WO2024192064A1

WO2024192064A1 - Compounds and compositions as smarca2/4 degraders and uses thereof

Info

Publication number: WO2024192064A1
Application number: PCT/US2024/019637
Authority: WO
Inventors: Zhenwu Li; Guozhang Xu; Lalgudi Harikrishnan; Shaomeng Wang; Lingying LENG; Lin Yang; Wenbin TU; Liyue HUANG; Rohan REJ; Weiguo XIANG; Zhixiang Chen; Mi Wang
Original assignee: Oncopia Therapeutics, Inc. D/B/A/ Proteovant Therapeutics, Inc.; Regents Of The University Of Michigan
Priority date: 2023-03-14
Filing date: 2024-03-13
Publication date: 2024-09-19

Abstract

Described herein are compounds of Formula I and their pharmaceutically acceptable salts, solvates, or stereoisomers, as well as their uses (e.g., as SMARCA2 or SMARCA4 degraders).

Description

COMPOUNDS AND COMPOSITIONS AS SMARCA2/4

DEGRADERS AND USES THEREOF

RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/598,442, filed November 13, 2023; U.S. Provisional Application No. 63/468,166, filed May 22, 2023; and U.S. Provisional Application No. 63/490,085, filed March 14, 2023, the contents of each of which are incorporated herein by reference in their entireties.

BACKGROUND

[0002] One of the most significant findings from the cancer genome profiling is the discovery of frequent mutations in various subunits of the mammalian SWI/SNF (SWItch/Sucrose Non- Fermentable) chromatin remodeling complex. Approximately 20% of human cancers are associated with somatic mutations in subunits of the SWI/SNF complex, a chromatin remodeling complex that influences gene regulation by disrupting histone-DNA contacts (PNAS February 25, 2014. Ill (8) 3128-3133).

[0003] SWI/SNF complexes contain either of two closely related and evolutionarily conserved catalytic ATPase subunits: Brahma (BRM/SMARCA2) or Brahma-related gene 1 (BRG1/SMARCA4). They share approximately 75% identity at the protein level. Although BRG1- and BRM-containing complexes show some redundancy, they may function distinctively. In human cancer, BRG1 seems to be one of the most frequently mutated subunit genes, whereas the BRM gene is rarely mutated. BRG1/SMARCA4 mutations occurring in 10-15% of lung adenocarcinomas. BRM/SMARCA2, is essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1 -deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me31.

[0004] In some tumor types, mutations within the SWI/SNF complex lead to context specific vulnerabilities such as the requirement of SMARCA2 for survival of tumor cells lacking SMARCA4. This finding of SMARCA2/4 synthetic lethal relationship translates in vivo which emphasizes SMARCA2 as a promising therapeutic target for the treatment SMARCA4-deficient cancers. Moreover, the SMARCA4-deficient patient population generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), which further emphasizes the potential of developing SMARC A2 inhibitors. Characterization of SMARCA4 function in tumors with high SMARCA4 levels, shows effects on signaling pathways that result in increased proliferation and survival. SMARC A4 knockdown in tumors that show elevated levels known to inhibit proliferation and other cancer cell properties. Studies have also shown that SMARCA4 knock down / modulation increases sensitivity to known chemotherapeutic agents, thereby indicating that SMARCA4 targeting could also be an adjuvant therapy to existing chemotherapeutic approaches. [0005] Contrary to genetic silencing of SMARCA2 leading to potent anti-proliferative activity in SMARCA4-deficient cancer cell lines, PFI-3, a selective cell permeable SMARC A2/4 bromodomain inhibitor capable of binding to SMARCA2 and SMARCA4 bromodomain, pharmacological studies fail to display an antiproliferative phenotype indicating that bromodomain function of SMARCA2/4 is dispensable for tumor cell proliferation, while the catalytic ATPase activity is essential. Therefore, in order to mimic the phenotype achieved by genetic silencing, approaches that lead to reduction or complete elimination of SMARCA2/4 may be needed.

[0006] The ubiquitin-proteasome system (UPS) is a major pathway that regulates the levels of intracellular proteins and provides a fine balance between protein synthesis and degradation required for normal maintenance of cellular function, including proliferation, differentiation, and cell death. Ubiquitination is a post-translational modification, where a small protein, ubiquitin, is covalently attached to lysine residues on a substrate protein carried out sequentially by a cascade of enzymatic reactions involving an intimate collaboration between El activating, E2 conjugating and E3 ligating enzymes and subsequent degradation of the tagged proteins.

[0007] Proteolysis targeting chimeras are the heterobifunctional molecules containing a ligand for a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase. Upon such bi-functional molecule-mediated heterodimerization of the two bound proteins, the target protein is ubiquitinated and degraded by the proteasome in cells. Many such bi-functional molecules have been developed to recruit E3 ubiquitin ligases to a variety of substrates using high-affinity ligands for the protein of interest. Proteins effectively degraded using these approaches include RIPK2 and ERRa, BRD4, BRD9, BCR/Abl and Abl and Era. E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. SUMMARY

[0008] In certain aspects, the present disclosure provides compounds of Formula I

T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: T is of Formula 1-1

L is of Formula 1-2

C is of Formula 1-3’

wherein each of the variables in Formulae 1-1, 1-2, and 1-3’ is described, embodied, and exemplified herein.

[0009] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.

[0010] In certain aspects, the present disclosure provides methods of degrading a SMARCA2 and/or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein.

[0011] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a SMARCA2 and/or SMARCA4 protein in a subject. [0012] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a SMARCA2 and/or SMARCA4 protein in a subject.

[0013] In certain aspects, the present disclosure provides methods of reducing the amount of a SMARCA2 and/or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject), comprising administering to the subject a compound disclosed herein.

[0014] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for reducing the amount of a SMARCA2 and/or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject). [0015] In certain aspects, the present disclosure provides compounds disclosed herein for use in reducing the amount of a SMARCA2 and/or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject).

[0016] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0017] In certain aspects, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0018] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0019] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0020] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0021] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder in a subject in need thereof.

DETAILED DESCRIPTION

[0022] The present disclosure relates to compounds and compositions that are useful as SMARCA2 and/or SMARCA4 protein degraders. The present disclosure also relates to methods of degrading a SMARCA2 and/or SMARCA4 protein comprising contacting the SMARCA2 and/or SMARCA4 protein with a SMARCA2 and/or SMARCA4 protein degrader disclosed herein. The invention also relates to methods of treating a SMARCA2 and/or SMARCA4 protein- mediated disease or condition in a subject in need thereof by administering (e.g., in a therapeutically effective amount) a SMARCA2 and/or SMARCA4 protein degrader disclosed herein. The invention further relates to methods of treating a SMARCA2 and/or SMARCA4 protein-mediated disease or condition in a subject in need thereof, comprising administering (e.g., in a therapeutically effective amount) a pharmaceutical composition comprising an amount of a SMARCA2 and/or SMARCA4 protein degrader disclosed herein. Compounds of the Application [0023] In certain aspects, the present disclosure provides compounds of Formula I T-L-C (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: T is of Formula I-1 1), wherein:

A¹ is CR^A1 or N; A² is CR^A2 or N; A³ is CR^A3 or N; A⁴ is CR^A4 or N; R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two R^C together form an oxo; or two R^C, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-

ocycle; each R^D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- ₁₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; d is an integer selected from 0 to 10, as valency permits; E¹ is CR^E1 or N; E² is CR^E2 or N; E³ is CR^E3 or N; E⁴ is CR^E4 or N; one of R^E2, R^E3, or R^E4 is R^E1, R^E2, and R^E4, R^E1, R^E3, and R independently hydrogen, halogen, -

CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, - NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, - OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; * denotes attachment to L; Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle; each R^F is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and f is an integer selected from 0 to 10, as valency permits; or R^E1, R^E2, R^E3, and R^E4 are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes

L is of Formula I-2 I 2), wherein:

* denotes attachment to T, and ** denotes attachment to C; each L^ is independently C_1-6 alkylene, C_1-6 heteroalkylene, C_2-6 alkenylene, C_2-6 alkynylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u; each occurrence of R^{L^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and l is an integer selected from 0 to 5, C is of Formula I-3^ ^), wherein:

H² is N or CR^H2; H³ is N or CR^H3; H⁴ is N or CR^H4; H⁵ is N or CR^H5; one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, wherein Ring G is optionally substituted C_5- 12 carbocycle or 5- to 16-membered heterocycle; when one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, then the remaining R^H4 and R^H5, R^H2 and R^H5, or R^H2 and R^H3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is ; denotes attachment to L; denotes an optional covalent bond between H¹ and J¹; i) when the bond between H¹ and J¹ is present: r is 1; H¹ is C; J¹ is -C(R^J1)₂- or -C(=O)-; each R^J1 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; or two R^J1, together with the carbon atom to which they are attached, form C3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u; and J² is N; ii) when the bond between H¹ and J¹ is absent: r is 0 or 1; H¹ is N or CR^H1; R^H1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2- 6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; J¹ is absent; or J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; J² is absent, N, or O; wherein i) when J² is N, then J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when J² is absent or O, then J¹ is absent; K¹ is N or CR^K1; R^K1 is hydrogen, deuterium, or C1-6 alkyl optionally substituted with one or more R^u; q is an integer from 0 to 2, each R^K is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and k is an integer selected from 0 to 5, wherein: each R^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R^u, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^z; each R^a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each R^c and R^d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and each R^z is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0024] In certain embodiments, the present disclosure provides compounds of Formula I T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: T is of Formula I-1 wherein: A¹ is CR^A1 or N; A² is CR^A2 or N;

A³ is CR^A3 or N; A⁴ is CR^A4 or N; R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^C is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two R^C together form an oxo; or two R^C, together with the carbon atom to which they are attached, form Ring D Ring D is C3-12 carbocycle or 3- to 1 le; each R^D is independently oxo, ha

ogen, - , - ₂, - H, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; d is an integer selected from 0 to 10, as valency permits; E¹ is CR^E1 or N; E² is CR^E2 or N; E³ is CR^E3 or N; E⁴ is CR^E4 or N; one of R^E2, R^E3, or R^E4 is R^E1, R^E2, and R^E4, R^E1, R^E3, and R^E

³ are independently hydrogen, halogen, - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, - NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, - OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; * denotes attachment to L; Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle; each R^F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and f is an integer selected from 0 to 10, as valency permits, L is of Formula I-2 2), wherein:

* denotes attachment to T and ** denotes attachment to C; each L^ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u; each occurrence of R^{L^} is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and l is an integer selected from 0 to 5, C is of Formula I-3 wherein: H² is N or CR^H2; H³ is N or CR^H3;

H⁴ is N or CR^H4; H⁵ is N or CR^H5; one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted C5-12 carbocycle or 5- to 16-membered heterocycle; and when one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G attached to L, then R^H4 and R^H5, R^H2 and R^H5, or R^H2 and R^H3, respectively, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is ; denotes atta

denotes an optional covalent bond between H¹ and J¹; i) when the bond between H¹ and J¹ is present: r is 1; H¹ is C; J¹ is -C(R^J1)2- or -C(=O)-; each R^J1 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; or two R^J1, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u; and J² is N; ii) when the bond between H¹ and J¹ is absent: r is 0 or 1; H¹ is N or CR^H1; R^H1 is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2- 6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; J¹ is absent; or J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; J² is absent, N, or O; wherein i) when J² is N, then J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when J² is absent or O, then J¹ is absent; R^K1 is hydrogen, deuterium, or C1-6 alkyl optionally substituted with one or more R^u; q is an integer from 0 to 2, each R^K is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and k is an integer selected from 0 to 5, wherein: each R^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R^u, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^z; each R^a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; each R^b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and each R^z is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0025] In certain embodiments, T is of Formula I-1 1), wherein:

A¹ is CR^A1 or N; A² is CR^A2 or N; A³ is CR^A3 or N; A⁴ is CR^A4 or N; R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^C is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two R^C together form an oxo; or two R^C, together with the carbon atom to which they are attached, form Ring D ; Ring D is C_3-12 carbocycle or 3- to 12-

ocycle; each R^D is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; d is an integer selected from 0 to 10, as valency permits; E¹ is CR^E1 or N; E² is CR^E2 or N; E³ is CR^E3 or N; E⁴ is CR^E4 or N; one of R^E2, R^E3, and R^E4 is R^E2, R^E3, and R^E4, R^E1, R^E2, and R^E4, or

R , R , and R^E4 are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, - NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, - OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; * denotes attachment to L; Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle; each R^F is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and f is an integer selected from 0 to 10, as valency permits. [0026] In certain embodiments, T is of Formula I-1-i or I-1-ii ii). [0027] In cert

, I-1-ii-2, or I-1- ii-3

[0028] In certain embodiments, T is of Formula I-l-i-4, I-l-i-5, I-l-i-6, I-l-ii-4, or I-l-ii-5, or I- l-ii-6

wherein:

R^A1 is halogen.

[0029] In certain embodiments, T is of Formula I-l-i-7, I-l-i-8, I-l-i-9, I-l-ii-7, or I-l-ii-8, or I- l-ii-9

[0030] In certain embodiments, T is of Formula I-l-i-1, 1-l-i-2, I-l-i-3, 1-l-ii-1, I-l-ii-2, I-l-ii- 3, I-l-i-7, I-l-i-8, 1-l-i-9, 1-l-ii-7, or Ll-ii-8, or I-l-ii-9

wherein R^A1 is halogen.

[0032] In certain embodiments, T is of Formula I-l-i-4, I-l-i-5, I-l-i-6, I-l-ii-4, or I-l-ii-5, 1-1- ii-6, I-l-i-10, I-l-i-11, I-l-i-12, 1-l-ii-10, 1-l-ii-11, or I-l-ii-12

2), wherein

[0033] In certain embodiments, A¹ is CR^A1 or N. In certain embodiments, A¹ is N. In certain embodiments, A¹ is CR^A1. [0034] In certain embodiments, A² is CR^A2 or N. In certain embodiments, A² is N. In certain embodiments, A² is CR^A2. [0035] In certain embodiments, A³ is CR^A3 or N. In certain embodiments, A³ is N. In certain embodiments, A³ is CR^A3. [0036] In certain embodiments, A⁴ is CR^A4 or N. In certain embodiments, A⁴ is N. In certain embodiments, A⁴ is CR^A4. [0037] In certain embodiments, none of A¹, A², A³, and A⁴ is N. In certain embodiments, one of A¹, A², A³, and A⁴ is N. In certain embodiments, two of A¹, A², A³, and A⁴ are N. In certain embodiments, three of A¹, A², A³, and A⁴ are N. In certain embodiments, each of A¹, A², A³, and A⁴ is N. [0038] In certain embodiments, R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), n-propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, - NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, - OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0039] In certain embodiments, R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0040] In certain embodiments, R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0041] In certain embodiments, R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0042] In certain embodiments, R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0043] In certain embodiments, R^A1 is hydrogen. In certain embodiments, R^A1 is halogen. In certain embodiments, R^A2 is hydrogen. In certain embodiments, R^A3 is hydrogen. In certain embodiments, R^A4 is hydrogen. [0044] In certain embodiments, each R^C is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), n-propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t- butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, - NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, - OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0045] In certain embodiments, each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0046] In certain embodiments, each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0047] In certain embodiments, each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0048] In certain embodiments, each R^C is independently hydrogen, halogen, -CN, -NO₂, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0049] In certain embodiments, each R^C is independently C1-6 alkyl optionally substituted with one or more R^u. In certain embodiments, at least one R^C is C1-6 alkyl optionally substituted with one or more R^u. [0050] In certain embodiments, two R^C together form an oxo. [0051] In certain embodiments, two R^C, together with the carbon atom to which they are attached, form Ring D . [0052] In certain embodiments, Ring

cycle (e.g., cyclopropyl (C3), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)) or3- to 12-membered heterocycle (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). [0053] In certain embodiments, Ring D is cyclopentane ring, cyclohexane ring, or tetrahydropyran ring. [0054] In certain embodiments, each R^D is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0055] In certain embodiments, each R^D is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0056] In certain embodiments, each R^D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C₆ aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0057] In certain embodiments, each R^D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0058] In certain embodiments, each R^D is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0059] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5. In certain embodiments, d is 6. In certain embodiments, d is 7. In certain embodiments, d is 8. In certain embodiments, d is 9. In certain embodiments, d is 10. [0060] In certain embodiments, E¹ is CR^E1 or N. In certain embodiments, E¹ is N. In certain embodiments, E¹ is CR^E1. [0061] In certain embodiments, E² is CR^E2 or N. In certain embodiments, E² is N. In certain embodiments, E² is CR^E2. [0062] In certain embodiments, E³ is CR^E3 or N. In certain embodiments, E³ is N. In certain embodiments, E³ is CR^E3. [0063] In certain embodiments, E⁴ is CR^E4 or N. In certain embodiments, E⁴ is N. In certain embodiments, E⁴ is CR^E4. [0064] In certain embodiments, none of E¹, E², E³, and E⁴ is N. In certain embodiments, one of E¹, E², E³, and E⁴ is N. In certain embodiments, two of E¹, E², E³, and E⁴ are N. In certain embodiments, three of E¹, E², E³, and E⁴ are N. In certain embodiments, each of E¹, E², E³, and E⁴ is N. [0065] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), n-propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, - NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, - OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0066] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0067] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0068] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0069] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0070] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently , hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), n-propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i- butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, - NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, - OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes attachment to L. [0071] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently ,hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6

nyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and

denotes attachment to L. [0072] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently ,hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes attachment to L. [0073] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently ,hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes attachment to L. [0074] In certain embodiments, R^E1, R^E2, R^E3, and R^E4 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes attachment to L. [0075] In certain embodiments, R^E1 is hydrogen. In certain embodiments, R^E2 is hydrogen. In certain embodiments, R^E3 is hydrogen. In certain embodiments, R^E4 is hydrogen. [0076] In certain embodiments, R^E1 is . In certain embodiments, R^E2 is . In certain embodiments, R^E3 is . In certain embodiments, R^E4 is . [0077] In certain embodiments, one of R^E2, R^E3, or R^E4 is [0078] In certain embodiments, Rin

yl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)) or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). [0079] In certain embodiments, Ring F is piperidinyl, 2,7-diazaspiro[3.5]nonanyl, or 3,9- diazaspiro[5.5]undecanyl. [0080] In certain embodiments, each R^F is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0081] In certain embodiments, each R^F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0082] In certain embodiments, each R^F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C₆ aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0083] In certain embodiments, each R^F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0084] In certain embodiments, each R^F is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0085] In certain embodiments, f is 0. In certain embodiments, f is 1. In certain embodiments, f is 2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5. In certain embodiments, f is 6. In certain embodiments, f is 7. In certain embodiments, f is 8. In certain embodiments, f is 9. In certain embodiments, f is 10. [0086] In certain embodiments, L is of Formula I-2 2), wherein:

* denotes attachment to T, and ** denotes attachment to C; each L^ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -O-, -S-, or -S(=O)₂-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u; each occurrence of R^{L^} is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, - S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and l is an integer selected from 0 to 5. [0087] In certain embodiments, each L^{^} is independently C_1-6 alkylene (e.g., methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (-CH₂CH₂CH₂-), butylene (-CH₂CH₂CH₂CH₂-), pentylene (- CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-)), C1-6 heteroalkylene (e.g., C1- 6 alkylene comprising 1-7 heteroatoms selected from N, O, and S), C2-6 alkenylene (e.g., ethenylene (C₂), 1-propenylene (C₃), 2-propenylene (C₃), 1-butenylene (C₄), 2-butenylene (C₄), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C2-6 alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1-butynylene (C4), 2-butynylene (C4), pentynylene (C₅), or hexynylene (C₆)), C_3-12 carbocyclylene (e.g., cyclopropylene (C₃), cyclopropenylene (C₃), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C₇), cycloheptadienylene (C₇), cycloheptatrienylene (C₇), cyclooctylene (C₈), cyclooctenylene (C₈), bicyclo[2.2.1]heptanylene (C₇), bicyclo[2.2.2]octanylene (C₈), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C10), cyclodecenylene (C10), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C10), or spiro[4.5]decanylene (C10)), 3- to 12-membered heterocyclylene (e.g., heterocyclylene comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)-, -N(R^L2)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u. [0088] In certain embodiments, each L^{^} is independently C_1-6 alkylene, C_1-6 heteroalkylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})- , or -O-, wherein the alkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u. [0089] In certain embodiments, each L^ is independently C1-6 alkylene, C1-6 heteroalkylene, 5- to 10-membered heteroarylene, C_6-10 arylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -S(=O)2-, or -O-, wherein the alkylene, heteroalkylene, heteroarylene, arylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u. [0090] In certain embodiments, each occurrence of R^{L^} is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0091] In certain embodiments, each occurrence of R^{L^} is independently hydrogen, C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- membered heteroaryl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0092] In certain embodiments, each occurrence of R^{L^} is independently hydrogen, C_1-6 alkyl, C_2- ₆ alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)₂R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0093] In certain embodiments, each occurrence of R^{L^} is independently hydrogen, C1-6 alkyl, C3- ₆ carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0094] In certain embodiments, each occurrence of R^{L^} is hydrogen. [0095] In certain embodiments, l is 0. In certain embodiments, l is 1. In certain embodiments, l is 2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is an integer selected from 1 to 4. [0096] In certain embodiments, L is C_1-12 alkylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -N(R^{L^})-, or -O-, wherein the alkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u. [0097] In certain embodiments, L is -O-(C_1-6 alkylene)-, -(C_1-6 alkylene)-O-, -N(R^{L^})-(C_1-6 alkylene)-, -(C1-6 alkylene)-N(R^{L^})-, -C(=O)-(C1-6 alkylene)-, -(C1-6 alkylene)-C(=O)-, -C(=O)-(3- to 12-membered heterocyclylene)-, -(3- to 12-membered heterocyclylene)-C(=O)-, -(3- to 12- membered heterocyclylene)-(C_1-6 alkylene)-, -(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, -(C1-6 alkylene)-(3- to 12-membered carbocyclylene)-, or -(3- to 12-membered carbocyclylene)-(C1-6 alkylene)-, wherein the alkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u. [0098] In certain embodiments, L is absent, -C(=O)-, C_1-12 alkylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(5- to 10- membered heteroarylene)-, *-(C1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C1-6 alkylene)-(C_3-12 carbocyclylene)-(5- to 10-membered heteroarylene)-, *-(C_3-12 carbocyclylene)- (C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-, *-(C1- 6 alkylene)-(C6-10 arylene)-C(=O)-, *-(C1-6 alkylene)-O-C(=O)-, *-(3- to 12-membered heterocyclylene)-S(=O)₂-, *-(C_1-6 alkylene)-S(=O)₂-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)- C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-N(R^{L^})-, *-(3- to 12- membered heterocyclylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)- C(=O)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(C_1-6 alkylene)-, *-(3- to 12- membered heterocyclylene)-(C1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C3-12 carbocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(C6-10 arylene)-(C_1-6 alkylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-C(=O)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12- membered heterocyclylene)-, C1-12 alkylene, 3- to 12-membered heterocyclylene, *-C1-12 alkylene- N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-, *-C(=O)-(C_3-12 carbocyclylene)-(C1-6 alkylene)-, *-C(=O)-(3- to 12-membered heterocyclylene)-(3- to 12- membered heterocyclylene)-, *-C(=O)-(C3-12 carbocyclylene)-N(R^{L^})-, *-C(=O)-(C1-6 alkylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-C_1-6 alkylene-C(=O)-(3- to 12- membered heterocyclylene)-, *-C1-6 alkylene-C(=O)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-, *- (C3-12 carbocyclylene)-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-(5- to 10- membered heteroarylene)-, or *-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, wherein each alkylene, heterocyclylene, heteroarylene, arylene, and carbocyclylene is independently optionally substituted with one or more R^u, and *denotes attachment to T. [0099] In certain embodiments, L is -(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, -(3- to 12-membered carbocyclylene)-(C_1-6 alkylene)-(3- to 12- membered carbocyclylene)-, -(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(3- to 12- membered carbocyclylene)-, -(3- to 12-membered carbocyclylene)-(C1-6 alkylene)-(3- to 12- membered heterocyclylene)-, -(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-, -(C1-6 alkylene)-(3- to 12-membered carbocyclylene)-(C1-6 alkylene)-, -(C1-6 alkylene)- (3- to 12-membered heterocyclylene)-(C(=O))-, -(C(=O))-(3- to 12-membered heterocyclylene)- (C_1-6 alkylene)-, -(C_1-6 alkylene)-(3- to 12-membered carbocyclylene)-(C(=O))-, -(C(=O))-(3- to 12-membered carbocyclylene)-(C1-6 alkylene)-, -(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(C(=O))-, -(C(=O))-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, -(3- to 12- membered carbocyclylene)-(C_1-6 alkylene)-(C(=O))-, -(C(=O))-(C_1-6 alkylene)-(3- to 12- membered carbocyclylene)-, -(C_1-6 alkylene)-(C(=O))-(3- to 12-membered heterocyclylene)-, or - (3- to 12-membered heterocyclylene)-(C(=O))-(C_1-6 alkylene)-, -(C_1-6 alkylene)-(C(=O))-(3- to 12- membered carbocyclylene)-, -(3- to 12-membered carbocyclylene)-(C(=O))-(C1-6 alkylene)-, -(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(3- to 12-membered carbocyclylene), -(3- to 12- membered heterocyclylene)-C(=O)-(3- to 12-membered carbocyclylene), -(3- to 12-membered heterocyclylene)-O-(3- to 12-membered carbocyclylene), -(3- to 12-membered heterocyclylene)- N(R^{L^})-(3- to 12-membered carbocyclylene), -(3- to 12-membered carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene), -(3- to 12-membered carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), -(3- to 12-membered carbocyclylene)-O-(3- to 12-membered heterocyclylene), or -(3- to 12-membered carbocyclylene)-N(R^{L^})-(3- to 12-membered heterocyclylene), wherein the alkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u. [0100] In certain embodiments, L is C1-12 alkylene, 3- to 12-membered heterocyclylene, *-C1-12 alkylene-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-, *-C(=O)-(C_3-12 carbocyclylene)-(C1-6 alkylene)-, *-C(=O)-(3- to 12-membered heterocyclylene)-(3- to 12- membered heterocyclylene)-, *-C(=O)-(C3-12 carbocyclylene)-N(R^{L^})-, *-C(=O)-(C1-6 alkylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-C_1-6 alkylene-C(=O)-(3- to 12- membered heterocyclylene)-, *-C1-6 alkylene-C(=O)-, *-(C3-12 carbocyclylene)-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-, or *-(C3-12 carbocyclylene)-(C1-6 alkylene)-, wherein the alkylene, heterocyclylene, or carbocyclylene is optionally substituted with one or more R^u, and *denotes attachment to T. [0101] In certain embodiments, L is C1-12 alkylene, *-(C1-6 alkylene)-(C3-12 carbocyclylene)- C(=O)-(3- to 12-membered heterocyclylene), *-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, or *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-.In certain embodiments, L is absent, -C(=O)-, C1-12 alkylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C_1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(5- to 10-membered heteroarylene)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-, *-(C1-6 alkylene)-(C6-10 arylene)-C(=O)-, *-(C_1-6 alkylene)-C(=O)-, *-(C_1-6 alkylene)-O-C(=O)-, *-C(=O)-(C_1-6 alkylene)-, *-C(=O)-(C_3-12 carbocyclylene)-NH-, *-C(=O)-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, *-C(=O)- (3- to 12-membered heterocyclylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12- membered heterocyclylene)-S(=O)2-, *-(C1-6 alkylene)-S(=O)2-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C3-12 carbocyclylene)-NH-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-, *-(C1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)- (C3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)- C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-NH-, *- (C1-6 alkylene)-(C3-12 carbocyclylene)-NH-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-NH-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)- (C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(C1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C_3-12 carbocyclylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(C6-10 arylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-C(=O)-, *-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-(5- to 10-membered heteroarylene)-, or *- (C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, wherein each alkylene, heterocyclylene, heteroarylene, arylene, and carbocyclylene is independently optionally substituted with one or more R^u. [0102] In certain embodiments, C is of Formula I-3^ ^), wherein:

