Compound for selectively degrading smarca2 / 4 and use thereof

Abstract

The present disclosure relates to a compound used as a SMARCA2 / 4 modulator. Specifically, the compound in the present disclosure on one end contains a ligand that binds to E3 ubiquitin ligase, and on the other end contains a ligand that binds to a target protein (SMARCA2 / 4), so that the target protein is placed near the ubiquitin ligase, so as to achieve degradation (or inhibition) of the target protein.

Description

Compounds selectively degrading smarca2 / 4 and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024110302904, filed on July 30, 2024, No. 2024114155834, filed on November 11, 2024, No. 2024117862004, filed on December 6, 2024, No. 2024119671158, filed on December 30, 2024, No. 2025100965116, filed on May 22, 2025, No. 2025102294262, filed on May 28, 2025, No. 2025104494085, filed on April 11, 2025, No. 2025105334295, filed on April 26, 2025, No. 2025106373649, filed on May 19, 2025, the contents of all of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present disclosure relates to the field of medicine, in particular to a compound or its pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph which can selectively degrade SMARCA2 / 4, and its use in preventing or treating diseases or disorders mediated by SMARCA2 / 4. BACKGROUND

[0003] SMARCA2 / 4 is an important subunit of SWI / SNF chromatin remodeling complex, also known as BAF complex. Chromatin is the carrier of genetic information in eukaryotes, which is composed of DNA and nucleosomes, and usually presents a highly condensed state. When the gene at a specific site needs to be transcribed, chromatin is converted from a condensed state to a loose state, which requires the participation of chromatin remodeling complexes. Chromatin remodeling complex uses the energy of ATP hydrolysis to reposition, assemble, migrate and recombine nucleosomes, changes the structure of chromatin, and thus changes the "accessibility" of local DNA to transcription factors and cellular proteins. When the chromatin structure tends to be loose under the action of chromatin remodeling factors, the accessibility of RNA polymerase II, transcription factors and other factors to chromatin DNA is increased, thereby initiating the transcription of genes; on the contrary, when the chromatin structure tends to be condensed, the accessibility of RNA polymerase II and transcription factors to chromatin DNA is reduced, thereby inhibiting the transcription of related genes. Chromatin remodeling, as an important part of epigenetic regulation, plays an important role in the process of DNA replication, transcription, recombination and DNA repair in eukaryotes, and thus controls cell proliferation, division and maturation. SWI / SNF can change the de-assembly of chromatin and the replacement of nucleosome-stabilizing proteins, thereby regulating gene expression. SMARCA4 (BRG1 protein) and SMARCA2 (BRM protein) are two mutually exclusive catalytic subunits of SWI / SNF complex, both of which have 75% homology at the protein level and have ATPase activity, providing the energy for chromatin remodeling. The ATP-dependent chromatin remodeling activity of SMARCA2 or SMARCA4 is essential, mainly involved in double-strand break and nucleotide excision repair, and plays an important role in double-strand damage repair. Therefore, SMARCA mutation can cause uncorrectable or improper repair of DNA damage, which constitutes a driving factor for tumor occurrence and development.

[0004] In certain tumor types, mutations within the SWI / SNF complex lead to vulnerabilities in specific contexts, such as SMARCA2 is required for survival of SMARCA4- deficient tumor cells. This discovery of a SMARCA2 / 4 synthetic lethal relationship is translated in vivo, which underscores SMARCA2 as a promising therapeutic target for treating SMARCA4-deficient cancers. Furthermore, the SMARCA4-deficient patient population generally lacks targetable oncogenes such as mutant EGFR or ALK translocations, which further underscores the potential for developing SMARCA2 inhibitors. Characterization of SMARCA4 function in tumors with high levels of SMARCA4 shows an effect on signaling pathways leading to elevated proliferation and increased survival. Knockdown of SMARCA4 showing elevated levels in tumors is known to inhibit proliferation and other cancerous properties. Studies also show increased sensitivity to known chemotherapeutics with SMARCA4 knockdown / modulation, indicating that SMARCA4 targeting can also be an adjunct therapy to existing chemotherapeutic approaches (PNAS February 25, 2014. 111(8) 3128-3133; J Pathol. 2016 Feb;238(3):389-400).

[0005] In contrast to genetic silencing of SMARCA2 leading to potent anti-proliferative activity in SMARCA4-deficient cancer cell lines, pharmacological studies with PFI-3, a selective cell-permeable SMARCA2 / 4 bromodomain inhibitor capable of binding to both SMARCA2 and SMARCA4 bromodomains, failed to exhibit an anti-proliferative phenotype, suggesting that bromodomain function of SMARCA2 / 4 is dispensable for tumor cell proliferation, whereas catalytic ATPase activity is essential (Cancer Res. 2015 Sep 15;75(18):3865-3878). Therefore, to mimic the phenotype achieved by genetic silencing, a means of reducing or completely eliminating SMARCA2 / 4 can be required.

[0006] Proteolysis-Targeting Chimeras (PROTACs) is a promising emerging technology that is expected to turn many potential targets that are umdruggable into druggable. Traditional small molecule drugs are often powerless to about 80% of the proteins in the human body that have no enzyme function, because these drugs usually need to bind to enzymes or receptors to function. PROTACs are composed of three parts: an amchor that recruits an E3 ubiquitin ligase, a warhead molecule that binds to the target protein (POI), and a linker that connects the two parts. Traditional small molecules need to be occupancy-driven to play a pharmacological role by occupying key sites of target proteins, so they need to maintain a certain drug concentration in the body, and the requirements for small molecule binding sites are high, while PROTACs achieve pharmacodynamic effects by degrading target proteins, which theoretically does not require very high drug concentrations.

[0007] SMARCA2 and SMARCA4 have two main functional regions, ATPase region and structural domain (Bromodomain), and the amino acid residues of the corresponding functional regions of the two proteins have more than 90% homology. It is difficult for small molecule inhibitors to achieve selectivity for SMARCA4 and SMARCA2, and they usually have strong killing ability to normal cells.

[0008] There is an urgent need in the clinic for PROTAC molecules with excellent stability and activity and simultaneous degradation activity for SMARCA2 and SMARCA4 or good selectivity for SMARCA2. SUMMARY

[0009] In one aspect of the present disclosure, a compound having the structure of Formula I is provided:

[0010] PTM-L-ULM (Formula I),

[0011] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopic derivative or polymorph thereof;

[0012] wherein:

[0013] L is a chemical linking moiety linking the ULM and the PTM;

[0014] The PTM is selected from the following structures:

[0015] wherein,

[0016] Ra7 , R a8 , and R a9 each occurrence is independently N or CR a ;

[0017] R b5 and R b6 is a single or double bond; when R b5 and R b6 are connected by a single bond, R b5 and R b6 are each independently selected from NR a and C(R a )2; when R b5 and R b6 are connected by a double bond, R b5 and R b6 are each independently selected from N and CR a ;

[0018] R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8 each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, optionally substituted halogenated alkyl, optionally substituted deuterated alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, nitro, carboxyl, amino, optionally substituted halogenated alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkoxy, cyano, hydroxyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -O-cycloalkyl; preferably R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , Ra10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 and R c8 each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, optionally substituted haloalkyl, optionally substituted deuterated alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxyl, amino, haloalkoxy, hydroxyalkyl, alkoxy, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -O-cycloalkyl;

[0019] p1and p2are each independently at each occurrence selected from the group consisting of 0, 1, 2, and 3;

[0020] Ring A and Ring B are each independently at each occurrence a 4-8 membered saturated or unsaturated carbocyclic ring, a 4-8 membered heterocyclic ring, a 6-8 membered aromatic ring, or a 5-8 membered heteroaromatic ring, each independently containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, said Ring A and Ring B being unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, oxo (=0), a deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxyl, 3-7 membered cycloalkyl, C1-C6haloalkyl, and C 1-6 hydroxyalkyl;

[0021] Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy 14 , Cy 15 , Cy 16 , and Cy 17each occurrence is independently selected from 4-8 membered cycloalkylene, 4-8 membered heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-8 membered arylene, 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-13 membered spirocyclylene, or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 4-12 membered fused cyclylene, or heterofused cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclylene, or heterobridged cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, said 4-8 membered cycloalkylene, 4-8 membered heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-8 membered arylene, 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-13 membered spirocyclylene, or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 4-12 membered fused cyclylene, or heterofused cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclylene, or heterobridged cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, can be optionally substituted with 0, 1, 2, or 3 R a substituents;

[0022] R L1 and R L2 each occurrence is independently selected from a single bond, C 2-6 alkylene, C 2-6 alkenylene, C 1-6 alkynylene, -O-, -C(O)-, -S-, -O-C a alkylene-, -NR a -, -NR a -C(O)-, and -NR 1-6 alkylene-;

[0023] ULM is an E3 ubiquitin ligase binding moiety; preferably, the ULM is a CRBN binding moiety; preferably, the ULM is selected from the following structures:

[0024] wherein:

[0025] W 1 and W 2 each occurrence is independently CR ab R bb or C(=O), and at least one of W 1 and W 2 is C(=O);

[0026] W 11 each occurrence is independently C(=O);

[0027] R 20 selected from N and CR 1 ;

[0028] R 3at selected from R 3a , NR m -T and T;

[0029] R 3bt selected from R 3b , NR m -T and T;

[0030] R 3ct selected from R 3c , NR m -T and T;

[0031] R 3dt selected from R 3d , NR m -T and T;

[0032] T represents a linking site to ULM and L, and there is one and only one linking site to L in the structure represented by Formula 2-A;

[0033] Cy9, and Cy 12 each occurrence is independently selected from cycloalkylene, heterocyclylene, arylene, and heteroarylene, each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl;

[0034] L C1 each occurrence is independently selected from a single bond, -NR ab -C(O)-, -C(O)-, and NR ab ;

[0035] Cy 13 selected from 5-13 membered spirocyclylene or heterospirocyclylene, and 4-12 membered fused or heterofused cyclylene, each independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo (=0), thioxo (=S), heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl;

[0036] G, Z, G1, and G2are each independently selected at each occurrence from O, S, and Se;

[0037] R 3a , R 3b , R 3c , R 3d , and R 3e are each independently selected at each occurrence from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; or, (a) R 3a and R 3b , (b) R 3b and R 3c , and (c) R 3c and R 3d , wherein at least one set of R and R 3a , R 3b , R 3c , R 3d , and R 3e are each independently selected at each occurrence from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl;

[0038] (e) R 3a1 and R 3b1 , (f) R 3b1 and R 3c1 , and (g) R3c1 and R 3d1 wherein at least one set of carbon atoms to which it is attached collectively forms and, when not participating in ring formation, R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently at each occurrence selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl;

[0039] B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 are each independently at each occurrence C(R m )2, NR m , C(=O), O, or S;

[0040] B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 , and W 41each occurrence is independently CR m or N;

[0041] C 31 , R t , R T , R t1 , and R T1 each occurrence is independently N or CR 2h ;

[0042] m1and m2are each independently 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6;

[0043] m3, m71, and m51are each independently 0, 1, 2, 3, 4, 5, 6, or 7, m4, m81, and m61are each independently 1, 2, 3, 4, 5, 6, 7, or 8, and m3+ m4≤ 8, m71+ m81≤ 8, and m51+ m61≤ 8;

[0044] m5and m6are each independently 0, 1, 2, 3, 4, 5, 6, or 7, and m5+ m6≤ 7;

[0045] m7and m8are each independently 0, 1, 2, 3, 4, 5, 6, or 7, and m7+ m8≤ 7;

[0046] m21, m31, and m41are each independently 0, 1, 2, or 3, and m21+ m31+ m41≤ 3;

[0047] R m , and R 2h each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl;

[0048] R 1 , R 11 , and R Neach occurrence is independently selected from hydrogen, halogen, deuterium, C1-C6alkyl, C1-C6alkoxy, hydroxyl, 3- to 7-membered cycloalkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl;

[0049] R w is selected from N and CH;

[0050] R 2m is independently selected at each occurrence from a single bond, -NR ab -C(O)-, and -NR ab -; and when PTM is ULM is Formula 2-C, R w is CH, R 2m is not a single bond; when PTM is ULM is Formula 2-D, R 2m is not a single bond;

[0051] R 2 , R 21 , R ab , and R bb is selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and C1-C6alkoxy; and

[0052] n and n1are each independently 0, 1, 2, or 3 at each occurrence;

[0053] wherein, when PTM is Formula 1-3, CLM is not and when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-A, and (a) R 3a and R 3b , (b) R 3b and R 3c , and (c) R 3c and R 3d of R , Formula 2-A is is and when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-A, R 3at , R 3bt , R 3ct , and R 3dt are each not T.

[0054] In one embodiment, the ULM is selected from the following structures:

[0055] wherein W 11 , R 20 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , R 3d1 , Cy9, Cy12, Cy13, L C1 , G, Z, G1, G2, Z1, B 1a , B 2a , B 3a , B 4a , B 5a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , W 3 , W 4 , W 3a , W 4a , C 31 , R t , R T , R t1 , R T1 , R 1 , R 11 , R N , R N1 , R 2m , R 2 , R 21 , m1, m2, m3, m4, m5, m6, m7, m8, m21, m31, m41, m51, m61, n and n1 are each defined as in claim 1 at each occurrence;

[0056] wherein when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46, Formula 2-41, 2-42, 2-43, 2-44, 2-45, and 2-46 are

[0057] In one embodiment, the ULM is selected from the following structures:

[0058] wherein W 1 , W 2 , R 3a , R 3b , R 3c , R 3d , G, Z, R m , R D , R E , R DD , R EE , R F , R G , R T , R 1 , R 2 , m3, m4, m71, m81, m7, m8 and n are each as defined above.

[0059] In one embodiment:

[0060] R a7 , R a8 , and R a9 are each independently selected from N, CH, C-halogen, C-C1-C6alkyl and C-C1-C6alkoxy; preferably, R a7 , R a8 , and R a9 are each independently selected from N, CH, C-F, C-Cl, C-Br, C-CH3and C-O-CH3; and / or

[0061] R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8each occurrence is independently selected from hydrogen, halogen, deuterium, cyano, C 1-6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro, amino, carboxyl, hydroxyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3-6 membered cycloalkyl, and -O-3-5 membered cycloalkyl; preferably, R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 and R c8 each occurrence is independently selected from hydrogen, F, Cl, Br, I, deuterium, cyano, C 1-6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro, amino, carboxyl, hydroxyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3-6 membered cycloalkyl, and -O-3-5 membered cycloalkyl; R a10 is selected from C 1-3 alkyl, 4-, 5-, or 6-membered cycloalkyl, and 4-, 5-, or 6-membered heterocycloalkyl containing one oxygen atom; preferably, R a10 is 5-membered cycloalkyl; and / or

[0062] each occurrence of ring A and ring B is independently a 5-6 membered saturated or unsaturated carbocyclic ring, a 5-6 membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, a 5-6 membered aromatic ring, or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; and / or

[0063] W 1 and W 2 each occurrence is independently CH2or C(=O), and at least one of W 1 and W 2 is C(=O); and / or

[0064] G, Z, G1, G2, and Z1are all O; and / or

[0065] R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently at each occurrence selected from hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuterated alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkyl-C(O), C1-C6alkyloxy-C(O), 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, 6-8 membered aryl, and 6-8 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, wherein the C1-C6alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, 6-8 membered aryl, amino and 6-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl and heteroaryl; preferably, R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently at each occurrence selected from hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, C1-C6haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C6hydroxyalkyl; more preferably, R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 and R 3d1each occurrence is independently selected from hydrogen, F, CI, Br, I, cyano, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -NH-C1-C3 alkyl, -NH-CO-C1-C3 alkyl, and C1-C3 hydroxyalkyl; and / or

[0066] B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each occurrence is independently C(R m )2, NR m , C(=O) or -O-; and / or

[0067] B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 and W 41 each occurrence is independently CR m or N, preferably CH or N; and / or

[0068] C 31 , R t , R T , R t1 and R T1 each occurrence is independently CR m or N, preferably N or CH; and / or

[0069] R m and R 2heach occurrence is selected independently from hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuterated alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkyl-C(O), C1-C6alkyloxy-C(O), 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S, 6-8 membered aryl, and 6-8 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S, wherein each of said C1-C6alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, 6-8 membered aryl, amino, and 6-8 membered heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; preferably, R m , and R 2h each occurrence is selected independently from hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, C1-C6haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C6hydroxyalkyl; preferably, R m , and R 2h each occurrence is selected independently from hydrogen, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3haloalkyl, C1-C3haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C3hydroxyalkyl; more preferably, R m , and R 2h each occurrence is selected independently from H, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3haloalkyl, and C1-C3hydroxyalkyl; and / or

[0070] R 1 , R 11 , and R N each occurrence is selected independently from H, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3haloalkyl, and C1-C3hydroxyalkyl; and / or

[0071] R 2mindependently at each occurrence selected from -NH-C(O)-, -NH-, and -N(CH3)-; and / or

[0072] R 2 , R 21 , R ab , and R bb are each independently at each occurrence selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkoxy; and / or

[0073] m1and m2are each independently at each occurrence 0, 1, 2, 3, or 4, and m1+ m2≤ 6; preferably, m1+ m2= 1, m1+ m2= 2, or m1+ m2= 3; and / or

[0074] m3, m71, and m51are each independently at each occurrence 0, 1, 2, 3, or 4, m4, m81, and m61are 1, 2, 3, 4, or 5, and m3+ m4≤ 5, m71+ m81≤ 5, and m51+ m61≤ 5; preferably, m3, m71, and m51are each independently at each occurrence 0, 1, 2, or 3, m4, m81, and m61are 1, 2, 3, or 4, and m3+ m4= 2, m3+ m4= 3, or m3+ m4= 4; m71+ m81= 2, m71+ m81= 3, or m71+ m81= 4; m51+ m61= 2, m51+ m61= 3, or m51+ m61= 4; and / or

[0075] m5and m6are each independently at each occurrence 0, 1, 2, 3, or 4, and m5+ m6≤ 7; preferably, m5+ m6= 1, m5+ m6= 2, m5+ m6= 3, or m5+ m6= 4; and / or

[0076] m7and m8are each independently at each occurrence 0, 1, 2, 3, or 4, and m7+ m8≤ 4; preferably, m7and m8are each independently at each occurrence 0, 1, 2, or 3, and m7+ m8= 2 or m7+ m8= 3; and / or

[0077] Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, Cy15, Cy16, and Cy17, each appearing individually or without any of the following: 5-6 membered cycloalkylene groups; 5-6 membered heterocyclic groups containing one or two heteroatoms independently selected from N and O; phenylene groups; 5-6 membered monocyclic heteroaryl groups containing one or two heteroatoms independently selected from N and O; 7-11 membered spirocyclic groups or heterocyclic groups containing one, two, or three heteroatoms independently selected from N, O, and S; 6-10 membered fused cyclic groups or heterocyclic groups containing one, two, or three heteroatoms independently selected from N, O, and S; and 5-10 membered bridged cyclic groups or groups containing... 1, 2, or 3 heteroatoms independently selected from N, O, and S; the 5-6 membered cycloalkylene group, the 5-6 membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N, O, and S, the phenylene group, the 5-6 membered monocyclic heteroaryl group containing 1 or 2 heteroatoms independently selected from N and O, the 7-11 membered spirocyclic group or the heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, the 6-10 membered fused cyclic group or the heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the 5-10 membered bridged cyclic group or the heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S may optionally be separated by 0, 1, or 2 R... a Replace; and / or

[0078] Cy9 and Cy12 are each independently selected from 3-7-membered cycloalkylene groups, 3-7-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10-membered aryl groups, and 5-8-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the cycloalkylene group, heterocyclic group, aryl group, and heteroaryl group are each optionally independently selected from halogens, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylamino, C 1-6 Alkyl-C(O), C 1-6 Alkyloxy-C(O), C 1-6one or more substituents selected from F, CI, Br, I, deuterium atom, Ci-C6alkyl, Ci-C6alkoxy, hydroxyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl; and / or

[0079] each occurrence of Cy13is independently selected from 5-13 membered spirocycloalkylene or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-12 membered fused cycloalkylene or heterofused cycloalkylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, each of which is independently optionally substituted with one or more substituents selected from F, CI, Br, I, Ci-C6alkyl, oxo (=0), thioxo (=S), C2-C6heteroalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, cyano, amino, nitro, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 2-6 alkenyl, C 2-6 alkynyl, Ci-C6alkylamino, Ci-C6alkyl-C(O), Ci-C6alkyloxy-C(O), Ci-C6alkyl-NH-C(O), 6-10 membered aryl, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; preferably, Cy13is selected from each occurrence of Cy13is independently selected from 5-13 membered spirocycloalkylene or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-12 membered fused cycloalkylene or heterofused cycloalkylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, each of which is independently optionally substituted with one or more substituents selected from F, CI, Br, I, Ci-C6alkyl, oxo (=0), thioxo (=S), C2-C6heteroalkyl, Ci-C6alkoxy, Ci-C6haloalkyl, hydroxyl, Ci-C6hydroxyalkyl, cyano, amino, nitro, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered aryl, 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and optionally substituted by one or more substituents selected from the group consisting of oxo (=0), thioxo (=S), F, CI, Br, I, Ci-C6alkyl, Ci-C6alkoxy, hydroxy, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl; and / or

[0080] n is 0 or 1 ; preferably, n is 1 ; and / or

[0081] L C1 each occurrence is independently selected from the group consisting of a single bond, -NH-C(O)-, -C(O)-, and -NH-, preferably a single bond.

[0082] In one embodiment, the ULM is selected from the following structures:

[0083] wherein W 1 , W 2 , W 3 , W 4 , W 31 , W 41 , W 11 , R 3a , R 3b , R 3c , R 3d , R 3a1 , R 3b1 , R 3c1 , R 3d1 , R d , R e , R f , R g , R D , R E , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , R N , R t , R T , R t1 , R T1 , B 1a , B 3a , B 4a , B 6a , C 1a , C 2a , C 31each occurrence of m3, m4, m5, m6, m21, m31, m41, m51, and m61 is defined as in any of the preceding embodiments;

[0084] each occurrence of m9 and m10 is independently 0, 1, 2, 3, 4, or 5, and m1+m9+m10 < 5; preferably each occurrence of m1, m9, and m10 is independently 0, 1, or 2, and m1+m9+m10 < 2, preferably m1+m9+m10 = 1 or m1+m9+m10 = 0;

[0085] each occurrence of m11 and m12 is independently 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12 < 6; preferably each occurrence of m7, m11, and m12 is independently 0, 1, 2, or 3, and m7+m11+m12 < 3, preferably m7+m11+m12 = 2 or m7+m11+m12 = 1;

[0086] preferably,

[0087] W 11 is C(=O); and / or

[0088] W 1 is C(=O), W 2 is CH2; W 1 is CH2, W 2 is C(=O); or W 1 is (=O), W 2 is C(=O); and / or

[0089] R D , R E , R F , and R G are each independently selected from CH2, C(C1-C6 alkyl)2, CH(C1-C6 alkyl), NH, N(C1-C6 alkyl), C(=O), or -O-, preferably CH2; and / or

[0090] R d , R e , R f , and R g are each independently selected from CH2, C(C1-C6 alkyl)2, CH(C1-C6 alkyl), NH, N(C1-C6 alkyl), C(=O), or -O-, preferably CH2; and / or

[0091] R d1 , R e1 , R f1 , and R g1each occurrence is independently selected from CH2, C(Ci-C6alkyl)2, CH(Ci-C6alkyl), NH, N(Ci-C6alkyl), C(=0) or -0, preferably CH2; and / or

[0092] R D1 , R E1 , R F1 and R G1 each occurrence is independently selected from CH2, C(Ci-C6alkyl)2, CH(Ci-C6alkyl), NH, N(Ci-C6alkyl), C(=0) or -0, preferably CH2; and / or

[0093] m3is independently at each occurrence selected from 0, 1, 2, and 3, m4is independently at each occurrence selected from 1, 2, and 3, and m3+m4< 5, preferably m3+m4= 2, m3+m4= 3, m3+m4= 4 or m3+m4= 5, more preferably m3is 1, m4is 1 ; or m3is 2, m4is 2; and / or

[0094] m5and m6are each independently at each occurrence 0, 1, 2, or 3, and m6+m5< 4; preferably m6+m5= 2, m6+m5= 3 or m6+m5= 4; and / or

[0095] W 3 , W 4 , W 31 and W 41 each occurrence is independently CH or N; and / or

[0096] R N is independently at each occurrence selected from H, F, CI, Br and Ci-C3alkyl, preferably methyl; and / or

[0097] B 1a , B 3a , B 6a , C 1a and C 2a each occurrence is independently selected from CH2, C(Ci-C6alkyl)2, CH(Ci-C6alkyl), NH, N(Ci-C6alkyl), C(=0) and -0, preferably CH2, NH or N(CH3), more preferably CH2; and / or

[0098] m21, m31and m41are each independently at each occurrence 0, 1, or 2, and m21+m31+m41< 3; preferably m21+m31+m41= 1 or m21+m31+m41= 2; preferably m21is 0, m31is 2, m41is 0; or m21is 1, m31is 1, m41is 0; and / or

[0099] Each time m51 and m61 appear, they are independently 0, 1, 2, or 3, and m61 + m51 ≤ 4. Preferably, m61 + m51 = 2, m61 + m51 = 3, or m61 + m5 = 4; preferably, m51 is 2 and m61 is 2; and / or

[0100] R 3a R 3b R 3c and R 3d Each of the following groups is independently selected from hydrogen, F, Cl, Br, I, cyano, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, -NH-C1-C3 alkyl, -NH-CO-C1-C3 alkyl, and C1-C3 hydroxyalkyl, preferably hydrogen, F, Cl, Br, cyano, methyl, or methoxy; and / or

[0101] R 3a1 R 3b1 R 3c1 and R 3d1 Each of the following groups, when appearing independently, is selected from hydrogen, F, Cl, Br, I, cyano, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -NH-C1-C3 alkyl, -NH-CO-C1-C3 alkyl, and C1-C3 hydroxyalkyl, preferably hydrogen, F, Cl, Br, cyano, methyl, or methoxy, more preferably hydrogen; and / or

[0102] C 31 R t R T R t1 and R T1 Each occurrence is independently represented by N; and / or

[0103] B 1a B 3a B 4a B 6a C 1a C 2a Each occurrence is independently CH2.

[0104] In one embodiment, the ULM is selected from the following structures:

[0105] In one embodiment, L is a covalent bond or is -(B L ) q -,

[0106] wherein B L is each independently selected for each occurrence from CR L1 R L2 , O, S, S(O), S(O)2, NR L1 , CONR L1 , C(O), monocycloalkylene, monoheterocycloalkylene, monohetero partially unsaturated cycloalkylidene, bridged cycloalkylidene, heterobridged cycloalkylidene, spirocycloalkylidene, heterospirocycloalkylidene, aralkylidene, and heteroaralkylidene, wherein the monocycloalkylene, monoheterocycloalkylene, monohetero partially unsaturated cycloalkylidene, bridged cycloalkylidene, heterobridged cycloalkylidene, spirocycloalkylidene, heterospirocycloalkylidene, monocycloalkylidene, and monoheterocycloalkylidene are each independently optionally substituted with 1, 2, 3, 4, 5, or 6 groups selected from R L1 ;

[0107] Preferably, B L is each independently selected for each occurrence from CR L1 R L2 , O, S, S(O), S(O)2, NR L1 , CONR L1 , C(O), 3-8 membered monocycloalkylene, 3-8 membered monoheterocycloalkylene, 3-8 membered monohetero partially unsaturated cycloalkylidene, 5-15 membered bridged cycloalkylidene, 5-15 membered spirocycloalkylidene, 6-15 membered aralkylidene, and 5-15 membered heteroaralkylidene, wherein the 3-8 membered monocycloalkylene, 3-8 membered monoheterocycloalkylene, 3-8 membered monohetero partially unsaturated cycloalkylidene, 5-15 membered bridged cycloalkylidene, 5-15 membered heterobridged cycloalkylidene, 5-15 membered spirocycloalkylidene, 5-15 membered heterospirocycloalkylidene, 6-15 membered monocycloalkylidene, and 5-15 membered monoheterocycloalkylidene are each independently optionally substituted with 1, 2, 3, or 4 groups selected from R L1 ; the 3-8 membered monoheterocycloalkylene, 3-8 membered monohetero partially unsaturated cycloalkylidene, 5-15 membered heterobridged cycloalkylidene, 5-15 membered heterospirocycloalkylidene, and 5-15 membered monoheterocycloalkylidene contain 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S;

[0108] R L1 , and R L2 are each independently selected for each occurrence from halogen, C 1-8 alkyl, -O-C 1-8alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, -N(C 1-8 alkyl)2, 3-11 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-11 membered heterocycloalkyl, -O-3-8 membered cycloalkyl, -O-3-11 membered heterocyclyl, -O-6-10 membered aryl, -O-5-10 membered heteroaryl, -S-3-8 membered cycloalkyl, -NH-3-8 membered cycloalkyl, -N(3-8 membered cycloalkyl)2, -N(3-8 membered cycloalkyl)(C 1-8 alkyl), -NH-3-8 membered heterocyclyl, -N(3-8 membered heterocyclyl)2, -N(3-8 membered heterocyclyl)(C 1-8 alkyl), -NH-6-10 membered aryl, -N(6-10 membered aryl)(C 1-8 alkyl), -NH-5-10 membered heteroaryl, -N(5-10 membered heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, -SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)OH, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2H, -SF5, -S(O)2NH-C 1-8 alkyl, -S(O)2N(C 1-8 alkyl)2, -S(O)NH-C 1-8 alkyl, -S(O)N(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), -N(C 1-8 alkyl)S(O)2N(C 1-8 alkyl)2, -NHS(O)2NH(C 1-8 alkyl), -NHS(O)2N(C 1-8 alkyl)2, and -NHS(O)2NH2, optionally, the C 1-8 alkyl, 3-11 membered cycloalkyl, 3-11 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, 6-10 membered aryl, 5-10 membered heteroaryl, halo 6-10 membered aryl, and halo 5-10 membered heteroaryl; 6-10 halo 5-10 membered heteroaryl;

[0109] R L1 , and R L2 are each independently selected for each occurrence from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)OH, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, each independently optionally substituted with one or more substituents selected from halogen, C 3-6 alkyl, C 1-6 cycloalkyl, and 3-6 membered heterocycloalkyl, each independently optionally substituted with one or more substituents selected from halogen, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered halocycloalkyl, 3-6 membered haloheteroalkyl, C 1-6 alkylamino, 6-10 membered aryl, 5-10 membered heteroaryl, 6-10 membered haloaryl, and 5-10 membered haloheteroaryl; and

[0110] q is an integer greater than or equal to 1;

[0111] Preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0112] In one embodiment, L is a covalent bond or is -(B L ) q -, B L is selected from one or more of the following divalent linkers: -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -C(O)-, -NH-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 7-azaspiro[3.5]nonane, 6-azaspiro[4.4]octane, 2-azaspiro[4.5]decane, 2-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecane, spiro[3.5]nonane, spiro[4.4]octane, spiro[4.5]decane, spiro[3.3]heptane, spiro[5.5]undecane, 2,5-diazabicyclo[2.2.2]octane, 2-oxa-4,9-diazaspiro[5.5]undecane, 3-azabicyclo[3.1.0]hexane, 1-oxa-8-azaspiro[4.5]decane, 4-azaspiro[2.5]octane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.2]octane, and phenylene, q number of B L are the same or different; wherein the divalent linker is optionally substituted with one or more groups selected from R L1 ;

[0113] Preferably, the divalent linker is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, fluorine substituted C1-C6 alkoxy, C3-C6 cycloalkyl, and 3- to 6-membered oxacycloalkyl; more preferably, the divalent linker is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, and oxetanyl;

[0114] Preferably, B L is selected from one or more of the following structures: -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -C(O)-, -NH-,

[0115] q is 1, 2, 3, 4, 5, 6, 7, or 8; preferably, q is 1, 2, 3, 4, 5, or 6; and

[0116] is a point of attachment.

[0117] In one embodiment, L is selected from the following structures:

[0118] covalent bond, -C(O)-, -C(O)-(CH2) j -, j -, p -NH-(CH2) s -, y -NH-(CH2) j -NH-(CH2) s -, p -C(O)-(CH2) s -, p -O-(CH2) s -, y -C(O)-(CH2) j -C(O)-(CH2) s -, y -O-(CH2) j -O-(CH2) s -, y -O-(CH2) j -CO-(CH2) s -, y -C(O)-(CH2) j -O-(CH2) s -, p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -, y -C(O)-(CH2) j -O-(CH2) s -NH-(CH2) p -, j, p, s, and y are each independently at each occurrence selected from 1, 2, 3, and 4;

[0119] preferably L is selected from the group consisting of a covalent bond, -C(O)-, -C(O)-CH2-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-,

[0120] preferably L is selected from the group consisting of:

[0121] wherein each occurrence of j1, j2, j3, and j4 is independently selected from the group consisting of 0, 1, 2, and 3, preferably from the group consisting of 0 and 1;

[0122] each occurrence of o1and o3is independently selected from the group consisting of 1, 2, and 3, each occurrence of o2and o4is independently selected from the group consisting of 0, 1, 2, and 3; and, o1+o2= 2, o1+o2= 3, or o1+o2= 4; o3+o4= 2, o3+o4= 3, or o3+o4= 4; preferably o1+o2= 4; preferably o3+o4= 4;

[0123] L a1 , L a3 , L b1 , and L b3 each occurrence is independently selected from the group consisting of NR tt , and C(R tt )2;

[0124] L a2 , L a4 , L b2 , and L b4 each occurrence is independently selected from the group consisting of N and CR tt ;

[0125] R tt each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, cyano, nitro, carboxyl, and C3-C5cycloalkyl; preferably R tt each occurrence is independently selected from the group consisting of hydrogen, F, Cl, Br, CH3, and CN;

[0126] preferably L is selected from the group consisting of:

[0127] In one embodiment, Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, Cy15, Cy16, and Cy17 are absent or each occurrence is independently selected from the group consisting of 0, 1, 2, or 3 R a substituted as follows:

[0128] wherein m, n1, m’ and n’ are each independently at each occurrence 1 or 2;

[0129] R a each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, cyano, nitro, carboxyl, C3-C5 cycloalkyl, -O-C3-C5 cycloalkyl, C3-C5 heterocycloalkyl containing 1 or 2 O atoms, and amino.

[0130] In one embodiment, the PTM is selected from the group consisting of the following structures:

[0131] wherein R a10 is selected from the group consisting of C 1-3 alkyl, 4-, 5-, or 6-membered cycloalkyl, and 4-, 5-, or 6-membered heterocycloalkyl containing one O atom; preferably, R a10 is selected from the group consisting of methyl, isopropyl, cyclobutyl, cyclohexyl, and cyclopentyl; and / or

[0132] R a2 is hydrogen, F, Cl, Br, I, deuterium, cyano, C 1-6 alkyl, or C1-C6 alkoxy; preferably, R a2 is Cl or Br; and / or

[0133] R a3 , R a4 , and R a5 are hydrogen, F, Cl, Br, I, deuterium, cyano, C 1-6 alkyl, or C1-C6 alkoxy; preferably, R a3 , R a4 , and R a5 are hydrogen; and / or

[0134] R a7 is CH; and / or

[0135] R a8 is CH, C-halogen, C-C1-C3 alkyl, or C-C1-C3 alkoxy; preferably, R a8is CH, C-F, C-Cl, C-Br, C-CH3, or C-O-CH3; and / or

[0136] R a9 is N or CH; and / or

[0137] Cy3is absent or selected from 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, and 7-11 membered spirocyclylene or 7-11 membered heterospiroclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; said 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, 7-11 membered spirocyclylene, or 7-11 membered heterospiroclylene can be optionally substituted with 0, 1, or 2 substituents selected from F, Cl, Br, I, cyano, C1-C3alkyl, and C1-C3alkoxy; preferably, Cy3is absent.

[0138] In one embodiment, the PTM is selected from the following structures:

[0139] wherein R aa is independently selected at each occurrence from hydrogen, halogen, C1-C3alkyl, and hydroxyl; preferably, R aa is independently at each occurrence hydroxyl; and / or

[0140] R a is independently selected at each occurrence from hydrogen, halogen, C1-C3alkyl, and hydroxyl; preferably, R a is hydrogen; and / or

[0141] Cy4and Cy5are each independently selected at each occurrence from phenylene, 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, 7-11 membered spirocyclylene, and 7-11 membered heterospiroclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, said phenylene, 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, 7-11 membered spirocyclylene, and 7-11 membered heterospiroclylene can be optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, I, cyano, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, cyano, nitro, carboxyl, C3-C5cycloalkyl, and C3-C5heterocycloalkyl containing 1 or 2 O atoms; preferably, Cy4and Cy5are each independently selected at each occurrence from and / or

[0142] Cy16is selected from the group consisting of 5-6 membered cycloalkylene and 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, said cycloalkylene and heterocyclylene being optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, cyano, hydroxyl, C1-C3alkyl, C1-C3alkoxy and C1-C3haloalkyl; preferably, Cy16is selected from the group consisting of said methylenedioxy and said methylenedioxy and and / or

[0143] Cy17is phenylene, said phenylene being optionally substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, cyano, hydroxyl, C1-C3alkyl, C1-C3alkoxy and C1-C3haloalkyl, preferably selected from the group consisting of and / or

[0144] R 11a and R 12a each occurrence is independently selected from the group consisting of hydrogen, halogen, deuterium, cyano, C1-6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, nitro, amino, carboxyl and hydroxyl, preferably, R 11a and R 12a each occurrence is independently hydrogen.

[0145] In one embodiment, the PTM is selected from the following structures:

[0146] In another aspect of the present disclosure, the following compounds or pharmaceutically acceptable salts thereof are provided, the compounds being selected from the following structures:

[0147] wherein, R a , R L2 , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 and RL1 each occurrence is independently defined as in any of the preceding embodiments;

[0148] Cy 10 and Cy 11 each occurrence is independently selected from 4-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-8 membered aryl, 5-8 membered heteroaryl, 5-13 membered spirocyclic or heterosprio cyclic group, 4-12 membered fused cyclic or heterofused cyclic group, and 5-10 membered bridged cyclic or heterobridged cyclic group, optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1-6 alkyl, amino, hydroxyl, halogen, oxo (=0), aldehyde, -O-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, and carboxyl;

[0149] Preferably:

[0150] R L2 is selected from a single bond, C2-C3 alkynylene, and C2-C3 alkenylene; preferably, R L2 is selected from a single bond and alkynylene; and / or

[0151] R a2 is independently selected at each occurrence from H, F, Cl, Br, I, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and cyano; preferably, R a2 is independently selected at each occurrence from H, F, Cl, Br, amino, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy; and / or

[0152] R a7 , R a8 , and R a9 is independently selected at each occurrence from CR a , preferably CH; and / or

[0153] R a , R a3 , R a4 , R a5 , R a6 , R 11a , and R 12aeach occurrence is independently selected from the group consisting of H, F, CI, Br, I, cyano, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, and cyano; preferably, R a , R a3 , R a4 , R a5 , R a6 , R 11a , and R 12a each occurrence is independently selected from the group consisting of H, F, CI, Br, cyano, C1-C3alkyl, and C1-C3alkoxy, more preferably H; and / or

[0154] R a10 each occurrence is independently selected from the group consisting of C 1-3 alkyl, 4-6 membered cycloalkyl, and 4-6 membered heterocycloalkyl containing one oxygen atom, preferably cyclopentyl; and / or

[0155] R L1 is selected from the group consisting of a single bond, C2-C3alkynylene, C2-C3alkenylene, NH, O, CO, NH-C1-C3alkylene, and O-C1-C3alkylene; and / or

[0156] Cy 10 each occurrence is independently selected from the group consisting of 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O, phenyl, 5-6 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl; said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O, phenyl, 5-6 membered heteroaryl, 7-11 membered spirocyclyl or heterospriocyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, halogen, oxo (=O), aldehyde, -O-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, and carboxyl; preferably said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O, phenyl, 5-6 membered heteroaryl, 7-11 membered spirocyclyl or heterospriocyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl is optionally substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4substituted with substituents selected from the group consisting of alkyl, amino, hydroxyl, halogen, and oxo (=0); preferably, Cy 10 independently at each occurrence selected from the group consisting of optionally substituted with 1, or 2 substituents selected from the group consisting of C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)-C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)O-C 1-4 substituted with substituents selected from the group consisting of alkyl, amino, hydroxyl, halogen, and oxo (=0); preferably, Cy

[0157] and / or

[0158] Cy 11 each occurrence is independently selected from the group consisting of NH2, 5-7 membered cycloalkyl, 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N and O, phenyl, 5-9 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl, said 5-7 membered cycloalkyl, 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N and O, phenyl, 5-9 membered heteroaryl, 7-11 membered spirocyclyl or heterospriocyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl optionally substituted with 0, 1, 2, 3, 4, 5, 6 substituents selected from the group consisting of C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)-C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)O-C 1-4 substituted with substituents selected from the group consisting of alkyl, amino, hydroxyl, halogen, oxo (=0), aldehyde, -O-C 1-6 substituted with substituents selected from the group consisting of alkyl, -C 1-6 substituted with substituents selected from the group consisting of alkylene-N(C 1-6 alkyl)2, and carboxyl; preferably, said 5-7 membered cycloalkyl, 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N and O, phenyl, 5-9 membered heteroaryl, 7-11 membered spirocyclyl or heterospriocyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl optionally substituted with 0, 1, or 2 substituents selected from the group consisting of C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)-C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)O-C 1-4 substituted with substituents selected from the group consisting of alkyl, amino, hydroxyl, F, Cl, Br, carboxyl, aldehyde, and oxo (=0); preferably, Cy 11 selected from the group consisting of NH2or optionally substituted with 0, 1, or 2 substituents selected from the group consisting of C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)-C 1-3 substituted with substituents selected from the group consisting of alkyl, -C(O)O-C 1-4 substituted with substituents selected from the group consisting of alkyl, amino, hydroxyl, F, Cl, Br, carboxyl, aldehyde, and oxo (=0); preferably, Cy

[0159] In one embodiment, the compound is selected from any one of the following structures:

[0160] In another aspect of the present disclosure, there is provided a compound as previously described or a pharmaceutically acceptable salt thereof.

[0161] In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising an effective amount of a compound as previously described, and a pharmaceutically acceptable carrier.

[0162] In another aspect of the present disclosure, there is provided a use of a compound as previously described or a pharmaceutical composition as previously described in the manufacture of a medicament for treating or preventing a disease or disorder mediated by SMARCA2 / 4; preferably, the disease or disorder is cancer; preferably, the cancer is lung cancer, cervical cancer or melanoma; preferably, the lung cancer is alveolar cell carcinoma or non-small cell carcinoma.

[0163] In another aspect of the present disclosure, there is provided a compound as previously described or a pharmaceutical composition as previously described for use in treating or preventing a disease or disorder mediated by SMARCA2 / 4; preferably, the disease or disorder is cancer; preferably, the cancer is lung cancer, cervical cancer or melanoma; preferably, the lung cancer is alveolar cell carcinoma or non-small cell carcinoma.

[0164] In another aspect of the present disclosure, there is provided a method of treating or preventing a disease or disorder mediated by SMARCA2 / 4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as previously described or a pharmaceutical composition as previously described; preferably, the disease or disorder is cancer; preferably, the cancer is lung cancer, cervical cancer or melanoma; preferably, the lung cancer is alveolar cell carcinoma or non-small cell carcinoma.

[0165] In another aspect of the present disclosure, there is provided a use of a compound as previously described in the manufacture of a medicament for treating or preventing a disease or disorder treated by degrading a target protein bound to a ligand of the target protein or in the manufacture of a proteolysis targeting chimera or molecular glue compound; preferably, the target protein is SMARCA2 / 4, preferably SMARCA2. DETAILED DESCRIPTION

[0166] The present disclosure is described in detail by way of specific embodiments below, but it will be readily apparent to those of ordinary skill in the art that other embodiments and adaptations without departing from the spirit and scope of the present disclosure are possible.

[0167] Terms and definitions

[0168] The term "alkyl" as used herein refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched groups comprising 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently optionally selected from one or more of a deuterium atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group.

[0169] SMARCA2 / 4 refers to a SMARCA2 or SMARCA4 protein.

[0170] The term "heteroalkyl" refers to one or more -CH2- groups replaced by heteroatoms selected from N, O, and S or one or more -CH- groups replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, the substituents are preferably independently optionally selected from one or more of a deuterium atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0171] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which includes, for example, fused, bridged, or spiro ring groups, the cycloalkyl ring can contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 4 to 7 carbon atoms. The term "3-8 membered monocycloalkyl (or C 3-8 The term "3-8 membered monocycloalkyl (or C 3-6 The term "3-8 membered monocycloalkyl (or C Non-limiting examples of monocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. The cycloalkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, the substituents are preferably independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0172] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of a deuterium atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0173] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The term "C 2-6 The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The term "C 2-4Alkenyl. Alkenyl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from one or more substituents selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0174] The term "alkynyl" refers to alkyl compounds containing a carbon-carbon triple bond, wherein alkyl is as defined above. The term "C 2-6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, further preferably an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, i.e., C 2-4 alkynyl. Particular examples of alkynyl include, but are not limited to, ethynyl, 1- propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from one or more substituents selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0175] The term "heterocycloalkyl" or "heterocycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon substituents containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m(where m is an integer from 0 to 2), but excluding ring moieties of -0-0-, -0-S-, or -S-S-, with the remainder of the ring atoms being carbon, including heterocycloalkyl, heterospirocycloalkyl, heterofused cycloalkyl, and heterobridged cycloalkyl. Preferably, 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl), of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. The term "3-8 membered monoheterocycloalkyl" refers to saturated or partially unsaturated monocyclic hydrocarbon groups having 3 to 8 ring atoms, one, two, or three of which are heteroatoms selected from nitrogen, oxygen, or S(O) m The term "heterocycloalkyl" or "heterocycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon substituents containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m(where m is an integer from 0 to 2), but excluding ring moieties of -0-0-, -0-S-, or -S-S-, with the remainder of the ring atoms being carbon, including heterocycloalkyl, heterospirocycloalkyl, heterofused cycloalkyl, and heterobridged cycloalkyl. Preferably, 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl), of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. The term "3-8 membered monoheterocycloalkyl" refers to saturated or partially unsaturated monocyclic hydrocarbon groups having 3 to 8 ring atoms, one, two, or three of which are heteroatoms selected from nitrogen, oxygen, or S(O) m The term "heterocycloalkyl" or "heterocycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon substituents containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m(where m is an integer from 0 to 2), but excluding ring moieties of -0-0-, -0-S-, or -S-S-, with the remainder of the ring atoms being carbon, including heterocycloalkyl, heterospirocycloalkyl, heterofused cycloalkyl, and heterobridged cycloalkyl. Preferably, 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl), of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. The term "3-8 membered monoheterocycloalkyl" refers to saturated or partially unsaturated monocyclic hydrocarbon groups having 3 to 8 ring atoms, one, two, or three of which are heteroatoms selected from nitrogen, oxygen, or S(O)

[0176] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing pairs of adjacent carbon atoms) groups having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring as described above, wherein the ring that is common to the parent structure is the aryl ring. The aryl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents are preferably independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0177] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl rings fused to an aryl, heterocycloalkyl, or cycloalkyl ring as described above, wherein the ring that is common to the parent structure is the heteroaryl ring. The heteroaryl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents are preferably independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

[0178] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0179] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

[0180] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0181] The term "amino" refers to -NH2.

