (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) gave 4-(((7-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carbonyl)-7-azaspiro[3.5]nonan-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (17.9 mg, 19% yield, white solid). LCMS: (ESI, m / z): [M+H] + = 815.3

[0727] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.54 (s, 1H), 9.50 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.63 (dd, J = 8.2, 1.7 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 6.78 - 6.69 (m, 2H), 6.50 (s, 1H), 5.04 (d, J = 5.1 Hz, 1H), 5.02 (d, J = 5.1 Hz, 1H), 4.71 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 16.7 Hz, 1H), 4.16 (d, J = 16.8 Hz, 1H), 3.91 (s, 3H), 3.64 - 5.52 (m, 4H), 3.39 (s, 1H), 3.33 (s, 1H), 3.20 - 3.17 (m, 2H), 2.95 - 2.83 (m, 2H), 2.64 - 2.55 (m, 1H), 2.42 - 2.29 (m, 1H), 2.21 - 2.15 (m, 3H), 2.10 - 1.90 (m, 2H), 1.71 - 1.65 (m, 3H).

[0728] Example 9

[0729] Benzyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate (400 mg, 1.38 mmol) was dissolved in NMP (4 mL) under nitrogen protection, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (419.9 mg, 1.52 mmol) and DIEA (535.9 mg, 4.15 mmol) were added, and stirred at 100 °C under nitrogen protection for 5 hours. After the reaction solution was cooled to room temperature, water (20 mL) was added dropwise, stirred for 5 min, and then filtered. The filter cake was dried under vacuum to obtain benzyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-ylmethyl)piperazine-1-carboxylate (476 mg, yield: 63.1%, green solid). LCMS: (ESI, m / z): [M+H] + = 546.2

[0730] Benzyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidin-3- ylmethyl)piperazin-l-ylcarboxylate (476 mg, 0.87 mmol) was dissolved in MeOH (12 mL) under nitrogen protection, 10% Pd / C (618.8 mg, 55% water) was added, and the reaction was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction was filtered, the filter cake was washed with MeOH (12 mL), and the filtrate was concentrated. The crude product was purified by flash purification (C18 column chromatography, 5%-45% acetonitrile / water; gradient 10 minutes, UV 220 nm) to give 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-l-ylmethyl)azetidin-l-yl)isoindoline-l,3-dione (160 mg, yield: 44.7%, yellow solid). LCMS: (ESI, m / z): [M+H] = 412.2 +

[0731] Benzyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidin-3- ylmethyl)piperazin-l-ylcarboxylate (476 mg, 0.87 mmol) was dissolved in MeOH (12 mL) under nitrogen protection, 10% Pd / C (618.8 mg, 55% water) was added, and the reaction was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction was filtered, the filter cake was washed with MeOH (12 mL), and the filtrate was concentrated. The crude product was purified by flash purification (C18 column chromatography, 5%-45% acetonitrile / water; gradient 10 minutes, UV 220 nm) to give 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-l-ylmethyl)azetidin-l-yl)isoindoline-l,3-dione (160 mg, yield: 44.7%, yellow solid). LCMS: (ESI, m / z): [M+H] = 412.2 +

[0732] 1 ​​H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.52 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.66 - 7.59 (m, 2H), 6.84 (s, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 8.4, 2.1 Hz, 1H), 5.72 (s, 2H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.15 (t, J = 8.2 Hz, 2H), 4.03 (d, J = 8.1 Hz, 2H), 3.87 (s, 3H), 3.72 (dd, J = 8.5, 5.4 Hz, 2H), 3.66 (s, 2H), 3.04 (dd, J = 13.4, 6.8 Hz, 1H), 2.88 (ddd, J = 17.2, 14.1, 5.5 Hz, 1H), 2.67 (d, J = 7.4 Hz, 2H), 2.62 - 2.53 (m, 2H), 2.48 (d, J = 5.2 Hz, 4H), 2.04 - 1.97 (m, 1H).

[0733] Example 10

[0734] tert-Butyl-4-amino-[1,4'-bipiperidine]-1'-carboxylate (10 g, 35.29 mmol) was dissolved in NMP (100 mL) under nitrogen protection, 1,2-difluoro-4-nitrobenzene (6.2 g, 38.81 mmol) and DIEA (13.7 g, 105.86 mmol) were added, and stirred at 100 °C under nitrogen protection for 5 hours. After the reaction was completed, it was cooled to room temperature, water (1000 mL) was added, and ethyl acetate (500 mL*3 times) was used for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%-MeOH:DCM = 1:20) to obtain tert-butyl-4-((2-fluoro-4-nitrophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate (10 g, yield: 67.1%, white oily substance). LCMS: (ESI, m / z): [M+H] + = 423.2

[0735] Tert-butyl-4-((2-fluoro-4-nitrophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate (10 g, 23.67 mmol) was dissolved in MeOH (250 mL) under nitrogen protection, 10% Pd / C (1.3 g, 55% water) was added, stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction solution was filtered, the filter cake was washed with MeOH (250 mL), the filtrate was concentrated and dried in vacuum to obtain tert-butyl-4-((4-amino-2-fluorophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate (9.24 g, yield: 99.5%, yellow oil). LCMS: (ESI, m / z): [M+H] = 393.3 + = 393.3

[0736] Tert-butyl-4-((4-amino-2-fluorophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate (6.5 g, 16.56 mmol) was dissolved in DMF (65 mL) under nitrogen protection, 3-bromopiperidine-2,6-dione (3.5 g, 18.22 mmol) and DIEA (6.4 g, 49.68 mmol) were added, stirred at 100°C for 5 hours under nitrogen atmosphere. The reaction was cooled to room temperature after completion, water (700 mL) was added, extracted with ethyl acetate (300 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%-MeOH:DCM = 1:9) to obtain tert-butyl-4-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate (3.5 g, yield: 42%, purple solid). LCMS: (ESI, m / z): [M+H] = 504.3 + = 504.3

[0737] Tert-butyl-4-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate (3.5 g, 6.95 mmol) was dissolved in DCM (35 mL) under nitrogen protection, TFA (8.8 mL) was added, stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was concentrated and purified by Flash (C18 column chromatography, 0%-30% acetonitrile / water; gradient 10 minutes, UV 254 nm), and then freeze-dried to obtain 3-((4-([1,4'-bipiperidine]-4-ylamino)-3-fluorophenyl)amino)piperidine-2,6-dione (2 g, yield: 71.3%, white solid). LCMS: (ESI, m / z): [M+H] = 404.2 + = 404.2

[0738] Under nitrogen, 3-((4-([1,4'-bipiperidin]-4-ylamino)-3-fluorophenyl)amino)piperidine- 2,6-dione (110 mg, 0.27 mmol) was dissolved in DMF (1.1 mL), and 5-(4-amino-3- (benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (116.6 mg, 0.29 mmol), EDCI (78.5 mg, 0.41 mmol), DIEA (105.5 mg, 0.82 mmol), and HOBT (55.2 mg, 0.41 mmol) were added. The reaction was stirred at 50 °C under nitrogen for 2 hours. The reaction was cooled to room temperature and purified by flash chromatography (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-((4-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-fluorophenyl)amino)piperidine- 2,6-dione (33 mg, yield: 15.3%, purple solid). LCMS: (ESI, m / z): [M+H] + = 792.3

[0739] 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.54 (s, 1H), 9.47 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.64 (dd, J = 8.2, 1.7 Hz, 1H), 7.14 (s, 2H), 6.98 (d, J = 3.0 Hz, 1H), 6.81 (t, J = 8.8 Hz, 1H), 6.59 (dd, J = 14.0, 2.4 Hz, 1H), 6.51 - 6.42 (m, 1H), 4.98 (d, J = 13.2 Hz, 1H), 4.69 (d, J = 12.7 Hz, 1H), 4.25 (dd, J = 11.4, 4.7 Hz, 1H), 3.91 (s, 3H), 3.54 (d, J = 11.2 Hz, 2H), 3.45 - 3.5 (m, 2H), 3.30 - 3.20 (m, 1H), 3.19 - 3.06 (m, 2H), 2.81 - 2.66 (m, 2H), 2.61 - 2.56 (m, 1H), 2.13 - 2.09 (m, 4H), 2.00 - 1.80 (m, 2H), 1.78 - 1.50 (m, 4H).

[0740] Example 11

[0741] Under nitrogen protection, 1-bromo-2-fluoro-4-nitrobenzene (2 g, 9.09 mmol) was dissolved in dioxane (20 mL), and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1- carboxylate (5.2 g, 18.18 mmol), Cs2CO3(7.4 g, 22.73 mmol), XPhos G3Pd (3.1 g, 3.64 mmol) and Pd2(dba)3(1.7 g, 1.82 mmol) were added. The reaction was stirred at 100 °C for 3 hours under nitrogen protection. The reaction was cooled to room temperature, water (160 mL) was added, and the organic phase was extracted with ethyl acetate (100 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain tert-butyl 4-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1- carboxylate (1.9 g, yield: 49.5%, gray solid). LCMS: (ESI, m / z): [M+H] + = 423.2

[0742] Under nitrogen protection, tert-butyl 4-((1-(2-fluoro-4-nitrophenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (1.9 g, 4.5 mmol) was dissolved in MeOH (50 mL), and 10% Pd / C (2.47 g, 55% water) was added. The reaction was stirred at room temperature for 2 hours under hydrogen protection. The reaction was filtered, the filter cake was washed with MeOH (50 mL), the filtrate was concentrated and dried in vacuum to obtain tert-butyl 4-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1- carboxylate (1.7 g, yield: 96.3%, white solid). LCMS: (ESI, m / z): [M+H] + = 393.3

[0743] Tert-butyl 4-((l-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-l- carboxylate (1.7 g, 4.33 mmol) was dissolved in NMP (17 mL) under nitrogen, 3- bromopiperidine-2,6-dione (914.8 mg, 4.76 mmol) and DIEA (1.7 g, 12.99 mmol) were added, and the reaction was stirred at 100 °C under nitrogen for 5 h. The reaction was cooled to room temperature, water (170 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over sodium sulfate, and concentrated. Flash purification (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 min, UV 254 nm) gave tert-butyl 4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (320 mg, 14.7% yield, purple solid). LCMS: (ESI, m / z): [M+H] + = 504.3

[0744] Tert-butyl 4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (320 mg, 0.64 mmol) was dissolved in DCM (3.2 mL) under nitrogen, TFA (0.8 mL) was added, and the reaction was stirred at room temperature under nitrogen for 3 h. The reaction was concentrated and dried in vacuo to give 3-((3-fluoro-4-(4-(piperazin-l-ylmethyl)piperidin-l-yl)phenyl)amino)piperidine- 2,6-dione (220 mg, 85.8% yield, white solid). LCMS: (ESI, m / z): [M+H] + = 404.3

[0745] Under nitrogen, 3-((3-fluoro-4-(4-(piperazin-l-ylmethyl)piperidin-l- yl)phenyl)amino)piperidine-2,6-dione (40 mg, 0.1 mmol) was dissolved in DMF (0.8 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylic acid (42.4 mg, 0.1 mmol), EDCI (28.6 mg, 0.15 mmol), DIEA (38.4 mg, 0.3 mmol), and HOBT (20.1 mg, 0.15 mmol) were added. The reaction was stirred at 50 °C for 2 h under nitrogen. The reaction was cooled to room temperature and purified by flash purification (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-((4-(4-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carbonyl)piperazin-l-yl)methyl)piperidin-l-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (41 mg, 52.2% yield, purple solid). LCMS: (ESI, m / z): [M+H] = 793.3. + 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.74 (s, 1H), 9.54 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.64 (dd, J = 8.3, 1.7 Hz, 1H), 7.24 (s, 2H), 7.06 (s, 1H), 6.97 (s, 1H), 6.56 (d, J = 13.5 Hz, 1H), 6.47 (d, J = 7.7 Hz, 1H), 5.13 (s, 1H), 4.60 (s, 1H), 4.30 (dd, J = 11.6, 4.8 Hz, 1H), 3.93 (s, 3H), 3.67 (br, 3H), 3.38 - 3.22 (m, 3H), 3.21 - 3.05 (m, 4H), 2.83 - 3.65 (m, 3H), 2.63 - 2.55 (m, 1H), 2.12 - 1.95 (m, 2H), 1.94 - 1.87 (m, 3H), 1.53 - 1.41 (m, 2H).

[0746] Example 12

[0747] ​Under nitrogen protection, 7-bromoisoquinolin-1-ol (500 mg, 2.23 mmol) was dissolved in dioxane (5 mL), pinacol diborane (1.1 g, 4.46 mmol), potassium acetate (547.4 mg, 5.58 mmol) and Pd(dppf)Cl2(326.2 mg, 0.45 mmol) were added, and stirred at 80 °C for 4 hours under nitrogen protection. The reaction was completed and cooled to room temperature, water (40 mL) was added, and the organic phase was extracted with ethyl acetate (25 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-ol (350 mg, yield: 57.9%, yellow oil). LCMS: (ESI, m / z): [M+H] + = 272.1

[0748] Under nitrogen protection, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-ol (170 mg, 0.63 mmol) was dissolved in dioxane (1.7 mL), ethyl 5-(4-amino-3-bromothieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (262.9 mg, 0.69 mmol), K3PO4(332.8 mg, 1.57 mmol) and Pd(dppf)Cl2(91.7 mg, 0.13 mmol) were added, and stirred at 100 °C for 3 hours under nitrogen protection. The reaction was completed and cooled to room temperature, water (14 mL) was added, and the organic phase was extracted with ethyl acetate (8.5 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain ethyl 5-(4-amino-3-(1-hydroxyisoquinolin-7-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (180 mg, yield: 64.4%, yellow solid). LCMS: (ESI, m / z): [M+H] + = 446.1

[0749] Ethyl 5-(4-amino-3-(l-hydroxyisoquinolin-7-yl)thieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylate (150 mg, 0.34 mmol) was dissolved in a mixture of water (0.8 mL) and THF (0.8 mL) under nitrogen, and lithium hydroxide monohydrate (24.2 mg, 1.01 mmol) was added. The reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was purified directly by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(4-amino-3-(l-hydroxyisoquinolin-7-yl)thieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylic acid (70 mg, yield: 49.8%, yellow solid). LCMS: (ESI, m / z): [M+H] = 418.1. + = 418.1.

[0750] Ethyl 5-(4-amino-3-(l-hydroxyisoquinolin-7-yl)thieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylate (150 mg, 0.34 mmol) was dissolved in a mixture of water (0.8 mL) and THF (0.8 mL) under nitrogen, and lithium hydroxide monohydrate (24.2 mg, 1.01 mmol) was added. The reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was purified directly by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(4-amino-3-(l-hydroxyisoquinolin-7-yl)thieno[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylic acid (70 mg, yield: 49.8%, yellow solid). LCMS: (ESI, m / z): [M+H] = 418.1. + = 418.1. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (d, J = 5.8 Hz, 1H), 10.78 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.82 (s, 2H), 7.68 (s, 1H), 7.27 (t, J = 6.4 Hz, 1H), 6.83 (s, 1H), 6.69 - 6.58 (m, 2H), 6.51 (d, J = 14.2 Hz, 1H), 6.38 (d, J = 6.1 Hz, 1H), 5.73 (s, 2H), 5.43 (s, 1H), 4.80 (d, J = 13.0 Hz, 1H), 4.58 (d, J = 12.6 Hz, 1H), 4.17 (s, 1H), 3.86 (s, 3H), 3.13 (d, J = 11.6 Hz, 2H), 2.95 (d, J = 10.8 Hz, 2H), 2.80 - 2.66 (m, 3H), 2.57 (d, J = 17.9 Hz, 1H), 2.39 (t, J = 21.4 Hz, 2H), 2.13 - 2.05 (m, 1H), 2.01 - 1.81 (m, 5H), 1.50 - 1.37 (m, 4H).

[0751] Example 13

[0752] (Example 8 intermediate) 3-(5-([1,4'-bipiperidinyl]-4-ylamino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (40 mg, 0.09 mmol) was dissolved in DMF (0.8 mL) under nitrogen and 5-(4-amino-3-(benzo[d]thiazol-6-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (38.6 mg, 0.1 mmol), EDCI (27.1 mg, 0.14 mmol), DIEA (36.4 mg, 0.28 mmol), and HOBT (19 mg, 0.14 mmol) were added. The reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was purified by flash purification (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-(5-((1'-(5-(4-amino-3-(benzo[d]thiazol-6-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (10.6 mg, 14.1% yield, white solid). LCMS: (ESI, m / z): [M+H] = 799.3. + = 799.3. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.67 (dd, J = 8.3, 1.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 - 6.66 (m, 2H), 6.26 (d, J = 7.6 Hz, 1H), 5.96 (s, 2H), 5.02 (d, J = 13.3 Hz, 1H), 4.77 (d, J = 12.9 Hz, 1H), 4.56 (d, J = 12.6 Hz, 1H), 4.26 (d, J = 16.8 Hz, 1H), 4.13 (d, J = 16.6 Hz, 1H), 3.88 (s, 3H), 3.29 (s, 2H), 3.18 - 3.10 (m, 1H), 2.93-2.86 (m, 3H), 2.75 (t, J = 12.1 Hz, 1H), 2.69 - 2.54 (m, 2H), 2.42 - 2.25 (m, 3H), 1.99 - 1.84 (m, 4H), 1.53 - 1.30 (m, 4H).

[0753] Example 14

[0754] Under nitrogen atmosphere, tert-butyl 3-(6-((tert-butoxycarbonyl)amino)-4- cyanochroman-4-yl)propanoate (1.9 g, 4.72 mmol) was dissolved in a mixture of DMSO (9.5 mL) and hydrogen peroxide (0.5 mL), sodium hydroxide (566.5 mg, 14.16 mmol) was added, and stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was directly purified by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm), and 3-(6-((tert-butoxycarbonyl)amino)-4- aminocarbonylchroman-4-yl)propanoic acid (1.2 g, yield: 69.8%, white solid) was obtained after lyophilization. LCMS: (ESI, m / z): [M+H] + = 365.2

[0755] Under nitrogen atmosphere, 3-(6-((tert-butoxycarbonyl)amino)-4- aminocarbonylchromane-4-yl)propanoic acid (1.2 g, 3.29 mmol) was dissolved in DMF (12 mL), 3-((4-([1,4'-bipiperidin]-4-ylamino)-3-fluorophenyl)amino)piperidine- 2,6-dione (1395.2 mg, 3.46 mmol), EDCI (948.4 mg, 4.94 mmol), DIEA (1274.4 mg, 9.88 mmol) and HOBT (666.8 mg, 4.94 mmol) were added, and the mixture was stirred at 50 °C for 5 hours under nitrogen atmosphere. The reaction was cooled to room temperature, water (120 mL) was added, and the mixture was extracted with ethyl acetate (60 mL*3 times). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. Flash purification (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) gave tert-butyl (2',6'-dioxospiro[chromane-4,3'-piperidin]-6-yl)carbamate (980 mg, yield: 85.9%, white solid). LCMS: (ESI, m / z): [M+H] + = 347.2

[0756] Under nitrogen atmosphere, tert-butyl (2',6'-dioxospiro[chromane-4,3'-piperidin]-6- yl)carbamate (980 mg, 2.83 mmol) was dissolved in HCl / dioxane solution (9.8 mL, 7M), and the mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The reaction was concentrated and dried in vacuum to give 6-aminospiro[chromane-4,3'- piperidin]-2',6'-dione (680 mg, yield: 97.6%, white solid). LCMS: (ESI, m / z): [M+H] + = 247.1

[0757] Under nitrogen atmosphere, 6-amino spiro [chromane-4, 3'-piperidin]-2', 6'-dione (56 mg, 0.23 mmol) was dissolved in DMF (0.8 mL), 7-((tert-butoxy carbonyl) amino) heptanoic acid (58.6 mg, 0.24 mmol), EDCI (65.5 mg, 0.34 mmol), DIEA (88 mg, 0.68 mmol) and HOBT (46 mg, 0.34 mmol) were added, stirred at room temperature for 4 hours under nitrogen atmosphere. The reaction was completed and cooled to room temperature, added water (6 mL), extracted with ethyl acetate (4 mL*3 times), combined organic phase, dried over anhydrous sodium sulfate, concentrated. Flash purification (C18 column chromatography, 20%-55% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give tert-butyl (7-((2', 6'-dioxospiro [chromane-4, 3'-piperidin]-6-yl) amino)-7-oxoheptyl) carbamate (79 mg, yield: 73.4%, white solid). LCMS: (ESI, m / z): [M+H] + = 474.3

[0758] Under nitrogen atmosphere, tert-butyl (7-((2', 6'-dioxospiro [chromane-4, 3'-piperidin]-6-yl) amino)-7-oxoheptyl) carbamate (79 mg, 0.17 mmol) was dissolved in HCl / dioxane solution (0.8 mL, 7M), stirred at room temperature for 5 hours under nitrogen atmosphere. After the reaction was concentrated and dried in vacuum, 7-amino-N-(2', 6'-dioxospiro [chromane-4, 3'-piperidin]-6-yl) heptanamide (30 mg, yield: 48.2%, white solid) was obtained. LCMS: (ESI, m / z): [M+H] + = 374.3

[0759] Under nitrogen protection, 7-amino-N-(2',6'-dioxospiro[4,3'-piperidin]-6-yl)heptanamide (30 mg, 0.08 mmol) was dissolved in DMF (0.8 mL), and 5-(4-amino-3-(benzo[d]thiazo-6-yl)furano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (33 mg, 0.08 mmol), EDCI (23.1 mg, 0.12 mmol), DIEA (31.1 mg, 0.24 mmol), and HOBT (16.3 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 4 hours under nitrogen protection. The reaction solution was purified by Flash chromatography (C18 column chromatography, 0%–40% acetonitrile / water; gradient 10 min, UV 254 nm) to give 5-(4-amino-3-(benzo[d]thiazo-6-yl)furano[3,2-c]pyridin-7-yl)-N-(7-((2',6'-dioxospiro[seromono-4,3'-piperidin]-6-yl)amino)-7-oxohepyl)-1-methyl-1H-pyrazole-3-carboxamide (3.8 mg, yield: 6.3%, white solid). LCMS: (ESI, m / z): [M+H] + =747.3.1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.71(s,1H),9.50(s,1H),8.35(d,J=8.3Hz,1H),8.26(d,J=1.6Hz,1 H),8.18-8.16(m,2H),8.04(s,1H),7.67(dd,J=8.3,1.7Hz,1H),7.36-7.34(m,2H),6.83(s,1H),6.73(d,J= 9.5Hz,1H),5.96(s,2H),4.13(t,J=5.4Hz,2H),3.88(s,3H),3.26-3.22(m,2H),2.74(td,J=11.5,11.1,5.6 Hz,1H),2.55(t,J=4.9Hz,1H),2.37-2.20(m,4H),2.14-1.97(m,2H),1.60-1.45(m,4H),1.35-1.23(m,4H). LC-MS:(ESI,m / z):[M+H] + =234.1

[0760] Example 15: Preparation of (R)-4-((1-((benzyloxy)carbonyl)pyrrolidine-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0761] To a solution of (S)-3-formylpyrrolidine-1-carboxylic acid benzyl ester (4.20 g, 18.01 mmol) in methanol (30 mL) was added tert-butyl piperazine-1-carboxylate (4.02 g, 21.61 mmol) under nitrogen protection, stirred at room temperature for 10 min, NaBH(OAc)3(7.63 g, 36.03 mmol) was added portionwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was complete, the reaction solution was slowly added to a cold saturated ammonium chloride solution (100 mL) to quench, extracted with ethyl acetate (100 mL*3), the combined extracts were washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (petroleum ether / ethyl acetate 0-20%) to give the target product (R)-tert-butyl 4-((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)piperazine-1-carboxylate (6.02 g, yield: 85.34%, white solid). LC-MS: (ESI, m / z): [M+H] = 404.2 +

[0762] Step four: preparation of (S)-tert-butyl 4-(pyrrolidin-3-ylmethyl)piperazine-1-carboxylate

[0763] To a solution of (R)-tert-butyl 4-((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)piperazine-1-carboxylate (2.00 g, 4.96 mmol) in methanol (10 mL) was added 10% palladium on carbon (0.2 g, 55% water content), the reaction solution was stirred at 50 °C for 2 hours under hydrogen protection. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to give the target product (S)-tert-butyl 4-(pyrrolidin-3-ylmethyl)piperazine-1-carboxylate (0.8 g, yield: 59.92%, off-white solid). LC-MS: (ESI, m / z): [M+H] = 270.2 +

[0764] Step five: preparation of tert-butyl 4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazine-1-carboxylate

[0765] ​​To a solution of (S)-tert-butyl 4-(pyrrolidin-3-ylmethyl)piperazine-l-carboxylate (0.40 g, 1.48 mmol) in NMP (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoro- isoindole-l,3-dione (0.49 g, 1.78 mmol), DIEA (0.58 g, 4.45 mmol) under nitrogen protection. The reaction mixture was stirred at 110 °C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL*3), the combined organic phase was washed with water (30 mL), saturated brine (30 mL), dried over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to give the target product tert-butyl 4-(((3S)-l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)pyrrolidin-3- yl)methyl)piperazine-l-carboxylate (0.29 g, yield: 37.16%, brown yellow solid). LC-MS: (ESI, m / z): [M+H] = 526.2 +

[0766] Step six: Preparation of tert-butyl 5-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanoate

[0767] To a solution of tert-butyl 4-(((3S)-l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)pyrrolidin-3-yl)methyl)piperazine-l-carboxylate (290 mg, 0.55 mmol) in DCM (5 mL) was added TFA (1.08 g, 11.03 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative reversed phase C18 column (0-25% ACN / H20 (0.3% FA)) to give the target product tert-butyl 5-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanoate (200 mg, yield: 85.19%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 426.5 +

[0768] ​​Step seven: Preparation of compound Example 15: 5-((S)-3-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0769] To a solution of tert-butyl 5-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanoate (100 mg, 0.24 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (115.00 mg, 0.28 mmol), EDCI (67.58 mg, 0.35 mmol), HOBT (47.64 mg, 0.35 mmol) and DIEA (121.50 mg, 0.94 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 hours. The reaction was directly purified by prep-HPLC (0-25% ACN / H2O (0.3% FA)) to give 5-((S)-3-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (32 mg, yield: 16.17%, yellow solid). LC-MS: (ESI, m / z): [M+H]+= 815.3.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.98 (s, 1H), 9.54 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.4, 1.6 Hz, 1H), 7.05 (s, 1H), 7.02 - 6.92 (br, 2H) 6.86 (dd, J = 8.4, 2.0 Hz, 1H), 5.17 (s, 1H), 5.07 (dd, J = 12.8, 5.6 Hz, 1H), 4.64 (s, 1H), 3.93 (s, 3H), 3.82 - 3.73 (m, 4H), 3.71 - 3.55 (m, 2H), 3.47 - 3.22 (m, 6H), 2.96 - 2.83 (m, 2H), 2.64 - 2.54 (m, 2H), 2.29 (s, 1H), 2.06 - 1.98 (m, 1H), 1.89 - 1.86 (m, 1H)

[0770] Example 16

[0771] 3-(6-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminothieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)piperidine-2,6-dione

[0772] Step one: Preparation of methyl 6-chloro-4-methylnicotinate

[0773] Under nitrogen protection, a solution of 6-chloro-4-methylpyridine-3-carboxylic acid (5.00 g, 29.14 mmol) in THF (60 mL) was cooled to 0 °C, and SOCl2(4.16 g, 34.97 mmol) was added dropwise. After addition, the mixture was stirred for 1 h. Then the reaction mixture was added to methanol (3 mL) and the reaction was continued for 2 h. After the reaction was completed, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with water (100 mL), saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the target product methyl 6-chloro-4-methylnicotinate (5.20 g, yield: 96.14%, brown-yellow solid). LC-MS: (ESI, m / z): [M+H] + = 186.6

[0774] Step two: Preparation of methyl 4-(bromomethyl)-6-chloronicotinate

[0775] To a solution of methyl 6-chloro-4-methylnicotinate (2.00 g, 10.78 mmol) in THF (35 mL) was added AIBN (0.35 g, 2.16 mmol), and the mixture was purged with nitrogen for 3 times. Then the mixture was heated to 80 °C, and NBS (2.3 g, 12.93 mmol) was added portionwise. After addition, the mixture was stirred at 80 °C for 4 h under nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate 0-10%) to give the target product methyl 4-(bromomethyl)-6-chloronicotinate (1.20 g, yield: 42.10%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 263.9

[0776] Step three: Preparation of 3-(6-chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione

[0777] To a solution of methyl 4-(bromomethyl)-6-chloronicotinate (1.20 g, 4.54 mmol) in acetonitrile (30 mL) was added 3-amino-2,6-piperidinedione (1.16 g, 9.07 mmol) under nitrogen protection, DIEA (2.35 g, 18.15 mmol) was added. The reaction mixture was stirred at 100 °C for 4 h. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL*3), the combined extracts were washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column (DCM / CH3OH 0-20%) to obtain the target product 3-(6-chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (0.72 g, yield: 56.74%, white solid). LC-MS: (ESI, m / z): [M+H] + = 280.0

[0778] Step four: Preparation of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-[1,4’- bipiperidine]-1’-carboxylate

[0779] To a solution of (3-(6-chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (1.05 g, 3.75 mmol) in NMP (10 mL) was added tert-butyl 4-amino-[1,4’-bipiperidine]-1’-carboxylate (2.13 g, 7.51 mmol), DIEA (1.94 g, 15.02 mmol) was added, and the reaction solution was stirred at 130 °C for 2 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL*3), the combined extracts were washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to obtain the target product tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-[1,4’-bipiperidine]-1’-carboxylate (0.1 g, yield: 5.06%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 527.3

[0780] Step five: Preparation of 3-(6-([1,4'-bipiperidinyl]-4-amino)-3-oxo-1,3-dihydro- 2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione

[0781] To a solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-6-yl)amino)-[1,4'-bipiperidinyl]-1'-carboxylate (0.10 g, 0.19 mmol) in DCM (3 mL) was added TFA (0.37 g, 3.80 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to obtain the target product 3-(6-([1,4'-bipiperidinyl]-4-amino)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (20 mg, yield: 24.69%, yellow solid).