H² is N or CR^H2; H³ is N or CR^H3; H⁴ is N or CR^H4; H⁵ is N or CR^H5; one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, wherein Ring G is optionally substituted C5- 12 carbocycle or 5- to 16-membered heterocycle; when one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, then the remaining R^H4 and R^H5, R^H2 and R^H5, or R^H2 and R^H3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is ;

denotes attachment to L; denotes an optional covalent bond between H¹ and J¹; i) when the bond between H¹ and J¹ is present: r is 1; H¹ is C; J¹ is -C(R^J1)2- or -C(=O)-; each R^J1 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; or two R^J1, together with the carbon atom to which they are attached, form C3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u; and J² is N; ii) when the bond between H¹ and J¹ is absent: r is 0 or 1; H¹ is N or CR^H1; R^H1 is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2- ₆ alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; J¹ is absent; or J¹ is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; J² is absent, N, or O; wherein i) when J² is N, then J¹ is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when J² is absent or O, then J¹ is absent; K¹ is N or CR^K1; R^K1 is hydrogen, deuterium, or C_1-6 alkyl optionally substituted with one or more R^u; q is an integer from 0 to 2, each R^K is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and k is an integer selected from 0 to 5. [0103] In certain embodiments, C is of Formula I-3 3), wherein: 2^H2

H is N or CR ; H³ is N or CR^H3; H⁴ is N or CR^H4; H⁵ is N or CR^H5; one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted C5-12 carbocycle or 5- to 16-membered heterocycle; and when one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G attached to L, then R^H4 and R^H5, R^H2 and R^H5, or R^H2 and R^H3, respectively, are independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is ; denotes attachment to L;

denotes an optional covalent bond between H¹ and J¹;

i) when the bond between H¹ and J¹ is present: r is 1; H¹ is C; J¹ is -C(R^J1)2- or -C(=O)-; each R^J1 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; or two R^J1, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u; and J² is N; ii) when the bond between H¹ and J¹ is absent: r is 0 or 1; H¹ is N or CR^H1; R^H1 is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2- 6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; J¹ is absent; or J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; J² is absent, N, or O; wherein i) when J² is N, then J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when J² is absent or O, then J¹ is absent; R^K1 is hydrogen, deuterium, or C1-6 alkyl optionally substituted with one or more R^u; q is an integer from 0 to 2, each R^K is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and k is an integer selected from 0 to 5. [0104] In certain embodiments, the bond between H¹ and J¹ is present. [0105] In certain embodiments, when the bond between H¹ and J¹ is present, J² is N, H¹ is C, and r is 1. [0106] In certain embodiments, C is of Formula I-3^-i i). [0107] In certain embodimen

3^-ii). [0108] In certain embodime

i). [0109] In certain embodimen

, 3-ii). [0110] In certain embodime

[0111] In certain embodiments, J¹ is absent. In certain embodiments, J¹ is hydrogen, C_1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), -S(=O)2R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0112] In certain embodiments, each R^J1 is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t- butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0113] In certain embodiments, each R^J1 is hydrogen. [0114] In certain embodiments, two R^J1, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u. [0115] In certain embodiments, the bond between H¹ and J¹ is absent. [0116] In certain embodiments, when the bond between H¹ and J¹ is absent, H¹ is N or CR^H1. [0117] In certain embodiments, R^H1 is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, - OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i- butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0118] In certain embodiments, R^H1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0119] In certain embodiments, R^H1 is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0120] In certain embodiments, R^H1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0121] In certain embodiments, when the bond between H¹ and J¹ is absent, r is 0 or 1. [0122] In certain embodiments, when the bond between H¹ and J¹ is absent, J¹ is absent, hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0123] In certain embodiments, when the bond between H¹ and J¹ is absent, J² is absent, N, or O. [0124] In certain embodiments, when J² is N, then J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0125] In certain embodiments, when J² is O, then J¹ is absent. [0126] In certain embodiments, J² is N and r is 0. [0127] In certain embodiments, J² is N and r is 1. [0128] In certain embodiments, J² is absent and r is 0. [0129] In certain embodiments, C is of Formula I-3^-iii 3^-iii). [0130] In certain embodiments,

3^-iv). [0131] In certain embodime

H O^N _O 3-iii). [0132] In certain embodiments,

3-iv). [0133] In certain embodim

embodiments, H² is N. In certain embodiments, H² is CR^H2. [0134] In certain embodiments, H³ is N or CR^H3. In certain embodiments, H³ is N. In certain embodiments, H³ is CR^H3. [0135] In certain embodiments, H⁴ is N or CR^H4. In certain embodiments, H² is N. In certain embodiments, H⁴ is CR^H4. [0136] In certain embodiments, H⁵ is N or CR^H5. In certain embodiments, H² is N. In certain embodiments, H⁵ is CR^H5. [0137] In certain embodiments, one of H², H³, H⁴, and H⁵ is N. In certain embodiments, two of H², H³, H⁴, and H⁵ are N. [0138] In certain embodiments, R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, - NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, - OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0139] In certain embodiments, R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 nyl, C2-6 alkynyl, C3-12

carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0140] In certain embodiments, R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-

enyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0141] In certain embodiments, R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6

enyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0142] In certain embodiments, R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0143] In certain embodiments, one of R^H2, R^H3, and R^H4 is ; R^H1, R^H5, and the other two of R^H2, R^H3, and R^H4 are independently hydrogen, halogen, -

CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0144] In certain embodiments, R^H3 is , R^H1 and R^H5 are independently halogen, and each of R^H2 and R^H4 is hydrogen. [0145] In certain embodiments, R^H2 and R^H3, R^H3 and R^H4, or R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted C_5-12 carbocycle or 5- to 16-membered heterocycle. [0146] In certain embodiments, one of R^H2 and R^H3, R^H3 and R^H4, or R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted C_5-12 carbocycle or 5- to 16-membered heterocycle. [0147] In certain embodiments, R^H2 and R^H3, together with the carbon atoms to which they are bonded, form Ring G attached to L. [0148] In certain embodiments, R^H3 and R^H4, together with the carbon atoms to which they are bonded, form Ring G attached to L. [0149] In certain embodiments, Ring G is optionally substituted 7- to 16-membered spiro heterocycle (e.g., heterocyclyl comprising two 4- to 8-membered spiro rings and 1-5 heteroatoms selected from N, O, and S). [0150] In certain embodiments, Ring G is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10- membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, - NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, - NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, - OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0151] In certain embodiments, Ring G is optionally substituted with one or more R^u, R^G1, R^{G1^}, R^G2, or R^{G2^}. [0152] In certain embodiments, R^u is R^G1. In certain embodiments, R^u is R^{G1^}. In certain embodiments, R^u is R^G2. In certain embodiments, R^u is R^{G2^}. [0153] In certain embodiments, Ring G is: , wherein:

** denotes attachment to L; Ring G^II is C4-8 carbocycle or 4- to 8-membered heterocycle; each G¹ is independently -C(R^G1)2-, -NR^{G1^}-, -O-, -S-, -S(=O)-, or -S(=O)2-; each G² is independently -C(R^G2)₂-, -NR^{G2^}-, -O-, -S-, -S(=O)-, or -S(=O)₂-; each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two geminal R^G1 or two geminal R^G2 together form oxo; or two geminal R^G1 or two geminal R^G2, together with the carbon atom to which they are attached, form C_3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more R^u; each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; g' and g'' are independently an integer selected from 0-3, wherein g' and g'' are not both 0; each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- ₁₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits. [0154] In certain embodiments, Ring G is: 1) . .

, cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), or bicyclo[2.2.2]octanyl (C₈)) or 3- to 8-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). [0157] In certain embodiments, each G¹ is independently -C(R^G1)₂-, -NR^{G1^}-, -O-, -S-, -S(=O)-, or -S(=O)2-. In certain embodiments, each G¹ is independently -C(R^G1)2-, -NR^{G1^}-, or -O-. [0158] In certain embodiments, each G² is independently -C(R^G2)2-, -NR^{G2^}-, -O-, -S-, -S(=O)-, or -S(=O)₂-. In certain embodiments, each G² is independently -C(R^G2)₂-, -NR^{G2^}-, or -O-. [0159] In certain embodiments, each occurrence of R^G1 and R^G2 is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, - NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, - OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0160] In certain embodiments, each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0161] In certain embodiments, each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0162] In certain embodiments, each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0163] In certain embodiments, each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0164] In certain embodiments, each occurrence of R^G1 and R^G2 is hydrogen. [0165] In certain embodiments, two geminal R^G1 or two geminal R^G2 together form oxo. [0166] In certain embodiments, two geminal R^G1 or two geminal R^G2, together with the carbon atom to which they are attached, form C_3-6 carbocycle (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more R^u. [0167] In certain embodiments, each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C_1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0168] In certain embodiments, each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- membered heteroaryl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0169] In certain embodiments, each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)₂R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0170] In certain embodiments, each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C_1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0171] In certain embodiments, each occurrence of R^{G1^} and R^{G2^} is independently hydrogen or C_1- 6 alkyl. In certain embodiments, each occurrence of R^{G1^} and R^{G2^} is hydrogen. [0172] In certain embodiments, g' is 0. In certain embodiments, g' is 1. In certain embodiments, g' is 2. In certain embodiments, g' is 3. [0173] In certain embodiments, g'' is 0. In certain embodiments, g'' is 1. In certain embodiments, g'' is 2. In certain embodiments, g'' is 3. [0174] In certain embodiments, g' and g'' are not both 0. [0175] In certain embodiments, each R^G is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0176] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0177] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0178] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0179] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0180] In certain embodiments, g is 0. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4, as valency permits. In certain embodiments, g is 5, as valency permits. In certain embodiments, g is 6, as valency permits. In certain embodiments, g is 7, as valency permits. In certain embodiments, g is 0. In certain embodiments, g is 8, as valency permits. [0181] In certain embodiments, R^G may be present on either Ring G^I or Ring G^II. [0182] In certain embodiments, Ring G is optionally substituted 7- to 16-membered fused heterocycle (e.g., heterocyclyl comprising two 4- to 8-membered fused rings and 1-5 heteroatoms selected from N, O, and S). [0183] In certain embodiments, Ring G is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10- membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, - NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, - NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, - OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0184] In certain embodiments, Ring G is optionally substituted with one or more R^u, R^Gx, or R^N. [0185] In certain embodiments, R^u is R^Gx. In certain embodiments, R^u is R^N. [0186] In certain embodiments, Ring G is , wherein:

Ring G^III and Ring G^IV are independently C_4-8 carbocycle or 4- to 8-membered heterocycle; wherein at least one of Ring G^III and Ring G^IV is 4- to 8-membered heterocycle; G³ and G⁴ are independently C, CR^Gx, or N; R^Gx is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits, wherein R^A may be present on either Ring G^III or Ring G^IV. [0187] In certain embodiments, Ring G^III and Ring G^IV are independently C4-8 carbocycle (e.g., cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), or cyclooctenyl (C₈)) or 4- to 8-membered heterocyclyl (e.g., heterocyclyl comprising one or two 4- to 8-membered rings and 1-3 heteroatoms selected from N, O, and S). [0188] In certain embodiments, G³ and G⁴ are independently C, CR^Gx, or N. [0189] In certain embodiments, R^Gx is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i- propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n- butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n- butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t- butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0190] In certain embodiments, R^Gx is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0191] In certain embodiments, R^Gx is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0192] In certain embodiments, R^Gx is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0193] In certain embodiments, each R^G is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0194] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0195] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0196] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0197] In certain embodiments, each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0198] In certain embodiments, g is 0. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4, as valency permits. In certain embodiments, g is 5, as valency permits. In certain embodiments, g is 6, as valency permits. In certain embodiments, g is 7, as valency permits. In certain embodiments, g is 8, as valency permits. [0199] In certain embodiments, Ring G is . [02

propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), - S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0201] In certain embodiments, R^N is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, 5- to 6-membered heteroaryl, -S(=O)₂R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0202] In certain embodiments, R^N is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0203] In certain embodiments, R^N is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0204] In certain embodiments, K¹ is N or CR^K1. In certain embodiments, K¹ is N. In certain embodiments, K¹ is CR^K1. [0205] In certain embodiments, R^K1 is hydrogen, deuterium, or C_1-6 alkyl (e.g., methyl (C₁), ethyl (C₂), n-propyl (C₃), i-propyl (C₃), n-butyl (C₄), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C6)) optionally substituted with one or more R^u. [0206] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0207] In certain embodiments, each R^K is independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, - NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C₄), s-butyl (C₄), t-butyl (C₄), pentyl (C₅), or hexyl (C₆)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i- butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C_2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0208] In certain embodiments, each R^K is independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0209] In certain embodiments, each R^K is independently halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0210] In certain embodiments, each R^K is independently halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R^u. [0211] In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is 5. [0212] In certain embodiments, each R^a is independently C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C₆)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2- butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0213] In certain embodiments, each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3- 6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0214] In certain embodiments, each R^a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- ₆ carbocyclyl, or 3- to 6-membered heterocyclyl. [0215] In certain embodiments, each R^a is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0216] In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl (e.g., methyl (C₁), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C₁₀)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0217] In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0218] In certain embodiments, each R^b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0219] In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. [0220] In certain embodiments, each R^c and each R^d is independently hydrogen, C_1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0221] In certain embodiments, each R^c and each R^d is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more R^u. [0222] In certain embodiments, R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more R^u. [0223] In certain embodiments, R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z. [0224] In certain embodiments, R^z is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0225] In certain embodiments, each R^u is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di- i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n- butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t- butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0226] In certain embodiments, each R^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0227] In certain embodiments, each R^u is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0228] In certain embodiments, each R^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, - CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0229] In certain embodiments, each R^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0230] In certain embodiments, two R^u, together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6- membered ring and 1-3 heteroatoms selected from N, O, and S), C6 aryl (i.e., phenyl), or 5- to 6- membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^z. [0231] In certain embodiments, two R^u, together with the carbon atom(s) to which they are attached, form C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^z. [0232] In certain embodiments, two geminal R^u, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^z. [0233] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I-1, I-2, and I-3, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, are also contemplated. [0234] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. For example, while various options for variables G¹ and G² are described herein, the disclosure may be interpreted as excluding structures for non-operable compounds caused by certain combinations of the options (e.g., when two adjacent G¹ or G² are both nitrogen or both oxygen; or one of the two adjacent G¹ or G² is nitrogen while the other is oxygen). [0235] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, ^C_1-6 alkyl^ is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1- 6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0236] In certain embodiments, the compound is selected from the compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

Table 1.

* denotes that the compound is racemic at the glutarimide position.

100

101

102

104

105

106

107

112

113

114

115

117

118

119

120

121

123

124

126

128

131

132

133

134

136

Table 2.

* denotes that the compound is racemic at the glutarimide position.

146

147

149

162

165

166

[0237] The compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known SMARCA2/4 degraders. For example, the compounds of the present disclosure may display more SMARCA2/4 activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, T_max, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure may be measured according to methods commonly available in the art, such as methods exemplified herein.

[0238] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration.

[0239] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate.

Pharmaceutically acceptable salts

[0240] In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0241] In certain embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0242] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6- dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0243] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3- phenylpropionic acid, tri methyl acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0244] In certain embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(CI-4 alkyl)4, and the like.

[0245] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

Solvates

[0246] “ Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the disclosure may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solutionphase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0247] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the disclosure.

[0248] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present disclosure.

[0249] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0250] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Isomers (stereoisomers, geometric isomer, tautomer, etc.)

[0251] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0252] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture” or “racemate”.

[0253] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0254] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)- compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0255] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)- compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0256] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)- compound in such compositions can, for example, comprise, at least about 95% by weight (R)- compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0257] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0258] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure.

[0259] In certain embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure.

[0260] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.

Tautomers

[0261] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0262] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Pharmaceutical Compositions

[0263] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)).

[0264] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0265] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0266] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0267] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

Preparation and Characterization of the Compounds

[0268] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g, a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and/or synthesis described herein (e.g., Examples). General Synthetic Method Scheme 1.

[0269] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0270] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0271] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modem Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527- 29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0272] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Analytical Methods, Materials, and Instrumentation

[0273] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Broker or Varian spectrometers at 400 MHz. Spectra are given in ppm (8) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS- 2020EV or Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C18 2.7 μm 4.6 X 100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL/min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min. Biological Assays [0274] The biological activities of the compounds of the present application can be assessed with methods and assays known in the art. [0275] In certain embodiments, protein degradation is measured using HiBiT Assay. For example, Hela cells are genetically modified via CRISPR/Cas9 to fuse HiBiT to the carboxy terminus of SMARCA2 (Promega CS302365) or SMARCA4 (Promega CS3023225). Cells are cultured and subsequently treated with serial dilutions of test compounds. Levels of SMARCA2 or SMARCA4 expression are assessed with Nano-Glo® HiBiT Lytic Detection Assay (Promega N3050). IC50 is obtained using the GraphPad Prism data analysis software. Methods of Use [0276] In certain aspects, the present disclosure provides methods of degrading a SMARCA2 and/or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein. [0277] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a SMARCA2 and/or SMARCA4 protein in a subject. [0278] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a SMARCA2 and/or SMARCA4 protein in a subject. [0279] In certain aspects, the present disclosure provides methods of reducing the amount of a SMARCA2 and/or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject), comprising administering to the subject a compound disclosed herein. [0280] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for reducing the amount of a SMARCA2 and/or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject). [0281] In certain aspects, the present disclosure provides compounds disclosed herein for use in reducing the amount of a SMARCA2 and/or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject). [0282] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount). [0283] In certain aspects, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount). [0284] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0285] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof. [0286] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. [0287] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder in a subject in need thereof. [0288] In certain embodiments, the disease or disorder is a SMARCA2 and/or SMARCA4 protein- mediated disease or disorder. [0289] In certain embodiments, the disease or disorder is cancer. [0290] In certain embodiments, the cancer is non-small cell lung cancer, small-cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.

[0291] In certain embodiments, the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).

[0292] In certain embodiments, the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC).

[0293] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers of Table A.

Table A.

[0294] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

Table B.

[0295] In certain embodiments, the subject is a mammal.

[0296] In certain embodiments, the subject is a human.

Definitions

[0297] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

Chemical Definitions

[0298] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

[0299] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). [0300] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0301] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, ^C_1-6 alkyl^ is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0302] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term ^substituted^ is to be defined as set out below. It should be further understood that the terms ^groups^ and ^radicals^ can be considered interchangeable when used herein. The articles ^a^ and ^an^ may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example ^an analogue^ means one analogue or more than one analogue. [0303] ^Alkyl^ as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (^C1-20 alkyl^). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (^C_1-12 alkyl^). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (^C_1-10 alkyl^). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (^C1-9 alkyl^). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (^C1-8 alkyl^). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (^C1-7 alkyl^). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (^C_1-6 alkyl^, which is also referred to herein as ^lower alkyl^). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (^C1-5 alkyl^). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (^C1-4 alkyl^). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (^C_1-3 alkyl^). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (^C1-2 alkyl^). In certain embodiments, an alkyl group has 1 carbon atom (^C1 alkyl^). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), n-pentyl (C₅), 3- pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an ^unsubstituted alkyl^) or substituted (a ^substituted alkyl^) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10 alkyl. Common alkyl abbreviations include Me (-CH₃), Et (-CH₂CH₃), i-Pr (-CH(CH₃)₂), n-Pr (-CH₂CH₂CH₃), n-Bu (-CH₂CH₂CH₂CH₃), or i-Bu (-CH2CH(CH3)2). [0304] ^Alkylene^ as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular ^alkylene^ group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An ^alkylene^ group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (- CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, - C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, - CH₂CH₂CH(CH₃)-, -C(CH₃)₂CH₂CH₂-, -CH₂C(CH3)₂CH₂-, -CH₂CH₂C(CH₃)₂-), and the like. [0305] ^Alkenyl^ as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (^C_2-20 alkenyl^). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (^C2- 10 alkenyl^). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (^C2-9 alkenyl^). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (^C_2-8 alkenyl^). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (^C2-7 alkenyl^). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (^C2-6 alkenyl^). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (^C_2-5 alkenyl^). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (^C_2-4 alkenyl^). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (^C_2-3 alkenyl^). In certain embodiments, an alkenyl group has 2 carbon atoms (^C₂ alkenyl^). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an ^unsubstituted alkenyl^) or substituted (a ^substituted alkenyl^) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C_2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C_2-10 alkenyl. [0306] ^Alkenylene^ as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular ^alkenylene^ group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An ^alkenylene^ group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH₃)=CH-, -CH=C(CH₃)-), substituted propylene (e.g., -C(CH₃)=CHCH₂-, - CH=C(CH₃)CH₂-, -CH=CHCH(CH₃)-, -CH=CHC(CH₃)₂-, -CH(CH₃)-CH=CH-,-C(CH₃)₂- CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. [0307] ^Alkynyl^ as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (^C2-20 alkynyl^). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (^C2-10 alkynyl^). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (^C2-9 alkynyl^). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (^C2-8 alkynyl^). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (^C_2-7 alkynyl^). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (^C_2-6 alkynyl^). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (^C_2-5 alkynyl^). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (^C2-4 alkynyl^). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (^C2-3 alkynyl^). In certain embodiments, an alkynyl group has 2 carbon atoms (^C₂ alkynyl^). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an ^unsubstituted alkynyl^) or substituted (a ^substituted alkynyl^) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2- 10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl. [0308] ^Alkynylene^ as used herein, refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular ^alkynylene^ group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An ^alkynylene^ group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. [0309] The term ^heteroalkyl,^ as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (^heteroC_1-10 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (^heteroC1-9 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (^heteroC_1-8 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (^heteroC_1-7 alkyl^). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (^heteroC1-6 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (^heteroC1-5 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (^heteroC1-4 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (^heteroC1-3 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (^heteroC_1-2 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (^heteroC1 alkyl^). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (^heteroC_2-6 alkyl^). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an ^unsubstituted heteroalkyl^) or substituted (a ^substituted heteroalkyl^) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC_1-10 alkyl. [0310] The term ^heteroalkenyl,^ as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (^heteroC_2-10 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (^heteroC2-9 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (^heteroC_2-8 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (^heteroC2-7 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (^heteroC_2-6 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (^heteroC2-5 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (^heteroC_2-4 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (^heteroC_2-3 alkenyl^). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (^heteroC2-6 alkenyl^). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an ^unsubstituted heteroalkenyl^) or substituted (a ^substituted heteroalkenyl^) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl. [0311] The term ^heteroalkynyl,^ as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (^heteroC2-10 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (^heteroC2-9 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (^heteroC2-8 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (^heteroC2-7 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (^heteroC2-6 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (^heteroC_2-5 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (^heteroC2-4 alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (^heteroC2- ₃ alkynyl^). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (^heteroC2-6 alkynyl^). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an ^unsubstituted heteroalkynyl^) or substituted (a ^substituted heteroalkynyl^) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl. [0312] Analogous to ^alkylene,^ ^alkenylene,^ and ^alkynylene^ as defined above, ^heteroalkylene,^ ^heteroalkenylene,^ and ^heteroalkynylene,^ as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular ^heteroalkylene,^ ^heteroalkenylene,^ or ^heteroalkynylene,^ group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. ^Heteroalkylene,^ ^heteroalkenylene,^ and ^heteroalkynylene^ groups may be substituted or unsubstituted with one or more substituents as described herein. [0313] ^Aryl^ refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (^C6-14 aryl^). In some embodiments, an aryl group has six ring carbon atoms (^C₆ aryl^; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (^C₁₀ aryl^; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (^C14 aryl^; e.g., anthracyl). [0314] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an ^unsubstituted aryl^) or substituted (a ^substituted aryl^) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14 aryl. In certain embodiments, the aryl group is substituted C6-14 aryl. [0315] ^Arylene^ as used herein, refers to an aryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular ^arylene^ group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An ^arylene^ group may be substituted or unsubstituted with one or more substituents as described herein. [0316] ^Heteroaryl^ refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0317] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0318] In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6- membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

[0319] Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0320] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0321] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl^). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (^C_5-10 carbocyclyl^). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (^C5-8 carbocyclyl^). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (^C5-6 carbocyclyl^). Exemplary C_3-6 carbocyclyl include, without limitation, cyclopropyl (C₃), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C_3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C_3-10 carbocyclyl include, without limitation, the aforementioned C_3-8 carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. [0322] In certain embodiments, ^carbocyclyl^ is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (^C_3-12 carbocyclyl^). In certain embodiments, ^carbocyclyl^ is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (^C3-10 carbocyclyl^). In certain embodiments, ^carbocyclyl^ is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (^C_3-8 carbocyclyl^). In certain embodiments, ^carbocyclyl^ is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (^C3-6 carbocyclyl^). In certain embodiments, ^carbocyclyl^ is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (^C_5-12 carbocyclyl^). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (^C_5-10 carbocyclyl^). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (^C5-8 carbocyclyl^). In certain embodiments, ^carbocyclyl^ is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (^C5-6 carbocyclyl^). Examples of C_5-6 carbocyclyl include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C_3-6 carbocyclyl include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an ^unsubstituted carbocyclyl^) or substituted (a ^substituted carbocyclyl^) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C_3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C_3-12 carbocyclyl. [0323] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (^monocyclic carbocyclyl^) or polycyclic (^polycyclic carbocyclyl^) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an ^unsubstituted carbocyclyl^) or substituted (a ^substituted carbocyclyl^) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C_3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3- 12 carbocyclyl. [0324] ^Fused carbocyclyl^ or ^fused carbocycle^ refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0325] ^Spiro carbocyclyl^ or ^spiro carbocycle^ refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded. [0326] ^Bridged carbocyclyl^ or ^bridged carbocycle^ refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded. [0327] ^Carbocyclylene^ as used herein, refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the carbocycle group. When a range or number of carbons is provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.