[0182] The term "cyano" refers to -CN.

[0183] The term "nitro" refers to -NO2.

[0184] The term "aminoacyl" refers to -NH-C(O).

[0185] The term "bond" refers to a covalent bond between two atoms, or two moieties. Unless otherwise specified, the bond can be a single bond, a double bond, or a triple bond.

[0186] The term "chemically linked" shall be understood to mean linked through an attractive force between atoms strong enough to allow the bound aggregate to function as a unit. This includes, but is not limited to, chemical bonds such as covalent bonds, non-covalent bonds such as ionic bonds, metal bonds, and bridging bonds, hydrophobic interactions, hydrogen bonds, and van der Waals interactions.

[0187] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. denotes a site of chemical bond linkage.

[0188] The term "moiety" refers to a specific fragment or functional group of a molecule. Chemical moieties are generally recognized chemical entities that are embedded in or appended to molecules.

[0189] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes ubiquitin to be attached to lysines on a target protein and subsequently targets the specific protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, is the cause of the transfer of ubiquitin to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, so that a second ubiquitin is attached to the first, a third to the second, and so on. Polyubiquitination marks a protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but can instead be altered in their cellular location or function, for example, via binding to other proteins that have domains capable of binding ubiquitin. To make matters more complicated, different lysines on ubiquitin can be targeted by E3s to make chains. The most common lysine is Lys48 on ubiquitin. This is the lysine on the ubiquitin chain that is recognized by the proteasome to make polyubiquitin.

[0190] The term "target protein" refers to proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with a cell's integrated functions, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme modulator activity, signal transduction factor activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, biological process regulation, development, cell differentiation, response to stimulus, behavioral protein, cell adhesion protein, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone modulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular structure and biological origin activity, translational regulator activity. The proteins include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, and numerous others, including humans, microorganisms, viruses, fungi, and parasites as targets for drug therapy, other animals including domesticated animals, microorganisms and other antimicrobials for which antibiotic targets are determined, plants, even viruses, and numerous others.

[0191] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group can or can not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0192] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of one another replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible, can be determined by the person skilled in the art without undue effort (experimentally or theoretically).

[0193] The term "compounds of the present invention or the present disclosure" refers to compounds of Formula I and subformulae thereof and isomers, such as stereoisomers (including diastereomers, enantiomers, and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties (e.g., polymorphs, solvates, and / or hydrates), unless otherwise indicated. Salts, particularly pharmaceutically acceptable salts, are also included where a moiety capable of forming a salt is present.

[0194] Those skilled in the art will recognize that the compounds of the present disclosure can contain chiral centers and therefore exist in different isomeric forms. The term "isomers" as used herein refers to different compounds that have the same molecular formula but differ in the arrangement of atoms or in the configuration of a molecule.

[0195] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to indicate the appropriate racemic mixture. When stereochemistry of a compound of the present disclosure is specified, the single stereoisomer having the known relative and absolute configuration for two chiral centers is designated using the conventional R-S system (e.g., (1S,2S)); the single stereoisomer having the known relative configuration but unknown absolute configuration is designated using an asterisk (e.g., (1R*,2R*)); and the racemate with two letters (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)). "Diastereomers" are stereoisomers that have at least two asymmetric carbon atoms, but they are not mirror images of one another. The absolute stereochemistry is specified using the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon atom can be specified by either R or S notation. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) by the direction (dextro- or levorotatory) which they rotate the plane of polarized light at the wavelength of the sodium D line. Alternatively, a resolved compound can be defined by its retention or diagnostic time in a corresponding chiral HPLC.

[0196] Certain compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms in addition to the absolute stereochemistry specified. It is intended that all such possible isomers and their

[0197] Geometric isomers occur when a compound contains a double bond or some other feature that provides the molecule with an amount of structural rigidity. If the compound contains a double bond, its substituents can be in the E or Z configuration. If the compound contains a double substituted cycloalkyl, the cycloalkyl substituents can have a cis- or trans- configuration.

[0198] Conformational isomers (or conformers) are isomers that differ by rotation about one or more bonds. Rotamers are conformers that differ by rotation about only one bond.

[0199] The term "atropisomers" refers to structural isomers based on axial or planar chirality, which results from restricted rotation in a molecule.

[0200] Unless otherwise stated, the compounds of the disclosure are intended to include all such possible isomers, including racemic mixtures, optionally in pure or substantially pure form and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on chiral SFC or HPLC chromatographic columns, such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp., or other equivalent columns, using appropriate solvents or mixed solvents to achieve good separation).

[0201] The compounds of the disclosure can be isolated in optically active or racemic forms. The optically active forms can be prepared by resolution of racemic forms or by synthesis of optically active starting materials. All processes used in making the compounds of the disclosure and intermediates made therein are considered to be part of the disclosure. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, e.g., by chromatography or fractional crystallization.

[0202] Depending on the process conditions, the end products of the disclosure are obtained in free (neutral) or salt form. Both the free forms and salts of these end products are within the scope of the disclosure. If desired, the compound in one form can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; mixtures of isomeric compounds of the disclosure can be separated into the individual isomers. Pharmaceutically acceptable salts are preferred. However, other salts can be useful, e.g., in isolation or purification steps, and are contemplated to be within the scope of the disclosure.

[0203] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is safe and effective for use in a mammal and possesses the desirable biological activity.

[0204] Any formula given herein is also intended to represent unlabelled forms as well as isotopically label led forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except for the fact that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be suitably incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,18F,31P,32P,35S,36CI,125I, respectively. The present disclosure includes various isotopically labeled compounds as described herein, for example those into which radioactive isotopes such as3H and14C are

[0205] Further, substitution with heavier isotopes such as deuterium (i.e.,2H or D), can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the present disclosure. The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein denotes the ratio between the isotopic abundance of a particular isotope and the natural abundance of that isotope. If a substituent in a compound of the present disclosure is represented by deuterium, then such a compound has an isotopic enrichment factor at each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0206] Isotopically-labeled compounds of the disclosure typically can be prepared by conventional techniques known to those skilled in the art or by the methods and procedures described in the Schemes or Examples herein or by the preparations described below (or analogously to the procedures described herein) by substituting an isotopically-labeled reagent for a non-isotopically labeled reagent that is otherwise employed. Such compounds have a variety of potential uses, for example, as standards and reagents for determining the ability of potential pharmaceutical compounds to bind to a target protein or receptor, or for imaging substances that bind to the biological receptors of the disclosure in vivo or in vitro.

[0207] The term "solvate" means the disclosure of a physical combination of one or more solvent molecules with a disclosed compound, whether or not the solvent is organic or inorganic. The physical combination includes hydrogen bonding. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the solid state of the compound. The solvent molecules in the solvate can be present in a regular or an irregular arrangement. The solvate can comprise a stoichiometric or non-stoichiometric amount of solvent molecules. "Solvate" includes solution phases and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0208] Examples

[0209] The following examples are directed to the intermediate compounds and final products identified in the specification and synthetic schemes. The following examples are used to describe the preparation of the compounds of the present application in detail, but the chemical reactions described are disclosed by their general applicability to the preparation of the compounds of the present application. Sometimes, the reactions described can not be applicable to every compound within the scope of the present application as described. The person skilled in the art can easily identify the compounds for which this can occur. In these cases, the reactions described can be successfully carried out by routine modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be easily prepared from known materials.

[0210] The starting materials, chemical reagents, solvents used in the present disclosure are commercially available, purchased from Anjieke Chemical, Shanghai Bide Pharmaceutical, Beijing Inokai, Jiangsu Aikang, China National Pharmaceutical Group, Beijing Bailingwei, Yunnan New Blue Sky, etc.

[0211] The compounds synthesized in the present application are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS) for their structures.

[0212] The determination of nuclear magnetic resonance (NMR) is carried out by Bruke AVANCE-400 / 600 nuclear magnetic instrument, and the deuterated solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0213] Mass spectrometry (MS) was determined by Waters Acquity Plus instrument.

[0214] High performance liquid preparation was performed using Waters 2489 instrument.

[0215] Medium pressure flash chromatography was performed using COMBIFLASH NEXTGEN 300+.

[0216] Thin layer chromatography silica gel plates were Silica gel 60 thin layer chromatography silica gel plates (aluminum, with fluorescence).

[0217] Silica gel for thin layer chromatography (100-200 mesh, 200-300 mesh) was purchased from E. Merck.

[0218] The system of developing solvents used for monitoring the reaction progress by thin layer chromatography (TLC) and eluents used for purifying the compounds by column chromatography in the examples included: petroleum ether / ethyl acetate system, dichloromethane / methanol system.

[0219] Synthesis of intermediate A0 in example 1

[0220] 2-(6-amino-5-bromopyridazin-3-yl)phenol (intermediate A0)

[0221] Synthesis scheme

[0222] First step: synthesis of 4-bromo-6-iodopyridazin-3-amine and 4,6-dibromopyridazin-3-amine (intermediate A0a)

[0223] 4-bromo-6-iodopyridazin-3-amine (5.00 g, 22.62 mmol) was dissolved in a single-necked flask containing acetonitrile (100 mL), N-bromosuccinimide (4.03 g, 22.62 mmol) was added slowly, and stirred for 1 h. After the reaction was completed, it was quenched with an aqueous sodium thiosulfate solution and extracted with ethyl acetate three times (20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a mixture of A0a and A0b as a yellow solid compound (2.02 g).

[0224] Second step: 2-(6-amino-5-bromopyridazin-3-yl)phenol (intermediate A0)

[0225] A mixture of intermediate A0a and A0b (555.00 mg, 1.85 mmol), (2- hydroxyphenyl)boronic acid (204.20 mg, 1.48 mmol), tetrakis(triphenylphosphine)palladium (213.86 mg, 185.06 mmol), and potassium carbonate (639.41 mg, 4.63 mmol) were dissolved in 1,4-dioxane (7 mL) and purified water (1 mL) and the reaction was stirred at 80 °C for 3 h under nitrogen protection. After the reaction was completed, the excess solvent was removed under reduced pressure, purified water was added, and the organic phase was extracted with ethyl acetate three times (20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain yellow solid intermediate A0 (147 mg).

[0226] 1 H NMR (600 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.82 (dd, J = 7.8, 1.3 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.92 (t, J = 8.2 Hz, 2H).

[0227] Synthesis of intermediate A1 in Example 2

[0228] 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexan-1-one (intermediate A1)

[0229] Synthesis scheme

[0230] First step: 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (intermediate A1a)

[0231] 1,4-dioxaspiro[4.5]dec-8-ylmethanol (500 mg, 2.90 mmol) was dissolved in DCM (3 mL) solvent, and PhI(OAc)2 (1.12 g, 3.48 mmol) and TEMPO (45.36 mg, 0.29 mmol) were sequentially added to the reaction system under ice bath conditions, and the reaction system was moved to room temperature and stirred for 3 h; TLC detection showed that the reaction was complete, and the reaction system was extracted with DCM (10 mL x 3), washed with a sodium bicarbonate aqueous solution (20 mL x 2), dried with anhydrous sodium sulfate, and concentrated to obtain a white oil A1a crude product (225 mg, 45.5%)

[0232] 1H NMR (600 MHz, Chloroform-d) δ 9.63 (s, 1H), 3.97 - 3.89 (m, 4H), 2.25 - 2.22 (m, 1H), 1.94 - 1.90 (m, 2H), 1.80 - 1.66 (m, 4H), 1.59 - 1.54 (m, 2H)

[0233] Second Step: 8-ethynyl-1,4-dioxaspiro[4.5]decane (Intermediate A1b)

[0234] The crude A1a (180 mg, 1.06 mmol) was dissolved in methanol (3 mL) solution, and potassium carbonate (438 mg, 3.17 mmol) was added to the system under ice bath environment. After 5 min, (1-diazo-2-oxopropyl) dimethyl phosphonate (264 mg, 1.37 mmol) was slowly added to the reaction system, and stirred at room temperature overnight. TLC detection showed that the reaction was completed, the reaction solution was concentrated, extracted with ethyl acetate (10 mL x 3), washed with sodium chloride aqueous solution (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain white oil A1b (120 mg, 68.27%)

[0235] 1 H NMR (600 MHz, Chloroform-d) δ 3.98 - 3.91 (m, 4H), 2.50 - 2.46 (m, 1H), 2.05 (d, J = 2.4 Hz, 1H), 1.92 - 1.81 (m, 4H), 1.78 - 1.73 (m, 2H), 1.61 - 1.51 (m, 2H).

[0236] Third Step: 2-(5-((1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Intermediate A1c)

[0237] The intermediate A0 (50 mg, 0.18 mmol) was dissolved in DMF (2 mL) solution, and intermediate A1b (34 mg, 0.21 mmol), triphenylphosphine palladium dichloride (13 mg, 0.018 mmol), cuprous iodide (4 mg, 0.018 mmol) and triethylamine (57 mg, 0.56 mmol) were added to the reaction system, replaced with nitrogen for three times, and stirred at 110 degrees for 2 h. TLC detection showed that the reaction was completed, extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride aqueous solution (10 mL x 2), dried over anhydrous sodium sulfate, concentrated organic phase and separated and purified by forward chromatography column (EA = 30%) to obtain light yellow solid A1c (34 mg, 51.49%)

[0238] LCMS (ESI): [M+H] + = 352.25

[0239] 1 H NMR (600 MHz, Chloroform-d) δ 13.34 (s, 1H), 7.86 (s, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.08 (dd, J = 8.3, 1.3 Hz, 1H), 6.95 - 6.92 (m, 1H), 5.32 (s, 2H), 4.00 (s, 4H), 2.83 - 2.80 (m, 1H), 2.12 - 1.99 (m, 2H), 1.93 - 1.87 (m, 4H), 1.70 - 1.65 (m, 4H).

[0240] Fourth Step: 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexan-1-one (Intermediate Al)

[0241] A1c (30 mg, 0.85 mmol) was dissolved in DCM (2 mL) solvent, trifluoroacetic acid (29 mg, 0.26 mmol) was added, stirred at room temperature overnight; LCMS detected that the reaction was completed, quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (5 mL x 3), washed with saturated sodium chloride (5 mL x 2) water, dried over anhydrous sodium sulfate, concentrated organic phase was separated by thin layer chromatography plate (PE:EA = 2:1) to obtain yellow solid A1 (13 mg, 49.54%).

[0242] LCMS (ESI): [M+H] + = 308.38

[0243] 1 H NMR (600 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.23 (s, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.29 - 7.21 (m, 1H), 6.96 - 6.82 (m, 4H), 3.34 - 3.23 (m, 1H), 2.51 - 2.47 (m, 2H), 2.41 - 2.36 (m, 2H), 2.20 - 2.15 (m, 2H), 2.08 - 2.00 (m, 2H).

[0244] Synthesis of Intermediate A2 in Example 3

[0245] 4-((3-amino-6-(2-hydroxyphenyl)pyrazin-4-yl)ethynyl)-4-methylcyclohexan-1-one (Intermediate A2)

[0246] Synthesis Scheme

[0247] First Step: (8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)methanol (Intermediate A2a)

[0248] Calcium chloride (607 mg, 5.48 mmol) was dissolved in a mixture of ethanol (3 mL) and THF (3 mL), and after the solution was clear, sodium borohydride (414 mg, 10.95 mmol) was added portionwise in an ice bath environment, followed by the addition of a THF solution of ethyl 8-methyl-1,4-dioxaspiro[4,5]decane-8-carboxylate (500 mg, 2.19 mmol) to the system, which was stirred at room temperature for 4 h; TLC detection showed that the reaction was complete, and the reaction was quenched with saturated aqueous sodium thiosulfate solution in an ice bath environment, neutralized with 2 M aqueous hydrochloric acid until the solution was clear, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a light yellow oil A2a (390 mg, 95.6%).

[0249] Second Step: 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (Intermediate A2b)

[0250] Synthesis method same as Intermediate A1a.

[0251] 1 H NMR (600 MHz, Chloroform-d) δ 9.45 (s, 1H), 3.92 (s, 4H), 1.98-1.94 (m, 2H), 1.69-1.64 (m, 3H), 1.55-1.49 (m, 3H), 1.03 (s, 3H).

[0252] Third Step: 8-ethynyl-8-methyl-1,4-dioxaspiro[4.5]decane (Intermediate A2c)

[0253] Synthesis method same as Intermediate A1b.

[0254] 1 H NMR (600 MHz, Chloroform-d) δ 3.99-3.92 (m, 4H), 2.13 (s, 1H), 2.00-1.94 (m, 2H), 1.81-1.73 (m, 2H), 1.69-1.61 (m, 2H), 1.57-1.52 (m, 2H), 1.27 (s, 3H).

[0255] Fourth Step: 2-(6-amino-5-((8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate A2d)

[0256] Synthesis method same as Intermediate A1c.

[0257] LCMS (ESI): [M+H] += 366.49

[0258] 1 H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.30 (s, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.28 - 7.24 (m, 1H), 6.96 - 6.87 (m, 2H), 6.82 (s, 2H), 2.81 - 2.67 (m, 2H), 2.28 - 2.13 (m, 4H), 1.86 - 1.79 (m, 2H), 1.46 (s, 3H).

[0259] Fifth Step: 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- methylcyclohexan-1-one (Intermediate A2)

[0260] Synthetic procedure is same as Intermediate Al.

[0261] LCMS (ESI): [M+H] + = 322.20

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.30 (s, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.28 - 7.24 (m, 1H), 6.96 - 6.87 (m, 2H), 6.82 (s, 2H), 2.81 - 2.67 (m, 2H), 2.28 - 2.13 (m, 4H), 1.86 - 1.79 (m, 2H), 1.46 (s, 3H).

[0263] Synthesis of Intermediate A3 in Example 4

[0264] 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-cyclopropylcyclohexan-1- one (Intermediate A3)

[0265] Synthetic procedure

[0266] First Step: Ethyl 8-cyclopropyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Intermediate A3a)

[0267] Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (3.5 g, 16.34 mmol) was dissolved in THF solvent, replaced with nitrogen three times, LDA (16.34 mL, 2M) was slowly added to the reaction system, stirred at -78 °C for 1 h, bromocyclopropane (1.96 mL, 24.50 mmol) was added to the reaction system, stirred at -78 °C for 1 h, then moved to room temperature and stirred overnight; TLC detected that the reaction was completed, quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride (30 mL x 2) water, dried over anhydrous sodium sulfate, concentrated organic phase was obtained by normal phase column chromatography (EA = 25%) to obtain yellow oil A3a (1.8 g, 43.33%).

[0268] 1 H NMR (400 MHz, Chloroform-d) δ 4.11 (q, J = 7.1 Hz, 2H), 3.89 (s, 4H), 2.06-1.97 (m, 2H), 1.67-1.59 (m, 2H), 1.56-1.48 (m, 2H), 1.45-1.41 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 0.94-0.81 (m, 1H), 0.31 (d, J = 7.1 Hz, 4H).

[0269] Second step: (8-cyclopropyl-1,4-dioxaspiro[4.5]dec-8-yl)methanol (intermediate A3b)

[0270] A3a (1.8 g, 7.08 mmol) was dissolved in THF solvent, lithium aluminum hydride (0.32 g, 8.49 mmol) was added to the reaction system in batches under ice bath environment, stirred at room temperature for 1 h; TLC detected that the reaction was completed, quenched with water under ice bath environment, extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride (30 mL x 2) water, dried over anhydrous sodium sulfate, concentrated organic phase to obtain yellow oil A3b crude product (1.4 g, 93.18%).

[0271] 1 H NMR (400 MHz, Chloroform-d) δ 3.91 (s, 4H), 3.52 (s, 2H), 1.64-1.57 (m, 4H), 1.48-1.39 (m, 2H), 1.35-1.21 (m, 2H), 0.80-0.73 (m, 1H), 0.36-0.28 (m, 4H).

[0272] Third step: 8-cyclopropyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (intermediate A3c)

[0273] Synthesis method same as intermediate A1a.

[0274] 1 H NMR (400 MHz, Chloroform-d) δ 9.48 (s, 1H), 3.92 (s, 4H), 1.94 - 1.87 (m, 2H), 1.71 - 1.64 (m, 2H), 1.52 - 1.47 (m, 4H), 0.78 - 0.69 (m, 1H), 0.43 - 0.308 (m, 2H), 0.37 - 0.30 (m, 2H).

[0275] Fourth Step: 8-cyclopropyl-8-ethynyl-1,4-dioxaspiro[4.5]decane (Intermediate A3d)

[0276] Synthetic procedure same as Intermediate Alb.

[0277] 1 H NMR (400 MHz, Chloroform-d) δ 3.98 - 3.95 (m, 4H), 2.03 (s, 1H), 1.98 - 1.94 (m, 2H), 1.86 - 1.78 (m, 2H), 1.72 - 1.65 (m, 4H), 0.75 - 0.69 (m, 1H), 0.51 - 0.38 (m, 2H), 0.37 - 0.31 (m, 2H).

[0278] Fifth Step: 2-(6-amino-5-((8-cyclopropyl-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate A3e)

[0279] Synthetic procedure same as Intermediate Alc.

[0280] LCMS (ESI): [M+H] = 392.49. +

[0281] Sixth Step: 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-cyclopropylcyclohexan-1-one (Intermediate A3)

[0282] Synthetic procedure same as Intermediate Al.

[0283] LCMS (ESI): [M+H] = 348.39. +

[0284] Synthesis of Intermediate A4 in Example 5

[0285] 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-isopropylcyclohexan-1-one (Intermediate A4)

[0286] Synthetic procedure ​​

[0287] First Step: 8-Isopropyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (Intermediate A4a)

[0288] Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 46.7 mmol) was dissolved in THF (100 mL) solution, slowly cooled to -78 °C under N2protection. LDA (1 g, 9.33 mmol) was added, after 30 min, 2-iodopropane (1.19 g, 7.0 mmol) was added, and the reaction was stirred at -78 °C for 1 h. After TLC detection of the reaction was completed, saturated NH4Cl solution (100 mL) was added to the reaction system, extracted with ethyl acetate (200 mL x 3), washed with saturated aqueous sodium chloride solution (200 mL x 2), dried over anhydrous sodium sulfate, concentrated the organic phase and separated by normal phase column chromatography (EA = 3%), and purified to obtain white oil A4a (4.8 g, 40%).

[0289] 1 H NMR (600 MHz, DMSO-d6) δ 4.12 (q, J = 7.1 Hz, 2H), 3.86 - 3.81 (m, 4H), 2.00 - 1.95 (m, 2H), 1.67-1.74 (m, 1H), 1.63 - 1.57 (m, 2H), 1.47 - 1.36 (m, 4H), 1.16-1.21 (m, 3H), 0.83 (d, J = 6.9 Hz, 6H).

[0290] Second Step: (8-Isopropyl-1,4-dioxaspiro[4.5]dec-8-yl)methanol (Intermediate A4b)

[0291] Synthesis method is the same as Intermediate A3b.

[0292] 1 H NMR (600 MHz, DMSO-d6) δ 3.83 (d, J = 1.4 Hz, 4H), 3.34 (d, J = 5.2 Hz, 2H), 1.69-1.77 (m, 1H), 1.45-1.54 (m, 4H), 1.43 - 1.36 (m, 4H), 0.83 (d, J = 6.9 Hz, 6H).

[0293] Third Step: 8-Isopropyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (Intermediate A4c)

[0294] Intermediate A4b (4 g, 18.66 mmol) was dissolved in acetonitrile (40 mL) solution, DMP (15.83 g, 37.33 mmol) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed by TLC detection, it was filtered, the organic phase was concentrated and purified by normal phase column chromatography (EA = 8%) to give white oil A4c (1 g, 25%).

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.23 (s, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.24 - 7.29 (m, 1H), 6.94 - 6.88 (m, 2H), 6.56 (s, 1H), 3.87 (s, 4H), 1.80 - 1.89 (m, 2H), 1.75 - 1.62 (m, 3H), 1.49 - 1.59 (m, 2H), 1.03 (d, J = 6.7 Hz, 6H).

[0296] Fourth Step: 8-Ethynyl-8-isopropyl-1,4-dioxaspiro[4.5]decane (Intermediate A4d)

[0297] Synthetic procedure same as Intermediate Alb.

[0298] 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.23 (s, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.24 - 7.29 (m, 1H), 6.94 - 6.88 (m, 2H), 6.56 (s, 1H), 3.87 (s, 4H), 1.80 - 1.89 (m, 2H), 1.75 - 1.62 (m, 3H), 1.49 - 1.59 (m, 2H), 1.03 (d, J = 6.7 Hz, 6H).

[0299] Fifth Step: 2-(6-amino-5-(8-isopropyl-1,4-dioxaspiro[4.5]decane-8- ethynyl)pyridazin-3-yl)phenol (Intermediate A4e)

[0300] Synthetic procedure same as Alc.

[0301] LCMS (ESI): [M+H] + = 394.49

[0302] 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.23 (s, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.24 - 7.29 (m, 1H), 6.94 - 6.88 (m, 2H), 6.56 (s, 1H), 3.87 (s, 4H), 1.80 - 1.89 (m, 2H), 1.75 - 1.62 (m, 3H), 1.49 - 1.59 (m, 2H), 1.03 (d, J = 6.7 Hz, 6H).

[0303] Step 6: 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- isopropylcyclohexan-1-one (Intermediate A4)

[0304] Synthetic method is same as Intermediate Al.

[0305] LCMS (ESI): [M+H] + = 350.29

[0306] Synthesis of Intermediate A5 in Example 6

[0307] 1-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-oxocyclohexan-1- enitrile (Intermediate A5)

[0308] Synthetic scheme

[0309] Step 1: Methyl 8-cyano-1,4-dioxaspiro[4.5]decane-8-carboxylate (Intermediate A5a)

[0310] Methyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (2.00 g, 9.99 mmol) was dissolved in THF (50 mL) solution, protected by nitrogen, cooled to -78 °C, then slowly added LDA (7.50 mL, 15.00 mmol) to the system, after stirring at this temperature for 2 hours, added 4-toluenesulfonyl cyanide (1.99 g, 10.99 mmol), and stirred overnight at room temperature; after the reaction was completed, water (100 mL) was added to dilute the reaction system, extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, concentrated the organic phase and separated and purified by normal phase column chromatography (EA / PE = 16%) to obtain white solid A5a (1.29 g, 57%).

[0311] LCMS (ESI): [M+H] + = 226.25

[0312] 1 H NMR (600 MHz, DMSO-d6) δ 3.93 - 3.87 (m, 4H), 3.78 (s, 3H), 2.13 (m, 2H), 2.01 (m, 2H), 1.79 (m, 2H), 1.66 (m, 2H).

[0313] Step 2: 8-(hydroxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (Intermediate A5b)

[0314] Intermediate A5a (1.00 g, 4.44 mmol) was dissolved in methanol (40 mL), and sodium borohydride (255 mg, 6.74 mmol) was added to the reaction system under ice bath condition. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, ice water (100 mL) was added to the reaction system for dilution, and ethyl acetate (100 mL x 2) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then separated and purified by a normal phase column (EA / PE = 40%) to obtain white solid A5b (790 mg, 90%).

[0315] LCMS (ESI): [M+H] + = 198.25

[0316] 1 H NMR (600 MHz, DMSO-d6) δ 5.43 (t, J = 5.7 Hz, 1H), 3.91-3.84 (m, 4H), 3.46 (d, J = 5.7 Hz, 2H), 1.88 (m, 2H), 1.73 (m, 2H), 1.62 m, 2H), 1.52 (m, 2H).

[0317] Third step: 8-formyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (intermediate A5c)

[0318] Oxalyl chloride (1.02 g, 8.01 mmol) was dissolved in dichloromethane solution (4 mL), and dimethyl sulfoxide (940 mg, 12.03 mmol) was slowly added dropwise to the reaction system under nitrogen protection and cooling to -78°C. After stirring for 30 minutes, intermediate A5b (790 mg, 4.01 mmol) in dichloromethane solution was added dropwise, and the stirring was continued for 2 hours. Then, DIEA (2.59 g, 20.03 mmol) was added dropwise, and the stirring was continued at room temperature for 3 hours. After the reaction was completed, the reaction liquid was concentrated, and the product A5c (600 mg, 76%) was separated and purified by a normal phase column (EA / PE = 40%) as yellow oil.

[0319] LCMS (ESI): [M+H] + = 196.20

[0320] 1 H NMR (600 MHz, DMSO-d6) δ 8.13 (s, 1H), 3.92-3.84 (m, 4H), 2.20 (m, 1H), 2.11-2.06 (m, 1H), 2.02 (m, 1H), 1.91 (m, 1H), 1.82-1.76 (m, 2H), 1.71 (m, 2H).

[0321] Fourth step: 8-ethynyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (intermediate A5d)

[0322] Synthetic procedure similar to Intermediate Alb.

[0323] LCMS (ESI): [M+H] + = 192.20

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 4H), 3.70 (s, 1H), 2.12 (m, 2H), 2.01 (m, 2H), 1.75 (m, 2H), 1.70 - 1.61 (m, 2H).

[0325] Fifth step: 8-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-1,4- dioxaspiro[4.5]decane-8-carbonitrile (Intermediate A5e)

[0326] Synthetic procedure similar to Intermediate Alc.

[0327] LCMS (ESI): [M+H] + = 377.30

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.32 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.27 (m, 1H), 7.06 (s, 2H), 6.91 (m, 2H), 3.91 (s, 4H), 2.36 - 2.21 (m, 4H), 1.86 (m, 2H), 1.72 (m, 2H).

[0329] Sixth step: 1-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- oxocyclohexane-1-carbonitrile (Intermediate A5)

[0330] Intermediate A5e (200 mg, 531.33 pmol) was dissolved in a mixed solvent of acetone and water (12 / 3 mL), p-toluenesulfonic acid (185 mg, 1.07 mmol) was added to the reaction system, and stirred at 70 °C overnight; after the reaction was completed, dichloromethane was extracted, and the organic phase was concentrated to obtain yellow solid A5 (180 mg, 101%).

[0331] LCMS (ESI): [M+H] + = 333.29

[0332] Synthesis of Intermediate A6 in Example 7

[0333] 4-bromo-7-cyclopentyl-9-(4-oxopiperidin-l-yl)benzo[4,5]imidazo[l,2- a]quinazolin-5(7H)-one (Intermediate A6)

[0334] Synthetic Scheme

[0335] First Step: 5-bromo-N-cyclopentyl-2-nitroaniline (Intermediate A6a)

[0336] To a solution of 4-bromo-2-fluoro-l-nitrobenzene (10 g, 45.46 mmol) in DMF (100 mL), cyclopentylamine (4.26 g, 50.00 mmol), potassium carbonate (15.71 g, 113.64 mmol) were added, stirred at room temperature for 3 h; TLC detection reaction was completed, the reaction system was diluted with water (1 L), extracted with ethyl acetate (200 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 2), dried over anhydrous sodium sulfate, concentrated the organic phase and separated and purified by normal phase column chromatography (EA = 5%) to obtain yellow solid A6a (13 g, 100%).

[0337] LCMS (ESI): [M+H] + = 285

[0338] 1 H NMR (600 MHz, DMSO-d6) δ 7.96 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 9.1, 2.0 Hz, 1H), 4.04 - 4.01 (m, 1H), 2.10 - 1.99 (m, 2H), 1.73 - 1.65 (m, 2H), 1.62 - 1.58 (m, 2H), 1.53 - 1.49 (m, 2H).

[0339] Second Step: 5-bromo-N 1 -cyclopentylbenzene-l,2-diamine (Intermediate A6b)

[0340] To a solution of intermediate A6a (2 g, 7.01 mmol) in a mixture solvent of acetic acid (20 mL) and water (2 mL), zinc powder (2.29 g, 35.07 mmol) was added in batches, stirred at room temperature for 1 h; LC detection reaction was completed, the reaction system was concentrated under reduced pressure and purified by normal phase column chromatography (EA = 30%) to obtain brown oil intermediate A6b (1.6 g, 83.14%).

[0341] LCMS (ESI): [M+H] + = 255.27

[0342] LCMS (ESI): [M+H]1 H NMR (600 MHz, DMSO-d6) δ 6.50 (dd, J = 8.1, 2.2 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 4.71 (s, 2H), 4.55 (d, J = 5.9 Hz, 1H), 3.70 - 3.64 (m, 1H), 1.96 - 1.91 (m, 2H), 1.74 - 1.60 (m, 2H), 1.59 - 1.52 (m, 2H), 1.51 - 1.43 (m, 2H).

[0343] Third Step: 6-Bromo-1-cyclopentyl-1H-benzo[d]imidazol-2-amine (Intermediate A6c)

[0344] After intermediate A6b (7 g, 27.43 mmol) was dissolved in methanol solution (70 mL), the reaction system was placed in an ice bath environment, and cyanogen bromide (4.36 g, 41.15 mmol) in methanol was slowly added dropwise into the system, and after the addition was completed, it was moved to room temperature and stirred for 2 h; after TLC detection, the reaction was completed, the reaction liquid was concentrated under reduced pressure, extracted with DCM, washed with sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated, and then purified by normal column chromatography (DCM / MeOH = 10 / 1) to obtain red solid intermediate A6c (7.5 g, 97.58%).

[0345] LCMS (ESI): [M+H] + = 280.28

[0346] 1 H NMR (600 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.07 (s, 2H), 6.51 (s, 2H), 4.75 - 4.09 (m, 1H), 2.06 - 1.88 (m, 6H), 1.70 - 1.63 (m, 2H).

[0347] Fourth Step: 1-Cyclopentyl-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1H-benzo[d]imidazol-2-amine (Intermediate A6d)

[0348] Intermediate A6c (1.5 g, 5.35 mmol) was dissolved in THF (60 mL), X-Phos Pd G3 (0.45 g, 0.53 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (1.92 g, 13.38 mmol) were added to the reaction system, and LiHMDS (26.77 mL, 1 M) was added dropwise to the system under nitrogen protection, and stirred at 85 °C for 1 h; after TLC detection, the reaction system was concentrated under reduced pressure and purified by normal column chromatography (DCM / MeOH = 10 / 1) to obtain intermediate A6d (1.8 g, 98.18%) as a gray solid.

[0349] 1 H NMR (600 MHz, DMSO-d6) δ 7.03 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.68 (dd, J = 8.5, 2.2 Hz, 1H), 6.26 (s, 2H), 4.76 - 4.70 (m, 1H), 3.90 (s, 4H), 3.13 - 3.09 (m, 4H), 2.10 - 2.01 (m, 2H), 1.97 - 1.90 (m, 4H), 1.80 - 1.73 (m, J = 5.7 Hz, 4H), 1.71 - 1.65 (m, 2H).

[0350] LCMS (ESI): [M+H] + = 343.39

[0351] Fifth step: 2-bromo-N-(1-cyclopentyl-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1H- benzo[d]imidazol-2-yl)-6-fluorobenzamide (intermediate A6e)

[0352] 2-bromo-6-fluorobenzoic acid (120 mg, 0.55 mmol) was dissolved in 1,4-dioxane (10 mL), CDI (97.7 mg, 0.60 mmol) was added to the reaction system, and after stirring at 95 °C for 2 h, it was removed to room temperature, HOBt (88.8 mg, 0.66 mmol) and intermediate A6d (375.3 mg, 0.55 mmol) were added to the reaction system, and again removed to 95 °C and stirred overnight; after TLC detection, the reaction system was concentrated under reduced pressure and purified by normal column chromatography (EA = 40%) to obtain intermediate A6e (120 mg, 40.3%) as a light purple solid.

[0353] LCMS (ESI): [M+H] + = 543.28

[0354] 1H NMR (400 MHz, Chloroform-d) δ 12.23 (s, 1H), 7.41 - 7.37 (m, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.17 (td, J = 8.2, 5.8 Hz, 1H), 7.08 (td, J = 8.5, 1.1 Hz, 1H), 6.97 (dd, J = 8.7, 2.1 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 5.39 - 5.23 (m, 1H), 4.04 (s, 4H), 3.35 - 3.28 (m, 4H), 2.27 - 2.16 (m, 2H), 2.16 - 2.05 (m, 2H), 2.04 - 1.90 (m, 6H), 1.78 - 1.73 (m, 2H).

[0355] Step 6: 4-bromo-7-cyclopentyl-9-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzo[4,5]imidazo[l,2- a]quinazolin-5(7H)-one (Intermediate A6f)

[0356] Intermediate A6e (110 mg, 0.20 mmol) was dissolved in DMF (5 mL) solution, potassium phosphate (64.5 mg, 0.30 mmol, 1.5 eq) was added to the reaction system, stirred overnight at 120 °C; after TLC detection of the completion of the reaction, the reaction system was cooled to room temperature, ice water was added to the system, the solid was filtered, ethanol (5 mL) was added to the system and stirred for 0.5 h, then filtered to obtain white solid intermediate A6f (56 mg, 52.8%).

[0357] LCMS (ESI): [M+H] + = 523.30

[0358] 1 H NMR (600 MHz, Chloroform-d) δ 8.11 (dd, J = 8.4, 1.0 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.79 (dd, J = 7.9, 0.9 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.02 - 6.92 (m, 2H), 5.60 - 5.54 (m, 1H), 4.05 (s, 4H), 3.45 - 3.38 (m, 4H), 2.26 - 2.13 (m, 4H), 2.07 - 2.01 (m, 2H), 1.96 - 1.90 (m, 4H), 1.87 - 1.83 (m, 2H).

[0359] Step 7: 4-bromo-7-cyclopentyl-9-(4-oxopiperidin-l-yl)benzo[4,5]imidazo[l,2-a]quinazolin- 5(7H)-one (Intermediate A6)

[0360] Intermediate A6f (56 mg, 0.11 mmol) was dissolved in DCM (5 mL) solution, trifluoroacetic acid (12.2 mg, 0.11 mmol) was added to the reaction system, stirred at room temperature overnight; TLC detection of some raw materials left, the reaction was diluted with water, neutralized with aqueous sodium bicarbonate solution, extracted with DCM, dried over anhydrous sodium sulfate, concentrated to give a light yellow solid intermediate A6 (52 mg, 100%), without purification for the next step.

[0361] LCMS (ESI): [M+H] + = 479.39

[0362] Synthesis of intermediate A7 in example 8

[0363] 1-(4-bromo-7-cyclopentyl-5-oxo-7,12-dihydro-5H-quinazolo[3,2-a]quinazolin-10-yl)piperidine-4-carbaldehyde (intermediate A7)

[0364] Synthesis scheme

[0365] First step: 2-(cyclopentylamino)-5-(4-(dimethoxymethyl)piperidin-1-yl)benzonitrile (intermediate A7a)

[0366] Intermediate C11a (5.00 g, 18.86 mmol), 4-(dimethoxymethyl)-piperidine (4.50 g, 28.29 mmol), palladium acetate (425 mg, 1.89 mmol), cesium carbonate (12.29 g, 37.71 mmol) and Xantphos (2.18 g, 3.77 mmol) were dissolved in 1.4-dioxane (40 mL) solvent, protected by nitrogen, stirred at 110°C overnight, after the reaction was completed, the reaction was concentrated and separated and purified by normal phase column (EA / PE = 16%) to give yellow solid product A7a (2.30 g, 35%).

[0367] LCMS (ESI): [M+H] + = 344.35

[0368] 1H NMR (400 MHz, Chloroform-d) δ 7.18 - 7.11 (m, 1H), 6.98 (s, 1H), 6.67 (d, J = 9.2 Hz, 1H), 4.13 - 4.09 (m, 1H), 3.86 - 3.79 (m, 1H), 3.48 - 3.41 (m, 2H), 3.39 (s, 6H), 2.63 - 2.51 (m, 2H), 2.09 - 2.00 (m, 2H), 1.92 - 1.84 (m, 2H), 1.81 - 1.47 (m, 15H).

[0369] 1.59 (m, 9H), 1.55 - 1.47 (m, 4H).

[0370] Second Step: 2-(aminomethyl)-N-cyclopentyl-4-(4-(dimethoxymethyl)piperidin-l- yl)aniline (Intermediate A7b)

[0371] Intermediate A7a (310 mg, 902.55 umol) was dissolved in super dry tetrahydrofuran (10 mL) under nitrogen protection, borane tetrahydrofuran solution (1.90 mL, 1.90 mmol) was added dropwise under ice bath condition, and the mixture was stirred at room temperature for 3 hours. TLC detection showed that the reaction was completed, and the reaction solution was concentrated to obtain yellow oil A7b (350 mg, >99%).

[0372] LCMS (ESI): [M+H] + = 348.49

[0373] Third Step: l-cyclopentyl-6-(4-(dimethoxymethyl)piperidin-l-yl)-l,4-dihydroquinazolin- 2-amine (Intermediate A7c)

[0374] Intermediate A7b (350 mg, 906.47 umol) was dissolved in ethanol (50 mL) solution, hydrogen bromide (100 mg, 944.09 umol) was added under ice water bath condition, and then triethylamine (100 mg, 988.21 umol) was added after the mixture was stirred at room temperature for 30 minutes. The organic phase was concentrated to obtain yellow solid A7c (430 mg, >99%), which was directly used in the next step without purification.

[0375] LCMS (ESI): [M+H] + = 373.40

[0376] Fourth Step: 2-bromo-N-(l-cyclopentyl-6-(4-(dimethoxymethyl)piperidin-l-yl)-l,4- dihydroquinazolin-2-yl)-6-fluorobenzamide (Intermediate A7d)

[0377] Intermediate A7c (430 mg, 900.37 pmol) and HOBt (150 mg, 1.11 mmol) were added after cooling to room temperature. The reaction was stirred at 95 °C overnight. After the reaction was completed, the reaction solution was concentrated and separated and purified by a normal phase column (EA / PE = 14.7%) to obtain yellow oil A7d (130 mg, 25%), which was directly used in the next step without purification.

[0378] LCMS (ESI): [M+H] + = 573.35

[0379] Fifth step: 4-bromo-7-cyclopentyl-10-(4-(dimethoxymethyl)piperidin-l-yl)-7,12- dihydro-5H-quinazolin-5-one (Intermediate A7e)

[0380] Intermediate A7d (130 mg, 226.68 mmol, 1.0 eq) was dissolved in DMF (5 mL), and potassium phosphate (70 mg, 329.78 mmol, 1.5 eq) was added. The reaction was stirred at 120 °C for two hours, and then cooled to room temperature. The reaction solution was extracted with ethyl acetate and washed with brine. The organic phase was concentrated and separated by a thin layer chromatography plate (PE:EA = 1:3) to obtain yellow solid A7e (47 mg, 37%), which was directly used in the next step without purification.

[0381] LCMS (ESI): [M+H] + = 553.38

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.14 - 7.07 (m, 2H), 6.96 (dd, J = 9.0, 2.7 Hz, 1H), 5.11 (s, 2H), 5.00 - 4.90 (m, 1H), 4.09 (d, J = 6.6 Hz, 1H), 3.68 (d, J = 12.3 Hz, 2H), 3.27 (s, 6H), 2.68 - 2.58 (m, 2H), 2.26 - 2.15 (m, 2H), 2.06 - 1.95 (m, 4H), 1.78 - 1.60 (m, 5H), 1.39 - 1.31 (m, 2H).

[0383] Sixth step: l-(4-bromo-7-cyclopentyl-5-oxo-7,12-dihydro-5H-quinazolo[3,2- a]quinazolin-10-yl)piperidine-4-carbaldehyde (Intermediate A7)

[0384] Intermediate A7e (40 mg, 72.27 pmol) was dissolved in formic acid (4 mL), after stirring at room temperature for one hour, the reaction was concentrated, dissolved in dichloromethane, and the pH was adjusted to basic with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated to obtain yellow solid A7 (35 mg, 95%), which was used directly in the next step without purification.

[0385] LCMS (ESI): [M+H] + = 507.35

[0386] Synthesis of Example 9 Intermediate A8

[0387] 4-Bromo-7-cyclopentyl-9-iodo-7,12-dihydro-5H-quinazolo[3,2- a]quinazolin-5-one (Intermediate A8)

[0388] Synthesis Scheme

[0389] First Step: 2-(Cyclopentylamino)-4-iodobenzonitrile (Intermediate A8a)

[0390] 4-Bromo-2-fluorobenzonitrile (20 g, 80.97 mmol) was dissolved in DMSO (80 mL), cyclopentylamine (10.34 g, 121.45 mmol) and DIEA (31.39 g, 242.90 mmol) were added, and stirred at 120 °C overnight. After the reaction was completed, the reaction was extracted with ethyl acetate, the organic phase was washed with brine, and the organic phase was concentrated and separated and purified by normal phase column chromatography (EA / PE = 9%) to obtain yellow solid product (A8a, 20 g, 95%).

[0391] LCMS (ESI): [M+H] + = 313.15

[0392] 1 H NMR (400 MHz, Chloroform-d) δ 7.09 - 7.04 (m, 2H), 7.00 (dd, J = 8.1, 1.4 Hz, 1H), 4.53 (d, J = 5.2 Hz, 1H), 3.87 - 3.77 (m, 1H), 2.16 - 2.01 (m, 2H), 1.85 - 1.64 (m, 4H), 1.58 - 1.49 (m, 2H).

[0393] Second Step: 2-(Aminomethyl)-N-cyclopentyl-5-iodoaniline (Intermediate A8b)

[0394] A solution of intermediate A8a (9.00 g, 28.83 mmol) in super dry tetrahydrofuran (200 mL) was prepared under nitrogen protection. Borane tetrahydrofuran solution (58 mL, 58.00 mmol) was added dropwise to the reaction mixture under ice bath condition. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. The reaction mixture was concentrated to give yellow oil (intermediate A8b, 10.20 g, >99%).

[0395] LCMS (ESI): [M+H] + = 317.20

[0396] 1 H NMR (400 MHz, Chloroform-d) δ 6.97 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 7.7 Hz, 1.7 Hz 1H), 6.72 (d, J = 7.7 Hz, 1H), 3.83 (s, 2H), 3.80 - 3.73 (m, 1H), 2.08 - 1.98 (m, 2H), 1.81 - 1.59 (m, 4H), 1.58 - 1.48 (m, 2H).

[0397] Third Step: 1-cyclopentyl-7-iodo-1,4-dihydroquinazoline-2-amine (intermediate A8c)

[0398] A solution of intermediate A8b (10.20 g, 29.03 mmol) in methanol (200 mL) was prepared. Hydrogen bromide (4.61 g, 43.55 mmol) was added under ice water bath condition. The reaction mixture was stirred at 50 °C overnight. Triethylamine (2.94 g, 29.03 mmol) was added. The reaction mixture was stirred at 50 °C for another hour. The reaction mixture was concentrated to give yellow solid intermediate A8c (11.60 g, >99%).

[0399] LCMS (ESI): [M+H] + = 342.15

[0400] Fourth Step: 2-bromo-N-(1-cyclopentyl-7-iodo-1,4-dihydroquinazolin-2-yl)-6- fluorobenzamide (intermediate A8d)

[0401] Intermediate A8c (11.60 g, 28.90 mmol,) and HOBt (4.69 g, 34.68 mmol) were added after cooling to room temperature. The reaction was stirred at 95 °C overnight. After the reaction was completed, the reaction solution was concentrated and separated and purified by normal phase column (EA / PE = 17%) to obtain yellow oil (Intermediate A8d, 8.70 g, 55%).