[0782] LC-MS: (ESI, m / z): [M+H] + = 426.2

[0783] Step six: Preparation of Example 16: 3-(6-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- aminothieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidinyl]-4- yl)amino)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione

[0784] To a solution of 3-(6-([1,4'-bipiperidin]-4-amino)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)piperidine-2,6-dione (20.00 mg, 0.05 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylic acid (5.72 mg, 0.07 mmol), EDCI (13.51 mg, 0.07 mmol), HOBT (9.53 mg, 0.07 mmol) and DIEA (24.31 mg, 0.19 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 hours, the reaction solution was directly prepared by reversed phase C18 column (0-25% ACN / H2O (0.3% FA)) purification to give 3-(6-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminothieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-oxo- 1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione (4.00 mg, yield: 10.16%, yellow solid).

[0785] LC-MS: (ESI, m / z): [M+H] + = 800.3

[0786] 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.03 (d, J = 6.8 Hz, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.27 (dd, J = 6.8, 1.6 Hz, 1H), 6.81 (s, 1H), 6.54 (s, 1H), 6.04 (s, 2H), 5.02 (dd, J = 13.2, 4.8 Hz, 1H), 4.77 (d, J = 12.8 Hz, 1H), 4.56 (d, J = 12.4 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 4.17 (d, J = 17.2 Hz, 1H), 3.86 (s, 3H), 3.14 (t, J = 12.4 Hz, 2H), 2.94 - 2.85 (m, 3H), 2.75 (t, J = 12.4 Hz, 1H), 2.59 - 2.51 (m, 2H), 2.37 - 2.24 (m, 4H), 1.96 - 1.87 (m, 4H), 1.45 - 1.35 (m, 4H).

[0787] Example 17: 3-(4-(4-(1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-3- fluorophenyl)amino)piperidine-2,6-dione

[0788] Step one: Preparation of benzyl 4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4- yl)methyl)piperazine-1-carboxylate

[0789] To a solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.00 g, 9.38 mmol) in DMSO (20 mL) was added DIEA (3.64 g, 28.13 mmol), benzyl piperazine-1-carboxylate (2.48 g, 11.25 mmol) under nitrogen protection. The reaction mixture was stirred at 120 °C for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*3). The combined organic extracts were washed with water (100 mL), saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate 0-10%) to give the target product benzyl 4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazine-1-carboxylate (3.80 g, yield: 93.47%, colorless transparent liquid). LC-MS: (ESI, m / z): [M+H] + = 434.3

[0790] Step two: Preparation of tert-butyl 4-hydroxy-4-(piperazin-1-ylmethyl)piperidine-1-carboxylate

[0791] To a solution of benzyl 4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazine-1-carboxylate (3.60 g, 8.30 mmol) in THF (40 mL) was added 10% palladium on carbon (0.4 g, 55% water). The reaction mixture was stirred at room temperature for 2 h under hydrogen protection. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate 0-100%) to give the target product tert-butyl 4-hydroxy-4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (2.30 g, yield: 92.51%, colorless transparent liquid). LC-MS: (ESI, m / z): [M+H] + = 300.2

[0792] Step three: Preparation of tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1- yl)methyl)-4-hydroxypiperidine-1-carboxylate

[0793] To a solution of tert-butyl 4-hydroxy-4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.30 g, 4.34 mmol) in NMP (30 mL) was added 1,2-difluoro-4-nitrobenzene (0.83 g, 5.21 mmol), DIEA (1.68 g, 13.03 mmol) under nitrogen protection. The reaction mixture was stirred at 80 °C for 4 h. After the reaction was completed, the reaction was cooled to room temperature, water (100 mL) was added to the reaction, extracted with ethyl acetate (30 mL*3), the combined extracts were washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (petroleum ether / ethyl acetate 0-100%) to give the target product (tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate (1.40 g, yield: 73.53%, colorless transparent liquid). LC-MS: (ESI, m / z): [M+H] = 439.2 +

[0794] 1 H NMR (400 MHz, DMSO-d6) d 8.01 - 7.93 (m, 2H), 7.14 (t, J = 9.2 Hz, 1H), 4.27 (s, 1H), 3.61 (d, J = 12.8 Hz, 2H), 3.27 (t, J = 4.8 Hz, 4H), 3.10 (s, 2H), 2.68 (d, J = 9.6 Hz, 4H), 2.31 (s, 2H), 1.46 (t, J = 4.6 Hz, 4H), 1.39 (s, 9H).

[0795] Step four: Preparation of tert-butyl 4-((4-(4-amino-2-fluorophenyl)piperazin-1-yl)methyl)-4- hydroxypiperidine-1-carboxylate

[0796] ​To a solution of tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)- 4-hydroxypiperidine-1-carboxylate (1.3 g, 2.96 mmol) in ethanol (50 mL) was added NH4Cl (0.63 g, 11.86 mmol), iron powder (0.83 g, 14.82 mmol), water (17 mL), the reaction was stirred at 80 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure. Added water (30 mL), extracted with ethyl acetate (30 mL*3), the combined extracts were washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to give the target product tert-butyl 4-((4-(4-amino-2-fluorophenyl)piperazin-1-yl)methyl)-4- hydroxypiperidine-1-carboxylate (1.00 g, yield: 82.57%, colorless transparent liquid).

[0797] LC-MS: (ESI, m / z): [M+H] + = 409.2

[0798] Step five: preparation of tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate

[0799] Under nitrogen protection, to a solution of tert-butyl 4-((4-(4-amino-2- fluorophenyl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate (0.90 g, 2.20 mmol) in NMP (10 mL) was added 3-bromopiperidine-2,6-dione (0.85 g, 4.41 mmol), DIEA (0.85 g, 6.61 mmol), the reaction mixture was stirred at 100 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added to the reaction, extracted with ethyl acetate (30 mL*3), the combined extracts were washed with water (30 mL), saturated brine (30 mL) successively, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to give the target product tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate (0.45 g, yield: 39.31%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 520.3

[0800] Step six: Preparation of 3-((3-fluoro-4-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin- 1-yl)phenyl)amino)piperidine-2,6-dione

[0801] To a solution of tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate (450.00 mg, 0.87 mmol) in dioxane (5 mL) was added HC1 / dioxane (4.33 mL, 17.32 mmol, 4 M) under nitrogen protection, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was prepared and purified by reversed-phase C18 column (0-25% ACN / H20 (0.3% FA)) to obtain the target product 3-((3-fluoro-4-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (330 mg, yield: 90.83%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 420.2

[0802] Step seven: Preparation of compound Example 17: 3-(4-(4-(1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0803] To a solution of 3-((3-fluoro-4-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione (75 mg, 0.18 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylic acid (84.00 mg, 0.21 mmol), EDCI (67.58 mg, 0.35 mmol), HOBT (47.64 mg, 0.35 mmol) and DIEA (121.50 mg, 0.94 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly prepared and purified by reverse phase C18 column (0-25% ACN / H2O (0.3% FA)) to give 3-(4-(4-(1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (6 mg, yield: 4.23%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 793.3 + = 793.3

[0804] 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 0.19H, formic acid), 8.05 (s, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 6.88 - 6.77 (m, 1H), 6.74 (s, 1H), 6.50 (dd, J = 15.2, 2.4 Hz, 1H), 6.41 (dd, J = 8.8, 2.5 Hz, 1H), 5.96 (s, 2H), 5.80 (d, J = 7.6 Hz, 1H), 4.40 - 4.36 (m, 2H) 4.31 - 4.12 (m, 2H), 3.87 (s, 3H), 3.54 (t, J = 11.6 Hz, 1H), 3.22 - 3.15 (m, 1H), 2.89 - 2.80 (m, 4H), 2.77 - 2.74 (m, 1H), 2.72 - 2.69 (m, 4H), 2.61 - 2.51 (m, 1H), 2.35 (s, 2H), 2.13 - 2.03 (m, 1H), 1.86 - 1.81 (m, 1H), 1.57 (s, 4H).

[0805] Example 18: 3-(4-(4-(1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-3- fluorophenyl)amino)piperidine-2,6-dione

[0806] Step one: Preparation of tert-butyl 4-((4-(3-fluoro-5-nitropyridin-2-yl)piperazin-1- yl)methyl)-4-hydroxypiperidine-1-carboxylate

[0807] To a solution of tert-butyl 4-hydroxy-4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.20 g, 4.01 mmol) in NMP (10 mL) was added 2-chloro-3-fluoro-5-nitropyridine (0.85 g, 4.81 mmol), DIEA (1.55 g, 12.02 mmol) under nitrogen protection. The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added to the reaction, extracted with ethyl acetate (50 mL*3), the combined extracts were washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (petroleum ether / ethyl acetate 0-100%) to give the target product tert-butyl 4-((4-(3-fluoro-5-nitropyridin-2-yl)piperazin-1-yl)methyl)-4- hydroxypiperidine-1-carboxylate (1.10 g, yield: 62.45%, white solid).

[0808] LC-MS: (ESI, m / z): [M+H] + = 440.2

[0809] Step four: Preparation of tert-butyl 4-((4-(5-amino-3-fluoropyridin-2-yl)piperazin-1- yl)methyl)-4-hydroxypiperidine-1-carboxylate

[0810] To a solution of tert-butyl 4-((4-(3-fluoro-5-nitropyridin-2-yl)piperazin-1- yl)methyl)-4-hydroxypiperidine-1-carboxylate (1.00 g, 2.28 mmol) in isopropanol (50 mL) was added NH4Cl (0.49 g, 9.10 mmol), iron powder (0.64 g, 11.38 mmol), water (17 mL), the reaction was stirred at 80 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to give the target product tert-butyl 4-((4-(5-amino-3-fluoropyridin-2-yl)piperazin-1-yl)methyl)-4- hydroxypiperidine-1-carboxylate (0.83 g, yield: 89.08%, off-white solid). LC-MS: (ESI, m / z): [M+H] = 410.2 +

[0811] Step five: Preparation of tert-butyl 4-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)amino)-3- fluoropyridin-2-yl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate

[0812] Under nitrogen protection, to a solution of tert-butyl 4-((4-(5-amino-3-fluoropyridin-2- yl)piperazin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate (0.61 g, 1.49 mmol) in DMF (10 mL) was added 2,6-bis(benzyloxy)-3-bromopyridine (1.10 g, 2.98 mmol), DIEA (0.58 g, 4.47 mmol), the reaction mixture was stirred at 100 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added to the reaction, extracted with ethyl acetate (30 mL*3), the combined extracts were washed with water (30 mL), saturated brine (30 mL) successively, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column (MeOH / DCM 0-20%) to give the target product tert-butyl 4-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)piperazin-1- yl)methyl)-4-hydroxypiperidine-1-carboxylate (0.54 g, yield: 51.82%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 699.4 +

[0813] Step six: Preparation of 3-((5-fluoro-6-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin-1- yl)pyridin-3-yl)amino)piperidine-2,6-dione

[0814] ​​To a solution of tert-butyl 4-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)amino)-3- fluoropyridin-2-yl)piperazin-1-yl)methyl)-4-hydroxypiperidin-1-carboxylate (450.00 mg, 0.77 mmol) in HFIP (5 mL) was added TFA (1 mL, 15.45 mmol), 10% palladium on carbon (0.1 g, 55% water) under hydrogen atmosphere. The reaction was stirred at 50 °C for 2 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative reverse phase C18 column (0-25% ACN / H2O (0.3% FA)) to give the target product 3-((5-fluoro-6-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)pyridin-3- yl)amino)piperidin-2,6-dione (170 mg, yield: 52.32%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 421.2 +

[0815] Step Seven: Preparation of compound Example 18: 3-(6-(4-(1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3-yl)amino)piperidin-2,6-dione

[0816] ​To a solution of 3-((5-fluoro-6-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin-1- yl)pyridin-3-yl)amino)piperidine-2,6-dione (50.00 mg, 0.12 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carboxylic acid (11, 55.85 mg, 0.14 mmol), EDCI (38.79 mg, 0.18 mmol), HOBT (23.82 mg, 0.18 mmol) and DIEA (60.75 mg, 0.47 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 hours. The reaction was directly purified by reverse phase C18 column (0-25% ACN / H2O (0.3% FA)) to give 3-(6-(4-(1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione (4.80 mg, yield: 5.08%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 794.3 +

[0817] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.20 - 8.14 (m, 1H), 8.05 (s, 1H), 7.68 (dd, J = 8.3, 1.7 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.25 (s, 0.5H), 7.21 (s, 1H), 6.99 (dd, J = 14.8, 2.4 Hz, 1H), 6.74 (s, 1H), 6.70 (s, 0.5H), 5.96 - 5.89 (m, 2H), 4.36 - 4.23 (m, 2H), 4.17 (d, J = 12.3 Hz, 1H), 3.87 (s, 2H), 3.09 (s, 3H), 2.71 - 2.60 (m, 4H), 2.35 (m, 2H), 2.11 - 1.95 (m, 4H), 1.95 - 1.83 (m, 1H), 1.58 (s, 3H), 1.46 (s, 1H), 1.24 (s, 4H).

[0818] ​Example 19: 3-(6-(4-(1-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-4- hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione

[0819] Step one: Preparation of compound Example 19: 3-(6-(4-(1-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-4- hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione

[0820] To a solution of 3-((5-fluoro-6-(4-(4-hydroxypiperidin-4-yl)methyl)piperazin-1- yl)pyridin-3-yl)amino)piperidine-2,6-dione (50.00 mg, 0.12 mmol) in DMF (1 mL) was added 5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofurano[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (53.56 mg, 0.14 mmol), EDCI (38.79 mg, 0.18 mmol), HOBT (23.82 mg, 0.18 mmol) and DIEA (60.75 mg, 0.47 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 hours. The reaction was directly prepared by reverse phase C18 column (0-25% ACN / H2O (0.3% FA)) purification to give 3-(6-(4-(1-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofurano[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-5- fluoropyridin-3-yl)amino)piperidine-2,6-dione (8.20 mg, yield: 8.87%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 778.3

[0821] 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.06 (d, J = 7.0 Hz, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.15 (s, 0.52H, formic acid), 8.06 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 7.0, 1.8 Hz, 1H), 6.99 (dd, J = 14.8, 2.4 Hz, 1H), 6.73 (s, 1H), 6.24 (s, 2H), 5.92 (d, J = 7.8 Hz, 1H), 4.42 - 4.23 (m, 3H), 4.17 (d, J = 12.6 Hz, 1H), 3.86 (s, 3H), 3.54 (t, J = 9.8 Hz, 1H), 3.21 - 3.16 (m, 1H), 3.10 - 3.07 (m, 4H), 2.79 - 2.63 (m, 5H), 2.63 - 2.52 (m, 1H), 2.35 (s, 2H), 2.15 - 2.05 (m, 1H), 1.88 (dt, J = 12.3, 6.1 Hz, 1H), 1.66 - 1.50 (m, 4H).

[0822] Example 20: 3-(3-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furan[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-2-fluorophenyl)piperidine- 2,6-dione

[0823] Step One: Preparation of tert-butyl 4-((3-bromo-2-fluorophenyl)amino)-[1,4'- bipiperidin]-1'-carboxylate

[0824] Under nitrogen protection, 3-bromo-2-fluoroaniline (2.0 g, 10.5 mmol) and tert-butyl 4-oxo-[l,4’-bipiperidin]-l’-carboxylate (6.0 g, 21.1 mol) were dissolved in THF (30 mL). 2-3 drops of glacial acetic acid were added dropwise under ice bath condition, followed by 2-3 drops of TMSCl, and stirring was continued for 30 minutes. NaBH(OAc)3(4.5 g, 21.1 mmol) was added to the reaction system, and the resulting mixture solution was stirred at room temperature overnight. Water (50 mL) was added to quench the reaction mixture. It was basified with 15% aqueous sodium hydroxide solution and extracted with ethyl acetate (3 x 50 mL), and the combined organic phase was dried and concentrated. The crude product was purified by column chromatography (EA / PE 0-30%) to obtain compound tert-butyl 4-((3-bromo-2-fluorophenyl)amino)-[l,4’-bipiperidin]-l’-carboxylate (3.0 g, yield: 63%, yellow oil). LC-MS: (ESI, m / z): [M+H] = 456.2 +

[0825] Step two: Preparation of tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2- fluorophenyl)amino)-[l,4’-bipiperidin]-l’-carboxylate

[0826] Tert-butyl 4-((3-bromo-2-fluorophenyl)amino)-[l,4’-bipiperidin]-l’-carboxylate (1.5 g, 3.3 mmol) was dissolved in dioxane (20 mL) and water (4 mL), and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.7 g, 4.0 mmol), Cs2CO3(2.1 g, 6.6 mmol) and Pd(dppf)Cl2(0.36 g, 0.5 mmol) were added, and nitrogen was replaced for three times, and the reaction was carried out at 100 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and it was extracted with ethyl acetate (20 mL*3 times), and the combined organic phase was dried, concentrated. The crude product was purified by column chromatography (EA / PE 0-50%) to obtain tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)amino)-[l,4’-bipiperidin]-l’-carboxylate (1.5 g, 2.2 mmol, yield: 68%, brown solid). LC-MS: (ESI, m / z): [M+H] = 667.3 +

[0827] Step three: Preparation of 3-(3-([l,4’-bipiperidin]-4-ylamino)-2-fluorophenyl)piperidine- 2,6-dione

[0828] ​​tert-Butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)amino)-[1,4'-bipiperidine]-1'- carboxylate (1.5 g, 2.2 mmol) was dissolved in HFIP (25 ml), 10% Pd / C (400 mg, 55% water) was added, 2-3 drops of TFA was added dropwise, replaced with hydrogen three times, and stirred at 50°C for 4 hours under a hydrogen atmosphere. After the raw material was completely reacted, it was cooled to room temperature, filtered, washed, and concentrated to obtain 3-(3-([1,4'-bipiperidine]-4-ylamino)-2-fluorophenyl)piperidine-2,6-dione (800 mg, yield: 92%, yellow oil) as a crude product. LC-MS: (ESI, m / z): [M+H] + = 388.2

[0829] Step four: Preparation of 3-(3-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidine]-4-yl)amino)-2-fluorophenyl)piperidine-2,6-dione

[0830] To a solution of 3-(3-([1,4'-bipiperidine]-4-ylamino)-2-fluorophenyl)piperidine-2,6-dione (200 mg, 0.51 mmol) in DMF (2 ml) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (202 mg, 0.51 mmol), EDCI (148 mg, 0.77 mmol), HOBT (104 mg, 0.77 mmol), and DIEA (330 mg, 2.6 mmol), replaced with nitrogen three times, and the reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly purified by preparative purification on a reverse phase C18 column (0-35% ACN / H2O (0.3% FA)) to obtain 3-(3-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidine]-4-yl)amino)-2-fluorophenyl)piperidine-2,6-dione (120 mg, yield: 31%, white solid). LC-MS: (ESI, m / z): [M+H] + = 762.3

[0831] 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.17 (s, 0.3H, formic acid), 8.05 (s, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.75 (s, 1H), 6.67 (t, J = 8.4 Hz, 1H), 6.41 (t, J = 8.0 Hz, 1H), 5.95 (s, 2H), 5.08 (d, J = 7.2 Hz, 1H), 4.76 (d, J = 12.8 Hz, 1H), 4.56 (d, J = 12.8 Hz, 1H), 3.93 (dd, J = 12.0, 4.8 Hz, 1H), 3.87 (s, 3H), 3.16 - 3.10 (m, 2H), 2.90 (d, J = 10.8 Hz, 2H), 2.76 - 2.69 (m, 2H), 2.63 - 2.53 (m, 2H), 2.35 - 2.29 (m, 2H), 2.17 - 2.13 (m, 1H), 2.01 - 1.97 (m, 1H), 1.91 - 1.83 (m, 4H), 1.48 - 1.41 (m, 4H).

[0832] Example 21: 3-((6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furan[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)oxy)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione

[0833] Step One: Preparation of tert-butyl 4-((3-fluoro-5-nitropyridin-2-yl)oxy)-[1,4'- bipiperidin]-1'-carboxylate

[0834] To a solution of 2-chloro-3-fluoro-5-nitropyridine (1.0 g, 5.66 mmol) in DMF (40 mL) was added 4-hydroxy-[l,4’-bipiperidin]-l’-carboxylic acid tert-butyl ester (3.2 g, 11.33 mmol) under nitrogen atmosphere, sodium hydride (453 mg, 11.33 mmol, 60% dispersion in mineral oil) was added portion wise under ice bath. After addition the reaction mixture was stirred at 50 °C for 2 h. After completion of reaction, it was cooled to room temperature, quenched with saturated ammonium chloride solution (400 mL) and extracted with ethyl acetate (3 x 100 ml), combined organic layer, dried, concentrated. Purification by column chromatography (MeOH / DCM 0-20%) afforded the target product 4-((3-fluoro-5-nitropyridin-2-yl)oxy)-[l,4’-bipiperidin]-l’-carboxylic acid tert-butyl ester (620 mg, yield: 26%, yellow oil). LC-MS: (ESI, m / z): [M+H] = 425.2 +

[0835] Step two: Preparation of 4-((5-amino-3-fluoropyridin-2-yl)oxy)-[l,4’-bipiperidin]-l’-carboxylic acid tert-butyl ester

[0836] To a solution of 4-((3-fluoro-5-nitropyridin-2-yl)oxy)-[l,4’-bipiperidin]-l’-carboxylic acid tert-butyl ester (620 mg, 1.46 mmol) in THF (35 mL) was added 10% Pd / C (100 mg, 55% water content), hydrogen was replaced for 3 times and stirred at room temperature for 4 h under hydrogen atmosphere. After completion of reaction, the reaction was filtered, the filtrate was concentrated under reduced pressure to afford 4-((5-amino-3-fluoropyridin-2-yl)oxy)-[l,4’-bipiperidin]-l’-carboxylic acid tert-butyl ester crude (550 mg, yield: 95%, yellow oil). LC-MS: (ESI, m / z): [M+H] = 395.2 +

[0837] Step three: Preparation of 4-((5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)oxy)-[l,4’-bipiperidin]-l’-carboxylic acid tert-butyl ester

[0838] ​​tert-Butyl 4-((5-amino-3-fluoropyridin-2-yl)oxy)-[1,4'-bipiperidin]-1'-carboxylate (550 mg, 1.4 mmol) was dissolved in dioxane (30 mL), 2,6-bis(benzyloxy)-3-bromopyridine (774 mg, 2.1 mmol), Cs2CO3(1.36 g, 4.2 mmol) and Pd2(dba)3(255 mg, 0.28 mmol) were added, nitrogen was replaced for three times, and heated to 100 °C under nitrogen for 3 hours. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (30 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (MeOH / DCM 0-10%) to obtain tert-butyl 4-((5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)oxy)-[1,4'-bipiperidin]-1'-carboxylate (540 mg, yield: 57%, brown solid). LC-MS: (ESI, m / z): [M+H] = 684.4 +

[0839] Step four: Preparation of 3-((6-([1,4'-bipiperidin]-4-yloxy)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione

[0840] tert-Butyl 4-((5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)oxy)-[1,4'-bipiperidin]-1'-carboxylate (540 mg, 0.79 mmol) was dissolved in HFIP (10 ml), 10% Pd / C (100 mg, 55% water content) was added, 1-2 drops of TFA were added dropwise, hydrogen was replaced for three times, and stirred at 50 °C under hydrogen for 4 hours. After the raw material was completely reacted, it was cooled to room temperature, filtered, washed and concentrated. 3-((6-([1,4'-bipiperidin]-4-yloxy)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione (300 mg, yield: 94%, brown solid) was obtained. LC-MS: (ESI, m / z): [M+H] = 406.2 +

[0841] Step five: Preparation of 3-((6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)oxy)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione

[0842] ​​To a solution of 3-((6-([1,4'-dipiperidin]-4-yloxy)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione (300 mg, 0.74 mmol) in DMF (2 ml) was added 5-(4-amino-3-(benzo[d]thiazol-5- yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (289 mg, 0.74 mmol), EDCI (212 mg, 1.11 mmol), HOBT (143 mg, 1.11 mmol) and DIEA (300 mg, 2.22 mmol). Nitrogen was purged for three times and stirred at 50 °C for 2 h under nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature and directly purified by reverse phase C18 column (0-35% ACN / H2O (0.3% FA)) to get 3-((6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carbonyl)-[1,4'-dipiperidin]-4-yl)oxy)-5-fluoropyridin-3-yl)amino)piperidine-2,6- dione (150 mg, yield: 26%, white solid). LC-MS: (ESI, m / z): [M+H] = 779.2. + 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.67 (dd, J = 8.4, 1.6 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.12 (dd, J = 12.8, 2.4 Hz, 1H), 6.75 (s, 1H), 5.96 (s, 2H), 5.92 (d, J = 7.6 Hz, 1H), 4.82 - 4.74 (m, 2H), 4.55 (d, J = 12.4 Hz, 1H), 4.31 - 4.25 (m, 1H), 3.87 (s, 3H), 2.74 - 2.79 (m, 1H), 2.74 - 2.69 (m, 2H), 2.60 - 2.57 (m, 1H), 2.41 - 2.35 (m, 3H), 2.04 - 1.94 (m, 4H), 1.87 - 1.83 (m, 2H), 1.60 (d, J = 10.0 Hz, 2H), 1.44 - 1.33 (m, 4H).