[0328] “Heterocyclyl” refers to a radical of a 3 - to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0329] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12- membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6- membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0330] As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl. [0331] ^Fused heterocyclyl^ or ^fused heterocycle^ refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0332] ^Spiro heterocyclyl^ or ^spiro heterocycle^ refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. [0333] ^Bridged heterocyclyl^ or ^bridged heterocycle^ refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. [0334] ^Heterocyclylene^ as used herein, refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocycle group. When a range or number of ring members is provided for a particular ^heterocyclylene^ group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A ^heterocyclylene^ group may be substituted or unsubstituted with one or more substituents as described herein. [0335] ^Alkoxy^ as used herein, refers to the group -OR, wherein R is alkyl as defined herein. C1- ₆ alkoxy refers to the group -OR, wherein each R is C_1-6 alkyl, as defined herein. Exemplary C_1-6 alkyl is set forth above. [0336] ^Alkylamino^ as used herein, refers to the group -NHR or -NR₂, wherein each R is independently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. [0337] ^Oxo^ refers to =O. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical. [0338] ^Halo^ or ^halogen^ refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [0339] ^Protecting group^ as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl- protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid- protecting groups, respectively. [0340] Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-iso- propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)). [0341] Common types of amino-protecting groups include but not limited to carbamates (e.g., t- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g., benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2-nitrophenylsulfenyl (Nps)). [0342] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)). [0343] Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline. [0344] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions [0345] ^Pharmaceutically acceptable^ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0346] ^Pharmaceutically acceptable salt^ refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0347] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0348] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylactically effective amount” refers to the effective amount for prophylactic treatment.

[0349] ‘ ‘Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).

[0350] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0351] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. Tn yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0352] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, or 5% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, or 3% of the stated number or numerical range.

[0353] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0354] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0355] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0356] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0357] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

[0358] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0359] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed.

EXEMPLARY EMBODIMENTS

Exemplary Embodiment 1. A compound of Formula I

T-L-C (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

T is of Formula 1-1

wherein:

A¹ is CR^A1 or N;

A² is CR^A2 or N;

A³ is CR^A3 or N;

A⁴ is CR^A4 or N; R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- ₁₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two R^C together form an oxo; or two R^C, together with the carbon atom to which they are attached, form Ring D ; Ring D is C_3-12 carbocycle or 3- to 12-m

embered eterocycle; each R^D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; d is an integer selected from 0 to 10, as valency permits; E¹ is CR^E1 or N; E² is CR^E2 or N; E³ is CR^E3 or N; E⁴ is CR^E4 or N; one of R^E2, R^E3, or R^E4 is ; R^E1, R^E2, and R^E4, R^E1, R^E3, and R^E4, or R^E3 are independently hydrogen, halogen, -

CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, - NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, - OS(=O)2R^a, -OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; * denotes attachment to L; Ring F is C_3-12 carbocyclyl or 3- to 12-membered heterocycle; each R^F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and f is an integer selected from 0 to 10, as valency permits; or R^E1, R^E2, R^E3, and R^E4 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes

L is of Formula I-2 2), wherein:

* denotes attachment to T, and ** denotes attachment to C; each L^ is independently C_1-6 alkylene, C_1-6 heteroalkylene, C_2-6 alkenylene, C_2-6 alkynylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -O-, -S-, or -S(=O)₂-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u; each occurrence of R^{L^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and l is an integer selected from 0 to 5, C is of Formula I-3^ ^), wherein: 2^H2

H is N or CR ; H³ is N or CR^H3; H⁴ is N or CR^H4; H⁵ is N or CR^H5; one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, wherein Ring G is optionally substituted C5- 12 carbocycle or 5- to 16-membered heterocycle; when one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, then the remaining R^H4 and R^H5, R^H2 and R^H5, or R^H2 and R^H3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is ; denotes atta

denotes an optional covalent bond between H¹ and J¹; i) when the bond between H¹ and J¹ is present: r is 1; H¹ is C; J¹ is -C(R^J1)2- or -C(=O)-; each R^J1 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; or two R^J1, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u; and J² is N; ii) when the bond between H¹ and J¹ is absent: r is 0 or 1; H¹ is N or CR^H1; R^H1 is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2- 6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; J¹ is absent; or J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; J² is absent, N, or O; wherein i) when J² is N, then J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when J² is absent or O, then J¹ is absent; K¹ is N or CR^K1; R^K1 is hydrogen, deuterium, or C_1-6 alkyl optionally substituted with one or more R^u; q is an integer from 0 to 2, each R^K is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and k is an integer selected from 0 to 5, wherein: each R^u is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R^u, together with the one or more intervening atoms, form C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^z; each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each R^b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; and each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and each R^z is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. Exemplary Embodiment 2. The compound of any one of the preceding exemplary embodiments, wherein T is of Formula I-1-i or I-1-ii ii), wherein each

, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 3. The compound of any one of the preceding exemplary embodiments, wherein T is of Formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-ii-1, I-1-ii-2, I-1-ii-3, I-1-i-7, I-1-i-8, I-1-i-9, I-1-ii-7, or I-1-ii-8, or I-1-ii-9

-9), wherein alkyl, C1-6

alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 4. The compound of any one of the preceding exemplary embodiments, wherein R^A1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- ₁₀ aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 5. The compound of any one of the preceding exemplary embodiments, wherein R^A1 is halogen. Exemplary Embodiment 6. The compound of any one of the preceding exemplary embodiments, wherein T is of Formula I-1-i-4, I-1-i-5, I-1-i-6, I-1-ii-4, or I-1-ii-5, I-1-ii-6, I-1-i- 10, I-1-i-11, I-1-i-12, I-1-ii-10, I-1-ii-11, or I-1-ii-12

2), wherei

each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and R^A1 is halogen. Exemplary Embodiment 7. The compound of any one of the preceding exemplary embodiments, wherein Ring F is 4- to 6-membered heterocycle or C4-6 carbocycle. Exemplary Embodiment 8. The compound of any one of the preceding exemplary embodiments, wherein each R^F is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 9. The compound of any one of the preceding exemplary embodiments, wherein f is 0. Exemplary Embodiment 10. The compound of any one of the preceding exemplary embodiments, wherein R^E1, R^E2, and R^E4, R^E1, R^E3, and R^E4, or R^E1, R^E2, and R^E3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 11. The compound of any one of the preceding exemplary embodiments, wherein each of R^E1, R^E2, and R^E4, each of R^E1, R^E3, and R^E4, or each of R^E1, R^E2, and R^E3 is hydrogen. Exemplary Embodiment 12. The compound of any one of the preceding exemplary embodiments, wherein one or two of E¹, E², and E⁴, one or two of E¹, E³, and E⁴, or one or two of E¹, E², and E³ are N. Exemplary Embodiment 13. The compound of any one of the preceding exemplary embodiments, wherein one or two of R^E1, R^E2, and R^E4, one or two of R^E1, R^E3, and R^E4, or one or two of R^E1, R^E2, and R^E3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 14. The compound of any one of the preceding exemplary embodiments, wherein one or two of R^E1, R^E2, and R^E4, one or two of R^E1, R^E3, and R^E4, or one or two of R^E1, R^E2, and R^E3 are hydrogen. Exemplary Embodiment 15. The compound of any one of the preceding exemplary embodiments, wherein each of R^A2, R^A3, and R^A4 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 16. The compound of any one of the preceding exemplary embodiments, wherein each of R^A2, R^A3, and R^A4 is hydrogen. Exemplary Embodiment 17. The compound of any one of the preceding exemplary embodiments, wherein Ring D is C3-12 carbocycle. Exemplary Embodiment 18. The compound of any one of the preceding exemplary embodiments, wherein Ring D is C_5-7 carbocycle. Exemplary Embodiment 19. The compound of any one of the preceding exemplary embodiments, wherein Ring D is 3- to 12-membered heterocycle. Exemplary Embodiment 20. The compound of any one of the preceding exemplary embodiments, wherein Ring D is 5- to 7-membered heterocycle. Exemplary Embodiment 21. The compound of any one of the preceding exemplary embodiments, wherein each R^D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 22. The compound of any one of the preceding exemplary embodiments, wherein d is 0. Exemplary Embodiment 23. The compound of any one of the preceding exemplary embodiments, wherein each R^C is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 24. The compound of any one of the preceding exemplary embodiments, wherein at least one R^C is C_1-6 alkyl. Exemplary Embodiment 25. The compound of any one of the preceding exemplary embodiments, wherein each of R^C is C1-6 alkyl. Exemplary Embodiment 26. The compound of any one of the preceding exemplary embodiments, wherein each L^ is independently C_1-6 alkylene, C_1-6 heteroalkylene, 5- to 10- membered heteroarylene, C6-10 arylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -S(=O)2-, or -O-, wherein the alkylene, heteroalkylene, heteroarylene, arylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u, and l is an integer selected from 0 to 4. Exemplary Embodiment 27. The compound of any one of the preceding exemplary embodiments, wherein L is absent, -C(=O)-, C_1-12 alkylene, C_3-12 carbocyclylene, 3- to 12- membered heterocyclylene, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-(5- to 10- membered heteroarylene)-, *-(C_1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C_1-6 alkylene)-(C3-12 carbocyclylene)-(5- to 10-membered heteroarylene)-, *-(C3-12 carbocyclylene)- (C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-, *-(C1- ₆ alkylene)-(C_6-10 arylene)-C(=O)-, *-(C_1-6 alkylene)-O-C(=O)-, *-(3- to 12-membered heterocyclylene)-S(=O)2-, *-(C1-6 alkylene)-S(=O)2-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)- C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-O-, *-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-N(R^{L^})-, *-(3- to 12- membered heterocyclylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)- C(=O)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(C1-6 alkylene)-, *-(3- to 12- membered heterocyclylene)-(C_1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C_3-12 carbocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(C6-10 arylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-, *-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-C(=O)-, *-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-(3- to 12- membered heterocyclylene)-, C1-12 alkylene, 3- to 12-membered heterocyclylene, *-C1-12 alkylene- N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-, *-C(=O)-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, *-C(=O)-(3- to 12-membered heterocyclylene)-(3- to 12- membered heterocyclylene)-, *-C(=O)-(C3-12 carbocyclylene)-N(R^{L^})-, *-C(=O)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-C1-6 alkylene-C(=O)-(3- to 12- membered heterocyclylene)-, *-C_1-6 alkylene-C(=O)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-, *- (C3-12 carbocyclylene)-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-(5- to 10- membered heteroarylene)-, or *-(C3-12 carbocyclylene)-(C1-6 alkylene)-, wherein each alkylene, heterocyclylene, heteroarylene, arylene, and carbocyclylene is independently optionally substituted with one or more R^u, and *denotes attachment to T. Exemplary Embodiment 28. The compound of any one of the preceding exemplary embodiments, wherein L is absent, -C(=O)-, C_1-12 alkylene, C_3-12 carbocyclylene, 3- to 12- membered heterocyclylene, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-(5- to 10- membered heteroarylene)-, *-(C_1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C_1-6 alkylene)-(C3-12 carbocyclylene)-(5- to 10-membered heteroarylene)-, *-(C3-12 carbocyclylene)- (C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-, *-(C1-6 alkylene)-(C_6-10 arylene)-C(=O)-, *-(C_1-6 alkylene)-C(=O)-, *-(C_1-6 alkylene)-O-C(=O)-, *-C(=O)- (C1-6 alkylene)-, *-C(=O)-(C3-12 carbocyclylene)-NH-, *-C(=O)-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-C(=O)-(3- to 12-membered heterocyclylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-S(=O)₂-, *-(C_1-6 alkylene)-S(=O)₂-, *-(C_3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C3-12 carbocyclylene)-NH-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-O-, *-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *- (C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12- membered heterocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-NH-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)- NH-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-NH-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)- C(=O)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(C1- 6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C_3-12 carbocyclylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, *-(C_1-6 alkylene)-(C_6-10 arylene)-(C_1-6 alkylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-C(=O)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C_1-6 alkylene)-(5- to 10-membered heteroarylene)-, or *-(C_1-6 alkylene)-(3- to 12- membered heterocyclylene)-, wherein each alkylene, heterocyclylene, heteroarylene, arylene, and carbocyclylene is independently optionally substituted with one or more R^u. Exemplary Embodiment 29. The compound of any one of the preceding exemplary embodiments, wherein C is of Formula I-3^-i i). Exemplary Embodiment of the preceding exemplary

embodiments, wherein R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is . Exemplary Embodiment 31. The compound of any one of the preceding exemplary embodiments, wherein R^H3 is , and each of R^H2, R^H4, and R^H5 is hydrogen. Exemplary Embodiment 32. The compound of any one of the preceding exemplary embodiments, wherein C is of Formula I-3^-iii 3^-iii). Exemplary Embodiment 33

y one of the preceding exemplary embodiments, wherein one of R^H2, R^H3, and R^H4 is ; R^H1, R^H5, and the other two of R^H2, R^H3, and R^H4 are independently hydrogen, halogen, -C

, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1- ₆ alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 34. The compound of any one of the preceding exemplary embodiments, wherein R^H3 is , R^H1 and R^H5 are independently halogen, and each of R^H2 and R^H4 is hydrogen. Exemplary Embodiment 35. The compound of any one of the preceding exemplary embodiments, wherein C is of Formula I-3^-i or I-3^-iii ii). Exemplar g exemplary

embodiments, wherein J¹ is CH₂, and i) R^H2 and R^H3, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted 5- to 16-membered heterocycle; or ii) R^H3 and R^H4, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted 5- to 16-membered heterocycle. Exemplary Embodiment 37. The compound of any one of the preceding exemplary embodiments, wherein i) H⁴ is CR^H4 and H⁵ is CR^H5, wherein R^H4 and R^H5 are independently hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or ii) H¹ is CR^H1, H² is CR^H2, and H⁵ is CR^H5, wherein R^H1, R^H2, and R^H5 are independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 38. The compound of any one of the preceding exemplary embodiments, wherein i) R^H4 and R^H5 are independently hydrogen or halogen; or ii) R^H1 and R^H5 are independently halogen. Exemplary Embodiment 39. The compound of any one of the preceding exemplary embodiments, wherein Ring G is optionally substituted 7- to 16-membered spiro heterocycle. Exemplary Embodiment 40. The compound of any one of the preceding exemplary embodiments, wherein Ring G is: , wherein:

** denotes attachment to L; Ring G^II is C_4-8 carbocycle or 4- to 8-membered heterocycle; each G¹ is independently -C(R^G1)₂-, -NR^{G1^}-, -O-, -S-, -S(=O)-, or -S(=O)₂-; each G² is independently -C(R^G2)2-, -NR^{G2^}-, -O-, -S-, -S(=O)-, or -S(=O)2-; each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two geminal R^G1 or two geminal R^G2 together form oxo; or two geminal R^G1 or two geminal R^G2, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more R^u; each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; g' and g'' are independently an integer selected from 0-3, wherein g' and g'' are not both 0; each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- ₁₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits. Exemplary Embodiment 41. The compound of any one of the preceding exemplary embodiments, wherein Ring G is: 1) .

ng exemplary embodiments, wherein each G¹ is independently -C(R^G1)₂-, -NR^{G1^}-, or -O-, and each G² is independently -C(R^G2)₂-, -NR^{G2^}-, or -O-. Exemplary Embodiment 43. The compound of any one of the preceding exemplary embodiments, wherein each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6- membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. Exemplary Embodiment 44. The compound of any one of the preceding exemplary embodiments, wherein each occurrence of R^G1 and R^G2 is hydrogen; and each occurrence of R^{G1^} and R^{G2^} is hydrogen. Exemplary Embodiment 45. The compound of any one of the preceding exemplary embodiments, wherein Ring G is . Exemplary

ng exemplary embodiments, wherein Ring G is optionally substituted 7- to 16-membered fused heterocycle. Exemplary Embodiment 47. The compound of any one of the preceding exemplary embodiments, wherein Ring G is , wherein:

Ring G^III and Ring G^IV are independently C_4-8 carbocycle or 4- to 8-membered heterocycle; wherein at least one of Ring G^III and Ring G^IV is 4- to 8-membered heterocycle; G³ and G⁴ are independently C, CR^Gx, or N; R^Gx is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits, wherein R^A may be present on either Ring G^III or Ring G^IV. Exemplary Embodiment 48. The compound of any one of the preceding exemplary embodiments, wherein Ring G is , wh

R^N is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits. Exemplary Embodiment 49. The compound of any one of the preceding exemplary embodiments, wherein R^N is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u. Exemplary Embodiment 50. The compound of any one of the preceding exemplary embodiments, wherein R^N is hydrogen or C1-6 alkyl. Exemplary Embodiment 51. The compound of any one of the preceding exemplary embodiments, wherein each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. Exemplary Embodiment 52. The compound of any one of the preceding exemplary embodiments, wherein g is 0. Exemplary Embodiment 53. The compound of any one of the preceding exemplary embodiments, wherein K¹ is CR^K1. Exemplary Embodiment 54. The compound of any one of the preceding exemplary embodiments, wherein R^K1 is hydrogen. Exemplary Embodiment 55. The compound of any one of the preceding exemplary embodiments, wherein K¹ is N. Exemplary Embodiment 56. The compound of any one of the preceding exemplary embodiments, wherein q is 1. Exemplary Embodiment 57. The compound of any one of the preceding exemplary embodiments, wherein k is 0. Exemplary Embodiment 58. A compound selected from the compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof. Exemplary Embodiment 59. A pharmaceutical composition comprising the compound of any one of the preceding exemplary embodiments, and a pharmaceutically acceptable excipient. Exemplary Embodiment 60. A method of degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample comprising contacting said patient or biological sample with a compound of any one of the preceding exemplary embodiments. Exemplary Embodiment 61. Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample.

Exemplary Embodiment 62. A compound of any one of the preceding exemplary embodiments for use in degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample.

Exemplary Embodiment 63. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound of any one of the preceding exemplary embodiments.

Exemplary Embodiment 64. Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for treating a disease or disorder.

Exemplary Embodiment 65. A compound of any one of the preceding exemplary embodiments for use in treating a disease or disorder.

Exemplary Embodiment 66. The method, use, or compound for use of any one of the preceding exemplary embodiments, wherein the disease or disorder is a SMARCA2 or SMARCA4 protein- mediated disease or disorder.

Exemplary Embodiment 67. The method, use, or compound for use of any one of the preceding exemplary embodiments, wherein the disease or disorder is cancer.

Exemplary Embodiment 68. The method, use, or compound for use of any one of the preceding exemplary embodiments, wherein the cancer is selected from NSCLC adenocarcinoma (LU AD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).

Exemplary Embodiment 69. The method, use, or compound for use of any one of the preceding exemplary embodiments, wherein the cancer is selected from NSCLC adenocarcinoma (LU AD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC).

EXAMPLES

[0360] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

I. Synthesis and Characterization

Compound Al. 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[l,2-a]quinazolin-9- yl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

Synthesis of tert-butyl 4-(2-oxoindolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate

(Intermediate 3)

[0361] To a mixture 5-bromoindolin-2-one (5.00 g, 1 eq, 23.6 mmol) in 1,4-dioxane (50.0 mL) and water (10 mL), was added l,T-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.73 g, 0.1 eq, 2.36 mmol), sodium carbonate (7.50 g, 3 eq, 70.7 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (10.9 g, 1.5 eq, 35.4 mmol) and stirred at 90 °C for 12 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate and concentrated under vacuum. The crude was purified by silica gel column chromatography (0-30% of ethyl acetate in petroleum ether) to afford tertbutyl 4-(2-oxoindolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (6.50 g, 20.7 mmol, 87.7%) as a yellow solid. LC purity (0.1%FA): 77.33 % (UV at 254 nm)/MS: 356.3 [M+42]; Retention time: 1.198 min.

Synthesis of tert-butyl 4-(2-oxoindolin-5-yl)piperidine-I -carboxylate (Intermediate 4)

[0362] To a mixture of tert-butyl 4-(2-oxoindolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (6.70 g, 1 eq, 21.3 mmol) in methanol (50 mL) was added 10% Pd/C (1.13 g, 0.05 eq, 1.07 mmol). The mixture was stirred at 20 °C for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated to afford tert-butyl 4-(2-oxoindolin-5- yl)piperidine-l -carboxylate (6.50 g, 20.5 mmol, 96.4 %) as a yellow solid . LC purity (0.1 %TFA): 85.53% (UV at 254 nm)/MS: 358.2 [M+42]; Retention time: 1.053 min.

Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-l -carboxylate (Intermediate 5)

[0363] To a mixture of tert-butyl 4-(2-oxoindolin-5-yl)piperidine-l -carboxylate (0.30 g, 1 eq, 0.95 mmol) and TMEDA (0.33 g, 3 eq, 2.8 mmol) in THF (10 mL) at -78 °C was added n-butyllithium (0.17 mL, 2 eq, 1.9 mmol) dropwise slowly at -78 °C, after 30 minutes, Mel (0.12 mL, 2 eq, 1.9 mmol) was added then stirred at -78 °C for 3 h. The mixture was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mLx2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The mixture was concentrated and the residue was purified by column chromatography on silica gel using 0-20% ethyl acetate/hexane to afford tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5- yl)piperidine-l -carboxylate (67.0 mg, 195 μmol, 21%) as a yellow solid. LC purity (0.03 %FA): 85.68 % (UV at 254 nm)/MS: 386.1 [M+42]; Retention time: 1.298 min.

Synthesis of tert-butyl 4-( I-(3-chloro-2-cyanophenyl)-3, 3-dimethyl-2-oxoindolin-5-yl)piperidine- 1 -carboxylate (Intermediate 7)

[0364] To a mixture of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-l-carboxylate (50.0 mg, 1 eq, 145 μmol) in acetonitrile (5 mL) was added cesium carbonate (142 mg, 3 eq, 435 µmol) and 2-chloro-6-fluorobenzonitrile (27.1 mg, 1.2 eq, 174 µmol). The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-20% ethyl acetate/hexane to afford tert-butyl 4-(1-(3-chloro-2- cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (40.0 mg, 83.3 µmol, 57.4%) as a white solid. LC purity (0.1%FA): 62.31 % (UV at 254 nm)/MS: 502.3 [M+23]; Retention time: 1.546 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (Intermediate 8) [0365] To a mixture of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidine-1-carboxylate (50.0 mg, 1 eq, 104 µmol) in DMSO (5.00 mL) was added potassium carbonate (43.2 mg, 3 eq, 313 µmol) at 0 ^oC then added hydrogen peroxide (35.4 mg, 31.9 µL, 10 eq, 1.04 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% ethyl acetate/hexane to afford tert- butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1- carboxylate (40.0 mg, 80 µmol, 77.3%) as a white solid. LC purity (0.1%FA): 88.62 % (UV at 254 nm)/MS: 520.1 [M+23]; Retention time: 1.354 min. Synthesis of tert-butyl 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carboxylate (Intermediate 9) [0366] To a mixture of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin- 5-yl)piperidine-1-carboxylate (0.20 g, 1 eq, 0.40 mmol) in methanol (5 mL) was added sodium methoxide (0.11 g, 5 eq, 2.0 mmol). The reaction mixture was stirred at 70 °C for 3 h. The mixture was poured into HCl（1M） (20 mL), extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase chromatography to afford tert-butyl 4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carboxylate (50.0 mg, 104 µmol, 26%) as a white solid. LC purity (0.1%FA): 31.93 % (UV at 254 nm)/MS: 480.3 [M+1]; Retention time: 1.465 min. Synthesis of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (Intermediate 10) [0367] A mixture of tert-butyl 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carboxylate (0.05 g, 1 eq, 0.1 mmol) in HCl/dioxane (3 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give 4-chloro-7,7-dimethyl-9- (piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (18.0 mg, 47.4 µmol, 50 %) as a white solid. LC purity (0.1%FA): 97.98 % (UV at 254 nm)/MS: 380.2 [M+1]; Retention time: 0.869 min.¹H NMR (400 MHz, DMSO) δ 9.10 (b, 1H), 8.92-8.94 (b, 1H), 8.40-8.42 (d, J = 8.8 Hz, 1H), 8.14- 8.16 (d, J = 8.4Hz, 1H), 7.81-7.85 (m, 1H), 7.63-7.65 (d, J = 8.0 Hz, 1H), 7.57-7.58 (m, 1H), 7.34- 7.36 (d, J = 8.4 Hz, 1H), 3.37-3.39 (m, 2H), 2.94-3.06 (m, 3H), 1.92-2.02 (m, 4H), 1.53 (s, 9H). Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0368] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (25 mg, 1 eq, 0.066 mmol) in DMSO (2 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione (27.3 mg, 1.5 eq, 0.987 mmol), DIEA (42.5 mg, 5 eq, 0.329 mmol). The mixture was stirred at 120 °C for 3 hours. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H₂O from 5% to 95% (0.1%FA) to give 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (15.37 mg, 0.024 mmol, 36.7 %). LC purity (0.1%FA): 89.42 % (UV at 254 nm)/MS: 636.2 [M+H]; Retention time: 1.60 min.¹H NMR (400 MHz, CD₃OD) δ 8.44-8.46 (m, 1H), 8.09-8.11 (m, 1H), 7.84-7.88 (m, 1H), 7.60-7.71 (m, 3H), 7.48-7.49 (m, 1H), 7.37-7.39 (m, 2H), 5.09-5.13 (m, 1H), 3.90-3.93 (m, 2H), 3.04-3.09 (m, 2H), 2.92- 2.80 (m, 2H), 2.81- 2.66 (m, 2H), 1.99-2.14 (m, 5H), 1.63 (s, 6H). Compound A2.5-((R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[0369] To a solution of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (100 mg, 1 eq, 497 μmol) in MeCN (5 mL) was added IBX (209 mg, 1.5 eq, 745 μmol) . The mixture was stirred at 90 °C for 2 hours. TLC indicated completion of reaction. The reaction was concentrated under vacuum to afford tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (177 mg, 888 μmol, 79 %) as white solid. Synthesis of tert-butyl (R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate [0370] To a solution of tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (177 mg, 3.4 eq, 888 umol), 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (99.9 mg, 1 eq, 263 micro mol) in MeOH (5 mL) was added TEA (106 mg, 4.0 eq, 1.1 mmol). The mixture was stirred at 25 °C for 0.5 hour. NaBH₃CN (33 mg, 526 umol) was added. The reaction was stirred at 25 ^oC for 16 hours. LCMS indicated completion of reaction. The reaction mixture was diluted with water (20 mL), extracted with DCM (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford tert-butyl (R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate (202 mg, 359 μmol, 40.4 %) as a yellow oil. LC purity (0.1%FA): 68 % (UV at 254 nm)/MS: 563.3 [M+H]; Retention time: 1.349 min. Synthesis of (S)-4-chloro-7,7-dimethyl-9-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one [0371] To a solution of tert-butyl (R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate (202 mg, 1 eq, 359 μmol) in DCM (6 mL) was added TFA (2.96 g, 2 mL, 72.4 eq, 26 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford (S)-4-chloro-7,7-dimethyl-9-(1-(pyrrolidin-3-ylmethyl)piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (166 mg, 359 umol, 78.37 %) as a green oil. LC purity (0.1% FA): 78 % (UV at 254 nm)/MS: 463.2 [M+H]; Retention time: 0.99 min. Synthesis of 5-((R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0372] To a solution of (S)-4-chloro-7,7-dimethyl-9-(1-(pyrrolidin-3-ylmethyl)piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (258 mg, 1 eq, 557 μmol) and 3-(5-fluoro-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (175 mg, 1.2 eq, 669 μmol) in DMSO (15 mL) was added DIEA (216 mg, 3 eq, 1.67 mmol). The mixture was stirred at 120 °C for 3 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 85% (0.1%FA) to afford5-((R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo- 5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (7.01 mg, 8.86 μmol, 1.59 %) as a yellow solid. LC purity (0.1%FA): 72.92 % (UV at 254 nm)/MS: 360.2 [ M+1]; Retention time: 1.23 min.¹H NMR (400 MHz, MeOD) δ 8.40-8.41 (d, J = 8.4 Hz, 1H), 8.08-8.09 (d, J = 8.4 Hz, 1H), 7.83-7.85 (t, J = 8.0 Hz, 1H), 7.64-7.65 (m, 2H), 7.58-7.60 (d, J = 1.6 Hz, 1H), 7.45-7.46 (dd, J = 8.4, 1.6 Hz, 1H), 6.97-6.98 (m, 1H), 6.78-6.87 (m, 1H), 5.05-5.07 (m, 1H), 3.69-3.78 (m, 1H), 3.53-3.64 (m, 2H), 3.48-3.50 (m, 2H), 3.03-3.05 (d, J = 6.0 Hz, 1H), 2.70-2.93 (m, 7H), 2.29-2.43 (m, 1H), 2.10- 2.14 (m, 4H), 1.92-1.94 (m, 1H), 1.62 (s, 6H). Compound A3.5-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