[0402] LCMS (ESI): [M+H] + = 542.15

[0403] 1 H NMR (400 MHz, Chloroform-d) δ 10.66 (s, 1H), 7.48 - 7.43 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 7.10 - 7.03 (m, 1H), 6.87 (d, J = 7.7 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.39 (d, J = 2.2 Hz, 2H), 2.37 - 2.26 (m, 2H), 2.04 - 1.94 (m, 2H), 1.87 - 1.76 (m, 2H), 1.58 - 1.49 (m, 2H).

[0404] Fifth step: 4-bromo-7-cyclopentyl-9-iodo-7,12-dihydro-5H-quinazolo[3,2- a]quinazolin-5-one (Intermediate A8)

[0405] Intermediate A8d (8.70 g, 16.05 mmol) was dissolved in DMF (5 mL), and potassium phosphate (5.11 g, 24.07 mmol) was added. After stirring at 120 °C for 4 hours, the reaction solution was extracted with ethyl acetate and washed with brine. The organic phase was concentrated and separated and purified by normal phase column (MeOH / DCM = 5%) to obtain yellow solid (Intermediate A8, 5.10 g, 60%).

[0406] LCMS (ESI): [M+H] + = 522.13

[0407] 1H NMR (400 MHz, Chloroform-d) δ 7.63 (dd, J = 6.9, 1.7 Hz, 1H), 7.57-7.54 (m, 1H), 7.49 (dd, J = 7.9, 1.3 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.05 (d, J = 7.9 Hz, 1H), 5.23 - 5.10 (m, 1H), 4.95 (s, 2H), 2.36 - 2.21 (m, 2H), 2.20 - 2.06 (m, 4H), 1.82 - 1.70 (m, 2H).

[0408] Synthesis of Example 10 intermediate A9

[0409] 4-bromo-7-cyclopentyl-9-(piperazin-l-yl)-7,12-dihydro-5H-quinazolo[3,2- a]quinazolin-5-one (intermediate A9)

[0410] Synthesis scheme

[0411] First step: synthesis of tert-butyl 4-(4-bromo-7-cyclopentyl-5-oxo-7,12-dihydro-5H- quinazolo[3,2-a]quinazolin-9-yl)piperazine- 1 -carboxylate (intermediate A9a)

[0412] Intermediate A 8 (100 mg, 0.19 mmol), tert-butyl piperazine- 1 -carboxylate (42.8 mg, 0.23 mmol), Pd2(dba)3(17.5 mg, 0.019 mmol), XantPhos (22.2 mg, 0.038 mmol) and Cs2CO3(124.8 mg, 0.38 mmol) were dissolved in 1,4-dioxane (3 mL), the reaction bottle was replaced with nitrogen three times, stirred at 100 °C overnight, after the reaction was completed, water (10 mL) was added to dilute the system, EA (3 x 10 mL) was extracted, the organic phase was collected, dried with anhydrous Na2SO4, the reaction solution was rotary evaporated, the crude product was purified by silica gel column (PE:EA = 1:1), and yellow solid intermediate A9a (20 mg, 18%) was obtained.

[0413] LC-MS (ESI): [M+H] + = 580.38

[0414] 1H NMR (400 MHz, DMSO-d6) δ 7.88 (dd, J = 8.2, 1.4 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.0 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 5.08 (s, 2H), 4.99 - 4.87 (m, 1H), 3.52 - 3.45 (m, 4H), 3.23 - 3.08 (m, 4H), 2.35 - 2.20 (m, 2H), 2.16 - 1.96 (m, 4H), 1.74 - 1.61 (m, 2H), 1.42 (s, 9H).

[0415] Second Step: Synthesis of 4-bromo-7-cyclopentyl-9-(piperazin-l-yl)-7,12-dihydro-5H- quinazolin[3,2-a]quinazolin-5-one (Intermediate A9)

[0416] To a solution of Intermediate A9a (20 mg, 0.034 mmol) in DCM (1 mL) was added hydrochloric acid 1,4-dioxane (4 M, 0.5 mL) dropwise, and stirred at room temperature for 0.5 h; after the reaction was completed, the reaction solution was concentrated under reduced pressure to give Intermediate A9 (26 mg, >99%) as a light yellow solid.

[0417] LC-MS (ESI): [M+H] + = 480.30

[0418] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.2, 1.4 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 8.3, 2.1 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 5.10 (s, 2H), 4.97 - 4.84 (m, 1H), 3.45 - 3.37 (m, 4H), 3.30 - 3.20 (m, 4H), 2.36 - 2.22 (m, 2H), 2.17 - 1.92 (m, 4H), 1.76 - 1.60 (m, 2H).

[0419] Synthesis of Intermediate A10 in Example 11

[0420] (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6Hspiro[furo[2,3- e]isoindol-3,4'-piperidin]-1'-yl)acetic acid (Intermediate A10)

[0421] Synthesis Scheme

[0422] First Step: Synthesis of (S)-tert-butyl 2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8- dihydro-2H,6H-spiro[furan[2,3-e]isoindol-3,4'-piperidin]-1'-yl)acetate (Intermediate A10a)

[0423] Intermediate D37 (120 mg, 0.34 mmol) was dissolved in DCM (4 mL), DIPEA (0.18 mL, 1.01 mmol) and tert-butyl bromoacetate (0.074 mL, 0.51 mmol) were added to the reaction system, stirred at room temperature overnight; after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column (PE:EA = 3:1) to obtain white solid intermediate A10a (80 mg, 50%)

[0424] LC-MS (ESI): [M+H] + = 470.45

[0425] 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 - 4.49 (m, 2H), 4.38 (d, J = 17.1 Hz, 1H), 4.21 (d, J = 17.1 Hz, 1H), 3.35 (s, 2H), 2.96 - 2.77 (m, 3H), 2.63 - 2.54 (m, 1H), 2.48 - 2.36 (m, 1H), 2.35 - 2.22 (m, 2H), 2.03 - 1.84 (m, 3H), 1.76 - 1.59 (m, 2H), 1.43 (s, 9H).

[0426] Second Step: Synthesis of (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furan[2,3-e]isoindol-3,4'-piperidin]-1'-yl)acetic acid (Intermediate A10)

[0427] Intermediate A10a (70 mg, 0.15 mmol) was dissolved in a mixed solvent of DCM (2 mL) and TFA (1 mL), stirred at room temperature overnight, after the reaction was completed, the reaction solution was concentrated under reduced pressure, and white solid intermediate A10 (45 mg, 73%) was obtained by reverse phase preparative separation

[0428] LC-MS (ESI): [M+H] + = 414.35

[0429] 1 H NMR (600 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.47 - 7.21 (m, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.707 - 4.57 (m, 2H), 4.40 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.2 Hz, 1H), 4.16 (s, 2H), 3.60-3.48 (m, 2H), 3.26 - 3.11 (m, 2H), 2.96 - 2.85 (m, 1H), 2.65 - 2.55 (m, 1H), 2.47 - 2.36 (m, 1H), 2.32 - 2.18 (m, 2H), 2.05 - 1.89 (m, 3H).

[0430] Synthesis of intermediate A11 in example 12

[0431] 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin- 10-yl)piperidine-4-carbaldehyde (intermediate A11)

[0432] Synthesis scheme

[0433] First step: 4-bromo-N-cyclopentyl-2-nitroaniline (intermediate A11a)

[0434] 4-bromo-1-fluoro-2-nitrobenzene (10 g, 45.46 mmol) was dissolved in THF (100 mL), DIEA (17.62 g, 136.37 mmol) and cyclopentylamine (11.61 g, 136.37 mmol) were added, and the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed, it was rotary evaporated, and the crude product was purified by silica gel column (EA / P = 1%) to obtain intermediate A11a (12.6 g, 97%) as a transparent oily liquid.

[0435] LC-MS (ESI): [M+H] + = 285.18

[0436] 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.65 (dd, J = 9.3, 2.5, 1H), 7.08 (d, J = 9.3 Hz, 1H), 4.09 - 3.97 (m, 1H), 2.13 - 1.99 (m, 2H), 1.76 - 1.48 (m, 6H).

[0437] Second step: 4-bromo-1-cyclopentylbenzene-1,2-diamine (intermediate A11b)

[0438] Intermediate A11a (6 g, 21.04 mmol) and NH4Cl (1.88 g, 35.1 mmol) were dissolved in EtOH / H2O (30 mL / 30 mL) and stirred to dissolve at 60 °C, after adding Fe powder (3.53 g, 63.13 mmol), the temperature was raised to 90 °C and reacted for 2 hours. After the reaction was completed, the solid was filtered with diatomite, the filter cake was washed with DCM and the filtrate was rotary evaporated to give intermediate A11b (4.2 g, 78%) as a brown oily liquid.

[0439] LC-MS (ESI): [M+H] + = 255.15

[0440] 1 H NMR (400 MHz, DMSO-d6) δ 6.64 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 8.3, 2.3 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 4.86 (s, 2H), 4.40 (d, J = 6.0 Hz, 1H), 3.70 - 3.61 (m, 1H), 1.97 - 1.87 (m, 2H), 1.73 - 1.62 (m, 2H), 1.59 - 1.50 (m, 2H), 1.51 - 1.39 (m, 2H).

[0441] Third Step: 5-Bromo-1-cyclopentyl-1H-benzo[d]imidazol-2-amine (Intermediate A11c)

[0442] Intermediate A11b (4.2 g, 16.46 mmol) was dissolved in MeOH, cyanogen bromide (2.09 g, 19.75 mmol) was added and the temperature was raised to 50 °C and reacted for 2 hours. After the reaction was completed, the solvent was rotary evaporated, DCM (200 mL) was added to the system, the organic phase was washed with saturated NaHCO3 (50 mL x 3) and H2O (50 mL x 1), the organic phase was dried with anhydrous Na2SO4, the organic phase was rotary evaporated, and the crude product was purified by silica gel column (DCM / MeOH = 8%) to give intermediate A11c (3.8 g, 82%) as a yellow solid.

[0443] LC-MS (ESI): [M+H] + = 280.18

[0444] 1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 1.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 8.4, 2.0 Hz, 1H), 6.56 (s, 2H), 4.78 - 4.67 (m, 1H), 2.05 - 1.87 (m, 6H), 1.71 - 1.62 (m, 2H).

[0445] Fourth Step: 1-Cyclopentyl-5-(4-(dimethoxymethyl)piperidin-l-yl)-lH- benzo[d]imidazol-2-amine (Intermediate A11d)

[0446] Intermediate A11c (500 mg, 1.78 mmol), 4-(dimethoxymethyl)piperidine (710.41 mg, 4.46 mmol) and X-Phos Pd G3 (151.06 mg, 0.18 mmol) were dissolved in THF, after N2 protection, LiHMDS (1.49 g, 8.92 mmol) was added, and the reaction was warmed to 85 °C overnight. After the reaction was completed, silica gel was added and spun dry to purify (DCM / MeOH = 6%), to give brown solid Intermediate A11d (0.6, 94%).

[0447] LC-MS (ESI): [M+H] + = 359.49

[0448] 1 H NMR (400 MHz, DMSO-d6) δ 7.03 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.62 - 6.49 (m, 3H), 4.74 - 4.63 (m, 1H), 4.09 (d, J = 6.8 Hz, 1H), 3.53 - 3.45 (m, 2H), 3.27 (s, 6H), 2.57 - 2.51 (m, 2H), 2.07 - 1.85 (m, 6H), 1.75 - 1.59 (m, 5H), 1.43 - 1.21 (m, 2H).

[0449] Fifth Step: 2-Bromo-N-(l-cyclopentyl-5-(4-(dimethoxymethyl)piperidin-l-yl)-l- benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate A11e)

[0450] Intermediate Alle (340 mg, 0.61 mmol) and K3PO4 (193.49 mg, 0.91 mmol) were dissolved in DMF, and the mixture was heated to 120 °C for 5 h. After the reaction was completed, water was added until no solid precipitated, and the mixture was filtered to obtain yellow solid intermediate Allf (300 mg, 91%).

[0451] LC-MS (ESI): [M+H] + = 559.38

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 7.49 - 7.45 (m, 1H), 7.38 - 7.25 (m, 3H), 7.17 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 9.0, 2.4 Hz, 1H), 5.20 - 5.09 (m, 1H), 4.10 (d, J = 6.5 Hz, 1H), 3.65 - 3.56 (m, 2H), 3.28 (s, 6H), 2.70 - 2.57 (m, 2H), 2.16 - 2.02 (m, 2H), 1.96 - 1.84 (m, 4H), 1.80 - 1.59 (m, 5H), 1.45 - 1.31 (m, 2H).

[0453] Sixth step: 4-bromo-7-cyclopentyl-10-(4-(dimethoxymethyl)piperidin-l- yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate Allf)

[0454] Intermediate Allf (300 mg, 0.55 mmol) was dissolved in DMF, and the mixture was heated to 120 °C for 5 h. After the reaction was completed, water was added until no solid precipitated, and the mixture was filtered to obtain yellow solid intermediate Allg (200 mg, 71%).

[0455] LC-MS (ESI): [M+H] + = 539.38

[0456] 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.69 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 8.9, 2.0 Hz, 1H), 5.27 - 5.16 (m, 1H), 3.73 - 3.62 (m, 2H), 2.98 - 2.86 (m, 2H), 2.57 - 2.50 (m, 1H), 2.25 - 2.12 (m, 2H), 2.07 - 2.00 (m, 6H), 1.80 - 1.63 (m, 4H).

[0457] Step 7: 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]oxazol-l- yl)piperidine-4-carbaldehyde (Intermediate Al l)

[0458] Intermediate Al l f (320 mg, 0.60 mmol) was dissolved in HCOOH and reacted at room temperature for 4 hours. After the reaction was completed, water was added to the system, the aqueous phase was extracted with DCM (10 mL x 3), and the organic phase was dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure to obtain yellow solid intermediate Al l (270 mg, 92%).

[0459] LC-MS (ESI): [M+H] + = 494.39

[0460] 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.69 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 8.9, 2.0 Hz, 1H), 5.27 - 5.16 (m, 1H), 3.73 - 3.62 (m, 2H), 2.98 - 2.86 (m, 2H), 2.57 - 2.50 (m, 1H), 2.25 - 2.12 (m, 2H), 2.07 - 2.00 (m, 6H), 1.80 - 1.63 (m, 4H).

[0461] Synthesis of intermediate Al 2 in Example 13

[0462] 9-(hydroxymethyl)-3-azaspiro[5.5]undec-8-ene-3-carboxylic acid tert-butyl ester (Intermediate Al 2)

[0463] Synthetic scheme

[0464] First step: tert-butyl 1-oxa-9-azaspiro[2.2.5 6 .2 3 ]tridecan-9-carboxylate (Intermediate A12a)

[0465] Iodine sulfinate (12.35 g, 56.10 mmol) and potassium tert-butoxide (5.46 g, 48.62 mmol) were placed in a three-necked flask, replaced with nitrogen once, and then replaced with nitrogen twice after the addition of DMSO (50 mL). The reaction system was stirred at room temperature for 1.5 h, and then stirred at 0 °C for 5 min. DME (25 mL) was slowly added, followed by the slow dropwise addition of a mixed solution of compound L-1 (10 g, 37.4 mmol, 1 eq) in DMSO (5 mL) and DME (15 mL) to the reaction system, and the stirring was maintained at 0 °C for 1 h. The reaction was detected by TLC, quenched with water, extracted with ethyl acetate, dried, concentrated, and then purified by normal phase column chromatography (EA = 30%) to obtain intermediate A12a (8.7 g, 82.66%) as a light yellow oil.

[0466] 1 H NMR (400 MHz, DMSO-d6) δ 3.34 - 3.27 (m, 4H), 2.54 (s, 2H), 1.61 - 1.53 (m, 2H), 1.52 - 1.46 (m, 4H), 1.42 - 1.33 (m, 15H).

[0467] Second step: tert-butyl 9-(hydroxymethyl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (Intermediate A12)

[0468] Intermediate A12a (13 g, 46.20 mmol) was dissolved in toluene (150 mL), and aluminum isopropoxide (47.18 g, 231 mmol) was added in portions at room temperature. The stirring was maintained at 110 °C overnight. The reaction was detected by TLC, quenched with water, and the solid was filtered. The filtrate was extracted with ethyl acetate, dried, concentrated, and then purified by normal phase column chromatography (EA = 40%) to obtain intermediate A12 (9.5 g, 73.08%) as a light yellow oil.

[0469] 1H NMR (400 MHz, DMSO-d6) δ 5.49 - 5.45 (m, 1H), 4.62 (t, J = 5.6 Hz, 1H), 3.77 (d, J = 5.6, 1.8 Hz, 2H), 3.36 - 3.32 (m, 2H), 3.25 - 3.19 (m, 2H), 1.94 - 1.83 (m, 4H), 1.44 (t, J = 6.4 Hz, 2H), 1.39 (s, 9H), 1.30 - 1.25 (m, 4H).

[0470] Synthesis of intermediate A13 in example 14

[0471] Synthesis scheme

[0472] First step: 4-(2-amino-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)cyclohex-3-ene-1- carboxylate (intermediate A13a)

[0473] Intermediate A6c (1.00 g, 3.57 mmol), 1-ethoxycarbonylcyclohex-3-ene-4-boronic acid pinacol ester (1.50 g, 5.35 mmol), potassium carbonate (1.48 g, 10.71 mmol) and Pd(dppf)Cl2(260 mg, 355.67 umol) were dissolved in a mixed solvent of 1.4-dioxane and water (30 / 5 mL), protected by nitrogen, stirred in an oil bath at 100 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was rotary evaporated to dryness and then separated and purified by a normal phase chromatographic column (MeOH / DCM = 5%) to obtain yellow solid A13a (1.05 g, 83%)

[0474] 1 H NMR (400 MHz, DMSO-d6) δ 7.17 - 7.10 (m, 1H), 7.09-7.00 (m, 2H), 6.40 (s, 2H), 6.03-5.98 (m, 1H), 4.80-4.67 (m, 1H), 4.14 - 4.05 (m, 2H), 2.64 - 2.54 (m, 1H), 2.48 - 2.27 (m, 3H), 2.13 - 1.86 (m, 8H), 1.78-1.62 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0475] LCMS (ESI): [M+H] + = 354.29

[0476] Second step: 4-(2-amino-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)cyclohexan-1- carboxylic acid ethyl ester (intermediate A13b)

[0477] A13a (700 mg, 1.98 mmol) was dissolved in methanol (40 mL), palladium on carbon (250 mg, 10%) and 3 drops of acetic acid were added to the reaction system, hydrogen was replaced, and it was stirred at 40 °C overnight. After the reaction was completed, the reaction solution was filtered and the filtrate was rotary evaporated to obtain yellow solid A13b (670 mg, 95%)

[0478] LCMS (ESI): [M+H] + = 356.49

[0479] Third step: 4-(2-(2-bromo-6-fluorobenzamido)-l-cyclopentyl-lH-benzo[d]imidazol-6- yl)cyclohexane- 1 -carboxylic acid ethyl ester (intermediate A13c)

[0480] 2-bromo-6-fluorobenzoic acid (415 mg, 1.89 mmol) and CDI (370 mg, 2.28 mmol) were dissolved in 1.4-dioxane (10 mL), stirred at 95 °C for two hours, then cooled to room temperature, A13b (670 mg, 1.88 mmol) and HOBt (350 mg, 2.59 mmol) were added, and stirred at 95 °C overnight. After the reaction was completed, the reaction solution was concentrated and separated and purified by normal phase column (EA / PE = 14%) to obtain yellow oil A13c (550 mg, 52%)

[0481] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.47 (m, 2H), 7.38 - 7.27 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 5.23 - 5.12 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.76 - 2.66 (m, 2H), 2.18 - 2.06 (m, 4H), 2.03 - 1.84 (m, 4H), 1.78 - 1.50 (m, 8H), 1.22 (t, J = 7.1 Hz, 3H).

[0482] LCMS (ESI): [M+H] + = 556.38 / 558.58

[0483] Fourth step: 4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazol-9-yl)cyclohexane- 1 -carboxylic acid ethyl ester (intermediate A13d)

[0484] A13c (550 mg, 988.36 umol) was dissolved in DMF (15 mL), potassium phosphate (315 mg, 1.48 mmol) was added, after stirring at 120 °C for two hours, it was cooled to room temperature, the reaction solution was extracted with ethyl acetate, washed with brine, and the organic phase was concentrated. The obtained crude product was dissolved in a mixed solvent (EA / PE = 15%) and then filtered, and the filter cake was washed with petroleum ether. The obtained filter cake was the product A13d (260 mg, 50%)

[0485] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 5.32 - 5.21 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.84 - 2.72 (m, 2H), 2.30 - 2.11 (m, 4H), 2.08 - 1.95 (m, 4H), 1.84 - 1.56 (m, 8H), 1.23 (t, J = 7.1 Hz, 3H).

[0486] LCMS (ESI): [M+H] + = 536.49 / 538.28

[0487] Fifth step: 4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazol-1,2-a]quinazolin-9-yl)cyclohexane-1-carboxylic acid (intermediate A13)

[0488] A13d (260 mg, 485.07 umol) was dissolved in MeOH / THF / H2O (5 / 5 / 2 mL), lithium hydroxide (200 mg, 487.80 umol) was added, after stirring at 50 °C for 2 hours, it was cooled to room temperature, the reaction solution was filtered and purified by high performance liquid preparation to obtain the product A13 (100 mg, 40%)

[0489] 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.5 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 5.30 - 5.18 (m, 1H), 2.77 - 2.66 (m, 1H), 2.38 - 2.21 (m, 3H), 2.09 - 1.87 (m, 8H), 1.79 - 1.69 (m, 2H), 1.66 - 1.44 (m, 4H).

[0490] Synthesis of Example 15 Intermediate A14

[0491] 4-bromo-7-cyclopentyl-9-iodobenzo[4,5]imidazo[1,2-a]quinazolin-5(7H)-one

[0492] Synthesis scheme

[0493] First step: synthesis of N-cyclopentyl-5-iodo-2-nitroaniline (Intermediate A14a)

[0494] Dissolve 2-fluoro-4-iodo-1-nitrobenzene (5 g, 18.73 mmol, 1 eq) in THF (50 mL), add DIPEA (7.26 g, 56.18 mmol, 3 eq) and cyclopentylamine (4.78 g, 58.18 mmol, 3 eq) successively, stir at room temperature for 2 h; after the reaction is completed, concentrate the reaction solution and twice wash with petroleum ether to obtain yellow solid intermediate A14a (6.20 g, 99.68%)

[0495] LC-MS (ESI): [M+H] + = 333.20

[0496] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.01 (dd, J = 9.0, 1.7 Hz, 1H), 4.18 - 3.92 (m, 1H), 2.13 - 1.99 (m, 2H), 1.84 - 1.75 (m, 2H), 1.69 - 1.63 (m, 4H).

[0497] Second step: synthesis of 1-cyclopentyl-5-iodobenzene-1,2-diamine (Intermediate A14b)

[0498] Intermediate Int-A14a (4.45 g, 13.40 mmol, 1 eq) was dissolved in a mixed solvent of acetic acid (20 mL) and water (2 mL), and zinc powder (4.38 g, 66.99 mmol, 5 eq) was added portionwise, and stirred at room temperature for 1 h; after the reaction was completed, the zinc powder was filtered, the reaction solution was concentrated and purified on a silica gel column (PE:EA = 5:1) to separate the yellow solid of intermediate Int-A14b (2 g, 49.40%)

[0499] LC-MS (ESI): [M+H] + = 303.20

[0500] 1 H NMR (400 MHz, DMSO-d6) δ 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 4.75 (s, 2H), 4.49 (s, 1H), 3.75 - 3.60 (m, 1H), 1.98 - 1.87 (m, 2H), 1.78 - 1.61 (m, 2H), 1.59 - 1.41 (m, 4H).

[0501] Step 3: Synthesis of cyclopentyl-6-iodo-1H-benzo[d]imidazol-2-amine (Intermediate Int-A14c)

[0502] Intermediate Int-A14b (1 g, 3.31 mmol, 1 eq) was dissolved in methanol (8 mL), and cyanogen bromide (0.53 g, 4.96 mmol, 1.5 eq) in methanol was slowly added dropwise to the reaction system, and triethylamine (0.33 g, 3.31 mmol, 1 eq) was added after stirring at 50 °C for 1 h, and stirring was continued at 50 °C for 1 h; after the reaction was completed, the reaction system was concentrated under reduced pressure to obtain a brown solid of crude intermediate Int-A14c (1.5 g, 100%)

[0503] LC-MS (ESI): [M+H] + = 328.13

[0504] Step 4: Synthesis of 2-bromo-N-(1-cyclopentyl-6-iodo-1H-benzo[d]imidazol-2-yl)-6- fluorobenzamide (Intermediate Int-A14d)

[0505] Intermediate A14 was synthesized according to the procedure described in Scheme 14. To a solution of 2-bromo-6-fluorobenzoic acid (0.7 g, 3.2 mmol, 1 eq) and CDI (0.57 g, 3.52 mmol, 1.1 eq) in 1,4-dioxane (10 mL) was stirred at 95 °C for 1 h. After the reaction mixture was cooled to room temperature, HOBT (0.52 g, 3.84 mmol, 1.2 eq) and intermediate A14c (1.05 g, 3.20 mmol, 1 eq) were added. The reaction mixture was stirred at 95 °C overnight. After the reaction was completed, the reaction mixture was concentrated and purified by silica gel column (PE:EA = 3:1) to give yellow solid intermediate A14d (0.96 g, 56.87%)

[0506] LC-MS (ESI): [M+H] + = 528.15

[0507] 1 H NMR (400 MHz, DMSO-d6) d 12.92 (s, 1H), 7.87 (s, 1H), 7.59 (d, J = 8.3, 1.4 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.36 - 7.25 (m, 2H), 5.21 - 5.02 (m, 1H), 2.24 - 2.06 (m, 2H), 2.06 - 1.76 (m, 4H), 1.76 - 1.48 (m, 2H).

[0508] Step 5: Synthesis of 4-bromo-7-cyclopentyl-9-iodobenzo[4,5]imidazo[l,2- a]quinazolin-5(7H)-one (intermediate A14)

[0509] Intermediate A14 was synthesized according to the procedure described in Scheme 14. To a solution of 2-bromo-6-fluorobenzoic acid (0.7 g, 3.2 mmol, 1 eq) and CDI (0.57 g, 3.52 mmol, 1.1 eq) in 1,4-dioxane (10 mL) was stirred at 95 °C for 1 h. After the reaction mixture was cooled to room temperature, HOBT (0.52 g, 3.84 mmol, 1.2 eq) and intermediate A14c (1.05 g, 3.20 mmol, 1 eq) were added. The reaction mixture was stirred at 95 °C overnight. After the reaction was completed, the reaction mixture was concentrated and purified by silica gel column (PE:EA = 3:1) to give yellow solid intermediate A14d (0.96 g, 56.87%)

[0510] LC-MS (ESI): [M+H] + = 508.10

[0511] 1H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.4, 1.0 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.74 (d, J = 1.6 Hz, 1H), 7.69 (dd, J = 8.7, 1.6 Hz, 1H), 7.56 (t, J = 8.2 Hz, 1H), 5.60 - 5.43 (m, 1H), 2.26 - 2.10 (m, 4H), 2.10 - 1.97 (m, 2H), 1.89 - 1.76 (m, 2H).

[0512] Synthesis of Example 16 Intermediate A15

[0513] 4-Bromo-7-cyclopentyl-9-(4-(dihydroxymethyl)-4-fluoropiperidin-l-yl)benzo[4,5]imidazo[l,2- a]quinazolin-5(7H)-one (Intermediate A15)

[0514] Synthesis Scheme

[0515] First Step: Ethyl 4-fluoropiperidine-4-carboxylate (Intermediate A15a)

[0516] Ethyl N-BOC-4-fluoro-4-piperidinecarboxylate (1.00 g, 3.63 mmol) was dissolved in dichloromethane (16 mL), trifluoroacetic acid (4 mL) was added to the reaction system, stirred at room temperature for 1 hour; TLC detection reaction was completed, the reaction solution was concentrated and dissolved with water, freeze-dried to obtain colorless oil A15a crude product (970 mg, >99%).

[0517] 1 H NMR (400 MHz, DMSO-d6) δ 4.21 (q, J = 7.1 Hz, 2H), 3.38 - 3.26 (m, 2H), 3.12 - 2.98 (m, 2H), 2.29 - 2.06 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H).

[0518] LCMS (ESI): [M+H] + = 176.25

[0519] Second Step: Ethyl l-(3-(cyclopentylamino)-4-nitrophenyl)-4-fluoropiperidine-4-carboxylate (Intermediate A15b)

[0520] Intermediate A15a (400 mg, 1.40 mmol), A15a (600 mg, 2.26 mmol), palladium acetate (32 mg, 142.53 umol), cesium carbonate (1.83 g, 5.61 mmol) and Xantphos (165 mg, 285.46 umol) were dissolved in 1.4-dioxane (40 mL) under nitrogen protection, stirred at 105 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and separated and purified by normal phase column (EA / PE = 13%) to obtain yellow oil A15b (390 mg, 73%)

[0521] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 6.6 Hz, 1H), 7.91 (d, J = 9.8 Hz, 1H), 6.47 (dd, J = 9.8, 2.5 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.13 - 4.04 (m, 1H), 4.01 - 3.93 (m, 2H), 3.30 - 3.21 (m, 2H), 2.13 - 1.93 (m, 6H), 1.75 - 1.57 (m, 4H), 1.55 - 1.45 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0522] LCMS (ESI): [M+H] + = 380.39

[0523] Third step: 1-(4-amino-3-(cyclopentylamino)phenyl)-4-fluoropiperidine-4-carboxylic acid ethyl ester (Intermediate A15c)

[0524] A15b (150 mg, 395.33 umol) was dissolved in methanol (10 mL), and palladium hydroxide carbon (350 mg, 10%) was added to the reaction system, replaced with hydrogen three times, and stirred at room temperature overnight. After the reaction was completed, it was filtered and the filtrate was directly used in the next step (theoretical: 138 mg)

[0525] LCMS (ESI): [M+H] + = 350.29

[0526] Fourth step: 1-(2-amino-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-4-fluoropiperidine-4-carboxylic acid ethyl ester (Intermediate A15d)

[0527] To a solution of A15c (130 mg, 372.01 umol) in methanol (30 mL) was added cyanogen bromide (60 mg, 566.45 umol) under ice water bath condition, after stirring at room temperature for 30 minutes, triethylamine (38 mg, 375.52 umol) was added; the reaction was continued for one hour. The reaction was concentrated to give yellow solid A15d (150 mg, 108%)

[0528] LCMS (ESI): [M+H] + = 375.39

[0529] Fifth step: 1-(2-(2-bromo-6-fluorobenzamido)-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-4-fluoropiperidine-4-carboxylic acid ester (intermediate A15e)

[0530] To a solution of 2-bromo-6-fluorobenzoic acid (80 mg, 365.28 umol) and CDI (70 mg, 431.69 umol) in 1.4-dioxane (10 mL) was stirred at 95 °C for two hours, after cooling to room temperature, A15d (150 mg, 372.54 umol) and HOBt (70 mg, 518.04 umol) were added, and stirred at 95 °C overnight. After the reaction was completed, the reaction was concentrated and separated and purified by normal phase column (EA / PE = 22%) to give yellow oil A15e (110 mg, 51%)

[0531] 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 7.52-7.43 (m, 2H), 7.38-7.27 (m, 2H), 7.13-7.02 (m, 2H), 5.20-5.08 (m, 1H), 4.25-4.18 (m, 2H), 3.64-3.55 (m, 2H), 3.09-2.97 (m, 2H), 2.29-1.84 (m, 10H), 1.69-1.56 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0532] LCMS (ESI): [M+H] + = 575.38 / 577.38

[0533] Sixth step: 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazol-9-yl)-4-fluoropiperidine-4-carboxylic acid methyl ester (intermediate A15f)

[0534] A15e (110 mg, 191.15 umol) was dissolved in DMF (5 mL), potassium phosphate (60 mg, 282.67 umol) was added, after stirring at 120 °C for two hours, it was cooled to room temperature, the reaction liquid was extracted with ethyl acetate, washed with brine, and the organic phase was concentrated and separated by thin layer chromatography (PE:EA = 1:3) to obtain yellow solid A15f (60 mg, 56%).

[0535] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 9.1, 2.2 Hz, 1H), 5.27-5.16 (m, 1H), 4.26-4.18 (m, 2H), 3.79-3.69 (m, 2H), 3.14-3.02 (m, 2H), 2.37-1.93 (m, 10H), 1.80-1.66 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0536] LCMS (ESI): [M+H] + = 555.38 / 557.28

[0537] Seventh step: 4-bromo-7-cyclopentyl-9-(4-fluoro-4-(hydroxymethyl)piperidin-l- yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (intermediate A15g)

[0538] A15f (50 mg, 92.35 umol) was dissolved in super dry tetrahydrofuran (10 mL), lithium borohydride (190 uL, 380.00 umol) was added under ice water bath conditions, guoye1 was stirred at room temperature, the reaction liquid was concentrated and separated by thin layer chromatography (MeOH:DCM = 1:15) to obtain yellow solid A15g (40 mg, 87%).

[0539] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 9.1, 2.1 Hz, 1H), 5.03 (t, J = 5.9 Hz, 1H), 3.69 - 3.62 (m, 2H), 3.48 (dd, J = 20.0, 6.0 Hz, 1H), 3.12 - 3.03 (m, 2H), 2.36 - 2.24 (m, 2H), 2.04 - 1.96 (m, 4H), 1.89 - 1.71 (m, 6H).

[0540] LCMS (ESI): [M+H] + = 513.39 / 515.29

[0541] Eighth Step: 4-Bromo-7-cyclopentyl-9-(4-(dihydroxymethyl)-4-fluoropiperidin-l- yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate A15)

[0542] A15g (40 mg, 77.91 umol) was dissolved in tetrahydrofuran (15 mL), and Dess-Martin oxidant (50 mg, 117.92 umol) was added under ice-water bath condition. After stirring at room temperature for 4 hours, the reaction solution was extracted with ethyl acetate, and the organic phase was concentrated to obtain yellow solid of intermediate A15 (35 mg, 84%).

[0543] LCMS (ESI): [M+H] + = 529.39 / 531.29

[0544] Synthesis of Example 17 Intermediate A16

[0545] Synthesis of 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinazolin-9-yl)-4-(dihydroxymethyl)piperidine-4-carbonitrile (Intermediate A16)

[0546] First Step: Methyl 4-cyanopiperidine-4-carboxylate (Intermediate A16a)

[0547] Synthesis method is the same as Intermediate A15a

[0548] 1H NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.47-3.43 (m, 2H), 3.07-2.96 (m, 2H), 2.37-2.29 (m, 2H), 2.22-2.12 (m, 2H).

[0549] LCMS (ESI): [M+H] + = 169.25

[0550] Second Step: 4-cyano-1-(3-(cyclopentylamino)-4-nitrophenyl)piperidine-4- carboxylic acid methyl ester (Intermediate A16b)

[0551] Synthetic procedure same as Intermediate A15b

[0552] 1 H NMR (600 MHz, DMSO-d6) δ 8.35 (d, J = 5.9 Hz, 1H), 7.92 (d, J = 9.8 Hz, 1H), 6.47 (dd, J = 9.8, 2.5 Hz, 1H), 6.09 (d, J = 2.3 Hz, 1H), 4.13-4.05 (m, 3H), 3.79 (s, 3H), 3.20-3.11 (m, 2H), 2.23-2.16 (m, 2H), 2.12-1.97 (m, 4H), 1.76-1.59 (m, 4H), 1.54-1.46 (m, 2H).

[0553] LCMS (ESI): [M+H] + = 373.49

[0554] Third Step: 1-(4-amino-3-(cyclopentylamino)phenyl)-4-cyanopiperidine-4- carboxylic acid methyl ester (Intermediate A16c)

[0555] Synthetic procedure same as Intermediate A15c

[0556] LCMS (ESI): [M+H] + = 343.19

[0557] Fourth Step: 1-(2-amino-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-4-cyanopiperidine-4- carboxylic acid methyl ester (Intermediate A16d)

[0558] Synthetic procedure same as Intermediate A15d

[0559] LCMS (ESI): [M+H] + = 368.49

[0560] Step 5: 1-(2-(2-bromo-6-fluorobenzamido)-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-4- cyanopiperidine-4-carboxylic acid methyl ester (Intermediate A16e)

[0561] Synthetic procedure similar to Intermediate A15e

[0562] LCMS (ESI): [M+H] + = 568.30 / 570.30

[0563] Step 6: 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazol-9-yl)-4- cyanopiperidine-4-carboxylic acid ester (Intermediate A16f)

[0564] Synthetic procedure similar to Intermediate A15f

[0565] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 9.1, 2.0 Hz, 1H), 5.28 - 5.14 (m, 1H), 3.91 - 3.83 (m, 2H), 3.82 (s, 3H), 3.05 - 2.93 (m, 2H), 2.39 - 2.09 (m, 6H), 2.08 - 1.94 (m, 4H), 1.80 - 1.65 (m, 2H).

[0566] LCMS (ESI): [M+H] + = 548.38 / 550.38

[0567] Step 7: 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9-yl)-4- (hydroxymethyl)piperidine-4-carbonitrile (Intermediate A16g)

[0568] Synthetic procedure similar to Intermediate A15g

[0569] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 9.1, 2.0 Hz, 1H), 5.76 (s, 1H), 5.26 - 5.17 (m, 1H), 3.88 - 3.82 (m, 2H), 3.55 (s, 2H), 2.98 - 2.87 (m, 2H), 2.38 - 2.24 (m, 2H), 2.10 - 1.94 (m, 6H), 1.79 - 1.63 (m, 4H).

[0570] LCMS (ESI): [M+H] + = 520.39 / 522.29

[0571] Eighth Step: 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2- a]quinolin-9-yl)-4-(dihydroxymethyl)piperidine-4-carbonitrile (Intermediate A16)

[0572] Synthetic procedure same as Intermediate A15

[0573] LCMS (ESI): [M+H] + = 536.29 / 538.28

[0574] Synthesis of Example 18 Intermediate A17

[0575] 1-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinolin-9-yl)piperidine-4- carbaldehyde (Intermediate A17)

[0576] Synthetic Scheme

[0577] First Step: 5-bromo-3,3-dimethylindolin-2-one (Intermediate A17a)

[0578] Dissolve 5-bromo oxindole (5.50 g, 25.94 mmol) in super dry tetrahydrofuran (200 mL), after nitrogen protection, cool to -75 °C, slowly add LDA (39.00 mL, 2.0 M) to the reaction system, keep stirring at -75 °C for 1 hour, then add iodomethane (7.36 g, 51.88 mmol), stir at room temperature for 2 hours, TLC detection shows that the reaction is complete, pour the reaction liquid into water and extract with ethyl acetate, concentrate the organic phase, separate and purify by normal phase chromatographic column (EA / PE = 14%) to obtain white solid A17a (3.5 g, 56%).

[0579] 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.2, 2.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 1.25 (s, 6H).

[0580] LCMS (ESI): [M+H] + = 240.16 / 242.16

[0581] Second step: 5-(4-(dimethoxymethyl)piperidin-1-yl)-3,3-dimethylindolin-2-one (intermediate A17b)

[0582] Dissolve A17a (1.40 g, 5.83 mmol), 4-(dimethoxymethyl)-piperidine (1.39 g, 8.75 mmol) and X-phos Pd G3 (490 mg, 579.19 umol) in 1.4-dioxane (40 mL), nitrogen protection, add LiHMDS (35 mL, 35.00 mmol) to the reaction system, stir at 85 °C for 1 hour, after the reaction is complete, concentrate the reaction liquid, separate and purify by normal phase chromatographic column (MeOH / DCM = 5%) to obtain yellow solid A17b (1.3 g, 70%).

[0583] 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 6.98 (d, J = 1.7 Hz, 1H), 6.73 - 6.65 (m, 2H), 4.09 (d, J = 6.9 Hz, 1H), 3.55 - 3.45 (m, 2H), 3.34 (s, 2H), 3.27 (s, 6H), 1.76 - 1.59 (m, 3H), 1.40 - 1.27 (m, 2H), 1.23 (s, 6H).

[0584] LCMS (ESI): [M+H] + = 319.30

[0585] Step 3: 2-bromo-6-(5-(4-(dimethoxymethyl)piperidin-l-yl)-3,3-dimethyl-2- oxindolin-l-yl)benzonitrile (Intermediate A17c)

[0586] A17b (1.70 g, 5.34 mmol), 2-fluoro-6-bromobenzonitrile (2.14 g, 10.68 mmol) and cesium carbonate (5.22 g, 16.02 mmol) were dissolved in acetonitrile (100 mL) and stirred at 80 °C overnight. After TLC monitoring of the reaction completion, it was concentrated and purified by normal phase column (MeOH / DCM = 5%) to give yellow solid A17c (2.40 g, 90%).

[0587] 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (dd, J = 8.2, 0.9 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.0, 0.9 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.6, 2.4 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.10 (d, J = 6.7 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.64 - 3.56 (m, 2H), 3.27 (s, 6H), 2.62 - 2.53 (m, 2H), 1.76 - 1.62 (m, 3H), 1.41 (d, J = 6.3 Hz, 6H).

[0588] LCMS (ESI): [M+H] + = 498.29 / 500.39

[0589] Step 4: 2-bromo-6-(5-(4-(dimethoxymethyl)piperidin-l-yl)-3,3-dimethyl-2- oxindolin-l-yl)benzamide (Intermediate A17d)

[0590] A17c (2.20 g, 4.41 mmol) was dissolved in DMSO (30 mL) solution, potassium carbonate (1.22 g, 8.83 mmol) and hydrogen peroxide (10 mL) were added and stirred at 50 °C overnight. After TLC monitoring of the reaction completion, the reaction was quenched with ice water, extracted with ethyl acetate, washed with brine and concentrated, purified by normal phase column (MeOH / DCM = 3%) to give yellow solid A17d (1.90 g, 83%).

[0591] 1H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 8.1, 1.0 Hz, 1H), 7.58-7.55 (s, 1H), 7.54-7.51 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 7.9, 1.0 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.67 (dd, J = 8.6, 2.4 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 4.11 - 4.08 (m, 1H), 3.59 - 3.50 (m, 2H), 3.27 (s, 6H), 2.58 - 2.51 (m, 2H), 1.77 - 1.60 (m, 3H), 1.40-1.29 (m, 8H).

[0592] LCMS (ESI): [M+H] + = 516.29 / 518.29

[0593] Fifth Step: 4-Bromo-9-(4-(dimethoxymethyl)piperidin-l-yl)-7,7-dimethylindolo[l,2- a]quinolin-5(7H)-one (Intermediate A17e)

[0594] A17d (300 mg, 589.90 umol) was dissolved in methanol (20 mL), sodium methoxide (540 uL, 2.92 mmol) was added to the reaction system, stirred at 70 °C overnight, cooled to room temperature, quenched with ice water, the organic phase was extracted with ethyl acetate and then rotary evaporated, the organic phase was purified by preparative plate (MeOH:DCM = 1:15) to obtain yellow oil A17e (170 mg, 58%).

[0595] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 9.1, 2.6 Hz, 1H), 4.13 - 4.11 (m, 1H), 3.81 (d, J = 12.2 Hz, 2H), 3.28 (s, 6H), 2.73-2.61 (m, 2H), 1.80-1.71 (m, 3H), 1.51 (s, 6H), 1.38 - 1.33 (m, 2H).

[0596] LCMS (ESI): [M+H] + = 498.29 / 500.29

[0597] Step 6: 1-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindol[1,2-a]quinazolin-9-yl)piperidine- 4-carbaldehyde (Intermediate A17)

[0598] A17e (15 mg, 30.10 umol) was dissolved in formic acid (3 mL) and stirred at room temperature for 30 min, adjusted to weak alkaline with sodium bicarbonate solution, extracted with dichloromethane, concentrated the organic phase to get yellow oil A17 (15 mg, 110%) which was used directly for the next step.

[0599] LCMS (ESI): [M+H] + = 452.29 / 454.29

[0600] Synthesis of Intermediate A18 in Example 19

[0601] 4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9-yl)cyclohexane- 1-carbaldehyde (Intermediate A18)

[0602] Synthetic Scheme

[0603] Step 1: 4-bromo-7-cyclopentyl-9-(4-(hydroxymethyl)cyclohexyl)benzo[4,5]imidazo[1,2- a]quinazolin-5(7H)-one (Intermediate A18a)

[0604] Intermediate A13 (100 mg, 196.69 umol) was dissolved in THF (15 mL) and protected by nitrogen, added borane tetrahydrofuran complex (1 mL, 1.00 mmol), stirred at room temperature for 5 hours, the reaction solution was quenched with methanol, dried by rotary evaporation and dissolved in methanol, purified by high performance liquid chromatography to obtain product A18a (30 mg, 30%)

[0605] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.52 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 5.33 - 5.20 (m, 1H), 3.53 (d, J = 7.2 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.34 - 2.21 (m, 2H), 2.09 - 1.85 (m, 5H), 1.83 - 1.52 (m, 10H).

[0606] LCMS (ESI): [M+H]+ = 494.39 / 496.39

[0607] Second Step: 4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinolin-9-yl)cyclohexane- 1 -carbaldehyde (Intermediate A18)

[0608] A18a (40 mg, 80.90 umol) was dissolved in a mixed solvent of tetrahydrofuran and dichloromethane (5 / 5 mL), Dess-Martin Oxidizing Reagent (65 mg, 153.30 umol) was added under ice water bath condition, after stirring at room temperature for 1 hour, the reaction solution was extracted with dichloromethane, and the organic phase was concentrated to obtain yellow oil Intermediate A18 (38 mg, 95%).

[0609] LCMS (ESI): [M+H] + = 492.29 / 494.39

[0610] Synthesis of Intermediate A19 in Example 20

[0611] 4-bromo-7-cyclopentyl-9-((2R,4R)-4-(dimethylamino)-2-methylpiperidin-l- yl)benzo[4,5]imidazo[l,2-a]quinolin-5(7H)-one (Intermediate A19)

[0612] Synthesis Scheme

[0613] First Step: 1-benzyl 4-methyl (2R,4R)-2-methylpiperidine-l,4-dicarboxylate (Intermediate A19a)

[0614] (2R,4R)-2-methylpiperidine-4-carboxylic acid methyl ester hydrochloride (1.0 g, 5.16 mmol), triethylamine (2.0 g, 15.5 mmol) were added to dichloromethane, benzyl chloroformate (1.06 g, 6.2 mmol) was added, and the reaction was stirred at room temperature for 5 h. After the reaction was completed as detected by LCMS, it was evaporated to dryness, and column chromatography was performed to give A19a (1.2 g, 80%) as colorless oil.

[0615] 1H NMR (400 MHz, chloroform-d) δ 7.42 - 7.30 (m, 5H), 5.19 - 5.10 (m, 2H), 4.35 - 4.25 (m, 1H), 3.99 - 3.91 (m, 1H), 3.73 (s, 3H), 3.25 - 3.15 (m, 1H), 2.66 - 2.59 (m, 1H), 2.09 - 1.93 (m, 3H), 1.82 - 1.71 (m, 1H), 1.13 (d, J = 6.9 Hz, 3H).

[0616] LCMS (ESI): [M+H] + = 292.25

[0617] Second step: Benzyl (2R,4R)-4-(hydroxymethyl)-2-methylpiperidine-l-carboxylate (Intermediate A19b)

[0618] Synthesis method same as Intermediate Blc

[0619] 1 H NMR (400 MHz, chloroform-d) δ 7.42 - 7.30 (m, 5H), 5.19 - 5.10 (m, 2H), 4.35 - 4.25 (m, 1H), 3.99 - 3.91 (m, 1H), 3.73 (s, 3H), 3.25 - 3.15 (m, 1H), 2.66 - 2.59 (m, 1H), 2.09 - 1.93 (m, 3H), 1.82 - 1.71 (m, 1H), 1.13 (d, J = 6.9 Hz, 3H).