[0843] UP05 intermediate

[0844] ​Methyl 5-bromo-l-methyl-lH-pyrazole-3-carboxylate (2 g, 9.13 mmol) was dissolved in dioxane (30 mL) under nitrogen protection, pinacol diborane (2.55 g, 10.04 mmol), KOAc (2.24 g, 22.83 mmol) and Pd(dppf)Cl2(0.67 g, 0.913 mmol) were added, and stirred at 80 °C for 4 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and ethyl acetate (100 mL*3 times) was used for extraction, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:4), and concentrated to obtain (3-methoxycarbonyl)-l-methyl-lH-pyrazol-5-yl boronic acid (1.1 g, yield: 65.5%, yellow oil).

[0845] LCMS: (ESI, m / z): [M+H] + = 185.1

[0846] 3-Bromo-4-chlorofuro[3,2-c]pyridine (10 g, 43.02 mmol) was dissolved in dioxane (200 ml) under nitrogen protection, and ammonia water (200 mL) was added, and stirred at 145 °C for 36 h under nitrogen protection. After cooling to room temperature, the reaction solution was concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%- DCM: MeOH = 50:1), and concentrated to obtain 3-bromo-furo[3,2-c]pyridin-4-amine (5.4 g, yield: 58.9%, yellow solid).

[0847] LCMS: (ESI, m / z): [M+H] + = 213.0

[0848] 3-Bromo-furo[3,2-c]pyridin-4-amine (5.4 g, 25.35 mmol) was dissolved in DMF (60 mL) under nitrogen protection, and 1-iodopyrrolidine-2,5-dione (6.27 g, 27.88 mmol) was added, and stirred at 50 °C for 4 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and sodium sulfite aqueous solution (600 mL, 5%) was added, and extracted with ethyl acetate (100 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1), and concentrated to obtain 3-bromo-7-iodofuro[3,2-c]pyridin-4-amine (6.5 g, yield: 75.6%, brown solid).

[0849] LCMS: (ESI, m / z): [M+H] + = 338.9

[0850] To a stirred solution of 3-bromo-7-iodofuro[3,2-c]pyridin-4-amine (1.0 g, 2.95 mmol) in dioxane (10 mL) and water (1 mL) was added (3-methoxycarbonyl)-1-methyl-1H-pyrazol-5-yl boronic acid (597 mg, 3.25 mmol), Cs2CO3 (2.4 g, 7.38 mmol) and Pd(dppf)Cl2 (212 mg, 0.29 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, DCM = 100% - DCM:MeOH = 20:1) to afford methyl 5-(4-amino-3-bromo furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (700 mg, yield: 67.3%) as brown solid. LCMS: (ESI, m / z): [M+H] + = 351.0

[0851] To a stirred solution of methyl 5-(4-amino-3-bromo furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (1 g, 2.85 mmol) in dioxane (10 mL) and water (1 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (892.1 mg, 3.42 mmol), Cs2CO3 (2.3 g, 7.12 mmol) and Pd(dppf)Cl2 (208.1 mg, 0.28 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, DCM = 100% - DCM:MeOH = 20:1) to afford methyl 5-(4-amino-3-(benzo[d]oxazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (560 mg, yield: 48.5%) as brown solid. LCMS: (ESI, m / z): [M+H] + = 406.1

[0852] Methyl 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylate (500 mg, 1.23 mmol) was dissolved in a mixture of water (2.5 mL) and THF (2.5 mL) under nitrogen, and lithium hydroxide monohydrate (155.4 mg, 3.7 mmol) was added. The reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was purified directly by flash purification (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (180 mg, yield: 37.3%, white solid). LCMS: (ESI, m / z): [M+H] = 392.1 + = 392.1

[0853] Methyl 5-(4-amino-3-bromofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylate (1 g, 2.85 mmol) was dissolved in dioxane (10 mL) and water (1 mL) under nitrogen, and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5- a]pyridine (837.5 mg, 3.42 mmol), Cs2CO3(2.3 g, 7.12 mmol), and Pd(dppf)Cl2(208.1 mg, 0.28 mmol) were added. The reaction was stirred at 100 °C under nitrogen for 3 hours. After the reaction was completed, it was cooled to room temperature, water (80 mL) was added, and the organic phase was extracted with ethyl acetate (50 mL x 3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100% to DCM:MeOH = 20:1) to give methyl 5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylate (560 mg, yield: 50.5%, brown solid). LCMS: (ESI, m / z): [M+H] = 390.1 + = 390.1

[0854] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 7.0, 0.9 Hz, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.33 (dd, J = 7.0, 1.9 Hz, 1H), 6.98 (s, 1H), 6.29 (s, 2H), 3.92 (s, 3H), 3.84 (s, 3H).

[0855] Methyl 5-(3-([l,2,4]triazolo[l,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylate (500 mg, 1.28 mmol) was dissolved in a mixture of water (2.5 mL) and THF (2.5 mL) under nitrogen protection, lithium hydroxide monohydrate (161.6 mg, 3.85 mmol) was added, stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was directly purified by Flash (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(3-([l,2,4]triazolo[l,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylic acid (175 mg, yield: 36.3%, white solid).

[0856] LCMS: (ESI, m / z): [M+H] + = 376.1

[0857] UP05 intermediate-route2

[0858] Methyl 5-bromo-l-methyl-lH-pyrazole-3-carboxylate (5 g, 22.83 mmol) was dissolved in a mixture of water (40 mL) and THF (40 mL) under nitrogen protection, lithium hydroxide monohydrate (2.87 g, 68.48 mmol) was added, stirred at room temperature for 2 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, adjusted to weakly acidic pH with dilute hydrochloric acid (3.0 M), extracted with ethyl acetate (100 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to give 5-bromo-l-methyl-lH-pyrazole-3-carboxylic acid crude (4.4 g, colorless oil).

[0859] LCMS: (ESI, m / z): [M+H] + = 205.0

[0860] Under nitrogen protection, 5-bromo-l-methyl-lH-pyrazole-3-carboxylic acid (4.4 g, 21.45 mmol) was dissolved in tert-butyl alcohol (100 mL), BOC2O (9.37 g, 42.93 mmol) was added, DMAP (0.26 g, 0.1 eq, 2.15 mmol), DIEA (8.32 g, 64.39 mmol) was added, and stirring was performed at room temperature under nitrogen for 5 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, water (100 mL) was added, and ethyl acetate (100 mL*3 times) was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) and concentrated to obtain tert-butyl 5-bromo-l-methyl-lH-pyrazole-3-carboxylate (5.0 g, yield: 89.3%, colorless oil).

[0861] LCMS: (ESI, m / z): [M+H] + = 261.0

[0862] Under nitrogen protection, tert-butyl 5-bromo-l-methyl-lH-pyrazole-3-carboxylate (500 mg, 1.91 mmol) was dissolved in dioxane (5 mL), pinacol diboronic acid (972.4 mg, 3.83 mmol), KOAc (469.8 mg, 4.79 mmol), and Pd(dppf)Cl2(140 mg, 0.19 mmol) were added, and stirring was performed at 80°C under nitrogen for 4 hours. After the reaction was completed, it was cooled to room temperature, water (40 mL) was added, and ethyl acetate (25 mL*3 times) was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:4) to obtain (3-(tert-butoxycarbonyl)-l-methyl-lH-pyrazol-5-yl)boronic acid (330 mg, yield: 76.3%, yellow oil).

[0863] LCMS: (ESI, m / z): [M+H] + = 227.1

[0864] Under nitrogen protection, 3-bromo-furo[3,2-c]pyridin-4-amine (6 g, 28.17 mmol) was dissolved in dioxane (60 mL) and water (6 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (8.1 g, 30.99 mmol), Cs2CO3(22.9 g, 70.42 mmol) and Pd(dppf)Cl2(2.1 g, 2.82 mmol) were added, and stirred at 100 °C for 3 hours under nitrogen. After the reaction was completed, it was cooled to room temperature, water (480 mL) was added, and the organic phase was extracted with ethyl acetate (300 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 20:1) to obtain 3-(benzothiazol-5-yl)furo[3,2-c]pyridin-4-amine (4.1 g, yield: 54.5%, yellow solid).

[0865] LCMS: (ESI, m / z): [M+H] + = 268.0

[0866] Under nitrogen protection, 3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-4-amine (4.1 g, 15.34 mmol) was dissolved in DMF (40 mL), NIS (3.8 g, 16.87 mmol) was added, and stirred at 50 °C for 4 hours under nitrogen. After the reaction was completed, it was cooled to room temperature, aqueous sodium sulfite solution (400 mL, 5%) was added, and the organic phase was extracted with ethyl acetate (100 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 50:1) to obtain 3-(benzo[d]thiazol-5-yl)-7-iodofuro[3,2-c]pyridin-4-amine (4.5 g, yield: 74.6%, brown solid).

[0867] LCMS: (ESI, m / z): [M+H] + = 393.9

[0868] Under nitrogen protection, 3-(benzo[d]thiazol-5-yl)-7-iodofuro[3,2-c]pyridin-4-amine (4.5 g, 11.44 mmol) was dissolved in dioxane (50 mL) and water (5 mL), (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-5-yl)boronic acid (3.1 g, 13.73 mmol), Cs2CO3(9.3 g, 28.61 mmol) and Pd(dppf)Cl2(836.6 mg, 1.14 mmol) were added, and stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (250 mL) was added, and DCM (150 mL*3 times) was used for extraction, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 20:1) to obtain tert-butyl 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (3.5 g, yield: 68.3%, brown solid).

[0869] LCMS: (ESI, m / z): [M+H] + = 448.1

[0870] Under nitrogen protection, tert-butyl 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (100 mg, 0.22 mmol) was dissolved in HCl / dioxane (1 mL, 4M), and stirred at room temperature for 3 hours under nitrogen protection. After the reaction solution was concentrated and dried in vacuum, 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (80 mg, yield: 91.4%, yellow solid) was obtained.

[0871] LCMS: (ESI, m / z): [M+H] + = 392.1

[0872] To a stirred solution of 3-bromo-[l,2,4]triazolo[l,5-a]pyridine (1 g, 5.48 mmol) in DMF (10 mL) was added 2-bromo-3-oxo-pentanoic acid ethyl ester (1.5 g, 6.62 mmol) and Cs2C03(3.6 g, 11.06 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with water (50 mL x 2), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, 0% to 10% MeOH in DCM) to afford 3-([l,2,4]triazolo[l,5-a]pyridin-7-yl)-5-oxo-pentanoic acid ethyl ester (1.2 g, 70% yield) as a yellow solid.

[0873] LCMS: (ESI, m / z): [M+H] + = 252.1

[0874] To a stirred solution of 3-([l,2,4]triazolo[l,5-a]pyridin-7-yl)-5-oxo-pentanoic acid ethyl ester (1.2 g, 4.82 mmol) in ethanol (10 mL) was added NaBH4(0.4 g, 10.61 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with water (50 mL x 2), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, 0% to 10% MeOH in DCM) to afford 3-([l,2,4]triazolo[l,5-a]pyridin-7-yl)-5-oxo-pentan-l-ol (0.8 g, 70% yield) as a yellow solid.

[0875] LCMS: (ESI, m / z): [M+H] + = 378.0

[0876] Under nitrogen protection, 3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-7-iodofuro[3,2- c]pyridin-4-amine (4.2 g, 11.14 mmol) was dissolved in dioxane (100 mL) and water (10 mL), (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-5-yl)boronic acid (3 g, 13.37 mmol), Cs2CO3(9.1 g, 27.84 mmol) and Pd(dppf)Cl2(814.2 mg, 1.11 mmol) were added, and stirred at 100 °C for 3 hours under nitrogen. After the reaction was completed, it was cooled to room temperature, water (300 mL) was added, and the organic phase was extracted with ethyl acetate (200 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 20:1) to obtain tert-butyl 5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylate (3.41 g, yield: 71%, brown solid).

[0877] LCMS: (ESI, m / z): [M+H]+= 432.2

[0878] Under nitrogen protection, tert-butyl 5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (100 mg, 0.23 mmol) was dissolved in HCl / 1,4-dioxane (1 mL, 4M), and stirred at room temperature for 3 hours under nitrogen. After the reaction was completed, it was concentrated and dried under vacuum to obtain 5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (81 mg, yield: 93.1%, yellow solid).

[0879] LCMS: (ESI, m / z): [M+H]+= 376.1

[0880] Example 22

[0881] Step one: Preparation of tert-butyl 4-((4-(4-bromo-3,5-difluorophenyl)piperazin-1- ylmethyl)piperidine-1-carboxylate

[0882] Under nitrogen protection, 2-bromo-1,3,5-trifluorobenzene (10 g, 47.39 mmol) was dissolved in DMF (100 mL), and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (13.4 g, 47.39 mmol) and K2CO3 (19.7 g, 142.18 mmol) were added, and stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (1000 mL) was added, and ethyl acetate (300 mL*3 times) was used for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 3:1) to obtain tert-butyl 4-((4-(4-bromo-3,5-difluorophenyl)piperazin-1- ylmethyl)piperidine-1-carboxylate (4.5 g, yield: 20%, white solid).

[0883] LCMS: (ESI, m / z): [M+H]+= 474.1

[0884] Step two: preparation of tert-butyl 4-((4-(4-(2,6-dibenzyloxy-pyridin-3-yl)-3,5- difluorophenyl)piperazin-1-ylmethyl)piperidine-1-carboxylate

[0885] Under nitrogen protection, tert-butyl 4-((4-(4-bromo-3,5-difluorophenyl)piperazin-1- ylmethyl)piperidine-1-carboxylate (1 g, 2.11 mmol) was dissolved in dioxane (10 mL) and water (1 mL), and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.1 g, 2.53 mmol), Cs2CO3 (1.7 g, 5.27 mmol) and Pd(dppf)Cl2 (154.1 mg, 0.21 mmol) were added, and nitrogen was replaced for three times, and stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (80 mL) was added, and ethyl acetate (50 mL*3 times) was used for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%- DCM:MeOH = 50:1) to obtain tert-butyl 4-((4-(4-(2,6-dibenzyloxy-pyridin-3-yl)-3,5- difluorophenyl)piperazin-1-ylmethyl)piperidine-1-carboxylate (648 mg, yield: 44.9%, brown solid). LCMS: (ESI, m / z): [M+H]+= 645.3

[0886] Step three: preparation of 3-(2,6-difluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine- 2,6-dione

[0887] tert-butyl 4-((4-(4-(2,6-dibenzyloxy-pyridin-3-yl)-3,5-difluoro-phenyl)-piperazin-l- ylmethyl)piperidin-l-ylcarbonyl)-piperidine-1-carboxylate (600 mg, 0.88 mmol) was dissolved in HFIP (10 mL) under nitrogen, 10% Pd / C (100 mg, 55% water content) was added, followed by TFA (0.1 mL), and the reaction was stirred at 60 °C under hydrogen for 16 h. After completion of the reaction, the reaction was cooled to room temperature, filtered, rinsed with HFIP (10 mL), and the filtrate was concentrated. The crude product was purified using column chromatography (100-200 mesh silica gel, DCM = 100% - DCM:MeOH = 20:1) to give 3-(2,6-difluoro-4-(4-(piperidin-4-ylmethyl)piperazin-l-yl)phenyl)piperidine-2,6-dione (195 mg, yield: 54.8%, brown oil).

[0888] LCMS: (ESI, m / z): [M+H]+= 407.2

[0889] Step four: Preparation of 3-(4-(4-((l-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-l- yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0890] tert-butyl 4-((4-(4-(2,6-dibenzyloxy-pyridin-3-yl)-3,5-difluoro-phenyl)-piperazin-l- ylmethyl)piperidin-l-ylcarbonyl)-piperidine-1-carboxylate (600 mg, 0.88 mmol) was dissolved in HFIP (10 mL) under nitrogen, 10% Pd / C (100 mg, 55% water content) was added, followed by TFA (0.1 mL), and the reaction was stirred at 60 °C under hydrogen for 16 h. After completion of the reaction, the reaction was cooled to room temperature, filtered, rinsed with HFIP (10 mL), and the filtrate was concentrated. The crude product was purified using column chromatography (100-200 mesh silica gel, DCM = 100% - DCM:MeOH = 20:1) to give 3-(2,6-difluoro-4-(4-(piperidin-4-ylmethyl)piperazin-l-yl)phenyl)piperidine-2,6-dione (195 mg, yield: 54.8%, brown oil).

[0891] LCMS: (ESI, m / z): [M+H] + = 796.3

[0892] 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.52 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.61 (dd, J = 8.2, 1.7 Hz, 1H), 6.79 (s, 1H), 6.67 - 6.63 (m, 2H), 5.71 (s, 2H), 4.68 (d, J = 13.1 Hz, 1H), 4.51 (d, J = 12.8 Hz, 1H), 4.06 (dd, J = 12.7, 5.2 Hz, 1H), 3.86 (s, 3H), 3.23 - 3.11 (m, 5H), 2.85 - 2.72 (m, 2H), 2.49 - 2.40 (m, 5H), 2.25 - 2.17 (m, 2H), 2.15 - 2.03 (m, 1H), 1.99 - 1.76 (m, 4H), 1.16 - 1.06 (m, 2H).

[0893] Example 23

[0894] Step one: Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0895] Under nitrogen protection, 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3 g, 9.29 mmol) was dissolved in dioxane (50 mL), tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1- carboxylate (5.3 g, 18.57 mmol), Cs2CO3(7.6 g, 23.21 mmol), X-Phos G3Pd (785.9 mg, 0.93 mmol) were added, replaced with nitrogen for three times, stirred at 100 °C for 3 hours under nitrogen environment. After the reaction was completed, it was cooled to room temperature, water (240 mL) was added, extracted with ethyl acetate (150 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1), concentrated to give tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1- carboxylate (510 mg, yield: 10.4%, light green solid). LCMS: (ESI, m / z): [M+H]+ = 526.3

[0896] Step two: Preparation of 3-(5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

[0897] Under nitrogen atmosphere, tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (200 mg, 0.38 mmol) was dissolved in DCM (2 mL), TFA (0.5 mL) was added, and stirred at room temperature for 3 hours under nitrogen atmosphere. The reaction was concentrated and directly purified by Flash (C18 column chromatography, 0% - 30% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-(5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (110 mg, yield: 67.9%, green solid). LCMS: (ESI, m / z): [M+H] + = 426.2

[0898] Step three: Preparation of 3-(5-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0899] Under nitrogen atmosphere, 3-(5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (1 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (50.3 mg, 0.12 mmol), EDCI (33.8 mg, 0.18 mmol), DIEA (45.5 mg, 0.35 mmol), and HOBT (23.8 mg, 0.18 mmol) were added. The reaction was stirred at 50 °C for 2 h under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was directly purified by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(5-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (24.0 mg, yield: 24%, white solid). LCMS: (ESI, m / z): [M+H] + = 815.3

[0900] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.52 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.61 (dd, J = 8.2, 1.7 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.07 - 7.05 (m, 2H), 6.80 (s, 1H), 5.70 (s, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.69 (d, J = 12.4 Hz, 1H), 4.52 (d, J = 12.8 Hz, 1H), 4.33 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 16.9 Hz, 1H), 3.86 (s, 3H), 3.31 - 3.28 (m, 4H), 3.17 (t, J = 12.5 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.79 (t, J = 12.4 Hz, 1H), 2.63 - 2.52 (m, 4H), 2.41 - 2.30 (m, 1H), 2.23 (d, J = 6.9 Hz, 2H), 2.01 - 1.77 (m, 5H), 1.14 - 1.10 (m, 2H).

[0901] Example 24

[0902] Under nitrogen, 3-((4-([1,4'-bipiperidin]-4-ylamino)-3-fluorophenyl)amino)piperidine- 2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (1 mL), and 5-(3-([1,2,4]triazolo[1,5- a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (48.8 mg, 0.13 mmol), EDCI (35.7 mg, 0.19 mmol), DIEA (48 mg, 0.37 mmol), and HOBT (25.1 mg, 0.19 mmol) were added. The reaction was stirred at room temperature for 4 hours under nitrogen. After the reaction was completed, the reaction was purified directly by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-[(4-[(1'-(5-(3-[(1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4- yl]amino)-3-fluorophenyl]amino]piperidine-2,6-dione (5.5 mg, yield: 5.8%, light purple solid). LCMS: (ESI, m / z): [M+H] + = 761.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.07 (dd, J = 7.1, 0.9 Hz, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.34 (dd, J = 7.0, 1.8 Hz, 1H), 6.75 (s, 1H), 6.61 (t, J = 9.3 Hz, 1H), 6.50 (dd, J = 14.3, 2.5 Hz, 1H), 6.38 (dd, J = 8.7, 2.5 Hz, 1H), 6.26 (s, 2H), 5.42 (d, J = 7.3 Hz, 1H), 4.75 (d, J = 13.0 Hz, 1H), 4.55 (d, J = 12.6 Hz, 1H), 4.22 - 4.03 (m, 2H), 3.87 (s, 3H), 3.20 - 3.00 (m, 2H), 2.86 - 2.84 (m, 2H), 2.78 - 2.66 (m, 2H), 2.66 - 2.55 (m, 2H), 2.35 - 2.19 (m, 2H), 2.15 - 2.04 (m, 1H), 2.04 - 1.96 (m, 1H), 1.92 - 1.75 (m, 5H), 1.47 - 1.30 (m, 3H).

[0903] Example 25

[0904] Under nitrogen, 3-((4-([1,4'-bipiperidin]-4-ylamino)-3-fluorophenyl)amino)piperidine- 2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (1 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (50.9 mg, 0.13 mmol), EDCI (35.7 mg, 0.19 mmol), DIEA (48 mg, 0.37 mmol), and HOBT (25.1 mg, 0.19 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 hours. The reaction was purified by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-((4-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-fluorophenyl)amino)piperidine-2,6-dione (5.0 mg, 5.2% yield, purple solid). LCMS: (ESI, m / z): [M+H] + = 777.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.51 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (s, 1H), 8.22 (s, 0.5H, formic acid hydrogen), 8.19 (s, 1H), 8.05 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 6.75 (s, 1H), 6.61 (t, J = 9.3 Hz, 1H), 6.51 (dd, J = 14.3, 2.6 Hz, 1H), 6.38 (dd, J = 8.7, 2.5 Hz, 1H), 5.96 (s, 2H), 5.42 (d, J = 7.3 Hz, 1H), 4.76 (d, J = 12.8 Hz, 1H), 4.55 (d, J = 12.7 Hz, 1H), 4.21 - 4.13 (m, 1H), 3.88 (s, 3H), 3.20 - 2.96 (m, 2H), 2.92 - 2.82 (m, 2H), 2.77 - 2.66 (m, 2H), 2.64 - 2.54 (m, 2H), 2.27 (t, J = 11.3 Hz, 2H), 2.15 - 2.05 (m, 1H), 1.90 - 1.76 (m, 5H), 1.46 - 1.28 (m, 4H).

[0905] Example 26

[0906] Step one: Preparation of methyl 5-(4-amino-3-(1-methyl-2-oxo-1,2-dihydropyridin-4- yl)thiophene[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate

[0907] Methyl 5-(4-amino-3-bromothiophene[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylate (180 mg, 0.51 mmol) was dissolved in dioxane (2 mL) and water (0.2 mL) under nitrogen protection, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2(1H)-one (144.6 mg, 0.62 mmol), K3PO4 (272 mg, 1.28 mmol) and Pd(dppf)Cl2(37.5 mg, 0.05 mmol) were added, stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (10 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100% - DCM:MeOH = 20:1) to obtain methyl 5-(4-amino-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)thiophene[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (125 mg, yield: 64.3%, brown solid). LCMS: (ESI, m / z): [M+H] = 379.2 +

[0908] Step two: Preparation of 5-(4-amino-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)thiophene[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

[0909] ​Methyl 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)furan[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carboxylate (125 mg, 0.329 mmol) was dissolved in a mixture of water (1 mL) and THF (1 mL) under nitrogen, and lithium hydroxide monohydrate (41.5 mg, 0.99 mmol) was added. The reaction was stirred at room temperature for 2 hours under nitrogen. The reaction was concentrated and the crude product was purified by Flash (C18 column chromatography, 5% to 45% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thiophene[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (63 mg, yield: 52.3%, white solid). LCMS: (ESI, m / z): [M+H] = 366.1 + = 366.1

[0910] Step Three: Preparation of 3-((4-((l'-(5-(4-amino-3-(l-methyl-2-oxo-l,2- dihydropyridin-4-yl)furan[3,2-c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carbonyl)- [l,4'-bipiperidin]-4-yl)amino)-3-fluorophenyl)amino)piperidine-2,6-dione

[0911] 3-((4-([l,4'-Bipiperidin]-4-ylamino)-3-fluorophenyl)amino)piperidine-2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (1 mL) under nitrogen, and 5-(4-amino-3-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)thiophene[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (47.6 mg, 0.13 mmol), EDCI (35.7 mg, 0.19 mmol), DIEA (48 mg, 0.37 mmol), and HOBT (25.1 mg, 0.19 mmol) were added. The reaction was stirred at room temperature for 4 hours under nitrogen. After the reaction was completed, the reaction was purified directly by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm), and 3-((4-((l'-(5-(4-amino-3-(l-methyl-2-oxo-l,2- dihydropyridin-4-yl)furan[3,2-c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carbonyl)- [l,4'-bipiperidin]-4-yl)amino)-3-fluorophenyl)amino)piperidine-2,6-dione (4.5 mg, yield: 4.8%, light purple solid) was obtained after lyophilization. LCMS: (ESI, m / z): [M+H] = 718.2 += 751.3

[0912] 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.24 (s, 1H), 8.22 (s, 0.75H, hydroxycarboxylic acid), 8.04 (s, 1H), 7.83 (d, J = 7.0 Hz, 1H), 6.72 (s, 1H), 6.61 (t, J = 9.3 Hz, 1H), 6.52 - 6.48 (m, 2H), 6.39 - 6.36 (m, 2H), 6.21 (s, 2H), 5.41 (d, J = 7.1 Hz, 1H), 4.73 (d, J = 13.0 Hz, 1H), 4.54 (d, J = 12.8 Hz, 1H), 4.15 (s, 1H), 3.84 (s, 3H), 3.47 (s, 3H), 3.13 - 3.03 (m, 2H), 2.92 - 2.82 (m, 2H), 2.80 - 2.67 (m, 2H), 2.65 - 2.55 (m, 2H), 2.33 - 2.22 (m, 2H), 2.16 - 2.03 (m, 1H), 1.89 - 1.74 (m, 5H), 1.47 - 1.28 (m, 4H).