S

ynthesis of tert-butyl ((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate [0373] To a solution of tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamate (150 mg, 1 eq, 660 μmol) in MeOH (2 mL) were added 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one (201 mg, 0.8 eq, 528 μmol), NaBH₃CN (166 mg, 4 eq, 2.64 mmol), and under N₂, The mixture was stirred at 25°C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL), extracted with EA (20 x 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford tert-butyl ((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate (160 mg, 0.26 mmol, 39 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 591.4 [M+H]; Retention time: 1.377 min. Synthesis of 9-(1-(((1r,4r)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one [0374] A mixture of tert-butyl ((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate (70.0 mg, 1 eq, 118 μmol) in HCl/EA (2 ml) was stirred at 25 °C for 2 hours under N2. LCMS indicated completion of reaction. The reaction was filtered, and the filter cake was dried to give 9-(1- (((1r,4r)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (63.0 mg, 0.12 mmol, 98% yield) as yellow solid. LC purity (0.1%FA): 93.76 % (UV at 254 nm)/MS: 493.3 [M+H]; Retention time: 1.01 min. Synthesis of 5-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0375] To a solution of 9-(1-(((1r,4r)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (30 mg, 1 eq, 61.1 μmol) in DMSO (0.5 mL) were added DIEA (79 mg, 10 eq, 611 μmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (25.3 mg, 1.5 eq, 91.6 μmol) under N2. The mixture was stirred at 130 °C for 5 hours. LCMS indicated completion of reaction. The reaction was poured into H₂O (30 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H₂O from 10% to 85% (0.1%FA) to give 5-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (5.87 mg, 7.27 μmol, 11.9 %) as a green solid. LC purity (0.1 %FA): 77.24 % (UV at 254 nm)/MS: 747.4 [M+H]; Retention time: 1.30 min.¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.41 (m, 4H), 8.04-8.07 (m,1H), 7.80-7.84 (m, 1H), 7.37-7.64 (m, 3H), 7.36-7.37 (m, 1H), 6.84-6.96 (m, 2H), 5.00-5.04 (m, 1H), 2.84-2.99 (m, 4H), 2.58-2.60 (m,1H), 2.16-2.17 (m, 2H), 2.16-2.17(m, 5H), 1.74-2.00 (m, 7H), 1.52 (s, 7H), 1.07-1.24 (m, 5H). Compound A4.4-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione Syn

, , , , azolin- 9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0376] To a solution of 9-(1-(((1r,4r)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (3 mg, 1 eq, 61.1 μmol) in DMSO (0.5 mL)was added DIEA (79 mg, 10 eq, 611 μmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (25.3 mg, 1.5 eq, 91.6 μmol) under N₂. The mixture was stirred at 130 °C for 3 hours. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 85% (0.1%FA) to give 4-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (5.87 mg, 7.27 μmol, 11.9 %) as a yellow solid. LC purity (0.1 %TFA): 100 % (UV at 254 nm)/MS: 747.4 [M+H]; Retention time: 1.37 min.¹H NMR (400 MHz, DMSO-d6) 8.39-8.42 (d, J = 8.0 Hz, 1H), 8.13-8.15 (d, J = 8.0 Hz,1H), 7.83-7.87 (m, 1H), 7.58-7.66 (m, 3H), 7.37-7.39 (d, J = 8.0 Hz, 1H), 7.18-7.20 (d, J = 8.0 Hz, 1H), 7.05-7.07 (d, J = 8.0 Hz, 1H), 5.02-5.07 (m, 1H), 3.53-3.63 (m, 4H), 2.84-3.09 (m, 6H), 2.06-2.09 (m, 7H), 1.89- 1.91(m, 3H), 1.54 (s, 6H), 1.21-1.41(m, 5H). Compound A5.4-((2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione S

n-9- yl)piperidin-1-yl)ethyl)carbamate [0377] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 mmol) in MeOH (4 mL) was added tert-butyl (2-oxoethyl)carbamate (50.3 mg, 1.2 eq, 0.316 mmol), TEA (133 mg, 5 eq, 1.32 mmol), NaBH3CN (165 mg, 10 eq, 2.63 mmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H₂O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed brine and dried over anhydrous , filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh size, 10% CH3OH in DCM) to give tert-butyl (2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)ethyl)carbamate (110 mg, 0.210 mmol, 79.9 %) as a yellow solid. LC purity (0.1% FA): 92.9% (UV at 214 nm)/MS: 523.2 [M+H]; Retention time: 0.94 min. Synthesis of 9-(1-(2-aminoethyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one [0378] A solution of tert-butyl (2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)ethyl)carbamate (110 mg, 1 eq, 0.210 mmol) in HCl/EA (2 mL) was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated and purified by prep-HPLC, eluted with CH₃CN in H₂O from 5% to 95% (0.1% FA) to give 9-(1-(2-aminoethyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)- one (80.0 mg, 0.189 mmol, 89.9 %) as a white solid. LC purity (0.1%FA): 93.66 % (UV at 214 nm)/MS: 423.2 [M+H]; Retention time: 0.93 min. Synthesis of 4-((2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0379] To a solution of 9-(1-(2-aminoethyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (40 mg, 1 eq, 0.09 mmol) in DMSO (2 mL) was added 2-(2,6- dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (39.2 mg, 1.5 eq, 0.142 mmol), DIEA (122 mg, 10 eq, 0.946 mmol). The mixture was stirred at 120 °C for 3 hours. LCMS indicated completion of reaction. The mixture was purified by prep-HPLC, eluted with CH₃CN in H₂O from 10% to 85% (0.1%NH4HCO3) to afford 4-((2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (10.13 mg, 0.013 mmol, 14.4 %) as a yellow solid. LC purity (0.03%TFA): 92.31 % (UV at 254 nm)/MS: 679.3 [M+H]; Retention time: 1.278 min.¹H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.42-8.43 (m, 1H), 8.08-8.09 (m, 1H), 7.83-7.84 (m, 1H), 7.63-7.65 (m, 2H), 7.38-7.40 (m, 1H), 7.05-7.13 (m, 2H), 6.84 (s, 1H), 5.09-5.10 (m, 1H), 3.07- 3.09 (m, 2H), 2.90-2.91 (m, 1H), 2.50-2.65 (m, 5H), 2.11-2.14 (m, 4H), 1.83-1.85 (m, 4H), 1.53 (s, 6H), 1.24-1.25 (m, 2H). Compound A6. (S)-3-(1'-(((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0380] To a solution of methyl (1R, 4R)-4-(hydroxymethyl)cyclohexane-1-carboxylate (200 mg, 1 eq, 1.16 mmol) in THF (4 mL) and water (1 mL) was added LiOH (111 mg, 4 eq, 4.65 mmol). The reaction was stirred at 25 °C for 16 hours. TLC indicated completion of reaction. The mixture was adjusted to pH=5 with 1N HCl under ice water. The mixture was extracted with DCM (20 mL X 3). The combined organics were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under vacuum to give (1R,4R)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid as colorless oil which used to the next step directly. Synthesis of 4-chloro-9-(1-((1r,4r)-4-(hydroxymethyl)cyclohexane-1-carbonyl)piperidin-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one [0381] To a solution of (1r,4r)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid (150 mg, 1 Eq, 948 μmol) in DMF (2 mL) were added DIEA (613 mg, 5 eq, 4.74 mmol), HATU (721 mg, 2 eq, 1.90 mmol) and 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (360 mg, 1 eq, 948 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to give 4-chloro-9-(1-((1r,4r)-4- (hydroxymethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one. LC purity (0.1%FA): 85.80 % (UV at 254 nm)/MS: 520 [M+H]; Retention time: 1.44 min. Synthesis of (1r,4r)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)cyclohexane-1-carbaldehyde [0382] To a solution of 4-chloro-9-(1-((1r,4r)-4-(hydroxymethyl)cyclohexane-1- carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 76.9 μmol) in DCM (1 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (48.9 mg, 1.5 eq, 115 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added H₂O (20 mL), extracted with EA (10 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of EtOAc) to afford (1r,4r)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexane-1-carbaldehyde (37 mg, 64 mmol, 83 %) as a yellow solid. LC purity (0.1%FA): 100.00 % (UV at 254 nm)/MS: 518.05 [M+H]; Retention time:1.49 min Synthesis of (S)-3-(1'-(((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0383] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (24.7 mg, 1.2 eq, 69.5 μmol) in DCM (0.5 mL) was added (1r,4r)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1- carbonyl)cyclohexane-1-carbaldehyde (30.0 mg, 1 eq, 57.9 μmol), triethylamine (8.79 mg, 1.5 eq, 86.9 μmol), acetic acid (5.91 mg, 1.7 eq, 98.4 μmol) and sodium triacetoxyborohydride (24.5 mg, 17.2 μL, 2 eq, 116 μmol). The mixture was stirred at 25 °C for 4 hours. The reaction was concentrated and purified by prep-HPLC, eluted with CH3CN in H2O from 5% to 95% (0.1%FA) to afford (S)-3-(1'-(((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.68 mg, 6.51 μmol, 11.2 %) as a white solid. LC purity (0.1 %FA): 85.74 % (UV at 254 nm)/MS: 857.4 [M+H]; Retention time: 1.25 min. ¹H NMR (400 MHz, MeOD) δ 8.40-8.43 (m, 1H), 8.06-8.08 (m, 1H), 7.84-7.86 (m, 1H), 7.64-7.66 (m, 1H), 7.57 (s, 1H), 7.36-7.43 (m, 3H), 5.10-5.13 (m, 1H), 4.72-4.83 (m, 1H), 4.58 (s, 2H), 4.35-4.47 (m, 2H), 4.21-4.23 (m, 1H), 3.22-3.26 (m, 1H), 3.05-3.08 (m, 2H), 3.01- 3.04 (m, 1H), 2.76-2.2.99 (m, 1H), 2.70-2.79 (m, 3H), 2.47-2.51 (m, 1H), 2.40-2.41 (m, 2H), 2.25- 2.29 (m, 2H), 2.10-2.17 (m, 3H), 1.94-2.07 (m, 4H), 1.80-1.92 (m, 4H), 1.65-1.78 (m, 3H), 1.84- 1.86 (m, 8H), 1.09-1.13 (m, 2H). Compound A7.5-(2-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidine-1-carbonyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione

-9- yl)piperidine-1-carbonyl)piperidine-1-carboxylate [0384] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (150 mg, 1 eq, 395 μmol) in DMF (1.5 mL) were added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin- 3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (180 mg, 1.2 eq, 474 μmol), 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (109 mg, 1.2 eq, 474 μmol), DIEA (255 mg, 5 eq, 1.97 mmol). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was poured into water (100 mL), extracted with EA (50 mL X 3). The combined organic layers were washed brine (20 mL X 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give tert-butyl (tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (200 mg, 270 μmol, 79.83 %) as a white solid. LC purity (0.1%TFA): 79.83 % (UV at 254 nm)/MS: 590 [M+H]; Retention time: 1.64 min. Synthesis of 4-chloro-7,7-dimethyl-9-(1-(piperidine-4-carbonyl)piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one [0385] To a solution of tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (230 mg, 1 eq, 389 μmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid (44.4 mg, 1 eq, 389 μmol), and the reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H₂O from 10% to 85% (0.1% FA) to afford 4-chloro-7,7-dimethyl-9-(1-(piperidine-4-carbonyl)piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (190 mg, 347 μmol, 89.3 %) as a white solid. LC purity (0.1% FA): 89.8 % (UV at 254 nm)/MS: 491.2 [M+H]; Retention time: 1.12 min. Synthesis of tert-butyl 2-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidine-1-carbonyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate [0386] To a solution of 4-chloro-7,7-dimethyl-9-(1-(piperidine-4-carbonyl)piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (190 mg, 1 eq, 387 μmol) in MeOH (2 mL) were added tert- butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (185 mg, 2 eq, 774 μmol), triethylamine (117 mg, 3 eq, 1.16 mmol) and sodium cyanotrihydroborate (72.9 mg, 3 eq, 1.16 mmol) and the reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H2O (50 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of EtOAc) to afford 2-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (126 mg, 176 μmol, 45.6 %) as a yellow solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 713 [M+H]; Retention time: 1.36 min. Synthesis of 9-(1-(1-(7-azaspiro[3.5]nonan-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-4-chloro- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one [0387] To a solution of tert-butyl 2-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (110 mg, 1 eq, 154 μmol) in EA (1 mL) was added 3 mol HCl/EA (4 mL, 1 eq, 154 μmol). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated under vacuum to give tert-butyl 9-(1-(1-(7- azaspiro[3.5]nonan-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (90 mg, 147 μmol, 100 %) as a yellow solid, LC purity (0.1%TFA): 100 % (UV at 254 nm)/MS: 613 [M+H]; Retention time: 1.17 min. Synthesis of 5-(2-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione [0388] To a solution of 9-(1-(1-(7-azaspiro[3.5]nonan-2-yl)piperidine-4-carbonyl)piperidin-4-yl)- 4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 65.1 μmol) in DMSO (0.5 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (21.6 mg, 1.2 eq, 78.1 μmol), DIEA (25.3 mg, 3 eq, 195 μmol) and the reaction was stirred at 120 °C for 6 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and the resulting residue was purified by prep-HPLC, eluted with MeCN in H₂O from 10% to 85% (0.1%FA) to afford 5-(2-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidine-1-carbonyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (1.00 mg, 1.13 μmol, 1.73 %) as a yellow solid. LC purity (0.1%TFA): 91.77 % (UV at 254 nm)/MS: 435 [M/2+H]; Retention time: 1.37 min. ¹H NMR (400 MHz, MeOD) δ 8.42 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.57 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 5.06 (dd, J = 12.4, 5.4 Hz, 1H), 4.21 (d, J = 12.1 Hz, 1H), 3,50-3.48 (m, 2H), 3.45-3.43 (m, 2H), 2.99-2.69 (m, 8H), 2.46-2.42 (m, 2H), 2.30-2.26 (m, 2H), 2.13^1.86 (m, 10H), 1.80-1.76 (m, 6H), 1.61 (s, 6H), 1.34-1.23 (m, 2H). Compound A8.5-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

n-9-

yl)piperidin-1-yl)cyclohexyl)carbamate [0389] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 0.263 μmol) in MeOH (2 mL) was added tert-butyl (4- oxocyclohexyl)carbamate (56.1 mg, 1 eq, 0.263 μmol) and TEA (12.6 mg, 3 eq, 125 μmol). The mixture was stirred for 30 min, sodium cyanoborohydride (165 mg, 10 eq, 2.63 μmol) was added. The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was poured into H2O (20 mL) and extracted with DCM (20 mL X 3). The combined organics was washed brine (20 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (10% of MeOH in DCM) to give tert-butyl (4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)cyclohexyl)carbamate (150 mg, 0.259 μmol, 65.5% yield) as a yellow solid. LC purity (0.1%FA): 66.3 % (UV at 254 nm)/MS: 577.4 [M+H]; Retention time: 1.37 min. Synthesis of 9-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0390] A solution of tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)carbamate (150 mg, 1 eq, 0.260 mmol) in HCl/EA (4 mL) was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford 9-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (120 mg, 0.251 mmol, 89.7 % yield) as a yellow solid. LC purity (0.1%FA): 92.72 % (UV at 254 nm)/MS: 477.2 [M+H]; Retention time: 0.91 min. Synthesis of 5-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0391] To a solution of 9-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 1 eq, 0.08 mmol) and 2-(2,6-dioxopiperidin- 3-yl)-5-fluoroisoindoline-1,3-dione (27.8 mg, 1.2 eq, 0.10 mmol) in DMSO (2 mL) was added DIEA (32.2 mg, 0.04 mL, 3 eq, 0.252 mmol). The mixture was stirred at 120 °C for 4 hours. LCMS indicated completion of reaction. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 85%(0.1%FA) to give 5-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (1.36 mg, 0.0019 mmol, 2.01 %) as a white solid. LC purity (0.1%FA): 90.88 % (UV at 254 nm)/MS: 733.4 [M+H]; Retention time: 1.30 min. ¹H NMR (400 MHz, MeOD) δ 8.39-8.42 (d, J = 8.4 Hz, 1H), 8.10-8.12 (d, J = 8.8 Hz, 1H), 7.80-7.85 (m, 1H), 7.62- 7.66 (d, J = 8.0 Hz, 1H), 7.51-7.64 (m, 2H), 7.46-7.49 (d, J = 8.0 Hz, 1H), 7.14-7.20 (d, J = 8.8 Hz, 1H), 7.08-7.10 (d, J = 7.0 Hz, 1H), 5.02-5.08 (m, 1H), 3.67-3.87 (m, 3H), 3.10-3.12 (m, 1H), 2.68-2.86 (m, 4H), 2.29-2.30 (m, 6H), 2.11-2.13 (m, 4H), 1.85-1.90 (m, 2H), 1.62 (s, 6H), 1.35- 1.59 (m, 4H). Compound A9.4-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

, , , yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0392] To a solution of 9-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 1 eq, 0.0838 mmol) and 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (27.8 mg, 1.2 eq, 0.101 mmol) in DMSO (2 mL) was added DIEA (32.2 mg, 3 eq, 0.252 mmol).The mixture was stirred at 120 °C for 4 h. LCMS indicated completion of reaction. The mixture was purified by prep-HPLC, eluted with CH₃CN in H₂O from 10% to 90% (0.1% NH₄HCO₃) to give 4-((4-(4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (2.19 mg, 0.003 mmol, 3.27 %) as a yellow solid. LC purity (0.1%NH₄HCO₃): 91.83 % (UV at 254 nm)/MS: 733.4 [M+H]; Retention time: 1.30 min. ¹H NMR (400 MHz, MeOD) δ 8.42-8.52 (d, J = 8.4 Hz, 1H), 8.07-8.21 (d, J = 8.4 Hz, 1H), 7.85- 7.90 (m, 1H), 7.65-7.68 (d, J = 7.6 Hz, 1H), 7.59^7.54 (m, 2H), 7.43-7.45 (d, J = 8.6 Hz, 1H), 7.07 (s, 1H), 6.93-6.98 (d, J = 10.0 Hz, 1H), 4.56-4.60 (m, 4H), 3.77-3.79 (m, 1H), 2.86-2.88 (m, 2H), 2.76-2.78 (m, 2H), 2.19-2.20 (m, 1H), 2.03-2.05 (m, 2H), 1.85-1.87 (m, 2H), 1.61 (s, 6H), 1.33- 1.40 (m, 6H), 0.90-0.93 (m, 4H). Compound A10.5-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione

y , y [0393] To a solution of 6-bromoindolin-2-one (20 g, 1 eq, 94.3 mmol) in THF (250 mL) was added LDA (30.3 g, 3 eq, 283 mmol), the mixture was stirred at -75 °C for 30 min. Then was added Methyl iodide (26.8 g, 2 eq, 189 mmol). The mixture was stirred at rt for 2 hours. LCMS indicated completion of reaction. The reaction was quenched by water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (EA/PE=1/10) to afford 6-bromo-3,3-dimethylindolin-2-one as a yellow solid. LC purity (0.1% FA): 44.56 % (UV at 254 nm)/MS: 240.1 [M+H]; Retention time: 1.29 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [0394] To a solution of 6-bromo-3,3-dimethylindolin-2-one (16.0 g, 1 eq, 66.6 mmol) in 1,4- dioxane (200 mL) was added K2CO3 (27.6 g, 3 eq, 200 mmol)，tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (41.2g, 2 eq, 133 mmol) PdCl₂(dppf) (2.44 g, 0.05 eq, 3.33 mmol). The reaction was stirred at 100°C for 16 hours. LCMS indicated completion of reaction. The mixture was concentrated under vacuum and purified by prep-HPLC, eluted with PE/EA to afford tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-3,6- dihydropyridine-1(2H)-carboxylate (12.0 g, 35.0 mmol, 52.6 %) as a yellow solid. LC purity (0.1%FA): 68.37 % (UV at 254 nm)/MS: 342.44 [M+H]; Retention time: 1.48 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)piperidine-1-carboxylate [0395] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)-3,6-dihydropyridine-1(2H)- carboxylate (6.00 g, 1 eq, 17.5 mmol) in MeOH (200 mL) was Pd/C (0.60 g, 0.32 eq, 5.6 mmol). And the reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was filtered and concentrated under vacuum to afford tert-butyl 4-(3,3-dimethyl-2- oxoindolin-6-yl)piperidine-1-carboxylate (6.0 g, 17.5 mmol, 100 %) as a yellow solid. LC purity (0.1%FA): 93.47 % (UV at 254 nm)/MS: 344.46 [M+H]; Retention time:1.48 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6-yl)piperidine- 1-carboxylate [0396] To a solution of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-6-yl)piperidine-1-carboxylate (13.0 g, 1 eq, 37.7 mmol) in ACN (150 mL) was added Cesium carbonate (36.9 g, 9.06 mL, 3 eq, 113 mmol), 2-chloro-6-fluorobenzonitrile (11.7 g, 2 eq, 75.5 mmol). The mixture was stirred at 80 °C for 16 hours. LCMS indicated completion of reaction. The reaction was quenched by water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (EA/PE=1/10) to afford tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperidine-1-carboxylate (16.0 g, 33.3 mmol, 88.3 %) as a yellow solid. LC purity (0.1%FA): 47.40 % (UV at 254 nm)/MS: 480.01 [M+H]; Retention time: 1.71 min. Synthesis of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperidine-1-carboxylate [0397] To a solution of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-6- yl)piperidine-1-carboxylate (8.0 g, 1 eq, 16.7 mmol) in DMSO (120 mL) was added K2CO3 (4.61 g, 2 eq, 33.3 mmol), H₂O₂ (40.0 g, 36.0 mL, 70.6 eq, 1.18 mol). The reaction was stirred at 50 °C for 16 hours. LCMS indicated completion of reaction. The reaction was quenched by water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (EA/PE=1/10) to afford tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin- 6-yl)piperidine-1-carboxylate (7.6 g, 15.26 mmol, 91.2 %) as a yellow solid. LC purity (0.1%FA): 98.11 % (UV at 254 nm)/MS: 498.02 [M+H]; Retention time: 1.48 min. Synthesis of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one [0398] To a solution of tert-butyl 4-(1-(2-carbamoyl-3-chlorophenyl)-3,3-dimethyl-2-oxoindolin- 6-yl)piperidine-1-carboxylate (10.0 g, 1 eq, 20.1 mmol) in Toluene (150 mL) was added Ts-OH (11.5 g, 3 eq, 60.2 mmol) .The mixture was stirred at 120 °C for 16 hour. LCMS indicated completion of reaction. The reaction was quenched by NaHCO3 (20 mL), extracted with DCM/MEOH=10/1 (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford 4-chloro-7,7-dimethyl-10-(piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (9.00 g, 23.7 mmol, 118 %) as a yellow solid. LC purity (0.1%FA): 100.00 % (UV at 254 nm)/MS: 379.89 [M+H]; Retention time: 0.85 min. ¹H NMR (400 MHz, MeOD-d4) δ 8.44-8.46 (d, J = 8.8 Hz, 1H), 7.94-8.03 (m, 1H), 7.80-7.85 (m, 1H), 7.62- 7.68 (m, 2H), 7.14-7.25 (d, J = 7.8 Hz, 1H), 2.49-2.54 (m, 2H), 2.29 (s, 3H), 1.95-1.96 (m, 4H), 1.51 (s, 6H). Synthesis of tert-butyl 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate [0399] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 μmol) in MeOH (2 mL) were added 7-Azaspiro[3.5]nonan-2-one, tert- butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (81.9 mg, 1.3 eq, 342 μmol) and TEA (79.9 mg, 110 μL, 3 eq, 790 μmol). The mixture was stirred at 20 °C for 30 min. Then sodium cyanoborohydride (49.6 mg, 46.6 μL, 3 eq, 790 μmol) was added and the mixture was stirred at 20 °C for 4 hours. LCMS indicated completion of reaction. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and purified by prep-TLC (5% MeOH in DCM) to give tert-butyl 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (110 mg, 0.16 mmol, 62 %) as yellow oil. LC purity (0.1%FA): 90 % (UV at 254 nm)/MS: 604.4 [M+H]; Retention time: 1.45 min. Synthesis of 10-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0400] A solution of tert-butyl 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (110 mg, 1 eq, 182 μmol) in HCl/EA (3 mL) was stirred at 20 °C for 2 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated under vacuum to give 10-(1-(7- azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)- one (75.0 mg, 149 μmol, 81.7 %) as a yellow solid. LC purity (0.1%TFA): 57 % (UV at 254 nm)/MS: 503.2 [M+H]; Retention time: 0.86 min. Synthesis of 5-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0401] To a solution of 10-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (35 mg, 1 eq, 69.6 μmol) in DMSO (0.5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (23.1 mg, 1.2 eq, 83.5 μmol) and DIEA (45.0 mg, 5 eq, 348 μmol). The reaction was stirred at 120 °C for 6 hours. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H₂O (0.05% TFA) from 10% to 90% to afford 5-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (5.02 mg, 6.35 μmol, 9.12 %) as a yellow solid. LC purity (0.1%FA): 95.98 % (UV at 254 nm)/MS: 759.4 [M+H]; Retention time: 1.806 min.¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.45-8.46 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.84-7.86 (t, J = 8.0Hz, 1H), 7.65-7.69 (m, 3H), 7.36 (s, 1H), 7.26-7.29 (m, 2H), 5.05-5.09 (m, 1H), 3.78-3.81 (m, 1H), 3.39-3.52 (m, 6H), 3.06-3.10 (m, 1H), 2.84-2.93 (m, 3H), 2.54-2.67 (m, 2H), 2.26-2.33 (m, 2H), 1.95-2.16 (m, 7H), 1.63-1.67 (m, 4H), 1.52(s, 6H). Compound A11. 4-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

lin- 10-yl)piperidin-1-yl)cyclohexyl)carbamate [0402] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (200 mg, 1 eq, 0.53 mmol) in MeOH (4 mL) was added tert-butyl (4-oxocyclohexyl)carbamate (336.9 mg, 3 eq, 1.58 mmol) and sodium cyanoborohydride (49.62 mg, 1.5 eq, 0.79 mmol) at room temperature. The reaction was stirred 80 °C for 5 hours under N2. LCMS indicated completion of reaction. The mixture was added water (50 mL), extracted with EA (30 mL X 3). The combined organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh size, 10 % MeOH in DCM) to give tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexyl)carbamate (99.9 mg, 0.17 mmol, 32.9 %) as a yellow oil. LC purity (0.1 %FA): 60.0 % (UV at 214 nm)/MS: 577.3 [M+H]; Retention time: 0.93 min. Synthesis of methyl 10-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0403] To a solution of tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)carbamate (100 mg, 1 eq, 0.17 mmol) in ethyl acetate (2 mL) was added HCl/ EA (2 mL, 46.2 eq, 8.00 mmol). The reaction was stirred 25 °C for 0.5 hour. LCMS indicated completion of reaction. The mixture was concentrated under vacuum. The resulting residue was purified prep-HPLC, eluted with CH₃CN in H₂O from 10% to 95% (0.1% FA) to give 10-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (4.23 mg, 0.01 mmol, 5.10 %) as a white solid. LC purity (0.1 %TFA): 93.35 % (UV at 214 nm)/MS: 477.2 [M+H]; Retention time: 0.88 min. Synthesis of 4-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0404] To a solution of 10-(1-(4-aminocyclohexyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (20 mg, 1 eq, 0.042 mmol) in DMSO (1.5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (34.8 mg, 3 eq, 0.13 mmol) and DIEA (27.1 mg, 5 eq, 0.21 mmol) at room temperature. The reaction was stirred at 120 °C for 3 hours under N₂. LCMS indicated completion of reaction. The reaction was purified by prep- HPLC, eluted with CH3CN in H2O from10% to 95% (0.1% NH3^.H2O) to give 4-((4-(4-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.02 mg, 0.002 mmol, 5.30 %) as a yellow solid. LC purity (0.1 %FA): 85.45 % (UV at 214 nm)/MS: 733.4 [M+H]; Retention time: 1.27 min.¹H NMR (400 MHz, MeOD) δ 8.44–8.46 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.85^7.89 (t, J = 8