[0620] LCMS (ESI): [M+H] + = 264.37

[0621] Third step: Benzyl (2R,4R)-4-formyl-2-methylpiperidine-l-carboxylate (Intermediate A19c)

[0622] Synthesis method same as Intermediate Bid

[0623] LCMS (ESI): [M+H] + = 262.30

[0624] Fourth step: Benzyl (2R,4R)-4-(dimethoxymethyl)-2-methylpiperidine-l-carboxylate (Intermediate A19d)

[0625] Synthesis method same as Intermediate B le

[0626] 1H NMR (400 MHz, chloroform-d) δ 7.39 - 7.32 (m, 5H), 5.17 - 5.10 (m, 2H), 4.17 (d, J = 6.7 Hz, 1H), 4.03 - 3.92 (m, 1H), 3.88-3.80 (m, 1H), 3.35 (d, J = 6.0 Hz, 6H), 3.14-3.05 (m, 1H), 1.95 - 1.80 (m, 3H), 1.47 - 1.38 (m, 1H), 1.33 - 1.26 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H).

[0627] LCMS (ESI): [M+H] + = 308.35

[0628] Fifth Step: (2R,4R)-4-(dimethoxymethyl)-2-methylpiperidine (Intermediate A19e)

[0629] Synthetic procedure same as Intermediate B1f

[0630] 1 H NMR (400 MHz, DMSO-d6) δ 3.96 (d, J = 6.9 Hz, 1H), 3.23 (s, 6H), 2.96 - 2.88 (m, 1H), 2.52 - 2.40 (m, 3H), 1.66 - 1.47 (m, 3H), 1.05 - 0.92 (m, 5H).

[0631] LCMS (ESI): [M+H] + = 174.35

[0632] Sixth Step: 1-cyclopentyl-6-((2R,4R)-4-(dimethoxymethyl)-2-methylpiperidin-l-yl)-lH- benzo[d]imidazol-2-amine (A19f)

[0633] Synthetic procedure same as Intermediate A6d.

[0634] LCMS (ESI): [M+H] + = 373.49

[0635] Seventh Step: 2-bromo-N-(l-cyclopentyl-6-((2R,4R)-4-(dimethoxymethyl)-2-methylpiperidin-l-yl)- lH-benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate A19g)

[0636] Synthetic procedure same as Intermediate A6e

[0637] LCMS (ESI): [M+H] + = 573.35 / 575.35

[0638] Eighth Step: 4-Bromo-7-cyclopentyl-9-((2R,4R)-4-(dimethoxymethyl)-2- methylpiperidin-l-yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate A19h)

[0639] Synthetic procedure same as Intermediate A6f

[0640] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.48 - 7.35 (m, 3H), 5.23 (s, 1H), 4.25 - 4.16 (m, 1H), 3.37 - 3.26 (m, 6H), 2.34 - 1.69 (m, 11H), 1.32 - 1.18 (m, 2H), 0.99 (d, J = 5.6 Hz, 3H).

[0641] LCMS (ESI): [M+H] + = 553.38 / 555.38

[0642] Ninth Step: 4-Bromo-7-cyclopentyl-9-((2R,4R)-4-(dimethoxymethyl)-2- methylpiperidin-l-yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate A19)

[0643] Synthetic procedure same as Intermediate A6

[0644] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 5.32 - 5.21 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.84 - 2.72 (m, 2H), 2.30 - 2.11 (m, 4H), 2.08 - 1.95 (m, 4H), 1.84 - 1.56 (m, 8H), 1.23 (t, J = 7.1 Hz, 3H).

[0645] LCMS (ESI): [M+H] + = 525.29 / 527.29

[0646] Synthesis of Example 21 Intermediate A20

[0647] 1-(4-bromo-7-methyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9- yl)piperidine-4-carbaldehyde (Intermediate A20)

[0648] Synthesis Scheme

[0649] First Step: 5-Bromo-N-methyl-2-nitroaniline (Intermediate A20a)

[0650] Synthesis method same as Intermediate A6a

[0651] 1 H NMR (400 MHz, chloroform-d) δ 8.05 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 9.1, 2.0 Hz, 1H), 3.04 (d, J = 5.1 Hz, 3H).

[0652] LCMS (ESI): [M+H] + = 231.16 / 233.26

[0653] Second Step: 5-Bromo-N-methylbenzene-1,2-diamine (A20b)

[0654] Synthesis method same as Intermediate A6b

[0655] 1 H NMR (400 MHz, chloroform-d) δ 6.79 (dd, J = 8.1, 2.1 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 3.26 (s, 3H), 2.86 (s, 3H).

[0656] LCMS (ESI): [M+H] + = 201.15 / 203.25

[0657] Third Step: 6-Bromo-1-methyl-1H-benzo[d]imidazol-2-amine (Intermediate A20c)

[0658] Synthesis method same as Intermediate A6c

[0659] 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 2H), 7.67 (d, J = 1.2 Hz, 1H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 3.57 (s, 3H).

[0660] LCMS (ESI): [M+H] + = 226.26 / 228.26

[0661] Fourth Step: 6-(4-(dimethoxymethyl)piperidin-l-yl)-l-methyl-lH-benzo[d]imidazol-2-amine (Intermediate A20d)

[0662] Synthetic procedure same as Intermediate A6d

[0663] LCMS (ESI): [M+H] + = 305.35

[0664] Fifth Step: 2-bromo-N-(6-(4-(dimethoxymethyl)piperidin-l-yl)-l-methyl-lH- benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate A20e)

[0665] Synthetic procedure same as Intermediate A6e

[0666] LCMS (ESI): [M+H] + = 505.30 / 507.30

[0667] Sixth Step: 4-bromo-9-(4-(dimethoxymethyl)piperidin-l-yl)-7-methylbenzo[4,5]imidazolin- 1,2-a]quinazolin-5(7H)-one (Intermediate A20f)

[0668] Synthetic procedure same as Intermediate A6f

[0669] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.20 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.12 (d, J = 6.5 Hz, 1H), 3.86 (d, J = 12.2 Hz, 2H), 3.64 (s, 3H), 3.29 (s, 6H), 2.81 - 2.69 (m, 2H), 2.03 - 1.94 (m, 1H), 1.80 - 1.72 (m, 2H), 1.46 - 1.32 (m, 2H).

[0670] LCMS (ESI): [M+H] + = 485.29 / 487.29

[0671] Step 7: 1-(4-bromo-7-methyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinolin-9-yl)piperidine-4-carbaldehyde (Intermediate A20)

[0672] Synthetic procedure same as Intermediate A6

[0673] LCMS (ESI): [M+H] + = 439.29 / 441.29

[0674] Synthesis of Example 22 Intermediate A21

[0675] 1-(4-chloro-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2-a]quinolin-9-yl)- 4-(dihydroxymethyl)piperidine-4-carbonitrile (Intermediate A21)

[0676] Synthetic procedure

[0677] Step 1: Methyl 1-(2-(2-chloro-6-fluorobenzamido)-l-cyclopentyl-lH- benzo[d]imidazol-6-yl)-4-cyanopiperidine-4-carboxylate (Intermediate A21a)

[0678] Synthetic procedure same as Intermediate A15e

[0679] 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.47-7.42 (m 1H), 7.41-7.36 (m, 1H), 7.35 - 7.31 (m, 1H), 7.29-7.22 (m, 1H), 7.09-7.06 (m, 1H), 7.01 (dd, J = 8.8, 1.8 Hz, 1H), 5.20-5.08 (m, 1H), 3.82 (s, 3H), 3.76-3.68 (m, 2H), 2.98-2.86 (m, 2H), 2.26-2.12 (m, 6H), 1.96-1.82 (m, 4H), 1.68-1.56 (m, 2H).

[0680] LCMS (ESI): [M+H] + = 524.39

[0681] Second Step: 1-(4-chloro-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazol-9-yl)-4- cyano piperidine-4-carboxylic acid methyl ester (Intermediate A21b)

[0682] Synthetic procedure similar to Intermediate A15f

[0683] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 9.1 Hz, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 9.1, 2.1 Hz, 1H), 5.26 - 5.16 (m, 1H), 3.90 - 3.84 (m, 2H), 3.82 (s, 3H), 3.05 - 2.93 (m, 2H), 2.38 - 2.21 (m, 4H), 2.19 - 2.10 (m, 2H), 2.07 - 1.94 (m, 4H), 1.78 - 1.66 (m, 2H).

[0684] LCMS (ESI): [M+H] + = 504.39

[0685] Third Step: 1-(4-chloro-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2- a]quinazolin-9-yl)-4-(hydroxymethyl)piperidine-4-carbonitrile (Intermediate A21c)

[0686] Synthetic procedure similar to Intermediate A15g

[0687] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.77 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 9.1, 2.0 Hz, 1H), 5.29 - 5.15 (m, 1H), 3.92 - 3.86 (m, 3H), 3.55 (s, 2H), 2.98 - 2.86 (m, 2H), 2.38 - 2.23 (m, 2H), 2.08 - 1.94 (m, 6H), 1.79 - 1.63 (m, 4H).

[0688] LCMS (ESI): [M+H] + = 476.35

[0689] Fourth Step: 1-(4-chloro-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinolin-9-yl)-4-(dihydroxymethyl)piperidine-4-carbonitrile (Intermediate A21)

[0690] Synthetic procedure is same as Intermediate A13

[0691] LCMS (ESI): [M+H] + = 492.39

[0692] Synthesis of Example 23 Intermediate A22

[0693] 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2-a]quinolin-9-yl)piperidine- 4-carboxylic acid (Intermediate A22)

[0694] Synthetic procedure

[0695] First Step: tert-butyl 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinolin-9-yl)piperidine-4-carboxylate (Intermediate A22a)

[0696] Intermediate A14 (100 mg, 0.2 mmol), tert-butyl piperidine-4-carboxylate (36.63 mg, 0.26 mmol), Pd2(dba)3(22.77 mg, 0.04 mmol), Xantphos (18.02 mg, 0.02 mmol), tBuONa (56.74 mg, 0.06 mmol) were dissolved in 1,4-dioxane (5 mL) and heated to 100 °C under N2 overnight. After the reaction was completed, the system was separated by column chromatography to obtain yellow solid A22a (80 mg, 77%).

[0697] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 9.1 Hz, 1H), 5.27 - 5.17 (m, 1H), 3.77 - 3.69 (m, 2H), 3.01 (t, J = 10.7 Hz, 2H), 2.50 - 2.43 (m, 1H), 2.35 - 2.22 (m, 2H), 2.05 - 1.93 (m, 6H), 1.80 - 1.68 (m, 4H), 1.42 (s, 9H).

[0698] LCMS (ESI): [M+H] + = 565.38 / 567.48

[0699] Second Step: (2R)-1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5] imidazo[1,2-a]quinolin-9-yl)-2-methylpiperidine-4-carboxylic acid (Intermediate A23)

[0700] Synthetic Method is same as Intermediate A6

[0701] LCMS (ESI): [M+H] + = 509.39 / 511.39

[0702] Synthesis of Intermediate A23 in Example 24

[0703] (2R)-1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5] imidazo[1,2-a]quinolin-9-yl)-2-methylpiperidine-4-carboxylic acid (Intermediate A23)

[0704] Synthetic Scheme

[0705] First Step: Methyl (2R)-1-(3-(cyclopentylamino)-4-nitrophenyl)-2- methylpiperidine-4-carboxylate (Intermediate A23a)

[0706] Synthetic Method is same as Intermediate A15b.

[0707] 1 H NMR (400 MHz, chloroform-d) δ 8.09 - 8.04 (m, 1H), 6.18 (dd, J = 9.8, 2.6 Hz, 1H), 5.85 (d, J = 2.5 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.96 - 3.86 (m, 1H), 3.75 (s, 3H), 3.62 - 3.54 (m, 1H), 3.40-3.31 (m, 1H), 2.68-2.59 (m, 1H), 2.22 - 1.96 (m, 7H), 1.71 - 1.62 (m, 5H), 1.20 (d, J = 6.6 Hz, 3H).

[0708] LCMS (ESI): [M+H] + = 362.49

[0709] Second Step: Methyl (2R)-1-(4-amino-3-(cyclopentylamino)phenyl)-2- methylpiperidine-4-carboxylate (Intermediate A23b)

[0710] Synthetic procedure similar to Intermediate A15c

[0711] LCMS (ESI): [M+H] + = 332.48

[0712] Third step: Methyl (2R)-1-(2-amino-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-2- methylpiperidine-4-carboxylate (Intermediate A23c)

[0713] Synthetic procedure similar to Intermediate A15d

[0714] LCMS (ESI): [M+H] + = 357.49

[0715] Fourth step: Methyl (2R)-1-(2-(2-bromo-6-fluorobenzamido)-1-cyclopentyl-1H- benzo[d]imidazol-6-yl)-2-methylpiperidine-4-carboxylate (Intermediate A23d)

[0716] Synthetic procedure similar to Intermediate A15e

[0717] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.42 - 4.30 (m, 2H), 5.21 - 5.10 (m, 1H), 4.02 - 3.92 (m, 1H), 3.69 (s, 4H), 3.02 - 2.93 (m, 1H), 2.33 (d, J = 13.7 Hz, 1H), 2.24 - 1.92 (m, 10H), 1.72 - 1.60 (m, 2H), 1.01 (d, J = 6.3 Hz, 3H).

[0718] LCMS (ESI): [M+H] + = 557.38 / 559.38

[0719] Fifth step: Methyl (2R)-1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2- a]quinolin-9-yl)-2-methylpiperidine-4-carboxylate (Intermediate A23e)

[0720] Synthetic procedure similar to Intermediate A15f

[0721] 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 7.7 Hz, 2H), 7.70 (t, J = 8.2 Hz, 1H), 7.57 (s, 1H), 5.27 - 5.16 (m, 1H), 3.89 - 3.76 (m, 1H), 3.68 (s, 4H), 2.94 - 2.81 (m, 1H), 2.33 - 1.66 (m, 13H), 1.01 (d, J = 6.2 Hz, 3H).

[0722] LCMS (ESI): [M+H] + = 537.38 / 539.38

[0723] Step 6: (2R)-1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2- a]quinolin-9-yl)-2-methylpiperidine-4-carboxylic acid (Intermediate A23)

[0724] Synthetic procedure same as Intermediate A15

[0725] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 17.0, 8.6 Hz, 2H), 7.83 (d, J = 7.7 Hz, 2H), 7.70 (t, J = 8.2 Hz, 1H), 7.57 (s, 1H), 5.26 - 5.16 (m, 1H), 3.94 - 3.82 (m, 1H), 3.61 (s, 1H), 2.82 - 2.73 (m, 1H), 2.35 - 1.67 (m, 13H), 1.02 (d, J = 6.3 Hz, 3H).

[0726] LCMS (ESI): [M+H] + = 523.29 / 525.29

[0727] Synthesis of Example 25 Intermediate A24

[0728] 2-(4-(4-bromo-7-cyclopentyl-5-oxo-7,12-dihydro-5H-quinoline[3,2-a]quinoxalin-9- yl)piperazin-1-yl)acetic acid (Intermediate A24)

[0729] Synthetic procedure

[0730] Step 1: tert-butyl 2-(4-(4-bromo-7-cyclopentyl-5-oxo-7,12-dihydro-5H-quinoline[3,2- a]quinoxalin-9-yl)piperazin-1-yl)acetate (Intermediate A24a)

[0731] Intermediate A9 (100 mg, 0.2 mmol) was dissolved in DCM, DIEA (80.71 mg, 0.62 mmol) was added and the reaction was allowed to proceed for 10 minutes at room temperature, then tert-butyl-2-bromoacetate (40 mg, 0.21 mmol) was added and the reaction was allowed to proceed overnight. After the reaction was completed, the system was separated by preparative column chromatography to obtain a white solid (10 mg, 20%). The system was separated by column chromatography to obtain a yellow solid A24a (120 mg, 96%).

[0732] LC-MS (ESI): [M+H] + = 584.48

[0733] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.86 (m, 1H), 7.62 - 7.54 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.2, 2.0 Hz, 1H), 6.68 (s, 1H), 5.07 (s, 2H), 4.99 - 4.89 (m, 1H), 3.21 - 3.13 (m, 5H), 2.70 - 2.62 (m, 4H), 2.31 - 2.20 (m, 2H), 2.12 - 2.00 (m, 4H), 1.72 - 1.62 (m, 2H), 1.43 (s, 8H), 0.89 - 0.78 (m, 2H).

[0734] Second Step: 2-(4-(4-bromo-7-cyclopentyl-5-oxo-7,12-dihydro-5H-quinoline[3,2- a]quinolin-9-yl)piperazin-1-yl)acetic acid (Intermediate A24)

[0735] Intermediate A24a (120 mg, 0.20 mmol) was dissolved in DCM (2 mL), TFA (2 mL) was added, and the reaction was allowed to proceed for 1 hour. After the reaction was completed, the system was separated by preparative column chromatography to obtain a white solid A24 (39 mg, 36%).

[0736] LC-MS (ESI): [M+H] + = 538.28

[0737] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, J = 8.5, 1.2 Hz, 1H), 7.64 - 7.53 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 5.06 (s, 2H), 4.94 - 4.81 (m, 1H), 4.20 (s, 2H), 3.60 - 3.32 (m, 7H), 2.31 - 2.18 (m, 2H), 2.14 - 1.97 (m, 4H), 1.72 - 1.57 (m, 2H).

[0738] Synthesis of Example 26 intermediate A25

[0739] 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]oxazolo[l,2-a]quinazolin-9-yl)- 4-methoxypiperidine-4-carbaldehyde (intermediate A25)

[0740] Synthesis scheme

[0741] First step: 1-(tert-butyl) 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (intermediate A25a)

[0742] 1-(tert-butyl) 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate (100 mg, 0.38 mmol) was dissolved in DMF (3 mL), NaH (92.55 mg, 3.86 mmol) was added at 0 °C. After the reaction was converted to room temperature for 1 h, CH3I (547.39 g, 3.86 mmol) was added and the reaction was continued for 3 h. After the reaction was completed, water was added to quench, and the water layer was extracted with EA (10 mL x 3), and the organic layer was dried over anhydrous Na2S04, and the reaction liquid was rotary evaporated, and the crude product was purified by silica gel column (EA / P = 18%) to obtain intermediate A25a (78 mg, 74%) as a transparent oily liquid.

[0743] LC-MS (ESI): [M+H-Boc] + = 174.35

[0744] 1 H NMR (600 MHz, DMSO-d6) δ 3.69 (s, 3H), 3.66 - 3.60 (m, 2H), 3.15 (s, 3H), 3.03 (s, 2H), 3.11 - 2.95 (m, 2H), 1.85 - 1.79 (m, 2H), 1.75 - 1.68 (m, 2H), 1.40 (s, 9H).

[0745] Step 2: methyl 4-methoxy-piperidine-4-carboxylate (Intermediate A25b)

[0746] Intermediate A25a (370 mg, 1.35 mmol) was dissolved in HC1-dioxane (5 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated to obtain white solid powder of Intermediate A25b (220 mg, 94%).

[0747] LC-MS (ESI): [M+H] + = 174.25

[0748] 1 H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3H), 3.16 (s, 3H), 3.16 - 3.09 (m, 2H), 2.99 - 2.87 (m, 2H), 2.07 - 2.00 (m, 4H).

[0749] Step 3: methyl l-(3-(cyclopentylamino)-4-nitrophenyl)-4-methoxy-piperidine-4- carboxylate (Intermediate A25c)

[0750] 5-bromo-N-pentyl-2-nitroaniline (300 mg, 1.05 mmol), Intermediate A25b (200 mg, 1.16 mmol), Pd(OAc)2(23.62 mg, 0.10 mmol), XantPhos (121.76 mg, 0.21 mmol), Cs2CO3(1.71 g, 5.26 mmol) were dissolved in dioxane (20 mL) and reacted at 110 °C under N2protection for 4 h. After the reaction was completed, the reaction solution was rotary evaporated and the crude product was purified by silica gel column (EA / P = 22%) to obtain yellow oily liquid of Intermediate A25c (170 mg, 43%).

[0751] LC-MS (ESI): [M+H] + = 378.35

[0752] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 6.6 Hz, 1H), 7.89 (d, J = 9.8 Hz, 1H), 6.44 (dd, J = 9.8, 2.5 Hz, 1H), 6.03 (d, J = 2.6 Hz, 1H), 4.11 - 3.99 (m, 1H), 3.79 - 3.71 (m, 2H), 3.69 (s, 3H), 3.31 - 3.21 (m, 2H), 3.20 (s, 3H), 2.13 - 2.02 (m, 2H), 1.96 - 1.85 (m, 4H), 1.77 - 1.45 (m, 6H).

[0753] Fourth Step: Methyl 1-(4-amino-3-(cyclopentylamino)phenyl)-4- methoxypiperidine-4-carboxylate (Intermediate A25d)

[0754] Intermediate A25c (500 mg) was dissolved in MeOH (5 mL), 10% Pd(OH)2(100 mg) was added, and the reaction was stirred under hydrogen overnight at room temperature. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was used directly in the next step.

[0755] LC-MS (ESI): [M+H] + = 348.39

[0756] Fifth Step: Methyl 1-(2-amino-1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-4- methoxypiperidine-4-carboxylate (Intermediate A25e)

[0757] Intermediate A25d (100 mg, 0.29 mmol) was dissolved in methanol (10 mL), and BrCN (36.58 mg, 0.35 mmol) was dissolved in methanol and added slowly. Et3N (87.37 mg, 0.86 mmol) was added, and the reaction was stirred under N2overnight. After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by silica gel column (MeOH / DCM = 15%) to give purple solid of Intermediate A25e (50 mg, 46%).

[0758] LC-MS (ESI): [M+H] + = 373.49

[0759] 1 H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.23 (m, 1H), 7.01 - 6.94 (m, 1H), 6.89 (d, J = 2.1 Hz, 1H), 4.85 - 4.76 (m, 1H), 3.73 (s, 3H), 3.38 - 3.28 (m, 2H), 3.18 (s, 3H), 3.04 - 2.95 (m, 2H), 2.14 - 1.92 (m, 8H), 1.74 - 1.65 (m, 2H), 1.51 (d, J = 7.0 Hz, 2H).

[0760] Sixth Step: Methyl 1-(2-(2-bromo-6-fluorobenzamido)-1-cyclopentyl-1H- benzo[d]imidazol-6-yl)-4-methoxypiperidine-4-carboxylate (Intermediate A25f)

[0761] Intermediate A25f (317 mg, 42%) was obtained as an oil after the reaction. MS (ESI): [M+H] = 573.28.

[0762] LC-MS (ESI): [M+H] + = 553.28

[0763] 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.49 - 7.40 (m, 2H), 7.35 - 7.25 (m, 2H), 7.03 - 6.95 (m, 2H), 5.21 - 5.09 (m, 1H), 3.71 (s, 3H), 3.41 - 3.35 (m, 2H), 3.19 (s, 3H), 3.07 - 2.97 (m, 2H), 2.25 - 2.12 (m, 2H), 2.09 - 1.82 (m, 8H), 1.70 - 1.56 (m, 2H).

[0764] Seventh step: methyl 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2- a]quinolin-9-yl)-4-methoxypiperidine-4-carboxylate (Intermediate A25g)

[0765] Intermediate A25g (230 mg, 77%) was obtained as a yellow solid after the reaction. MS (ESI): [M+H] = 553.28.

[0766] LC-MS (ESI): [M+H] + = 553.28

[0767] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 9.1 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.00 (dd, J = 9.2, 2.3 Hz, 1H), 5.27 - 5.17 (m, 1H), 3.71 (s, 3H), 3.57 - 3.47 (m, 2H), 3.21 (s, 3H), 3.16 - 3.04 (m, 2H), 2.36 - 2.23 (m, 2H), 2.09 - 1.94 (m, 8H), 1.79 - 1.65 (m, 2H).

[0768] Eighth Step: 4-Bromo-7-cyclopentyl-9-(4-(hydroxymethyl)-4- methoxypiperidin-l-yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate A25h)

[0769] Intermediate A25g (190 mg, 0.34 mmol) was dissolved in THF (5 mL), LiBH4(14.96 mg, 0.69 mmol) was added slowly, and the reaction was stirred at 60 °C for 4 h. After the reaction was completed, methanol was added to quench the reaction, and the reaction mixture was concentrated. The crude product was purified by silica gel column (MeOH / DCM = 9%) to give yellow solid of Intermediate A25h (160 mg, 88%).

[0770] LC-MS (ESI): [M+H] + = 525.29

[0771] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.30 - 7.18 (m, 1H), 7.14 - 7.01 (m, 1H), 5.29 - 5.17 (m, 1H), 3.58 - 3.48 (m, 2H), 3.41 (s, 2H), 3.20 (s, 3H), 3.17 - 3.05 (m, 2H), 2.36 - 2.23 (m, 2H), 2.09 - 1.94 (m, 4H), 1.89 - 1.63 (m, 6H).

[0772] Ninth Step: l-(4-Bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]oxazolo[l,2- a]quinazolin-9-yl)-4-methoxypiperidine-4-carbaldehyde (Intermediate A25)

[0773] Intermediate A25h (60 mg, 0.11 mmol) was dissolved in CH3CN (2 mL), IBX (47.96 mmol, 0.17 mmol) was added, and the reaction was stirred at 70 °C for 4 h. After the reaction was completed, the reaction solution was rotary evaporated, dissolved in DCM, and washed with water (3 mL x 3). The organic layer was dried over anhydrous Na2SO4, and the reaction solution was rotary evaporated to give yellow solid intermediate A25 (50 mg, 83%).

[0774] LC-MS (ESI): [M+H] + = 523.29

[0775] Synthesis of intermediate A26 in example 27

[0776] 1-(4-bromo-7-isopropyl-5-oxo-5,7-dihydrobenzo[4,5]oxazolo[1,2-a]quinazolin-9- yl)piperidine-4-carbaldehyde (intermediate A26)

[0777] Synthesis scheme

[0778] First step: 5-bromo-2-nitro-N-isopropylaniline (intermediate A26a)

[0779] 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol) was dissolved in THF (20 mL), DIEA (3.52 g, 27.27 mmol) and cyclopentanamine (1.61 g, 27.27 mmol) were added, and the reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was rotary evaporated, and the crude product was purified by silica gel column (EA / P = 1%) to give yellow solid intermediate A26a (2.2 g, 94%).

[0780] LC-MS (ESI): [M+H] + = 259.17

[0781] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 9.1 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 9.1, 2.0 Hz, 1H), 4.03 - 3.93 (m, 1H), 1.25 (d, J = 6.4 Hz, 6H).

[0782] Second step: 5-(4-(dimethoxymethyl)piperidin-1-yl)-N-isopropyl-2-nitrobenzene (intermediate A26b)

[0783] Intermediate A26a (2 g, 7.72 mmol), 4-(dimethoxymethyl)piperidine (1.35 g, 8.49 mmol), Pd(OAc)2 (173.30 mg, 0.77 mmol), XantPhos (893.28 mg, 1.54 mmol), Cs2CO3 (7.54 g, 23.16 mmol) were dissolved in dioxane (20 mL) and the reaction was carried out at 110 °C for 4 h under N2 protection. After the reaction was completed, the reaction solution was rotary evaporated and the crude product was purified by silica gel column (EA / P = 25%) to give brown solid intermediate A26b (1.33 g, 50%).

[0784] LC-MS (ESI): [M+H] + = 338.39

[0785] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 9.8 Hz, 1H), 6.41 (dd, J = 9.9, 2.5 Hz, 1H), 5.97 (d, J = 2.5 Hz, 1H), 4.10 - 3.99 (m, 3H), 3.98 - 3.88 (m, 1H), 3.26 (s, 6H), 2.97 - 2.88 (m, 2H), 1.95 - 1.84 (m, 1H), 1.74 - 1.65 (m, 2H), 1.30 - 1.15 (m, 8H).

[0786] Third step: 5-(4-(dimethoxymethyl)piperidin-l-yl)-Nl-isopropylbenzene-l,2-diamine (Intermediate A26c)

[0787] Intermediate A26b (2.5 g, 7.41 mmol) was dissolved in THF (30 mL) and 10% Pd(OH)2 (454 mg) was added. The reaction was carried out overnight at room temperature under hydrogen protection. After the reaction was completed, the reaction solution was filtered through celite and the filtrate was rotary evaporated to give purple solid intermediate A26c (2.20 g, 96%).

[0788] LC-MS (ESI): [M+H] + = 308.38

[0789] Fourth step: 6-(4-(dimethoxymethyl)piperidin-l-yl)-l-isopropyl-lH-benzo[d imidazol-2-amine (Intermediate A26d)

[0790] Intermediate A26c (2.28 g, 7.42 mmol) was dissolved in methanol (30 mL), BrCN (942.64 mg, 8.90 mmol) was dissolved in methanol and added slowly, Et3N (2.25 g, 22.25 mmol) was added, the reaction was protected by N2 overnight. After the reaction was completed, the reaction solution was rotary evaporated, the crude product was purified by silica gel column (MeOH / DCM = 10%) to obtain purple solid intermediate A26d (400 mg, 16%).

[0791] LC-MS (ESI): [M+H] + = 333.39

[0792] Fifth step: 2-bromo-N-(6-(4-(dimethoxymethyl)piperidin-l-yl)-l- isopropyl-lH-benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate A26e)

[0793] 2-Fluoro-6-bromobenzoic acid (289.78 mg, 1.32 mmol) and CDI (223.88 mg, 1.38 mmol) were dissolved in 1,4-dioxane, reacted at 95 °C for 2 hours, after cooling to room temperature, intermediate A26d (382.50 mg, 1.15 mmol) and HOBT (209.88 mg, 1.55 mmol) were added, and the reaction was heated to 95 °C for 2 hours. After the reaction was completed, the solvent was rotary evaporated, and the crude product was purified by silica gel column (EA / P = 48%) to obtain yellow solid intermediate A26e (350 mg, 57%).

[0794] LC-MS (ESI): [M+H] + = 533.29

[0795] 1 H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 7.49 - 7.45 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.06 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.9, 2.1 Hz, 1H), 5.09 - 4.98 (m, 1H), 4.15 - 4.09 (m, 1H), 3.73 - 3.63 (m, 2H), 3.28 (s, 6H), 2.69 - 2.58 (m, 2H), 1.78 - 1.71 (m, 3H), 1.51 (d, J = 7.0 Hz, 6H), 1.45 - 1.33 (m, 2H).

[0796] Sixth step: 4-bromo-9-(4-(dimethoxymethyl)piperidin-l-yl)-7-isopropylbenzo[4,5] imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate A26f)

[0797] Intermediate A26e (350 mg, 0.66 mmol) and K3PO4 (208.91 mg, 0.98 mmol) were dissolved in DMF, and the reaction mixture was heated to 120 °C for 5 h. After the reaction was completed, water was added, and a solid precipitated, which was filtered to give yellow solid intermediate A26f (220 mg, 65%).

[0798] LC-MS (ESI): [M+H] + = 513.39

[0799] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.37 (m, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.77 (dd, J = 7.9, 0.9 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 9.2, 2.3 Hz, 1H), 5.18 - 5.06 (m, 1H), 4.14 - 4.09 (m, 1H), 3.88 - 3.78 (m, 2H), 3.28 (s, 6H), 2.76 - 2.66 (m, 2H), 1.79 - 1.72 (m, 3H), 1.60 (d, J = 6.9 Hz, 6H), 1.44 - 1.31 (m, 2H).

[0800] Seventh step: 1-(4-bromo-7-isopropyl-5-oxo-5,7-dihydrobenzo[4,5]oxazol[l,2- a]quinolin-9-yl)piperidine-4-carbaldehyde (intermediate A26)

[0801] Intermediate A26f (120 mg, 0.23 mmol) was dissolved in HCOOH (2 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated, and the pH was adjusted to neutral with saturated NaHC03 solution. The mixture was extracted with DCM (5 mL x 3). The organic layer was dried over anhydrous Na2S04, and the reaction mixture was concentrated to give yellow solid intermediate A26 (99 mg, 90%).

[0802] LC-MS (ESI): [M+H] + = 467.29

[0803] Synthesis of intermediate A27 in example 28

[0804] 1-(4-bromo-7-cyclopentyl-8-fluoro-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinolin-9-yl)piperidine-4-carbaldehyde (intermediate A27)

[0805] Synthesis scheme

[0806] First Step: 3-Bromo-N-cyclopentyl-2-fluoro-6-nitroaniline (Intermediate A27a)

[0807] Synthesis method same as Intermediate A26a

[0808] LC-MS (ESI): [M+H] + = 303.18

[0809] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 9.4, 1.9 Hz, 1H), 7.74 (dd, J = 7.4, 2.5 Hz, 1H), 7.01 (dd, J = 9.4, 6.3 Hz, 1H), 4.34 - 4.23 (m, 1H), 2.02 - 1.90 (m, 2H), 1.75 - 1.51 (m, 6H).

[0810] Second Step: N-cyclopentyl-3-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluoro-6- nitroaniline (Intermediate A27b)

[0811] Synthesis method same as Intermediate A16b

[0812] LC-MS (ESI): [M+H] + = 382.49

[0813] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 - 7.78 (m, 2H), 6.45 (dd, J = 9.8, 8.2 Hz, 1H), 4.32 - 4.21 (m, 1H), 4.09 (d, J = 6.8 Hz, 1H), 3.69 - 3.60 (m, 2H), 3.27 (s, 6H), 2.92 - 2.82 (m, 2H), 1.97 - 1.88 (m, 2H), 1.85 - 1.47 (m, 9H), 1.40 - 1.26 (m, 2H).

[0814] Third Step: Nl-cyclopentyl-5-(4-(dimethoxymethyl)piperidin-l-yl)-6-fluorobenzene- 1,2-diamine (Intermediate A27c)

[0815] Synthesis method same as Intermediate A26c

[0816] LC-MS (ESI): [M+H] + = 352.49

[0817] 1H NMR (400 MHz, DMSO-d6) δ 6.40 - 6.27 (m, 2H), 4.52 (s, 2H), 4.09 (d, J = 6.8 Hz, 1H), 3.72 - 3.62 (m, 1H), 3.59 - 3.52 (m, 1H), 3.26 (s, 6H), 3.14 - 3.05 (m, 2H), 2.49 - 2.40 (m, 2H), 1.74 - 1.63 (m, 7H), 1.54 - 1.28 (m, 6H).

[0818] Fourth Step: 1-Cyclopentyl-6-(4-(dimethoxymethyl)piperidin-l-yl)-7-fluoro-lH- benzo[d]imidazol-2-amine (Intermediate A27d)

[0819] Synthetic procedure same as Intermediate A26d

[0820] LC-MS (ESI): [M+H] + = 377.49

[0821] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 2H), 7.11 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 8.1 Hz, 1H), 4.93 - 4.80 (m, 1H), 4.12 (d, J = 6.5 Hz, 1H), 3.28 (s, 6H), 3.26 - 3.20 (m, 2H), 2.68 - 2.58 (m, 2H), 2.14 - 2.02 (m, 2H), 1.96 - 1.79 (m, 4H), 1.77 - 1.62 (m, 5H), 1.49 - 1.34 (m, 2H).

[0822] Fifth Step: 2-Bromo-N-(l-cyclopentyl-6-(4-(dimethoxymethyl)piperidin-l-yl)-7- fluoro-lH-benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate A27e)

[0823] Synthetic procedure same as Intermediate A26e

[0824] LC-MS (ESI): [M+H] + = 577.38

[0825] 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.53 - 7.48 (m, 1H), 7.41 - 7.29 (m, 3H), 7.12 - 7.04 (m, 1H), 5.34 - 5.20 (m, 1H), 4.13 (d, J = 6.4 Hz, 1H), 3.35-3.26 (m, 8H), 2.87 - 2.66 (m, 2H), 2.07 - 1.80 (m, 6H), 1.80 - 1.57 (m, 5H), 1.53 - 1.38 (m, 2H).

[0826] Step 6: 4-bromo-7-cyclopentyl-9-(4-(dimethoxymethyl)piperidin-l-yl)-8- fluoro[4,5]imidazo[l,2-a]quinolin-5(7H)-one (Intermediate A27f)

[0827] Synthetic procedure same as Intermediate A26f

[0828] LC-MS (ESI): [M+H] + = 557.38

[0829] Step 7: l-(4-bromo-7-cyclopentyl-8-fluoro-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinolin-9-yl)piperidine-4-carbaldehyde (Intermediate A27)

[0830] Synthetic procedure same as Intermediate A26

[0831] LC-MS (ESI): [M+H] + = 511.39

[0832] Synthesis of Intermediate A28 in Example 29

[0833] l-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]pyrido[l,2-a]quinazolin-9- yl)piperidine-4-carboxylate (Intermediate A28)

[0834] Synthetic procedure

[0835] Step 1: 5-bromo-N-cyclobutyl-2-nitroaniline (Intermediate A28a)

[0836] Synthetic procedure same as Intermediate A26a

[0837] LC-MS (ESI): [M+H] + = 273.20

[0838] 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 6.2 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 9.1, 2.0 Hz, 1H), 4.22 - 4.11 (m, 1H), 2.47 - 2.37 (m, 2H), 2.07 - 1.94 (m, 2H), 1.83 - 1.71 (m, 2H).

[0839] Second Step: N-cyclobutyl-5-(4-(dimethoxymethyl)piperidin-l-yl)-2-nitrobenzene (Intermediate A28b)

[0840] Synthetic procedure similar to Intermediate A26b

[0841] LC-MS (ESI): [M+H] + = 350.49

[0842] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.9 Hz, 1H), 7.87 (d, J = 9.8 Hz, 1H), 6.42 (dd, J = 9.9, 2.6 Hz, 1H), 5.81 (d, J = 2.5 Hz, 1H), 4.20 - 4.10 (m, 1H), 4.09 - 4.05 (m, 1H), 4.05 - 3.96 (m, 2H), 3.26 (s, 6H), 2.98 - 2.87 (m, 2H), 2.48 - 2.39 (m, 2H), 2.00 - 1.85 (m, 3H), 1.85 - 1.75 (m, 2H), 1.73 - 1.65 (m, 2H), 1.29 - 1.20 (m, 2H).

[0843] Third Step: N1-cyclobutyl-5-(4-(dimethoxymethyl)piperidin-l-yl)benzene-l,2-diamine (Intermediate A28c)

[0844] Synthetic procedure similar to Intermediate A26c

[0845] LC-MS (ESI): [M+H] + = 320.48

[0846] Fourth Step: l-cyclobutyl-6-(4-(dimethoxymethyl)piperidin-l-yl)-lH-benzo[d]oxazol-2-amine (Intermediate A28d)

[0847] Synthetic procedure similar to Intermediate A26d

[0848] LC-MS (ESI): [M+H] + = 345.49

[0849] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.8, 2.1 Hz, 1H), 5.05 - 4.93 (m, 1H), 4.16 - 4.11 (m, 1H), 3.70 - 3.62 (m, 2H), 3.30 (s, 6H), 2.86 - 2.73 (m, 2H), 2.72 - 2.62 (m, 2H), 2.51 - 2.42 (m, 2H), 2.06 - 1.64 (m, 5H), 1.48 - 1.31 (m, 2H).

[0850] Step 5: 2-bromo-N-(l-cyclobutyl-6-(4-(dimethoxymethyl)piperidin-l-yl)-lH- benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate A28e)

[0851] Synthetic procedure same as Intermediate A26e

[0852] LC-MS (ESI): [M+H] + = 545.38

[0853] 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.48 (dd, J = 7.4, 1.7 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.14 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.9, 2.1 Hz, 1H), 5.29 - 5.17 (m, 1H), 4.11 (d, J = 6.5 Hz, 1H), 3.72 - 3.65 (m, 2H), 3.28 (s, 6H), 3.07 - 2.93 (m, 2H), 2.71 - 2.61 (m, 2H), 2.35 - 2.23 (m, 2H), 1.92 - 1.66 (m, 5H), 1.47 - 1.32 (m, 2H).

[0854] Step 6: 4-bromo-7-cyclobutyl-9-(4-(dimethoxymethyl)piperidin-l-yl)benzo[4,5]pyrido[l,2- a]quinazolin-5(7H)-one (Intermediate A28f)

[0855] Synthetic procedure same as Intermediate A26f

[0856] LC-MS (ESI): [M+H] + = 525.39

[0857] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 6.99 - 6.92 (m, 1H), 5.35 - 5.22 (m, 1H), 4.15 - 4.09 (m, 1H), 3.91 - 3.79 (m, 2H), 3.29 (s, 6H), 3.19 - 3.11 (m, 2H), 2.79-2.65 (m, 2H), 2.40 - 2.31 (m, 2H), 2.06 - 1.69 (m, 5H), 1.48 - 1.31 (m, 2H).

[0858] Step 7: 1-(4-bromo-7-cyclobutyl-5-oxo-5,7-dihydrobenzo[4,5]pyrido[1,2- a]quinazolin-9-yl)piperidine-4-carboxylate (Intermediate A28)

[0859] Synthetic procedure same as Intermediate A26

[0860] LC-MS (ESI): [M+H] + = 479.29

[0861] Synthesis of Example 30 Intermediate A29

[0862] 4-(4-bromo-7-isopropyl-5-oxo-5,7-dihydrobenzo[4,5]pyrido[1,2-a]quinazolin-9- yl)cyclohexane-1-carboxylic acid (Intermediate A29)

[0863] Synthetic procedure

[0864] Step 1: 5-bromo-N1-isopropylbenzene-1,2-diamine (Intermediate A29a)

[0865] Synthetic procedure same as Intermediate A6b.

[0866] LC-MS (ESI): [M+H] + = 229.26

[0867] 1 H NMR (400 MHz, DMSO-d6) δ 6.52 - 6.41 (m, 3H), 4.69 (s, 2H), 4.40 (d, J = 7.5 Hz, 1H), 3.57 - 3.45 (m, J = 6.4 Hz, 1H), 1.14 (d, J = 6.3 Hz, 6H).

[0868] Second Step: 6-Bromo-l-isopropyl-lH-benzo[d]imidazol-2-amine (Intermediate A29b)

[0869] Synthesis method same as Intermediate A6c.

[0870] LC-MS (ESI): [M+H] + = 254.07

[0871] Third Step: 4-(2-amino-l-isopropyl-lH-benzo[d]imidazol-6-yl)cyclohex-3-ene-l- carboxylic acid ethyl ester (Intermediate A29c)

[0872] Synthesis method same as Intermediate A13a.

[0873] LC-MS (ESI): [M+H] + = 327.98

[0874] 1 H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 1.5 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.33 (s, 2H), 6.05 - 6.00 (m, 1H), 4.63 - 4.54 (m, 1H), 4.14 - 4.06 (m, 2H), 2.64 - 2.54 (m, 1H), 2.48 - 2.27 (m, 3H), 2.13 - 2.04 (m, 1H), 1.78 - 1.65 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H), 1.25 - 1.16 (m, 3H).

[0875] Fourth Step: 4-(2-amino-l-isopropyl-lH-benzo[d]imidazol-6-yl)cyclohexane-l- carboxylic acid ethyl ester (Intermediate A29d)

[0876] Synthesis method same as Intermediate A13b.

[0877] LC-MS (ESI): [M+H] + = 330.68

[0878] Fifth Step: 4-(2-(2-bromo-6-fluorobenzamide)-l-isopropyl-lH-benzo[d]imidazol-6- yl)cyclohexane-l-carboxylic acid ethyl ester (Intermediate A29e)

[0879] Synthesis method same as Intermediate A13c.

[0880] LC-MS (ESI): [M+H] + = 530.39

[0881] Step 6: 4-(4-bromo-7-isopropyl-5-oxo-5,7-dihydrobenzo[4,5]pyridino[1,2- a]quinoxalin-9-yl)cyclohexane-1 -carboxylic acid ethyl ester (Intermediate A29f)

[0882] Synthetic procedure same as Intermediate A13d.

[0883] LC-MS (ESI): [M+H] + = 510.39

[0884] Step 7: 4-(4-bromo-7-isopropyl-5-oxo-5,7-dihydrobenzo[4,5]pyridino[1,2- a]quinazolin-9-yl)cyclohexane-1 -carboxylic acid (Intermediate A29)

[0885] Synthetic procedure same as Intermediate A13.

[0886] LC-MS (ESI): [M+H] + = 482.29

[0887] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.80 (dd, J = 7.9, 0.8 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.27 (dd, J = 8.6, 1.6 Hz, 1H), 5.19 - 5.09 (m, 1H), 2.77 - 2.66 (m, 1H), 2.40 - 2.29 (m, 1H), 2.08 - 1.98 (m, 2H), 1.94 - 1.86 (m, 2H), 1.71 - 1.64 (m, 2H), 1.61 (d, J = 7.0 Hz, 6H), 1.57 - 1.43 (m, 2H).

[0888] Synthesis of Example 31 Intermediate B1

[0889] Synthesis of (1S,4S)-4-((1-(3-amino-6-(2-hydroxyphenyl)pyrazin-4-yl)piperidin-4- yl)oxy)cyclohexane-1 -carboxaldehyde (Intermediate B1)

[0890] Synthetic Scheme

[0891] Step 1: Synthesis of (1S,4S)-4-((trimethylsilyl)oxy)cyclohexane-1 -carboxylic acid methyl ester (Intermediate B1a)

[0892] Methyl (1S,4S)-4-hydroxycyclohexane-1-carboxylate (50 g, 316 mmol), imidazole (51.6 g, 758 mmol) were dissolved in DMF (500 mL) at room temperature, the system was cooled to 0 °C, then trimethylsilyl chloride (41.2 g, 379 mmol) was added dropwise to the system, after the addition was completed, the temperature was raised to room temperature, and the reaction was stirred overnight. TLC detection, after the reaction was completed, it was dissolved in ethyl acetate, washed with water three times, the aqueous phase was extracted with ethyl acetate three times, combined with ethyl acetate, dried with anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography, mobile phase EA / PA = 20% peak. The collected liquid was concentrated to give the intermediate B1a (59 g, 97%) as a colorless oil.

[0893] 1 H NMR (400 MHz, DMSO-d6) δ 3.85 (p, J = 4.2 Hz, 1H), 3.58 (s, 3H), 2.42-2.29 (m, 1H), 1.87-1.73 (m, 2H), 1.60-1.45 (m, 6H).

[0894] Second step: synthesis of benzyl 4-(((1S,4S)-4-(methoxycarbonyl)cyclohexyl)oxy)piperidine-1-carboxylate (intermediate B1b)

[0895] Intermediate B1a (11 g, 47.7 mmol), 1-Cbz-piperidin-4-one (9.9 g, 42.4 mmol) were dissolved in super dry dichloromethane, replaced with nitrogen for 3 times, under the protection of nitrogen, the system was cooled to -78 °C, then trimethylsilyl trifluoromethanesulfonate (1.1 g, 4.9 mmol) was slowly added dropwise. After the addition was completed, the reaction was stirred at -78 °C for 1 hour. Then a solution of triethylsilane (5.8 g, 49.9 mmol) in dichloromethane (10 mL) was slowly added dropwise. After the addition was completed, the system was moved to room temperature, and the reaction was stirred at room temperature overnight. TLC detection, after the reaction was completed, the reaction liquid was concentrated, stirred, purified by column chromatography, mobile phase system EA / PE = 30% peak, and the collected liquid was concentrated to give the intermediate B1b (13.7 g, 73%) as a yellow oil.