[0913] Example 27

[0914] Under nitrogen atmosphere, 3-(2,6-difluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)phenyl)piperidine-2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (1 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylic acid (48.1 mg, 0.12 mmol), EDCI (36 mg, 0.18 mmol), DIEA (47.7 mg, 0.37 mmol) and HOBT (24.9 mg, 0.18 mmol) were added. The reaction was stirred at 50 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature and purified directly by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-[4-[4-[[1-[5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl]piperidin-4-yl]methyl]piperazin-1-yl]-2,6-difluorophenyl]piperidine-2,6-dione (3.0 mg, yield: 3.13%, white solid). LCMS: (ESI, m / z): [M+H] + = 780.3. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.51 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 8.2, 1.7 Hz, 1H), 6.73 (s, 1H), 6.67 - 6.63 (m, 2H), 5.96 (s, 2H), 4.68 (d, J = 13.2 Hz, 1H), 4.51 (d, J = 12.8 Hz, 1H), 4.06 (dd, J = 12.6, 5.1 Hz, 1H), 3.87 (s, 3H), 3.25 - 3.14 (m, 5H), 2.86 - 2.73 (m, 2H), 2.48 - 2.45 (m, 3H), 2.22 (d, J = 7.0 Hz, 2H), 2.12 - 1.94 (m, 3H), 1.92 - 1.75 (m, 3H), 1.26 - 1.23 (m, 2H), 1.15 - 1.05 (m, 1H).

[0915] Example 29

[0916] Step one: Preparation of 7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one

[0917] Under nitrogen protection, 2-amino-4-bromobenzoic acid (1.0 g, 4.63 mmol) was dissolved in acetic anhydride (5 mL), and stirred at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The concentrate was purified by slurry with petroleum ether:EA (2:1), and filtered to obtain 7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (500 mg, yield: 45.0%, white solid). LCMS: (ESI, m / z): [M+H] + = 240.0

[0918] Step two: Preparation of 3-(7-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione

[0919] Under nitrogen protection, 7-bromo-2-methyl-4H-benzo[d][l,3]oxazin-4-one (500 mg, 2.08 mmol) was dissolved in DMF (10 mL), 3-aminopiperidine-2,6-dione hydrochloride (411 mg, 2.5 mmol), triphenyl phosphite (969 mg, 3.12 mmol) were added, and the reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and the organic phase was extracted with ethyl acetate (30 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to obtain 3-(7-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (305 mg, yield: 41.8%, white solid). LCMS: (ESI, m / z): [M+H] + = 350.0

[0920] Step three: Preparation of tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo- 3,4-dihydroquinazolin-7-yl)piperazin-l-yl)piperidine-l-carboxylate

[0921] Under nitrogen protection, 3-(7-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine- 2,6-dione (285 mg, 0.81 mmol) was dissolved in dioxane (5 mL), tert-butyl 4-(piperazin- 1-yl)piperidine-l-carboxylate (329 mg, 1.22 mmol), K3PO4 (432.1 mg, 2.04 mmol), Pd(dtbpf)Cl2 (106 mg, 0.16 mmol) were added, and the reaction was stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added, and the organic phase was extracted with ethyl acetate (15 mL*3 times), combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%- DCM:MeOH = 20:1) to obtain tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo- 3,4-dihydroquinazolin-7-yl)piperazin-l-yl)piperidine-l-carboxylate (115 mg, yield 26.2%, gray solid). LCMS: (ESI, m / z): [M+H] + = 539.3

[0922] Step four: Preparation of 3-(2-methyl-4-oxo-7-(4-(piperidin-4-yl)piperazin-l-yl)quinazolin- 3(4H)-yl)piperidine-2,6-dione

[0923] Under nitrogen atmosphere, tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo- 3,4-dihydroquinazolin-7-yl)piperazin-1-yl)piperidine-1-carboxylate (100 mg, 0.19 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and stirred at room temperature for 3 hours under nitrogen atmosphere. After the reaction solution was concentrated, it was purified by Flash (C18 column chromatography, 0% - 30% acetonitrile / water; gradient 10 minutes, UV 254 nm) to obtain 3-(2-methyl-4-oxo-7-(4-(piperidin-4-yl)piperazin-1-yl)quinazolin-3(4H)-yl)piperidine- 2,6-dione (72 mg, yield 86.0%, brownish yellow oil). LCMS: (ESI, m / z): [M+H] + = 439.5

[0924] Step five: Preparation of 3-[7-(4-{1-[5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl]piperidin-4-yl}piperazin-1-yl)-2-methyl-4- oxoquinazolin-3(4H)-yl]piperidine-2,6-dione

[0925] Under nitrogen atmosphere, 3-(2-methyl-4-oxo-7-(4-(piperidin-4-yl)piperazin-1-yl)quinazolin- 3(4H)-yl)piperidine-2,6-dione (50 mg, 0.11 mmol) was dissolved in DMF (1 mL), 5-[4-amino- 3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-carboxylic acid (48.8 mg, 0.12 mmol), EDCI (32.8 mg, 0.17 mmol), DIEA (44.1 mg, 0.34 mmol), and HOBT (23.1 mg, 0.17 mmol) were added, and stirred at room temperature for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was directly purified by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to obtain 3-[7-(4-{1-[5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl]piperidin-4-yl}piperazin-1-yl)-2-methyl-4- oxoquinazolin-3(4H)-yl]piperidine-2,6-dione (5.5 mg, yield: 5.8%, white solid). LCMS: (ESI, m / z): [M+H] + = 828.3

[0926] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.94 (s, 1H), 9.53 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.11 (s, 1H), 7.91 - 7.84 (m, 2H), 7.62 (dd, J = 8.2, 1.7 Hz, 1H), 7.25 (dd, J = 9.1, 2.4 Hz, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 6.70 (s, 1H), 5.19 (dd, J = 11.5, 5.7 Hz, 1H), 5.00 (d, J = 13.2 Hz, 1H), 4.69 (d, J = 12.6 Hz, 1H), 4.20 (d, J = 11.7 Hz, 2H), 3.90 (s, 3H), 3.67 - 3.62 (m, 4H), 3.26 - 3.17 (m, 4H), 2.88 - 2.75 (m, 3H), 2.70 - 2.54 (m, 5H), 2.28 - 2.10 (m, 4H).

[0927] Example 30

[0928] Step one: Preparation of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate

[0929] Under nitrogen protection, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) was dissolved in NMP (5 mL), tert-butyl 2-amino-7-azaspiro[3.5]nonane-7- carboxylate (435 mg, 1.81 mmol) and DIEA (701.9 mg, 5.43 mmol) were added, and stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (25 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to obtain tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (210 mg, yield: 23.4%, white solid). LCMS: (ESI, m / z): [M+H] = 497.2 +

[0930] ​Step two: Preparation of 5-((7-azaspiro[3.5]nonan-2-yl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[0931] Under nitrogen protection, tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (210 mg, 0.42 mmol) was dissolved in DCM (2 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection. After concentration and vacuum drying, 5-((7-azaspiro[3.5]nonan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (115 mg, yield: 68.6%, brown oil) was obtained. LCMS: (ESI, m / z): [M+H] + = 397.2

[0932] Step three: Preparation of 5-((7-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-7-azaspiro[3.5]nonan-2-yl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[0933] Under nitrogen protection, 5-((7-azaspiro[3.5]nonan-2-yl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (115 mg, 0.29 mmol) was dissolved in DMF (2 mL), 5-[4-amino-3- (benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-carboxylic acid (124.1 mg, 0.3 mmol), EDCI (83.6 mg, 0.44 mmol), DIEA (112.3 mg, 0.87 mmol), and HOBT (58.7 mg, 0.44 mmol) were added, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. After the reaction was completed, the reaction mixture was directly purified by Flash (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-((7-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carbonyl)-7-azaspiro[3.5]nonan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (37 mg, yield: 6.2%, white solid). LCMS: (ESI, m / z): [M+H]+ = 786.2

[0934] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.53 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 6.90 (s, 2H), 6.85 - 6.68 (m, 2H), 5.03 (dd, J = 12.8, 5.4 Hz, 1H), 4.07 (s, 1H), 3.92 - 3.87 (m, 4H), 3.83 (s, 1H), 3.66 - 3.63 (m, 2H), 2.93 - 2.83 (m, 1H), 2.67 - 2.53 (m, 2H), 2.49 - 2.41 (m, 3H), 2.03 - 1.95 (m, 1H), 1.72 (s, 4H), 1.61 (s, 2H).

[0935] Example 31

[0936] Step one: Preparation of phenyl 4-((1-(tert-butoxycarbonyl)-4- hydroxypiperidin-4-yl)methyl)piperazine-1-carboxylate

[0937] Under nitrogen protection, tert-butyl 1-oxo-6-azaspiro[2.5]octane-6-carboxylate (5 g, 23.44 mmol) was dissolved in NMP (50 mL), phenyl piperazine-1-carboxylate (5.2 g, 23.44 mmol) and DIEA (9.1 g, 70.32 mmol) were added, and stirred at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (500 mL) was added, and ethyl acetate (250 mL*3 times) was used for extraction, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to obtain phenyl 4-((1-(tert-butoxycarbonyl)-4- hydroxypiperidin-4-yl)methyl)piperazine-1-carboxylate (8.9 g, yield: 87.6%, white solid).

[0938] LCMS: (ESI, m / z): [M+H] + = 434.3

[0939] Step two: Preparation of phenyl 4-((4-hydroxypiperidin-4-yl)methyl)piperazine-1- carboxylate

[0940] Benzyl 4-((l-(3-fluoro-5-nitropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperazine- 1 -carboxylate + = 334.3

[0941] Step three: Preparation of benzyl 4-((l-(3-fluoro-5-nitropyridin-2-yl)-4- hydroxypiperidin-4-yl)methyl)piperazine-1-carboxylate

[0942] Benzyl 4-((l-(3-fluoro-5-nitropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperazine- 1 -carboxylate

[0943] LCMS: (ESI, m / z): [M+H] + = 474.2

[0944] Step four: Preparation of benzyl 4-((l-(5-amino-3-fluoropyridin-2-yl)-4- hydroxypiperidin-4-yl)methyl)piperazine-1-carboxylate

[0945] Benzyl 4-((l-(5-amino-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperazine-l- carboxylate (600 mg, 1.35 mmol) was dissolved in dioxane (6 mL) and water (0.6 mL) under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (677.5 mg, 1.62 mmol), KOAc (331.9 mg, 3.38 mmol) and Pd(dppf)Cl2(98.9 mg, 0.14 mmol) were added, and stirring was performed at 100 °C under nitrogen protection for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and extraction was performed with DCM (30 mL*3 times). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 20: 1) to obtain benzyl 4-((l-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)-4- hydroxypiperidin-4-yl)methyl)piperazine-l-carboxylate (500 mg, yield: 50.4%, brown solid). LCMS: (ESI, m / z): [M+H] + = 733.3

[0946] Step four: preparation of benzyl 4-((l-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3- fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperazine-l-carboxylate

[0947] Benzyl 4-((l-(5-amino-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperazine-l- carboxylate (600 mg, 1.35 mmol) was dissolved in dioxane (6 mL) and water (0.6 mL) under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (677.5 mg, 1.62 mmol), KOAc (331.9 mg, 3.38 mmol) and Pd(dppf)Cl2(98.9 mg, 0.14 mmol) were added, and stirring was performed at 100 °C under nitrogen protection for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and extraction was performed with DCM (30 mL*3 times). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 20: 1) to obtain benzyl 4-((l-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)-4- hydroxypiperidin-4-yl)methyl)piperazine-l-carboxylate (500 mg, yield: 50.4%, brown solid). LCMS: (ESI, m / z): [M+H] + = 733.3

[0948] Step five: Preparation of 3-((5-fluoro-6-(4-hydroxy-4-(piperazin-l- ylmethyl)piperidin-l-yl)pyridin-3-yl)amino)piperidine-2,6-dione

[0949] Benzyl 4-((l-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)-4- hydroxypiperidin-4-yl)methyl)piperazine-l-carboxylate (450 mg, 0.61 mmol) was dissolved in MeOH (10 mL), 10% Pd / C (500 mg, 55% water content) was added and stirred at 50 °C under hydrogen atmosphere for 16 h. The reaction was filtered, the filter cake was washed with MeOH (10 mL), the filtrates were combined and concentrated and dried in vacuum. Purification with Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 min, UV 254 nm) gave 3-((5-fluoro-6-(4-hydroxy-4-(piperazin-l- ylmethyl)piperidin-l-yl)pyridin-3-yl)amino)piperidine-2,6-dione (210 mg, yield: 81.3%, off-white solid). LCMS: (ESI, m / z): [M+H] + = 421.2

[0950] Step six: Preparation of 3-((6-(4-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carbonyl)piperazin-l-yl)methyl)-4-hydroxypiperidin-l-yl)-5-fluoropyridin-3- yl)amino)piperidine-2,6-dione

[0951] Under nitrogen, 3-((5-fluoro-6-(4-hydroxy-4-(piperazin-l-ylmethyl)piperidin-l- yl)pyridin-3-yl)amino)piperidine-2,6-dione (110 mg, 0.26 mmol) was dissolved in DMF (1 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carboxylic acid (107.5 mg, 0.27 mmol), EDCI (75.3 mg, 0.39 mmol), DIEA (101.2 mg, 0.78 mmol), and HOBT (53 mg, 0.39 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 hours. After the reaction was complete, the reaction was purified directly by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-((6-(4-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carbonyl)piperazin-l-yl)methyl)-4-hydroxypiperidin-l-yl)-5- fluoropyridin-3-yl)amino)piperidine-2,6-dione (9.8 mg, yield: 4.7%, white solid). LCMS: (ESI, m / z): [M+H] = 794.3 +

[0952] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.50 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 6.98 (d, J = 14.6, 2.4 Hz, 1H), 6.76 (s, 1H), 5.94 (s, 2H), 5.87 (d, J = 7.8 Hz, 1H), 4.32 - 4.25 (m, 1H), 4.16 (s, 1H), 4.14 - 4.09 (m, 2H), 3.97 (s, 2H), 3.87 (s, 3H), 3.64 (s, 2H), 3.09 (t, J = 11.4 Hz, 2H), 2.73 - 2.67 (m, 1H), 2.64 - 2.57 (m, 5H), 2.33 (s, 2H), 2.14 - 2.07 (m, 1H), 1.92 - 1.84 (m, 1H), 1.72 - 1.65 (m, 2H), 1.60 - 1.55 (m, 2H).

[0953] Example 32

[0954] ​Step one: Preparation of tert-butyl 4-((4-(6-chloro-5-fluoropyridin-3-yl)piperazin-l- ylmethyl)piperidine-l-carboxylate

[0955] Under nitrogen protection, 5-bromo-2-chloro-3-fluoropyridine (3 g, 14.26 mmol) was dissolved in dioxane (30 mL), tert-butyl 4-(piperazin-l-ylmethyl)piperidine-l- carboxylate (8.1 g, 28.52 mmol), Cs2CO3(11.6 g, 35.65 mmol), BINAP (887.9 mg, 1.43 mmol) and Pd(OAc)2(646 mg, 2.85 mmol) were added, and the mixture was stirred at 100 °C for 4 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, water (240 mL) was added, and the mixture was extracted with ethyl acetate (150 mL*3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1: 1) to give tert-butyl 4-((4-(6-chloro-5-fluoropyridin-3-yl)piperazin-l- ylmethyl)piperidine-l-carboxylate (2.5 g, yield: 42.5%, brown solid). LCMS: (ESI, m / z): [M+H] + = 413.2

[0956] Step two: Preparation of tert-butyl 4-((4-(2',6'-dibenzyloxy-3-fluoro-[2,3'- bipyridin]-5-yl)piperazin-l-ylmethyl)piperidine-l-carboxylate

[0957] Under nitrogen protection, tert-butyl 4-((4-(6-chloro-5-fluoropyridin-3- yl)piperazin-1-ylmethyl)piperidine-1-carboxylate (2.5 g, 6.05 mmol) was dissolved in dioxane (25 mL) and water (2.5 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (3 g, 7.27 mmol), Cs2CO3(4.9 g, 15.14 mmol) and Pd(dppf)Cl2(442.6 mg, 0.61 mmol) were added, stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (200 mL) was added, extracted with DCM (125 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM = 100% - DCM:MeOH = 20:1) to obtain tert-butyl 4-((4-(2',6'-dibenzyloxy-3-fluoro-[2,3'-bipyridin]-5-yl)piperazin-1- ylmethyl)piperidine-1-carboxylate (1.7 g, yield: 42%, brown solid). LCMS: (ESI, m / z): [M+H] + = 668.4

[0958] Step three: Preparation of 3-(3-fluoro-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pyridin-2- yl)piperidine-2,6-dione

[0959] Under nitrogen protection, tert-butyl 4-((4-(2',6'-dibenzyloxy-3-fluoro-[2,3'-bipyridin]-5- yl)piperazin-1-ylmethyl)piperidine-1-carboxylate (1.1 g, 1.65 mmol) was dissolved in HFIP (20 mL), 10% Pd / C (1.0 g, containing 55% water) and TFA (1 mL) were added, stirred at 60 °C for 16 hours under hydrogen protection. After cooling to room temperature, the reaction solution was filtered, the filter cake was washed with HFIP (40 mL), and the filtrate was combined and concentrated, purified by Flash (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to obtain 3-(3-fluoro-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pyridin-2- yl)piperidine-2,6-dione (300 mg, yield: 46.8%, white solid). LCMS: (ESI, m / z): [M+H] + = 390.2

[0960] Step four: Preparation of 3-(5-(4-((l-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2- c]pyridin-7-yl)-l-methyl-lH-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-l- yl)-3-fluoropyridin-2-yl)piperidine-2,6-dione

[0961] Under nitrogen atmosphere, 3-(3-fluoro-5-(4-(piperidin-4-ylmethyl)piperazin-l- yl)pyridin-2-yl)piperidine-2,6-dione (120 mg, 0.31 mmol) was dissolved in DMF (1.5 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-l-methyl- lH-pyrazole-3-carboxylic acid (126.6 mg, 0.32 mmol), EDCI (88.7 mg, 0.46 mmol), DIEA (119.2 mg, 0.92 mmol), and HOBT (62.4 mg, 0.46 mmol) were added. The reaction was stirred at room temperature for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction was directly purified by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-(5-(4-((l-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-l- methyl-lH-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-l-yl)-3-fluoropyridin-2- yl)piperidine-2,6-dione (9.4 mg, yield: 4%, white solid). LCMS: (ESI, m / z): [M+H] + = 763.3

[0962] 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.50(s,1H),8.34(d,J=8.3Hz,1H),8.25(s,1H),8.18(s,1H),8.10(s,1H),8.04(s,1H) ,7.67(dd,J=8.2,1.7Hz,1H),7.26(dd,J=13.3,2.3Hz,1H),6.73(s,1H),5.95(s,2H),4.67(d,J=13.2Hz,1H),4.50(d,J=12.7 Hz,1H),4.10(dd,J=10.7,5.2Hz,1H),3.87(s,3H),3.26–3.22(m,3H),3.15(t,J=12.5Hz,1H),2.77(t,J=14.2Hz,1H),2.71–2 .60(m,1H),2.28–2.16(m,3H),2.07–1.97(m,2H),1.93–1.76(m,3H),1.57–1.40(m,1H),1.28–1.23(m,4H),1.15–1.03(m,2H).

[0963] Example 33: 3-[[6-[4-[(1-[5-[3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-formyl]piperidin-4-yl]methyl]piperazin-1-yl]-5-fluoropyridin-3-yl]amino]piperidin-2,6-dione

[0964] Step 1: Preparation of tert-butyl-4-[[4-(3-fluoro-5-nitropyridin-2-yl)piperazin-1-yl]methyl]piperidine-1-carboxylic acid ester

[0965] To a solution of 2-chloro-3-fluoro-5-nitropyridine (2 g, 11.33 mmol) in dioxane (20 mL), tert-butyl-4-(piperazin-1-methyl)piperidine-1-carboxylate (3.53 g, 12.46 mmol) and DIEA (7.32 g, 56.65 mmol) were added. The reaction mixture was stirred at 110 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether 0-30%) to give the target product tert-butyl-4-[[4-(3-fluoro-5-nitropyridin-2-yl)piperazin-1-yl]methyl]piperidine-1-carboxylate (4.65 g, yield: 97%, yellow solid). LC-MS: (ESI, m / z): [M+H] + =423.9.

[0966] Step two: Preparation of tert-butyl-4-[[4-(5-amino-3-fluoropyridin-2-yl)piperazin-1- yl]methyl]piperidine-1-carboxylate

[0967] To a solution of tert-butyl-4-[[4-(3-fluoro-5-nitropyridin-2-yl)piperazin-1-yl]methyl]piperidine-1- carboxylate (2.0 g, 4.72 mmol) in THF (20 mL) was added 10% Pd / C (200 mg, 55% water), replaced with hydrogen gas for 3 times and stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to give tert-butyl-4-[[4-(5-amino-3-fluoropyridin-2-yl)piperazin-1-yl]methyl]piperidine-1- carboxylate crude (1.9 g, brown solid). LC-MS: (ESI, m / z): [M+H] + = 394.2

[0968] Step three: Preparation of tert-butyl-4-[[4-[5-[(2,6-dioxopiperidin-3-yl)amino]-3-fluoropyridin-2- yl]piperazin-1-yl]methyl]piperidine-1-carboxylate

[0969] To a solution of tert-butyl-4-[[4-(5-amino-3-fluoropyridin-2-yl)piperazin-1-yl]methyl]piperidine-1- carboxylate (1.9 g, 4.83 mmol) in dioxane (20 mL) was added 3-bromopiperidine-2,6-dione (4.64 g, 24.14 mmol) and DIEA (3.12 g, 24.14 mmol). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, it was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The crude was purified by column chromatography (MeOH / DCM 0-20%) to give tert-butyl-4-[[4-[5-[(2,6-dioxopiperidin-3-yl)amino]-3-fluoropyridin-2-yl]piperazin-1- yl]methyl]piperidine-1-carboxylate (1.54 g, yield: 63%, yellow-brown solid). LC-MS: (ESI, m / z): [M+H] + = 505.2

[0970] 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.56 (s, 1H), 6.99 (dd, J = 14.8, 2.4 Hz, 1H), 5.92 (d, J = 7.8 Hz, 1H), 4.34-4.25 (m, 1H), 3.92 (d, J = 12.8 Hz, 2H), 3.10-3.07 (m, 4H), 2.76-2.67 (m, 3H), 2.61-2.55 (m, 1H), 2.47-2.44 (m, 4H), 2.18-2.07 (m, 3H), 1.93-1.82 (m, 1H), 1.69-1.66 (m, 3H), 1.39 (s, 9H), 1.01-0.88 (m, 2H).

[0971] Step four: Preparation of 3-[[5-fluoro-6-[4-(piperidin-4-yl)piperazin-1-yl]pyridin-3- yl]amino]piperidine-2,6-dione

[0972] To tert-butyl-4-[[4-[5-[(2,6-dioxopiperidin-3-yl)amino]-3-fluoropyridin-2-yl]piperazin-1- yl]methyl]piperidine-1-carboxylate (700 mg, 1.39 mmol) was added HC1 / dioxane (10 mL, 4M), then the reaction was stirred at room temperature for 2 hours. The reaction was directly concentrated under reduced pressure to give 3-[[5-fluoro-6-[4-(piperidin-4-yl)piperazin-1- yl]pyridin-3-yl]amino]piperidine-2,6-dione crude (600 mg, yellow-green solid).

[0973] LC-MS: (ESI, m / z): [M+H] + = 405.1

[0974] Step five: 3-[[6-[4-[(1-[5-[3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7- yl]-1-methyl-1H-pyrazole-3-carbonyl]piperidin-4-yl]methyl]piperazin-1-yl]-5-fluoropyridin- 3-yl]amino]piperidine-2,6-dione

[0975] To a solution of 3-[[5-fluoro-6-[4-(piperidin-4-yl)piperazin-1-yl]pyridin-3- yl]amino]piperidine-2,6-dione (81 mg, 0.20 mmol) in DMF (1 mL) was added 5-(3-(['1,2,4']triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carboxylic acid (50 mg, 0.13 mmol), EDCI (38 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol) and DIEA (52 mg, 0.40 mmol). The reaction mixture was stirred at 50 °C for 2 h. After the reaction was cooled to room temperature, it was directly purified by prep HPLC (0-25% acetonitrile / water (0.3% FA)) to give 3-[[6-[4-[(1-[5-[3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furo[3,2-c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-carbonyl]piperidin-4-yl]methyl] piperazin-1-yl]-5-fluoropyridin-3-yl]amino]piperidine-2,6-dione (15.0 mg, yield: 10%, white solid). LC-MS: (ESI, m / z): [M+H] = 762.2 +

[0976] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.06 (d, J = 7.0 Hz, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.16 (s, 0.6H, formate salt), 8.06 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 7.0, 1.8 Hz, 1H), 7.00 (dd, J = 14.8, 2.4 Hz, 1H), 6.72 (s, 1H), 6.24 (s, 2H), 5.93 (d, J = 7.8 Hz, 1H), 4.67 (d, J = 13.2 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1H), 4.32 - 4.27 (m, 1H), 3.86 (s, 3H), 3.17 - 3.06 (m, 6H), 2.79 - 2.69 (m, 2H), 2.62 - 2.58 (m, 1H), 2.22 - 2.18 (m, 2H), 2.13 - 2.07 (m, 1H), 1.94 - 1.72 (m, 5H), 1.27 - 0.96 (m, 4H).

[0977] ​Example 34: 3-((6-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3- yl)amino)piperidine-2,6-dione

[0978] Step one: Preparation of 3-((6-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3- yl)amino)piperidine-2,6-dione

[0979] To a solution of 3-[[5-fluoro-6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]pyridin-3-yl]amino]piperidine- 2,6-dione (78 mg, 0.19 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.13 mmol), EDCI (37 mg, 0.19 mmol), HOBT (26 mg, 0.19 mmol) and DIEA (50 mg, 0.38 mmol). The reaction mixture was stirred at 50 °C for 2 h. After the reaction was cooled to room temperature, it was directly purified by prep HPLC (0-35% acetonitrile / water (0.3% FA)) to give 3-((6-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoropyridin-3- yl)amino)piperidine-2,6-dione (11.5 mg, yield: 11%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 779.2. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.21-8.15 (m, 2H, including formate 1H), 8.05 (s, 1H), 7.67 (dd, J = 8.2, 1.6 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 14.8, 2.4 Hz, 1H), 6.73 (s, 1H), 6.00-5.90 (m, 3H), 4.67 (d, J = 13.0 Hz, 1H), 4.51 (d, J = 12.8 Hz, 1H), 4.29 (m, 1H), 3.90-3.85 (m, 3H), 3.14-3.07 (m, 4H), 2.83-2.68 (m, 3H), 2.62-2.57 (m, 1H), 2.25-2.18 (m, 2H), 2.13-2.07 (m, 1H), 1.91-1.74 (m, 4H), 1.17-1.09 (m, 6H).

[0980] Example 35: 3-((6-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furan [3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'- bipiperidin]-4-yl)amino)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione

[0981] Step one: Preparation of tert-butyl 4-((3-fluoro-5-nitropyridin-2-yl)amino)-[1,4'- b i piperidin] -1 '-carboxylate

[0982] To a solution of 2-chloro-3-fluoro-5-nitropyridine (3.6 g, 20.39 mmol) in dioxane (40 mL) was added tert-butyl 4-amino-[1,4'-bipiperidin]-1'-carboxylate (5.78 g, 20.39 mmol) and DIEA (13.2 g, 101.95 mmol). The reaction was purged with nitrogen for 3 times, the reaction mixture was stirred at 110 °C for 2 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, purified by column chromatography (MeOH / DCM 0-10%) to give the target product tert-butyl 4-((3-fluoro-5-nitropyridin-2-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (3.4 g, yield: 39%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 424.2. + 1 ​H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.3 Hz, 1H), 8.15 - 8.07 (m, 2H), 4.06 - 3.92 (m, 4H), 2.89 - 2.87 (m, 2H), 2.68 (s, 2H), 2.24 (s, 2H), 1.87 - 1.81 (m, 2H), 1.73 - 1.70 (m, 2H), 1.61 - 1.55 (m, 2H), 1.39 (s, 9H), 1.30 - 1.23 (m, 2H).