Hz, 1H), 7.65^7.67 (d, J = 7.4 Hz, 1H), 7.55^7.59 (m, 2H), 7.33^7.35 (d, J = 7.6 Hz, 1H), 7.10^7.11 (m, 1H), 7.03^7.10 (m, 1H), 4.88^4.91 (m, 1H), 3.13-3.15 (m, 1H), 2.81^2.87 (m, 2H), 2.72^2.79 (m, 4H), 2.59^2.65 (m, 2H), 2.22^2.23 (m, 3H), 2.09^2.12 (m, 4H), 1.97^2.03 (m, 5H), 1.64^1.65 (m, 2H), 1.60 (s, 6H). Compound A12. 5-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidine-1-carbonyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-

dioe

Synthesis of tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)cyclohexyl)carbamate [0405] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (50 mg, 1 eq, 0.132 mmol) in DMF (3 mL) were 4-((tert-butoxycarbonyl)amino)cyclohexane- 1-carboxylic acid (48 mg, 1.5 eq, 0.197 mmol), HATU (75.1 mg, 1.5 eq, 0.197 mmol), DIEA (40 mg, 0.055 mL, 3 eq, 0.395 mmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H₂O (20 mL) and extracted with EA (20 mL X 3). The combined organics was washed brine (20 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (4% of MeOH in DCM) to afford tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)carbamate (70 mg, 0.115 mmol, 74.7 %) as white oil. LC purity (0.1%FA): 85.03 % (UV at 254 nm)/MS: 605.3 [M+H]; Retention time: 1.66 min. Synthesis of 9-(1-(4-aminocyclohexane-1-carbonyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one [0406] To a solution of tert-butyl (4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)carbamate (70 mg, 1 eq, 0.119 mmol) in HCl/EA (4 mL).The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford 9-(1-(4-aminocyclohexane-1- carbonyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50 mg, 0.099 mmol, 84.1 % yield) as a yellow solid. LC purity (0.1% FA): 100.0% (UV at 254 nm)/MS: 505.3 [M+H]; Retention time: 1.43 min. Synthesis of 5-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0407] To a solution of 9-(1-(4-aminocyclohexane-1-carbonyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 0.08 mmol) and 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (26.3 mg, 1.2 eq, 0.1 mmol) in DMSO (2 mL) was added DIEA (30.7 mg, 3 eq, 0.24 mmol). The mixture was stirred at 120 °C for 4 hours. LCMS indicated completion of reaction. The mixture was purified by prep-HPLC, eluted with CH₃CN in H₂O from 10% to 95% (0.1%NH₄HCO₃) to give 5-((4-(4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carbonyl)cyclohexyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (1.05 mg, 0.001 mmol, 1.63 %) as a yellow solid. LC purity (0.1%NH4HCO3): 93.52 % (UV at 254 nm)/MS: 761.4 [M+H]; Retention time: 1.583 min. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.40-8.42 (d, J = 8.4 Hz, 1H), 8.07-8.10 (d, J = 8.4 Hz, 1H), 7.67-7.82 (m, 1H), 7.59^7.67 (m, 2H), 7.55-7.58 (d, J = 8.4 Hz, 1H), 7.37-7.40 (d, J = 8.4 Hz, 1H), 7.00-7.01 (m, 1H), 6.89-6.90 (d, J = 8.4 Hz, 1H), 4.91-5.03 (m, 1H), 4.62-4.65 (d, J = 12.8 Hz, 1H), 4.14-4.16 (d, J = 12.4 Hz, 1H), 3.43-3.45 (m, 1H), 3.15-3.17 (m, 1H), 2.73-2.86 (m, 2H), 2.74^2.59 (m, 2H), 2.08^1.94 (m, 4H), 1.86-1.88 (m, 2H), 1.77-1.80 (m, 2H), 1.59^1.69 (m, 2H), 1.52 (s, 6H), 1.27^1.38 (m, 2H), 1.23-1.25 (m, 4H). Compound A13. (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 3-hydroxy-4-methylene-piperidine-1-carboxylate [0408] The suspension of SeO2 (61.8 g, 558 mmol, 0.55 eq) in DCM (3000 mL) was cooled to - 10 °C, before 2-hydroperoxy-2-methyl-propane in H2O (274 g, 291 mL, 2.10 eq, 70% purity) was added dropwise, and the resulting mixture was stirred for 30 min at -10 °C. The reaction mixture was further cooled to -30 °C, before a solution of compound 5-1 (200 g, 1.01 mol, 1 eq) in DCM (1000 mL) was added dropwise, and the resulting mixture was stirred for another 1 hr at -30 °C. The reaction mixture was warmed to 20 °C, and stirred for further 18 hrs, before the mixture was cooled to 0 °C, and was added ice chips and water (1.0 L). The resulting mixture was stirred at 0 °C for 30 min. The organic phase was separated, and the aqueous phase was extracted with DCM (500 mL), before the combined organic phase was added 10% w/v NaHSO₃ solution (1000 mL) portion-wise at 0 °C, during which period the temperature was maintained below 10 °C, and the mixture was stirred for further 5 min after the addition. The organic phase was separated, and the aqueous phase was extracted with DCM (500 mL). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate = 100/1 to 1/1). Compound 5-3 (370 g) was obtained as a white solid and the typical yield was 34.2%. ¹HNMR (400 MHz, DMSO-d₆) δ = 5.22 (br d, J = 3.9 Hz, 1H), 4.98 (s, 1H), 4.79 (s, 1H), 3.93 - 3.76 (m, 2H), 3.71 (td, J = 4.3, 12.6 Hz, 1H), 2.92 - 2.77 (m, 1H), 2.76 - 2.53 (m, 1H), 2.30 (td, J = 3.5, 13.4 Hz, 1H), 2.10 - 1.95 (m, 1H), 1.40 (s, 9H). Synthesis of tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0409] To the solution of Compound 5-3 (100 g, 469 mmol, 1.00 eq) in toluene (2000 mL) was add 2,6-dimethylpyridine (55.2 g, 60.0 mL, 516 mmol, 1.10 eq) at 15 °C. The mixture was cooled to 0 °C, before SOCl2 (66.9 g, 40.8 mL, 563 mmol, 1.20 eq) was added dropwise to the mixture under N₂ atmosphere, during which period the temperature was maintained below 10 °C. The mixture was stirred at 110 °C for 3 hrs, before cooled to 20 °C. Brine (2 x 600 mL) was added and the resulting mixture was stirred at 20 °C for 30 min. The organic phase was separated, before saturated NaHCO₃ solution (600 mL) was added portion-wise at 15 °C. The organic phase was separated, washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 5 (200 g) was obtained as a red oil and the typical yield was 49.0%.¹HNMR (400 MHz, CDCl₃-d) δ = 5.72 (br s, 1H), 3.98 (s, 2H), 3.88 (br s, 2H), 3.49 (br t, J = 5.6 Hz, 2H), 2.17 (br s, 2H), 1.43 (s, 9H). Synthesis of methyl 4-bromo-2-formyl-3-hydroxybenzoate [0410] The solutio

L) was added HMTA (485 g, 3.46 mol, 4.00 eq) at 20 °C, before the resulting mixture was stirred at 125 °C for 12 hrs. The mixture was cooled to 20 °C, quenched with 2N HCl solution (5 V), and yellow precipitate was observed. The mixture was stirred for 10 min, before additional H2O (5 V) was added, and the reaction mixture was stirred for further 1 hr. The mixture was filtered, and the filter cake was dissolved in DCM (2.0 L), filtered over celite, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Compound 2 (144 g) was obtained as a gray solid, and the typical yield was 64.2%.¹HNMR (400 MHz, DMSO-d₆) δ = 12.06 (br s, 1H), 10.38 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 3.87 (s, 3H). Synthesis of (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0411] To the s

alt) in MeOH (300 mL) was added DIPEA (9.37 g, 72.4 mmol, 12.6 mL, 1.05 eq), compound 2, (17.8 g, 69.0 mmol, 1.00 eq) and AcOH (6.22 g, 103 mmol, 5.92 mL, 1.50 eq) at 20 °C and stirred for 1.5 hrs, before NaBH₃CN (8.67 g, 138 mmol, 2.00 eq) was added portion-wise at 20 °C, and the resulting mixture was stirred at 20 °C for 3 hrs. The mixture was quenched by H2O (200 mL) at 20 °C and concentrated under reduced pressure. The solvent residue was then extracted with EtOAc (3 x 150 mL), and the combined organic layer was washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate = 1/1 to 100% Ethyl acetate). Compound 4 (23.0 g) was obtained as a yellow solid and the typical yield was 78.4%.¹HNMR (400 MHz, DMSO- d6) δ = 10.44 (s, 1H), 7.67 - 7.55 (m, 2H), 7.20 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.58 (d, J = 17.9 Hz, 1H), 4.39 (d, J = 17.9 Hz, 1H), 2.23 - 2.07 (m, 3H), 2.03 - 1.91 (m, 1H), 1.32 (s, 9H). Synthesis of (S)-tert-butyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1- oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate [0412] To the

so ut on o compound ( 50 g, 363 mmo , .00 eq) n eCN ( 000 mL) was added K2CO3 (150.49 g, 1.09 mmol, 3.00 eq), NaI (5.44 g, 0.36 mmol, 0.10 eq) and compound 5 (136 g, 472 mmol, 1.30 eq, 80% purity) at 20 °C. The reaction mixture was stirred at 60 °C for 12 hrs, before being cooled to 20 °C again. The resulting mixture was filtered, and filter cake was washed with DCM (2 x 500 mL). The filtrate was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate = 100/1 to 1/1). Compound 6 (337 g) was obtained as a red solid, and the typical yield was 72.4%.¹HNMR (400 MHz, CDCl3-d) δ = 7.67 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.33 (br s, 1H), 5.86 (br s, 1H), 5.48 (br s, 1H), 4.90 (dd, J = 6.3, 8.6 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.53 (s, 1H), 4.50 (br s, 2H), 3.98 (br s, 2H), 3.60 (br t, J = 5.5 Hz, 2H), 2.43 - 2.10 (m, 7H), 1.49 (s, 9H), 1.41 (s, 9H). Synthesis of tert-butyl 7-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-oxo-spiro[2,8- dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate [0413] T

L) was added AIBN (5.06 g, 0.03 mmol, 0.15 eq) and Bu3SnH (270 mL, 1.02 mmol, 4.98 eq) at 20 °C. The reaction mixture was stirred at 110 °C for 12 hrs, before being cooled to 20 °C. Saturated KF solution (1000 mL) was added and the resulting mixture was stirred at 20 °C for further 2 hrs. The mixture was filtered and the filter cake was washed by EtOAc (2 x 500 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate = 100/1 to 1/1). Compound 7 (160 g) was obtained as a white solid, and the typical yield was 56.6%.¹HNMR (400 MHz, CDCl₃-d) δ = 7.40 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.41 (br s, 1H), 5.61 (br s, 1H), 4.92 - 4.85 (m, 1H), 4.55 - 4.49 (m, 2H), 4.12 (q, J = 7.1 Hz, 3H), 2.88 (br t, J = 12.0 Hz, 2H), 2.40 - 2.09 (m, 5H), 1.94 - 1.82 (m, 2H), 1.77 - 1.68 (m, 2H), 1.50 - 1.47 (m, 9H), 1.42 - 1.40 (m, 9H). Synthesis of (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-7- yl)piperidine-2,6-dione benzenesulfonate [04 MeCN

(400 mL) was heated to 100 °C, before a solution of compound 7 (47.0 g, 62.1 mmol, 1.00 eq, 70% purity) in MeCN (100 mL) was added dropwise to the mixture. The mixture was stirred at 100 °C for 12 hrs, before being cooled to 20 °C. The mixture was filtered, and the filter cake was dried under reduce pressure. The title compound (37.0 g) was obtained as a white solid, and the typical yield was 92.8%.¹HNMR (400 MHz, D2O-d2) δ = 7.75 (br d, J = 7.4 Hz, 2H), 7.55 - 7.36 (m, 5H), 5.11 (br dd, J = 5.2, 13.4 Hz, 1H), 4.64 (s, 2H), 4.53 - 4.35 (m, 2H), 3.49 (br d, J = 13.2 Hz, 2H), 3.20 - 3.06 (m, 2H), 2.99 - 2.78 (m, 2H), 2.48 (dq, J = 5.3, 13.1 Hz, 1H), 2.25 - 2.08 (m, 3H), 2.05 - 1.93 (m, 5H). Synthesis of (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-7- yl)piperidine-2,6-dione hydrochloric acid

ne]-7- yl)piperidine-2,6-dione benzenesulfonate (37 g) in HCl/dioxane (4 M, 370 mL) was stirred at 20 °C for 12 hrs, before the mixture was filtered and the cake was washed with MeCN (2 x 200 mL). The filtered cake was dried under reduced pressure. The title compound (24.0 g) was obtained as a red solid, and the typical yield was 80.7%.¹HNMR (400 MHz, D₂O-d₂) δ = 7.48 - 7.36 (m, 2H), 5.12 (dd, J = 5.3, 13.3 Hz, 1H), 4.69 - 4.61 (m, 2H), 4.53 - 4.37 (m, 2H), 3.51 (br dd, J = 3.4, 13.3 Hz, 2H), 3.22 - 3.06 (m, 2H), 2.98 - 2.80 (m, 2H), 2.56 - 2.43 (m, 1H), 2.29 - 2.08 (m, 3H), 2.05 - 1.90 (m, 2H). Synthesis of 4-chloro-9-(1-(3-hydroxypropyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0416] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (150.0 mg, 1 eq, 0.39 mmol) in DMF (3 mL) were added 3-bromopropan-1-ol (82.32 mg, 1.5 eq, 0.59 mmol), sodium bicarbonate (331.7 mg, 10 eq, 3.95 mmol). The mixture was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added water (20 mL), extracted with EA (20 mL X 3). The combined organics were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh size, 10 % MeOH in DCM) to give 4-chloro-9-(1-(3-hydroxypropyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 0.23 mmol, 57.8 %) as a yellow solid. LC purity (0.1%FA): 100 % (UV at 214 nm)/MS: 438.2 [M+H]; Retention time: 1.08 min. Synthesis of 4-chloro-9-(1-(3-hydroxypropyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0417] To a solution of 4-chloro-9-(1-(3-hydroxypropyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (50.0 mg, 1 eq, 0.114mmol) in DCM (3 mL) was added MsCl (19.6 mg, 1.5 eq, 0.171 mmol) at 0 ℃, TEA (34.7 mg, 3 eq, 0.342 mmol). The mixture was stirred at 0 °C for 1 hour. LCMS indicated completion of reaction. The mixture was added water (20 mL), extracted with EA (20 mL X 3). The combined organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh size, 10 % MeOH in DCM) to give 4-chloro-9-(1-(3- hydroxypropyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50 mg, 1 eq, 0.114 mmol) as yellow oil. LC purity (0.1%FA): 94.05 % (UV at 214 nm)/MS: 516.2 [M+H]; Retention time: 1.14 min. Synthesis of (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0418] To a solution of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)propyl methanesulfonate (50 mg, 1 eq, 0.097 mmol) in DMF (3 mL) was added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (41.3 mg, 1.2 eq, 0.116 mmol), sodium bicarbonate (8.14 mg, 1 eq, 0.09 mmol). The mixture was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The mixture was purified by prep-HPLC, eluted with CH₃CN in H₂O from 10% to 90% (0.1%FA) to give (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (4.91 mg, 0.006 mmol, 6.2 %) as a white solid. LC purity (0.03%TFA): 99.43 % (UV at 254 nm)/MS: 775.4 [M+H]; Retention time: 1.167 min. ¹H NMR (400 MHz, CD₃OD) δ 8.40-8.42 (m, 1H), 8.08-8.10 (m, 1H), 7.82-7.86 (m, 1H), 7.65-7.67(m, 1H), 7.59 (s, 1H), 7.47-7.49 (m, 1H), 7.37-7.42 (m, 2H), 5.10-5.13 (m, 1H), 4.61 (s, 2H), 4.40-4.43 (m, 2H), 3.59-3.61 (m, 2H), 3.17-3.20 (m, 2H), 3.09-3.11 (m, 2H), 2.90-2.95 (m, 4H), 2.74-2.79 (m, 3H), 2.41-2.43 (m , 2H), 2.22-1.95 (m, 10H), 1.88-1.91 (m, 2H), 1.61 (s, 6H). Compound A14. (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)acetate [0419] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (80.0 mg, 1 eq, 225 μmol) in DMF (1 mL) were added sodium bicarbonate (37.8 mg, 2 eq, 450 μmol) and tert-butyl 2-bromoacetate (52.7 mg, 1.2 eq, 270 μmol).The reaction was stirred at 20 °C for 2 hours. LCMS indicated completion of reaction. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20mL X 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give tert-butyl (S)-2-(7-(2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'- yl)acetate (70 mg, 149 μmol, 66 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 470.3[ M+1]; Retention time: 0.84 min. Synthesis of (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)acetic acid [0420] A mixture of tert-butyl (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)acetate (35.0 mg, 1 eq, 74.5 μmol) in TFA (0.50 mL) and DCM (1.5 mL) was stirred at 20 °C for 3 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo- 7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)acetic acid (30 mg, 72.6 μmol, 97.3 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 414.2 [M+H]; Retention time: 0.49 min. Synthesis of (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0421] To a solution of (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)acetic acid (30.0 mg, 1 eq, 72.6 μmol) in DMF (1 mL) were added 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (30.3 mg, 1.1 eq, 79.8 μmol), HATU (33.1 mg, 1.2 eq, 87.1 μmol) and DIEA (28.1 mg, 37.9 μL, 3 eq, 218 μmol). The reaction was stirred at 20°C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H₂O from 10% to 90%(10 mmol/L NH₄HCO₃) to afford (S)-3-(1'-(2-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-2-oxoethyl)- 6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.17 mg, 6.45 μmol, 8.89 %) as a white solid. LC purity (0.1%FA): 96.73 % (UV at 254 nm)/MS: 775.4 [M+H]; Retention time: 1.533 min.¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.39- 8.42 (d, J = 8.8 Hz ,1H), 8.08-8.10 (d, J = 8.4 Hz ,1H), 7.80-7.84 (m, 1H), 7.62-7.63 (m, 1H), 7.35- 7.38 (t, J = 8.0 Hz, 2H), 7.26-7.28 (d, J = 7.6 Hz, 1H), 5.07-5.12 (m, 1H), 4.56-4.57 (m, 3H), 4.37- 4.41 (d, J = 17.2 Hz, 1H), 4.21-4.25 (m, 2H), 3.29-3.30 (m, 1H), 3.15-3.22 (m, 2H), 2.86-2.96 (m, 4H), 2.57-2.67 (m, 2H), 2.40-2.44 (m, 1H), 2.16-2.22 (m, 2H), 1.85-2.00 (m, 5H), 1.73-1.78 (m, 3H), 1.56-1.58 (m, 1H), 1.51 (s, 6H) Compound A15.3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