[0896] LCMS (ESI) [M+H] + = 376.40

[0897] 1 H NMR (400 MHz, DMSO-d6) δ 7.40-7.25 (m, 5H), 5.07 (s, 2H), 3.75-3.65 (m, 2H), 3.61-3.47 (m, 5H), 3.13 (s, 2H), 2.42-2.32 (m, 2H), 1.83-1.28 (m, 12H).

[0898] Step 3: Synthesis of benzyl 4-(((1S,4S)-4-(hydroxymethyl)cyclohexyl)oxy)piperidine-1- carboxylate (Intermediate B1c)

[0899] Intermediate B1b (6.8 g, 18.1 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, the system was filled with nitrogen for 3 times, lithium aluminum hydride (0.82 g, 21.6 mmol) was slowly added under ice bath, and the reaction was carried out for 3 h under ice bath. TLC was used to detect the reaction, after the reaction was completed, water was added dropwise under ice bath for quenching, filtration was carried out, the filtrate was evaporated to dryness and sample was mixed, column chromatography was used for purification, the mobile phase system was EA / PE = 47% out of peak. The collected liquid was concentrated to obtain Intermediate B1c (4.5 g, 71%) in colorless oil.

[0900] LCMS (ESI) [M+H] + = 348.35

[0901] 1 H NMR (600 MHz, DMSO-d6) δ 7.41-7.30 (m, 5H), 5.07 (s, 2H), 4.36 (t, J = 5.3 Hz, 1H), 3.73-3.66 (m, 2H), 3.64-3.60 (m, 1H), 3.55-3.50 (m, 1H), 3.22 (t, J = 5.8 Hz, 2H), 3.18-3.06 (m, 2H), 1.77-1.71 (m, 2H), 1.70-1.63 (m, 2H), 1.47-1.20 (m, 9H).

[0902] Step 4: Synthesis of benzyl 4-(((1S,4S)-4-formylcyclohexyl)oxy)piperidine-1-carboxylate (Intermediate B1d)

[0903] Oxalyl chloride (3.3 g, 26 mmol) was dissolved in dichloromethane (300 mL), filled with nitrogen for 3 times, cooled to -80 °C, then slowly added dropwise a solution of DMSO (2.7 g, 34.6 mmol) in dichloromethane (10 mL), after the dropwise addition was completed, the temperature was kept for 15 min, then slowly added dropwise a solution of Intermediate B1c (6 g, 17.3 mmol) in dichloromethane (10 mL), after the reaction was carried out for 20 min under stirring at -80 °C, slowly added dropwise a solution of triethylamine (7.0 g, 69.2 mmol) in dichloromethane (5 mL), after the dropwise addition was completed, the reaction system was slowly warmed to room temperature, and stirred at room temperature for 20 min, then water (5 mL) was added dropwise for quenching. The reaction system was washed with water for 3 times, the dichloromethane solution was dried with anhydrous sodium sulfate, then filtered, the filtrate was concentrated, purified by column chromatography, the mobile phase system was EA / PE = 30% out of peak, the collected liquid was evaporated to dryness to obtain Intermediate B1d (4 g, 67%) in anhydrous oil.

[0904] LCMS (ESI) [M+H] = 346.39 + = 346.39

[0905] 1 H NMR (600 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.40 - 7.30 (m, 5H), 5.06 (s, 2H), 3.73-3.63 (m, 2H), 3.59 - 3.51 (m, 2H), 3.20-3.05 (m, 2H), 2.37-2.31 (m, 1H), 1.77 - 1.67 (m, 4H), 1.62-1.53 (m, 4H), 1.53 - 1.45 (m, 2H), 1.36 - 1.28 (m, 2H).

[0906] Step 5: Synthesis of benzyl 4-(((1S,4S)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine-1- carboxylate (Intermediate B1e)

[0907] Intermediate B1d (1.6 g, 4.6 mmol) was dissolved in methanol (7 mL) at room temperature, then p-toluenesulfonic acid (80 mg, 0.46 mmol) was added at once, and the system was warmed to 35 °C and stirred for 3 h. After the reaction was detected by TLC, the system was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution until pH = 8, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with a mobile phase system of EA / PE = 10% to give colorless oil of intermediate B1e (1.4 g, 78%).

[0908] 1 H NMR (600 MHz, DMSO-d6) δ 7.45 - 7.27 (m, 5H), 5.07 (s, 2H), 4.04 (d, J = 7.2, 1H), 3.73 - 3.66 (m, 2H), 3.65 - 3.61 (m, 1H), 3.55 - 3.49 (m, 1H), 3.23 (s, 6H), 3.19 - 3.05 (m, 2H), 1.78 - 1.67 (m, 4H), 1.61-1.53 (m, 1H), 1.45 - 1.27 (m, 8H).

[0909] Step 6: Synthesis of 4-(((1S,4S)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (Intermediate B1f)

[0910] Intermediate Blf (0.7 g, 96%) was obtained as colorless oil after the reaction was completed by TLC detection. The palladium carbon was filtered and the filtrate was concentrated.

[0911] LCMS (ESI) [M+H] + = 258.47

[0912] 1 H NMR (400 MHz, DMSO-d6) δ 4.03 (d, J = 7.2 Hz, 1H), 3.64 - 3.54 (m, 1H), 3.45 - 3.28 (m, 2H), 3.23 (s, 6H), 2.98 - 2.83 (m, 2H), 2.56 - 2.41 (m, 2H), 1.80 - 1.62 (m, 4H), 1.61 - 1.49 (m, 1H), 1.48 - 1.18 (m, 8H).

[0913] Seventh Step: Synthesis of 6-chloro-4-(4-(((1S,4S)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)pyridazin-3-amine (Intermediate Blg)

[0914] 3-amino-4-bromo-6-chloropyridazine (500 mg, 2.40 mmol) was dissolved in acetonitrile (5 mL), and Intermediate Blf (926 mg, 0.36 mmol) was added, and the reaction was carried out at 80 °C overnight. After the reaction was completed, the reaction solution was concentrated and purified by column (petroleum ether: ethyl acetate = 2: 1) to obtain Intermediate Blg (700 mg, 76%) as colorless oil.

[0915] LCMS (ESI): [M+H] + = 385.25

[0916] 1 H NMR (600 MHz, Methanol-d4) δ 6.93 (s, 1H), 4.07 (d, J = 7.5 Hz, 1H), 3.73 - 3.68 (m, 1H), 3.64 - 3.58 (m, 1H), 3.38 - 3.32 (m, 8H), 2.92 - 2.84 (m, 2H), 2.01 - 1.96 (m, 2H), 1.86 - 1.80 (m, 2H), 1.78 - 1.70 (m, 2H), 1.67 - 1.59 (m, 1H), 1.56 - 1.49 (m, 2H), 1.48 - 1.41 (m, 4H).

[0917] Eighth Step: Synthesis of 2-(6-amino-5-(4-(1S,4S)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)pyrazin-3-yl)phenol (Intermediate B1h)

[0918] Intermediate B1g (650 mg, 1.69 mmol), 2-hydroxybenzeneboronic acid (349 mg, 2.53 mmol), BrettPhos Pd G3 (153 mg, 0.168 mmol) and K2CO3 (700 mg, 5.07 mmol) were dissolved in a reaction flask containing 11 mL of 1,4-dioxane / H2O (5 / 1) and reacted at 80 °C under a nitrogen atmosphere overnight. After the reaction was completed, the organic phase was washed with saturated brine and extracted with ethyl acetate and concentrated to obtain a crude product, which was purified by column (petroleum ether: ethyl acetate = 1:3) to obtain yellow solid intermediate B1h (330 mg, 44%).

[0919] LCMS (ESI): [M+H] + = 443.30.

[0920] 1 H NMR (600 MHz, Methanol-d4) δ 6.95 (s, 1H), 4.09 (d, J = 7.5 Hz, 1H), 3.73 (s, 1H), 3.67 - 3.60 (m, 1H), 3.35 (s, 9H), 2.90 (dd, J = 15.0, 5.7 Hz, 2H), 2.02 - 1.98 (m, 2H), 1.88 - 1.82 (m, 2H), 1.78 (dd, J = 8.7, 3.4 Hz, 2H), 1.65 (dd, J = 6.5, 3.3 Hz, 1H), 1.58 - 1.53 (m, 2H), 1.51 - 1.43 (m, 4H).

[0921] Ninth Step: Synthesis of (1S,4S)-4-((1-(3-amino-6-(2-hydroxyphenyl)pyrazin-4-yl)piperidin-4-yl)oxy)cyclohexane-1-carbaldehyde (Intermediate B1)

[0922] Intermediate B1h (330 mg, 0.745 mmol) was dissolved in 3 mL of dichloromethane, 1 mL of formic acid was added and reacted for 1 hour. After the reaction was completed, the reaction was quenched with an appropriate amount of saturated sodium bicarbonate solution and extracted with ethyl acetate three times (20 mL x 3), and the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product intermediate B1 (290 mg, 98%), which was used directly in the next step without purification.

[0923] LCMS (ESI): [M+H] + = 397.49.

[0924] Synthesis of intermediate B3 in example 32

[0925] Synthesis of 4-bromo-6-(lH-indazol-7-yl)pyridazine-3-amine (intermediate B3)

[0926] Synthesis scheme

[0927] First step: Synthesis of 4-bromo-6-iodopyridazine-3-amine and 4,6-dibromopyridazine-3-amine (intermediate B3a)

[0928] Dissolve 6-iodopyridazine-3-amine (20.0 g, 90.5 mmol, 1 eq.) in a single-neck flask containing acetonitrile (200 mL), slowly drop N-bromosuccinimide (19.33 g, 108.6 mmol, 1.2 eq.) in methanol solution, the system is stirred at room temperature overnight. After the reaction is completed, the system is concentrated and diluted with ethyl acetate, quenched with saturated aqueous sodium thiosulfate solution, and extracted with ethyl acetate (3 x 200 mL), the organic phase is combined, concentrated to give the crude product. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 0-53%) to give yellow solid intermediate B3a (12.5 g, 46%).

[0929] LCMS (ESI): [M+H] + = 299.98.

[0930] 1 H NMR (600 MHz, DMSO-d6) δ 8.13 (s, 1H), 6.98 (s, 2H)

[0931] Second step: Synthesis of 4-bromo-6-(lH-indazol-7-yl)pyridazine-3-amine (intermediate B3)

[0932] Dissolve intermediate B3a (200 mg, 0.67 mmol, 1.0 eq), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (114 mg, 0.47 mmol, 0.7 eq), potassium carbonate (276.5 mg, 2.0 mmol, 3 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48.8 mg, 0.067 mmol, 0.1 eq) in 12 mL of a mixture of dioxane: water (5:1), the system is reacted at 80°C under nitrogen protection for 16 hours. Concentrate the reaction system, the obtained crude product is purified by reverse column to give white solid intermediate B3 (61 mg, 23%).

[0933] LCMS (ESI): [M+H] + = 290.18.

[0934] 1 H NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.35 (s, 2H), 7.25 (t, J = 7.6 Hz, 1H).

[0935] Synthesis of intermediate B4 in example 33

[0936] Synthesis of (1-(3-(3-amino-6-(2-hydroxyphenyl)pyrazin-4-yl)prop-2-yn-1-yl)piperidin-4- yl)methanol (intermediate B4)

[0937] Synthesis scheme

[0938] First step: 4-(dimethoxymethyl)-1-(prop-2-yn-1-yl)piperidine (intermediate B4a)

[0939] To a solution of 4-(dimethoxymethyl)piperidine (1.0 g, 6.28 mmol, 1.0 eq) in chloroform and water (10 mL / 10 mL) was added 3-bromoprop-1-yne (1.12 g, 9.42 mmol, 1.12 eq), cesium carbonate (5.12 g, 15.7 mmol, 2.5 eq). The system was stirred at 25 °C under nitrogen protection for 12 hours. After the reaction was completed, water was added for quenching, and dichloromethane was used for extraction for 3 times, the organic phase was combined and washed with saturated sodium chloride aqueous solution for 3 times. The organic phase was concentrated under reduced pressure, and the concentrated crude product was purified by column chromatography to obtain yellow oil intermediate B4a (866 mg, 70%).

[0940] LCMS (ESI): [M+H]+= 198.35.

[0941] 1 H NMR (600 MHz, Chloroform-d) δ 4.03 (d, J = 7.5 Hz, 1H), 3.33 (s, 6H), 3.28 (s, 2H), 2.90 (d, J = 11.1 Hz, 2H), 2.23 (s, 1H), 2.15 (t, J = 11.7 Hz, 2H), 1.76 (d, J = 12.9 Hz, 2H), 1.64 - 1.55 (m, 1H), 1.40 - 1.32 (m, 2H).

[0942] Second step: 2-(6-amino-5-(3-(4-(dimethoxymethyl)piperidin-1-yl)prop-1-yn-1-yl)pyridazin-3- yl)phenol (intermediate B4b)

[0943] Intermediate B4a (89.0 mg, 450.96 pmol), intermediate A0 (100 mg, 375.80 pmol), bis(triphenylphosphine)palladium dichloride (26.38 mg, 37.58 pmol), copper(I) iodide (7.16 mg, 37.58 pmol) and triethylamine (76.06 mg, 751.60 mmol) were dissolved in a single-neck flask containing DMF (2.5 mL), after nitrogen protection, the reaction system was heated to 80 °C and stirred for 16 hours. After the reaction was completed, purified water was added, and the organic phase was extracted with ethyl acetate three times (20 mL), the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by reverse phase column (acetonitrile: water) to obtain intermediate B4b (34 mg, 24%) as colorless oil.

[0944] LCMS (ESI): [M+H]+=383.49

[0945] Third step: (1-(3-(3-amino-6-(2-hydroxyphenyl)pyrazin-4-yl)prop-2-yn-1-yl)piperidin-4-yl)methanol (intermediate B4)

[0946] Intermediate B4b (34 mg, 0.09 mmol, 1.0 eq) was dissolved in formic acid (1 mL), and the reaction system was stirred at 25 °C for 16 hours. The obtained reaction system was concentrated under reduced pressure to obtain a crude product intermediate B4, which was directly used in the next step reaction.

[0947] LCMS (ESI): [M+H]+=355.49

[0948] Synthesis of intermediate B5 in example 34

[0949] Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)benzaldehyde (intermediate B5)

[0950] Synthesis scheme

[0951] Synthesis method is the same as intermediate B4b.

[0952] LCMS (ESI): [M+H] + = 316.28

[0953] 1H NMR (600 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.07 (s, 1H), 8.38 (s, 1H), 8.04 - 7.97 (m, 4H), 7.89 (d, J = 7.9 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.17 (s, 2H), 6.96 - 6.90 (m, 2H).

[0954] Synthesis of Example 35 Intermediate B6

[0955] Synthesis of 3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)benzaldehyde (Intermediate B6)

[0956] Synthesis Scheme

[0957] The synthesis method is the same as Intermediate B4b.

[0958] LCMS (ESI): [M+H] + = 316.28

[0959] Synthesis of Example 36 Intermediate B7

[0960] Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- methoxycyclohexan-1-one (Intermediate B7)

[0961] Synthesis Scheme

[0962] Step 1: Synthesis of 8-((trimethylsilyl)ethynyl)-1,4-dioxaspiro[4.5]decan-8-ol (Intermediate B7a)

[0963] 1,4-Dioxaspiro[4.5]decan-8-one (5.00 g, 32.01 mmol) and trimethylsilyl acetylene (4.72 g, 48.02 mmol) were dissolved in a three-necked flask containing tetrahydrofuran (20 mL), after nitrogen protection, it was cooled to 0 °C, and then LDA (22.41 mL, 44.41 mmol) was slowly added, and the stirring was continued at 0 °C for 0.5 h. It was transferred to room temperature and the stirring was continued for 1 h. After the reaction was completed, it was cooled to 0 °C, and then purified water was added for quenching, and the excess solvent was removed under reduced pressure, and then the organic phase was extracted with ethyl acetate for three times (20 mL), and then the saturated brine was used for washing, and then the anhydrous sodium sulfate was used for drying, and then it was concentrated after filtration to obtain the crude product. The crude product was purified by column (petroleum ether: ethyl acetate = 5:1) to obtain colorless oil intermediate B7a (5.4 g, 66.3%).

[0964] 1H NMR (600 MHz, Chloroform-d) δ 3.94 (s, 4H), 2.04 (s, 1H), 1.97 - 1.94 (m, 2H), 1.91 - 1.86 (m, 2H), 1.78 (t, J = 4.9 Hz, 4H), 0.16 (s, 9H).

[0965] Second Step: Synthesis of ((8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)trimethylsilane (Intermediate B7b)

[0966] Intermediate B7a (5.00 g, 20.63 mmol) was dissolved in a three-necked flask containing tetrahydrofuran (20 mL), cooled to 0 °C, sodium hydride (907.54 mg, 22.69 mmol) was added slowly, and stirring was maintained at 0 °C for 0.5 h. Iodomethane (5.86 g, 41.26 mmol) was added slowly, and stirring was maintained at 0 °C for 0.5 h before being transferred to room temperature and continued for 1 h. After the reaction was completed, the reaction was quenched by adding purified water, the excess solvent was removed under reduced pressure, and the organic phase was extracted with ethyl acetate three times (20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain colorless oil intermediate B7b (4.8 g, 91%).

[0967] Third Step: Synthesis of 8-ethynyl-8-methoxy-1,4-dioxaspiro[4.5]decane (Intermediate B7c)

[0968] Intermediate B7b (4.80 g, 17.88 mmol) and potassium carbonate (4.94 g, 35.76 mmol) were dissolved in a three-necked flask containing methanol (20 mL) and stirred for 1 h. After the reaction was completed, the excess solvent was removed under reduced pressure, purified water was added, and the organic phase was extracted with ethyl acetate three times (20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain colorless oil intermediate B7c (2.7 g, 76.94%).

[0969] 1 H NMR (600 MHz, Chloroform-d) δ 3.94 (s, 4H), 2.73 (s, 1H), 1.94 (dd, J = 12.3, 6.2 Hz, 2H), 1.91 - 1.83 (m, 2H), 1.80 - 1.73 (m, 4H), 0.15 (s, 9H).

[0970] Fourth Step: Synthesis of 2-(6-amino-5-((8-methoxy-1,4-dioxaspiro[4.5]dec-8- yl)ethynyl)pyridazin-3-yl)phenol (Intermediate B7d)

[0971] Intermediate B7c (2.35 g, 8.83 mmol), intermediate A0 (1.73 g, 8.83 mmol), dichlorobis(triphenylphosphine)palladium (619.87 mg, 883.13 pmol), copper(I) iodide (168.19 mg, 883.13 pmol) and triethylamine (1.79 g, 17.66 mmol) were dissolved in a three-necked flask containing DMF (20 mL), which was stirred overnight after being heated to 80 °C under nitrogen protection. After the reaction was completed, purified water was added, and the organic phase was extracted with ethyl acetate three times (20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain yellow solid intermediate B7d (630 mg, 13.79%).

[0972] LCMS (ESI): [M+H] + = 382.19

[0973] 1 H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.33 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.08 (dd, J = 8.3, 1.1 Hz, 1H), 6.98 - 6.92 (m, 1H), 5.37 (s, 2H), 4.00 (d, J = 1.9 Hz, 4H), 3.47 (s, 3H), 2.21 - 2.08 (m, 4H), 1.89 (ddd, J = 13.6, 7.9, 5.8 Hz, 2H), 1.82 - 1.71 (m, 2H).

[0974] Fifth step: synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- methoxycyclohexan-1-one (intermediate B7)

[0975] Intermediate B7d (630 mg, 1.65 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (2.5 mL) was added, and stirred for 1 h. After the reaction was completed, the excess solvent was removed under reduced pressure, purified water was added, and the organic phase was extracted with ethyl acetate three times (20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain yellow solid compound intermediate B7 (425 mg, 76.26%).

[0976] LCMS (ESI): [M+H] + = 338.29

[0977] 1 H NMR (400 MHz, Chloroform-d) δ 7.94 (s, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.33 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.09 (dd, J = 8.2, 1.2 Hz, 1H), 6.99 - 6.91 (m, 1H), 5.39 (s, 2H), 3.57 (s, 3H), 2.72 - 2.58 (m, 2H), 2.46 (ddt, J = 15.7, 9.9, 4.5 Hz, 4H), 2.32 - 2.21 (m, 2H).

[0978] Synthesis of Example 37 Intermediate B8

[0979] Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- ethoxy cyclohexan-1-one (Intermediate B8)

[0980] Synthesis Scheme

[0981] First Step: 8-ethoxy-8-ethynyl-1,4-dioxaspiro[4.5]decane (Intermediate B8a)

[0982] Intermediate B7a (500 mg, 1.97 mmol) was dissolved in a single-neck flask containing tetrahydrofuran (5 mL), cooled to 0 °C, and sodium hydride (235.83 mg, 5.9 mmol) was slowly added. After stirring at 0 °C for 0.5 h, iodomethane (3.07 g, 19.65 mmol) was slowly added, and the reaction was stirred at 60 °C for 12 h. After the reaction was completed, the reaction was cooled to 0 °C and quenched with purified water, and extracted with ethyl acetate three times (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain yellow oil of intermediate B8a (284 mg, 51%).

[0983] 1 H NMR (600 MHz, Chloroform-d) δ 3.94 (s, 4H), 3.59 (q, J = 7.0 Hz, 2H), 2.42 (s, 1H), 1.99 - 1.90 (m, 2H), 1.81 - 1.75 (m, 2H), 1.75 - 1.68 (m, 2H), 1.20 (t, J = 7.0 Hz, 3H).

[0984] Second Step: 2-(6-amino-5-((8-ethoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate B8b)

[0985] Synthetic procedure similar to Intermediate B4b.

[0986] LCMS (ESI): [M+H]+= 396.59

[0987] 1 H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H), 7.76 (dd, J = 8.4, 1.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.96 - 6.90 (m, 2H), 3.96 (s, 4H), 3.72 (q, J = 7.0 Hz, 2H), 2.15 - 2.09 (m, 4H), 1.88 - 1.80 (m, 2H), 1.78 - 1.69 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H).

[0988] Third Step: 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- ethoxycyclohexan-1-one (Intermediate B8)

[0989] Intermediate B8b (55 mg, 139.08 μmol) was dissolved in a single-neck flask containing dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added, and stirring was performed for 16 hours. After the reaction was completed, intermediate B8 was obtained as a yellow solid by concentration under reduced pressure and was directly used in the next step.

[0990] LCMS (ESI): [M+H]+= 352.39

[0991] Synthesis of Intermediate B9 in Example 38

[0992] Synthesis of 4-((3-amino-6-(1H-indazol-7-yl)pyridazin-4-yl)ethynyl)-4- methoxycyclohexan-1-one (Intermediate B9)

[0993] Synthetic procedure

[0994] First Step: 6-(1H-indazol-7-yl)-4-((8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-amine (Intermediate B9a)

[0995] Synthetic procedure similar to Intermediate B4b.

[0996] LCMS (ESI): [M+H]+= 406.49

[0997] Second Step: Synthesis of 4-((3-amino-6-(lH-indazol-7-yl)pyridazin-4- yl)ethynyl)-4-methoxycyclohexan-l-one (Intermediate B9)

[0998] The synthesis method is the same as Intermediate B7.

[0999] LCMS (ESI): [M+H]+=362.39

[1000] Synthesis of Intermediate B10 in Example 39

[1001] Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan- 2-one (Intermediate B10)

[1002] Synthesis Scheme

[1003] First Step: Synthesis of 1,1-dichloro-2-oxospiro[3.5]nonane-7-carboxylate (Intermediate B10a)

[1004] Ethyl 4-methylene cyclohexane-l-carboxylate (10 g, 59.44 mmol) was dissolved in ethylene glycol dimethyl ether (100 mL), zinc copper reagent (10 g, 154 mmol) was added, and trichloroacetyl chloride (25 mL, 224 mmol) was slowly added dropwise to the reaction system under ice water bath cooling. The reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution was slowly added to quench the reaction system under ice bath, the solid was filtered with diatomite, and the filtrate was extracted with ethyl acetate three times (100 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain brown oil crude product Intermediate B10a (16.6 g). The crude product was directly used in the next step without purification.

[1005] Second Step: Synthesis of 2-oxospiro[3.5]nonane-7-carboxylate (Intermediate B10b)

[1006] Intermediate B10a (16.6 g, 59.46 mmol) and ammonium chloride solid (12.72 g, 237.86 mmol) were dissolved in methanol (160 mL), and zinc powder (38 g, 594 mmol) was slowly added in batches under ice water bath. The reaction was carried out overnight. After the reaction was completed, the solid was filtered with diatomite, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain colorless oil liquid Intermediate B10b (10.45 g, 83.57%).

[1007] 1H NMR (600 MHz, DMSO-d6) δ 4.06 (q, J = 7.1 Hz, 2H), 2.74 (s, 4H), 2.36 - 2.31 (m 1H), 1.83 - 1.79 (m 2H), 1.76 - 1.65 (m, 2H), 1.60 - 1.55 (m, 2H), 1.44 - 1.38 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[1008] Step 3: Synthesis of ethyl 2,2-dimethoxyspiro[3.5]nonane-7-carboxylate (Intermediate B10c)

[1009] Intermediate B10b (10.45 g, 50 mmol), trimethyl orthoformate (67 mL, 612 mmol) and p-toluenesulfonic acid pyridine salt (3.75 g, 15 mmol) were dissolved in methanol (100 mL) and reacted at 75 °C overnight. After the reaction was completed, the solvent was evaporated, 5 mL of water was added, and it was extracted with 30 mL of ethyl acetate three times, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain yellow oily liquid intermediate B10c (12 g, 94.19%).

[1010] 1 H NMR (600 MHz, DMSO-d6) δ 4.03 (q, J = 7.1 Hz, 2H), 3.01 (s, 6H), 2.28 - 2.16 (m, 1H), 1.80 (d, J = 7.7 Hz, 4H), 1.70 - 1.65 (m, 2H), 1.64 - 1.54 (m, 2H), 1.40 - 1.29 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H).

[1011] Step 4: Synthesis of 2,2-dimethoxyspiro[3.5]nonane-7-methanol (Intermediate B10d)

[1012] Intermediate B10c (12 g, 46 mmol) was dissolved in tetrahydrofuran (120 mL), and lithium aluminum hydride (2.67 g, 70 mmol) was slowly added in batches under ice bath. It was reacted at room temperature for four hours, and after the reaction was completed, a small amount of water was added to quench the reaction system under ice water bath, filtered with diatomite, and the filtrate was dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain colorless transparent liquid intermediate B10d (7.7 g, 76.75%).

[1013] 1H NMR (600 MHz, DMSO-d6) δ 4.33 (t, J = 5.3 Hz, 1H), 3.17 (dd, J = 6.4, 5.3 Hz, 2H), 3.00 (s, 6H), 1.79 - 1.77 (m, 4H), 1.65 - 1.48 (m, 4H), 1.31 - 1.20 (m, 3H), 0.95 - 0.79 (m, 2H).

[1014] Step 5: Synthesis of 2,2-dimethoxyspiro[3.5]nonane-7-carbaldehyde (Intermediate B10e)

[1015] Intermediate B10d (15.4 g, 71.86 mmol), sodium bicarbonate (30 g, 355 mmol) and Dess-Martin reagent (45.72 g, 107.8 mmol) were dissolved in dichloromethane (150 mL) and stirred at room temperature for two hours. After the reaction was completed, a small amount of water was added to quench the reaction system under ice water bath, and then filtered with diatomite. The filtrate was dried and concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain colorless transparent liquid intermediate B10e (10.35 g, 67.85%).

[1016] 1 H NMR (600 MHz, DMSO-d6) δ 9.55 (s, 1H), 3.01 (s, 6H), 2.22 (tt, J = 9.9, 3.9 Hz, 1H), 1.82 - 1.76 (m, 4H), 1.73 - 1.66 (m, 2H), 1.59 - 1.53 (m, 2H), 1.40 - 1.34 (m, 2H), 1.33 - 1.25 (m, 2H).

[1017] Step 6: Synthesis of 7-ethynyl-2,2-dimethoxyspiro[3.5]nonane (Intermediate B10f)

[1018] Intermediate B10e (6.33 g, 29.82 mmol) was dissolved in methanol (60 mL), and then potassium carbonate (12.36 g, 89.45 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (7.45 g, 38.76 mmol) were added dropwise under ice bath. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction liquid was concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain colorless transparent liquid intermediate B10f (3.02 g, 48.62%).

[1019] 1H NMR (600 MHz, DMSO-d6) δ 3.00 (s, 6 H), 2.83 (d, J = 2.4 Hz, 1 H), 2.32 (s, 1 H), 1.79 (dd, J = 15.7, 1.5 Hz, 4 H), 1.65 - 1.57 (m, 4 H), 1.37 - 1.31 (m, 4 H).

[1020] Step 7: Synthesis of 6-chloro-4-(2,2-dimethoxyspiro[3.5]nonan-7-yl)ethynyl)pyridazin-3-amine (Intermediate B10g)

[1021] Intermediate B10f (3 g, 14.4 mmol), 3-amino-4-bromo-6-chloropyridazine (2.5 g, 12 mmol), dichlorobis(triphenylphosphine)palladium (842 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol) and triethylamine (6.26 mL, 4.8 mmol) were dissolved in a three-necked flask containing DMF (100 mL), which was protected by nitrogen, and then heated to 110 °C for two hours. After the reaction was completed, the silica gel was filtered, 400 mL of purified water was added to the filtrate, and the organic phase was extracted with ethyl acetate three times (30 mL x 3). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain yellow solid intermediate B10g (2.37 g, 58.84%).

[1022] LCMS (ESI): [M+H]+= 336.35

[1023] 1 H NMR (600 MHz, DMSO-d6) δ 7.48 (s, 1 H), 6.71 (s, 2 H), 3.02 (s, 6 H), 2.67 (s, 1 H), 1.85 - 1.81 (m, 4 H), 1.79 - 1.72 (m, 2 H), 1.68 - 1.61 (m, 2 H), 1.57 - 1.47 (m, 2 H), 1.41 - 1.37 (m, 2 H).

[1024] Step 8: Synthesis of 2-(6-amino-5-((2,2-dimethoxyspiro[3.5]nonan-7-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate B10h)

[1025] Intermediate B10g (3.5 g, 10.42 mmol), 2-hydroxybenzeneboronic acid (4.31 g, 31.27 mmol), methane sulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (94.5 mg, 1.04 mmol), potassium carbonate (4.32 g, 31.2 mmol) were dissolved in 1,4-dioxane (40 mL) and water (4 mL), after nitrogen protection, the reaction mixture was stirred at 80 °C overnight. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give yellow solid intermediate B10h (2.23 g, 58.84%).

[1026] LCMS (ESI): [M+H] + = 394.39

[1027] 1 H NMR (600 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.15 (s, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.93 - 6.86 (m, 2H), 6.78 (s, 2H), 3.02 (s, 6H), 2.71 (s, 1H), 1.88 - 1.82 (m, 4H), 1.80 (s, 2H), 1.70 - 1.63 (m, 2H), 1.60 - 1.51 (m, 2H), 1.45 - 1.38 (m, 2H).

[1028] Ninth step: synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-one (intermediate B10)

[1029] Intermediate B10h (100 mg, 254.14 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (375 μL, 5.08 mmol) was added, and the reaction was allowed to proceed for 2 h. After the reaction was completed, the reaction mixture was directly concentrated to give yellow solid intermediate B10 (76 mg, 91.83%).

[1030] LCMS (ESI): [M+H] + = 348.35

[1031] 1H NMR (600 MHz, Methanol-d4) δ 8.34 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.1, 1.8 Hz, 1H), 7.39 (td, J = 7.7, 7.3, 1.6 Hz, 1H), 7.01 (dd, J = 7.9, 6.5 Hz, 2H), 2.82 (dt, J = 13.0, 1.9 Hz, 4H), 2.12 - 1.85 (m, 5H), 1.82 - 1.66 (m, 4H).

[1032] Synthesis of Example 41 Intermediate B12

[1033] Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-7- methoxyspiro[3.5]nonan-2-one (Intermediate B12)

[1034] Synthesis Scheme

[1035] First Step: 8-methoxy-l,4-dioxaspiro[4.5]decane-8-carboxylic acid methyl ester (Intermediate B12a)

[1036] Synthesis method is same as Intermediate B4b.

[1037] LCMS (ESI): [M+H]+= 418.59

[1038] Second Step: 7-((3-amino-6-(lH-indazol-7-yl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2- one (Intermediate B11)

[1039] Synthesis method is same as Intermediate B7.

[1040] LCMS (ESI): [M+H]+= 372.49

[1041] Synthesis of Example 41 Intermediate B12

[1042] Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-7- methoxyspiro[3.5]nonan-2-one (Intermediate B12)

[1043] Synthesis Scheme

[1044] First Step: 8-methoxy-l,4-dioxaspiro[4.5]decane-8-carboxylic acid methyl ester (Intermediate B12a)

[1045] Intermediate B12a (28.0 g, 121.6 mmol, 1.0 eq.) was dissolved in 30 mL of dichloromethane, and hydrochloric acid 1,4-dioxane solution (15.0 mL, 6 M) was added dropwise. The system was stirred at room temperature for 4 hours. After the reaction was completed, the system was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain colorless oil intermediate B12b (7.0 g, 31%).

[1046] 1 H NMR (600 MHz, Chloroform-d) δ 3.96 (s, 3H), 3.95 (s, 3H), 3.20 (s, 4H), 1.86 - 1.81 (m, 4H), 1.71 - 1.66 (m, 4H).

[1047] Second step: 1-methoxy-4-oxocyclohexane-1-carboxylate (intermediate B12b)

[1048] Intermediate B12a (28.0 g, 121.6 mmol, 1.0 eq.) was dissolved in 30 mL of dichloromethane, and hydrochloric acid 1,4-dioxane solution (15.0 mL, 6 M) was added dropwise. The system was stirred at room temperature for 4 hours. After the reaction was completed, the system was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain colorless oil intermediate B12b (7.0 g, 31%).

[1049] 1 H NMR (600 MHz, Chloroform-d) δ 3.75 (s, 3H), 3.32 (s, 3H), 2.59 - 2.49 (m, 2H), 2.32 - 2.24 (m, 4H), 2.15 - 2.05 (m, 2H).

[1050] Third step: 1-methoxy-4-methylene cyclohexane-1-carboxylate (intermediate B12c)

[1051] Methyltriphenylphosphonium bromide (10.1 g, 28.2 mmol, 1.5 eq.) was dissolved in a three-necked flask containing tetrahydrofuran (30 mL) and cooled to -78 °C under nitrogen protection. n-Butyllithium solution in tetrahydrofuran (18.8 mL, 1.6 M, 30.1 mmol, 1.6 eq.) was added dropwise slowly. The system was stirred at -78 °C for 1 h. Then a solution of intermediate B12b (3.5 g, 18.8 mmol, 1.0 eq.) in tetrahydrofuran (10 mL) was added dropwise. The system was slowly returned to room temperature and stirred for 2 h. After the reaction was completed, purified water was used for quenching and extracted with ethyl acetate (3 x 100 mL). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give intermediate B12c (1.5 g, 43%) as yellow oil.

[1052] 1 H NMR (400 MHz, Chloroform-d) δ 4.66 (s, 2H), 3.75 (s, 3H), 3.28 (s, 3H), 2.32 - 2.26 (m, 2H), 2.15 (dt, J = 13.7, 4.1 Hz, 2H), 2.03 - 1.99 (m, 2H), 1.83 (td, J = 13.1, 4.5 Hz, 2H).

[1053] Fourth step: methyl 1,1-dichloro-7-methoxy-2-oxospiro[3.5]nonane-7-carboxylate (intermediate B12d)

[1054] Synthetic method same as intermediate B10a.

[1055] Fifth step: methyl 7-methoxy-2-oxospiro[3.5]nonane-7-carboxylate (intermediate B12e)

[1056] Synthetic method same as intermediate B10b.

[1057] 1 H NMR (400 MHz, Chloroform-d) δ 3.73 (s, 3H), 3.23 (s, 3H), 2.78 - 2.72 (m, 4H), 1.97 - 1.84 (m, 4H), 1.81 - 1.70 (m, 2H), 1.61 - 1.52 (m, 2H).

[1058] Sixth step: methyl 2,2,7-trimethoxyspiro[3.5]nonane-7-carboxylate (intermediate B12f)

[1059] Synthetic method same as intermediate B10c.

[1060] Seventh step: (2,2,7-trimethoxyspiro[3.5]nonan-7-yl)methanol (Intermediate B12g)

[1061] Synthetic procedure similar to Intermediate B10d.

[1062] 1 H NMR (400 MHz, Chloroform-d) δ 3.45 (d, J = 4.0 Hz, 2H), 3.18 (s, 3H), 3.12 (s, 6H), 1.89 (s, 2H), 1.87 (s, 2H), 1.71 - 1.57 (m, 4H), 1.52 - 1.41 (m, 2H), 1.32 - 1.26 (m, 2H).

[1063] Eighth step: 2,2,7-trimethoxyspiro[3.5]nonane-7-carbaldehyde (Intermediate B12h)

[1064] Synthetic procedure similar to Intermediate B10e.

[1065] Ninth step: 7-ethynyl-2,2,7-trimethoxyspiro[3.5]nonane (Intermediate B12i)

[1066] Synthetic procedure similar to Intermediate B10f.

[1067] Tenth step: 2-(6-amino-5-((2,2,7-trimethoxyspiro[3.5]non-7-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate B12j)

[1068] Synthetic procedure similar to Intermediate B4b.

[1069] LCMS (ESI): [M+H]+= 424.35

[1070] Eleventh step: 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-7-methoxyspiro[3.5]nonan-2-one (Intermediate B12)

[1071] Synthetic procedure similar to Intermediate B7.

[1072] LCMS (ESI): [M+H]+= 378.30

[1073] Synthesis of Intermediate B13 in Example 42

[1074] Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-(oxetan-3-yl)cyclohexan-1-one (Intermediate B13)

[1075] Synthetic procedure LCMS (ESI): [M+H]+= 378.30

[1076] First Step: 8-(Oxetan-3-yl)-l,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (Intermediate B13a)

[1077] Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (1.0 g, 4.67 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (20 mL) and 2M LDA (5.15 mL, 10.27 mmol, 2.2 eq.) was added slowly dropwise at -78 °C under nitrogen protection. The system was allowed to recover to room temperature and stirred for half an hour. The system was cooled to -78 °C again and a solution of 3-iodooxetane (1.72 g, 9.33 mmol, 2.0 eq.) in tetrahydrofuran (5 mL) was added slowly dropwise under nitrogen protection. The system was continued to stir for 1 hour under this condition and then slowly recovered to room temperature and stirred overnight. After the reaction was completed, saturated aqueous ammonium chloride solution was added for quenching and extracted with ethyl acetate for 3 times. The organic phase was combined and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain intermediate B13a (551 mg, 44%) as a light yellow oil.

[1078] LCMS (ESI): [M+H]+= 271.30

[1079] 1 H NMR (400 MHz, Chloroform-d) δ 4.66-4.59 (m, 1H), 3.97-3.84 (m, 8H), 3.53 (s, 1H), 3.38 (s, 1H), 2.56-2.16 (m, 1H), 1.83-1.70 (m, 4H), 1.66-1.57 (m, 4H).

[1080] Second Step: (8-(oxetan-3-yl)-l,4-dioxaspiro[4.5]decane-8-yl)methanol (Intermediate B13b)

[1081] Synthetic method is the same as Intermediate Blc.

[1082] LCMS (ESI): [M+H]+= 229.20

[1083] 1 H NMR (400 MHz, Chloroform-d) δ 4.66-4.59 (m, 1H), 3.97-3.84 (m, 8H), 3.53 (s, 1H), 3.38 (s, 1H), 2.56-2.16 (m, 1H), 1.83-1.70 (m, 4H), 1.66-1.57 (m, 4H).

[1084] Third step: 8-ethynyl-8-(oxetan-3-yl)-l,4-dioxaspiro[4.5]decane (Intermediate B13d)

[1085] Synthetic method is the same as Intermediate B10e.

[1086] LCMS (ESI): [M+H]+= 227.25

[1087] 1 H NMR (400 MHz, Chloroform-d) δ 9.65 (s, 1H), 4.68 (dd, J = 8.2, 6.6 Hz, 2H), 4.55 (t, J = 6.5 Hz, 2H), 3.94 - 3.92 (m, 4H), 3.08 (tt, J = 8.2, 6.4 Hz, 1H) 2.09 - 2.03 (m, 2H), 1.74 - 1.67 (m, 4H), 1.55 - 1.49 (m, 2H).

[1088] Fourth step: 8-ethynyl-8-(oxetan-3-yl)-l,4-dioxaspiro[4.5]decane (Intermediate B13d)

[1089] Synthetic method is the same as Intermediate B10f.

[1090] 1 H NMR (400 MHz, Chloroform-d) δ 4.80 - 4.74 (m, 2H), 4.69 (dd, J = 8.2, 6.2 Hz, 2H), 3.99 - 3.89 (m, 4H), 3.01 - 2.92 (m, 1H), 2.32 (s, 1H), 2.03 - 1.93 (m, 2H), 1.69 - 1.60 (m, 4H), 1.42 - 1.32 (m, 2H).

[1091] Fifth step: 2-(6-amino-5-((8-(oxetan-3-yl)-l,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate B13e)

[1092] Synthetic method is the same as Intermediate B4b.

[1093] LCMS (ESI): [M+H]+= 408.49

[1094] 1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.36 (s, 1H), 7.94 (dd, J = 7.9, 1.4 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.94 - 6.86 (m, 4H), 4.77 (dd, J = 7.6, 6.7 Hz, 2H), 4.64 (t, J = 6.0 Hz, 2H), 3.88 (dd, J = 5.1, 3.4 Hz, 4H), 3.02 - 2.94 (m, 1H), 1.90 (td, J = 13.3, 3.6 Hz, 2H), 1.69 - 1.59 (m, 4H), 1.44 - 1.37 (m, 2H).

[1095] Step 6: Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- (oxetan-3-yl)cyclohexan-1-one (Intermediate B13)

[1096] Synthetic method is same as Intermediate B7.

[1097] LCMS (ESI): [M+H]+=364.39

[1098] Synthesis of Example 43 Intermediate B14

[1099] Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4- (oxetan-3-yl)cyclohexan-1-one (Intermediate B13)

[1100] Synthetic scheme

[1101] Step 1: Synthesis of 8-ethynyl-1,4-dioxaspiro[4.5]dec-8-ol (Intermediate B14a)

[1102] Intermediate B7a (6.61 g, 25.97 mmol, 1.0 eq.) and potassium carbonate (7.18 g, 51.95 mmol, 2.0 eq.) were dissolved in 180 mL of methanol and stirred at room temperature for 4 h. After the reaction was completed, the system was filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 0-20%) to obtain colorless oil Intermediate B14a (4.47 g, 94%)

[1103] 1 H NMR (400 MHz, Chloroform-d) δ 3.94 (s, 4H), 2.48 (s, 1H), 2.09 (s, 1H), 2.03 - 1.90 (m, 4H), 1.82 - 1.76 (m, 4H).

[1104] Second Step: 8-(Difluoromethoxy)-8-ethynyl-1,4-dioxaspiro[4.5]decane (Intermediate B14b)

[1105] Intermediate B14a (2.0 g, 10.98 mmol, 1.0 eq.) and potassium fluorohydride (6.86 g, 87.81 mmol, 8.0 eq.) were dissolved in 40 mL of a mixture solvent of dichloromethane and water (1 / 3), and stirred at room temperature for 5 minutes. After the system was clarified, (bromodifluoromethyl)trimethylsilane was added, and the system was stirred vigorously at room temperature overnight. After the reaction was completed, the system was diluted with 20 mL of dichloromethane and 10 mL of water, and the aqueous phase was extracted with dichloromethane three times (3 x 20 mL). The organic phases were combined and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 0-7%) to obtain Intermediate B14b (120.5 mg, 5%) as a colorless oil.

[1106] 1 H NMR (400 MHz, Chloroform-d) δ 6.59 (t, J = 75.3 Hz, 1H), 3.95 (s, 4H), 2.69 (s, 1H), 2.14 - 1.99 (m, 4H), 1.91 - 1.81 (m, 2H), 1.80 - 1.70 (m, 2H).

[1107] Third Step: 2-(6-amino-5-((8-(difluoromethoxy)-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate B14c)

[1108] The synthesis method is the same as that of Intermediate B4b.

[1109] LCMS (ESI): [M+H]+=418.39

[1110] Fourth Step: 8-(Difluoromethoxy)-8-ethynyl-1,4-dioxaspiro[4.5]decane (Intermediate B14)

[1111] The synthesis method is the same as that of Intermediate B7.

[1112] LCMS (ESI): [M+H]+=374.39

[1113] Synthesis of Intermediate B15 in Example 44

[1114] 2-(5-chloropyridazin-3-yl)phenol (Intermediate B15)

[1115] Synthesis scheme:

[1116] A mixture of 3,5-dichloropyridazine (500 mg, 3.36 mmol, 1.0 eq) and o-hydroxybenzoic acid (463 mg, 3.36 mmol, 1.0 eq), palladium acetate (38 mg, 0.17 mmol, 0.05 eq), DPPF (93 mg, 0.17 mmol, 0.05 eq), cesium carbonate (2.73 g, 8.39 mmol, 2.5 eq) in 17 mL of a mixture of dioxane:water (4:1) was stirred at 70 °C under nitrogen for 20 h. The reaction mixture was concentrated and the resulting crude product was purified by normal phase column to give the light yellow solid intermediate B15 (148 mg, 20%).

[1117] LCMS (ESI): [M+H] + = 207.25.

[1118] 1 H NMR (400 MHz, CDC13) δ 13.25 (s, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.0, 1.3 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.12 (dd, J = 8.3, 0.7 Hz, 1H), 7.04 - 6.94 (m, 1H).

[1119] Synthesis of intermediate B16 in example 45

[1120] 1-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylic acid (intermediate B16)

[1121] Synthesis scheme:

[1122] First step: synthesis of tert-butyl 1-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate (intermediate B16a)

[1123] A mixture of intermediate A0 (200.0 mg, 0.752 mmol, 1.0 equiv) and tert-butyl piperidine-4-carboxylate (278.5 mg, 1.5 mmol, 2.0 equiv) in 6.5 mL of DMSO was added diisopropylethylamine (790 μL, 4.51 mmol, 6.0 equiv). The mixture was stirred at 80 °C for 60 h. After the reaction was completed, the reaction mixture was diluted with water, extracted with EA three times, the combined organic phase was washed with brine five times, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 0-5%) to give the brown solid intermediate B16a (260.3 mg, 93%).

[1124] LCMS (ESI): [M+H] + = 371.49.

[1125] 1 H NMR (400 MHz, DMSO-d6) δ 14.26 (s, 1H), 7.92 (dd, J = 8.4, 1.2 Hz, 1H), 7.49 (s, 1H), 7.24 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 - 6.84 (m, 2H), 6.27 (s, 2H), 3.43 (d, J = 12.2 Hz, 2H), 2.74 (t, J = 10.3 Hz, 2H), 2.46 - 2.37 (m, 1H), 1.97 - 1.79 (m, 4H), 1.43 (s, 9H).