[0983] Step two: Preparation of tert-butyl-4-((5-amino-3-fluoropyridin-2-yl)amino)-[1,4'- bipiperidinyl]-1'-carboxylate

[0984] To a solution of tert-butyl-4-((3-fluoro-5-nitropyridin-2-yl)amino)-[1,4'- bipiperidinyl]-1'-carboxylate (3.4 g, 8.03 mmol) in THF (35 mL) was added 10% Pd / C (500 mg, 55% water), replaced with hydrogen gas for 3 times, and stirred at room temperature for 4 hours under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude tert-butyl-4-((5-amino-3-fluoro-pyridin-2-yl)amino)-[1,4'-bipiperidinyl]-1'-carboxylate (2.65 g, brown oil). LC-MS: (ESI, m / z): [M+H] + = 394.2

[0985] Step three: Preparation of tert-butyl-4-((5-((2,6-dioxopiperidin-3-yl)amino)-3- fluoropyridin-2-yl)amino)-[1,4'-bipiperidinyl]-1'-carboxylate

[0986] To a solution of tert-butyl-4-((5-amino-3-fluoro-pyridin-2-yl)amino)-[1,4'-bipiperidine]-1'- carboxylate (2.65 g, 6.73 mmol) in dioxane (40 mL) was added 3-bromopiperidine-2,6-dione (6.47 g, 33.67 mmol) and DIEA (4.35 g, 33.67 mmol). The reaction mixture was purged with nitrogen 3 times and stirred at 110 °C for 16 h under nitrogen. After completion of the reaction, it was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (MeOH / DCM 0-20%) to get the target product tert-butyl-4-((5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)amino)-[1,4'- bipiperidine]-1'-carboxylate (2.0 g, yield: 59%, yellowish brown solid). LC-MS: (ESI, m / z): [M+H] = 505.3 + = 505.3

[0987] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.96 (dd, J = 13.6, 2.3 Hz, 1H), 5.46-5.34 (m, 2H), 4.19-4.11 (m, 1H), 3.99-3.90 (m, 2H), 3.68-3.57 (m 1H), 2.85 (s, 2H), 2.76-2.65 (m, 3H), 2.63-2.52 (m, 2H), 2.32-2.15 (m, 2H), 2.13-2.07 (m, 1H), 1.90-1.81 (m, 3H), 1.72 (d, J = 12.2 Hz, 2H), 1.49-1.41 (s, 2H), 1.39 (s, 9H), 1.30-1.23 (m, 2H).

[0988] Step four: Preparation of 3-((6-([1,4'-bipiperidine]-4-ylamino)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione

[0989] To a solution of 4-((5-((2,6-dioxopiperidin-3-yl)amino)-3- fluoropyridin-2-yl)amino)-[1,4’-bipiperidine]-1’-carboxylate (500 mg, 0.99 mmol) in HCl / dioxane (10 mL, 4 M), the reaction was stirred at room temperature for 2 hours. The reaction was directly concentrated under reduced pressure to give crude 3-((6-([1,4’-bipiperidin]-4-ylamino)-5- fluoropyridin-3-yl)amino)piperidine-2,6-dione (400 mg, yellow green solid). LC-MS: (ESI, m / z): [M+H] = 404.9 +

[0990] Step five: Preparation of compound Example 35: 3-((6-((1’-(5-(3-([1,2,4]triazolo[1,5- a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)- [1,4’-bipiperidin]-4-yl)amino)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione

[0991] To a solution of 3-((6-([1,4’-bipiperidin]-4-ylamino)-5-fluoropyridin-3-yl)amino) piperidine-2,6-dione (100 mg, 0.25 mmol) in DMF (1 mL), 5-(3-(['1,2,4']triazolo[1,5- a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (93 mg, 0.25 mmol), TCFH (112 mg, 0.40 mmol) and NMI (66 mg, 0.80 mmol) were added. The reaction mixture was purged with nitrogen for 3 times, and stirred at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction was directly purified by prep-HPLC (0-25% acetonitrile / water (0.3% FA)) to give 3-((6-((1’-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4’-bipiperidin]-4-yl)amino)-5-fluoropyridin-3-yl)amino) piperidine-2,6-dione (20.3 mg, yield: 11%, white solid). LC-MS: (ESI, m / z): [M+H] = 761.9 +

[0992] 1 ​​H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.06 (d, J = 7.0 Hz, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.18 (s, 0.35H, formate), 8.07 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 7.0, 1.8 Hz, 1H), 6.96 (dd, J = 13.4, 2.4 Hz, 1H), 6.75 (s, 1H), 6.25 (s, 2H), 5.41 (d, J = 7.0 Hz, 2H), 4.76 (d, J = 13.0 Hz, 1H), 4.55 (d, J = 12.4 Hz, 1H), 4.19 - 4.13 (m, 1H), 3.87 (s, 3H), 3.68 - 3.58 (m, 2H), 3.14 - 3.08 (m, 1H), 2.90 - 2.85 (m, 2H), 2.74 - 2.66 (m, 2H), 2.63 - 2.54 (m, 2H), 2.29 - 2.21 (m, 2H), 2.14 - 2.08 (m, 1H), 1.89 - 1.78 (m, 4H), 1.48 - 1.37 (m, 4H).

[0993] Example 36: 3-[[6-[[1'-[[5-(4-amino-3-(benzo[d]thiazol-5-yl)furan[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido]-[1,4'-bipiperidin]-4-yl]amino]-5-fluoropyridin-3- yl]amino]piperidine-2,6-dione

[0994] Step one: Preparation of 3-[[6-[[1'-[[5-(4-amino-3-(benzo[d]thiazol-5-yl)furan[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido]-[1,4'-bipiperidin]-4-yl]amino]-5-fluoropyridin-3- yl]amino]piperidine-2,6-dione

[0995] To a solution of 3-((6-([1,4'-bipiperidin]-4-ylamino)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione (78 mg, 0.19 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5- yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.13 mmol), EDCI (37 mg, 0.19 mmol), HOBT (26 mg, 0.19 mmol) and DIEA (50 mg, 0.38 mmol). The reaction mixture was purged with nitrogen 3 times, stirred at 50 °C for 2 h under nitrogen protection. The reaction was directly prepared purified by reverse phase C18 column (0-35% acetonitrile / water (0.3% FA)) to give -[[6-[[1'-[[5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carbonyl]-[1,4'-bipiperidin]-4-yl]amino]-5-fluoropyridin-3-yl]amino]piperidine- 2,6-dione (17.2 mg, yield: 11%, white solid). LC-MS: (ESI, m / z): [M+H] = 778.2 + = 778.2

[0996] 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.19 (s, 1H), 8.18 (s, 0.6H, formate salt), 8.05 (s, 1H), 7.67 (dd, J = 8.2, 1.6 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 13.4, 2.2 Hz, 1H), 6.76 (s, 1H), 5.96 (s, 2H), 5.49 - 5.39 (m, 2H), 4.79 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 12.6 Hz, 1H), 4.19 - 4.13 (m, 1H), 3.88 (s, 3H), 3.70 - 3.66 (m, 1H), 3.16 - 3.10 (m, 1H), 2.98 - 2.93 (m, 2H), 2.75 - 2.66 (m, 3H), 2.63 - 2.55 (m, 2H) 2.40 - 2.33 (m, 2H), 2.13 - 2.08 (m, 1H), 1.91 - 1.76 (m, 4H), 1.58 - 1.41 (m, 4H).

[0997] Example 37: 3-((2-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furan[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)-[1,4'-bipiperidin]-4-yl)amino)pyrimidin-5-yl)amino)piperidine- 2,6-dione

[0998] Step one: Preparation of tert-butyl-4-((5-nitropyrimidin-2-yl)amino)-[1,4'-bipiperidin]-1'- carboxylate

[0999] To a solution of 2-chloro-5-nitropyrimidine (1.1 g, 6.90 mmol) in dioxane (20 mL) was added tert-butyl-4-amino-[1,4'-bipiperidin]-1'-carboxylate (1.95 g, 6.90 mmol) and DIEA (4.05 g, 34.50 mmol). The reaction mixture was stirred at 50 °C for 2 h. After the reaction was completed, it was cooled to room temperature and the reaction mixture was concentrated under reduced pressure and purified by column chromatography (MeOH / DCM 0-10%) to give the target product tert-butyl-4-((5-nitropyrimidin-2-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.0 g, yield: 71%, yellow solid).

[1000] LC-MS: (ESI, m / z): [M+H] + = 407.2.0

[1001] Step two: Preparation of tert-butyl-4-((5-aminopyrimidin-2-yl)amino)-[1,4'-bipiperidin]-1'- carboxylate

[1002] To a solution of tert-butyl-4-((5-aminopyrimidin-2-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.0 g, 4.92 mmol) in THF (20 mL) was added 10% Pd / C (400 mg, 55% water content), replaced with hydrogen gas for 3 times and stirred at room temperature for 3 h under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to give tert-butyl-4-((5-aminopyrimidin-2-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate crude (1.65 g, brown oil).

[1003] LC-MS: (ESI, m / z): [M+H] + = 377.3

[1004] Step three: Preparation of tert-butyl-4-((5-((2,6-dioxopiperidin-3-yl)amino)pyrimidin-2- yl)amino)-[l,4'-bipiperidin]-l'-carboxylate

[1005] To a solution of tert-butyl-4-((5-amino pyrimidin-2-yl)amino)-[l,4'-bipiperidin]-l'- carboxylate (650 mg, 1.73 mmol) in dioxane (10 mL) was added 3-bromopiperidine-2,6- dione (1.66 g, 8.63 mmol) and DIEA (1.12 g, 8.63 mmol). The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, it was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (MeOH / DCM 0-20%) to get the desired product tert-butyl-4-((5-((2,6-dioxopiperidin-3-yl)amino)pyrimidin-2-yl)amino)-[l,4'-bipiperidin]-l'- carboxylate (300 mg, yield: 35.6%, yellowish brown solid). LC-MS: (ESI, m / z): [M+H] + = 488.8

[1006] 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.21 (s, 1H), 7.91 (s, 2H), 6.24 (d, J = 7.8 Hz, 1H), 5.25 (s, 1H), 4.18-4.13 (m, 1H), 3.96 (d, J = 12.8 Hz, 2H), 3.58-3.53 (m, 1H), 2.91-2.86 (m, 2H), 2.73-2.63 (m, 3H), 2.61-2.57 (m, 1H), 2.34-2.27 (m, 2H), 2.13-2.06 (m, 1H), 1.89-1.83 (m, 3H), 1.74 (d, J = 12.3 Hz, 2H), 1.34-1.38 (m, 11H), 1.32-1.25 (m, 2H).

[1007] Step four: Preparation of 3-((2-([l,4'-bipiperidin]-4-ylamino)pyrimidin-5-yl)amino)piperidine- 2,6-dione

[1008] To 4-((5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)amino)-[1,4'- bipiperidine]-1'-carboxylate (300 mg, 0.61 mmol) was added HC1 / dioxane (5 mL, 4 M) and the reaction was stirred at room temperature for 2 hours. The reaction was directly concentrated under reduced pressure to give crude 3-((6-([1,4'-bipiperidine]-4-ylamino)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione (260 mg, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 388.9

[1009] Step five: Preparation of compound Example 37 (hereinafter, for the convenience of description, the compound prepared in the corresponding example will be referred to as "a certain example", for example, Example 37 refers to the compound prepared in Example 37): 3-((2-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-dipiperidine]-4-yl)amino)pyrimidin-5-yl)amino)piperidine-2,6-dione

[1010] To a solution of 3-((6-([1,4'-bipiperidine]-4-ylamino)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione (75 mg, 0.19 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (30 mg, 0.08 mmol), EDCI (22 mg, 0.11 mmol), HOBT (16 mg, 0.11 mmol) and DIEA (30 mg, 0.23 mmol). The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was cooled to room temperature, it was directly purified by reverse phase C18 column (0-35% acetonitrile / water (0.3% FA)) to give the preparation of 3-((2-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-dipiperidine]-4-yl)amino)pyrimidin-5-yl)amino)piperidine-2,6-dione (9.7 mg, yield: 17%, gray solid). LC-MS: (ESI, m / z): [M+H] + = 762.1. 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.18 (s, 2H), 8.05 (s, 1H), 7.91 (s, 2H), 7.67 (dd, J = 8.2, 1.7 Hz, 1H), 6.75 (s, 1H), 6.24 (d, J = 7.8 Hz, 1H), 5.96 (s, 2H), 5.26 (d, J = 7.4 Hz, 1H), 4.77 (d, J = 13.0 Hz, 1H), 4.56 (d, J = 12.6 Hz, 1H), 4.18 - 4.14 (m, 1H), 3.87 (s, 3H), 3.59 - 3.54 (m, 2H), 3.15 - 3.10 (m, 1H), 2.92 - 2.85 (m, 2H), 2.70 - 2.64 (m, 2H), 2.62 - 2.57 (m, 1H), 2.34 - 2.29 (m, 2H), 2.13 - 2.08 (m, 1H), 1.85 - 1.83 (m, 2H), 1.46 - 1.41 (m, 2H), 1.16 - 1.12 (m, 4H).

[1011] Example 38: 3-((6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)-[1,4'-bipiperidin]-4-yl)amino)-5-fluoropyridin-3- yl)amino)piperidine-2,6-dione

[1012] Step One: Preparation of 3-((6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7- yl)-1-methyl-1H-pyrazole-3-carboxamido)-[1,4'-bipiperidin]-4-yl)amino)-5-fluoropyridin-3- yl)amino)piperidine-2,6-dione

[1013] To a solution of 3-((6-([1,4'-bipiperidin]-4-ylamino)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione (50 mg, 0.12 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (50.4 mg, 0.12 mmol), HATU (70.5 mg, 0.18 mmol) and DIEA (48 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was directly prepared purified by reverse phase C18 column (0-25% acetonitrile / water (0.3% FA)) to give 3-((6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione (10.0 mg, yield: 10% white solid). LC-MS: (ESI, m / z): [M+H] = 794.2 + = 794.2

[1014] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.52 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.20 (s, 1H), 8.17 (s, 0.8H, formate salt), 8.01 (s, 1H), 7.68 (s, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 13.4, 2.2 Hz, 1H), 6.82 (s, 1H), 5.71 (s, 2H), 5.44 - 5.39 (m, 2H), 4.78 (d, J = 12.8 Hz, 1H), 4.57 (d, J = 12.8 Hz, 1H), 4.19 - 4.14 (m, 1H), 3.86 (s, 3H), 3.70 - 3.64 (m, 1H), 3.17 - 3.11 (m, 1H), 2.93 - 2.88 (m, 2H), 2.75 - 2.64 (m, 3H), 2.34 - 2.28 (m, 2H), 2.13 - 2.08 (m, 1H), 1.89 - 1.83 (m, 6H), 1.50 - 1.40 (m, 4H).

[1015] Example 39: 3-(5-(4-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[1016] Step one: Preparation of tert-butyl-4-((1-(3-cyano-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate

[1017] Methyl 2-cyano-4-fluorobenzoate (1.8 g. 10.05 mmol), tert-butyl 4-(piperidin-4- ylmethyl)piperazine-1-carboxylate (3.42 g, 12.06 mmol). DIEA (3.9 g, 30.15 mmol) were dissolved in DMSO (20 mL), the reaction mixture was stirred at 100 °C for 2 hours, after the reaction was completed, the reaction liquid was cooled to room temperature, poured into 300 mL water, extracted with ethyl acetate (150 mL*2), the combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by column chromatography (ethyl acetate / petroleum ether 0-60%) to give tert-butyl-4-((1-(3-cyano-4- (methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (2.5 g, yield: 56.2%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 443.3

[1018] Step two: Preparation of tert-butyl-4-((1-(3-formaldehyde-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate

[1019] To a solution of tert-butyl-4-((l-(3-cyano-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (2.5 g, 5.65 mmol) in water (25 mL) was added Raney-Ni slurry (750 mg), pyridine (52.5 mL), acetic acid (69 mL). After warming to 70 °C, a mixture of H3PO2(3.75 g) in water (75 mL) was added dropwise to the reaction, and the addition was completed in 30 min. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (500 mL x 3), washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether 0-50%) to give tert-butyl-4-((l-(3-formaldehyde-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (800 mg, yield: 31.7%, white solid).

[1020] LC-MS: (ESI, m / z): [M+H] + = 446.9

[1021] Step three: Preparation of tert-butyl-4-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperidin-4-ylmethyl)piperazine-l-carboxylate

[1022] To a solution of tert-butyl-4-((l-(3-formaldehyde-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-l-carboxylate (800 mg, 1.80 mmol) in MeOH (10 mL) was added 3- aminopiperidine-2,6-dione (276 mg, 2.15 mmol), acetic acid (216.2 mg, 3.6 mmol) under ice bath. The reaction was purged with nitrogen for 3 times, and sodium cyanoborohydride (169.7 mg, 2.7 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. After concentration, water (50 mL) was added to quench, and extracted with DCM (50 mL x 3). The organic phase was combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM 0-13%) to give the target product tert-butyl-4-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperidin-4-ylmethyl)piperazine-l-carboxylate (940 mg, yield: 99.6%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 526.2

[1023] 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.05-7.02 (m, 2H), 5.06-5.00 (m, 1H), 4.31 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.87 (d, J = 12.4 Hz, 2H), 3.35-3.31 (m, 4H), 2.91-2.78 (m, 3H), 2.62-2.55 (m, 1H), 2.31-2.25 (m, 4H), 2.17-2.12 (m, 2H), 1.98-1.93 (m, 1H), 1.80-1.74 (m, 3H), 1.39 (s, 9H), 1.25-1.13 (m, 3H).

[1024] Step four: Preparation of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1- yl)isoindolin-2-yl)piperidine-2,6-dione

[1025] To tert-butyl-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- ylmethyl)piperazine-1-carboxylate (200 mg, 0.38 mmol) was added HC1 / dioxane (5 mL, 4 M), then the reaction was stirred at room temperature for 2 hours. The reaction was directly concentrated under reduced pressure to give the crude 3-(1-oxo-5-(4-(piperazin-1- ylmethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione crude (150 mg, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 425.9

[1026] Step five: Preparation of 3-(5-(4-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxamido)piperazin-1-yl)methyl)piperidin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[1027] To a solution of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (40 mg, 0.09 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (38.3 mg, 0.09 mmol), EDCI (28 mg, 0.13 mmol), HOBT (20 mg, 0.13 mmol) and DIEA (64 mg, 0.45 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was directly purified by preparative reverse phase C18 column (0-20% acetonitrile / water (0.3% TFA)) to give 3-(5-(4-((4-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (8.7 mg, yield: 11%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 815.3 +

[1028] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.52 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.61 (dd, J = 8.2, 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.07 - 7.02 (m, 2H), 6.83 (s, 1H), 5.71 (s, 2H), 5.08 - 5.03 (m, 1H), 4.35 - 4.30 (m, 1H), 4.22 - 4.17 (m, 1H), 4.04 - 3.98 (m, 2H), 3.90 - 3.86 (m, 4H), 3.69 - 3.63 (m, 2H), 3.52 - 3.47 (m, 1H), 2.91 - 2.82 (m, 3H), 2.45 - 2.49 (m, 4H), 2.23 - 2.17 (m, 2H), 2.02 - 1.96 (m, 2H), 1.84 - 1.78 (m, 3H), 1.22 - 1.16 (m, 3H).

[1029] ​Example 40: 1-(6-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin- 1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1030] Step one: Preparation of tert-butyl (6-bromo-1-methyl-1H-indazol-3-yl)carbamate

[1031] To a solution of 6-bromo-1-methyl-1H-indazol-3-amine (2.2 g, 9.73 mmol) in EtOH (30 mL) was added Boc2O (3.19 g, 14.6 mmol). The reaction mixture was stirred at 50 °C overnight. After the reaction was completed, it was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (ethyl acetate / petroleum ether 0-30%) to give tert-butyl-(6-bromo-1-methyl-1H-indazol-3-yl)carbamate (3.1 g, yield: 97.8%, yellow solid).

[1032] LC-MS: (ESI, m / z): [M+H] + = 327.2

[1033] Step two: Preparation of benzyl-4-((4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H- indazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[1034] To a solution of tert-butyl-6-bromo-l-methyl-lH-indazole-3-carboxylate (2.21 g, 6.77 mmol) in dioxane (30 mL) was added benzyl 4-(piperazin-l-ylmethyl)piperidine-l-carboxylate (2.15 g, 6.77 mmol), Pd(OAc)2(152 mg, 0.68 mmol), BINAP (211 mg, 0.34 mmol) and Cs2CO3(6.62 g, 20.32 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 120 °C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using column chromatography (MeOH / DCM 0-10%) to obtain benzyl-4-((4-(3-((tert-butoxycarbonyl)amino)-l-methyl-lH-indazol-6-yl)piperazin-l- yl)methyl)piperidine-l-carboxylate (3.0 g, yield: 78.7%, yellow solid).

[1035] LC-MS: (ESI, m / z): [M+H] + = 563.4

[1036] Step three: Preparation of benzyl-4-((4-(3-amino-l-methyl-lH-indazol-6-yl)piperazin-l- yl)methyl)piperidine-l-carboxylate

[1037] To tert-butyl-4-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4- ylmethyl)piperazin-l-carboxylate (3 g, 5.34 mmol) was added HC1 / dioxane (20 mL, 4 M) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly concentrated under reduced pressure to obtain benzyl-4-((4-(3-amino-l-methyl-lH-indazol-6-yl)piperazin-l- yl)methyl)piperidine-l-carboxylate crude (2.4 g, yellow solid).

[1038] LC-MS: (ESI, m / z): [M+H] + = 463.2

[1039] Step four: Preparation of 3-((6-(4-((l-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazin-l- yl)-l-methyl-lH-indazol-3-yl)amino)propanoic acid

[1040] To a solution of benzyl-4-((4-(3-amino-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (2.4 g, 5.19 mmol) in water (20 mL) was added acrylic acid (449 mg, 6.23 mmol) and acetic acid (249 mg, 4.15 mmol). The reaction mixture was stirred at 100 °C overnight. After the reaction was completed, it was cooled to room temperature and extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (MeOH / DCM 0-10%) to give 3-((6-(4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)amino)propanoic acid (500 mg, yield: 18%, yellow oil).

[1041] LC-MS: (ESI, m / z): [M+H] + = 534.9

[1042] Step five: Preparation of 1-(1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1043] To a solution of 3-((6-(4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)amino)propanoic acid (100 mg, 0.18 mmol) in AcOH (5 mL) was added sodium cyanate (24.3 mg, 0.37 mmol). The reaction mixture was stirred at 100 °C overnight, to the reaction was added HCl / dioxane (2 mL, 4 M), then the reaction was stirred at 65 °C for 2 h. After the reaction was completed, it was cooled to room temperature and extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (MeOH / DCM 0-10%) to give 1-(1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, yield: 75.3%, yellow solid).

[1044] LC-MS: (ESI, m / z): [M+H] + = 426.1

[1045] Step six: Preparation of 1-(6-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin-1- yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1046] To a solution of 1-(1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, 0.14 mmol) in DMF (1 mL) was added 5-(4- amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (69 mg, 0.17 mmol), EDCI (41 mg, 0.21 mmol), HOBT (29 mg, 0.21 mmol) and DIEA (183 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was directly prepared purified by reverse phase C18 column (0-35% acetonitrile / water (0.3% TFA)) to give 1-(6-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxamido)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.9 mg, yield: 1.6%, white solid). LC-MS: (ESI, m / z): [M+H] = 815.2 +

[1047] 1 ​H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.53 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 4.70 (d, J = 12.8 Hz, 1H), 4.53 (d, J = 12.6 Hz, 1H), 3.91 - 3.85 (m, 7H), 3.27 - 3.17 (m, 5H), 2.82 - 2.70 (m, 3H), 2.57 - 2.54 (m, 3H), 2.28 - 2.22 (m, 2H), 1.97 - 1.79 (m, 4H), 1.18 - 1.03 (m, 3H).

[1048] Example 41: 5-[(2-{4-[5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylato]piperazin-1-yl}-2-oxoethyl)amino]-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione

[1049] Step one: Preparation of tert-butyl 4-glycylpiperazine-1-carboxylate

[1050] To a solution of tert-butyl 4-(((benzyloxy)carbonyl)glycyl)piperazine-1-carboxylate (5 g, 13.25 mmol) in MeOH (50 mL) was added 10% Pd / C (800 mg, 55% water content), replaced with hydrogen gas for 3 times, and stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure to give crude tert-butyl 4-glycylpiperazine-1-carboxylate (3.5 g, brown solid).

[1051] LC-MS: (ESI, m / z): [M+H] + = 243.9

[1052] Step two: Preparation of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)glycyl)piperazine-1-carboxylate

[1053] To a solution of tert-butyl 4-glycylpiperazine-1-carboxylate (2.4 g, 9.86 mmol) in NMP (30 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (4.09 g, 14.80 mmol) and DIEA (3.82 g, 29.59 mmol). The reaction mixture was stirred at 110 °C for 2 h. After the reaction was completed, it was cooled to room temperature, and the reaction solution was added dropwise into water (200 mL) and extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether 0-45%) to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazine-1-carboxylate (470 mg, yield: 9.5%, yellow solid).

[1054] LC-MS: (ESI, m / z): [M+H] + = 500.3

[1055] Step three: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[(2-oxo-2-piperazin-1-ylethyl)amino]isoindoline-1,3-dione

[1056] To tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazine-1-carboxylate (470 mg, 0.94 mmol) was added HCl / dioxane (5 mL, 4 M), and then the reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-5-[(2-oxo-2-piperazin-1-ylethyl)amino]isoindoline-1,3-dione (220 mg, yellow solid) as a crude product.

[1057] LC-MS: (ESI, m / z): [M+H] + = 400.3

[1058] Step four: Preparation of 5-[(2-{4-[5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxyl]piperazin-1-yl}-2-oxoethyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1059] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[(2-oxo-2-piperazin-1-yl- ethyl)amino]isoindoline-1,3-dione (50 mg, 0.12 mmol) in DMF (1 mL) was added 5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carboxylic acid (40.8 mg, 0.10 mmol), EDCI (36 mg, 0.18 mmol), HOBT (25.6 mg, 0.18 mmol) and DIEA (81.2 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was directly purified by preparative reverse phase C18 column (0-25% acetonitrile / water (0.3% TFA)) to give 5-[(2-{4-[5-(4-amino-3-(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxyl]piperazin-1-yl}-2-oxoethyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (27.6 mg, yield: 27.9%, yellow solid). LC-MS: (ESI, m / z): [M+H] = 789.0 + = 789.0

[1060] 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.54 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.65 (dd, J = 8.2, 1.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.20 - 6.98 (m, 6H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.24 - 4.14 (m, 4H), 4.11 - 4.03 (m, 2H), 3.92 (s, 3H), 3.81 - 3.72 (m, 2H), 3.69 - 3.66 (m, 2H), 2.93 - 2.86 (m, 1H), 2.64 - 2.54 (m, 2H), 2.04 - 1.98 (m, 1H).