yl)piperidin-1-yl)ethyl methanesulfonate [0422] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 μmol) in DMF (1 mL) was added 2-bromoethan-1-ol (526 mg, 16 eq, 4.21 mmol) and K2CO3 (109 mg, 3 eq, 789 μmol). The mixture was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL X 2), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 4-chloro-10-(1-(2-hydroxyethyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (50.0 mg, 0.11 mmol, 40 %, 90% Purity) as a yellow oil. LC purity (0.1%FA): 89.60 % (UV at 254 nm)/MS: 424.2 [M+H]; Retention time: 1.06 min. Synthesis of 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)ethyl methanesulfonate [0423] To a solution of 4-chloro-10-(1-(2-hydroxyethyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (300 mg, 1 eq, 708 μmol) in DCM (1 mL) was added TEA (215 mg, 296 μL, 3 eq, 2.12 mmol)，MsCl (122 mg, 82.7 μL, 1.5 eq, 1.06 mmol). The mixture was stirred at 25 °C for 1 hour under N₂. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL X 2), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 6% of MeOH in DCM) to afford2-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)ethyl methanesulfonate (328 mg, 0.59 mmol, 83 %, 90% Purity) as a yellow solid. LC purity (0.1%FA): 97.94 % (UV at 254 nm)/MS: 502.1 [M+H]; Retention time: 1.111 min. Synthesis of 3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0424] To a solution of 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)ethyl methanesulfonate (36.0 mg, 1.1 eq, 71.7 μmol) in DMF (1 mL) were added sodium bicarbonate (16.4 mg, 7.61 μL, 3 eq, 196 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride (25.5 mg, 1 eq, 65.2 μmol). The mixture was stirred at 65 °C for 16 hours under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the resulting residue was purified by prep-HPLC, eluted with CH₃CN in H₂O from 10% to 95% (0.1%TFA) to afford 3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.67 mg, 7.24 μmol, 11.1 %) as a white solid. LC purity (0.1%FA): 97.48 % (UV at 254 nm)/MS: 761.3 [M+H]; Retention time: 1.098 min.¹H NMR (400 MHz, MeOD) δ 8.43-8.45 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.85-7.89 (t, J = 8.3 Hz, 1H), 7.61- 7.68 (m, 2H), 7.36-7.41 (m, 3H), 5.11-5.16 (m, 1H), 4.62 (s, 2H), 4.36-4.48 (m, 2H), 3.60-3.62 (d, J = 11.8 Hz, 2H), 3.13-3.20 (m, 4H), 3.01-3.09 (m, 1H), 2.85-2.99 (m, 5H), 2.73-2.82 (m, 1H), 2.40-2.54 (m, 3H), 2.12- 2.21 (m, 7H), 1.86-1.89 (d, J = 11.8 Hz, 2H), 1.60 (s, 6H). Compound A16.3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0425] To a solution of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)propyl methanesulfonate (35.0 mg, 1.1 eq, 67.8 μmol) in DMF (1 mL) were added sodium bicarbonate (15.5 mg, 7.19 μL, 3 eq, 185 μmol)，(S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride (24.2 mg, 1 eq, 61.7 μmol). The mixture was stirred at 65 °C for 16 hours under N₂. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95% (0.1% TFA) to afford 3-(1'-(3-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)propyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.17 mg, 6.52 μmol, 10.6 %) as a white solid. LC purity (0.1%FA): 92.71 % (UV at 254 nm)/MS: 775.4 [M+H]; Retention time: 1.028 min.¹H NMR (400 MHz, MeOD) δ 8.44-8.46 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.84-7.88 (t, J = 8.2 Hz, 1H), 7.62-7.68 (m, 2H), 7.36-7.44 (m, 3H), 5.12-5.17 (m, 1H), 4.70 (s, 2H), 4.38-4.50 (m, 2H), 3.65-3.85 (m, 4H), 3.13-3.29 (m, 7H), 2.71-2.98 (m, 3H), 2.43-2.57(m, 1H), 2.11-2.40 (m, 12H), 1.60 (s, 6H). Compound A17. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one [0426] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (300 mg, 1 eq, 790 μmol) in MeOH (2 mL) were added TEA (240 mg, 330 μL, 3 eq, 2.37 mmol), 4-(hydroxymethyl)cyclohexan-1-one (202 mg, 2 eq, 1.58 mmol), sodium cyanoborohydride (99.2 mg, 93.1 μL, 2 eq, 1.58 mmol) and the reaction was stirred at 65 °C for 4 hours. LCMS indicated completion of reaction. The reaction was concentrated and purified by prep-TLC (10% MeOH in DCM) to afford 4-chloro-10-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (220 mg, 0.42 mmol, 54 %, 95% purity) as a yellow solid. LC purity (0.1%TFA): 90 % (UV at 254 nm)/MS: 492.4 [M+H]; Retention time: 1.220 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde [0427] To a solution of 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (65.0 mg, 1 eq, 132 μmol) in DCM (1.5 mL) was added DMP (112 mg, 2 eq, 264 μmol), and the reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated and purified by prep-TLC (20% MeOH in DCM) to give 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (25.0 mg, 46 μmol, 35 %) as a white solid. LC purity (0.1%TFA): 84.5 % (UV at 254 nm)/MS: 490.4 [M+H]; Retention time: 1.247 min. Synthesis of (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0428] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (30.0 mg, 1 eq, 61.2 μmol) in DCM (0.5 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (26.1 mg, 1.2 eq, 73.5 μmol), TEA (9.29 mg, 12.8 μL, 1.5 eq, 91.8 μmol), AcOH (6.25 mg, 5.96 μL, 1.7 eq, 104 μmol) and sodium triacetoxyborohydride (25.9 mg, 18.1 μL, 2 eq, 122 μmol). The reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was purified by prep-HPLC, eluted with MeCN in H2O from 5% to 95% (0.1% FA) to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (15.39 mg, 18.49 μmol, 30.2 %) as a white solid. LC purity (0.1%FA): 96.07 % (UV at 254 nm)/MS: 829.4 [M+H]; Retention time: 1.06 min.¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s,1H), 8.46-8.47 (d, J = 8.8 Hz,1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.86-7.82 (m,,1H), 7.64-7.59 (m, 2H), 7.40-7.38 (m, 1H), 7.28- 7.25 (m, ,1H), 5.10-5.06 (m, 1H), 4.52 (s, 2H), 4.37 (d, J = 17.6 Hz,1H), 4.23-4.19 (m, 1H), 2.99- 2.95 (m, 3H), 2.90-2.79 (m, 3H), 2.67-2.56 (m, 3H), 2.40-2.32 (m, 4H), 2.12-2.10 (m, 3H), 1.98- 1.95 (m, 4H), 1.92-1.70 (m, 7H), 1.67-1.66 (m, 2H),1.50 (s, 6H),1.30-1.27 (m, 2H), 0.90-0.88 (m, 2H). Compound A18. (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-4-oxobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoate [0429] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (30 mg, 1 eq, 84.4 μmol) in DMF (1 mL) were added sodium bicarbonate (21.3 mg, 3 eq, 253 μmol) and tert-butyl 4-bromobutanoate (28.3 mg, 1.5 eq, 127 μmol). The re action was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added H2O (10 mL), extracted with EA (10 mL X 3). The combined organics were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under vacuum to afford tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)butanoate (37.0 mg, 59 μmol, 70 %, 81% purity) as white solid. LC purity (0.1%TFA): 81.89 % (UV at 254 nm)/MS: 498.4 [M+H]; Retention time: 0.939 min. Synthesis of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)butanoic acid [0430] To a solution of tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoate (60 mg, 1 eq, 121 μmol) in DCM (2 mL) was added TFA (20.6 mg, 13.9 μL, 1.5 eq, 181 μmol). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was filtered and the filtrate was concentrated under vacuum to afford (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro- 2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoic acid (49.0 mg, 0.10 mmol, 84 %, 91% purity) as white oil. LC purity (0.1%FA): 83.47 % (UV at 254 nm)/MS: 441.4 [M+H]; Retention time: 1.07 min. Synthesis of (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-4-oxobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0431] To a solution of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)butanoic acid (30 mg, 1 eq, 68.0 μmol) in DMF (1 mL) was added DIEA (26.3 mg, 3 eq, 204 μmol) and HATU (51.7 mg, 2 eq, 136 μmol). The mixture was stirred at room temperature for 0.5 hour. Then 4-chloro-7,7-dimethyl-9-(piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (31.0 mg, 1.2 eq, 81.5 μmol) was added and the reaction was stirred at 25 °C for 3 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 5% to 90% (0.03%NH4HCO3) to afford (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)-4-oxobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.13 mg, 3.74 μmol, 5.50 %) as a white solid. LC purity (0.1%NH4HCO3): 88.65 % (UV at 254 nm)/MS:803.4 [M+H]; Retention time: 1.27 min.¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.40-8.41 (d, J = 8.7 Hz, 1H), 8.08-8.10 (d, J = 8.5 Hz, 1H), 7.81-7.83 (t, J = 8.2 Hz, 1H), 7.67-7.56 (m, 2H), 7.37-7.39 (d, J = 7.0 Hz, 2H), 7.27-7.29 (d, J = 7.2 Hz, 1H), 5.11-5.06 (m, 1H), 4.75-4.46 (m, 3H), 4.38-4- 40 (d, J = 17.2 Hz, 1H), 4.21-4.23 (d, J = 17.4 Hz, 1H), 4.10-4.01(m, 1H), 3.17-3.11 (m, 2H), 2.99- 2.81 (m, 4H), 2.68-2.55 (m, 3H), 2.35-2.46 (m, 4H), 2.03-1.64 (m, 12H), 1.52 (s, 6H). Compound A19.5-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

in-

9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate [0432] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (70.0 mg, 1 eq, 184 μmol) in MeOH (1 mL) was added sodium cyanoborohydride (11.6 mg, 10.9 μL, 1 eq, 184 μmol), tert-butyl ((1s,4s)-4-formylcyclohexyl)carbamate (50.3 mg, 1.2 eq, 221 μmol), TEA (18.6 mg, 25.7 μL, 1 eq, 184 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (50% of EtOAc in PE) to afford tert-butyl ((1s,4s)-4-((4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1 yl)methyl)cyclohexyl)carbamate (86.0 mg, 87 μmol, 47 %)as a white solid. LC purity (0.1%TFA): 70 % (UV at 254 nm)/MS: 591 [M+H]; Retention time: 1.04 min. Synthesis of 9-(1-(((1s,4s)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one [0433] To a solution of tert-butyl ((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate (86.0 mg, 1eq, 145 μmol) in EA (1 mL) was added HCl/EA (0.3 mL) and the reaction was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The reaction was filtered and the residue was concentrated under vacuum to afford 9-(1-(((1s,4s)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4- chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50.0 mg, 102 μmol, 70.0 %) as a yellow solid. LC purity (0.1%FA): 79.56 % (UV at 254 nm)/MS: 491.2 [M+H]; Retention time: 0.91 min. Synthesis of 5-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0434] To a solution of 9-(1-(((1s,4s)-4-aminocyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 81.5 μmol) in DMSO (1 mL) was added DIEA (31.6 mg, 3 eq, 244 μmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione (33.7 mg, 1.5 eq, 122 μmol), and the reaction was stirred at 120 °C for 8 hours. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH₃CN in H₂O (0.1%FA) to give 5-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4.00 mg, 4.84 μmol, 5.94 %) as a yellow solid. LC purity (0.1 %FA): 97.69 % (UV at 254 nm)/MS: 747.4 [M+H]; Retention time: 1.28 min.¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.39-8.41 (d, J = 8.4Hz, 1H), 8.23 (s, 1H), 8.05-8.07 (d, J = 8.4 Hz, 1H), 7.79-7.83 (t, J = 16.4 Hz, 1H), 7.55^7.65 (m, 3H), 7.35-7.37 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 6.91-6.94 (m, 2H), 5.00-5.05 (m, 1H), 3.69-3.70 (m, 1H), 2.97-2.99 (d, J = 11.2Hz, 2H), 2.83-2.91 (m, 1H), 2.58-2.60 (m, 2H), 2.22-2.23 (d, J = 6.8 Hz, 2H), 1.96-2.03 (m, 3H), 1.78-1.73 (m, 5H), 1.63-1.55 (m, 6H), 1.52-1.53 (m, 7H), 1.38-1.43 (m, 2H). Compound A20. (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoate [0435] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (60.0 mg, 1 eq, 169 μmol) in DMF (4 mL) was added sodium bicarbonate (284 mg 20.0 eq, 3.38 mmol) and tert-butyl 3-bromopropanoate (106 mg, 3 eq, 506 μmol). The mixture was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H₂O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with saturated brine (20 mL X 3), dried over sodium sulfate, concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-70% of ethyl acetate in petroleum ether) to get tert-butyl (S)-3-(7-(2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'- yl)propanoate (40.0 mg, 79 μmol, 47 %) as a yellow solid. LC purity (0.1%FA): 87.87 % (UV at 254 nm)/MS: 631.4 [M+H]. Retention time: 1.023 min. Synthesis of (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid [0436] A solution of tert-butyl (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoate (40 g, 1 eq, 82.7 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to give (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo- 7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid (40.0 mg, 84 μmol, 0.10 %) as yellow oil. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 428.2 [M+H]; Retention time: 0.420 min. Synthesis of (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0437] To a solution of (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid (20.0 mg, 1 eq, 46.8 μmol) in DMF (1 mL) was added DIEA (18.1 mg, 3 eq, 140 μmol), 4-chloro-7,7-dimethyl-9-(piperidin-4- yl)indolo[1,2-a]quinazolin-5(7H)-one (17.8 mg, 1.0 eq, 46.8 μmol) and HATU (35.6 mg, 2 eq, 93.6 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction was poured into H₂O (20 mL) and extracted with EA (20 mL X 3). The combined organic layers were washed with saturated brine (20 mL X 3), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.05%FA) to give (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.10 mg, 1.15 μmol, 2.45 %) as a white solid. LC purity (0.1% FA): 100 % (UV at 254 nm)/MS: 789.4 [M+H]; Retention time: 1.350 min. ¹H NMR (400 MHz, MeOD) δ 8.42-8.45 (d, J = 8.6 Hz, 1H), 8.07-8.12 (t, J = 7.7 Hz, 1H), 7.84- 7.89 (t, J = 8.3 Hz, 1H), 7.54-7.69 (m, 2H), 7.29-7.51 (m, 2H), 5.08-5.39 (m, 1H), 4.73-4.75 (m, 1H), 4.61 (s, 1H), 4.41-4.56 (q, J = 17.1 Hz, 1H), 3.93-3.95 (m, 1H), 3.40- 3.60 (m, 1H), 3.15 (s, 3H), 2.98-3.02 (m, 4H), 2.91-2.93 (m, 1H), 2.79-2.81 (m, 2H), 2.47-2.50 (m, 1H), 2.15-2.17 (m, 2H), 2.03-2.05 (m, 2H), 1.81-1.83 (m, 4H), 1.61 (d, J = 4.1 Hz, 6H), 1.44-1.45 (m, 1H), 1.31-1.33 (m, 2H), 1.30-1.32 (m, 2H). Compound A21. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-chloro-9-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0438] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (200 mg, 1 eq, 526 μmol) in MeOH (2 mL) were added triethylamine (213 mg, 4 eq, 2.11 mmol), 4-(hydroxymethyl)cyclohexan-1-one (135 mg, 2 eq, 1.05 mmol) and sodium cyanotrihydroborate (66.2 mg, 2 eq, 1.05 mmol), and the reaction was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 30-40% of ethyl acetate in petroleum ether) to afford 4-chloro-9-(1-(4-(hydroxymethyl)cyclohexyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (320 mg, 0.52 mmol, 99 %) as yellow oil. LC purity (0.1%FA): 80 % (UV at 254 nm)/MS: 492.0 [M+H]; Retention time: 1.219 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde [0439] To a solution of 4-chloro-9-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (300 mg, 1 eq, 610 μmol) in DCM (2 mL) were added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (517 mg, 2 eq, 1.22 mmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford 4-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1- carbaldehyde (320 mg, 0.62 mmol, 100 %) as colorless oil. LC purity (0.1%FA): 92.55 % (UV at 254 nm)/MS: 490.3 [M+H]; Retention time: 1.193 min. Synthesis of tert-butyl 4-(2-oxoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [0440] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (60.0 mg, 1 eq, 122 μmol) in DCM (3 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (52.2 mg, 1.2 eq, 147 μmol), TEA (18.6 mg, 25.6 μL, 1.5 eq, 184 μmol), AcOH (12.5 mg, 11.9 μL, 1.7eq, 208 μmol), sodium triacetoxyborohydride (51.9 mg, 36.3 μL, 2 eq, 245 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH₃CN in H₂O (0.1%FA) to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.08 mg, 1.28 μmol, 1.04 %) as a white solid. LC purity (0.1%FA): 98.23 % (UV at 254 nm)/MS: 415.4 [1/2M+H]; Retention time: 8.214 min.¹H NMR (400 MHz, MeOD) δ 8.40 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.83-7.85 (m, 1H), 7.64-7.66 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.44- 7.46 (d, J = 8.4 Hz, 1H), 7.35-7.40 (m, 2H), 5.11-5.15 (m, 1H), 4.60-4.61 (d, J = 2.0 Hz, 2H), 4.36-4.48 (m, 2H), 3.62-3.69 (m, 2H), 3.14- 3.25 (m, 4H), 2.95-3.05 (m, 1H), 2.84-2.90 (m, 1H), 2.75-2.82 (m, 2H), 2.45-2.57 (m, 4H), 2.02- 2.30 (m, 10H), 1.94-1.96 (m, 2H), 1.85-1.89 (m, 2H), 1.65-1.83 (m, 4H), 1.61 (s, 6H), 1.18-1.28 (m 1H). Compound A22. (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione Sy

zolin- 5(7H)-one [0441] To a mixture of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 0.263 mmol), 2-bromoethan-1-ol (32.9 mg, 1 eq, 0.263 mmol) in DMF (3 mL) was added sodium bicarbonate (221 mg, 0.102 mL, 10 eq, 2.63 mmol). The mixture was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-10% of methanol in dichloromethane) to afford 4-chloro-9-(1-(2-hydroxyethyl)piperidin-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 0.236 mmol, 89.6 %) as a yellow solid. LC purity (0.1% FA): 39.29 % (UV at 254 nm)/MS: 423.9 [M+H]; Retention time: 1.26 min. Synthesis of 4-chloro-9-(1-(2-chloroethyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one [0442] To a mixture of 4-chloro-9-(1-(2-hydroxyethyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (100 mg, 1 eq, 0.236 mmol) in DCM (2 mL) and TEA (71.6 mg, 0.099 mL, 3 eq, 0.708 mmol)was added MsCl (40.5 mg, 0.028 mL, 1.5 eq, 0.354 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford 4-chloro-9-(1-(2-chloroethyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (80.0 mg, 0.0181 mmol, 76.7 %) as yellow oil. LC purity (0.1% FA): 58.65 % (UV at 254 nm)/MS: 442.2 [M+H]; Retention time: 1.16 min. Synthesis of (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0443] To a mixture of 4-chloro-9-(1-(2-chloroethyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (80.0 mg, 1 eq, 0.181 mmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (70.7 mg, 1.1 eq, 0.199 mmol) in DMF (1 mL) was added sodium bicarbonate (152 mg, 0.070 mL, 10 eq, 1.81 mmol). The mixture was stirred at 65 °C for 16 hours, LCMS indicated completion of reaction. The reaction was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by prep-HPLC (0.1% FA) to afford (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.30 mg, 0.002 mmol, 0.81 %) as a white solid. LC purity (0.03%TFA): 85.4% (UV at 214 nm)/MS: 761.3 [M+H]; Retention time: 5.685 min.¹H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.38-8.40 (m, 1H), 8.07-8.08 (m, 1H), 7.82-7.83 (m, 1H), 7.57-7.66 (m, 3H), 7.33-7.41 (m, 2H), 5.08-5.10 (m, 1H), 4.53-4.54 (m, 2H), 4.38-4.40 (m, 2H), 4.22-4.24 (m, 2H), 3.04 (d, J = 11.2 Hz, 3H), 2.90-2.92 (m, 3H), 2.67- 2.68 (m, 1H), 2.61-2.62 (m, 2H), 2.31- 2.45 (m, 2H), 2.08-2.10 (m, 4H), 1.85-2.02 (m, 4H), 1.79- 1.80 (m, 2H), 1.70-1.72 (m, 2H), 1.52 (s, 6H). Compound A23. (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione N Br N DMP, DCM N N OH N N N NH O OH N O Synt

olo[1,2- a]quinazolin-5(7H)-one [0444] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 μmol) in ACN (200 mL) was added4-bromobutan-1-ol (201 mg, 5 eq, 1.32 mmol)，K2CO3 (182 mg, 5 eq, 1.32 mmol) .The mixture was stirred at 25 °C for 16 hours under N₂. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 13% of MeOH in DCM) to afford4-chloro-10-(1-(4-hydroxybutyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (70.0 mg, 0.14 mmol, 53 %, 90% Purity) as a yellow solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 452.8 [M+H]; Retention time: 1.12 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)butanal [0445] To a solution of 4-chloro-10-(1-(4-hydroxybutyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (20.0 mg, 1 eq, 44.2 μmol) in DCM (1mL) was added DMP (28.2 mg, 1.5 eq, 66.4 μmol).The mixture was stirred at 25 °C for 3 hour under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum to afford 4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)butanal (25.0 mg, 55.6 μmol, 126 %) as a white solid. LC purity (0.1%FA): 50 % (UV at 254 nm)/MS: 450.2 [M+H]; Retention time: 1.09 min. Synthesis of (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)butyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0446] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)butanal (20.0 mg, 1 eq, 44.4 μmol) in DCM (1 mL) was added(S)-3-(6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (15.8 mg, 1 eq, 44.4 μmol)，triethylamine (6.75 mg, 1.5 eq, 66.7 μmol) and acetic acid (4.54 mg, 1.7 eq, 75.6 μmol).The mixture was stirred at 25 °C for 1 hour. Then sodium triacetoxyhydroborate (18.8 mg, 2 eq, 88.9 μmol) was added in the mixture and stirred 25 °C for 1 hour. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the resulting residue was purified by prep-HPLC, eluted with CH₃CN in H₂O from 10% to 95% (0.1% FA) to afford (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.82 mg, 1.98 μmol, 4.46 %) as a white solid. LC purity (0.1%FA): 84.4 % (UV at 254 nm)/MS: 791.4 [M+H]; Retention time: 1.157 min.¹H NMR (400 MHz, MeOD-d4) δ 8.42-8.49 (d, J = 8.4 Hz, 1H), 8.15-8.31 (m, 1H), 7.99 (s, 1H), 7.83-7.91 (m, 1H), 7.61-7.68 (m, 2H), 7.37 (s, 2H), 4.63 (s, 2H), 4.36-4.48 (m, 3H), 3.58-3.64 (m, 2H), 2.81- 3.31 (m, 10H), 2.43-2.65 (m, 3H), 2.10-2.23 (m, 7H), 1.73-2.02 (m, 7H), 1.60 (s, 6H). Compound A24. (S)-3-(1'-((3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-chloro-9-(1-(3-(hydroxymethyl)cyclobutyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one [0447] To a solution of 3-(hydroxymethyl)cyclobutan-1-one (50 mg, 1 eq, 499 μmol) in MeOH (2 mL) were added 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (133 mg, 0.7 eq, 350 μmol), TEA (50.5 mg, 69.6 μL, 1 eq, 499 μmol), NaCNBH₄ (94.1 mg, 3 eq, 1.50 mmol). The mixture was stirred at 25 °C for 4 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10 % of MeOH in DCM) to afford 4-chloro-9-(1-(3- (hydroxymethyl)cyclobutyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (70.0 mg, 0.14 mmol, 27 %) as a yellow solid. LC purity (0.1%FA): 86.5 % (UV at 254 nm)/MS: 464.2 [M+H]; Retention time: 1.09 min. Synthesis of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclobutane-1-carbaldehyde [0448] To a solution of 4-chloro-9-(1-(3-(hydroxymethyl)cyclobutyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (50. mg, 1 eq, 108 μmol) in DCM (2 mL) was added DMP (137 mg, 3 eq, 323 μmol), the mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10 % of MeOH in DCM) to afford 3- (4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)cyclobutane-1-carbaldehyde (30. mg, 52 μmol, 48 %) as a yellow solid. LC purity (0.1% TFA): 90 % (UV at 254 nm)/MS: 462.1 [M+H]; Retention time: 1.09 min. Synthesis of tert-butyl (S)-3-(1'-((3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0449] To a solution of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclobutane-1-carbaldehyde (10 mg, 1 eq, 21.65 μmol) in MeOH (1 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (9.231 mg, 1.2 eq, 25.97 μmol), AcOH (1.30 mg, 1.239 μL, 1 eq, 21.65 μmol), TEA (2.19mg, 3.02 μL, 1 eq, 21.65 μmol) and NaCNBH4 (4.081 mg, 3 eq, 64.94 μmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The reaction mixture was diluted with water (20 mL), extracted with DCM (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95% (0.1% FA) to afford (S)-3-(1'-((3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.32 mg, 4.12 μmol, 19.0 %) as a white solid. LC purity (0.1%FA): 89.49 % (UV at 254 nm)/MS: 801.4 [M+H]; Retention time: 1.15 min.¹H NMR (400 MHz, MeOD-d₄) δ 8.43-8.49 (d, J = 8.8 Hz, 1H), 8.11-8.17 (d, J = 8.8 Hz, 1H), 7.83-7.87 (m, 1H), 7.65-7.57 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 8Hz, 1H), 7.36-7.42 (m, 2H), 5.11-5.15 (m, 1H), 4.59-4.61 (m, 2H), 4.37-4.48 (m, 2H), 3.43-3.48 (m, 2H), 3.13-3.17 (m, 2H), 2.44-2.95 (m, 14H), 2.10-2.18 (m, 5H), 1.88-1.99 (m, 6H), 1.62 (s, 6H). Compound A25. (S)-3-(1'-((3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0450] To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (50.0 mg, 1 eq, 294 μmol) in THF (1 mL) was added BH3^.THF (42.4 mg, 48.2 μL, 1.9 eq, 558 μmol) at 0 ^oC .The mixture was stirred at 25 °C for 2 hours . TLC indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.¹H NMR (400 MHz, CDCl₃) δ 3.61 (s, 4H), 3.56 (s, 2H), 1.94-2.03 (d, J = 10.0 Hz, 6H), 1.88 (s, 1H). Synthesis of tert-butyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid [0451] To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (50.0 mg, 1 eq, 320 μmol) in MeOH (0.5 mL) was added methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane- 1-carboxylate (50.0 mg, 1 eq, 320 μmol), NaOH (25.6 mg, 2 eq, 640 μmol). The mixture was stirred at 25 °C for 2 hours. TLC indicated completion of reaction. The reaction was concentrated under vacuum and the residue resuspended in water (10 mL). The aqueous phase was washed with DCM (10 mL X 3) then acidified to ~pH 1 with 3 M HCl. The acidified aqueous phase was extracted with EtOAc (10 mL X3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1- carboxylic acid (6.00 mg, 21 μmol, 6.6 %,) as a white solid.¹H NMR (400 MHz, MeOD-d₄) δ 3.52 (s, 2H), 1.94 (s, 6H). Synthesis of tert-butyl 4-chloro-9-(1-(3-(hydroxymethyl)bicyclo[1.1.1]pentane-1- carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one [0452] To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (110 mg, 1 eq, 774 μmol) in DMF (5 mL) was added HATU (441 mg, 1.5 eq, 1.16 mmol) ,4-chloro-7,7-dimethyl- 9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (441 mg, 1.5 eq, 1.16 mmol), DIEA (300 mg, 404 μL, 3 eq, 2.32 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (50% EtOAc in PE) to afford as a white solid. LC purity (0.1%FA): 88.62 % (UV at 254 nm)/MS: 503[M+1]; Retention time: 1.487 min. Synthesis of tert-butyl (3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate [0453] To a solution of 4-chloro-9-(1-(3-(hydroxymethyl)bicyclo[1.1.1]pentane-1- carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50.0 mg, 1 eq, 99.2 μmol) in DCM (1 mL) was added methanesulfonyl chloride (17.0 mg, 11.5 μL, 1.5 eq, 149 μmol), TEA (30.1 mg, 41.5 μL, 3 eq, 298 μmol). The mixture was stirred at 25 °C for 1 hour. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (10% of MeOH in DCM) to afford tert-butyl (3-(4-(4-chloro-7,7-dimethyl- 5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1- yl)methyl methanesulfonate as a yellow solid. LC purity (0.1%FA): 64.15 % (UV at 254 nm)/MS: 582 [M+1]; Retention time: 1.579 min. Synthesis of (S)-3-(1'-((3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0454] To a mixture of (3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (100 mg, 1 eq, 172 μmol) in DMF (4 mL) was added sodium bicarbonate (144 mg, 66.8 μL, 10 eq, 1.72 mmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (61.1 mg, 1 eq, 172 μmol). The mixture was stirred at 65 °C for 16 hours. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted by CH3CN in H2O (0.1%FA) to afford (S)-3-(1'-((3-(4-(4-chloro-7,7-dimethyl- 5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1- yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (1.60 mg, 1.89 μmol, 1.10 %) as a white solid. LC purity (0.1%FA): 50% (UV at 254 nm)/MS: 841 [M+H]; Retention time: 1.30 min.¹H NMR (400 MHz, MeOD-d₄) δ 8.42-8.46 (d, J = 8.0 Hz, 1H), 8.07-8.13 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 16 Hz 1H), 7.64-7.67 (m, 1H), 7.57-7.58 (m, 1H),7.35-7.44 (m, 3H), 5.10-5.17 (m, 2H), 4.58-4.61 (m, 7H), 4.36-4.47 (m, 2H), 3.47-3.49 (m, 1H), 3.13-3.17 (m, 2H), 2.75-2.90 (m, 4H), 2.36-2.51 (m, 3H), 2.21-2.27 (m, 5H), 2.09-2.17 (m, 3H), 1.91-1.92 (m, 4H), 1.64-1.71(m, 1H), 1.60-1.67(s, 6H). Compound A26. (S)-3-(1'-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A27. (S)-3-(1'-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Syn