[1126] Second Step: Synthesis of 1-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4- carboxylic acid (Intermediate B16)

[1127] Intermediate B16a (160 mg, 0.432 mmol, 1.0 equiv) was dissolved in 5.5 mL of dichloromethane, 1.1 mL of trifluoroacetic acid was added, and the system was stirred at room temperature for 4 hours. After the reaction was completed, the system was concentrated under reduced pressure to obtain brown solid intermediate B16 (224.5 mg, purity 66.8%, >99%), which was directly used in the next step.

[1128] LCMS (ESI): [M+H] + = 315.38.

[1129] Synthesis of Intermediate B17 in Example 46

[1130] 1-(4-bromo-7-cyclohexyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9-yl)piperidine- 4-carbaldehyde (Intermediate B17)

[1131] Synthesis Scheme:

[1132] First Step: Synthesis of 5-bromo-N-cyclohexyl-2-nitroaniline (Intermediate B17a)

[1133] To a stirred solution of 4-bromo-2-fluoro-1 -nitrobenzene (1.0 g, 4.55 mmol, 1.0 eq.) and cyclohexylamine (572 μL, 5.0 mmol, 1.1 eq.) in dimethylformamide (15 mL) was added potassium carbonate (1.57 g, 11.36 mmol, 2.5 eq.) at room temperature and the solution was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with ice-cold water and the solid product obtained was filtered and rinsed with water. The filter cake was dried under reduced pressure to get the crude product B17a as an orange yellow solid (1.34 g, 99%).

[1134] LCMS (ESI): [M+H] + = 299.18.

[1135] 1 H NMR (400 MHz, CDC13) δ 8.02 (d, J = 9.1 Hz, 1 H), 7.01 (d, J = 1.8 Hz, 1 H), 6.70 (dd, J = 9.1, 2.0 Hz, 1 H), 3.52 - 3.38 (m, 1 H), 2.09 - 1.98 (m, 2H), 1.87 - 1.76 (m, 2H), 1.71 - 1.62 (m, 1 H), 1.50 - 1.27 (m, 5H).

[1136] Second step: synthesis of 5-bromo-N1-cyclohexylbenzene-1,2-diamine (intermediate B17b)

[1137] To a stirred solution of B17a (1.33 g, 4.46 mmol, 1.0 eq.) in 15 mL of ethanol and water (7 / 3) was added iron powder (1.25 g, 22.3 mmol, 5.0 eq.) and ammonium chloride (1.19 g, 22.3 mmol, 5.0 eq.) and the mixture was stirred at 80 °C overnight. After completion of the reaction, the reaction was cooled to room temperature and filtered through a bed of celite followed by washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue obtained was washed with water three times and dried in vacuum to get B17b as a brown black solid (1.15 g, 96%).

[1138] LCMS (ESI): [M+H] + = 269.27.

[1139] 1H NMR (400 MHz, CDC13) δ 6.75 - 6.69 (m, 2H), 6.59 - 6.54 (m, 1H), 3.28 (s, 2H), 3.23 - 3.13 (m, 1H), 2.05 (dd, J = 12.8, 3.1 Hz, 2H), 1.83 - 1.72 (m, 2H), 1.71 - 1.61 (m, 1H), 1.46 - 1.31 (m, 2H), 1.29 - 1.12 (m, 3H).

[1140] Third Step: Synthesis of 6-bromo-1-cyclohexyl-1H-benzo[d]imidazol-2-amine (Intermediate B17c)

[1141] To a solution of B17b (1.05 g, 3.9 mmol, 1.0 eq.) in methanol (30 mL) was added slowly dropwise a solution of cyanogen bromide (620 mg, 5.85 mmol, 1.5 eq.) in methanol (5 mL) at 0 °C ice bath. The solution was stirred at 50 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated, and the obtained residue was dissolved in dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product B17c (1.19 g, >99%) as a brown solid.

[1142] LCMS (ESI): [M+H] + = 294.20.

[1143] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.04 (s, 2H), 6.50 (s, 2H), 4.15 (tt, J = 12.1, 3.5 Hz, 1H), 2.13 - 1.98 (m, 2H), 1.83 (d, J = 10.7 Hz, 2H), 1.71 (d, J = 11.8 Hz, 2H), 1.65 (s, 1H), 1.41 (p, J = 12.8 Hz, 3H).

[1144] Fourth Step: Synthesis of 1-cyclohexyl-6-(4-(dimethoxymethyl)piperidin-1-yl)-1H- benzo[d]imidazol-2-amine (Intermediate B17d)

[1145] B17c (1.15 g, 3.91 mmol, 1.0 eq.), 4-(dimethoxymethyl)piperidine (1.56 g, 9.77 mmol, 2.5 eq.) and Ruphos-Pd-G3 (327 mg, 0.391 mmol, 0.10 eq.) were dissolved in THF (35 mL), to this reaction mixture was added dropwise 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (27.5 mL, 27.4 mmol, 7.0 eq.) at room temperature under nitrogen, the system was stirred at 85 °C for 25 min. After the reaction was completed, the reaction mixture was cooled to room temperature and diluted with dichloromethane and saturated ammonium chloride solution. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 0-6.9% with 0.1% NEt3) to give black-brown solid B17d (983.8 mg, 68%).

[1146] LCMS (ESI): [M+H] + = 373.49.

[1147] 1 H NMR (400 MHz, DMSO-d6) d 7.07 (d, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.77 - 6.69 (m, 1H), 4.25 - 4.14 (m, 1H), 4.10 (d, J = 6.7 Hz, 1H), 3.51 (d, J = 11.7 Hz, 2H), 3.27 (s, 6H), 2.57 (t, J = 11.3 Hz, 2H), 2.18 - 2.01 (m, 2H), 1.85 (d, J = 11.8 Hz, 2H), 1.79 - 1.56 (m, 6H), 1.50 - 1.28 (m, 5H).

[1148] Fifth step: synthesis of 2-bromo-N-(1-cyclohexyl-6-(4- (dimethoxymethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-6-fluorobenzamide (intermediate B17e)

[1149] To a stirred solution of B17e (1.03 g, 1.8 mmol, 1.0 eq.) in dimethylformamide (8.0 mL) was added potassium phosphate (571.8 mg, 2.69 mmol, 1.50 eq.) at room temperature and the reaction mixture was stirred at 120 °C for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ice cold water. The precipitated solid was filtered off, washed with a small amount of ethanol and dried under reduced pressure to get light brown solid B17f (876.6 mg, 88%).

[1150] LCMS (ESI): [M+H] + = 575.38.

[1151] Sixth step: Synthesis of 4-bromo-7-cyclohexyl-9-(4- (dimethoxymethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate B17f)

[1152] To a stirred solution of B17e (1.03 g, 1.8 mmol, 1.0 eq.) in dimethylformamide (8.0 mL) was added potassium phosphate (571.8 mg, 2.69 mmol, 1.50 eq.) at room temperature and the reaction mixture was stirred at 120 °C for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ice cold water. The precipitated solid was filtered off, washed with a small amount of ethanol and dried under reduced pressure to get light brown solid B17f (876.6 mg, 88%).

[1153] LCMS (ESI): [M+H] + = 553.38.

[1154] 1H NMR (400 MHz, CDC13) δ 8.09 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 9.1, 2.2 Hz, 1H), 4.99 (t, J = 12.9 Hz, 1H), 4.12 (d, J = 7.1, 1H), 3.72 (d, J = 12.1 Hz, 2H), 3.39 (s, 6H), 2.78 (td, J = 12.1, 2.3 Hz, 2H), 2.33 - 2.16 (m, 2H), 2.00 - 1.88 (m, 6H), 1.86 - 1.75 (m, 2H), 1.62 - 1.47 (m, 4H), 1.38 - 1.28 (m, 1H).

[1155] Step 7: Synthesis of 1-(4-bromo-7-cyclohexyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinazolin-9-yl)piperidine-4-carbaldehyde (Intermediate B17)

[1156] B17f (100 mg, 0.18 mmol, 1.0 eq.) was dissolved in formic acid (2.0 mL) solution, the reaction mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and then diluted with DCM, the pH of the system was adjusted to 7-8 with saturated sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was washed with DCM three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the light yellow product crude B17 (71.6 mg, 78%), which was used directly in the next step.

[1157] LCMS (ESI): [M+H] + = 509.29.

[1158] Synthesis of Intermediate B18 in Example 47

[1159] 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2-a]quinazolin-9-yl)azepane- 4-carbaldehyde (Intermediate B18)

[1160] Synthesis scheme:

[1161] Step 1: Synthesis of 4-(methoxymethylene)azepane-1-carboxylate benzyl ester (Intermediate B18a)

[1162] To a solution of methoxy methyltriphenylphosphonium chloride (10.4 g, 30.33 mmol, 1.5 eq.) in tetrahydrofuran (50 mL) was added a solution of potassium tert-butoxide (40.5 mL, 1 M, 2.0 eq.) in tetrahydrofuran under nitrogen protection at 0 °C and the solution was stirred at 0 °C for 1 h. Then a solution of benzyl 4-oxoazepane-1-carboxylate (5.0 g, 20.22 mmol, 1.0 eq.) in tetrahydrofuran (15 mL) was added at 0 °C and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate twice. The organic phase was combined and concentrated under reduced pressure, and then purified by column chromatography (PE:EA = 0-16%) to give colorless oily liquid B18a (5.05 g, 91%).

[1163] LCMS (ESI): [M+H] + = 276.37.

[1164] 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.27 (m, 5H), 5.88 - 5.62 (m, 1H), 5.13 (s, 2H), 3.54 - 3.49 (m, 3H), 3.49 - 3.38 (m, 4H), 2.45 (dd, J = 12.6, 6.4 Hz, 1H), 2.26 - 2.14 (m, 2H), 2.09 (dd, J = 12.4, 7.1 Hz, 1H), 1.73 - 1.59 (m, 2H).

[1165] Second Step: Synthesis of benzyl 4-formylazepane-1-carboxylate (Intermediate B18b)

[1166] B18a (3.49 g, 12.67 mmol, 1.0 eq.) was dissolved in 35 mL of hydrochloric acid-1,4-dioxane solution at room temperature and the system was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and the pH of the system was adjusted to about 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate three times. The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give colorless oily liquid B18b (3.32 g, >99%).

[1167] LCMS (ESI): [M+H] + = 262.30.

[1168] 1H NMR (400 MHz, CDC13) δ 9.64 (d, J = 5.1 Hz, 1H), 7.42 - 7.28 (m, 5H), 5.13 (s, 2H), 3.66 (tt, J = 14.7, 5.1 Hz, 1H), 3.59 - 3.43 (m, 2H), 3.36 - 3.19 (m, 1H), 2.40 - 2.28 (m, 1H), 2.25 - 2.04 (m, 2H), 1.98 - 1.84 (m, 1H), 1.78 - 1.56 (m, 2H), 1.53 - 1.38 (m, 1H).

[1169] Third Step: Synthesis of 4-(dimethoxymethyl)azepane-1-carboxylic acid benzyl ester (Intermediate B18c)

[1170] To a solution of B18b (3.32 g, 12.7 mmol, 1.0 eq.) and trimethyl orthoformate (13.47 g, 127.0 mmol, 10.0 eq.) in 40 mL of methanol was added p-toluenesulfonic acid (655.8 mg, 3.81 mmol, 0.3 eq.) at room temperature, and the system was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give B18c (3.85 g, 99%) as a colorless oily liquid.

[1171] LCMS (ESI): [M+H] + = No Mass signal.

[1172] 1 H NMR (400 MHz, CDC13) δ 7.39 - 7.27 (m, 5H), 5.13 (d, J = 2.9 Hz, 2H), 4.04 (dd, J = 6.2, 3.2 Hz, 1H), 3.69 - 3.53 (m, 2H), 3.40 - 3.24 (m, 8H), 2.03 - 1.82 (m, 3H), 1.74 - 1.67 (m, 1H), 1.62 - 1.35 (m, 2H), 1.25 - 1.15 (m, 1H).

[1173] Fourth Step: Synthesis of 4-(dimethoxymethyl)azepane (Intermediate B18d)

[1174] To a solution of B18c (1.39 g, 4.52 mmol, 1.0 eq.) in 30 mL of methanol was added palladium on carbon (278 mg) at room temperature, and the system was stirred at room temperature under hydrogen overnight. After the reaction was completed, the reaction mixture was filtered with diatomite, and the filtrate was concentrated to give B18d (776.2 mg, 99%) as a light yellow oily liquid.

[1175] LCMS (ESI): [M+H] + = 174.35.

[1176] 1 H NMR (400 MHz, Methanol-d4) δ 4.10 (d, J = 5.7 Hz, 1H), 3.34 (s, 6H), 2.99 - 2.84 (m, 2H), 2.82 - 2.70 (m, 2H), 1.94 - 1.77 (m, 4H), 1.64 - 1.51 (m, 1H), 1.50 - 1.37 (m, 2H).

[1177] Fifth Step: Synthesis of 1-cyclopentyl-6-(4-(dimethoxymethyl)azepan-1-yl)-1H- benzo[d]imidazol-2-amine (Intermediate B18e)

[1178] Synthetic procedure same as B17d.

[1179] LCMS (ESI): [M+H] + = 373.45.

[1180] 1 H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 8.9, 2.1 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 4.89 (p, J = 8.8 Hz, 1H), 4.05 (d, J = 6.3 Hz, 1H), 3.61 - 3.51 (m, 2H), 3.45 - 3.33 (m, 2H), 3.32 (s, 6H), 2.27 - 2.03 (m, 5H), 2.02 - 1.92 (m, 3H), 1.91 - 1.78 (m, 3H), 1.77 - 1.63 (m, 2H), 1.61 - 1.48 (m, 1H), 1.30 - 1.21 (m, 1H).

[1181] Sixth Step: Synthesis of 2-bromo-N-(1-cyclopentyl-6-(4-(dimethoxymethyl)azepan-1-yl)-1H- benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate B18f)

[1182] Synthetic procedure same as B17e.

[1183] LCMS (ESI): [M+H] + = 573.38.

[1184] Seventh Step: Synthesis of 4-bromo-7-cyclopentyl-9-(4-(dimethoxymethyl)azepan-1-yl)benzo[4,5] imidazo[1,2-a]quinazolin-5(7H)-one (Intermediate B18g)

[1185] Synthetic procedure similar to B17f.

[1186] LCMS (ESI): [M+H] + = 553.38.

[1187] 1 H NMR (400 MHz, CDC13) δ 8.05 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 6.65 (dd, J = 9.1, 2.3 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 4.06 (d, J = 6.1 Hz, 1H), 3.69 - 3.58 (m, 2H), 3.52 - 3.34 (m, 3H), 3.33 (d, J = 1.7 Hz, 6H), 2.23 - 2.08 (m, 5H), 2.07 - 1.96 (m, 4H), 1.86 - 1.79 (m, 2H), 1.77 - 1.69 (m, 2H), 1.65 - 1.55 (m, 2H).

[1188] Eighth step: synthesis of 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2- a]quinazolin-9-yl)azepane-4-carbaldehyde (intermediate B18)

[1189] Synthetic procedure similar to B17.

[1190] LCMS (ESI): [M+H] + = 507.29.

[1191] Synthesis of intermediates B19 and B20 in example 48

[1192] (1r,4r)-4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydropyrido[2',3':4,5]imidazo[1,2- a]quinazolin-9-yl)cyclohexane-1-carboxylic acid (intermediate B19)

[1193] (1s,4s)-4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydropyrido[2',3':4,5]imidazo[1,2- a]quinazolin-9-yl)cyclohexane-1-carboxylic acid (intermediate B20)

[1194] Synthetic procedure:

[1195] First Step: Synthesis of 6-bromo-N-cyclopentyl-3-nitropyridin-2-amine (Intermediate B19a)

[1196] Synthetic procedure same as Intermediate B17a.

[1197] LCMS (ESI): No Mass signal

[1198] 1 H NMR (400 MHz, CDC13) δ 8.19 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 4.61 - 4.49 (m, 1H), 2.20 - 2.10 (m, 2H), 1.81 - 1.75 (m, 2H), 1.71 - 1.65 (m, 2H), 1.59 - 1.51 (m, 2H).

[1199] Second Step: Synthesis of 6-bromo-N2-cyclopentylpyridine-2,3-diamine (Intermediate B19b)

[1200] Synthetic procedure same as Intermediate B17b.

[1201] LCMS (ESI): No Mass signal

[1202] 1 H NMR (400 MHz, CDC13) δ 6.68 (d, J = 7.7 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 4.38 - 4.26 (m, 1H), 2.21 - 2.04 (m, 2H), 1.79 - 1.56 (m, 4H), 1.48 - 1.34 (m, 2H).

[1203] Third Step: Synthesis of 5-bromo-3-cyclopentyl-3H-imidazo[4,5-b]pyridin-2-amine (Intermediate B19c)

[1204] Synthetic procedure same as Intermediate B17c.

[1205] LCMS (ESI): [M+H] + = 283.18.

[1206] 1 H NMR (600 MHz, DMSO-d6) δ 7.41 (d, J = 8.1 Hz, 1H), 7.35 (s, 2H), 7.18 (d, J = 8.1 Hz, 1H), 4.71 (p, J = 8.2 Hz, 1H), 2.30 - 2.16 (m, 2H), 2.04 - 1.88 (m, 4H), 1.69 - 1.56 (m, 2H).

[1207] Step 4: Synthesis of 4-(2-amino-3-cyclopentyl-3H-imidazo[4,5-b]pyridin-5-yl)cyclohex-3- ene-1-carboxylic acid ethyl ester (Intermediate B19d)

[1208] Intermediate B19c (719.83 mg, 1.0 eq.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3- ene-1-carboxylic acid ethyl ester (1.43 g, 2.0 eq.), Pd(dppf)Cl2 (187.3 mg, 0.1 eq.) and potassium carbonate (1.06 g, 3.0 eq.) were dissolved in 1,4-dioxane and water (24 mL, 7 / 1), and the system was stirred at 100 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then purified by column chromatography (DCM:MeOH = 0-5%) to obtain brown solid intermediate B19d (654.7 mg, 72%).

[1209] LCMS (ESI): [M+H] + = 355.49.

[1210] 1 H NMR (600 MHz, DMSO-d6) δ 7.30 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.68 (s, 2H), 6.54 (s, 1H), 4.69 (p, J = 8.4 Hz, 1H), 4.14 - 4.03 (m, 2H), 2.71 - 2.55 (m, 2H), 2.48 - 2.40 (m, 2H), 2.40 - 2.29 (m, 3H), 2.11 - 2.05 (m, 1H), 2.04 - 1.96 (m, 2H), 1.95 - 1.88 (m, 2H), 1.77 - 1.67 (m, 1H), 1.67 - 1.57 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H).

[1211] Step 5: Synthesis of 4-(2-amino-3-cyclopentyl-3H-imidazo[4,5-b]pyridin-5-yl)cyclohexane-1- carboxylic acid ethyl ester (Intermediate B19e)

[1212] To a solution of intermediate B19d (773.5 mg) in MeOH (25.0 mL) was added Pd / C (390 mg) and 500 μL AcOH, and the system was stirred at 45 °C for 16 hours after being replaced with hydrogen gas for five times. After the reaction was completed, the reaction mixture was filtered with diatomite and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain brown oil crude product B19e (900 mg, 99%), which was directly used in the next step.

[1213] LCMS (ESI): [M+H]+ = 357.59.

[1214] Step 6: Synthesis of ethyl 4-(2-(2-bromo-6-fluorobenzamido)-3- cyclopentyl-3H-imidazo[4,5-b]pyridin-5-yl)cyclohexane-1-carboxylate (Intermediate B19f)

[1215] Synthetic method is same as Intermediate B17e.

[1216] LCMS (ESI): [M+H] + = 557.38.

[1217] 1 H NMR (400 MHz, CDC13) δ 7.47 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.11 - 7.00 (m, 2H), 5.34 - 5.22 (m, 1H), 4.22 - 4.12 (m, 2H), 2.88 - 2.78 (m, 1H), 2.68 (p, J = 4.3 Hz, 1H), 2.50 - 2.35 (m, 2H), 2.28 - 2.18 (m, 1H), 2.16 - 1.96 (m, 5H), 1.91 - 1.80 (m, 3H), 1.75 - 1.58 (m, 5H), 1.28 (t, J = 7.1 Hz, 3H).

[1218] Step 7: Synthesis of ethyl 4-(4-bromo-7-cyclopentyl-5-oxo-5,7- dihydropyrido[2',3':4,5]imidazo[l,2-a]quinazolin-9-yl)cyclohexane-1-carboxylate (Intermediate B19g)

[1219] Synthetic method is same as Intermediate B17f.

[1220] LCMS (ESI): [M+H] + = 537.38.

[1221] 1 H NMR (400 MHz, DMSO) δ 8.62 (t, J = 7.9 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 5.33 - 5.17 (m, 1H), 4.18 - 4.02 (m, 2H), 2.97 - 2.65 (m, 2H), 2.44 - 2.27 (m, 2H), 2.19 - 1.92 (m, 6H), 1.88 - 1.40 (m, 7H), 1.37 - 1.11 (m, 4H).

[1222] Eighth Step: Synthesis of (1r,4r)-4-(4-bromo-7-cyclopentyl-5-oxo-5,7- dihydropyrido[2',3':4,5]imidazo[l,2-a]quinazolin-9-yl)cyclohexane- 1 -carboxylic acid (Intermediate B19)

[1223] B19g (200 mg, 0.37 mmol, 1.0 eq.) was dissolved in a mixture solvent of methanol, tetrahydrofuran and water (2 / 2 / 1, 10.0 mL), and lithium hydroxide monohydrate (156.2 mg, 3.72 mmol, 10.0 eq.) was added at room temperature. The reaction mixture was stirred at 50 degrees for 3 hours. After the reaction was completed, the reaction mixture was purified by a reverse phase preparative column (pure water / acetonitrile) to obtain white solid of Intermediate B19 (14 mg, 7%) and Intermediate B20 (61.7 mg, 33%) respectively.

[1224] B19: LCMS (ESI): [M+H] + = 511.29.

[1225] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.5 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.31 - 5.20 (m, 1H), 2.85 - 2.74 (m, 1H), 2.45 - 2.22 (m, 4H), 2.14 - 1.92 (m, 6H), 1.80 - 1.40 (m, 7H).

[1226] B20: LCMS (ESI): [M+H] + = 511.19.

[1227] 1H NMR (600 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.30 - 5.16 (m, 1H), 2.92 - 2.84 (m, 1H), 2.65 - 2.59 (m, 1H), 2.42 - 2.32 (m, 2H), 2.15 - 2.03 (m, 4H), 2.03 - 1.96 (m, 2H), 1.90 - 1.81 (m, 2H), 1.80 - 1.74 (m, 2H), 1.74 - 1.67 (m, 2H), 1.68 - 1.58 (m, 2H).

[1228] Synthesis of Example 49 Intermediate C3

[1229] 2-(6-amino-5-(4-((1r,4r)-4-(dimethoxymethylcyclohexyl)oxy)piperidin-1-yl)pyridazin-3-yl)phenol (Intermediate C3)

[1230] Synthesis Scheme

[1231] First Step: Synthesis of (1r,4r)-4-((trimethylsilyl)oxy)cyclohexane-1-carboxylate (Intermediate C3a)

[1232] Synthesized as for Intermediate B1a.

[1233] 1 H NMR (600 MHz, DMSO-d6) δ 3.57 (s, 3H), 2.22 (tt, J = 11.7, 3.7 Hz, 1H), 1.88 - 1.83 (m, 2H), 1.82 - 1.76 (m, 2H), 1.43 - 1.33 (m, 2H), 1.29 - 1.19 (m, 2H), 0.06 (s, 9H).

[1234] Second Step: Synthesis of Benzyl 4-(((1r,4r)-4-(methoxycarbonyl)cyclohexyl)oxy)piperidine-1-carboxylate (Intermediate C3b)

[1235] Synthesized as for Intermediate B1b.

[1236] LCMS (ESI): [M+H] + = 376.49

[1237] 1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.27 (m, 5H), 5.06 (s, 2H), 3.74 - 3.64 (m, 2H), 3.63 - 3.53 (m, 4H), 3.35 - 3.28 (m, 1H), 3.19 - 3.01 (m, 2H), 2.25 (tt, J = 11.6, 3.5 Hz, 1H), 1.95 - 1.81 (m, 5H), 1.79 - 1.68 (m, 2H), 1.45 - 1.25 (m, 4H), 1.24 - 1.12 (m, 2H).

[1238] Step 3: Synthesis of benzyl 4-(((1r,4r)-4-formylcyclohexyl)oxy)piperidine-1- carboxylate (Intermediate C3d)

[1239] Synthetic method is same as Intermediate B1d.

[1240] LCMS (ESI): [M+H] + = 348.49

[1241] 1 H NMR (600 MHz, DMSO-d6) δ 7.40 - 7.28 (m, 5H), 5.06 (s, 2H), 4.41 (t, J = 5.3 Hz, 1H), 3.73 - 3.68 (m, 2H), 3.63 - 3.55 (m, 1H), 3.33 - 3.23 (m, 1H), 3.19 (t, J = 5.8 Hz, 2H), 3.17 - 3.03 (m, 2H), 1.94 - 1.87 (m, J = 12.8, 4.0 Hz, 2H), 1.77 - 1.67 (m, 4H), 1.35 - 1.23 (m, 3H), 1.20 - 1.05 (m, 3H), 0.93 - 0.83 (m, 2H).

[1242] Step 4: Synthesis of benzyl 4-(((1r,4r)-4-formylcyclohexyl)oxy)piperidine-1- carboxylate (Intermediate C3d)

[1243] Synthetic method is same as Intermediate B1d.

[1244] LCMS (ESI): [M+H] + = 346.49

[1245] 1H NMR (600 MHz, DMSO-d6) δ 9.57 (d, J = 1.2 Hz, 1H), 7.41 - 7.29 (m, 5H), 5.06 (s, 2H), 3.73 - 3.68 (m, 2H), 3.63 - 3.58 (m, 1H), 3.35 - 3.31 (m, 1H), 2.26 - 2.18 (m, 1H), 1.94 - 1.87 (m, 4H), 1.78 - 1.72 (m, 2H), 1.36 - 1.28 (m, 2H), 1.28 - 1.17 (m, 4H).

[1246] Step 5: Synthesis of benzyl 4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine-1- carboxylate (Intermediate C3e)

[1247] Synthesis method is same as Intermediate B1e.

[1248] 1 H NMR (600 MHz, Chloroform-d) δ 7.41 - 7.31 (m, 5H), 5.14 (s, 2H), 4.01 (d, J = 6.9 Hz, 1H), 3.87 (s, 2H), 3.65 - 3.57 (m, 1H), 3.36 (s, 6H), 3.33 - 3.25 (m, 1H), 3.23 - 3.15 (m, 2H), 2.03 - 1.97 (m, 2H), 1.89 - 1.75 (m, 4H), 1.64 - 1.49 (m, 3H), 1.28 - 1.19 (m, 2H), 1.11 - 1.01 (m, 2H).

[1249] Step 6: Synthesis of 4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (Intermediate C3f)

[1250] Synthesis method is same as Intermediate B1f.

[1251] LCMS (ESI): [M+H] + = 258.20

[1252] Step 7: Synthesis of 2-(6-amino-5-(4-((1r,4r)-4-(dimethoxymethylcyclohexyl)oxy)piperidin-1- yl)pyridazin-3-yl)phenol (Intermediate C3)

[1253] Intermediate A0 (195.75 mg, 0.74 mmol) was dissolved in 10 mL of acetonitrile, and intermediate C3f (284.00 mg, 1.10 mmol) and N,N-diisopropylethylamine (475.39 mg, 3.68 mmol) were added. The reaction was stirred at 80 °C overnight. After the reaction was completed, the reaction solution was rotary evaporated, and then dissolved in ethyl acetate and purified by silica gel column (EA% = 0-51.8%) to obtain yellow solid intermediate C3 (145 mg, 44.54%).

[1254] LC-MS (ESI): [M+H] + = 443.59

[1255] 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.31 (s, 1H), 7.29 - 7.26 (m, 1H), 7.04 (dd, J = 8.3, 1.3 Hz, 1H), 6.93 - 6.86 (m, 1H), 4.84 (s, 2H), 4.00 (d, J = 6.7 Hz, 1H), 3.72 - 3.65 (m, 1H), 3.46 - 3.26 (m, 9H), 2.97 - 2.86 (m, 2H), 2.06 - 1.96 (m, 4H), 1.90 - 1.82 (m, 2H), 1.81 - 1.73 (m, 2H), 1.63 - 1.56 (m, 1H), 1.29 - 1.23 (m, 2H), 1.14 - 1.01 (m, 2H).

[1256] Synthesis of intermediate C4 in Example 50

[1257] 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9- yl)piperidine-4-carbaldehyde (intermediate C4)

[1258] Synthesis scheme

[1259] First step: 1-cyclopentyl-6-(4-(dimethoxymethyl)piperidin-1-yl)-1H-benzo[d]imidazol- 2-amine (intermediate C4d)

[1260] Intermediate A6c (100 mg, 356.93 pmol), 4-(dimethoxymethyl)piperidine (142.08 mg, 892.32 pmol) and 2-amino-1,1'-biphenyl-2-yl)palladium(II) (29.85 mg, 35.69 pmol) were dissolved in tetrahydrofuran (5 mL) and purged with nitrogen for 3 times. Then 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.5 mL) was added dropwise to the reaction mixture and stirred at 85 °C for 20 min. After the reaction was completed, the reaction was cooled to room temperature and diluted with dichloromethane (3 x 10 mL) and saturated ammonium chloride solution (3 x 10 mL) for extraction. The organic layer was concentrated under reduced pressure and purified by column chromatography to give blue-black solid intermediate C4d (92.7 mg, 72.45%).

[1261] LCMS (ESI): [M+H] + = 359.49

[1262] 1 H NMR (400 MHz, DMSO-d6) d 7.05 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.5, 2.2 Hz, 1H), 6.65 (s, 2H), 4.79 - 4.68 (m, 1H), 4.10 (d, J = 6.8 Hz, 1H), 3.51 - 3.46 (m, 2H), 3.27 (s, 6H), 2.60 - 2.53 (m, 2H), 2.11 - 1.87 (m, 6H), 1.76 - 1.60 (m, 5H), 1.44 - 1.32 (m, 2H).

[1263] Second Step: 2-bromo-N-(1-cyclopentyl-6-(4-(dimethoxymethyl)piperidin-1-yl)-1H- benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate C4e)

[1264] 2-bromo-6-fluorobenzoic acid (56.63 mg, 258.59 pmol) and N,N'-carbonyldiimidazole (46.12 mg, 284.45 pmol) were dissolved in 1,4-dioxane solution (5.0 mL) and stirred at 95 °C for 2 hours. After cooling to room temperature, 1-hydroxybenzotriazole (41.93 mg, 310.31 pmol) and intermediate C4d (92.70 mg, 258.59 pmol) were added and stirred at 95 °C overnight. After the reaction was completed, the reaction was concentrated and purified by silica gel column to give yellow oil intermediate C4e (87.2 mg, 60.27%).

[1265] LCMS (ESI): [M+H] + = 559.38

[1266] 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.38 (m, 1H), 7.37 - 7.24 (m, 2H), 6.98 - 6.89 (m, 2H), 5.20 - 5.06 (m, 1H), 4.10 (d, J = 6.5 Hz, 1H), 3.70 - 3.61 (m, 2H), 3.27 (s, 6H), 2.67 - 2.59 (m, 2H), 2.21 - 2.11 (m, 2H), 1.98 - 1.80 (m, 4H), 1.78 - 1.56 (m, 5H), 1.47 - 1.31 (m, 2H).

[1267] Third Step: 4-Bromo-7-cyclopentyl-9-(4-(dimethoxymethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate C4f)

[1268] Intermediate C4e (82.6 mg, 147.64 μmol) was dissolved in N,N-dimethylformamide (5.0 mL), potassium phosphate (47.01 mg, 221.46 μmol) was added, stirred at 120 °C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ice water, and filtered to obtain yellowish solid intermediate C4f (50.20 mg, 63.03%).

[1269] LCMS (ESI): [M+H] + = 541.28

[1270] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (dd, J = 8.5, 1.0 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.76 (dd, J = 7.9, 0.9 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 9.2, 2.3 Hz, 1H), 5.27 - 5.16 (m, 1H), 4.11 (d, J = 6.5 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.28 (s, 6H), 2.77 - 2.67 (m, 2H), 2.35 - 2.23 (m, 2H), 2.04 - 1.95 (m, 4H), 1.78 - 1.72 (m, 5H), 1.44 - 1.33 (m, 2H).

[1271] Fourth Step: 1-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinazolin-9-yl)piperidine-4-carbaldehyde (Intermediate C4)

[1272] Intermediate C4f (50 mg, 92.68 pmol) was dissolved in 1 mL of dichloromethane, 1.5 mL of formic acid was added, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 10 mL of dichloromethane was added to the reaction system, and then it was washed with saturated aqueous sodium bicarbonate solution (3 x 10 mL) and water (3 x 10 mL) in sequence. Finally, it was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain yellow solid of Intermediate C4 (34.7 mg, 75.88%).

[1273] LCMS (ESI): [M+H] + = 493.29

[1274] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (d, J = 0.9 Hz, 1H), 8.45 - 8.34 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.76 (dd, J = 7.9, 0.9 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.96 (dd, J = 9.1, 2.3 Hz, 1H), 5.29 - 5.14 (m, 1H), 3.70 (dt, J = 12.6, 4.2 Hz, 2H), 2.93 (ddd, J = 12.6, 10.8, 2.9 Hz, 2H), 2.58 - 2.52 (m, 1H), 2.35 - 2.22 (m, 2H), 2.07 - 1.91 (m, 6H), 1.78 - 1.58 (m, 4H).

[1275] Synthesis of Intermediate C5 in Example 51

[1276] 4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2-a]quinazoline-9- carbaldehyde (Intermediate C5)

[1277] Synthesis Scheme

[1278] First Step: 3-(cyclopentylamino)-4-nitrobenzoic acid methyl ester (Intermediate C5a)

[1279] Methyl 3-fluoro-4-nitrobenzoate (1.00 g, 5.02 mmol) was dissolved in 30 mL of N,N-dimethylformamide (30 mL), and cyclopentylamine (1.41 g, 16.57 mmol) and triethylamine (3.35 g, 33.14 mmol) were added, and stirred at 80 °C oil bath for 4 hours. After the reaction was completed, the mixture was poured into water, and then extracted with ethyl acetate (3 x 50 mL), and then purified by silica gel column (EA% = 0~20%), to obtain orange oil intermediate C5a (1.52 g, >99%).

[1280] LCMS (ESI): [M+H] + = 265.37

[1281] 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 6.5 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.16 (dd, J = 8.9, 1.7 Hz, 1H), 4.13 - 4.04 (m, 1H), 3.89 (s, 3H), 2.13 - 2.02 (m, 2H), 1.78 - 1.52 (m, 6H).

[1282] Second step: Methyl 4-amino-3-(cyclopentylamino)benzoate (intermediate C5b)

[1283] Intermediate C5a (1.50 g, 5.68 mmol) was dissolved in 10 mL of acetic acid and 20 mL of methanol, and zinc powder (2.60 g, 39.73 mmol) was added, and stirred at room temperature for 6 hours. After the reaction was completed, it was filtered with diatomite, and the filtrate was concentrated and washed with saturated aqueous sodium bicarbonate solution (3 x 10 mL). After extraction with ethyl acetate (3 x 20 mL), it was purified by silica gel column (EA% = 0~40%), to obtain yellow-white solid intermediate C5b (0.99 g, 74.27%).

[1284] LCMS (ESI): [M+H] + = 235.36

[1285] 1 H NMR (400 MHz, Chloroform-d) δ 7.43 (dd, J = 8.0, 1.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H), 3.78 - 3.69 (m, 1H), 2.13 - 2.02 (m, 2H), 1.81 - 1.70 (m, 2H), 1.69 - 1.59 (m, 2H), 1.56 - 1.45 (m, 2H).

[1286] Step 3: 2-Amino-1-cyclopentyl-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate C5c)

[1287] Intermediate C5b (100 mg, 426.81 pmol) was dissolved in methanol (3 mL) and placed in an ice bath environment, cyanogen bromide (90.42 mg, 853.61 pmol) was added slowly in portions, stirred at room temperature overnight. After the reaction was complete, the reaction was concentrated, then diluted with dichloromethane (5 mL), washed with aqueous sodium bicarbonate solution (3 x 5 mL), dried over anhydrous sodium sulfate, and concentrated to give white solid Intermediate C5c (104.00 mg, 93.97%).

[1288] LCMS (ESI): [M+H] + = 260.57

[1289] 1 H NMR (400 MHz, DMSO-d6) d 7.71 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.3, 1.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.79 (s, 2H), 4.78 (p, J = 8.6 Hz, 1H), 3.81 (s, 3H), 2.07 - 1.98 (m, 4H), 1.98 - 1.89 (m, 2H), 1.77 - 1.65 (m, 2H).

[1290] Step 4: 2-(2-Bromo-6-fluorobenzamido)-1-cyclopentyl-1H-benzo[d]imidazole-6- carboxylic acid methyl ester (Intermediate C5d)

[1291] 2-Bromo-6-fluorobenzoic acid (87.84 mg, 401.08 pmol) and N,N'- carbonyldiimidazole (71.54 mg, 441.17 pmol) were dissolved in 1,4-dioxane solution (5.0 mL) and stirred at 95 °C for 2 hours. After cooling to room temperature, 1- hydroxybenzotriazole (65.03 mg, 481.28 pmol) and Intermediate C5c (104.00 mg, 401.07 pmol) were added, stirred at 95 °C overnight. After the reaction was complete, the reaction was concentrated, purified by silica gel column to give light yellow solid Intermediate C5d (99.7 mg, 54.01%).

[1292] LCMS (ESI): [M+H] + = 460.29

[1293] 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.04 (s, 1H), 7.94 - 7.88 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.41 - 7.26 (m, 2H), 5.21 (p, J = 8.7 Hz, 1H), 3.88 (s, 3H), 2.23 - 2.10 (m, 2H), 2.09 - 1.95 (m, 2H), 1.95 - 1.81 (m, 2H), 1.75 - 1.60 (m, 2H).

[1294] Step 5: methyl 4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinoline-9-carboxylate (Intermediate C5e)

[1295] Intermediate C5d (99.7 mg, 216.60 pmol) was dissolved in N,N-dimethylformamide (5.0 mL), potassium phosphate (68.96 mg, 324.89 pmol) was added, stirred at 120 °C for 1 hour. After the reaction was completed, the reaction was cooled to room temperature, diluted with ice water, filtered to obtain light yellow solid of Intermediate C5e (74.50 mg, 78.12%).

[1296] LCMS (ESI): [M+2+H] + = 440.29.

[1297] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 - 8.43 (m, 2H), 8.11 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 5.38 - 5.22 (m, 1H), 3.92 (s, 3H), 2.36 - 2.16 (m, 2H), 2.17 - 1.90 (m, 4H), 1.86 - 1.65 (m, 2H).

[1298] Step 6: 4-bromo-7-cyclopentyl-9-(hydroxymethyl)benzo[4,5]imidazo[l,2-a]quinolin- 5(7H)-one (Intermediate C5f)

[1299] Intermediate C5e (100 mg, 0.227 mmol) was dissolved in dry THF, then lithium aluminum hydride in tetrahydrofuran (0.23 mL, 0.227 mmol) was added slowly. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched with water, the aqueous phase was extracted with EA three times, the organic phase was combined and washed with saturated sodium chloride three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by Pre-TLC (EA = 100%) to give white solid intermediate C5f (29 mg, 26%).

[1300] LCMS (ESI): [M+H] + = 414.29

[1301] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 8.3 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 5.43 (t, J = 5.8 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H), 2.28 - 2.20 (m, 2H), 2.05 - 2.00 (m, 4H), 1.80 - 1.70 (m, 2H).

[1302] Seventh step: 4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinazoline-9-carbaldehyde (Intermediate C5)

[1303] Intermediate C5f (21 mg, 0.050 mmol) was dissolved in acetonitrile (2 mL), Dess-Martin Oxidizer (32.4 mg, 0.076 mmol) was added in an ice bath environment, and stirred at room temperature. After the reaction was completed, the filtrate was filtered and concentrated, and purified by Pre-TLC (EA = 100%) under reduced pressure to give white solid intermediate C5 (12 mg, 46%).

[1304] LCMS (ESI): [M+H] + = 410.29

[1305] 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.97 (dd, J = 8.5, 1.2 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 8.2 Hz, 1H), 5.33 - 5.26 (m, 1H), 2.31 - 2.23 (m, 2H), 2.09-2.02 (m, 4H), 1.80 - 1.73 (m, 2H).

[1306] Synthesis of Example 52 Intermediate C6

[1307] 1-(4-Chloro-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9- yl)piperidine-4-carbaldehyde (Intermediate C6)

[1308] Synthesis Scheme

[1309] First Step: 2-Chloro-N-(1-cyclopentyl-6-(4-(dimethoxymethyl)piperidin-1-yl)-1H- benzo[d]imidazol-2-yl)-6-fluorobenzamide (Intermediate C6a)

[1310] Synthesized as for Intermediate C4e.

[1311] LC-MS (ESI): [M+H] + = 515.49.

[1312] Second Step: 4-Chloro-7-cyclopentyl-9-(4-(dimethoxymethyl)piperidin-1-yl)benzo[4,5] imidazol-1,2-a]quinazolin-5(7H)-one (Intermediate C6b)

[1313] Synthesized as for Intermediate C4f.

[1314] LC-MS (ESI): [M+H] + = 495.40.

[1315] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.75 (t, J = 8.2 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 9.1, 2.3 Hz, 1H), 5.29 - 5.16 (m, 1H), 4.10 (d, J = 6.4 Hz, 1H), 3.80 (d, J = 12.0 Hz, 2H), 3.28 (s, 6H), 2.71 - 2.64 (m, 2H), 2.34 - 2.21 (m, 2H), 2.05 - 1.95 (m, 4H), 1.80 - 1.67 (m, 5H), 1.44 - 1.32 (m, 2H).

[1316] Step 3: 1-(4-chloro-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinazolin-9-yl)piperidine-4-carbaldehyde (Intermediate C6)

[1317] Synthetic procedure same as Intermediate C4

[1318] LC-MS (ESI): [M+H] + = 449.30.

[1319] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.23 - 8.12 (m, 1H), 7.75 (t, J = 8.2 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 9.2, 2.3 Hz, 1H), 5.27 - 5.15 (m, 1H), 3.75 - 3.65 (m, 2H), 2.99 - 2.89 (m, 2H), 2.60 - 2.51 (m, 1H), 2.36 - 2.22 (m, 2H), 2.06 - 1.96 (m, 4H), 1.79 - 1.59 (m, 4H), 1.27 - 1.20 (m, 2H).

[1320] Synthesis of Intermediate C7 in Example 53

[1321] 4-(2R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5-methylmorpholin-2-yl)benzoic acid (Intermediate C7)

[1322] Synthetic procedure

[1323] First Step: 4-((2R,5R)-4-benzyl-5-methylmorphin-2-yl)benzoic acid methyl ester (Intermediate C7-1)

[1324] Methyl 4-(2-bromoacetyl)benzoate (10 g, 38.90 mmol) was added to a suspension of (R)-2-(benzylamino)propan-1-ol (6.43 g, 28.9 mmol) and potassium carbonate (5.38 g, 38.90 mmol) in acetonitrile (200 mL) at 0 °C. The system was stirred at 0 °C for 5 min and then reacted at 25 °C for 22 h. The reaction was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure and dissolved in 1,2-dichloroethane (60 mL) and trifluoroacetic acid (60 mL), and triethylsilane (6.78 g, 58.35 mmol) was added. The reaction was stirred at 60 °C for 2 h. After the reaction was completed, most of the trifluoroacetic acid was concentrated under reduced pressure, and then the pH was adjusted to >7 with an aqueous potassium carbonate solution, and the aqueous phase was extracted with dichloromethane three times. The organic phase was concentrated under reduced pressure, and the resulting residue was separated by column chromatography to obtain Intermediate C7-1 (4.0 g, 32%) as a yellowish oil.

[1325] LCMS (ESI): [M+H] + = 326.30.

[1326] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.38 - 7.30 (m, 4H), 7.27 - 7.22 (m, 1H), 4.59 (dd, J = 9.7, 3.1 Hz, 1H), 3.84 (s, 3H), 3.82 - 3.77 (m, 1H), 3.71 (dd, J = 10.9, 1.3 Hz, 1H), 3.64 - 3.52 (m, 2H), 2.84 - 2.76 (m, 1H), 2.55 (dd, J = 11.9, 3.3 Hz, 1H), 2.49 - 2.44 (m, 1H), 1.12 - 1.05 (m, 3H).

[1327] Second Step: 4-((2R,5R)-5-methylmorphin-2-yl)benzoic acid methyl ester (Intermediate C7-2)

[1328] Intermediate C7-1 (4 g, 12.29 mmol) was dissolved in methanol (70 mL), palladium on carbon (400 mg) was added at 25 °C, and stirred at 50 °C for 6 h. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate C7-2 (2.89 g, 99%) as a yellow oil.

[1329] LCMS (ESI): [M+H] += 236.06.

[1330] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.91 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 4.49 (dd, J = 8.6, 3.1 Hz, 1H), 3.84 (s, 3H), 3.69 (dd, J = 11.0, 3.0 Hz, 1H), 3.55 (dd, J = 11.0, 2.8 Hz, 1H), 2.95 - 2.86 (m, 2H), 2.79 (dd, J = 12.8, 3.2 Hz, 1H), 1.14 (d, J = 6.8 Hz, 3H).

[1331] Third Step: Methyl 4-((2R,5R)-4-(3-amino-6-chloropyridazin-4-yl)-5- methylmorpholin-2-yl)benzoate (Intermediate C7-3)

[1332] Dimethyl sulfoxide (55 mL) and N,N-diisopropylethylamine (3.06 g, 23.69 mmol) were added to a mixture of Intermediate C7-2 (2.23 g, 9.48 mmol) and 4-bromo-6-chloropyridazin-3-amine (4.94 g, 23.69 mmol). The resulting mixture was stirred at 130 °C for 40 h. After completion of the reaction, the reaction was quenched with water and the aqueous phase was extracted with ethyl acetate three times and the organic phases were combined and washed with saturated sodium chloride three times. The resulting residue was separated by column chromatography to obtain Intermediate C7-3 (540 mg, 16%) as a yellow oil.

[1333] LCMS (ESI): [M+H] + = 363.39.

[1334] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 6.25 (s, 2H), 4.70 (dd, J = 10.7, 2.7 Hz, 1H), 4.22 (dd, J = 11.4, 2.8 Hz, 1H), 3.93 - 3.88 (m, 1H), 3.86 (s, 3H), 3.80 (d, J = 11.4 Hz, 1H), 3.31 - 3.21 (m, 1H), 3.06 (dd, J = 12.3, 2.3 Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H).

[1335] Fourth Step: Methyl 4-(2R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5- methylmorpholin-2-yl)benzoate (Intermediate C7-4)

[1336] To a solution of intermediate C7-3 (230 mg, 633.93 pmol) in 1,4-dioxane (18 mL) and water (3 mL) was added (2-hydroxyphenyl)boronic acid (131.16 mg, 950.90 pmol), methylsulfonic acid (2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (51.12 mg, 63.39 pmol), 2-dicyclohexylphosphino-2'6'-bis(N,N-dimethylamino)-1,1'-biphenyl (27.68 mg, 63.39 pmol) and potassium carbonate (262.84 mg, 1.9 mmol). Deoxygenate, nitrogen protection, and stir at 80 °C for 16 hours. After the reaction was completed, the obtained residue was separated by column chromatography to obtain yellow solid intermediate C7-4 (90 mg, 34%).