[1061] Example 42: 4-{4-[4-(5-{4-amino-3-[(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-carboxylyl}piperazin-1-ylcarbonyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1062] Step one: Preparation of tert-butyl 4-{1-[(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl]piperidine-4-carbonyl}piperazine-1-carboxylate

[1063] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (4 g, 14.48 mmol) in NMP (40 mL) was added tert-butyl 4-(piperidine-4-carbonyl)piperazine-1-carboxylate (4.31 g, 14.88 mmol) and DIEA (5.61 g, 43.44 mmol). The reaction mixture was stirred at 110 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was added dropwise into water (200 mL), and a large amount of yellow solid was precipitated, which was filtered and washed to give tert-butyl 4-{1-[(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl]piperidine-4-carbonyl}piperazine-1-carboxylate (4.22 g, yellow solid) as a crude product.

[1064] LC-MS: (ESI, m / z): [M+H] + = 554.6

[1065] Step two: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-{4-[(piperazine-1-carbonyl)piperidin-1- yl]isoindoline-1,3-dione

[1066] To a solution of tert-butyl 4-{1-[(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl]piperidine-4- carbonyl}piperazine-1-carboxylate (4.22 g, 7.62 mmol) in DCM (40 mL) was added TFA (10 mL) and stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-4-{4-[(piperazine-1-carbonyl)piperidin-1-yl]isoindoline-1,3-dione (3.56 g, yellow solid) as a crude product. LC-MS: (ESI, m / z): [M+H] + = 454.3

[1067] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.73 - 7.66 (m, 1H), 7.34 (dd, J = 7.8, 3.4 Hz, 2H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.72 (d, J = 11.8 Hz, 2H), 3.57 - 3.42 (m, 4H), 3.04 - 2.70 (m, 8H), 2.67 - 2.52 (m, 2H), 2.08 - 1.96 (m, 1H), 1.84 - 1.68 (m, 4H).

[1068] Step three: Preparation of 4-{4-[4-(5-{4-amino-3-[(benzo[d]thiazol-5-yl)thieno[3,2- c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-carboxamido}piperazin-1-yl)carbonyl]piperidin- 1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1069] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-{4-[(piperazin-1-yl)piperidin-1-yl] isoindoline-1,3-dione (50 mg, 0.12 mmol) in DMF (1 mL) was added 5-(4-amino-3- (benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (66.8 mg, 0.15 mmol), EDCI (35.3 mg, 0.18 mmol), HOBT (24.9 mg, 0.18 mmol) and DIEA (79.3 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was directly purified by preparative reverse phase C18 column (0-25% acetonitrile / water (0.3% TFA)) to give 4-{4-[4-(5-{4-amino-3-[(benzo[d]thiazol-5-yl)thieno[3,2-c]pyridin-7-yl]-1- methyl-1H-pyrazole-3-carboxamido}piperazin-1-yl)carbonyl]piperidin-1-yl}-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (7.3 mg, yield: 7%, yellow solid). LC-MS: (ESI, m / z): [M+H] + = 843.2

[1070] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.53 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.72-7.68 (m, 2H), 7.62 (dd, J = 8.2, 1.6 Hz, 1H), 7.38-7.32 (m, 2H), 6.90 (s, 1H), 5.73 (s, 2H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.16-4.03 (m, 2H), 3.89 (s, 3H), 3.76-3.59 (m, 8H), 3.01-2.85 (m, 4H), 2.65-2.54 (m, 2H), 2.06-2.00 (m, 1H), 1.84-1.73 (m, 4H).

[1071] Example 49

[1072] Step 1: Preparation of benzyl 4-((6-bromo-5-fluoropyridin-2-yl)amino)-[1,4'- bipiperidinyl]-1'-carboxylate

[1073] Benzyl 4-amino-[1,4'-bipiperidinyl]-1'-carboxylate (1.2 g, 3.78 mmol) was dissolved in NMP (12 mL) under nitrogen atmosphere, 2-bromo-3,6-difluoropyridine (802.7 mg, 4.16 mmol) and DIEA (1.5 g, 11.35 mmol) were added and the reaction was carried out at 160 °C under microwave for 5 h. The reaction was cooled to room temperature, water (120 mL) was added and the reaction was extracted with ethyl acetate (60 mL*3 times), the organic layers were combined, dried over anhydrous Na2SO4and concentrated. The crude was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1:20) and concentrated to get benzyl 4-((6-bromo-5-fluoropyridin-2-yl)amino)-[1,4'-bipiperidinyl]-1'-carboxylate (600 mg, yield: 32.4%, white solid).

[1074] LCMS: (ESI, m / z): [M+H] + = 491.1

[1075] Step 2: Preparation of benzyl 4-((2',6'-bis(benzyloxy)-3-fluoro-[2,3'-bipyridinyl]-6- yl)amino)-[1,4'-bipiperidinyl]-1'-carboxylate

[1076] Benzyl 4-((6-bromo-5-fluoropyridin-2-yl)amino)-[1,4'-bipiperidin]-1'- carboxylate (600 mg, 1.22 mmol) was dissolved in a mixture of dioxane (6 mL) and water (1.5 mL) under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (561.8 mg, 1.35 mmol), potassium phosphate (649.8 mg, 3.06 mmol) and Pd(dtbpf)Cl2 (159.4 mg, 0.24 mmol) were added, and the mixture was stirred at 80 °C for 4 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, water (48 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3 times). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1:1) to give benzyl 4-((2',6'-bis(benzyloxy)-3-fluoro-[2,3'-bipyridin]-6-yl)amino)-[1,4'- bipiperidin]-1'-carboxylate (420 mg, yield: 48.9%, white solid).

[1077] LCMS: (ESI, m / z): [M+H] + = 702.3

[1078] Step 3: Preparation of 3-(6-([1,4'-bipiperidin]-4-ylamino)-3-fluoropyridin-2-yl)piperidine- 2,6-dione

[1079] Benzyl 4-((2',6'-bis(benzyloxy)-3-fluoro-[2,3'-bipyridin]-6-yl)amino)-[1,4'- bipiperidin]-1'-carboxylate (370 mg, 0.53 mmol) was dissolved in HFIP (9 mL) under nitrogen protection, 10% Pd / C (481 mg, containing 55% water) and TFA (1 drop) were added, and the mixture was stirred at 55 °C for 16 h under hydrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, the filter cake was washed with DCM (9 mL), and the filtrate was concentrated and dried under vacuum to give 3-(6-([1,4'-bipiperidin]-4-ylamino)-3-fluoropyridin-2-yl)piperidine-2,6-dione (120 mg, yield: 58.4%, brown oil).

[1080] LCMS: (ESI, m / z): [M+H] + = 390.2

[1081] Step 4: Preparation of 3-(6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3- fluoropyridin-2-yl)piperidine-2,6-dione

[1082] Under nitrogen, 3-(6-([1,4'-bipiperidin]-4-ylamino)-3-fluoropyridin-2-yl)piperidine-2,6- dione (40 mg, 0.1 mmol) was dissolved in DMF (0.8 mL), and 5-(4-amino-3-(benzo[d]thiazol- 6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (42.2 mg, 0.11 mmol), EDCI (29.6 mg, 0.15 mmol), DIEA (39.8 mg, 0.31 mmol), and HOBT (20.8 mg, 0.15 mmol) were added. The reaction was stirred at 50 °C under nitrogen for 2 h. The reaction was cooled to room temperature and purified directly by flash chromatography (C18 column, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(6-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3- fluoropyridin-2-yl)piperidine-2,6-dione (4.4 mg, 5.5% yield, white solid).

[1083] LCMS: (ESI, m / z): [M+H] + = 763.3

[1084] 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.51 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.68 (dd, J = 8.3, 1.4 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 6.76 (s, 1H), 6.47 - 6.34 (m, 2H), 5.96 (s, 2H), 4.76 (d, J = 11.7 Hz, 1H), 4.56 (d, J = 10.8 Hz, 1H), 4.02 (t, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.15 (d, J = 19.7 Hz, 2H), 2.89 - 2.78 (m, 2H), 2.77 - 2.61 (m, 1H), 2.63 - 2.56 (m, 3H), 2.26 (t, J = 10.8 Hz, 2H), 2.12 (q, J = 6.5 Hz, 2H), 1.92 - 1.74 (m, 4H), 1.50 - 1.26 (m, 4H).

[1085] Example 48

[1086] Step 1: Preparation of 2,6-bis(benzyloxy)-3-(3-bromo-2,5-difluorophenyl)pyridine

[1087] Under nitrogen protection, 1,3-dibromo-2,5-difluorobenzene (3 g, 11.12 mmol) was dissolved in dioxane (30 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.1 g, 12.23 mmol), K3PO4 (5.9 g, 27.8 mmol) and Pd(dppf)Cl2 (1.6 g, 2.22 mmol) were added, and stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (240 mL) was added, and ethyl acetate (150 mL*3 times) was used for extraction. The organic phase was combined, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:4) to obtain 2,6-bis(benzyloxy)-3-(3-bromo-2,5-difluorophenyl)pyridine (2.98 g, yield: 55.7%, white solid). LCMS: (ESI, m / z): [M+H] + = 482.0

[1088] Step 2: Preparation of tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylate

[1089] Under nitrogen protection, 2,6-bis(benzyloxy)-3-(3-bromo-2,5-difluorophenyl)pyridine (3 g, 6.24 mmol) was dissolved in dioxane (30 mL), and tert-butyl 4-amino-[1,4'-bipiperidin]-1'-carboxylate (3.5 g, 12.47 mmol), Cs2CO3(5.1 g, 15.59 mmol), XPhos G3Pd (2.1 g, 2.49 mmol) were added, and stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (240 mL) was added, and ethyl acetate (150 mL*3 times) was used for extraction, and the organic phase was combined, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to obtain tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)amino)-[1,4'-bipiperidin]-1'-carboxylate (520 mg, 0.76 mmol, yield: 12.2%, gray solid). LCMS: (ESI, m / z): [M+H] + = 685.3 h

[1090] Step 3: Preparation of tert-butyl 4-([3-(2,6-dioxopiperidin-3-yl)-2,4-difluorophenyl]amino)-[1,4'-bipiperidin]-1'-carboxylate

[1091] Under nitrogen protection, tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)amino)-[1,4'-bipiperidin]-1'-carboxylate (500 mg, 0.73 mmol) was dissolved in a mixed solution of HFIP (13 mL) and TFA (3 mL), and 10% Pd / C (650 mg, containing 55% water) was added, and stirred at 50 °C for 16 hours under hydrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with DCM (13 mL), and the filtrate was combined, concentrated and dried in vacuum to obtain tert-butyl 4-([3-(2,6-dioxopiperidin-3-yl)-2,4-difluorophenyl]amino)-[1,4'-bipiperidin]-1'-carboxylate (230 mg, yield: 62.2%, yellow oil). LCMS: (ESI, m / z): [M+H] + = 406.2

[1092] Step 4: Preparation of 3-(3-((1'-(5-(3-((1,2,4)triazolo[1,5-a]pyridin-7-yl)-4- amino furano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'- bipiperidin]-4-yl)amino)-2,5-difluorophenyl)piperidine-2,6-dione

[1093] Tert-butyl 4-([3-(2,6-dioxopiperidin-3-yl)-2,4-difluorophenyl]amino)-[1,4'- bipiperidin]-1'-carboxylate (60 mg, 0.12 mmol) was dissolved in DMF (0.8 mL) and 5-(3-((1,2,4)triazolo[1,5-a]pyridin-7-yl)-4-aminofurano[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (46.7 mg, 0.12 mmol), EDCI (34.1 mg, 0.18 mmol), DIEA (45.9 mg, 0.36 mmol), and HOBT (24 mg, 0.18 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 hours. The reaction was purified directly by flash (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) and lyophilized to give 3-(3-((1'-(5-(3-((1,2,4)triazolo[1,5-a]pyridin-7-yl)-4-aminofurano[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-2,5-difluorophenyl) piperidine-2,6-dione (16 mg, yield: 17.7%, white solid). LCMS: (ESI, m / z): [M+H] + = 764.3

[1094] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (br, 1H), 9.08 (br, 1H), 8.57 (br, 1H), 8.31 (br, 2H), 8.07 (br, 1H), 7.97 (br, 1H), 7.34 (br, 1H), 6.75 (br, 1H), 6.51 (br, 1H), 6.27 (br, 2H), 5.52 (br, 1H), 4.75 (br, 1H), 4.56 (br, 1H), 3.95 (br, 1H), 3.87 (br, 3H), 3.22-3.18 (m, 2H), 2.89 (br, 2H), 2.73 (br, 2H), 2.61 (br, 1H), 2.33 (br, 3H), 2.17 (br, 1H), 1.98 (br, 1H), 1.86 (br, 4H), 1.46 (br, 4H).

[1095] Example 43

[1096] Step 1: Preparation of benzyl 4-((3-fluoro-4-iodopyridin-2-yl)amino)-[1,4'-bipiperidin]-1'- carboxylate

[1097] Benzyl 4-amino-[1,4'-bipiperidin]-1'-carboxylate (5 g, 15.75 mmol) was dissolved in NMP (50 mL) under nitrogen atmosphere, 2,3-difluoro-4-iodopyridine (4.2 g, 17.33 mmol) and DIEA (6.1 g, 47.26 mmol) were added and stirred at 100 °C under nitrogen atmosphere for 5 h. Reaction was completed and cooled to room temperature, water (500 mL) was added and extracted with ethyl acetate (250 mL * 3 times), combined organic phase was dried over anhydrous Na2S04and concentrated. The crude product was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1:20) to get benzyl 4-((3-fluoro-4-iodopyridin-2-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.2 g, yield: 25.9%, white solid). LCMS: (ESI, m / z): [M+H] = 539.1 + = 539.1

[1098] Step 2: Preparation of benzyl 4-((2,6-di(benzyloxy)-3'-fluoro-[3,4'-bipyridin]-2'-yl)amino)-[1,4'- bipiperidin]-1'-carboxylate

[1099] Benzyl 4-((3-fluoro-4-iodopyridin-2-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.2 g, 4.09 mmol) was dissolved in dioxane (22 mL) under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.9 g, 4.49 mmol), K3PO4 (2.2 g, 10.22 mmol) and Pd(dppf)Cl2 (597.4 mg, 0.82 mmol) were added, stirred at 100 °C for 3 h under nitrogen protection. The reaction was completed and cooled to room temperature, added water (150 mL), extracted with ethyl acetate (100 mL*3 times), combined the organic phase, dried over anhydrous Na2SO4, concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to give benzyl 4-((2,6-bis(benzyloxy)-3'-fluoro-[3,4'-bipyridin]-2'-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (2.0 g, yield: 69.7%, yellow solid). LCMS: (ESI, m / z): [M+H] = 702.1 +

[1100] Step 3: Preparation of 3-(2-([1,4'-bipiperidin]-4-ylamino)-3-fluoropyridin-4-yl)piperidine-2,6-dione

[1101] Benzyl 4-((2,6-bis(benzyloxy)-3'-fluoro-[3,4'-bipyridin]-2'-yl)amino)-[1,4'-bipiperidin]-1'-carboxylate (500 mg, 0.71 mmol) was dissolved in HFIP (13 mL) under nitrogen protection, 10% Pd / C (650 mg, 55% water) was added, stirred at room temperature for 16 h under hydrogen protection. The reaction liquid was filtered, the filter cake was washed with DCM (13 mL), the filtrate was combined and concentrated and dried in vacuum to give 3-(2-([1,4'-bipiperidin]-4-ylamino)-3-fluoropyridin-4-yl)piperidine-2,6-dione (70 mg, yield: 25.2%, brown oil). LCMS: (ESI, m / z): [M+H] = 390.1 +

[1102] Step 4: Preparation of 3-(2-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-fluoropyridin-4-yl)piperidine-2,6-dione ​​

[1103] Under nitrogen, 3-(2-([1,4'-bipiperidin]-4-ylamino)-3-fluoropyridin-4-yl)piperidine-2,6-dione (70 mg, 0.18 mmol) was dissolved in DMF (0.8 mL), and 5-[3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl]-1-methyl-1H-pyrazole-3-carboxylic acid (70.8 mg, 0.19 mmol), EDCI (51.8 mg, 0.27 mmol), DIEA (69.6 mg, 0.54 mmol), and HOBT (36.4 mg, 0.27 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 h. The reaction was purified directly by flash (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(2-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-fluoropyridin-4-yl)piperidine-2,6-dione (35 mg, yield: 26.1%, white solid). LCMS: (ESI, m / z): [M+H] + = 747.1

[1104] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.06 (d, J = 7.0 Hz, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.34 (d, J = 6.9 Hz, 1H), 6.75 (s, 1H), 6.41 (t, J = 4.8 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 6.24 (s, 2H), 4.84 - 4.68 (m, 1H), 4.61 - 4.47 (m, 1H), 4.02 (dd, J = 12.5, 4.7 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 1H), 3.12 (t, 1H), 2.90 (d, J = 9.2 Hz, 2H), 2.80 - 2.68 (m, 2H), 2.64 - 2.53 (m, 2H), 2.39 - 2.21 (m, 2H), 2.21 - 2.11 (m, 1H), 2.03 - 1.93 (m, 1H), 1.93 - 1.76 (m, 4H), 1.61 - 1.47 (m, 2H), 1.47 - 1.33 (m, 2H).

[1105] Example 44

[1106] Step 1 : Preparation of tert-butyl 4-((3-bromo-2,4-difluorophenyl)amino)-[1,4'- bipiperidinyl]-1 '-carboxylate

[1107] Under nitrogen atmosphere, 3-bromo-2,4-difluoroaniline (5 g, 24.17 mmol) was dissolved in THF (50 mL), tert-butyl 4-oxo-[1,4'-bipiperidinyl]-1 '-carboxylate (7.5 g, 26.58 mmol) and trimethylchlorosilane (2.9 g, 26.58 mmol) were added, sodium triacetoxyborohydride (5.6 g, 26.58 mmol) was added portion wise under ice water bath, stirred at room temperature for 5 h under nitrogen atmosphere. Reaction was completed, water (350 mL) was added, extracted with ethyl acetate (250 mL * 3 times), combined organic phase, dried over anhydrous Na2S04, concentrated. The crude product was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - MeOH:DCM = 1 :40) to get tert-butyl 4-((3-bromo-2,4-difluorophenyl)amino)-[1,4'-bipiperidinyl]-1 '- carboxylate (2.2 g, yield: 19.2%, white solid). LCMS: (ESI, m / z): [M+H] = 474.2 +

[1108] Step 2: Preparation of tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,4- difluorophenyl)amino)-[1,4'-bipiperidinyl]-1 '-carboxylate

[1109] Under nitrogen atmosphere, tert-butyl 4-((3-bromo-2,4-difluorophenyl)amino)-[1,4'- bipiperidinyl]-1 '-carboxylate (1 g, 2.11 mmol) was dissolved in dioxane (10 mL), 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (970.3 mg, 2.33 mmol), potassium phosphate (1.1 g, 5.28 mmol) and Pd(dppf)CI2(309 mg, 0.42 mmol) were added, stirred at 100 °C for 3 h under nitrogen atmosphere. Reaction was completed, cooled to room temperature, water (80 mL) was added, extracted with ethyl acetate (50 mL * 3 times), combined organic phase, dried over anhydrous Na2S04, concentrated. The crude product was purified using column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1 :1 ) to get tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,4-difluorophenyl)amino)-[1,4'- bipiperidinyl]-1 '-carboxylate (900 mg, yield: 62.2%, yellow solid). LCMS: (ESI, m / z): [M+H] = 774.3​+ = 685.3

[1110] Step 3: Preparation of tert-butyl 4-([3-(2,6-dioxopiperidin-3-yl)-2,4- difluorophenyl]amino)-[1,4’-bipiperidin]-1’-carboxylate

[1111] Tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-2,4-difluorophenyl)amino)- [1,4’-bipiperidin]-1’-carboxylate (900 mg, 1.32 mmol) was dissolved in MeOH (23 mL) under nitrogen protection, 10% Pd / C (1.17 g, 55% water) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with MeOH (23 mL), the filtrate was concentrated and dried under vacuum to give tert-butyl 4-([3-(2,6-dioxopiperidin-3-yl)-2,4-difluorophenyl]amino)-[1,4’-bipiperidin]-1’-carboxylate (490 mg, yield: 73.6%, brown oil).

[1112] LCMS: (ESI, m / z): [M+H] + = 507.3

[1113] Step 4: Preparation of 3-[3-([1,4’-bipiperidin]-4-ylamino)-2,6-difluorophenyl]piperidine- 2,6-dione

[1114] Tert-butyl 4-([3-(2,6-dioxopiperidin-3-yl)-2,4-difluorophenyl]amino)-[1,4’-bipiperidin]-1’-carboxylate (490 mg, 0.97 mmol) was dissolved in DCM (4.9 mL) under nitrogen protection, TFA (1.2 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The reaction solution was concentrated and purified by Flash (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-[3-([1,4’-bipiperidin]-4-ylamino)-2,6-difluorophenyl]piperidine-2,6-dione (260 mg, 0.64 mmol, yield: 66.1%, white solid).

[1115] LCMS: (ESI, m / z): [M+H] + = 407.2

[1116] Step 5: Preparation of 3-(2-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'- bipiperidin]-4-yl)amino)-3-fluoropyridin-4-yl)piperidine-2,6-dione

[1117] Under nitrogen, 3-[3-([1,4'-bipiperidin]-4-ylamino)-2,6-difluorophenyl]piperidine- 2,6-dione (130 mg, 0.32 mmol) was dissolved in DMF (1.3 mL), and 5-(4-amino-3- (benzo[d]thiazol-5-yl)furan[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (131.4 mg, 0.34 mmol), EDCI (92.2 mg, 0.48 mmol), DIEA (123.9 mg, 0.96 mmol), and HOBT (64.8 mg, 0.48 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 h. The reaction was directly purified by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(2-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3-fluoropyridin-4-yl)piperidine-2,6-dione (88 mg, yield: 36.8%, white solid). LCMS: (ESI, m / z): [M+H] + = 780.3

[1118] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.51 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 6.86 (t, J = 9.1 Hz, 1H), 6.76 (s, 1H), 6.74 - 6.63 (m, 1H), 5.96 (s, 2H), 4.99 (d, J = 7.4 Hz, 1H), 4.76 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.9 Hz, 1H), 4.17 (dd, J = 12.3, 4.7 Hz, 1H), 3.88 (s, 3H), 3.22 - 3.12 (m, 2H), 2.89 (d, J = 9.9 Hz, 2H), 2.84 - 2.71 (m, 2H), 2.69 - 2.54 (m, 2H), 2.36 - 2.26 (m, 2H), 2.21 - 2.05 (m, 1H), 2.05 - 1.94 (m, 1H), 1.94 - 1.75 (m, 4H), 1.52 - 1.31 (m, 4H).

[1119] Example 45

[1120] Step 1: Preparation of 3-(3-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'- bipiperidin]-4-yl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[1121] Under nitrogen, 3-(3-([1,4'-Bipiperidin]-4-ylamino)-2,6-difluorophenyl)piperidine-2,6-dione (160 mg, 0.39 mmol) was dissolved in DMF (1.6 mL), and 5-(3-([1,2,4]Triazolo[1,5-a]pyridin-7-yl)-4- aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (155.1 mg, 0.41 mmol), EDCI (113.4 mg, 0.59 mmol), DIEA (152.4 mg, 1.18 mmol), and HOBT (79.8 mg, 0.59 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 h. The reaction was purified directly by flash (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(3-((1'-(5-(3-([1,2,4]Triazolo[1,5-a]pyridin-7-yl)-4- aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-2,6-difluorophenyl)piperidine-2,6-dione (15 mg, 5% yield, white solid). LCMS: (ESI, m / z): [M+H] = 764.3 +

[1122] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.07 (dd, J = 7.0, 0.7 Hz, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.34 (dd, J = 7.0, 1.8 Hz, 1H), 6.86 (t, J = 9.4 Hz, 1H), 6.75 (s, 1H), 6.74 - 6.63 (m, 1H), 6.25 (s, 2H), 4.99 (d, J = 7.0 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.56 (d, J = 10.7 Hz, 1H), 4.17 (dd, J = 12.3, 5.2 Hz, 1H), 3.87 (s, 3H), 3.23 - 3.09 (m, 2H), 2.86 (d, J = 12.9 Hz, 2H), 2.84 - 2.67 (m, 2H), 2.66 - 2.52 (m, 2H), 2.36 - 2.23 (m, 2H), 2.15 - 1.97 (m, 2H), 1.93 - 1.75 (m, 4H), 1.53 - 1.33 (m, 4H).

[1123] Example 46

[1124] ​Step 1 : Preparation of 3-(4-(4-((1-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperidin-4- yl)methyl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[1125] Under nitrogen, 3-(2,6-difluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine- 2,6-dione (100 mg, 0.25 mmol) was dissolved in DMF (1 mL), and 5-(3-([1,2,4]triazolo[1,5- a]pyridin-7-yl)-4-aminofurano[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (97 mg, 0.26 mmol), EDCI (70.9 mg, 0.37 mmol), DIEA (95.3 mg, 0.74 mmol), and HOBT (49.9 mg, 0.37 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 h. The reaction was directly purified by Flash (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(4-(4-((1-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofurano[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2,6-difluorophenyl)piperidine- 2,6-dione (7.2 mg, yield: 3.8%, white solid). LCMS: (ESI, m / z): [M+H] + = 764.3

[1126] 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.06 (dd, J = 7.1, 0.9 Hz, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.33 (dd, J = 7.0, 1.9 Hz, 1H), 6.72 (s, 1H), 6.64 (d, J = 12.8 Hz, 2H), 6.24 (s, 2H), 4.67 (d, J = 13.0 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1H), 4.06 (dd, J = 12.6, 5.2 Hz, 1H), 3.86 (s, 3H), 3.24 - 3.17 (m, 4H), 3.16 - 3.10 (m, 1H), 2.83 - 2.72 (m, 2H), 2.49 - 2.43 (m, 4H), 2.25 - 2.17 (m, 2H), 2.12 - 1.96 (m, 2H), 1.96 - 1.74 (m, 4H), 1.15 - 1.03 (m, 2H).

[1127] Example 47

[1128] Step 1: Preparation of 3-(2-((1'-(5-(4-amino-3-(benzo[d]thiazole-6-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-3- fluoropyridin-4-yl)piperidine-2,6-dione

[1129] Under nitrogen, 3-(2-([1,4'-dipiperidin]-4-ylamino)-3-fluoropyridin-4-yl)piperidine-2,6-dione (100 mg, 0.26 mmol) was dissolved in DMF (1 mL), and 5-(4-amino-3-(benzo[d]thiazol-6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (105.5 mg, 0.27 mmol), EDCI (74 mg, 0.39 mmol), DIEA (99.4 mg, 0.77 mmol), and HOBT (52 mg, 0.39 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 h. The reaction was purified directly by Flash (C18 column chromatography, 10-50% acetonitrile / water; gradient 10 min, UV 254 nm) to give 3-(2-((1'-(5-(4-amino-3-(benzo[d]thiazol-6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-dipiperidin]-4-yl)amino)-3-fluoropyridin-4-yl)piperidine-2,6-dione (7.2 mg, yield: 3.7%, white solid). LCMS: (ESI, m / z): [M+H] + = 763.3

[1130] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.50 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.67 (dd, J = 8.3, 1.5 Hz, 1H), 6.75 (s, 1H), 6.41 (t, J = 4.9 Hz, 1H), 6.37 (d, J = 6.8 Hz, 1H), 5.96 (s, 2H), 4.76 (d, J = 11.7 Hz, 1H), 4.56 (d, J = 10.9 Hz, 1H), 4.03 (dd, J = 12.5, 4.9 Hz, 1H), 3.88 (s, 3H), 3.83 (br, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.97 - 2.83 (m, 2H), 2.81 - 2.67 (m, 2H), 2.66 - 2.52 (m, 2H), 2.38 - 2.21 (m, 2H), 2.22 - 2.11 (m, 1H), 2.03 - 1.95 (m, 1H), 1.92 - 1.78 (m, 4H), 1.60 - 1.47 (m, 2H), 1.47 - 1.28 (m, 2H).