y y y y y , y , o[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0455] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (200.0 mg, 1 eq, 562.8 μmol) in MeOH (1 mL) was added TEA (20.0 mg, 27.5 μL, 0.351eq, 198 μmol) and AcOH (20.0 mg, 19.1 μL, 0.592 eq, 333 μmol) and 4-(hydroxymethyl)cyclohexan-1-one (86.56 mg, 1.2 eq, 675.3 μmol) and sodium cyanoborohydride (42.44 mg, 39.81 μL, 1.2 eq, 675.3 μmol). The reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added water (20 mL), extracted with (MeOH/DCM= 10/1) (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by prep-TLC (MeOH/DCM=1/10) to get (S)-3-(1'-(4-(hydroxymethyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (200 mg, 428 μmol, 76.0 %) as a yellow solid. LC purity (0.03% TFA): 95.0 % (UV at 254 nm)/MS: 468.4 [M+H]; Retention time: 0.566 min. Synthesis of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)cyclohexane-1-carbaldehyde [0456] To a solution of (S)-3-(1'-(4-(hydroxymethyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (200 mg, 1 eq, 428 μmol) in DCM (2 mL) was added DMP (363 mg, 2 eq, 855 μmol). The reaction was stirred at 25 °C for 2 hours. LCMS indicated completion of reaction. The mixture was added water (20 mL), extracted with MeOH/DCM (10/1) (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica prep-TLC (MeOH: DCM=1:10) to give (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)cyclohexane-1-carbaldehyde (150 mg, 322 μmol, 75.3 %) as a yellow solid. LC purity (0.03% FA): 96.34 % (UV at 254 nm)/MS: 466.3 [M+H]; Retention time: 0.585 min. Synthesis of (S)-3-(1'-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0457] To a solution of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)cyclohexane-1-carbaldehyde (30.0 mg, 1 eq, 64.4 μmol) in DCM (2 mL) was added 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one (29.4 mg, 1.2 eq, 77.3 μmol) and AcOH (20.0 mg, 19.1 μL, 5.17 eq, 333 μmol) and TEA (20.0 mg, 27.5 μL, 3.07 eq, 198 μmol) and sodium triacetoxyborohydride (27.3 mg, 19.1 μL, 2 eq, 129 μmol). The reaction was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The mixture was added water (20 mL), extracted with MeOH/DCM (1/1) (30 mL). The organic layer was dried over Anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1%FA) to give compound 26 (S)-3-(1'-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.19 mg, 1.31 μmol, 2.04 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 829.4 [M+H]; Retention time: 0.684 min. ¹H NMR (400 MHz, MeOD) δ 8.42-8.47 (d, J = 8.4 Hz, 1H), 8.09-8.14 (d, J = 8.4 Hz, 1H), 7.85- 7.91 (t, J = 8.3 Hz, 1H), 7.66-7.80 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.30-7.52 (m, 3H), 5.135.24 (dd, J = 13.1, 5.2 Hz, 2H), 4.62-4.63 (m, 3H), 4.20-4.53 (m, 3H), 3.13-3.15 (m, 1H), 2.71-3.01 (m, 6H), 2.63-2.65 (m, 4H), 2.47-2.55 (m, 1H), 2.21-2.30 (m, 5H), 2.01-2.05 (m, 7H), 1.86-1.88 (m, 1H), 1.71-1.72 (m, 1H), 1.61 (s, 6H), 1.53-1.55 (m, 2H), 1.07-1.41 (m, 2H), and compound 27 (S)- 3-(1'-(4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.65 mg, 1.75 μmol, 2.72 %) as a white solid. LC purity (0.1%FA): 100 % (UV at 254 nm)/MS: 829.4 [M+H]; Retention time: 0.708 min.¹H NMR (400 MHz, MeOD-d4) δ 8.44-8.49 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.87-7.93 (t, J = 8.4 Hz, 1H), 7.67-7.72 (d, J = 8.0 Hz, 1H), 7.60-7.64 (d, J = 7.6 Hz, 1H), 7.16-7.53 (m, 3H), 5.13-5.15 (m, 1H), 4.63 (s, 2H), 4.42- 4.45 (m, 2H), 3.13-3.15 (m, 1H), 2.83-2.90 (m, 7H), 2.63-2.65 (m, 3H), 2.50-2.52 (m, 1H), 2.34- 2.36 (m, 1H), 2.16-2.20 (m, 5H), 2.05-2.07 (m, 5H), 1.99-2.01 (m, 3H), 1.87-1.90 (m, 1H), 1.72- 1.75 (m, 2H), 1.56 (s, 6H), 1.41-1.53 (m, 2H), 1.30 (d, J = 5.7 Hz, 1H), 1.17-1.20 (m, 1H). Compound A28. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0458] To a solution of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (100 mg, 1 eq, 504 μmol) in THF (2 mL) was added BH₃ ^.THF (49.8 mg, 328 μL, 2.00 molar, 1.3 eq, 656 μmol) at 0 °C for 15 mins. The mixture was stirred at 25 °C for 16 hours under N₂. LCMS indicated completion of reaction. The reaction was quenched with MeOH, and refluxed at 70 ℃. The reaction was poured into water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (30% ethyl acetate in petroleum ether)) to afford methyl 4- (hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate (70.0 mg, 380 μmol, 75.3 %) as yellow oil. LC purity (0.1%FA): 62.80 % (UV at 280 nm)/MS: 185.2 [M+H]; Retention time: 1.18 min. Synthesis of 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylic acid [0459] To a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate (70.0 mg, 1 eq, 380 μmol) in H₂O (1mL) and THF (3 mL) was added LiOH (18.2 mg, 2 eq, 760 μmol). The mixture was stirred at 25 °C for 2 hours under N₂. LCMS indicated completion of reaction. The reaction was diluted with water (20 mL), adjusted with 1M HCl until pH = 5. The mixture was extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1- carboxylic acid (60.0 mg, 353 μmol, 92.8 %) as a yellow solid. LC purity (0.1%FA): 49.41 % (UV at 280 nm)/MS: 171.0 [M+H]; Retention time: 0.64 min. Synthesis of 4-chloro-10-(1-(4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carbonyl)piperidin-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one [0460] To a solution of 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylic acid (60.0 mg, 1 eq, 353 μmol) in DMF (2 mL) was added HATU (201 mg, 1.5 eq, 529 μmol), 4-chloro-7,7- dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one (134 mg, 1 eq, 353 μmol) and DIEA (137 mg, 184 μL, 3 eq, 1.06 mmol). The mixture was stirred at 25 °C for 16 hours under N2. LCMS indicated completion of reaction. The reaction was poured into water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (MeOH/DCM=1/30) to afford 4-chloro-10-(1-(4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carbonyl)piperidin-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (60.0 mg, 113 μmol, 32.0 %) as a yellow solid. LC purity (0.1%FA): 51.25 % (UV at 254 nm)/MS: 532.2 [M+H]; Retention time: 1.52 min. Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin- 6-yl)butyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide [0461] To a solution of 4-chloro-10-(1-(4-(hydroxymethyl)bicyclo[2.2.1]heptane-1- carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 75.2 μmol) in DCM (2 mL) was added DMP (63.8 mg, 2 eq, 150 μmol) at 0℃ . The mixture was stirred at 25 °C for 2 hours under N₂. LCMS indicated completion of reaction. The reaction was poured into water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (MeOH / DCM=1 / 20) to afford 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptane-1- carbaldehyde as a yellow solid. LC purity (0.1%FA): 27.64 % (UV at 254 nm)/MS: 530.2 [M+H]; Retention time: 1.54 min Synthesis of (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0462] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptane-1-carbaldehyde (20.0 mg, 1 eq, 37.7 μmol) in MeOH (2.00 mL)was added(S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (13.4 mg, 1 eq, 37.7 μmol), AcOH (4.53 mg, 4.32 μL, 2 eq, 75.5 μmol), TEA (7.64 mg, 10.5 μL, 2 eq, 75.5 μmol) and Sodium cyanoborohydride (3.79 mg, 3.56 μL, 1.6 eq, 60.4 μmol). The mixture was stirred at 25 °C for 5 hours. LCMS indicated completion of reaction. The reaction was quenched by water (30 mL), washed with EA (30 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The reaction was concentrated and purified by prep-HPLC, eluted with MeCN in H₂O (0.1%FA) to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.00 mg, 2.26 μmol, 6.00 %) as a white solid. LC purity (0.1%FA): 77.63 % (UV at 254 nm)/MS: 869.8 [M+H]; Retention time: 1.32 min.¹H NMR (400 MHz, MeOD-d4) δ 8.44-8.45 (m, 1H), 7.97 (s, 1H), 7.86- 7.88 (m, 1H), 7.66-7.75 (dd, J = 7.9, 0.7 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.37-7.40 (m, 3H), 5.13-5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.62 (s, 2H), 4.42 (q, J = 17.0 Hz, 3H), 3.34-3.35 (m, 1H), 3.24-3.25 (m, 1H), 3.10-3.12 (m, 2H), 2.85-2.96 (m, 3H), 2.73-2.82 (m, 2H), 2.66-2.67 (m, 2H), 2.50-2.54 (m, 1H), 2.12-2.24 (m, 3H), 1.96-2.07 (m, 6H), 1.81-1.91 (m, 6H), 1.63-1.78 (m, 4H), 1.59 (s, 6H), 1.20-1.44 (m, 1H). Compound A29. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Syn

- - - - - y y y y . . p - - y p p n-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one [0463] To a solution of 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylic acid (100 mg, 1 eq, 588 μmol) in DMF (2 mL) was added HATU (335 mg, 1.5 eq, 881 μmol) and DIEA (228 mg, 307 μL, 3 eq, 1.76 mmol) and 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (211 mg, 1 eq, 588 μmol). The mixture was stirred at 25 °C for 16 hours under N₂. LCMS indicated completion of reaction. LCMS indicated completion of reaction. The reaction was poured into water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (DCM/MeOH=20/1) to afford 4-chloro-9-(1-(4- (hydroxymethyl)bicyclo[2.2.1]heptane-1-carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (80.0 mg, 150 μmol, 25.6 %) as a yellow solid. LC purity (0.1%FA): 48.28 % (UV at 254 nm)/MS: 532.2 [M+H]; Retention time: 1.52 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptane-1-carbaldehyde [0464] To a solution of 4-chloro-9-(1-(4-(hydroxymethyl)bicyclo[2.2.1]heptane-1- carbonyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40.0 mg, 1 eq, 75.2 μmol) in DCM (2 mL) was added DMP (63.8 mg, 2 eq, 150 μmol) at 0 °C for 15 minutes. The mixture was stirred at 25 °C for 2 hours under N₂. LCMS indicated completion of reaction. The reaction was quenched by aq. sodium thiosulfate (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-TLC (5% MeOH in DCM) to afford 4-(4-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidine-1- carbonyl)bicyclo[2.2.1]heptane-1-carbaldehyde (20.0 mg, 37.7 μmol, 50.2 %) as a yellow solid. LC purity (0.1% FA): 64.11% (UV at 254 nm)/MS: 530.2[M+H]; Retention time: 1.58 min. Synthesis of (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0465] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptane-1-carbaldehyde (20.0 mg, 1 eq, 37.7 μmol) in MeOH (2 mL)was added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (13.4 mg, 1 eq, 37.7 μmol), AcOH (4.53 mg, 4.32 μL, 2 eq, 75.5 μmol), TEA (7.64 mg, 10.5 μL, 2 eq, 75.5 μmol) and sodium cyanoborohydride (3.79 mg, 3.56 μL, 1.6 eq, 60.4 μmol). The mixture was stirred at 25 °C for 5 hours. LCMS indicated completion of reaction. The reaction was poured into water (20 mL), extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H₂O (0.1%FA) to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidine-1-carbonyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.04 mg, 2.34 μmol, 6.21 %) as a white solid. LC purity (0.1%FA): 78.4 % (UV at 254 nm)/MS: 869.8 [M+H]; Retention time: 1.32 min.¹H NMR (400 MHz, MeOD-d4) δ 8.42-8.47 (d, J = 8.6 Hz, 1H), 8.07-8.12 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.35-7.44 (m, 3H), 5.13-5.23 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (s, 2H), 4.42-4.56 (q, J = 17.0 Hz, 3H), 3.34-3.35 (m, 1H), 3.20-3.22 (m, 1H), 2.98-3.00 (m, 2H), 2.89-2.91 (m, 3H), 2.71-2.81 (m, 2H), 2.60-2.62 (m, 2H), 2.52-2.43 (m, 1H), 2.17-2.20 (m, 3H), 1.97-2.03 (m, 6H), 1.83-1.86 (m, 6H), 1.72-1.63 (m, 4H), 1.61 (s, 6H), 1.36-1.38 (m, 1H). Compound A30. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione S

y y y y y y p p y , y 1,2- a]quinazolin-5(7H)-one (Intermediate 3) [0466] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-3-yl)indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 μmol) in MeOH (4 mL) was added sodium cyanoborohydride (24.8 mg, 23.3 μL, 1.5 eq, 395 μmol) and 4-(hydroxymethyl)cyclohexan-1-one (67.5 mg, 2 eq, 526 μmol) and TEA (133 mg, 183 μL, 5 eq, 1.32 mmol). The mixture was stirred at 60 °C for 16 hours. LCMS indicated completion of reaction. The reaction mixture was poured into water (20 mL), extracted with DCM (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concerntrated under vacuum. The resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 4-chloro-10-(4-(4- (hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (117 mg, 238 μmol, 90.3 %) as a yellow solid. LC purity (0.1%FA): 84.36 % (UV at 254 nm)/MS: 492.2 [M+H]; Retention time: 1.17 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperazin-1-yl)cyclohexane-1-carbaldehyde [0467] To a solution of 4-chloro-10-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (20.0 mg, 1 eq, 40.6 μmol) in MeCN (3 mL) was added DMP (28.5 mg, 2.5 eq, 102 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reactionwas filtered and the filtrate was concerntrated under vacuum. The resulting residue was concentrated under vacuum to afford 4-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1-yl)cyclohexane-1- carbaldehyde (15.0 mg, 30.6 μmol, 75.3 %) as colorless oil. LC purity (0.1%FA): 81.88 % (UV at 254 nm)/MS: 490.2 [M+H]; Retention time: 1.24 min. Synthesis of (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-1 0-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4' -piperidin]-7-yl)piperidine-2,6-dione [0468] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (15.0 mg, 1 eq, 30.5 μmol) in DCM (3.00 mL) was added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (10.9 mg, 1 eq, 30.5 μmol) and AcOH (16.6 mg, 15.9 μL, 9.2 eq, 277 μmol) and TEA (24.7 mg, 34.1 μL, 8.0 eq, 244 μmol) and Sodium triacetoxyborohydride (69.1 mg, 10.0 eq, 326 μmol). The mixture was stirred at 25 °C for 16 hours. LCMS indicated completion of reaction. The reaction mixture was poured into water (20 mL), extracted with DCM (20 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concerntrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1%FA) to give (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.14 mg, 1.25 μmol, 3.06 %) as a white solid. LC purity (0.1%FA): 92.0 % (UV at 254 nm)/MS: 830.4 [M+H]; Retention time: 0.88 min.¹H NMR (400 MHz, MeOD-d₄) δ 8.40-8.41 (m, 1H), 7.83-7.92 (m, 1H), 7.62-7.71 (m, 2H), 7.55-7.66 (m, 1H), 7.41-7.49 (m, 2H), 7.07-7.12 (s, 1H), 4.71-4.86 (s, 2H), 4.37-4.49 (m, 2H), 3.73-3.89 (s, 4H), 3.16-3.26 (s, 3H), 2.91-3.02 (s, 2H), 2.80-2.88 (s, 1H), 2.51- 2.62 (m, 2H), 2.37-2.44 (m, 4H), 2.11-2.19 (m, 7H), 1.97-2.10 (m, 3H), 1.86-1.96 (m, 3H), 1.74- 1.86 (m, 2H), 1.57-1.66 (m, 6H), 1.28-1.34 (m, 2H). Compound A31. (S)-3-(1'-(1-((1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)piperidine-1-carboxylate (Intermediate 3) [0469] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 141 μmol) in MeOH (3 mL) was added tert- butyl 4-oxopiperidine-1-carboxylate (56.1 mg, 2 eq, 281 μmol). Sodium cyanoborohydride (13.3 mg, 1.5 eq, 211 μmol) was added after 1 h. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl (S)-4-(7-(2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'- yl)piperidine-1-carboxylate (42.0 mg, 78.0 μmol, 55.4%) as a white solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 539.4 [M+H]; Retention time: 1.12 min. Synthesis of (S)-3-(6-oxo-1'-(piperidin-4-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (Intermediate 4) [0470] To a solution of tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)piperidine-1-carboxylate (42.0 mg, 1 eq, 78.0 μmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at 0 °C for 1 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford (S)-3-(6- oxo-1'-(piperidin-4-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (62.0 mg, 110 μmol, 141%) as a yellow solid. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 439.2 [M+H]; Retention time: 0.14 min. Synthesis of (1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-4-yl)methyl methanesulfonate (Intermediate 6) [0471] To a solution of 4-chloro-10-(4-(hydroxymethyl)piperidin-1-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (65.0 mg, 1 eq, 159 μmol) in DCM (1 mL) were added TEA (48.1 mg, 3 eq, 476 μmol)，MsCl (27.2 mg, 1.5 eq, 238 μmol). The mixture was stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-4-yl)methyl methanesulfonate (70 mg, 0.13 mmol, 81%) as a yellow oil. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 488.2 [M+H]; Retention time: 1.88 min. Synthesis of (S)-3-(1'-(1-((1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0472] To a solution of (S)-3-(6-oxo-1'-(piperidin-4-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (60 mg, 1 eq, 137 μmol) in DMF (2 mL) were added sodium bicarbonate (34.5 mg, 3 eq, 410 μmol)， (1-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-4-yl)methyl methanesulfonate (73.4 mg, 1.1 eq, 151 μmol) and sodium iodide (20.5 mg, 1 eq, 137 μmol). The mixture was stirred at 65 °C for 16 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC, eluted with CH3CN in H2O from 10% to 95% (0.1% FA) to afford (S)- 3-(1'-(1-((1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-4- yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.93 mg, 2.17 μmol, 1.58%) as a yellow solid. LC purity (0.1% FA): 90.96% (UV at 254 nm)/MS: 415.8 [1/2M+H]; Retention time: 1.184 min.1H NMR (400 MHz, MeOD-d4) δ 8.40-8.42 (d, J = 8.3 Hz, 1H), 7.83-7.87 (t, J = 8.3 Hz, 1H), 7.64-7.66 (d, J = 7.4 Hz, 1H), 7.43-7.32 (m, 3H), 7.11 (s, 1H), 6.59-63.61 (m, 1H), 5.15-5.10 (m, 1H), 4.60 (s, 2H), 4.35- 4.47 (m, 2H), 3.65- 3.47 (m, 6H), 3.21-3.07 (m, 4H), 2.98-3.05 (m, 2H), 2.90-2.85 (m, 1H), 2.73- 2.82 (m, 3H), 2.47-2.58 (m, 3H), 2.39-2.45 (m, 1H), 2.26-2.34 (m, 1H), 2.05-2.21 (m, 5H), 1.96 - 1.81 (m, 6H), 1.52-1.60 (m, 6H). Compound A32. (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(6-oxo-1'-(1,4-dioxaspiro[4.5]decan-8-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 3) [0473] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (60 mg, 1 eq, 169 μmol) in MeOH (2 mL) were added 1,4- dioxaspiro[4.5]decan-8-one (31.6 mg, 1.2 eq, 203 μmol), TEA (20 mg, 1.17 eq, 198 μmol), AcOH (20 mg, 1.97 eq, 333 μmol) and sodium cyanoborohydride (12.7 mg, 1.2 eq, 203 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with DCM (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford to afford (S)-3-(6-oxo-1'-(1,4-dioxaspiro[4.5]decan-8-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (60 mg, 121 μmol, 71.7 %) as a yellow solid. LC purity (0.1% FA): 95% (UV at 254 nm)/MS: 496.2 [M+H]; Retention time: 1.23 min. Synthesis of (S)-3-(6-oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 4) [0474] To a solution of (S)-3-(6-oxo-1'-(1,4-dioxaspiro[4.5]decan-8-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 101 μmol) in H2O (6 mL) was added HCl (2 mL, 2 N). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford (S)-3-(6-oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione (30 mg, 66.4 μmol, 65.9%) as a yellow solid. LC purity (0.1% FA): 94.79% (UV at 254 nm)/MS: 452.2 [M+H]; Retention time: 0.43 min. Synthesis of (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0475] To a solution of (S)-3-(6-oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (30 mg, 1 eq, 66.4 μmol) in DCM (3 mL) were added 4-chloro-7,7-dimethyl-9-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)-one (30.3 mg, 1.2 eq, 79.7 μmol), TEA (20 mg, 3 eq, 198 μmol), AcOH (20 mg, 5 q, 333 μmol) and sodium triacetoxyborohydride (42.2 mg, 3 eq, 199 μmol). The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1% FA) to afford (S)-3-(1'-(4- (4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (3.75 mg, 4.41 μmol, 6.64%) as a white solid. LC purity (0.1% FA): 96.62% (UV at 254 nm)/MS: 815.4 [M+H]; Retention time: 1.25 min. 1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 8.4 Hz, 1H), 7.68 (t, J = 13.2 Hz, 1H), 7.58 (s, 1H), 7.49-7.21 (m, 3H), 5.24-5.08 (m, 1H), 4.61 (d, J = 5.2 Hz, 2H), 4.40 (t, J = 14.4 Hz, 2H), 3.72 (d, J = 11.9 Hz, 1H), 3.58 (s, 1H), 3.07-2.98 (m, 4H), 2.83-2.67 (m, 4H), 2.70-2.43 (m, 2H), 2.32-2.13 (m, 4H), 2.16-2.01 (m, 8H), 1.92-1.86 (m, 3H), 1.67-1.56 (m, 3H), 1.61 (s, 6H), 1.50-1.15 (m, 1H). Compound A33 and A34. (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and Compound A34. (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0476] To a solution of 4'-chloro-10'-(piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (150 mg, 1 eq, 178 μmol) in MeOH (2 mL) were added TEA (54.1 mg, 3 eq, 535 μmol), 4-(hydroxymethyl)cyclohexan-1-one (91.3 mg, 4 eq, 713 μmol) and NaCNBH3 (33.6 mg, 3 eq, 535 μmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (20 mL X 3), The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford 4'-chloro-10'-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1- yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (130 mg, 0.12 mmol, 68%) as yellow oil. LC purity (0.1% FA): 45.61% (UV at 254 nm)/MS: 533.2 [M+1]; Retention time: 1.33 min. Synthesis of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4) [0477] To a solution of 4'-chloro-10'-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (40. mg, 1 eq, 75.0 μmol) in DCM (3 mL) was added DMP (95.5 mg, 3 eq, 225 μmol). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (20 mL X 3), The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 10% of MEOH in DCM) to afford 4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperazin-1- yl)cyclohexane-1-carbaldehyde (30 mg, 28 μmol, 38%) as a yellow solid. LC purity (0.1% FA): 58.34% (UV at 254 nm)/MS: 531.1 [M+1]; Retention time: 1.38 min. Synthesis of (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-((4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperazin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0478] To a solution of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (20 mg, 1 eq, 22.6 μmol) in DCM (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (8.83 mg, 1.1 eq, 24.9 μmol), AcOH (4.07 mg, 3 eq, 67.8 μmol), TEA (6.86 mg, 3 eq, 67.8 μmol) and sodium triacetoxyborohydride (14.4 mg, 3 eq, 67.8 μmol). The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with DCM (30 mL), then washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/NH4HCO3/H2O) from 63% to 70% to get (S)-3-(1'-((4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperazin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.15 mg, 1.20 μmol, 5.29%) as a white solid and (S)-3-(1'-((4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperazin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.32 mg, 1.41 μmol, 6.23%) as a white solid. [0479] P1 (A33): LC purity (0.1% FA): 87.47% (UV at 254 nm)/MS: 870.4 [M+H]; Retention time: 1.245 min.1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J=8.4Hz, 1H), 7.82-7.86 (m, 1H), 7.75 (d, J=8.4Hz, 1H), 7.60-7.65 (m, 2H), 7.34-7.39 (m, 1H) 6.98-7.00 (m, 1H), 5.10-5.15 (m, 1H), 4.58 (s, 2H), 4.35-4.67 (m, 2H).3.47-3.48 (m, 1H), 3.12-3.14 (m, 1H), 2.97-3.00 (m, 2H), 2.75- 2.90 (m, 6H), 2.35-2.50 (m, 4H), 2.00-2.18 (m, 10H), 1.88-1.92 (m, 4H), 1.57-1.85 (m, 14H). [0480] P2 (A34): LC purity (0.1% FA): 92.89% (UV at 254 nm)/MS: 870.4 [M+H]; Retention time: 2.265 min.1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J=8.4Hz, 1H), 7.82-7.86 (m, 1H), 7.75 (d, J=8.4Hz, 1H), 7.60-7.65 (m, 2H), 7.34-7.39 (m, 1H), 6.98-7.00 (m, 1H), 5.10-5.15 (m, 1H), 4.58 (s, 2H), 4.35-4.67 (m, 2H).3.47-3.48 (m, 1H), 3.12-3.14 (m, 1H), 2.97-3.00 (m, 2H), 2.75- 2.90 (m, 6H), 2.35-2.50 (m, 4H), 2.00-2.18 (m, 10H), 1.88-1.92 (m, 4H), 1.57-1.85 (m, 14H). Compound A35. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A36. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A37. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A38. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-chloro-10-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (cis and trans) (Intermediate 3) [0481] To a solution of 4-chloro-7,7-dimethyl-10-(piperazin-1-yl) indolo[1,2-a]quinazolin-5(7H)- one (500 mg, 1 eq, 1.31 mmol) in MeOH (8 mL) were added TEA (399 mg, 3 eq, 3.94 mmol)， and 4-(hydroxymethyl)cyclohexan-1-one (337 mg, 2 eq, 2.63 mmol). The reaction was stirred at 60 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford 4-chloro-10-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (168 mg, 341 μmol, 26.0%) as a yellow solid and 4-chloro-10-(4-(4- (hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (170 mg, 345 μmol, 26.3%) as a yellow solid. [0482] 3-P1: LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 493.4 [M+H]; Retention time: 1.14 min. [0483] 3-P2: LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 493.4 [M+H]; Retention time: 1.15 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4) [0484] To a solution of 4-chloro-10-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (3-P1, 120 mg, 1 eq, 243 μmol) in DCM (6 mL) was added DMP (310 mg, 3 eq, 730 μmol), and the reaction was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. Filtered and concentrated under vacuum, the resulting residue was purified by silica gel column chromatography (100-200 mesh silica gel, 5% MeOH in DCM) to afford 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin- 1-yl)cyclohexane-1-carbaldehyde (4-P1,120 mg, 0.21 mmol, 85%) as a yellow solid. LC purity (0.1% FA): 82.11% (UV at 254 nm)/MS: 491.2 [M+H]; Retention time: 1.18 min. [0485] 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin- 1-yl)cyclohexane-1-carbaldehyde (120 mg, 0.21 mmol, 85%, 85% Purity) (4-P2) was prepared according to the same method as 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (4-P1). LC purity (0.1% FA): 88.98% (UV at 254 nm)/MS: 491.2 [M+H]; Retention time: 1.26 min. Synthesis of (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0486] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (4-P1, 100 mg, 1 eq, 204 μmol) and (S)-3-(6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride (95.8 mg, 1.2 eq, 244 μmol) in DCM (2.5 mL) were added TEA (30.9 mg, 1.5 eq, 305 μmol) and AcOH (20.8 mg, 1.7 eq, 346 μmol). The reaction was stirred at 25 °C for 10 min. Sodium triacetoxyborohydride (86.3 mg, 2 eq, 407 μmol) was added and the reaction was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L%NH4HCO) from 50% to 60% to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo- 5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (A36, 12.6 mg, 14.4 μmol, 7.088%) as a white solid and a crude product. The crude product was then purified by prep- HPLC, eluted with MeCN in H2O (0.1% FA) from 10% to 20% to afford (S)-3-(1'-((4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (A35, 9.10 mg, 10.6 μmol, 5.22%) as a white solid. [0487] P1-1 (A35): LC purity (0.1% FA): 97.47% (UV at 254 nm)/MS: 830.4 [M+H]; Retention time: 1.221 min.1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J = 8.6 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.70- 7.59 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.38 (q, J = 7.7 Hz, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.13 (dd, J = 13.4, 5.1 Hz, 1H), 4.61 (s, 2H), 4.42 (q, J = 17.0 Hz, 2H), 3.43 (s, 4H), 3.21- 3.19 (m, 2H), 3.10-3.08 (m, 4H), 2.88-2.84 (m, 3H), 2.59-2.40 (m, 5H), 2.20-2.16 (m, 5H), 2.04 (d, J = 13.2 Hz, 2H), 1.88 (d, J = 11.7 Hz, 2H), 1.72 (s, 1H), 1.57 (s, 6H), 1.51-1.48 (m, 2H), 1.20- 1.05 (m, 2H). [0488] P1-2 (A36): LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 830.4 [M+H]; Retention time: 1.058 min.1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.7 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.70-7.58 (m, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.39 (s, 2H), 7.03 (d, J = 8.7 Hz, 1H), 5.13 (d, J = 9.0 Hz, 1H), 4.60 (s, 2H), 4.45-4.42 (m, 2H), 3.43-3.40 (m, 4H), 3.20-3.17 (m, 2H), 3.02-2.72 (m, 6H), 2.69-2.33 (m, 6H), 2.16-2.14 (m, 3H),2.04-2.02 (m, 1H), 1.91-1.60 (m, 10H), 1.57 (s, 6H). Synthesis of (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0489] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (4-P2, 100 mg, 1 eq, 204 μmol) and (S)-3-(6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride (95.8 mg, 1.2 eq, 244 μmol) in DCM (2.5 mL) were added TEA (30.9 mg, 1.5 eq, 305 μmol) and AcOH (20.8 mg, 1.7 eq, 346 μmol). The reaction was stirred at 25 °C for 10 min. Sodium triacetoxyborohydride (86.32 mg, 2 eq, 407.3 μmol) was added and the reaction was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L%NH4HCO) from 50% to 60% to afford (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo- 5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (15.4 mg, 17.5 μmol, 10.1%) as a white solid and (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.52 mg, 2.56 μmol, 1.48%) as a white solid. [0490] P2-1 (A37): LC purity (0.1% FA): 99.88% (UV at 254 nm)/MS: 830.4 [M+H]; Retention time: 1.019 min.1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.63 (dd, J = 15.4, 4.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.37 (q, J = 7.7 Hz, 2H), 7.04-6.98 (m, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (s, 2H), 4.41 (q, J = 16.9 Hz, 2H), 3.40-3.37 (m, 4H), 3.03 (d, J = 11.0 Hz, 2H), 2.97-2.84 (m, 5H), 2.82-2.73 (m, 1H), 2.53-2.50 (m, 2H), 2.35 (d, J = 6.4 Hz, 2H), 2.18-2.14 (m, 7H), 2.01 (d, J = 12.6 Hz, 2H), 1.84-1.82 (m, 2H), 1.63-1.62 (m, 1H), 1.57 (s, 6H), 1.45-1.36 (m, 2H), 1.13-1.00 (m, 2H). [0491] P2-2 (A38): LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 830.4 [M+H]; Retention time: 1.058 min.1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.67-7.57 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.40-7.36 (m, 1H), 7.01 (d, J = 8.5 Hz, 1H), 5.13 (dd, J = 13.2, 5.2 Hz, 1H), 4.57 (s, 1H), 4.45-4.40 (m, 2H), 3.34 (s, 4H), 3.05-2.72 (m, 8H), 2.56- 2.31 (m, 4H), 2.21-1.87 (m, 7H), 1.77-1.75 (d, J = 9.6 Hz, 5H), 1.70-1.51 (m, 10H). Compound A39. (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0492] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (300 mg, 1 eq, 714 μmol) in MeOH (2 mL) were added TEA (361 mg, 5 eq, 3.57 mmol), 4-(hydroxymethyl)cyclohexan-1-one (183 mg, 2 eq, 1.43 mmol) and NaBH3CN (89.8 mg, 2 eq, 1.43 mmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford 4'-chloro-10'-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (260 mg, 0.44 mmol, 62%) as a yellow solid. LC purity (0.1% FA): 85.83% (UV at 254 nm)/MS: 532.4 [M+1]; Retention time: 1.29min. Synthesis of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4) [0493] To a solution of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (240 mg, 1 eq, 451 μmol) in DCM (4 mL) was added DMP (574 mg, 3 eq, 1.35 mmol). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction was filtered and the filtrate was purified by prep- TLC (6% MeOH in DCM) to afford 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (75.0 mg, 0.13 mmol, 28%) as a yellow solid. LC purity (0.03%TFA): 90.00% (UV at 254 nm)/MS: 530.4 [M+H]; Retention time: 1.329 min. Synthesis of (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0494] To a solution of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (70 mg, 1 eq, 132 μmol) in DCM (1 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (56.3 mg, 1.2 eq, 158 μmol), TEA (20 mg, 1.5 eq, 198 μmol), AcOH (13.5 mg, 1.7 eq, 224 μmol) and sodium triacetoxyborohydride (56.0 mg, 2 eq, 264 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/NH4HCO3/H2O) from 46% to 51% to afford (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.00 mg, 5.47 μmol, 4.14%) as a white solid. LC purity (0.1%FA): 97.45% (UV at 254 nm)/MS: 870.4 [M+H]; Retention time: 1.148 min. 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.87-7.82 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.39-7.32 (m,3H), 5.15-5.11 (m, 1H), 4.58 (s, 2H), 4.47-4.35 (m,2H), 3.50-3.48 (m, 2H), 3.12-2.72 (m, 8H), 2.55 -2.43 (m, 2H), 2.32- 1.95 (m, 17H), 1.95 -1.40 (m, 14H). [0495] Compound A159 and A160 were separated from Compound A39. Compound A159. (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A160. (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione in]-