[1337] LCMS (ESI): [M+H] + = 421.49.

[1338] 1 H NMR (400 MHz, DMSO-d6) d 8.00 (d, J = 8.4 Hz, 2H), 7.93 (dd, J = 8.1, 1.4 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.50 (s, 1H), 7.24 - 7.18 (m, 1H), 6.87 (dd, J = 8.2, 1.0 Hz, 1H), 6.85 - 6.78 (m, 1H), 6.41 (s, 2H), 4.75 (dd, J = 10.5, 2.3 Hz, 1H), 4.34 - 4.26 (m, 1H), 3.98 - 3.90 (m, 1H), 3.87 (s, 3H), 3.84 (d, J = 11.2 Hz, 1H), 3.53 - 3.44 (m, 1H), 3.11 (dd, J = 12.3, 2.4 Hz, 1H), 1.06 (d, J = 6.6 Hz, 3H).

[1339] Fifth step: 4-(2R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5- methylmorpholin-2-yl)benzoic acid (intermediate C7)

[1340] To a solution of intermediate C7-4 (153 mg, 363.88 μmol) in tetrahydrofuran / water (6 mL / 2 mL) was added lithium hydroxide monohydrate (76.35 mg, 1.82 mmol). The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the pH was adjusted to 5 by slowly adding 2M aqueous hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate for 3 times, the combined organic phase was washed with saturated aqueous sodium chloride solution for 2 times, and the mixture was concentrated under reduced pressure. The obtained residue was separated by column chromatography to obtain intermediate C7 (99 mg, 67%) as a light yellow solid.

[1341] LC-MS (ESI): [M+H] + = 407.37.

[1342] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.3 Hz, 2H), 7.93 (dd, J = 8.1, 1.4 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.50 (s, 1H), 7.24 - 7.18 (m, 1H), 6.87 (dd, J = 8.2, 1.1 Hz, 1H), 6.84 - 6.79 (m, 1H), 6.41 (s, 2H), 4.74 (dd, J = 10.5, 2.2 Hz, 1H), 4.30 (d, J = 9.0 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.84 (d, J = 11.0 Hz, 1H), 3.53 - 3.44 (m, 1H), 3.10 (dd, J = 12.3, 2.3 Hz, 1H), 1.06 (d, J = 6.6 Hz, 3H).

[1343] Synthesis of intermediate C8 in example 54

[1344] 1-(4-((2R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5-methylmoφholin-2- yl)benzoyl)piperidine-4-carbaldehyde (intermediate C8)

[1345] Synthesis scheme

[1346] First step: (4-((2R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5-methylmoφholin-2- yl)phenyl)(4-(dimethoxymethyl)piperidin-l-yl)methanone (intermediate C8-1)

[1347] To a solution of intermediate C7 (63 mg, 155 μmol) in N,N-dimethylformamide (2 mL) was added 4-(dimethoxymethyl)piperidine (29.62 mg, 186 μmol), HATU (70.73 mg, 186.μmol), DIEA (60.10 mg, 465.01 μmol). The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, quenched with water, the aqueous phase was extracted with ethyl acetate for 3 times, the combined organic phase was washed with saturated aqueous sodium chloride solution for 3 times. The organic phase was concentrated under reduced pressure, the obtained residue was separated by column chromatography to obtain yellow solid intermediate C8-1 (75 mg, 88%).

[1348] LCMS (ESI): [M+H] + = 548.48.

[1349] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.92 (m, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.25 - 7.18 (m, 1H), 6.90 - 6.85 (m, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.40 (s, 2H), 4.69 (dd, J = 8.5 Hz, 1H), 4.57 - 4.42 (m, 1H), 4.29 (dd, J = 9.2 Hz, 1H), 4.09 (d, J = 6.8 Hz, 1H), 4.00 - 3.90 (m, 1H), 3.83 (d, J = 11.0 Hz, 1H), 3.67 - 3.56 (m, 1H), 3.55 - 3.47 (m, 1H), 3.26 (s, 6H), 3.13 - 3.06 (m, 1H), 3.05 - 2.96 (m, 1H), 1.92 - 1.81 (m, 1H), 1.79 - 1.53 (m, 2H), 1.27 - 1.12 (m, 3H), 1.06 (d, J = 6.6 Hz, 3H).

[1350] Second step: 1-(4-((2R,5R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-5- methylmorpholin-2-yl)benzoyl)piperidine-4-carbaldehyde (intermediate C8-2)

[1351] Intermediate C8-1 (75 mg, 136.95 μmol) was dissolved in formic acid (2 mL), the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, most of the formic acid was removed by concentration under reduced pressure. The pH was adjusted to 7 by adding aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane for 3 times, the combined organic phase was washed with saturated sodium chloride solution for 1 time. The filtrate was concentrated under reduced pressure to obtain yellow solid intermediate C8-2 (68 mg, 98%).

[1352] LCMS (ESI): [M+H] @ 406.1 + = 502.45.

[1353] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.97 - 7.92 (m, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.25 - 7.19 (m, 1H), 6.87 (dd, J = 8.2, 1.1 Hz, 1H), 6.85 - 6.79 (m, 1H), 6.40 (s, 2H), 4.70 (dd, J = 10.5, 2.2 Hz, 1H), 4.36 - 4.18 (m, 2H), 3.99 - 3.90 (m, 1H), 3.83 (d, J = 10.9 Hz, 1H), 3.60 - 3.47 (m, 2H), 3.20 - 2.98 (m, 3H), 2.68 - 2.60 (m, 1H), 2.02 - 1.73 (m, 2H), 1.57 - 1.40 (m, 2H), 1.06 (d, J = 6.6 Hz, 3H).

[1354] Synthesis of Example 55, Intermediate C9

[1355] 6-bromo-1-cyclopentyl-5-fluoro-1H-benzo[d]imidazol-2-amine (Intermediate C9)

[1356] Synthesis scheme

[1357] First step: 5-bromo-N-cyclopentyl-4-fluoro-2-nitroaniline (Intermediate C9-1)

[1358] Dissolve 1-bromo-2,5-difluoro-4-nitrobenzene (5.00 g, 21.01 mmol) in dimethyl sulfoxide (30 mL), then add cyclopentylamine (1.97 g, 23.11 mmol) and N,N-diisopropylethylamine (2.99 g, 23.11 mmol) to the system, stir the mixture at 120 °C for 2 hours, after the reaction is complete, pour the mixture into water, extract with ethyl acetate, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum. Isolate the orange solid C9-1 (6.23 g, 98%) by column chromatography.

[1359] LC-MS (ESI): [M+H] + = 303.15.

[1360] 1H NMR (400 MHz, Chloroform-d) δ 8.01 - 7.90 (m, 2H), 7.11 (d, J = 5.8 Hz, 1H), 3.96 - 3.83 (m, 1H), 2.18 - 2.03 (m, 2H), 1.89 - 1.52 (m, 6H).

[1361] Second Step: 5-Bromo-N-cyclopentyl-4-fluoro-benzene-1,2-diamine (Intermediate C9-2)

[1362] Intermediate C9-1 (4.00 g, 13.20 mmol) and zinc powder (4.31 g, 65.98 mmol) were dissolved in acetic acid (40 mL) and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The crude product was separated and purified by column chromatography to give Intermediate C9-2 (3.10 g, 86%) as brown oil.

[1363] LC-MS (ESI): [M+H] + = 273.17.

[1364] 1 H NMR (400 MHz, Chloroform-d) δ 6.74 (d, J = 6.6 Hz, 1H), 6.51 (d, J = 9.5 Hz, 1H), 3.74 - 3.64 (m, 1H), 2.07 - 1.95 (m, 2H), 1.75 - 1.61 (m, 4H), 1.51 - 1.43 (m, 2H).

[1365] Third Step: 6-Bromo-1-cyclopentyl-5-fluoro-1H-benzo[d]imidazol-2-amine (Intermediate C9)

[1366] Intermediate C9-2 (2.00 g, 7.32 mmol) was dissolved in MeOH (100 mL) and cyanogen bromide (1.16 g, 10.98 mmol) was added dropwise at 0 °C. The reaction was stirred overnight, after which the reaction was concentrated under reduced pressure and washed with EA / PE to give Intermediate C9 (0.75 g, 34%) as a white solid.

[1367] LC-MS (ESI): [M+H] + = 298.28.

[1368] 1H NMR (400 MHz, Chloroform-d) δ 7.29 - 7.26 (m, 2H), 7.16 (d, J = 9.2 Hz, 1H), 4.94 (s, 2H), 4.55 - 4.38 (m, 1H), 2.14 - 1.95 (m, 6H), 1.86 - 1.76 (m, 2H).

[1369] Synthesis of Example 56 Intermediate C10

[1370] 2-(6-amino-5-(8-(3-(4-(dimethoxymethyl)piperidin-l-yl)-4-fluorophenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol (Intermediate C10)

[1371] Synthetic Scheme

[1372] First Step: l-(5-bromo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (Intermediate C10-1)

[1373] To a solution of 4-bromo-l-fluoro-2-iodobenzene (2.00 g, 6.65 mmol), 4- (dimethoxymethyl)piperidine (1.06 g, 6.65 mmol), L-proline (0.15 g, 1.33 mmol), copper iodide (0.25 g, 1.33 mmol) and potassium phosphate (4.23 g, 19.94 mmol) in DMF (10 mL) was purged with nitrogen for 3 times, and then stirred at 100 °C overnight. After completion of the reaction, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give yellow solid of Intermediate C10-1 (0.43 g, 20%).

[1374] LCMS (ESI): [M+H] + = 332.29.

[1375] 1 H NMR (400 MHz, Chloroform-d) δ 6.98 - 6.81 (m, 3H), 4.09 (d, J = 7.2 Hz, 1H), 3.51 - 3.41 (m, 2H), 3.37 (s, 6H), 2.67 - 2.54 (m, 2H), 1.89 - 1.81 (m, 2H), 1.81 - 1.67 (m, 1H), 1.58 - 1.42 (m, 2H).

[1376] Second Step: 8-(3-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluorophenyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (Intermediate C10-2)

[1377] Intermediate C10-1 (0.33 g, 0.99 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3- carboxylate (0.25 g, 1.19 mmol), RuPhos Pd G3 (0.1 mmol, 10%), RuPhos (0.1 mmol, 10%) and cesium carbonate (0.65 g, 1.99 mmol) were added to 1,4-dioxane (10 mL) followed by nitrogen purging for 3 times. The system was stirred at 90 °C overnight. After the reaction was completed, the system was concentrated under vacuum. The crude product was separated and purified by column chromatography to obtain yellow solid of Intermediate C10-2 (0.36 g, 78%).

[1378] LCMS (ESI): [M+H] + = 464.49.

[1379] 1 H NMR (400 MHz, DMSO-d6) δ 6.90 (dd, J = 12.4, 8.7 Hz, 1H), 6.49 - 6.31 (m, 2H), 4.25 - 4.14 (m, 2H), 4.10 (d, J = 6.5 Hz, 1H), 3.58 - 3.44 (m, 2H), 3.34 - 3.29 (m, 2H), 3.27 (s, 6H), 3.17 - 3.09 (m, 1H), 3.00 (d, J = 12.7 Hz, 1H), 2.63 - 2.53 (m, 2H), 1.91 - 1.81 (m, 2H), 1.74 - 1.57 (m, 5H), 1.44 - 1.26 (m, 11H).

[1380] Third Step: 8-(3-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluorophenyl)-3,8- diazabicyclo[3.2.1]octane (Intermediate C10-3)

[1381] Intermediate C10-2 (400.00 mg, 0.86 mmol), 4M HCl in MeOH (6 mL) were added to a 25 mL reaction flask, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, saturated NaHCO3 aqueous solution was added to the reaction system to adjust the pH to neutral. The aqueous phase was extracted with DCM, and then the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated to obtain yellow solid of Intermediate C10-3 (283.00 mg, 90%).

[1382] LCMS (ESI): [M+H]+ = 364.49.

[1383] Fourth Step: 2-(6-amino-5-(8-(3-(4-(dimethoxymethyl)piperidin-l-yl)-4- fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol (Intermediate C10)

[1384] Intermediate C10-3 (0.25 g, 0.69 mmol), 2-(6-amino-5-bromopyrazin-3-yl)phenol (0.18 g, 0.69 mmol), DIEA (0.53 g, 4.13 mmol) were dissolved in DMSO (5 mL), the system was stirred at 80 °C overnight, after the reaction was completed, the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic layer was dried over anhydrous Na2S04, filtered, concentrated in vacuo. The crude product was separated and purified by column chromatography to give yellow solid intermediate C10 (0.03 g, 8%).

[1385] LCMS (ESI): [M+H] + = 549.48.

[1386] Synthesis of Intermediate C11 in Example 57

[1387] (R)-4-bromo-7-cyclopentyl-9-(2-(dimethoxymethyl)morpholino)benzo[4,5]imidazo[l,2- a]quinazolin-5(7H)-one (Intermediate C11)

[1388] Synthesis Scheme

[1389] First Step: (R)-benzyl 2-(hydroxymethyl)morpholine-4-carboxylate (Intermediate C11-1)

[1390] (R)-morpholin-2-ylmethanol (3 g, 19.79 mmol) was dissolved in acetonitrile / water (30 mL / 30 mL), then sodium bicarbonate (4.99 g, 59.37 mmol) was added to the system, then benzyl chloroformate (1.2 g, 23.75 mmol) was slowly added, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the mixture was concentrated in vacuo, and purified by column chromatography to give intermediate C11-1 (4.9 g, 98.53%).

[1391] LC-MS (ESI): [M+H] + = 252.25

[1392] 1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.34 (m, 5H), 5.11 (s, 2H), 4.82 (s, 1H), 4.00 - 3.92 (m, 1H), 3.89 - 3.73 (m, 2H), 3.51 - 3.29 (m, 4H), 3.04 - 2.82 (m, 1H), 2.79 - 2.56 (m, 1H).

[1393] Second Step: (R)-2-Formylmorpholine-4-carboxylic acid benzyl ester (Intermediate C11-2)

[1394] Under -78 o C, oxalyl chloride (1.01 g, 7.96 mmol) was dissolved in dichloromethane (10 mL), dimethyl sulfoxide (932 mg, 11.94 mmol) in dichloromethane (10 mL) was added slowly, the system was flushed with nitrogen three times, then stirred at -78 °C for 1 h, then intermediate C11-1 (1 g, 3.98 mmol) was dissolved in dichloromethane (10 mL) and added to the above reaction solution, and reacted for 1 h. Finally, triethylamine (2.01 g, 19.9 mmol) was dissolved in dichloromethane (10 mL) and added to the reaction solution, and reacted for half an hour at -78 °C and half an hour at room temperature. After the reaction was completed, the mixture was poured into water and extracted with EA (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The system was separated by column chromatography to obtain yellow oil crude product intermediate C11-2 (700 mg, 70.57%), which was directly used in the next step.

[1395] LC-MS (ESI): [M+H] + = 250.25

[1396] Third Step: (R)-2-(Dimethoxymethyl)morpholine-4-carboxylic acid benzyl ester (Intermediate C11-3)

[1397] Intermediate C11-2 (100 mg, 0.40 mmol) was dissolved in methanol (1 mL), then p-toluenesulfonic acid (13 mg, 0.08 mmol) was added to the system, and trimethyl orthoformate (212 mg, 2.01 mmol) was added. The mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum, and column chromatography was used for purification to obtain colorless oil intermediate C11-3 (110 mg, 92.84%)

[1398] LC-MS (ESI): [M+H] + = 296.30

[1399] 1H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.29 (m, 5H), 5.10 (s, 2H), 4.26 (d, J = 5.9 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.81 - 3.73 (m, 1H), 3.46 - 3.37 (m, 2H), 3.31 (s, 3H), 3.29 (s, 3H), 3.06 - 2.66 (m, 2H).

[1400] Fourth Step: (R)-2-(dimethoxymethyl)morpholine (Intermediate C11-4)

[1401] Intermediate C11-3 (110 mg, 0.37 mmol) was dissolved in methanol (2 mL), then palladium on carbon (30 mg, 30 wt%) was added to the system, the system was replaced with nitrogen three times, replaced with hydrogen, and then reacted at room temperature for 1 hour. After the reaction was completed, the mixture was filtered through diatomite, concentrated in vacuo, and Intermediate C11-4 (50 mg, 83.28%) was obtained as a yellow oil. The product was used directly in the next step without purification.

[1402] LC-MS (ESI): [M+H] + = 162.25

[1403] 1 H NMR (400 MHz, DMSO-d6) δ 4.15 (d, J = 6.3 Hz, 1H), 3.69 (dt, J = 11.0, 1.6 Hz, 1H), 3.41 - 3.31 (m, 2H), 3.27 (s, 3H), 3.26 (s, 3H), 2.74 (dd, J = 12.2, 2.0 Hz, 1H), 2.66 - 2.53 (m, 2H), 2.40 (dd, J = 12.2, 10.1 Hz, 1H).

[1404] Fifth Step: (R)-4-bromo-7-cyclopentyl-9-(2-(dimethoxymethyl)morpholino)benzo[4,5]imidazo[l,2-a]quinazolin-5(7H)-one (Intermediate C11)

[1405] Intermediate A14 (300 mg, 0.59 mmol) was dissolved in DMF (3 mL), and intermediate C11-4 (95 mg, 0.59 mmol), xantphos (34 mg, 0.059 mmol), Pd2(dba)3 (54 mg, 0.059 mmol), cesium carbonate (577 mg, 1.77 mmol) were added. The system was replaced with nitrogen three times, and then stirred at 100 °C for 2 hours. After the reaction was completed, the mixture was poured into water and extracted with EA (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The system was separated by column chromatography to obtain white solid intermediate C11 (120 mg, 37.54%).

[1406] LC-MS (ESI): [M+H] + = 541.35

[1407] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 9.1, 2.0 Hz, 1H), 5.23 (p, J = 8.5 Hz, 1H), 4.38 (d, J = 5.9 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.73 - 3.64 (m, 2H), 3.64 - 3.54 (m, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 2.80 (td, J = 11.6, 3.2 Hz, 1H), 2.70 - 2.62 (m, 1H), 2.35 - 2.22 (m, 2H), 2.06 - 1.98 (m, 4H), 1.79 - 1.67 (m, 2H).

[1408] Synthesis of intermediate D1 in example 58

[1409] 1-(spiro[azetidine-3,2'-chromane]-6'-yl)dihydropyrimidine-2,4(1H,3H)-dione (intermediate D1)

[1410] Synthesis scheme

[1411] First step: tert-butyl 6'-bromo-4'-oxospiro(azetidine-3,2'-chromane)-1-carboxylate (intermediate D1a)

[1412] Dissolve 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (10.0 g, 46.50 mmol, 1.0 eq) in methanol (100 mL), add tert-butyl 3-oxoazetidine-1-carboxylate (8.76 g, 51.15 mmol, 1.1 eq) and tetrahydropyrrole (11.39 g, 51.15 mmol, 1.1 eq) to the reaction system. Warm the reaction to 70 °C and react at this temperature for 16 hours. Treat the mixture with water and extract twice with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride solution, dry and concentrate. Purify the resulting crude product by normal phase column chromatography to give yellow solid intermediate D1a (8 g, 46.42%).

[1413] LCMS (ESI): [M- t Bu+H] + = 314.15.

[1414] Second step: tert-butyl 6'-bromo-4'-hydroxyspiro(azetidine-3,2'-chromene)-1-carboxylate (Intermediate D1b)

[1415] Dissolve intermediate D1a (8 g, 10.86 mmol, 1.0 eq) in methanol (100 mL) and cool to 0 °C before adding sodium borohydride (1.64 g, 43.45 mmol, 2.0 eq). After the addition is complete, allow the reaction to warm to room temperature and react for 1 hour. Quench the reaction with saturated aqueous ammonium chloride solution and extract twice with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride solution, dry and concentrate to give crude product yellow solid intermediate D1b (8 g, 99.46%) which is used directly in the next step.

[1416] LCMS (ESI): [M-Boc+H] + = 270.20.

[1417] Third step: 6'-bromospiro(azetidine-3,2'-chromene) (Intermediate D1c)

[1418] Dissolve intermediate D1b (8 g, 21.61 mmol, 1.0 eq) in toluene (100 mL) and add p-toluenesulfonic acid (7.44 g, 43.21 mmol, 2.0 eq) to the reaction system. Warm the reaction to 110...