[1131] Example 50

[1132] Step 1: Preparation of 2,6-bis(benzyloxy)-2',5'-difluoro-3,4'-bipyridine

[1133] Under nitrogen protection, 4-bromo-2,5-difluoropyridine (5.0 g, 25.78 mmol) was dissolved in dioxane (50 mL) and water (5 mL). 2,6-bis(benzoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (11.83 g, 28.35 mmol), Cs₂CO₃ (21 g, 64.44 mmol), and Pd(dppf)Cl₂ (942 mg, 1.29 mmol) were added, and the mixture was stirred at 100 °C for 4 hours under nitrogen. After the reaction was complete, the mixture was cooled to room temperature, and water (400 mL) was added. The mixture was extracted with ethyl acetate (250 mL * 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100% - petroleum ether: ethyl acetate = 1:1) to give 2,6-bis(benzyloxy)-2',5'-difluoro-3,4'-bipyridine (6.5 g, yield: 62%, brown solid).

[1134] LCMS: (ESI, m / z): [M+H] + =405.1

[1135] Step 2: Preparation of tert-butyl 4-(2,6-bis(benzyloxy)-5'-fluoro-[3,4-bipyridine]-2'-yl)oxy)-[1,4'-bipiperidine]-1'-carboxylic acid

[1136] Under nitrogen protection, 2,6-bis(benzyloxy)-2',5'-difluoro-3,4'-bipyridine (2.0 g, 4.95 mmol) was dissolved in DMF (20 mL), and 4-hydroxy-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (1.55 g, 5.44 mmol) and potassium tert-butoxide (1.11 g, 9.89 mmol) were added. The mixture was stirred at room temperature for 5 hours under nitrogen. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL * 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to column chromatography (100–200 mesh silica gel, DCM = 100% -

[1137] DCM:MeOH = 30:1) was purified to give tert-butyl 4-(2,6-bis(benzyloxy)-5'-fluoro-[3,4-bipyridin]-2'-yl)oxy)-[1,4'-bipiperidine]-1'-carboxylic acid (1.55 g, yield: 46.86%, white solid).

[1138] LCMS: (ESI, m / z): [M+H] + = 669.3

[1139] Step three: Preparation of 3-(2-([1,4'-bipiperidinyl]-4-yloxy)-5-fluoropyridin-4- yl)piperidine-2,6-dione

[1140] tert-Butyl 4-(2,6-bis(benzyloxy)-5'-fluoro-[3,4-bipyridinyl]-2'-yloxy)-[1,4'- bipiperidinyl]-1'-carboxylate (750 mg, 1.12 mmol) was dissolved in HFIP (7.5 mL) under nitrogen protection, 10% Pd / C (500 mg, 55% water content) and TFA (0.5 mL) were added, and stirring was performed at 60 °C under hydrogen atmosphere for 16 hours. After cooling to room temperature, the reaction solution was filtered, the filter cake was washed with HFIP (40 mL), and the filtrate was combined and concentrated. Purification was performed using Flash (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to obtain 3-(2-([1,4'-bipiperidinyl]-4-yloxy)-5-fluoropyridin-4-yl)piperidine-2,6-dione (350 mg, yield: 79.93%, white solid).

[1141] LCMS: (ESI, m / z): [M+H] + = 391.2

[1142] Step four: Preparation of 3-(5-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1- yl)-3-fluoropyridin-2-yl)piperidine-2,6-dione

[1143] Under nitrogen, 3-(2-([1,4'-bipiperidin]-4-yloxy)-5-fluoropyridin-4-yl)piperidine-2,6-dione (75 mg, 0.19 mmol) was dissolved in DMF (1.5 mL), and 5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (75.2 mg, 0.19 mmol), EDCI (55.2 mg, 0.29 mmol), DIEA (74.5 mg, 0.58 mmol), and HOBT (38.9 mg, 0.29 mmol) were added. The reaction was stirred at room temperature for 4 hours under nitrogen. After the reaction was completed, the reaction solution was directly purified by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-(2-((1'-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)oxy)-5-fluoropyridin-4-yl)piperidine-2,6-dione (27.9 mg, yield: 19%, white solid). LCMS: (ESI, m / z): [M+H] + = 764.3

[1144] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.51 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 8.05 (s, 1H), 7.68 (dd, J = 8.3, 1.7 Hz, 1H), 6.80 (d, J = 4.9 Hz, 1H), 6.76 (s, 1H), 5.96 (s, 2H), 4.95 - 4.85 (m, 1H), 4.77 (d, J = 13.1 Hz, 1H), 4.56 (d, J = 12.7 Hz, 1H), 4.09 (dd, J = 12.9, 4.9 Hz, 1H), 3.88 (s, 3H), 3.13 (t, J = 12.7 Hz, 1H), 2.86 - 2.68 (m, 4H), 2.66 - 2.53 (m, 2H), 2.45 - 2.32 (m, 2H), 2.32 - 2.16 (m, 1H), 2.04 - 1.96 (m, 3H), 1.91 - 1.73 (m, 2H), 1.69 - 1.55 (m, 2H), 1.50 - 1.34 (m, 2H).

[1145] Example 51

[1146] Step one: Preparation of 3-(5-(4-((1-(5-(4-amino-3-(benzo[d]thiazol-5-yl)furo[3,2- c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-3- fluoropyridin-2-yl)piperidine-2,6-dione

[1147] Under nitrogen atmosphere, 3-(2-([1,4'-bipiperidin]-4-yloxy)-5-fluoropyridin-4-yl)piperidine- 2,6-dione (75 mg, 0.19 mmol) was dissolved in DMF (1.5 mL), and 5-(3-([1,2,4]triazolo[1,5- a]pyridin-7-yl)-4-aminofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (72.1 mg, 0.19 mmol), EDCI (55.2 mg, 0.29 mmol), DIEA (74.5 mg, 0.58 mmol), and HOBT (38.9 mg, 0.29 mmol) were added. The reaction was stirred at room temperature for 4 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was directly purified by Flash (C18 column chromatography, 10% - 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-(2-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- amino furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)oxy)-5- fluoropyridin-4-yl)piperidine-2,6-dione (20.6 mg, yield: 14.3%, white solid). LCMS: (ESI, m / z): [M+H] + = 748.3

[1148] 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.07 (dd, J = 6.9, 0.9 Hz, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.13 - 8.03 (m, 2H), 7.96 (s, 1H), 7.34 (dd, J = 7.0, 1.9 Hz, 1H), 6.80 (d, J = 4.9 Hz, 1H), 6.75 (s, 1H), 6.26 (s, 2H), 4.95 - 4.84 (m, 1H), 4.76 (d, J = 13.0 Hz, 1H), 4.56 (d, J = 12.7 Hz, 1H), 4.09 (dd, J = 12.8, 4.9 Hz, 1H), 3.87 (s, 3H), 3.13 (t, J = 12.4 Hz, 1H), 2.90 - 2.67 (m, 4H), 2.66 - 2.52 (m, 2H), 2.46 - 2.32 (m, 2H), 2.30 - 2.18 (m, 1H), 2.05 - 1.95 (m, 3H), 1.89 - 1.76 (m, 2H), 1.69 - 1.54 (m, 2H), 1.50 - 1.36 (m, 2H).

[1149] Example 52

[1150] Step one: Preparation of methyl 5-(4-amino-3-(quinolin-6-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylate

[1151] Methyl 5-(4-amino-3-bromofuro[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (1.0 g, 2.85 mmol) was dissolved in dioxane (10 mL) and water (1 mL) under nitrogen protection, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (765.8 mg, 2.99 mmol), K3PO4 (1.81 g, 8.54 mmol) and Pd(dppf)Cl2 (104 mg, 0.14 mmol) were added, stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (10 mL*3 times), the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, DCM = 100%-DCM:MeOH = 20:1) to give methyl 5-(4-amino-3-(quinolin-6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylate (450 mg, yield: 39.5%, brown solid). LCMS: (ESI, m / z): [M+H]+ = 401.1

[1152] Step two: Preparation of 5-(4-amino-3-(quinoxalin-6-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carboxylic acid

[1153] Methyl 5-(4-amino-3-(quinoxalin-6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H- pyrazole-3-carboxylate (430 mg, 1.07 mmol) was dissolved in a mixture of water (3 mL) and 3HF (1 mL) under nitrogen protection, and lithium hydroxide monohydrate (135 mg, 3.22 mmol) was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. The reaction was concentrated and the crude product was purified by Flash (C18 column chromatography, 5% to 45% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 5-(4-amino-3-(quinoxalin-6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carboxylic acid (130 mg, yield: 31.3%, white solid). LCMS: (ESI, m / z): [M+H] + = 387.1

[1154] Step three: Preparation of 3-((6-((1'-(5-(4-amino-3-(quinoxalin-6-yl)furo[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione

[1155] Under nitrogen, 3-((6-([1,4'-bipiperidin]-4-ylamino)-5-fluoropyridin-3-yl)amino)piperidine- 2,6-dione (50 mg, 0.12 mmol) was dissolved in DMF (1 mL), and 5-(4-amino-3-(quinoxalin-6- yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (47.7 mg, 0.12 mmol), EDCI (35.7 mg, 0.19 mmol), DIEA (48 mg, 0.37 mmol), and HOBT (25.1 mg, 0.19 mmol) were added. The reaction was stirred at room temperature for 4 hours under nitrogen. After the reaction was completed, the reaction solution was directly purified by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-((6-((1'-(5-(4-amino-3-(quinoxalin-6-yl)furo[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3- carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-5-fluoropyridin-3-yl)amino)piperidine-2,6-dione (13 mg, yield: 14%, white solid). LCMS: (ESI, m / z): [M+H] + = 773.3

[1156] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.08 - 8.97 (m, 2H), 8.32 (s, 1H), 8.28 - 8.22 (m, 2H), 8.08 (s, 1H), 8.05 (dd, J = 8.6, 2.0 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.97 (dd, J = 13.5, 2.3 Hz, 1H), 6.76 (s, 1H), 6.11 (s, 2H), 5.48 - 5.36 (m, 2H), 4.76 (d, J = 13.0 Hz, 1H), 4.62 - 4.48 (m, 1H), 4.21 - 4.13 (m, 1H), 3.88 (s, 3H), 3.67 - 3.58 (m, 1H), 3.12 (t, J = 12.4 Hz, 1H), 2.91 - 2.82 (m, 2H), 2.72 - 2.67 (m, 2H), 2.61 - 2.56 (m, 2H), 2.26 - 2.21 (m, 2H), 2.12 - 2.09 (m, 1H), 2.01 - 1.97 (m, 1H), 1.88 - 1.81 (m, 4H), 1.47 - 1.37 (m, 4H).

[1157] Example 53

[1158] Step one: Preparation of tert-butyl 4-((4-bromo-3,5-difluorophenyl)amino)- [1,4’-bipiperidine]-1’-carboxylate

[1159] Under nitrogen protection, 4-bromo-3,5-difluoroaniline (1.0 g, 4.81 mmol) was dissolved in anhydrous THF (20 mL), tert-butyl 4-oxo-[1,4’-bipiperidine]-1’-carboxylate (4.07 g, 14.42 mmol), glacial acetic acid (144 mg, 2.4 mmol) and trimethylchlorosilane (261 mg, 2.4 mmol) were added, sodium triacetylboration hydride (2.04 g, 12.02 mmol) was added in batches under ice bath, and the reaction was stirred at room temperature under nitrogen protection for 16 hours. After the reaction was completed, water (100 mL) was added, and ethyl acetate (50 mL*3 times) was used for extraction, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 2:1) to obtain tert-butyl 4-((4-bromo-3,5-difluorophenyl)amino)-[1,4’-bipiperidine]-1’-carboxylate (800 mg, yield: 35.08%, white solid).

[1160] LCMS: (ESI, m / z): [M+H] + = 474.1

[1161] Step two: Preparation of tert-butyl 4-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5- difluorophenyl)amino)-[1,4’-bipiperidine]-1’-carboxylate

[1162] Under nitrogen protection, 4-((4-bromo-3,5-difluorophenyl)amino)-[1,4'-bipiperidine]-1'- carboxylic acid tert-butyl ester (800 mg, 1.69 mmol) was dissolved in dioxane (10 mL) and water (1 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (774 mg, 1.86 mmol), Cs2CO3(1.37 g, 4.22 mmol) and Pd(dppf)Cl2(124 mg, 0.17 mmol) were added, stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (400 mL) was added, and ethyl acetate (250 mL*3 times) was used for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether = 100%- petroleum ether: ethyl acetate = 1:1) to obtain 4-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)-[1,4'-bipiperidine]-1'- carboxylic acid tert-butyl ester (610 mg, yield: 52.8%, brown solid).

[1163] LCMS: (ESI, m / z): [M+H] + = 685.3

[1164] Step three: Preparation of 3-(4-([1,4'-bipiperidine]-4-amino)-2,6-difluorophenyl)piperidine-2,6- dione

[1165] Under nitrogen protection, 4-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (610 mg, 0.89 mmol) was dissolved in HFIP (10 mL), 10% Pd / C (500 mg, containing 55% water) and TFA (0.5 mL) were added, and stirred at 60 °C for 16 hours under hydrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with HFIP (40 mL), and the filtrate was concentrated. The crude product was purified by Flash (C18 column chromatography, 10%-50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to obtain 3-(4-([1,4'-bipiperidine]-4-amino)-2,6-difluorophenyl)piperidine-2,6-dione (150 mg, yield: 41.4%, white solid).

[1166] LCMS: (ESI, m / z): [M+H] + = 407.2

[1167] Step four: Preparation of 3-(4-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- aminofuran[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4- yl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[1168] Under nitrogen, 3-(4-([1,4'-bipiperidin]-4-amino)-2,6-difluorophenyl)piperidine-2,6- dione (150 mg, 0.37 mmol) was dissolved in DMF (1.5 mL), and 5-(3-([1,2,4]triazolo[1,5- a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (138.5 mg, 0.37 mmol), EDCI (106 mg, 0.55 mmol), DIEA (143 mg, 1.11 mmol), and HOBT (74.8 mg, 0.55 mmol) were added. The reaction was stirred at room temperature under nitrogen for 4 hours. After the reaction was completed, the reaction solution was directly purified by Flash (C18 column chromatography, 10% to 50% acetonitrile / water; gradient 10 minutes, UV 254 nm) to give 3-(4-((1'-(5-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-aminofuran[3,2-c]pyridin-7-yl)-1- methyl-1H-pyrazole-3-carbonyl)-[1,4'-bipiperidin]-4-yl)amino)-2,6-difluorophenyl)piperidine- 2,6-dione (12 mg, yield: 4.3%, white solid). LCMS: (ESI, m / z): [M+H] + = 764.3

[1169] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.10 - 9.04 (m, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.18 (s, 0.6H, formate salt), 8.07 (s, ...

Claims

1. A compound of Formula V: ###0001### or a pharmaceutically acceptable salt thereof. wherein E3 is an E3 ligase ligand; For L2 is attached to the end of E3; L2, L3and L4are independently a single bond, NH, S, O, urea, -OCONH-, amide, ester, carbonyl, -SO-, -SO2-, -NHSO2-, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, C 2-6 alkynylene, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -NH(C 1-6 heteroalkylene)-, -CO-(C 1-6 alkylene)-, -CO-(C 1-6 heteroalkylene), -SO2-(C 1-6 alkylene)-, -SO2-(C 1-6 heteroalkylene), -CONH-(C 1-6 heteroalkylene), -OCO-(C 1-6 heteroalkylene), -COO-(C 1-6 heteroalkylene) or -(CH2CH2O) i , i is an integer from 1 to 8; Ring D, Ring E, and Ring F are independently absent, 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, or C 6-14 aryl; ii, iii, and iv are independently 0, 1, 2, or 3; R D , R E , and R F are independently deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 heteroalkyl, -OC 1-6 heteroalkyl, amino, -NHC 1-6 heteroalkyl, -SC 1-6 heteroalkyl, amido, carboxyl, cyano, or C 1-6 ester; is independently a single bond or a double bond; R 2 R 2L R 2b -Y- wherein R 2L is connected to the end of ring F; R 2L is a single bond, NH, S, O, amido, ureido, carbonyl, or -C 1-6 alkylene-; R 2b is a single bond, -NR 2b-1 -, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, - COR 2b-4 - or end and R 2L connect; R 2b-1 H, C 1-6 alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-12 membered heteroaryl; R 2b-3 is a single bond, C 1-6 alkylene, C 2-6 heteroalkylene, C 2b-3-1 substituted with one or more R 1-6 alkylene and C 2b-3-2 substituted with one or more R 2-6 heteroalkylene; R 2b-3-1 and R 2b-3-2 are independently H, deuterium, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino; R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkyleneamino or C 1-6 alkylene sulfide; z is 0, 1, 2, 3, or 4; The ring C is a 5-12-membered heteroaryl, 5-8-membered cycloalkenyl, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, or C 6-14 Aryl; L5 is a single bond or a carbonyl group; R 2b-5 independently halogen, deuterium, CN, OH, C 1-6 alkyl, C 1-6 alkyl-CO-R 2b-5-1 , C 1-6 heteroalkyl or -CO-R 2b-5-1 ; R 2b-5-1 OH, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio; Y is a single bond, O, -NR Y-1 -, S, C 1-6 alkylene, C 1-6 heteroalkylene, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, C 2-6 alkenylene, -CO-, ureido, ureido R Y-1 -, -COO-, -CONR Y-1 -, -SO2-, -SO-, -SO2NR Y-1 -, -NHS(O)2-, -NHSO-, -SONR Y-1 -, -NHC(O)-, -NHCOO-, -NHC(O)-NR Y-1 -, -OC(O)-NR Y-1 -, -NHC(O)-R Y-1 -, or -NHSO2-NR Y-1 -; R Y-1 independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-12 membered heteroaryl; X1 is CH or N; X2 and X3 are independently O, S, NH, N, or CH; X4, X5, and X6 are independently CH, C, or N; and X2, X3, X4, X5, and X6 are not simultaneously N; k is 0, 1, 2, 3, or 4; R 1 independently hydrogen, deuterium, halogen, CN, C 1-6 1-6C-alkyl, C 1-6 1-6C-alkyl, OR a , SR a , -NR b R c , -COOR a , -CONR b R c , -NHCONR b R c , SO2R a , SOR a , SO2NR b R c or -NHS(O)2R a ; R a , R b , and R c are independently H, C 1-6 1-6 alkyl, C 1-6 2-6 haloalkyl, C 6-14 2-6 heteroalkyl, 3-10 cycloalkyl, 3-10 heterocycloalkyl, C b 6 aryl, or 5-12 membered heteroaryl; or, R c , R a-1 , and the atom to which they are attached form a 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl, which is optionally substituted with one or more R R a-1 independently deuterium, halogen, hydroxyl, CN, or C 1-6 alkyl; Ring A is X7 is S, N, carbonyl, CH2, or CH; X8 is CH, NH, CH2, or N; X9is O, S, N, NH, -NR g -CH=CH-, -CH=N-, CH, CR h or CH2; X 10 is CH, N or C; X 11 is N or CH; X 12 is CH or N; X 13 is N or CH; X 14 is -CONH-, NH or CH2; X 15 is CH or N; X 16 is CH or N; and X 10 , X 11 , X 12 , X 15 and X 16 are not simultaneously N; n is 0, 1, 2, or 3; R 3 independently H, deuterium, hydroxyl, halogen, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3-1 substituted C 1-6 alkyl; R 3-1 independently halogen, deuterium, or hydroxyl; R g and R h are independently C 1-6 alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-12 membered heteroaryl, -COR i , -CONHR i , -COC 1-6 alkyl-R i , -SR i , -NR j R k , -COOR i , -CONR j R k , -NHCONR j R k , -SO2R i , -SOR i , -SO2NR j R k , or -NHS(O)2R i ; R i , R j , and R k are independently H, C 1-6 1-6 alkyl, C 1-6 2-6 haloalkyl, 3-10 cycloalkyl, 3-10 heterocycloalkyl, C 6-14 6 aryl, 5-12 heteroaryl, 3-10 cycloalkyl substituted with one or more R i-1 8, 3-10 heterocycloalkyl substituted with one or more R i-2 8, C i-3 6 aryl substituted with one or more R 6-14 8, or 5-12 heteroaryl substituted with one or more R i-4 8; or, R j , R k , and the atom to which they are attached form a 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl, optionally substituted with one or more R i-5 8. R i-1 R i-2 R i-3 R i-4 and R i-5 Independently deuterium, halogen, hydroxyl, CN, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 1-6 alkyl; C 1-6 heteroalkyl, C 2-6 heteroalkyl, 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl, C 1- the heteroatoms in the 6 heteroalkylene are independently selected from one or more of N, O, S, and P, and the number of heteroatoms is independently 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula V, The compound of Formula V is any one of the following: Scheme 1: The E3 ligase ligand is A1 is N or CH; A2 is CH2 or a single bond; L1 is a single bond, NH, CONH, or O; Ring B is a 5-12 membered heteroaryl or C 6-10 aryl; m is 0, 1, 2, 3, or 4; R 4 independently halogen, cyano, hydroxy, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or oxo; The 5-12 membered heteroaryl independently has 1, 2, 3, or 4 heteroatoms selected from the group consisting of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4. Preferably, the 5-12 membered heteroaryl independently has 1, 2, 3, or 4 heteroatoms selected from the group consisting of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4. Further preferably, when L1 is NH, CONH, or O, ring B is a monocyclic ring. Scheme 2: The E3 ligase ligand is R 5 , R 6 , R 7 , R 8 and R 9 are independently H, D, halogen, hydroxyl, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or oxo; Preferably, R 5 , R 6 , R 7 and R 8 are independently H, hydroxy or C 1-6 alkyl; Preferably, R 9 is H, D or C 1-6 alkyl; Scheme 3: E3、 as claimed in claim 1; is independently a single bond or a double bond; R 2 R 2L R 2b -Y- wherein R 2L is attached to the end of ring F; R 2L is a single bond, NH, S, O, amido, carbonyl, or -C 1-6 alkylene; Y is a single bond; R 2b is a single bond, - COR 2b-4 - or R 2b-3 is a single bond or C 1-6 alkylene; R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkylene sulfenyl, or C 1-6 alkyleneamino; z is 0, 1, 2, 3, or 4; The ring C is a 5-12-membered heteroaryl, 5-8-membered cycloalkenyl, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, or C 6-14 Aryl; L5 is a single bond or a carbonyl group; R 2b-5 independently C 1-6 alkyl; X1 is CH or N; X2 and X3 are independently O, S, NH, N, or CH; X4, X5, and X6 are independently C or N; k is 0, 1, 2, or 3; R 1 independently hydrogen or C 1-6 alkyl; Ring A is X7 is N, carbonyl, or CH; X8 is CH, NH, or N; X9 is O, S, N, NH, -CH=CH-, -CH=N-, CH, or CH2; X 10 is N or C; X 11 is N or CH; X 12 is CH or N; X 13 is N or CH; X 14 is -CONH-, NH or CH2; X 15 is CH or N; X 16 is CH or N; n is 0, 1, 2, or 3; R 3 independently H or C 1-6 alkyl; The 3-10 membered heterocycloalkyl and the 5-12 membered heteroaryl independently have 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, and S, and the number of heteroatoms is independently 1, 2, 3, or 4.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula V, The compound of Formula V is any one of the following: Scheme 1: The E3 ligase ligand is A1 is N or CH; A2 is CH2 or a single bond; L1 is a single bond, NH, CONH, or O; Ring B is a 5-12 membered heteroaryl or C 6-10 aryl, wherein the 5-12 membered heteroaryl has heteroatoms independently selected from 1, 2, 3, or 4 of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; R 4 independently halogen, cyano, hydroxy, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or oxo; For wherein L2 is attached to ring B; L2and L3are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene) or -OCONH-(C 1-6 alkylene). ii and iii are independently 0, 1, 2, or 3; Ring D is a 3-12 membered heterocycloalkyl or a 3-12 cycloalkyl, wherein the 3-12 membered heterocycloalkyl independently has 1, 2, or 3 heteroatoms selected from the group consisting of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4. Ring E is a 3-12 membered heterocycloalkyl or a 3-12 cycloalkyl, wherein the 3-12 membered heterocycloalkyl independently has 1, 2, or 3 heteroatoms selected from the group consisting of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4. R D and R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; is independently a single bond or a double bond; R 2 R 2L R 2b -Y- wherein R 2L is connected to the end of ring F; R 2L is a single bond, NH, S, O, amido, carbonyl, or -C 1-6 alkylene; Y is a single bond; R 2b is a single bond, -COR 2b-4 - or R 2b-3 is a single bond or C 1-6 alkylene; R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkylenethio or C 1-6 alkylenamino; z is 0, 1, 2, 3, or 4; CycloC is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, or C 6-14 aryl, wherein the heteroatoms in the 3-10 membered heterocycloalkyl are independently selected from one or more of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4, and the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4; L5 is a single bond or a carbonyl group; R 2b-5 independently C 1-6 alkyl; X1 is CH or N; X2 and X3 are independently O, S, NH, N, or CH; X4, X5, and X6 are independently C or N; k is 0, 1, 2, or 3; R 1 independently hydrogen or C 1-6 alkyl; Ring A is X7 is N, carbonyl, or CH; X8 is CH, NH, or N; X9 is O, S, N, NH, -CH=CH-, -CH=N-, CH, or CH2; X 10 is N or C; X 11 is N or CH; X 12 is CH or N; X 13 is N or CH; X 14 is -CONH-, NH or CH2; X 15 is CH or N; X 16 is CH or N; n is 0, 1, 2, or 3; R 3 independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3-1 alkyl substituted with one or more R 1-6 alkyl; R 3-1 independently halogen, deuterium, or hydroxyl; Scheme II: The E3 ligase ligand (E3-) is A1 is CH; A2 is CH2; L1 is a single bond or NH; Ring B is a 5-12 membered heteroaryl or C 6-10 aryl, wherein the 5-12 membered heteroaryl has heteroatoms independently selected from 1, 2, 3, or 4 of S, N, O, and P, and the number of heteroatoms is independently 1, 2, 3, or 4; m is 1 or 2; R 4 independently halogen or oxo, oxo substituting on a non-aromatic ring; For wherein L2 is attached to ring B; L2and L3are independently a single bond, NH, or -C 1-6 alkylene-; ii and iii are independently 0 or 1 ; R D and R E independently halogen or hydroxy; ring D is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl has 1, 2, or 3 heteroatoms independently selected from S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4; ring E is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl has 1, 2, or 3 heteroatoms independently selected from S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4; independently a single bond or a double bond; R 2 -R 2L -R 2b -Y- wherein R 2L is linked to Linker; R 2L is carbonyl; Y is a single bond; R 2b for z is 1; ring C is a 5-12 membered heteroaryl (5-6 membered heteroaryl), wherein the 5-12 membered heteroaryl has 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; L5 is a single bond; R 2b-5 independently C 1-6 alkyl; X1 is CH; X2 is O or S; X3 is CH; X4, X5, and X6 are independently C; k is 0; Ring A is X7 is N or CH; X8 is CH; X9 is S, N, or -CH=N-; X 10 is N or C; X 11 is CH; X 12 is CH; X 15 is CH; X 16 is CH; n is 0, 1, 2, or 3; R 3 independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3-1 alkyl substituted with one or more R 1-6 alkyl; R 3-1 independently halogen, deuterium, or hydroxyl.