Claims

Compounds having the structure of Formula I: PTM-L-ULM (Formula I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopic derivative, or polymorph thereof; wherein: L is a chemical linking moiety connecting ULM and PTM; The PTM is selected from the following structures: wherein, R a7 , R a8 , and R a9 each occurrence is independently N or CR a ; R b5 and R b6 are single or double bonds; when R b5 and R b6 are connected by a single bond, R b5 and R b6 are each independently selected from NR a and C(R a )2; when R b5 and R b6 are connected by a double bond, R b5 and R b6 are each independently selected from N and CR a ; R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8 are each independently selected at each occurrence from hydrogen, deuterium, halogen, alkyl, optionally substituted haloalkyl, optionally substituted deuterated alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, nitro, carboxyl, amino, optionally substituted haloalkoxy, optionally substituted hydroxyalkyl, optionally substituted alkoxy, cyano, hydroxyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -O-cycloalkyl; preferably R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8 are each independently selected at each occurrence from hydrogen, deuterium, halogen, alkyl, optionally substituted haloalkyl, optionally substituted deuterated alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxyl, amino, haloalkoxy, hydroxyalkyl, alkoxy, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -O-cycloalkyl; p1and p2are each independently at each occurrence selected from 0, 1, 2, and 3; each occurrence of ring A and ring B is independently a 4-8 membered saturated or unsaturated carbocyclic ring, a 4-8 membered heterocyclic ring, a 6-8 membered aromatic ring, or a 5-8 membered heteroaromatic ring, each of said 4-8 membered heterocyclic ring and 5-8 membered heteroaromatic ring independently containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, said ring A and ring B being unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, oxo (=0), a deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, 3-7 membered cycloalkyl, C1-C6 haloalkyl, and C 1-6 substituted with a substituent selected from halo, oxo (=0), a deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, 3-7 membered cycloalkyl, C1-C6 haloalkyl, and C Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy 14 , Cy 15 , Cy 16 , and Cy 17 is absent or each occurrence is independently selected from 4-8 membered alkylenes monocycloalkyl, 4-8 membered heteroalkylenes monocyclo, 6-8 membered arylene, 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-13 membered spiroalkylenes or heterospiroalkylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 4-12 membered fusions alkylenes or heterofusions alkylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged alkylenes or heterobridged alkylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which 4-8 membered alkylenes monocycloalkyl, 4-8 membered heteroalkylenes monocyclo, 6-8 membered arylene, 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-13 membered spiroalkylenes or heterospiroalkylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 4-12 membered fusions alkylenes or heterofusions alkylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged alkylenes or heterobridged alkylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, can be optionally substituted with 0, 1, 2, or 3 R a ; R L1 and R L2 each independently at each occurrence is selected from a single bond, C 2-6 alkylene, C 2-6 alkenylene, C 1-6 alkylene, -O-, -C(O)-, -S-, -O-C a alkylene-, -NR a -, -NR a -C(O)- and -NR 1-6 alkylene-; ULM is an E3 ubiquitin ligase binding moiety; preferably, the ULM is a CRBN binding moiety; preferably, the ULM is selected from the following structures: wherein: W 1 and W 2 each occurrence is independently CR ab R bb or C(=O), and at least one of W 1 and W 2 is C(=O); W 11 each occurrence is independently C(=O); R 20 selected from N and CR 1 ; R 3at selected from R 3a , NR m -T and T; R 3bt selected from R 3b , NR m -T and T; R 3ct selected from R 3c , NR m -T and T; R 3dt selected from R 3d , NR m -T and T; T represents a site of attachment of ULM and L, and there is one and only one site of attachment of the structure shown in Formula 2-A to L; Cy9, and Cy 12 each occurrence is selected independently from the group consisting of cycloalkylene, heterocyclylene, arylene, and heteroarylene, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkylNH-C(O), aryl, and heteroaryl; L C1 each occurrence is selected independently from a single bond, -NR ab -C(O)-, -C(O)- and NR ab ; Cy 13 is selected from a 5-13 membered spiro or heterospiro group and a 4-12 membered fused or heterofused group, each independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo (=0), thioxo (=S), heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; G, Z, G1, and G2are each independently at each occurrence selected from O, S, and Se; R 3a , R 3b , R 3c , R 3d , and R 3e are each independently at each occurrence selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; or, (a) R 3a and R 3b , (b) R 3b and R 3c , and (c) R 3c and R 3d , at least one of the groups and the carbon atoms to which they are attached together form a And when not involved in circulatory formation, R 3a R 3b R 3c R 3d and R 3e Each of the following groups is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, amino, and heteroaryl groups are each independently and optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl groups; (e) R 3a1 and R 3b1 , (f) R 3b1 and R 3c1 , and (g) R 3c1 and R 3d1 , at least one group of carbon atoms to which it is attached collectively form and, when not involved in ring formation, R 3a1 , R 3b1 , R 3c1 , and R 3d1 are each independently at each occurrence selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O), O, or S; B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 , and W 41 each occurrence is independently CR m or N; C 31 , R t , R T , R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; m1and m2are each independently at each occurrence 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6; m3, m71, and m51are each independently at each occurrence 0, 1, 2, 3, 4, 5, 6, or 7, m4, m81, and m61are each independently at each occurrence 1, 2, 3, 4, 5, 6, 7, or 8, and m3+ m4≤ 8, m71+ m81≤ 8, and m51+ m61≤ 8; m5and m6are each independently at each occurrence 0, 1, 2, 3, 4, 5, 6, or 7, and m5+ m6≤ 7; m7and m8are each independently at each occurrence 0, 1, 2, 3, 4, 5, 6, or 7, and m7+ m8≤ 7; m21, m31, and m41are each independently at each occurrence 0, 1, 2, or 3, and m21+ m31+ m41≤ 3; R m and R 2h each occurrence is selected independently from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; R 1 , R 11 , and R N each occurrence is independently selected from hydrogen, halogen, deuterium, C1-C6alkyl, C1-C6alkoxy, hydroxyl, 3- to 7-membered cycloalkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; R w is selected from N and CH; R 2m is independently at each occurrence selected from a single bond, -NR ab -C(O)- and -NR ab -; and when PTM is ULM is of formula 2-C, R w is CH, R 2m is not a single bond; when PTM is ULM is of formula 2-D, R 2m is not a single bond; R 2 , R 21 , R ab and R bb are each independently at each occurrence selected from hydrogen, Ci-C6alkyl, C3-C6cycloalkyl and Ci-C6alkoxy; and n and n1are each independently at each occurrence 0, 1, 2, or 3; wherein when PTM is Formula 1-3, CLM is not and when the PTM is of Formula 1-4 or Formula 1-5, the CLM is of Formula 2-A, and (a) R 3a and R 3b , (b) R 3b and R 3c , and (c) R 3c and R 3d , only one of the groups and R at time t, formula 2-A For and when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-A, R 3at , R 3bt , R 3ct and R 3dt are not T. The compound of claim 1, wherein, The ULM is selected from the following structures: wherein W 11 , R 20 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , R 3d1 , Cy9, Cy12, Cy13, L C1 , G, Z, G1, G2, Z1, B 1a , B 2a , B 3a , B 4a , B 5a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , W 3 , W 4 , W 3a , W 4a , C 31 , R t , R T , R t1 , R T1 , R 1 , R 11 , R N , R N1 , R 2m , R 2 , R 21 , m1, m2, m3, m4, m5, m6, m7, m8, m21, m31, m41, m51, m61, n and n1 are each, at each occurrence, as defined in claim 1; wherein when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46, Formula 2-41, 2-42, 2-43, 2-44, 2-45, and 2-46 are, respectively, The compound of claim 1, wherein, The ULM is selected from the following structures: wherein W 1 , W 2 , R 3a , R 3b , R 3c , R 3d , G, Z, R m , R D , R E , R DD , R EE , R F , R G , R T , R 1 , R 2 , m3, m4, m71, m81, m7, m8 and n are each, at each occurrence, as defined in claim 1. The compound of any one of claims 1-3, wherein: R a7 , R a8 , and R a9 each occurrence is independently selected from the group consisting of N, CH, C-halogen, C-C1-C6alkyl, and C-C1-C6alkoxy; preferably, R a7 , R a8 , and R a9 each occurrence is independently selected from the group consisting of N, CH, C-F, C-Cl, C-Br, C-CH3, and C-O-CH3; and / or R a R 11a R 12a R a2 R a3 R a4 R a5 R a6 R a10 R b1 R b2 R b3 R b4 R b7 R c1 R c2 R c3 R c4 R c5 R c6 R c7 and R c8 Each occurrence is independently selected from hydrogen, halogen, deuterium, cyano, and C. 1-6 Alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro, amino, carboxyl, hydroxyl, 3-7 membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O and S, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3-6 membered cycloalkyl and -O-3-5 membered cycloalkyl; preferably, R a R 11a R 12a R a2 R a3 R a4 R a5 R a6 R b1 R b2 R b3 R b4 R b7 R c1 R c2 R c3 R c4 R c5 R c6 R c7 and R c8 Each occurrence is independently selected from hydrogen, F, Cl, Br, I, deuterium, cyano, and C. 1-6 Alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro, amino, carboxyl, hydroxyl, 3-7 membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3-6 membered cycloalkyl, and -O-3-5 membered cycloalkyl; R a10 Selected from C 1-3 alkyl, 4-, 5- or 6-membered cycloalkyl and 4-, 5- or 6-membered heterocycloalkyl containing one oxygen atom; preferably R a10 is 5-membered cycloalkyl; and / or each occurrence of ring A and ring B is independently a 5-6 membered saturated or unsaturated carbocyclic ring, a 5-6 membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, a 5-6 membered aromatic ring, or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; and / or W 1 and W 2 each occurrence is independently CH2or C(=O), and W 1 and W 2 at least one of which is C(=O); and / or G, Z, G1, G2, and Z1are all O; and / or R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , and R 3d1 are each, at each occurrence, independently selected from hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuterated alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkyl-C(O), C1-C6alkyloxy-C(O), 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S, 6-8 membered aryl, and 6-8 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S, wherein the C1-C6alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, 6-8 membered aryl, amino, and 6-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; preferably, R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , and R 3d1 are each, at each occurrence, independently selected from hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, C1-C6haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C6hydroxyalkyl; more preferably, R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , and R 3d1 each occurrence is selected independently from the group consisting of hydrogen, F, Cl, Br, I, cyano, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -NH-C1-C3 alkyl, -NH-CO-C1-C3 alkyl, and C1-C3 hydroxyalkyl; and / or B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O) or -O-; and / or B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 and W 41 each independently at each occurrence is CR m or N, preferably CH or N; and / or C 31 , R t , R T , R t1 and R T1 are each independently of each other CR m or N, preferably N or CH; and / or R m and R 2h each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuterated alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkyl-C(O), C1-C6alkyloxy-C(O), 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, O, and S, 6-8 membered aryl, and 6-8 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein each of said C1-C6alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, 6-8 membered aryl, amino, and 6-8 membered heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkyl-C(O), alkyloxy-C(O), alkyl-NH-C(O), aryl, and heteroaryl; preferably, R m , and R 2h each occurrence is independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, C1-C6haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C6hydroxyalkyl; preferably, R m , and R 2h each occurrence is independently selected from the group consisting of hydrogen, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3haloalkyl, C1-C3haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C3hydroxyalkyl; more preferably, R m , and R 2h each occurrence is independently selected from the group consisting of H, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3haloalkyl, and C1-C3hydroxyalkyl; and / or R 1 , R 11 , and R N are each independently at each occurrence selected from H, F, CI, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; and / or R 2m is independently at each occurrence selected from -NH-C(O)-, -NH-, and -N(CH3)-; and / or R 2 , R 21 , R ab and R bb are each independently at each occurrence selected from the group consisting of H, C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy; and / or m1and m2are each independently at each occurrence 0, 1, 2, 3, or 4, and m1+ m2≤ 6; preferably, m1+ m2= 1, m1+ m2= 2, or m1+ m2= 3; and / or m3, m71, and m51are each independently at each occurrence 0, 1, 2, 3, or 4, m4, m81, and m61are 1, 2, 3, 4, or 5, and m3+ m4≤ 5, m71+ m81≤ 5, and m51+ m61≤ 5; preferably, m3, m71, and m51are each independently at each occurrence 0, 1, 2, or 3, m4, m81, and m61are 1, 2, 3, or 4, and m3+ m4= 2, m3+ m4= 3, or m3+ m4= 4; m71+ m81= 2, m71+ m81= 3, or m71+ m81= 4; m51+ m61= 2, m51+ m61= 3, or m51+ m61= 4; and / or m5and m6are each independently at each occurrence 0, 1, 2, 3, or 4, and m5+ m6≤ 7; preferably, m5+ m6= 1, m5+ m6= 2, m5+ m6= 3, or m5+ m6= 4; and / or each occurrence of m7 and m8 is independently 0, 1, 2, 3, or 4, and m7+m8 < 4; preferably, each occurrence of m7 and m8 is independently 0, 1, 2, or 3, and m7+m8 = 2 or m7+m8 = 3; and / or Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, Cy15, Cy16, and Cy17are each independently, at each occurrence, selected from the group consisting of 5-6 membered cycloalkylene, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from N and O, phenylene, 5-6 membered heteromonocyclyl containing 1 or 2 heteroatoms each independently selected from N and O, 7-11 membered heterospirocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered fused cyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, said 5-6 membered cycloalkylene, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from N and O, phenylene, 5-6 membered heteromonocyclyl containing 1 or 2 heteroatoms each independently selected from N and O, 7-11 membered heterospirocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered fused cyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, being optionally substituted with 0, 1, or 2 R a substituents; and / or Cy9 and Cy12 are each independently selected from 3-7-membered cycloalkylene groups, 3-7-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10-membered aryl groups, and 5-8-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the cycloalkylene group, heterocyclic group, aryl group, and heteroaryl group are each optionally independently selected from halogens, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylamino, C 1-6 Alkyl-C(O), C 1-6 Alkyloxy-C(O), C 1-6 The alkyl-NH-C(O), 6-10 aryl, and 5-10 heteroaryl groups are substituted with one or more substituents; preferably, Cy9 is independently selected each time it appears from a 6-10 arylene and a 5-8 heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the 6-10 arylene and 5-8 heteroarylene are optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; and / or, Cy12 is independently selected each time it appears from a 5-7 cycloalkyl and 5 -7-membered heterocyclic group, wherein the 5-7-membered heterocyclic group and the 5-7-membered heterocyclic group are optionally substituted by one or more substituents selected from F, Cl, Br, I, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; more preferably, Cy9 is independently selected from phenylene and pyridylene each time it appears, wherein the phenylene and pyridylene are optionally substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; preferably, Cy12 is each time it appears as optionally substituted with one or more substituents selected from the group consisting of halogen, deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; and / or Cy13is, at each occurrence, independently selected from 5-13 membered spirocyclylenes or heterospirocyclylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-12 membered fused cyclylenes or heterofused cyclylenes containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6alkyl, oxo (=0), thioxo (=S), C2-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxy, C1-C6hydroxyalkyl, cyano, amino, nitro, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered aryl, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; preferably, Cy13is selected from 2-6 alkenyl, C 2-6 alkynyl, C1-C6alkylamino, C1-C6alkyl-C(O), C1-C6alkyloxy-C(O), C1-C6alkyl-NH-C(O), 6-10 membered aryl, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; preferably, Cy13is selected from optionally substituted with one or more substituents selected from the group consisting of oxo (=0), thioxo (=S), F, Cl, Br, I, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; and / or n is 0 or 1; preferably, n is 1; and / or L C1 each occurrence is independently selected from the group consisting of a single bond, -NH-C(O)-, -C(O)-, and -NH-, preferably a single bond. The compound of any one of claims 1-4, wherein, The ULM is selected from the following structures: wherein W 1 , W 2 , W 3 , W 4 , W 31 , W 41 , W 11 , R 3a , R 3b , R 3c , R 3d , R 3a1 , R 3b1 , R 3c1 , R 3d1 , R d , R e , R f , R g , R D , R E , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , R N , R t , R T , R t1 , R T1 , B 1a , B 3a , B 4a , B 6a , C 1a , C 2a , C 31 , m3, m4, m5, m6, m21, m31, m41, m51 and m61 are each, at each occurrence, as defined in claim 1 or 4; each occurrence of m9 and m10 is independently 0, 1, 2, 3, 4, or 5, and m1+m9+m10 < 5; preferably, each occurrence of m1, m9 and m10 is independently 0, 1, or 2, and m1+m9+m10 < 2, preferably m1+m9+m10 = 1 or m1+m9+m10 = 0; each occurrence of m11 and m12 is independently 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12 < 6; preferably, each occurrence of m7, m11 and m12 is independently 0, 1, 2, or 3, and m7+m11+m12 < 3, preferably m7+m11+m12 = 2 or m7+m11+m12 = 1; preferably, W 11 is C(=O); and / or W 1 is C(=O), W 2 is CH2; W 1 is CH2, W 2 is C(=O); or W 1 is (=O), W 2 is C(=O); and / or R D , R E , R F and R G are each independently at each occurrence selected from CH2, C(C1-C6alkyl)2, CH(C1-C6alkyl), NH, N(C1-C6alkyl), C(=O) or -O-, preferably CH2; and / or R d , R e , R f and R g are each independently at each occurrence selected from CH2, C(C1-C6alkyl)2, CH(C1-C6alkyl), NH, N(C1-C6alkyl), C(=O) or -O-, preferably CH2; and / or R d1 , R e1 , R f1 and R g1 are each independently at each occurrence selected from CH2, C(C1-C6alkyl)2, CH(C1-C6alkyl), NH, N(C1-C6alkyl), C(=O) or -O-, preferably CH2; and / or R D1 , R E1 , R F1 and R G1 are each independently at each occurrence selected from CH2, C(C1-C6alkyl)2, CH(C1-C6alkyl), NH, N(C1-C6alkyl), C(=O) or -O-, preferably CH2; and / or each occurrence of m3 is independently selected from 0, 1, 2, and 3, each occurrence of m4 is independently selected from 1, 2, and 3, and m3+m4 < 5, preferably, m3+m4 = 2, m3+m4 = 3, m3+m4 = 4 or m3+m4 = 5, more preferably, m3 is 1, m4 is 1; or m3 is 2, m4 is 2; and / or each occurrence of m5 and m6 is independently 0, 1, 2, or 3, and m6+m5 < 4; preferably, m6+m5 = 2, m6+m5 = 3 or m6+m5 = 4; and / or W 3 , W 4 , W 31 and W 41 each independently at each occurrence is CH or N; and / or R N independently at each occurrence selected from the group consisting of H, F, CI, Br, and C1-C3 alkyl, preferably methyl; and / or B 1a , B 3a , B 6a , C 1a and C 2a each independently in each occurrence is selected from the group consisting of CH2, C(C1-C6alkyl)2, CH(C1-C6alkyl), NH, N(C1-C6alkyl), C(=O), and -O-, preferably CH2, NH, or N(CH3), more preferably CH2; and / or each occurrence of m21, m31 and m41 is independently 0, 1, or 2, and m21+m31+m41 < 3; preferably, m21+m31+m41 = 1 or m21+m31+m41 = 2; preferably, m21 is 0, m31 is 2, m41 is 0; or m21 is 1, m31 is 1, m41 is 0; and / or each occurrence of m51 and m61 is independently 0, 1, 2, or 3, and m61+m51 < 4, preferably, m61+m51 = 2, m61+m51 = 3 or m61+m5 = 4; preferably, m51 is 2, m61 is 2; and / or R 3a , R 3b , R 3c and R 3d are each independently at each occurrence selected from the group consisting of hydrogen, F, Cl, Br, I, cyano, C1-C3alkyl, C1-C3alkoxy, hydroxy, C1-C3haloalkyl, C1-C3haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C3hydroxyalkyl, preferably hydrogen, F, Cl, Br, cyano, methyl or methoxy; and / or R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently at each occurrence selected from the group consisting of hydrogen, F, Cl, Br, I, cyano, C1-C3alkyl, C1-C3alkoxy, hydroxy, C1-C3haloalkyl, C1-C3haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C3hydroxyalkyl, preferably from hydrogen, F, Cl, Br, cyano, methyl or methoxy, more preferably from hydrogen; and / or C 31 , R t , R T , R t1 , and R T1 , each occurrence is independently N; and / or B 1a , B 3a , B 4a , B 6a , C 1a , C 2a each occurrence is independently CH2. The compound of any one of claims 1-5, wherein, The ULM is selected from the following structures: The compound of any one of claims 1-6, wherein, L is a covalent bond or is -(B L ) q -, B L each occurrence is selected independently from CR L1 R L2 , O, S, S(O), S(O)2, NR L1 , CONR L1 , C(O), cycloalkylene, heterocycloalkylene, hetero-partially unsaturated cycloalkylene, bridged cycloalkylene, hetero-bridged cycloalkylene, spirocycloalkylene, hetero-spirocycloalkylene, arylene, and hetero-arylene, wherein each of said cycloalkylene, heterocycloalkylene, hetero-partially unsaturated cycloalkylene, bridged cycloalkylene, hetero-bridged cycloalkylene, spirocycloalkylene, hetero-spirocycloalkylene, arylene, and hetero-arylene is independently optionally substituted with 1, 2, 3, 4, 5, or 6 groups selected from R L1 ; B is preferably selected from the group consisting of C(R L each occurrence is independently selected from CR L1 R L2 , O, S, S(O), S(O)2, NR L1 , CONR L1 , C(O), 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenemonoheterocycloalkyl, 3-8 membered alkylenemonoheteropartially unsaturated cycloalkyl, 5-15 membered alkylenabicycloalkyl, 5-15 membered alkylenaspiroalkyl, 6-15 membered alkylenearomatic, and 5-15 membered alkylenaheteroaromatic, wherein each of said 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenemonoheterocycloalkyl, 3-8 membered alkylenemonoheteropartially unsaturated cycloalkyl, 5-15 membered alkylenabicycloalkyl, 5-15 membered alkylenaspiroalkyl, 6-15 membered alkylenearomatic, and 5-15 membered alkylenaheteroaromatic is independently optionally substituted with 1, 2, 3, or 4 groups selected from R L1 ; said 3-8 membered alkylenemonoheterocycloalkyl, 3-8 membered alkylenemonoheteropartially unsaturated cycloalkyl, 5-15 membered alkylenaheterobicycloalkyl, 5-15 membered alkylenaheterospiroalkyl, and 5-15 membered alkylenaheteroaromatic contains 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S; R L1 , and R L2 each independently for each occurrence is selected from halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, -N(C 1-8 alkyl)2, 3-11 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-11 membered heterocycloalkyl, -O-3-8 membered cycloalkyl, -O-3-11 membered heterocyclyl, -O-6-10 membered aryl, -O-5-10 membered heteroaryl, -S-3-8 membered cycloalkyl, -NH-3-8 membered cycloalkyl, -N(3-8 membered cycloalkyl)2, -N(3-8 membered cycloalkyl)(C 1-8 alkyl), -NH-3-8 membered heterocyclyl, -N(3-8 membered heterocyclyl)2, -N(3-8 membered heterocyclyl)(C 1-8 alkyl), -NH-6-10 membered aryl, -N(6-10 membered aryl)(C 1-8 alkyl), -NH-5-10 membered heteroaryl, -N(5-10 membered heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, -SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)OH, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2H, -SF5, -S(O)2NH-C 1-8 alkyl, -S(O)2N(C 1-8 alkyl)2, -S(O)NH-C 1-8 alkyl, -S(O)N(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C 1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), -N(C 1-8 alkyl)S(O)2N(C 1-8 alkyl)2, -NHS(O)2NH(C 1-8 alkyl), -NHS(O)2N(C 1-8 alkyl)2, and -NHS(O)2NH2, optionally, each instance of said C 1-8 alkyl, 3-11 membered cycloalkyl, 3-11 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, halocycloalkyl, haloheterocycloalkyl, alkylamino, 6-10 membered aryl, 5-10 membered heteroaryl, halo C 6-10 aryl, and halo 5-10 membered heteroaryl; Preferably, R L1 and R L2 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl groups, -C(O)OH, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, 3-6 membered cycloalkyl groups, and 3-6 membered heterocycloalkyl groups, wherein the alkyl group, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic alkyl groups are each independently selected from halogens, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 3-6 membered halocycloalkyl, 3-6 membered haloheteroalkyl, C 1-6 Substituted by one or more substituents of alkylamino, 6-10 aryl, 5-10 heteroaryl, 6-10 haloaryl, and 5-10 haloheteroaryl; and q is an integer greater than or equal to 1; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The compound of any one of claims 1-7, wherein, L is a covalent bond or is -(B L ) q -, B L is selected from one or more of the following divalent linkers: -0-, -S-, -S(O)-, -S(0)2-, -CH2-, -C(O)-, -NH-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 7-azaspiro[3.5]nonane, 6-azaspiro[4.4]octane, 2-azaspiro[4.5]decane, 2-azaspirocyclo[3.3]heptane, 3-azaspiro[5.5]undecane, spiro[3.5]nonane, spiro[4.4]octane, spiro[4.5]decane, spiro[3.3]heptane, spiro[5.5]undecane, 2,5-diazabicyclo[2.2.2]octane, 2-oxa-4,9-diazaspiro[5.5]undecane, 3-azabicyclo[3.1.0]hexane, 1-oxa-8-azaspiro[4.5]decane, 4-azaspiro[2.5]octane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.2]octane, and phenylene, q B L are the same or different; wherein the divalent linker is optionally substituted with one or more groups selected from R L1 ; Preferably, the bivalent linker is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, fluorine substituted C1-C6 alkoxy, C3-C6 cycloalkyl, and 3- to 6-membered oxacycloalkyl; more preferably, the bivalent linker is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, and oxetanyl; Preferably, B L is selected from one or more of the following structures: -0-, -S-, -S(O)-, -S(0)2-, -CH2-, -C(O)-, -NH-, q is 1, 2, 3, 4, 5, 6, 7, or 8; preferably, q is 1, 2, 3, 4, 5, or 6; and is a point of attachment. The compound of any one of claims 1-8, wherein, L is selected from the following structures: Covalent bond, -C(O)-, -C(O)-(CH2) j -, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -C(O)-(CH2) s -, -(CH2) p -O-(CH2) s -, -(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -, -(CH2) y -O-(CH2) j -O-(CH2) s -, -(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -C(O)-(CH2) j -O-(CH2) s -, -(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -C(O)-(CH2) j -O-(CH2) s -NH-(CH2) p -, j, p, s, and y are each independently at each occurrence selected from 1, 2, 3, and 4; Preferably, L is selected from the following structures: a covalent bond, -C(O)-, -C(O)-CH2-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-, Preferably, L is selected from the following structures: wherein j1, j2, j3, and j4are each independently at each occurrence selected from 0, 1, 2, and 3, preferably 0 and 1; o1and o3are each independently at each occurrence selected from 1, 2, and 3, o2and o4are each independently at each occurrence selected from 0, 1, 2, and 3; and, o1+o2= 2, o1+o2= 3, or o1+o2= 4; o3+o4= 2, o3+o4= 3, or o3+o4= 4; preferably, o1+o2= 4; preferably, o3+o4= 4; L a1 , L a3 , L b1 and L b3 each occurrence is independently selected from NR tt and C(R tt )2; L a2 , L a4 , L b2 and L b4 each occurrence is independently selected from N and CR tt ; R tt each occurrence is independently selected from hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, carboxyl, and C3-C5 cycloalkyl; preferably, R tt each occurrence is independently selected from hydrogen, F, Cl, Br, CH3, and CN; Preferably, L is selected from the following structures: The compound of any one of claims 1-9, wherein, Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, Cy15, Cy16, and Cy17 either do not exist or each occurrence is independently selected from 0, 1, 2, or 3 R's. a The following structures are replaced: wherein m, n1, m’, and n’ are each independently at each occurrence 1 or 2; R a each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, cyano, nitro, carboxyl, C3-C5 cycloalkyl, -O-C3-C5 cycloalkyl, C3-C5 heterocycloalkyl containing one or two O atoms, and amino. The compound of any one of claims 1-10, wherein, The PTM is selected from the following structures: wherein R a10 is selected from C 1-3 alkyl, 4-, 5- or 6-membered cycloalkyl and 4-, 5- or 6-membered heterocycloalkyl containing one oxygen atom; preferably R a10 is selected from methyl, isopropyl, cyclobutyl, cyclohexyl and cyclopentyl; and / or R a2 is hydrogen, F, Cl, Br, I, deuterium, cyano, C 1-6 alkyl, or C1-C6 alkoxy; preferably, R a2 is Cl or Br; and / or R a3 , R a4 , and R a5 are hydrogen, F, Cl, Br, I, deuterium, cyano, C 1-6 alkyl or C a3 -C6alkoxy; preferably, R a4 , R a5 are hydrogen; and / or R a7 is CH; and / or R a8 is CH, C-halogen, C-C1-C3alkyl or C-C1-C3alkoxy; preferably, R a8 is CH, C-F, C-Cl, C-Br, C-CH3or C-O-CH3; and / or R a9 is N or CH; and / or Cy3is absent or selected from 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, and 7-11 membered spirocyclylene or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; said 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, 7-11 membered spirocyclylene or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S can be optionally substituted with 0, 1, or 2 substituents selected from F, Cl, Br, I, cyano, C1-C3 alkyl, and C1-C3 alkoxy; preferably, Cy3is absent. The compound of any one of claims 1-10, wherein, The PTM is selected from the following structures: wherein R aa each occurrence is independently selected from hydrogen, halogen, C1-C3alkyl, and hydroxyl; preferably, R aa each occurrence is independently hydroxyl; and / or R a each occurrence is independently selected from hydrogen, halogen, C1-C3alkyl, and hydroxyl; preferably, R a is hydrogen; and / or Cy4 and Cy5, each time appearing, are absent or independently selected from phenylene, 5-6-membered cyclohexane, 5-6-membered heterocyclic groups containing 1 or 2 heteroatoms independently selected from N or O, 7-11-membered spirocyclic groups, and 7-11-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. The phenylene, 5-6-membered cyclohexane, 5-6-membered heterocyclic groups containing 1 or 2 heteroatoms independently selected from N or O, 7-11-membered spirocyclic groups, and 7-11-membered spirocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S are all mentioned. Alternatively, the 7-11 heterospirocyclic group consisting of three independent heteroatoms selected from N, O, and S may be optionally substituted with one or two substituents independently selected from F, Cl, Br, I, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, carboxyl, C3-C5 cycloalkyl, and C3-C5 heterocyclic alkyl containing one or two O atoms; preferably, Cy4 and Cy5 are absent each time they appear or are each independently selected from and / or Cy16is selected from a 5-6 membered cycloalkylene and a 5-6 membered heterocyclylene containing 1 or 2 heteroatoms each independently selected from N or O, said cycloalkylene and heterocyclylene being optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, cyano, hydroxyl, C1-C3alkyl, C1-C3alkoxy and C1-C3haloalkyl; preferably, Cy16is selected from a morpholinylene and said methylenedioxy group and optionally substituted by 1 or 2 C1-C3alkyl groups, more preferably selected from and / or Cy17is phenylene, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of F, CI, Br, I, cyano, hydroxy, C1-C3-alkyl, C1-C3-alkoxy and C1-C3-halogenalkyl, preferably selected from the group consisting of and / or R 11a and R 12a each occurrence is independently selected from the group consisting of hydrogen, halogen, deuterium, cyano, Ci-6alkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, nitro, amino, carboxyl, and hydroxyl, preferably R 11a and R 12a each occurrence is independently hydrogen. The compound of any one of claims 1-12, wherein, The PTM is selected from the following structures: a compound having the structure of Formula I: PTM-L-ULM (Formula I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, wherein: L is a chemical linking moiety linking ULM and PTM; The PTM is selected from the following structures: wherein, R a7 , R a8 , and R a9 are each independently selected for each occurrence from N or CR a ; R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8 are each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated-alkyl, heteroalkyl, alkenyl, alkynyl, amino, haloalkoxy, hydroxyalkyl, alkoxy, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -O-cycloalkyl; R b5 and R b6 are single or double bonds; when R b5 and R b6 are connected by a single bond, R b5 and R b6 are each independently selected from NR a and C(R a )2; when R b5 and R b6 are connected by a double bond, R b5 and R b6 are each independently selected from N and CR a ; p1and p2are each independently at each occurrence selected from 0, 1, 2, and 3; Ring A and Ring B are 4-8 membered saturated or unsaturated carbocyclic, 4-8 membered heterocyclic, 5-8 membered aromatic, or 5-8 membered heteroaromatic ring, each of which independently contains 1, 2, or 3 heteroatoms independently selected from N, O, S; said Ring A and Ring B are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, oxo (=0), deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, 3-7 membered cycloalkyl, C1-C6 haloalkyl, C 1-6 substituted with a substituent selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 alkylaminoalkyl, C1-C6 dialkylaminoalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 cyanoalkylcarbonyl, C1-C6 cyanoalkoxycarbonyl, C1-C6 aminoalkylcarbonyl, C1-C6 alkylaminoalkylcarbonyl, C1-C6 dialkylaminoalkylcarbonyl, C1-C6 alkyls Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, and Cy15 are absent or each occurrence is independently selected from 4-8 membered cycloalkylene, 4-8 membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-8 membered arylene, 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-13 membered spirocyclylene, or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 4-12 membered fused cyclylene or heterofused cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclylene or heterobridged cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; said 4-8 membered cycloalkylene, 4-8 membered heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-8 membered arylene, 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-13 membered spirocyclylene, or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 4-12 membered fused cyclylene or heterofused cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclylene or heterobridged cyclylene can be optionally substituted with 0, 1, 2, or 3 R a substituents; R L1 and R L2 Each occurrence is independently selected from single keys, C 2-6 imidene group, C 2-6 -ynyl group, -O-, -C(O)-, -S-, -OC 1-6 Alkylene-, -NR a -、-NR a -C(O)- and -NR a -C 1-6 alkylene-; ULM is an E3 ubiquitin ligase binding moiety; preferably, the ULM is a CRBN ligand binding moiety; preferably, it is selected from the following structures: wherein: W 1 and W 2 each independently is CR ab R bb or C(=O), and at least one of W 1 and W 2 is C(=O); W 11 is C(=O); R 20 is selected from N and CR1; Cy9, and Cy12are each independently at each occurrence selected from cycloalkylene, heterocyclylene, arylene, and heteroarylene, each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; L C1 each occurrence is independently selected from the group consisting of a single bond, -NR ab -C(O)-, -C(O)- and NR ab ; Cy13is selected from a 5-13 membered cycloalkylene or heterocycloalkylene group and a 4-12 membered fused or heterofused ring group, each independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo (=0), thioxo (=S), heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; G, Z, G1, G2, and Z1are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O), O, or S; B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 and W 41 each occurrence is independently CR m or N; C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; m1and m2are each independently 0, 1, 2, 3, 4, 5, or 6 at each occurrence, and m1+ m2≤ 6; m3, m71, and m51are each independently 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4, m81, and m61are 1, 2, 3, 4, 5, 6, 7, or 8, and m3+ m4≤ 8, m71+ m81≤ 8; m51+ m61≤ 8; m5and m6are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+ m6≤ 7; m7and m8are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+ m8≤ 7; m21, m31, and m41are each independently 0, 1, 2, or 3 at each occurrence, and m21+ m31+ m41≤ 3; R m and R 2h each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; preferably, R m and R 2h each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, 6-8 membered aryl, and 6-8 membered heteroaryl containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, wherein the C1-C6alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, 6-8 membered aryl, amino, and 6-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; R 1 , R 11 , and R N are each independently selected from hydrogen, halogen, deuterium, C1-C6alkyl, C1-C6alkoxy, hydroxyl, 3- to 7-membered cycloalkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; R 2m selected from a single bond, -NR ab -C(O)- and -NR ab -; R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl and Ci-C6-alkoxy; and n and n1are each independently 0, 1, 2, or 3; wherein when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46, Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46 is, respectively or, wherein: L is a bond or a chemical linking moiety connecting the ULM and the PTM; The PTM is selected from the following structures: wherein, R a7 , R a8 , R a9 each occurrence is independently selected from N or CR a ; R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 and R c8 are each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterium-substituted alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -O-cycloalkyl; R b5 and R b6 are single or double bonds; when R b5 and R b6 are connected by a single bond, R b5 and R b6 are each independently selected from NR a and C(R a )2; when R b5 and R b6 are connected by a double bond, R b5 and R b6 are each independently selected from N and CR a ; p1and p2are each independently selected from 0, 1, 2, and 3 at each occurrence; Ring A and Ring B are 4-8 membered saturated or unsaturated carbocyclic, 4-8 membered heterocyclic, 5-8 membered aromatic, or 5-8 membered heteroaromatic ring, each independently containing 1 or 2 heteroatoms optionally selected from N, O, S; Ring A and Ring B are unsubstituted or substituted with 1, 2, 3 substituents selected from halogen, oxo (=0), deuterium, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cycloalkyl, C1-C6 haloalkyl, hydroxyalkyl; Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, Cy15 are each independently absent or selected from 4-8 membered cycloalkylene, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-8 membered arylene, 5-8 membered heteroarylene, 5-13 membered spirocyclylene or heterospirocyclylene, 4-12 membered fused cyclylene or heterofused cyclylene, and 5-10 membered bridged cyclylene or heterobridged cyclylene; said 4-8 membered cycloalkylene, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-8 membered arylene, 5-8 membered heteroarylene, 5-13 membered spirocyclylene or heterospirocyclylene, 4-12 membered fused cyclylene or heterofused cyclylene, and 5-10 membered bridged cyclylene or heterobridged cyclylene can be optionally substituted with 0, 1, 2, 3 R a substituents; R L1 and R L2 each occurrence is independently selected from the group consisting of a single bond, alkenylene, alkynylene, -0-, -C(O)-, -S-, -O-C 1-6 alkylene-, -NR a -, -NR a -C(O)- and -NR a -C 1-6 alkylene-; ULM is an E3 ubiquitin ligase binding moiety; preferably, the ULM is a CRBN ligand binding moiety; preferably, it is selected from the following structures: wherein: W 1 and W 2 each independently is CR ab R bb or C(=O), and at least one of W 1 and W 2 is C(=O); W 11 is C(=O); R 20 is selected from N and CR1; Cy9, Cy12are each independently at each occurrence selected from cycloalkylene, heterocyclylene, arylene, and heteroarylene, each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; L C1 each occurrence is independently selected from the group consisting of a single bond, -NR ab -C(O)-, -C(O)- and NR ab ; Cy13is selected from 5-13 membered spirocyclylene or heterosprio cyclylene, and 4-12 membered fused cyclylene or heterofused cyclylene, each independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo (=0), thio (=S), heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; G, Z, G1, and Z1are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , B 4a , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O), O, or S; B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 and W 41 each occurrence is independently CR m or N; C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; m1and m2are each independently at each occurrence 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6; m3, m71, and m51are each independently at each occurrence 0, 1, 2, 3, 4, 5, 6, or 7, m4, m81, and m61are 1, 2, 3, 4, 5, 6, 7, or 8, and m3+ m4≤ 8, m71+ m81≤ 8; m51+ m61≤ 8; m5and m6are each independently at each occurrence an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5+ m6≤ 7; m7and m8are each independently at each occurrence an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+ m8≤ 7; m21, m31, and m41are each independently 0, 1, 2, or 3 at each occurrence, and m21+ m31+ m41≤ 3; R m each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; R 2h selected from hydrogen, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylacyl, alkyloxyacyl, and alkylaminoacyl; R 1 , R 11 , and R N are each independently selected from hydrogen, halogen, deuterium, C1-C6alkyl, C1-C6alkoxy, hydroxy, cycloalkyl, C1-C6haloalkyl, and hydroxyalkyl; R 2m selected from NR ab -C(O) and NR ab ; R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, C3-C6cycloalkyl and Ci-C6alkoxy; and n and n1are each independently 0, 1, 2, or 3; wherein when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46, Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46 is, respectively or, wherein: L is a bond or a chemical linking moiety connecting ULMand PTM; The PTM is selected from the following structures: wherein, R a7 , R a8 , R a9 each occurrence is independently selected from N or CR a ; R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8 are each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterium-substituted alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -O-cycloalkyl; R b5 and R b6 are single or double bonds; when R b5 and R b6 are connected by a single bond, R b5 and R b6 are each independently selected from NR a and C(R a )2; when R b5 and R b6 are connected by a double bond, R b5 and R b6 are each independently selected from N and CR a ; p1and p2are each independently at each occurrence selected from 0, 1, 2, and 3; Ring A and Ring B are 4-8 membered saturated or unsaturated carbocyclic, 4-8 membered heterocyclic, 5-8 membered aromatic, or 5-8 membered heteroaromatic ring, each independently containing 1 or 2 heteroatoms optionally selected from N, O, S; Ring A and Ring B are unsubstituted or substituted with 1, 2, 3 substituents selected from halogen, oxo (=0), deuterium, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cycloalkyl, C1-C6 haloalkyl, hydroxyalkyl; Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, Cy15 are each independently absent or selected from 4-8 membered cycloalkylene, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-8 membered arylene, 5-8 membered heteroarylene, 5-13 membered spirocyclylene or heterospirocyclylene, 4-12 membered fused cyclylene or heterofused cyclylene, and 5-10 membered bridged cyclylene or heterobridged cyclylene; said 4-8 membered cycloalkylene, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-8 membered arylene, 5-8 membered heteroarylene, 5-13 membered spirocyclylene or heterospirocyclylene, 4-12 membered fused cyclylene or heterofused cyclylene, and 5-10 membered bridged cyclylene or heterobridged cyclylene can be optionally substituted with 0, 1, 2, 3 R a substituents; R L1 and R L2 each occurrence is independently selected from the group consisting of a single bond, alkenylene, alkynylene, -0-, -C(O)-, -S-, -O-C 1-6 alkylene-, -NR a -, -NR a -C(O)- and -NR a -C 1-6 alkylene-; ULM is an E3 ubiquitin ligase binding moiety; preferably, the ULM is a CRBN ligand binding moiety; preferably, it is selected from the following structures: wherein: W 1 and W 2 each independently is CR ab R bb or C(=O), and W 1 and W 2 at least one of which is C(=O); W 11 is C(=O); R 20 is selected from N and CR1; Cy9, Cy12are each independently for each occurrence selected from the group consisting of cycloalkylene, heterocyclylene, arylene, and heteroarylene, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; L C1 each occurrence is independently selected from the group consisting of a single bond, -NR ab -C(O)-, -C(O)- and NR ab ; Cy13is selected from the group consisting of 5-13 membered spiro or heterospiro cyclylene and 4-12 membered fused or heterofused cyclylene, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, oxo (=0), thioxo (=S), heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; G, Z, G1, and Z1are each independently selected from the group consisting of O, S, and Se; R 1a , R 2a , R 3a , R 4a , R 5a , R3, R4, R5, R6, R7, R 3a , R 3b , R 3c , R 3d , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, amino, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; Preferably, R 1a R 2a R 3a R 4a R 5a R3, R4, R5, R6, R7, R 3a R 3b R 3c R 3d R 3a1 R 3b1 R 3c1 and R 3d1 Each of the following groups is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl groups; B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , B 4a , R 3a , R 4a , R 3b , R 4b , R 3A , R 4A , R 3B , R 4B , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O), O, or S; B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 , and W 41 each occurrence is independently CR m or N; C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; m1and m2are each independently for each occurrence an integer from 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6; m3, m71, and m51are each independently for each occurrence an integer from 0, 1, 2, 3, 4, 5, 6, or 7, m4, m81, and m61are an integer from 1, 2, 3, 4, 5, 6, 7, or 8, and m3+ m4≤ 8, m71+ m81≤ 8; m51+ m61≤ 8; m5and m6are each independently for each occurrence an integer from 0, 1, 2, 3, 4, 5, 6, or 7, and m5+ m6≤ 7; m7and m8are each independently for each occurrence an integer from 0, 1, 2, 3, 4, 5, 6, or 7, and m7+ m8≤ 7; m21, m31, and m41are each independently 0, 1, 2, or 3 at each occurrence, and m21+ m31+ m41≤ 3; R m each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; R 2h selected from hydrogen, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylacyl, alkyloxyacyl, and alkylaminoacyl; R 1 , R 11 , R 1s and R N are each independently selected from hydrogen, halogen, deuterium, C1-C6alkyl, C1-C6alkoxy, hydroxy, cycloalkyl, C1-C6haloalkyl and hydroxyalkyl; R 2m selected from NR ab -C(O) and NR ab ; R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, C3-C6cycloalkyl and Ci-C6alkoxy; and n and n1are each independently 0, 1, 2, or 3; wherein when PTM is Formula 1-4 or Formula 1-5, CLM is Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46, Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46 is, respectively or, wherein: the L is a bond or a chemical linking moiety connecting the ULM and the PTM; The PTM is selected from the following structures: wherein, R a7 , R a8 , R a9 each occurrence is independently selected from N or CR a ; R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , and R c8 are each independently selected from H, a deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -O-cycloalkyl; R b5 and R b6 are single or double bonds; when R b5 and R b6 are connected by a single bond, R b5 and R b6 are each independently selected from NR a and C(R a )2; when R b5 and R b6 are connected by a double bond, R b5 and R b6 are each independently selected from N and CR a ; p1and p2are each independently for each occurrence selected from the group consisting of 0, 1, 2, and 3; Ring A and Ring B are 4-8 membered saturated or unsaturated carbocyclic ring or heterocyclic ring containing 1, 2 heteroatoms optionally selected from N, O, S, 5-8 membered aromatic ring or heteroaromatic ring containing 1, 2 heteroatoms optionally selected from N, O, S; the Ring A and Ring B are unsubstituted or substituted with 1, 2, 3 substituents selected from halogen, oxo (=0), deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cycloalkyl, C1-C6 haloalkyl, hydroxyalkyl; Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, and Cy8 are absent or each occurrence is independently selected from 4-8 membered cycloalkylene, 4-8 membered heterocyclyl containing 1, 2, 3 N, O, S heteroatoms, 5-8 membered arylene, 5-8 membered heteroarylene, 5-13 membered spiro or heterospiro cyclyl, 4-12 membered fused or heterofused cyclyl, and 5-10 membered bridged or heterobridged cyclyl; said 4-8 membered cycloalkylene, 4-8 membered heterocyclyl containing 1, 2, 3 N, O, S heteroatoms, 5-8 membered arylene, 5-8 membered heteroarylene, 5-13 membered spiro or heterospiro cyclyl, 4-12 membered fused or heterofused cyclyl, and 5-10 membered bridged or heterobridged cyclyl can be optionally substituted with 0, 1, 2, 3 R a substituents; R L1 and R L2 each occurrence is independently selected from the group consisting of a single bond, alkenylene, alkynylene, -0-, -CO-, -S-, -O-C 1-6 alkylene-, -NR a -, -NR a -CO- and -NR a -C 1-6 alkylene-; The ULM is an E3 ubiquitin ligase binding moiety; preferably, the ULM is a CRBN ligand binding moiety; preferably, it is selected from any one of the following structures: wherein: W 1 and W 2 are each independently CR ab R bb or C(=O), and at least one of W 1 and W 2 is C(=O); W 11 selected from C(=O); G, Z, G1, and Z1are each independently selected from the group consisting of O, S, and Se; R 1a , R 2a , R 3a , R 4a , R 5a , R3, R4, R5, R6, R7, R 3a , R 3b , R 3c , R 3d , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently selected from H, a deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , B 4a , R 3a , R 4a , R 3b , R 4b , R 3A , R 4A , R 3B , R 4B , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O), O, or S; B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 , and W 41 each occurrence is independently CR m or N; C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; m1and m2are each independently for each occurrence an integer from 0, 1, 2, 3, 4, 5, or 6, and m1+ m2≤ 6; m3, m71, and m51are each independently for each occurrence an integer from 0, 1, 2, 3, 4, 5, 6, or 7, m4, m81, and m61are an integer from 1, 2, 3, 4, 5, 6, 7, or 8, and m3+ m4≤ 8, m71+ m81≤ 8; m51+ m61≤ 8; each occurrence of m5 and m6 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5+m6 < 7; each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+m8 < 7; m21, m31, and m41 are each independently 0, 1, 2, or 3 at each occurrence, and m21+ m31+ m41< 3; R m each occurrence is independently selected from the group consisting of H, a deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; R 2h H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylacyl, alkyloxyacyl, and alkylaminoacyl; R 1 , R 11 , R 1s and R N are each independently selected from H, halogen, deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxy, cycloalkyl, C1-C6haloalkyl and hydroxyalkyl; R 2m selected from -NR ab -CO- and NR ab ; R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of H, C1-C3alkyl, C3-C6cycloalkyl and C1-C6alkoxy; and each of n and n1 is independently 0, 1, 2, or 3; wherein when PTM is Formula 1-4 or Formula 1-5, CLM is not Formula 2-41, 2-42, 2-43, 2-44, 2-45, or 2-46. The compound of claim 14, wherein: R a R 11a R 12a R a2 R a3 R a4 R a5 R a6 R a10 R b1 R b2 R b3 R b4 R b7 R c1 R c2 R c3 R c4 R c5 R c6 R c7 and R c8 Each occurrence is independently selected from hydrogen, halogen, deuterium, cyano, and C. 1-6 Alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro, amino, carboxyl, hydroxyl, 3-7 membered heterocyclic alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3-6 membered cycloalkyl and -O-3-5 membered cycloalkyl; preferably, R a R 11a R 12a R a2 R a3 R a4 R a5 R a6 R b1 R b2 R b3 R b4 R b7 R c1 R c2 R c3 R c4 R c5 R c6 R c7 and R c8 Each occurrence is independently selected from hydrogen, F, Cl, Br, I, deuterium, cyano, and C. 1-6 Alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro, amino, carboxyl, hydroxyl, 3-7 membered heterocyclic alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3-6 membered cycloalkyl and -O-3-5 membered cycloalkyl; and / or R a10 selected from C 1-3 alkyl, 4-, 5- or 6-membered cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl containing one oxygen atom; preferably R a10 is 5-membered cycloalkyl; and / or each of ring A and ring B is a 5-6 membered saturated or unsaturated carbocyclic ring, a 5-6 membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, a 5-6 membered aromatic ring, or a 5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; and / or W 1 and W 2 each independently is CH2or C(=O), and W 1 and W 2 at least one of which is C(=O); and / or each of G, Z, G1, G2, and Z1 is O; and / or R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , and R 3d1 are each independently selected from hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxyl, C1-C6hydroxyalkyl, nitro, cyano, amino, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S, 6-8 membered aryl, and 6-8 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S, wherein the C1-C6alkyl, C2-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, 6-8 membered aryl, amino, and 6-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; preferably, R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , and R 3d1 are each independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, C1-C6haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C6hydroxyalkyl; more preferably, R 3a , R 3b , R 3c , R 3d , R 3e , R 3a1 , R 3b1 , R 3c1 , and R 3d1 each independently is selected from the group consisting of hydrogen, F, CI, Br, I, Ci-C3alkyl, Ci-C3alkoxy, hydroxyl, Ci-C3haloalkyl, Ci-C3haloalkoxy, -NH-Ci-C3alkyl, -NH-CO-Ci-C3alkyl, and Ci-C3hydroxyalkyl; and / or B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , B 4a , R 3a , R 4a , R 3b , R 4b , R 3A , R 4A , R 3B , R 4B , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O) or -O-; and / or B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 , and W 41 each occurrence is independently CR m or N; and / or C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; and / or R m , and R 2h each independently in each occurrence is selected from hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6halogenated alkyl, C1-C6halogenated alkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C6hydroxyalkyl; preferably, R m , and R 2h each independently in each occurrence is selected from hydrogen, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3halogenated alkyl, C1-C3halogenated alkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and C1-C3hydroxyalkyl; more preferably, R m , and R 2h each independently in each occurrence is selected from H, F, Cl, Br, I, C1-C3alkyl, C1-C3alkoxy, hydroxyl, C1-C3halogenated alkyl, and C1-C3hydroxyalkyl; R 1 , R 11 , and R N are each independently at each occurrence selected from H, F, CI, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; and / or R 2m -NH-C(O)-, -NH-, and -N(CH3)-; and / or R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of H, C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy; and / or each occurrence of m3, m71, and m51 is independently an integer of 0, 1, 2, 3, or 4, each of m4, m81, and m61 is an integer of 1, 2, 3, 4, or 5, and m3+m4 < 5, m71+m81 < 5, m51+m61 < 5; each occurrence of m3, m71, and m51 is independently an integer of 0, 1, 2, or 3, each of m4, m81, and m61 is an integer of 1, 2, 3, or 4, and m3+m4 = 2, m3+m4 = 3, m3+m4 = 4; m71+m81 = 2, m71+m81 = 3, m71+m81 = 4; m51+m61 = 2, m51+m61 = 3, m51+m61 = 4; and / or each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3, or 4, and m7+m8 < 4; each occurrence of m7 and m8 is independently an integer of 0, 1, 2, or 3, and m7+m8 = 2 or m7+m8 = 3; and / or Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, and Cy8are each independently absent or selected from 5-6 membered cycloalkylene, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from N and O, phenylene, 5-6 membered heteromonocyclic arylene containing 1 or 2 heteroatoms each independently selected from N and O, 7-11 membered spirocyclylene or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered fused cyclylene or heterofused cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclylene or heterobridged cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which 5-6 membered cycloalkylene, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from N and O, phenylene, 5-6 membered heteromonocyclic arylene containing 1 or 2 heteroatoms each independently selected from N and O, 7-11 membered spirocyclylene or heterospirocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered fused cyclylene or heterofused cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 5-10 membered bridged cyclylene or heterobridged cyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, can be optionally substituted with 0, 1, or 2 R a substituents; or, R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 and R c8 are each independently selected for each occurrence from hydrogen, halogen, deuterium, cyano, C 1-6 alkyl, C1-C6alkoxy, C1-C6haloalkoxy, nitro, amino, carboxyl, hydroxyl, C3-C6heterocycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C6cycloalkyl, and -O-C3-C5cycloalkyl; preferably, R a10 is selected from C5and C6cycloalkyl; preferably, R a10 is selected from C 1-3 alkyl, C4-C6cycloalkyl, C4-C6heterocycloalkyl containing one oxygen atom; and / or each of ring A and ring B is a 5-6 membered saturated or unsaturated carbocyclic ring, a 5-6 membered heterocyclic ring, a 5-6 membered aromatic ring, or a 5-6 membered heteroaromatic ring, each of the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring independently contains 1 or 2 heteroatoms optionally selected from N, O, and S; and / or W 1 and W 2 each independently is CH2or C(=O), and W 1 and W 2 at least one of which is C(=O); and / or each of G, Z, G1, and Z1 is O; and / or R 1a , R 2a , R 3a , R 4a , R 5a , R3, R4, R5, R6, R7, R 3a , R 3b , R 3c , R 3d , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, C1-C6haloalkyl, C1-C6haloalkoxy, -NH-C1-C3alkyl, -NH-CO-C1-C3alkyl, and hydroxyalkyl; and / or B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , B 4a , R 3a , R 4a , R 3b , R 4b , R 3A , R 4A , R 3B , R 4B , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O) or -O-; and / or B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 , and W 41 each occurrence is independently CR m or N; and / or C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; and / or R m , R 2h , R 1 , R 11 , R 1s , and R N are each independently at each occurrence selected from H, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, C1-C6haloalkyl, and hydroxyalkyl; and / or R 2m -NR ab -C(O)- and NR ab ; preferably R 2m is selected from -NH-C(O)-, -NH- and -N(CH3)-; and / or R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of H, C1-C3alkyl, C3-C6cycloalkyl and C1-C6alkoxy; and / or each occurrence of m3, m71, and m51 is independently an integer of 0, 1, 2, 3, or 4, each of m4, m81, and m61 is an integer of 1, 2, 3, 4, or 5, and m3+m4 < 5, m71+m81 < 5, m51+m61 < 5; each occurrence of m3, m71, and m51 is independently an integer of 0, 1, 2, or 3, each of m4, m81, and m61 is an integer of 1, 2, 3, or 4, and m3+m4 = 2, m3+m4 = 3, m3+m4 = 4; m71+m81 = 2, m71+m81 = 3, m71+m81 = 4; m51+m61 = 2, m51+m61 = 3, m51+m61 = 4; and / or each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3, or 4, and m7+m8 < 4; Preferably, m7and m8are each independently an integer of 0, 1, 2, or 3 at each occurrence, and m7+ m8= 2 or m7+ m8= 3; and / or Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8are each independently at each occurrence selected from 5-6 membered cycloalkylene, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O, 5-6 membered arylene, 5-6 membered heteroarylene, 7-11 membered spiro or heterospiro cyclylene, 6-10 membered fused or heterofused cyclylene, and 5-10 membered bridged or heterobridged cyclylene, said 5-6 membered cycloalkylene, 5-6 membered heterocyclyl containing 1, 2 N, O heteroatoms, 5-6 membered arylene, 5-6 membered heteroarylene, 7-11 membered spiro or heterospiro cyclylene, 6-10 membered fused or heterofused cyclylene, and 5-10 membered bridged or heterobridged cyclylene can be optionally substituted with 0, 1, 2 R a substituents; and / or n is 0 or 1; preferably n is 1; or, R a , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a10 , R b1 , R b2 , R b3 , R b4 , R b7 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 and R c8 are each independently selected from the group consisting of H, halogen, deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxy, cycloalkyl, C1-C6haloalkyl, hydroxyalkyl, C3-C6cycloalkyl and -O-C3-C5cycloalkyl; preferably, R a10 is selected from C5and C6cycloalkyl; and / or Ring A and Ring B are 5-6 membered saturated or unsaturated carbocyclic ring or heterocyclic ring containing 1, 2 heteroatoms optionally selected from N, O, S, 5-6 membered aromatic ring or heteroaromatic ring containing 1, 2 heteroatoms optionally selected from N, O, S; and / or W 1 and W 2 each independently is CH2or C(=O), and W 1 and W 2 at least one of which is C(=O); and / or G, Z, G1, and Z1are all O; and / or R 1a , R 2a , R 3a , R 4a , R 5a , R3, R4, R5, R6, R7, R 3a , R 3b , R 3c , R 3d , R 3a1 , R 3b1 , R 3c1 and R 3d1 are each independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, C1-C6haloalkyl, and hydroxyalkyl; and / or B 1a , B 2a , B 3a , B 6a , C 1a , C 2a , B 4a , R 3a , R 4a , R 3b , R 4b , R 3A , R 4A , R 3B , R 4B , R d , R e , R f , R g , R D , R E , R DD , R EE , R F , R G , R d1 , R e1 , R f1 , R g1 , R D1 , R E1 , R F1 , R G1 , and R N1 each independently at each occurrence is C(R m )2, NR m , C(=O), or O; and / or B 4a , B 5a , W 3a , W 4a , W 3 , W 4 , W 31 and W 41 each occurrence is independently CR m or N; and / or C 31 , R aa , R AA , R t , R T , R, R t1 and R T1 are each, independently for each occurrence, N or CR 2h ; and / or R m , R 2h , R 1 , R 11 , R 1s and R N are each independently at each occurrence selected from H, halogen, Ci-C6alkyl, Ci-C6alkoxy, hydroxy, Ci-C6haloalkyl, and hydroxyalkyl; and / or R 2m -NR ab -CO- and NR ab ; preferably, R 2m is selected from -NH-CO-, -NH- and -N(CH3)-; and / or R 2 , R 21 , R ab and R bb are each independently selected from the group consisting of H, C1-C3alkyl, C3-C6cycloalkyl and C1-C6alkoxy; and / or m3, m71, and m51are each independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4, m81, and m61are an integer of 1, 2, 3, 4, or 5, and m3+ m4≤ 5, m71+ m81≤ 5, m51+ m61≤ 5; preferably, m3, m71, and m51are each independently an integer of 0, 1, 2, or 3 at each occurrence, m4, m81, and m61are an integer of 1, 2, 3, or 4, and m3+ m4= 2, m3+ m4= 3, m3+ m4= 4; m71+ m81= 2, m71+ m81= 3, m71+ m81= 4; m51+ m61= 2, m51+ m61= 3, m51+ m61= 4; and / or m7and m8are each independently an integer of 0, 1, 2, 3, or 4 at each occurrence, and m7+ m8≤ 4; preferably, m7and m8are each independently an integer of 0, 1, 2, or 3 at each occurrence, and m7+ m8= 2 or m7+ m8= 3; and / or Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, and Cy8are each independently selected for each occurrence from 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1, 2 N, O heteroatoms, 5-6 membered arylene, 5-6 membered heteroarylene, 7-11 membered spiro or heterospiro cyclylene, 6-10 membered fused or heterofused cyclylene, and 5-10 membered bridged or heterobridged cyclylene, which 5-6 membered cycloalkylene, 5-6 membered heterocyclylene containing 1, 2 N, O heteroatoms, 5-6 membered arylene, 5-6 membered heteroarylene, 7-11 membered spiro or heterospiro cyclylene, 6-10 membered fused or heterofused cyclylene, and 5-10 membered bridged or heterobridged cyclylene can be optionally substituted with 0, 1, 2 R a substituents; and / or n is 0 or 1; preferably n is 1; and / or Cy9, and Cy12are each independently selected for each occurrence from 3-7 membered cycloalkylene, 3-7 membered heterocyclylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered arylene, and 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, each independently optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, 6-10 membered aryl, and 5-10 membered heteroaryl; Preferably, Cy9is selected at each occurrence from 6-10 membered arylene and 5-8 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, said 6-10 membered arylene and 5-8 membered heteroarylene being optionally substituted with one or more substituents selected from F, Cl, Br, I, a deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; and / or Cy12is selected at each occurrence from 5-8 membered cyclyl ene and 5-8 membered heterocyclyl ene, said 5-8 membered cyclyl ene and 5-8 membered heterocyclyl ene being optionally substituted with one or more substituents selected from F, Cl, Br, I, a deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; More preferably, Cy9is selected at each occurrence from phenylene and pyridylene, said phenylene and pyridylene being optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; and / or Cy12 appears each time as which is optionally substituted with one or more substituents selected from halogen, a deuterium atom, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; and / or Cy13is selected from 5-13 membered cycloalkylene or heterocycloalkylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-12 membered fused ring alkylene or heteroalkylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6alkyl, oxo (=0), thioxo (=S), C2-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, hydroxy, C1-C6hydroxyalkyl, cyano, amino, nitro, 3-7 cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-10 membered aryl, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; 2-6 alkenyl, C 2-6 alkynyl, C1-C6alkylamino, C1-C6alkylacyl, C1-C6alkyloxyacyl, C1-C6alkylaminoacyl, 6-10 membered aryl, and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; Preferably, Cy13 is selected from optionally substituted with one or more substituents selected from oxo (=0), thioxo (=S), F, Cl, Br, I, C1-C6alkyl, C1-C6alkoxy, hydroxyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl; and / or n is 0 or 1; preferably n is 1; Preferably: wherein L is a covalent bond or is -(B L ) q -, wherein B L a divalent linker selected from one or more of the following groups: -0-, -S-, -S(O)-, -S(0)2-, -CH2-, -C(O)-, -NH-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 7-azaspiro[3.5]nonane, 6-azaspiro[4.4]octane, 2-azaspiro[4.5]decane, 2-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecane, spiro[3.5]nonane, spiro[4.4]octane, spiro[4.5]decane, spiro[3.3]heptane, spiro[5.5]undecane, 2,5-diazabicyclo[2.2.2]octane, 2-oxa-4,9-diazaspiro[5.5]undecane, 3-azabicyclo[3.1.0]hexane, 1-oxa-8-azaspiro[4.5]decane, 4-azaspiro[2.5]octane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.2]octane, and phenylene, q number of B L are the same or different; wherein said divalent linker is optionally substituted with one or more groups selected from R L1 and R L2 ; Preferably, the bivalent linker is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, fluorosubstituted C1-C6alkoxy, C3-C6cycloalkyl, and 3- to 6-membered oxacycloalkyl; More preferably, the bivalent linker is substituted with 1, 2, 3, 4, or 5 substituents selected from fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, and oxetanyl; Preferably, B L Selected from one or more of the following structural fragments: -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -C(O)-, -NH-, q is 1, 2, 3, 4, 5, 6, 7, or 8; preferably, q is 1, 2, 3, 4, 5, or 6; and is a point of attachment; or, L is a covalent bond or is -(B L ) q -, B L each occurrence is selected independently from CR L1 R L2 , O, S, S(O), S(O)2, NR L1 , CONR L1 , C(O), cycloalkylene, heterocycloalkylene, hetero-partially unsaturated cycloalkylene, bridged cycloalkylene, hetero-bridged cycloalkylene, spirocycloalkylene, hetero-spirocycloalkylene, arylene, and hetero-arylene, wherein said cycloalkylene, heterocycloalkylene, hetero-partially unsaturated cycloalkylene, bridged cycloalkylene, hetero-bridged cycloalkylene, spirocycloalkylene, hetero-spirocycloalkylene, arylene, and hetero-arylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 groups selected from R L1 and R L2 ; Preferably, B L each independently selected from the group consisting of CR L1 R L2 , O, S, S(O), S(O)2, NR L1 , CONR L1 , C(O), 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenemonoheterocycloalkyl, 3-8 membered alkylenemonoheteropartially unsaturated cycloalkyl, 5-15 membered alkylenabicycloalkyl, 5-15 membered alkylenaspiroalkyl, 6-15 membered alkylenearomatic, and 5-15 membered alkylenaheteroaromatic, wherein said 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenemonoheterocycloalkyl, 3-8 membered alkylenemonoheteropartially unsaturated cycloalkyl, 5-15 membered alkylenabicycloalkyl, 5-15 membered alkylenaspiroalkyl, 6-15 membered alkylenearomatic, and 5-15 membered alkylenaheteroaromatic, are optionally substituted with 0, 1, 2, 3, or 4 groups selected from R L1 and R L2 ; said 3-8 membered alkylenemonoheterocycloalkyl, 3-8 membered alkylenemonoheteropartially unsaturated cycloalkyl, 5-15 membered alkylenaheterobicycloalkyl, 5-15 membered alkylenaheterospiroalkyl, and 5-15 membered alkylenaheteroaromatic, contain 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S; R L1 、and R L2 each independently at each occurrence is selected from hydrogen, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, -N(C 1-8 alkyl)2, 3-11 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-11 membered heterocycloalkyl, -O-3-8 membered cycloalkyl, -O-3-11 membered heterocyclyl, -O-6-10 membered aryl, -O-5-10 membered heteroaryl, -S-3-8 membered cycloalkyl, -NH-3-8 membered cycloalkyl, -N(3-8 membered cycloalkyl)2, -N(3-8 membered cycloalkyl)(C 1-8 alkyl), -NH-3-8 membered heterocyclyl, -N(3-8 membered heterocyclyl)2, -N(3-8 membered heterocyclyl)(C 1-8 alkyl), -NH-6-10 membered aryl, -N(6-10 membered aryl)(C 1-8 alkyl), -NH-5-10 membered heteroaryl, -N(5-10 membered heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, -SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)OH, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2H, -SF5, -S(O)2NH-C 1-8 alkyl, -S(O)2N(C 1-8 alkyl)2, -S(O)NH-C 1-8 alkyl, -S(O)N(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), -N(C) 1-8 alkyl)S(O)2N(C 1-8 alkyl)2、-NHS(O)2NH(C 1-8 Alkyl), -NHS(O)2N(C 1-8 Alkyl)2 and -NHS(O)2NH2, optionally, the C 1-8 Alkyl, 3-11 membered cycloalkyl, 3-11 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl are each independently selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, 6-10 membered aryl, 5-10 membered heteroaryl, and halogenated C 6-10 The aryl group is substituted with one or more substituents of a 5-10 halogenated heteroaryl group; Preferably, R L1 and R L2 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl groups, -C(O)OH, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, 3-6 membered cycloalkyl groups, and 3-6 membered heterocycloalkyl groups, wherein the alkyl group, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic alkyl groups are each independently selected from halogens, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 3-6 membered halocycloalkyl, 3-6 membered haloheteroalkyl, C 1-6 It is substituted by one or more substituents of alkylamino, 6-10 aryl, 5-10 heteroaryl, 6-10 haloaryl and 5-10 haloheteroaryl; q is an integer greater than or equal to 1; Preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Preferably, wherein L is selected from the following structures: Covalent bond, -C(O)-, -C(O)-(CH2) j -, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -C(O)-(CH2) s -, -(CH2) p -O-(CH2) s -, -(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -, -(CH2) y -O-(CH2) j -O-(CH2) s -, -(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -C(O)-(CH2) j -O-(CH2) s -, -(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -C(O)-(CH2) j -O-(CH2) s -NH-(CH2) p -, ; j, p, s, and y are each independently selected from 1, 2, 3, and 4; Preferably, L is selected from the following structures: a covalent bond, -C(O)-, -C(O)-CH2-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-, The compound of claim 14 or 15, wherein, Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8, Cy14, and Cy15 either do not exist or each occurrence is independently selected from 0, 1, 2, or 3 R's. a The following structures are replaced: wherein, m, n1, m’, and n’ are each independently 1 or 2; R a each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, cyano, nitro, carboxyl, C3-C5 cycloalkyl, -O-C3-C5 cycloalkyl, and amino. The following compounds: Preferably, the compound is selected from: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopic derivative, or polymorph thereof. a compound selected from the following structures: wherein R a , R L2 , R 11a , R 12a , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 and R L1 are each independently at each occurrence as defined in any one of claims 1 to 4; Cy 10 and Cy 11 each occurrence is selected independently from 4-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-8 membered aryl, 5-8 membered heteroaryl, 5-13 membered spirocyclic or heterosprio cyclic group, 4-12 membered fused cyclic or heterofused cyclic group, and 5-10 membered bridged cyclic or heterobridged cyclic group, said 4-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 6-8 membered aryl, 5-8 membered heteroaryl, 5-13 membered spirocyclic or heterosprio cyclic group, 4-12 membered fused cyclic or heterofused cyclic group, and 5-10 membered bridged cyclic or heterobridged cyclic group being optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1-6 alkyl, amino, hydroxyl, halo, oxo (=O), aldehyde, -O-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, and carboxyl; Preferably: R L2 is selected from a single bond, C2-C3alkynylene and C2-C3alkenylene; preferably, R L2 is selected from a single bond and alkynylene; and / or R a2 independently at each occurrence selected from H, F, CI, Br, I, cyano, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and cyano; preferably, R a2 independently at each occurrence selected from H, F, CI, Br, amino, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy; and / or R a7 , R a8 , and R a9 are each independently at each occurrence selected from CR a , preferably CH; and / or R a , R a3 , R a4 , R a5 , R a6 , R 11a and R 12a are each independently at each occurrence selected from the group consisting of H, F, CI, Br, I, cyano, hydroxy, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy and cyano; preferably R a , R a3 , R a4 , R a5 , R a6 , R 11a and R 12a are each independently at each occurrence selected from the group consisting of H, F, CI, Br, cyano, C1-C3alkyl and C1-C3alkoxy, more preferably H; and / or R a10 independently at each occurrence selected from C 1-3 alkyl, 4-6 membered cycloalkyl and 4-6 membered heterocycloalkyl containing one oxygen atom, preferably cyclopentyl; and / or R L1 is selected from a single bond, C2-C3alkynylene, C2-C3alkenylene, NH, O, CO, NH-C1-C3alkylene, and O-C1-C3alkylene; and / or Cy 10 independently selected at each occurrence from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O, phenyl, 5-6 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl; said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O, phenyl, 5-6 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, halo, oxo (=O), aldehyde, -O-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, and carboxyl; preferably, said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O, phenyl, 5-6 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl are optionally substituted with 0, 1, or 2 substituents independently selected from C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, halo, and oxo (=O); preferably, Cy 10 is independently selected at each occurrence from optionally substituted C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, halo, and oxo (=O); preferably, Cy and / or Cy 11 each occurrence is independently selected from NH2, 5-7 membered cycloalkyl, 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N and O, phenyl, 5-9 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl, optionally substituted with 0, 1, 2, 3, 4, 5, 6 substituents selected from C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, halo, oxo (=O), aldehyde, -O-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, and carboxyl; preferably, the 5-7 membered cycloalkyl, 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N and O, phenyl, 5-9 membered heteroaryl, 7-11 membered spirocyclyl or heterosprio cyclyl, 6-9 membered fused cyclyl or heterofused cyclyl, and 5-9 membered bridged cyclyl or heterobridged cyclyl is optionally substituted with 0, 1, or 2 substituents selected from C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, F, Cl, Br, carboxyl, aldehyde, and oxo (=O); preferably, Cy 11 is selected from NH2or optionally substituted with 0, 1, or 2 substituents selected from C 1-3 alkyl, -C(O)-C 1-3 alkyl, -C(O)O-C 1-4 alkyl, amino, hydroxyl, F, Cl, Br, carboxyl, aldehyde, and oxo (=O); preferably, Cy A compound according to claim 18 selected from any one of the following structures: The following compounds or pharmaceutically acceptable salts thereof: A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-20, and a pharmaceutically acceptable carrier. Use of a compound of any one of claims 1-20 or a pharmaceutical composition of claim 21 in the manufacture of a medicament for treating or preventing a disease or disorder mediated by SMARCA2 / 4; preferably, the disease or disorder is cancer; preferably, the cancer is lung cancer, cervical cancer, or melanoma; preferably, the lung cancer is alveolar cell carcinoma or non-small cell carcinoma. A compound of any one of claims 1-20 or a pharmaceutical composition of claim 21 for use in treating or preventing a disease or disorder mediated by SMARCA2 / 4; preferably, the disease or disorder is cancer; preferably, the cancer is lung cancer, cervical cancer, or melanoma; preferably, the lung cancer is alveolar cell carcinoma or non-small cell carcinoma. A method of treating or preventing a disease or disorder mediated by SMARCA2 / 4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-20 or a pharmaceutical composition of claim 21; preferably, the disease or disorder is cancer; preferably, the cancer is lung cancer, cervical cancer, or melanoma; preferably, the lung cancer is alveolar cell carcinoma or non-small cell carcinoma. Use of a compound according to any one of claims 18-20 for the manufacture of a medicament for the treatment or prevention of a disease or disorder treated by degrading a target protein to which a ligand binds, preferably the target protein is SMARCA2 / 4, preferably SMARCA2, or for the manufacture of a proteolysis targeting chimera or molecular glue compound.

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