4. The compound of claim 2, represented by Formula V: ###0002### or a pharmaceutically acceptable salt thereof. E3 ligase ligand is any one of the following schemes: Scheme I: The For A1 is N or CH; A2 is CH2 or a single bond; A3 is -CH2- or -CO-; A4 and A5 are -CH- or N; Scheme II: The In particular, ring B is Scheme III: The For independently a single bond or a double bond; A1 is N or CH; A2 is CH2 or a single bond; A6 is S, N, -CO-, CH2, or CH; A7 is CH, CH2, NH, or N; A8 is O, S, N, NH, -CH=CH-, -CH=N-, CH, or CH2.

5. The compound of Formula V or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the compound of Formula V is any one of the following schemes: (1) For (2) the 5-12 membered heteroaryl is a 5-6 membered monocyclic heteroaryl or a 9-12 membered annelated heteroaryl, the heteroatoms can be one or both of N or O, the number of heteroatoms can be one or two, for example the 5-12 membered heteroaryl is The 5-6 membered monocyclic heteroaryl is for example (3) in the E3 ligase ligand, in ring B, said C 6-10 aryl is phenyl or naphthyl, for example phenyl; (4) the halogen is independently fluorine, chlorine, or bromine, for example fluorine or chlorine; (5) the C 1-6 alkylamino is independently -NH-methyl, -NH-ethyl, -NH-n-propyl, -NH-i-propyl, -NH-n-butyl, -NH-i-butyl, -NH-sec-butyl, or -NH-t-butyl; (6) the C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, for example methyl; (7) said C 1-6 alkoxy is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-i-propyl, -O-n-butyl, -O-i-butyl, -O-s-butyl, or -O-t-butyl; (8) said C 1-6 alkylthio is independently -S-methyl, -S-ethyl, -S-n-propyl, -S-i-propyl, -S-n-butyl, -S-i-butyl, -S-sec-butyl, or -S-t-butyl; (9) the C 1-6 alkylene is independently methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, or t-butylene; (10) said C 1-6 in the heteroalkylene group is one or two of N, O and S, the number of heteroatoms being independently one or two, said C 1-6 heteroalkylene is for example C 3-4 heteroalkyl, can be -CH2NHCH2-, -CH2OCH2-, -CH2SCH2-, -CH(CH3)NH- or -CH2N(CH3)-, preferably C 1-6 alkyleneoxy, C 1-6 alkyleneamino or C 1-6 alkylthio; (11) said C 2-6 Alkylene contains 1, 2 or 3 carbon-carbon double bonds, preferably said C 2-6 Alkylene is C2-C3alkylene, for example ethylene or propylene; (12) said C 2-6 Alkynylene contains one, two or three carbon-carbon triple bonds, preferably said C 2-6 Alkynylene is C2-C3alkynylene, for example ethynylene or propynylene; (13) the 5-8 membered cycloalkenyl is independently a 5-6 membered monocyclic cycloalkenyl, preferably having 1 or 2 carbon-carbon double bonds, and the heteroatom can be N, O, or S; (14) the 3-12 membered cycloalkyl is a monocyclic, fused, spiro, or bridged 3-12 membered cycloalkyl, for example a 3-6 membered monocyclic cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl; (15) the 3-12 membered heterocycloalkyl is a monocyclic, annelated, spiro or bridged 3-12 membered heterocycloalkyl, the heteroatoms can be 1 or 2 of N, S or O, preferably a 7-12 membered annelated or spiro heterocycloalkyl; the 3-6 membered monocyclic heterocycloalkyl is, for example, The 7-12 membered fused or spirocyclic heterocycloalkyl group is for example (16) said C 6-14 aryl is phenyl or naphthyl; (17) said C 2-6 in the heteroalkylene group is one or two of N, O and S, the number of heteroatoms being independently one or two, said C 2-6 heteroalkylene is for example C 3-4 heteroalkyl, can be -CH2NHCH2-, -CH2OCH2-, -CH2SCH2-, -CH(CH3)NH- or -CH2N(CH3)-, preferably C 2-6 alkoxy, C 2-6 alkylthio or C 2-6 alkylamino; (18) said C 1-6 ester groups are independently -COO-C 1-4 alkyl, for example -COO-methyl, -COO-ethyl, -COO-n-propyl, -COO-i-propyl or -COO-n-butyl; (19) the 3-10 membered cycloalkyl can be a monocyclic, fused, spiro, or bridged 3-10 membered cycloalkyl, for example a 3-6 membered monocyclic cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl; (20) the 3-10 membered heterocycloalkyl can be a monocyclic, fused, spiro, or bridged 3-10 membered heterocycloalkyl, and the heteroatom can be 1 or 2 of N, S, or O, preferably a 3-6 membered monocyclic heterocycloalkyl; (21) said C 6-10 aryl is phenyl or naphthyl; (22) said C 1-6 alkyleneoxy is methyleneoxy, ethyleneoxy, n-propyleneoxy, i-propyleneoxy, n- butyleneoxy, i-butyleneoxy, sec-butyleneoxy or t-butyleneoxy; (23) said C 1-6 alkylthio is methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio or t-butylthio; (24) said C 1-6 Heteroaryloxy is, for example, 2-furyloxy, 2-thienyloxy, 5-hydroxythien-2- yloxy, 3-hydroxythien-2-yloxy, 2-benzofuryloxy, 5-benzofuryloxy, 6-benzofuryloxy, 7-benzofuryloxy, 8-benzofuryloxy, 2-chromen-2-yloxy, 3-chromen-3-yloxy, 4-chromen-4-yloxy, 2- isochromen-1 - 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula V, which satisfies one or more of the following conditions: (1) in ring A, For (2) in ring A, For (3) in ring A, For (4) R 2L is a single bond, NH, S, O, amido, carbonyl, or -C 1-6 alkylene, e.g., R 2L is a single bond, O, carbonyl, or -C 1-6 alkylene; (5) is not a single bond; (6) Y is a single bond; (7) R 2b is a single bond, - COR 2b-4 - or Preferably, -R 2L -R 2b In -Y-, -R 2b - is - Y- is a single bond, L5 is a single bond or a carbonyl group, R 2L is a single bond, NH or C 1-6 alkylene; or -R 2L -R 2b in -Y-, -R 2b is -Y- and R 2b-3 is a single bond, R 2L is a single bond, O or C 1-6 alkylene; or -R 2L -R 2b in -Y- 2L is - Y- is a single bond, R 2L is a single bond, R 2b-3 is a single bond or C 1-6 alkylene; (8) R 2b-4 is a single bond; (9) z is 0 or 1; (10) ring C is a 5-12 membered heteroaryl or a 3-10 membered heterocycloalkyl; (11) R 2b-5 independently C 1-6 alkyl or -CO-R 2b-5-1 , for example C 1-6 alkyl; (12) k is 0 or 1; (13) R 1 independently hydrogen or C 1-6 alkyl, for example C 1-6 alkyl; (14) X8 is CH or NH; (15) X9 is S, N, -CH=CH- or -CH=N-; (16) X 11 and X 13 is CH; (17) n is 0; (18) R 3 independently hydrogen or C 1-6 alkyl, for example C 1-6 alkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula V, which satisfies one or more of the following conditions: (1) -L2-L3-L4-, L2 is connected to ring B; (2) Ring D, Ring E, and Ring F are independently 3-12 membered heterocycloalkyl, for example, are Preferably, is any of the following: Scheme 1: L2, L3and L4are independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), -C 1-6 alkylene-, -0(C 1- alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), -COO-(C 1-6 alkylene) or -(CH2CH2O) i , i is an integer from 1 to 8; Preferably, L2, L3and L4are independently a single bond, NH, O, amido, ester, carbonyl, C 1-6 alkylene, -NH(C 1-6 alkylene)- or -(CH2CH2O) i , i being an integer from 1 to 8; further preferably, L2is independently a single bond, NH, S, O, amido (-CONH-), carbonyl (-CO-), or C 1-6 alkylene; L3and L4are C 1-6 alkylene or -(CH2CH2O) i , i being an integer from 1 to 8; Scheme 2: L2is a single bond, NH, O, S, -O(C 1-6 alkylene)-, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -S(C 1- 6alkylene)-, -NH(C 1-6 heteroalkylene)-, -NH(C 1-6 alkylene)-, amido, or carbonyl; L3is a single bond, C 1-6 alkylene, C 1-6 heteroalkylene, amido, or carbonyl; L4is a single bond, NH, amido, carbonyl, or -CO-(C 1-6 alkylene)-; Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; iii is independently 0, 1, 2 or 3; R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; said 3-12 membered heterocycloalkyl, C 1-6 in the heteroalkylene group, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4; Preferably, ring E is 3-12 membered heterocycloalkyl, L2is NH or -NH(C 1-6 alkylene)-; L3is a single bond, C 1-6 alkylene or carbonyl; L4 is a single bond; iii is independently 0, 1, 2 or 3; R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; Scheme 3: L2and L3are independently a single bond, NH, S, O, amido, carbonyl, -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1- 6alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene) or -OCONH-(C 1-6 alkylene); ii and iii are independently 0, 1, 2 or 3; Ring D is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; R D and R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; In the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, Ring D is 3-12 membered heterocycloalkyl; Ring E is 3-12 membered heterocycloalkyl L2and L3are independently a single bond, NH, S, O, amido, carbonyl, or -C 1-6 alkylene-; ii and iii are independently 0, 1, 2 or 3; R D and R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; Scheme Four: L2, L3, and L4are independently a single bond, NH, S, O, amido, carbonyl, -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene), or -OCONH-(C 1-6 alkylene). ii, iii and iV are independently 0, 1, 2 or 3; Ring D is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; Ring F is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; R D , R E , R F independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; In the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, ring D is 3-12 membered heterocycloalkyl; Ring E is 3-12 membered heterocycloalkyl; Ring F is 3-12 membered heterocycloalkyl; ii, iii and iV are independently 0, 1, 2 or 3; R D , R E , R F independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; L2, L3and L4are independently a single bond or -C 1-6 alkylene-.

8. The compound of formula V as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, which satisfies one or more of the following conditions: (1) A1 is CH; (2) A2 is CH2; (3) L1 is a single bond or NH; (4) Ring B is a 5-12 membered heteroaryl or C 6-10 aryl, preferably 6 or 9 membered heteroaryl or phenyl, wherein the heteroatoms in the heteroaryl are independently selected from 1, 2, 3 or 4 of S, N, O and P, and the number of heteroatoms is independently 1, 2, 3 or 4; (5) m is 1 or 2; (6) R 4 independently halogen or oxo, oxo substituting on a non-aromatic ring; (7) ii and iii are independently 0 or 1; (8) R D and R E independently halogen or hydroxy; (9) L2and L3are independently a single bond, NH, or -C 1-6 alkylene-; (10) Ring D is 3-12 membered heterocycloalkyl, preferably 5-6 membered heterocycloalkyl, wherein in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; (11) Ring E is 3-12 membered heterocycloalkyl, preferably 5-6 membered heterocycloalkyl, wherein in the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; (12) R 2L is carbonyl; (13) Y is a single bond; (14) R 2b For (15) z is 1; (16) Ring C is a 5-12 membered heteroaryl, preferably a 5-6 membered heteroaryl, for example wherein in the heteroaryl, the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; (17) L5 is a single bond; (18) R 2b-5 independently C 1-6 alkyl, for example methyl; (19) X1 is CH; (20) X2 and X3 are independently O, S or CH, preferably X2 is O or S; X3 is CH; (21) X4, X5 and X6 are independently C; (22) k is 0, 1, 2 or 3, for example 0; (23) R 1 independently hydrogen or C 1-6 alkyl; (24) Ring A is (25) X7 is N or CH; (26) X8 is CH; (27) X9 is S, N or -CH=N-; (28) X 10 is N or C; (29) X 11 is CH; (30) X 12 is CH; (31) X 15 is CH; (32) X 16 is CH; (33) n is 0; (34) R 3 independently H, deuterium, halogen, hydroxyl, cyano, C 1-6 heteroalkyl, C 1-6 alkyl or C 3-1 substituted C 1-6 alkyl; (35) R 3-1 independently halogen, deuterium, or hydroxyl.

9. The compound of Formula V as claimed in claim 1, or pharmaceutically acceptable salts thereof, wherein, which satisfies one or more of the following conditions: (1) For (2) For (3) the For either of the following structures:

10. The compound of formula V as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, the compound of Formula V is a compound of Formula V-1; A2, L1, Ring B, m, R 4 , X1, X2, X3, X4, X5, X6, k, R 2 , Ring A, n, R 1 , X1, X2, X3, X4, X5, X6, k, R 3 as in any one of claims 1-3; -L2-L3-L4-; L2 is attached to the end of ring B; L2, L3and L4are independently a single bond, NH, S, O, amido, carbonyl, -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1- 6alkylene), -COO-(C 1-6 alkylene) or -(CH2CH2O) i i is an integer from 1 to 8; Preferably; L2is independently a single bond, NH, S, O, amido, carbonyl, or C 1-6 alkylene; L3and L4are C 1-6 alkylene or -(CH2CH20) i i is an integer from 1 to 8; Further preferably; For wherein is attached to ring B; Alternatively, the compound of Formula V is a compound of Formula V-2; A2, A1, L1, ring B, m, R 4 , X1, X2, X3, X4, X5, X6, k, R 2 , ring A, n, R 1 , X1, X2, X3, X4, X5, X6, k, R 3 as in any one of claims 1-3; For L2 is attached to the end of ring B; L2is a single bond, NH, O, S, -O(C 1-6 alkylene)-, -O(C 1-6 heteroalkylene)-, -S(C 1-6 heteroalkylene)-, -S(C 1- alkylene)-, -NH(C 1-6 heteroalkylene)-, -NH(C 1-6 alkylene)-, amido, or carbonyl; L3is a single bond, C 1-6 alkylene, C 1-6 heteroalkylene, amido, or carbonyl; L4is a single bond, NH, amido, carbonyl, or -CO-(C 1-6 alkylene)-; Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; iii is independently 0, 1, 2 or 3; R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; said 3-12 membered heterocycloalkyl, C 1-6 in the heteroalkylene group, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4; Preferably, Ring E is a 3-12 membered heterocycloalkyl, L2is NH or -NH(C 1-6 alkylene)-, L3is a single bond, C 1-6 alkylene or carbonyl, L4is a single bond; Further preferably, For wherein is attached to ring B; Alternatively, the compound of Formula V is a compound according to Formula V-3; A2, A1, L1, ring B, m, R 4 , X1, X2, X3, X4, X5, X6, k, R 2 , ring A, n, R 1 , X1, X2, X3, X4, X5, X6, k, R 3 as in any one of claims 1-3; For L2 is attached to the end of ring B; L2and L3are independently a single bond, NH, S, O, amido, carbonyl, -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1- 6alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1-6 alkylene) or -OCONH-(C 1-6 alkylene); ii and iii are independently 0, 1, 2 or 3; Ring D is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; R D and R E independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; In the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, Ring D is 3-12 membered heterocycloalkyl; Ring E is 3-12 membered heterocycloalkyl; L2and L3are independently a single bond, NH, S, O, amido, carbonyl, or -C 1-6 alkylene-; Further preferably, For wherein is attached to ring B; Alternatively, the compound of Formula V is a compound of Formula V-4; A2, A1, L1, ring B, m, R 4 , X1, X2, X3, X4, X5, X6, k, R 2 , ring A, n, R 1 , X1, X2, X3, X4, X5, X6, k, R 3 as in any one of claims 1-3; For L2 is attached to the end of ring B; L2, L3and L4are independently a single bond, NH, S, O, amido, carbonyl, -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1- 6alkylene) or -OCONH-(C 1-6 alkylene); ii, iii and iv are independently 0, 1, 2 or 3; Ring D is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; Ring E is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; Ring F is 3-12 membered heterocycloalkyl or 3-12 membered cycloalkyl; R D , R E , R F is independently deuterium, halogen, hydroxyl or C 1-6 alkyl; In the 3-12 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, Ring D is 3-12 membered heterocycloalkyl; Ring E is 3-12 membered heterocycloalkyl; Ring F is 3-12 membered heterocycloalkyl; ii, iii and iv are independently 0, 1, 2 or 3; R D , R E , R F is independently deuterium, halogen, hydroxyl or C 1-6 alkyl; L2, L3and L4are independently a single bond or -C 1-6 alkylene-; Alternatively, the compound of Formula V is a compound of Formula V-5; R 5 , R 6 , R 9 , R 7 , R 8 , R 2 , X1, X2, X3, X4, X5, X6, k, R 1 , ring A, n, R 3 as in claim 1 ; -L2-L3-L4-, L4is attached to R 2 terminal connection; L2, L3and L4are independently a single bond, NH, S, O, amido, carbonyl, -C 1-6 alkylene-, -0(C 1-6 alkylene)-, -S(C 1-6 alkylene)-, -NH(C 1-6 alkylene)-, -CO-(C 1-6 alkylene)-, -SO2-(C 1-6 alkylene)-, -CONH-(C 1- 6alkylene), -COO-(C 1-6 alkylene) or -(CH2CH2O) i i is an integer from 1 to 8; Preferably, L2is independently a single bond, NH, S, O, amido, carbonyl, or C 1-6 alkylene; L3and L4are C 1-6 alkylene or -NH(C 1-6 alkylene)-; Further preferably, For wherein End with R 2 Connection.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, having the formula V, it meets one or more of the following conditions: (1) Ring D is 3-12 membered heterocycloalkyl; Ring E is 3-12 membered heterocycloalkyl; (2) In the compound represented by formula V-3, A1 and A2 are CH; (3) In the compound represented by formula V-3, when A1 is CH, ring B is phenyl or 6-membered heteroaryl; (4) in the compound of Formula V-3, R 2 is -R 2L is -R 2b is -R 2L and -Y- is a single bond, R 2b is (5) In the compound represented by formula V-3, ring C is 5-12 membered heteroaryl; (6) in the compound represented by Formula V-3, R 2b-3 is a single bond; (7) in the compound of Formula V-3, R 2b-5 is C 1-6 alkyl; (8) a compound represented by V-3, For (9) Ring B is a 9-10 membered fused heterocycloalkyl, wherein the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4, for example, Ring B is (10) Ring B is C 10-14 heteroaryl, said C 10-14 The fused aryl group can be formed by two aromatic rings, an aromatic ring or a non-aromatic ring fused ring; (11) Ring B is a 6-membered heteroaromatic ring or a benzene ring, which contains 0-2 N atoms, for example For either of the following structures (12) In ring D, ring E, ring F, the 3-12 membered heterocycloalkyl is 4-6 membered heterocycloalkyl, wherein the heteroatoms are independently selected from N, and the number of heteroatoms is independently 1 or 2; (13) In ring D, ring E, ring F, the 3-12 membered heterocycloalkyl is 4-6 membered cycloalkyl, such as cyclobutyl, cyclopentyl or cyclohexyl; (14) L2 and L3 are not single bonds at the same time; (15) In ring A, the 5-12 membered heteroaryl is a fused ring, wherein the heteroatoms are independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatoms is independently 1, 2, 3 or 4; (16) L2and L3are independently a single bond, NH, S, O, amido, carbonyl, or -C 1-6 alkylene-.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula V, The compound of Formula V is any one of the following compounds:

13. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof. wherein, X1, X2, X3, X4, k, R 1 , Y, R 2b , ring A, n and R 3 as in any one of claims 1-10; R 2a is hydrogen, halogen, CN, hydroxyl, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio; Ring A is Preferably, the compound represented by formula I meets any of the following conditions: (1) in the compound of Formula I, X2is O, NH, N, NR 1 or CR 1 ; (2) In the compound represented by formula I, X7 is carbonyl, and X8 is NH; (3) in the compound of formula I, X7is N, X9is O or S; or X8, X9and X 10 containing 1, 2 or 3 N; (4) in the compound of formula I, X 15 and / or X 16 is N; (5) in the compound of formula I, ring A is 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein It is any of the following schemes: Scheme One: In the compound of formula I or its pharmaceutically acceptable salt, wherein, is independently a single bond or a double bond; X1 is CH or N; X2 is O, S, NH, N or CH; X3 is CH, N or NH; X4 is C or N; k is 0, 1, 2 or 3; R 1 independently hydrogen or C 1-6 alkyl; R 2a is hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkylthio or C 1-6 alkylamino; Y is a single bond; R 2b is a single bond, - COR 2b-4 - or R 2b-3 is a single bond, C 1-6 alkylene or C 2b-3-1 alkylene substituted by 1, 2 or 3 R 1-6 alkylene; R 2b-3-1 is H, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 alkylthio; R 2b-4 is a single bond, C 1-6 alkyleneoxy, C 1-6 alkyleneamino or C 1-6 alkylene sulfide; z is 0, 1, 2, 3 or 4; Cycloalkyl is a saturated or partially saturated carbocyclic ring of 3 to 10 carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can be unsubstituted or substituted with one or more substituents as described herein. Cycloalkyl groups can be attached to the rest of the molecule through a carbon atom of the cycloalkyl group. Ring C is a 5-12 membered heteroaryl, a 5-8 membered cycloalkenyl, a 3-10 membered cycloalkyl, a 3-10 membered heterocycloalkyl, or a C 6-14 Aryl; in the 5-12 membered heteroaryl, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4; in the 3-10 membered heterocycloalkyl, the heteroatoms are independently selected from 1, 2, or 3 of S, N, and O, and the number of heteroatoms is independently 1, 2, 3, or 4. L5is a single bond or carbonyl; R 2b-5 independently deuterium, halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, or C 1-6 alkylamino; Ring A is X7 is N, carbonyl or CH; X8 is CH, NH or N; X9 is O, S, N, NH, -CH=CH-, -CH=N-, CH or CH2; X 10 is N or C; X 11 is N or CH; X 12 is CH or N; X 13 is N or CH; X 14 is -CONH-, NH or CH2; X 15 is CH or N; X 16 is CH or N; and X 10 , X 11 , X 12 , X 15 and X 16 are not simultaneously N; n is 0, 1, 2 or 3; R 3 independently H, deuterium, hydroxyl, halogen or C 1-6 alkyl, preferably H, deuterium, halogen or C 1-6 alkyl; Scheme 2: the compound of formula I, wherein independently single bond or double bond; X1is CH or N; X2is O, S, NH, N or CH; X3is CH, N or NH; X4is C or N; k is 0 or 1; R 1 is C 1-6 alkyl; R 2a is hydrogen, hydroxyl, halogen or C 1-6 alkoxy; Y is single bond; R 2b is a single bond, -COR 2b-4 - or R 2b-3 for C 1-6 alkylene; R 2b-3-1 is C 1-6 alkoxy; R 2b-4 is a single bond; L5is single bond or carbonyl; z is 0, 1 or 2; Ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl or 3-10 membered heterocycloalkyl; in the 5-12 membered heteroaryl, the heteroatom is independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatom is independently 1, 2, 3 or 4; in the 3-10 membered heterocycloalkyl, the heteroatom is independently selected from 1, 2 or 3 of S, N and O, and the number of heteroatom is independently 1, 2, 3 or 4; R 2b-5 independently C 1-6 alkyl; Ring A is X7is S, N, carbonyl or CH2; X8is CH, NH or N; X9is O, S, N, NH, -CH=CH- or -CH=N-; X 10 is N or C; X 11 is N or CH; X 12 is CH or N; X 15 is CH or N; X 16 is CH or N; n is 0.

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein which satisfies one or more of the following conditions: (1) in the compound of formula I, X2is O or S; X3is CH, and X4is C; (2) in the compound of formula I, X2is NH or NCH3, and X3is N; (3) For the terminal is connected with X4; Alternatively, X7is N, X8is CH, X9is O or S, X 10 is C, X 11 is CH, X 15 is CH, X 16 is CH, X 12 is CH; Alternatively, X7is N, X8is CH, X9is N, X 10 is N, X 11 is CH, X 15 is CH, X 16 is CH, X 12 is CH; Alternatively, X7is carbonyl, X8is NH, X9is -CH=CH-, X 10 is C, X 11 is CH, X 15 is CH, X 16 is CH, X 12 is CH; (4) For -Y-R 2b -R 2a H, halogen, or -COR 2b-4 -R 2a ; (5) Ring C is a 5-12 membered aromatic heterocycle, C 6-14 membered aromatic ring, a 3-10 membered cycloalkyl, or a 3-10 membered heterocycloalkyl, for example, -Y-R 2b -R 2a is (6) the compound of formula I satisfies any one of the following conditions: (a) when X2is S, X7, X8and X9are -N=CH-S-, R 2b is L5is carbonyl; (b) when X2is S, X7, X8and X9are -N=CH-O-, R 2b is Ring C is 5-12 membered heteroaryl, 5-8 membered cycloalkenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl or naphthyl; (c) when X2is S and X9is NH, X7is S, N, carbonyl or CH2.

16. The compound of claim 13 having the formula I: ###0002### or a pharmaceutically acceptable salt thereof. which satisfies one or more of the following conditions: (1) For (2) For (3) R 1 is methyl; (4) For I, H, 17. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein The compound of Formula I is any one of the following compounds:

18. A pharmaceutical composition, characterized by, which is any one of the following schemes: Scheme (1): comprising the compound of formula V as claimed in any one of claims 1-12 or a pharmaceutically acceptable salt thereof, and pharmaceutical adjuvants; Scheme (2): comprising the compound of formula I as claimed in any one of claims 13-17 or a pharmaceutically acceptable salt thereof, and pharmaceutical adjuvants.

19. Use of the compound of formula V as claimed in any one of claims 1-12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of scheme (1) as claimed in claim 18; the use comprises: (1) as a receptor-interacting protein-2 degrader; (2) for preparing a drug for treating or preventing a disease or disorder mediated by receptor-interacting protein-2; for example, diseases related to inflammation and immune response, preferably diseases related to abnormal activation of NOD signaling pathway; Further preferably, the disease is an inflammatory disease, for example, inflammatory bowel disease, rheumatoid arthritis, inflammatory skin disease, cancer, autoimmune disease, metabolic disease, allergic disease, atherosclerosis or cardiovascular disease or irritable bowel syndrome; the inflammatory bowel disease is for example Crohn's disease or ulcerative colitis, the autoimmune disease is for example multiple sclerosis or systemic lupus erythematosus; the metabolic disease is for example type 2 diabetes; the allergic disease is for example asthma and allergic rhinitis.

20. Use of a compound of Formula I: ###0002### or a pharmaceutically acceptable salt thereof. wherein, X1, X2, X3, X4, k, R 1 , Y, R 2b , R 2a , ring A, n and R 3 as in any one of claims 1-17; Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof is the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 13-17; The use includes: (1) as a receptor-interacting protein-2 inhibitor; (2) for preparing a medicament for treating or preventing a receptor-interacting protein-2 mediated disease or disorder; for example, a disease associated with inflammation and immune response, preferably a disease associated with abnormal activation of NOD signaling pathway; Preferably, the medicament, the inhibitor further comprises a pharmaceutical excipient; Further preferably, the disease is an inflammatory disease, for example, a sepsis enteropathy, rheumatoid arthritis, an inflammatory skin disease, a cancer, an autoimmune disease, a metabolic disease, an allergic disease, atherosclerosis or a cardiovascular disease, or irritable bowel syndrome; the inflammatory bowel disease is, for example, Crohn's disease or ulcerative colitis, the autoimmune disease is, for example, multiple sclerosis or systemic lupus erythematosus; the metabolic disease is, for example, type 2 diabetes; the allergic disease is, for example, asthma and allergic rhinitis.

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