10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione [0496] The crude (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.00 mg, 1 eq, 8.90 μmol) was purified by SFC to get (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.20 mg, 1.42 μmol, 15.9%) as a white solid and (S)-3-(1'-((4-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.84 mg, 2.23 μmol, 25.0%) as a white solid. [0497] P1 (A159): LC purity (0.1% FA): 79.80% (UV at 254 nm)/MS: 786.5 [M+H]; Retention time: 1.466 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H), 7.85 (t, J = 8.4 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.41 (s, 1H), 7.35-7.24 (m, 2H), 5.13-5.04 (m, 1H), 4.56 (s, 2H), 4.39 (d, J = 16.5 Hz, 1H), 4.22 (d, J = 17.2 Hz, 1H), 2.96 (s, 2H), 2.67 (s, 2H), 2.11-1.93 (m, 10H), 1.73 (d, J = 18.9 Hz, 18H), 0.85 (d, J = 6.8 Hz, 2H) [0498] P2 (A160): LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 786.5 [M+H]; Retention time: 1.468 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.43 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 2H), 5.14-5.02 (m, 1H), 4.53 (d, J = 10.4 Hz, 2H), 4.39 (d, J = 17.2 Hz, 1H), 4.22 (d, J = 17.1 Hz, 1H), 2.95-2.82 (m, 3H), 2.70 (d, J = 11.5 Hz, 1H), 2.21 (d, J = 6.0 Hz, 2H), 2.12-1.88 (m, 14H), 1.81-1.64 (m, 10H), 1.14-1.00 (m, 3H), 0.84 (d, J = 6.9 Hz, 1H). [0499] The following targets were prepared in a manner analogous to Compound A39. Compound A43. (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 841.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.89-7.75 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.30-7.31 (m, 3H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (s, 2H), 4.41 (q, J = 17.0 Hz, 2H), 3.19-3.08 (m, 2H), 2.99 (d, J = 12.1 Hz, 2H), 2.92-2.71 (m, 4H), 2.66-2.28 (m, 5H), 2.25- 1.95 (m, 14H), 1.90-1.68 (m, 12H). Compound A44. (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 841.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.43 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.89-7.79 (m, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.40-7.31 (m, 3H), 5.13 (dd, J = 13.3, 5.0 Hz, 1H), 4.58 (s, 2H), 4.41 (q, J = 16.9 Hz, 2H), 3.15-3.13 (m, 2H), 3.00-2.98 (m, 2H), 2.90-2.73 (m, 4H), 2.65-2.40 (m, 6H), 2.23-1.98 (m, 14H), 1.93-1.68 (m, 12H). Compound A51. (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 841.4 [M+H]; 1H NMR (400 MHz, DMSO- d6) 10.97 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 5.08 (s, 1H), 4.51 (s, 2H), 4.38 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 17.1 Hz, 1H), 2.95 (s, 2H), 2.80 (s, 2H), 2.67 (s, 2H), 2.37 (s, 2H), 2.33 (s, 1H), 2.20 (s, 3H), 2.04 (s, 6H), 1.89 (s, 5H), 1.76 (d, J = 10.3 Hz, 16H), 1.47-.43 (m, 1H). Compound A40. (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

in]- 10'-yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 2) [0500] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (300 mg, 1 eq, 714 μmol) in MeOH (4 mL) were added triethylamine (361 mg, 5 eq, 3.57 mmol)，tert-butyl 4-oxopiperidine-1-carboxylate (214 mg, 1.5 eq, 1.07 mmol) and sodium cyanotrihydroborate (44.9 mg, 1 eq, 714 μmol). The mixture was stirred at 60 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with DCM (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 4-(4'-chloro-5'- oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)-[1,4'-bipiperidine]-1'- carboxylate (310 mg, 514 μmol, 71.9%) as a yellow oil. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 603.3 [M+H]; Retention time: 0.78 min. Synthesis of 10'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 3) [0501] To a solution of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidine]-1'-carboxylate (318 mg, 1 eq, 527 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 10'-([1,4'-bipiperidin]-4-yl)-4'- chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (220 mg, 437 μmol, 82.9%) as a yellow solid. LC purity (0.1% FA): 94.79% (UV at 254 nm)/MS: 503.3 [M+H]; Retention time: 0.23 min. Synthesis of (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0502] To a solution of 10'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 59.6 μmol) in DCM (3 mL) were added DIEA (23.1 mg, 3 eq, 179 μmol) and triphosgene (17.7 mg, 1 eq, 59.6 μmol) at 0 °C. The reaction was stirred 0 °C for 2 h, then (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (31.8 mg, 1.5 eq, 89.4 μmol) was added. The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) to afford (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)-[1,4'- bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (7.93 mg, 8.38 μmol, 14.1%) as a white solid. LC purity (0.1% FA): 96.62% (UV at 254 nm)/MS: 884.4 [M+H]; Retention time: 1.35 min. 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.5 Hz, 1H), 7.97 (s, 1H), 7.84 (t, J = 7.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.26-7.42 (m, 3H), 5.15 (d, J = 4.6 Hz, 1H), 4.65 (s, 2H), 4.56 (s, 3H), 4.42 (d, J = 11.8 Hz, 1H), 3.89 (d, J = 13.0 Hz, 2H), 3.75 (d, J = 10.7 Hz, 2H), 3.44 (d, J = 8.8 Hz, 2H), 2.80-3.08 (m, 10H), 1.99-2.16 (m, 12H), 1.67-1.91 (m, 10H). Compound A45. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidine-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0503] Compound A45 was also prepared in the same manner as Compound A40 and the data is show below: [0504] LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 856.6 [M+H]; Retention time: 1.322 min.1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.37 (q, J = 7.7 Hz, 2H), 5.18-5.07 (m, 1H), 4.68-4.56 (m, 2H), 4.43-4.30 (m, 5H), 4.14 (s, 1H), 3.90 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.5 Hz, 2H), 3.17-2.99 (m, 5H), 2.95-2.84 (m, 1H), 2.83-2.73 (m, 1H), 2.57- 2.40 (m, 1H), 2.29-1.75 (m, 20H). Compound A41. (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-10'-(1'-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 2) [0505] To a solution of 10'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (130 mg, 1 eq, 258 μmol) in DMF (3 mL) were added sodium bicarbonate (217 mg, 10 eq, 2.58 mmol) and 2-bromoethan-1-ol (64.6 mg, 2 eq, 517 μmol) at rt. The reaction was stirred 65 °C for 16 h. LCMS indicated completion of reaction. The mixture was added EA (30 mL), extracted with water, dried over Na2SO4 and concentrated. The crude product was purified by silica gel prep-TLC (MeOH/DCM=1/10) to get 4'-chloro-10'-(1'-(2- hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'- one (110 mg, 201 μmol, 77.8%) as a white solid. LC purity (0.1% FA): 88.8% (UV at 254 nm)/MS: 547.2 [M+ H]; Retention time: 1.10 min. Synthesis of 4'-chloro-10'-(1'-(2-chloroethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0506] To a solution of 4'-chloro-10'-(1'-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (110 mg, 1 eq, 201 μmol) in DCM (5 mL) were added TEA (61.0 mg, 3 eq, 603 μmol) and MsCl (69.1 mg, 3 eq, 603 μmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The resulting mixture was added DCM (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford 4'-chloro-10'-(1'-(2-chloroethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (70 mg, 124 μmol, 61.6%) as a yellow solid. LC purity (0.1% FA): 78.08% (UV at 254 nm)/MS: 566.3 [M+H]; Retention time: 1.13 min. Synthesis of (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0507] To a solution of 4'-chloro-10'-(1'-(2-chloroethyl)-[1,4'-bipiperidin]-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (60 mg, 1 eq, 106 μmol) in DMF (1 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (41.5 mg, 1.1 eq, 117 μmol) and sodium hydrogen carbonate (89.1 mg, 10 eq, 1.06 mmol) at room temperature. The reaction was stirred 65 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.03% NH4HCO3) from 45%- 53% to afford (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)- [1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (2.18 mg, 2.30 μmol, 2.17 %) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 884.5 [M+H]; Retention time: 1.785 min.1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.84 (dd, J = 16.1, 7.9 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.29-7.39 (m, 3H), 4.58 (s, 3H), 4.41 (d, J = 11.6 Hz, 2H), 3.09-3.20 (m, 5H), 3.01 (d, J = 11.9 Hz, 2H), 2.75-2.81 (m, 2H), 2.62 (s, 4H), 2.39-2.49 (m, 4H), 2.13 (ddd, J = 39.5, 19.0, 12.3 Hz, 12H), 1.72-1.98 (m, 15H). [0508] The following targets were prepared in a manner analogous to Compound A41. Compound A47. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)ethyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 925.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.90-7.77 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.48-7.22 (m, 3H), 5.22 -5.05 (m, 1H), 4.62-4.52 (m, 2H), 4.41 (q, J = 17.0 Hz, 2H), 3.15 (d, J = 11.4 Hz, 2H), 3.03 (d, J = 11.9 Hz, 2H), 2.97-2.83 (m, 3H), 2.85- 2.72 (m, 5H), 2.69 (d, J = 6.9 Hz, 4H), 2.55-2.44 (m, 1H), 2.23 (t, J = 11.8 Hz, 2H), 2.19-1.90 (m, 14H), 1.97-1.57 (m, 16H). Compound A54. (S)-3-(1'-(2-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 856.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.51-7.29 (m, 3H), 5.17-5.04 (m, 1H), 4.59 (s, 2H), 4.39 (t, J = 15.0 Hz, 2H), 4.00 (s, 2H), 3.74-3.39 (m, 3H), 3.25 (s, 1H), 3.19-2.66 (m, 10H), 2.66- 2.45 (m, 2H), 2.28-1.76 (m, 22H). Compound A46. (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Sy

9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 2) [0509] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (300 mg, 1 eq, 714 μmol) in MeOH (6 mL) were added TEA (361 mg, 5 eq, 3.57 mmol) and NaBH3CN (89.8 mg, 2 eq, 1.43 mmol). The mixture was stirred at 60 °C for 3 h. LCMS indicated completion of reaction. The resulting mixture was extracted with DCM (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 90% of EA in PE) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-[1,4'- bipiperidine]-1'-carboxylate (300 mg, 497 μmol, 69.6%) as a yellow solid. LC purity (0.1% FA): 97.40% (UV at 254 nm)/MS: 603.4 [M+H]; Retention time: 1.35 min. Synthesis of 9'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 3) [0510] To a solution of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (300 mg, 1 eq, 497 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 9'-([1,4'-bipiperidin]-4-yl)-4'- chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (240 mg, 477 μmol, 95.9%) as a yellow solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 503.2 [M+H]; Retention time: 0.57 min. Synthesis of (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0511] To a solution of 9'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (80 mg, 1 eq, 159 μmol) in DCM (3 mL) were added DIEA (61.7 mg, 3 eq, 477 μmol) and triphosgene (47.2 mg, 1 eq, 159 μmol) at 0 °C. The reaction was stirred 0 °C for 2 h. To the mixture was added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (84.8 mg, 1.5 eq, 239 μmol). The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1% FA) to afford (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.32 mg, 8.18 μmol, 5.15%) as a white solid. LC purity (0.1% FA): 87.35% (UV at 254 nm)/MS: 884.8 [M+H]; Retention time: 1.32 min.1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.86 (t, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.37-7.44 (m, 2H), 5.13 - 5.18 (m, 1H), 4.68 (s, 2H), 4.45 (d, J = 12.7 Hz, 2H), 3.95 (d, J = 12.8 Hz, 2H), 3.75 (dd, J = 21.1, 13.6 Hz, 4H), 2.87- 3.15 (m, 7H), 2.78-2.84 (m, 1H), 2.53 (dt, J = 13.5, 8.6 Hz, 1H), 2.15-2.33 (m, 8H), 1.94-2.12 (m, 6H), 1.84 (t, J = 12.9 Hz, 10H). Compound A48. (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

in- 5(7H)-one (Intermediate 3) [0512] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (80 mg, 1 Eq, 211 μmol) and trimethylamine (42.6 mg, 58.7 μL, 2 Eq, 421 μmol) in DCM was added 2-chloroacetyl chloride (35.7 mg, 1.5 Eq, 316 μmol). The solution was stirred at room temperature for 1 h. The mixture was concentrated to give crude product. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1-30:1) to afford 4-chloro-10-(1-(2- chloroacetyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (50 mg, 211 μmol, 52.0%) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 456.2 [M +H]; Retention time: 1.609 min. Synthesis of (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0513] To a solution of 4-chloro-10-(1-(2-chloroacetyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (25.0 mg, 1 Eq, 54.8 μmol) and potassium carbonate (15.1 mg, 6.42 μL, 2 Eq, 110 μmol) in DMF (0.70 mL) was added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (19.5 mg, 1 Eq, 54.8 μmol). The solution was stirred at room temperature for 3 h. The mixture was quenched with water and exacted with EtOAc. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1- 15:1) to afford (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (20 mg, 54.8 μmol, 47.1%) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 775.6 [M +H]; Retention time: 3.402 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.438 (t, J = 8.8 Hz, 2H), 7.97 (s, 1H), 7.80-7.76 (m, 1H), 7.65-7.58 (m, 2H), 7.35-7.23 (m, 3H), 5.11-5.06 (m, 1H), 4.60-4.54 (m, 4H), 4.40 (s, 1H), 4.36-4.19 (m, 2H), 3.18 (s, 2H), 3.14-3.11 (m, 2H), 3.06-3.01 (m, 4H), 2.98 (s, 1H), 2.99-2.90 (m, 2H), 2.00 ^ 1.98 (m, 6H), 1.51-1.46 (m, 8H). Compound A49. (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

ro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 2) [0514] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (60 mg, 1 eq, 169 μmol) in DMF (2 mL) were added 1,4- dioxaspiro[4.5]decan-8-one (31.6 mg, 1.2 eq, 203 μmol), TEA (20 mg, 1.17 eq, 198 μmol), AcOH (20 mg, 1.97 eq, 333 μmol) and sodium cyanoborohydride (12.7 mg, 1.2 eq, 203 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with DCM (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford to afford (S)-3-(6-oxo-1'-(1,4-dioxaspiro[4.5]decan-8-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (60 mg, 121 μmol, 71.7 %) as a yellow solid. LC purity (0.1% FA): 95% (UV at 254 nm)/MS: 496.2 [M+H]; Retention time: 1.23 min. Synthesis of (S)-3-(6-oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 3) [0515] To a solution of (S)-3-(6-oxo-1'-(1,4-dioxaspiro[4.5]decan-8-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 101 μmol) in H2O (2 mL) was added HCl (1 mL, 6 N). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was concentrated under to afford (S)-3-(6- oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (30 mg, 66.4 μmol, 65.9%) as a yellow solid. LC purity (0.1% FA): 94.79% (UV at 254 nm)/MS: 452.5 [M+H]; Retention time: 0.43 min. Synthesis of (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0516] To a solution of (S)-3-(6-oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 111 μmol) in MeOH (3 mL) were added 10'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (52.6 mg, 1 eq, 111 μmol), potassium acetate (21.7 mg, 2 eq, 221 μmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (13.9 mg, 2 eq, 221 μmol) was added to the above mixture. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1% FA) to afford (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (14.2 mg, 15.1 μmol, 13.7 %) as a white solid. LC purity (0.1% FA): 96.72% (UV at 254 nm)/MS: 910.5 [M+H]; Retention time: 0.76 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.4Hz, 1H), 7.95 (s, 1H), 7.84 (t, J = 8.0 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.37-7.21 (m, 3H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.61 (d, J = 9.2 Hz, 2H), 4.42 (q, J = 17.2 Hz, 2H), 3.87-3.72 (m, 2H), 3.34 (s, 4H), 3.21 (d, J = 8.4 Hz, 2H), 3.14 (s, 1H), 3.00 (d, J = 11.2 Hz, 2H), 2.79-2.64 (m, 6H), 2.55-2.41 (m, 2H), 2.11-1.98 (m, 11H), 2.02-1.81 (m, 11H), 1.74-1.56 (m, 3H), 1.48 (d, J = 11.0 Hz, 1H), 1.17 (d, J = 12.8 Hz, 1H). Compound A50. (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(1-(4-(3-(4-(4-chloro-5-oxo-5H-spiro[cyclohexane-1,7-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0517] To a solution of (S)-3-(6-oxo-1'-(4-oxocyclohexyl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 111 μmol) in MeOH (3 mL) were added 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (52.6 mg, 1 eq, 111 μmol), potassium acetate (10.9 mg, 1 eq, 111 μmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (6.96 mg, 1 eq, 111 μmol) was added to above mixture. The mixture was stirred at 25 °C for 1 h. Then the sodium cyanoborohydride (13.9 mg, 2 eq, 221 μmol) was added to the above mixture. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep- HPLC，eluted with MeCN in H2O (0.1%FA) to afford (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.30 mg, 7.76 μmol, 7.01%) as a white solid. LC purity (0.1% FA): 96.72% (UV at 254 nm)/MS: 910.5 [M+H]; Retention time: 0.76 min. 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.39- 7.12 (m 3H), 5.13 (dd, J = 13.4, 5.2 Hz, 1H), 4.62 (d, J = 9.2 Hz, 2H), 4.49-4.37 (m, 2H), 3.82 (s, 2H), 3.34-3.12 (m, 3H), 3.22 (d, J = 10 Hz, 2H), 3.14 (s, 1H), 3.04-2.82 (m, 4H), 2.74-2.53 (m, 5H), 2.55-2.44 (m, 2H), 2.19-2.05 (m, 12H), 1.95-1.76 (m, 11H), 1.49 (d, J = 10.4 Hz, 2H), 1.17- 1.01 (m, 2H). Compound A52. (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-9'-(1'-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 2) [0518] To a solution of 9'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (160 mg, 1 eq, 318 μmol) in DMF (3 mL) were added sodium hydrogen carbonate (267 mg, 10 eq, 3.18 mmol) and 2-bromoethan-1-ol (199 mg, 5 eq, 1.59 mmol) at rt. The reaction was stirred 65 °C for 16 h. LCMS indicated completion of reaction. The mixture was added EA (30 mL), extracted with water, dried over Na2SO4 and concentrated. The crude product was purified by silica gel prep-TLC (MeOH:DCM=1:20) to get 4'-chloro-9'-(1'-(2- hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'- one (90 mg, 164 μmol, 51.7 %) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 547.3 [M+H]; Retention time: 1.06 min. Synthesis of 4'-chloro-9'-(1'-(2-chloroethyl)-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0519] To a solution of 4'-chloro-9'-(1'-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (90 mg, 1 eq, 164 μmol) in DCM (5 mL) were added triethylamine (83.2 mg, 5 eq, 822 μmol) and methanesulfonyl chloride (94.2 mg, 5 eq, 822 μmol) at 0 °C. The mixture was stirred at 25 °C for 1h. LCMS indicated completion of reaction. The resulting mixture was extracted with DCM (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford 4'-chloro-9'-(1'-(2-chloroethyl)-[1,4'- bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (70 mg, 124 μmol, 75.2%) as a yellow solid. LC purity (0.1% FA): 95.12% (UV at 254 nm)/MS: 565.8 [M+H]; Retention time: 1.13 min. Synthesis of (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0520] To a solution of 4'-chloro-9'-(1'-(2-chloroethyl)-[1,4'-bipiperidin]-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (70 mg, 1 eq, 124 μmol) in DMF (1 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (66.0 mg, 1.5 eq, 186 μmol) and sodium hydrogen carbonate (104 mg, 10 eq, 1.24 mmol) at rt. The reaction was stirred 65 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep- HPLC，eluted with MeCN in H2O (0.1% FA) to afford (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)ethyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (9.83 mg, 10.9 μmol, 8.85%) as a white solid. LC purity (0.1% FA): 94.93% (UV at 254 nm)/MS: 884.8 [M+H]; Retention time: 1.20 min.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.81 (t, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 11.9, 8.2 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H), 4.58 ^ 4.49 (m, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.1 Hz, 1H), 3.08-2.96 (m, 5H), 2.90 (d, J = 11.1 Hz, 3H), 2.71-2.60 (m, 3H), 2.57 (s, 1H), 2.35 (dd, J = 39.1, 7.7 Hz, 4H), 2.12-1.94 (m, 8H), 1.79 (ddd, J = 32.7, 21.4, 10.5 Hz, 18H), 1.50 (d, J = 10.2 Hz, 2H). Compound A55. (S)-3-(1'-(2-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0521] Compound A55 was prepared in a manner analogous to Compound A52. MS: 856.6 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.88-7.76 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.46-7.23 (m, 3H), 5.19 -5.08 (m, 1H), 4.59 (s, 2H), 4.39 (t, J = 15.0 Hz, 2H), 4.23-4.13 (m, 2H), 3.95-3.79 (m, 2H), 3.40 -3.34 (m, 1H), 3.28-3.24 (m, 1H), 3.13-3.00 (m, 4H), 2.93-2.69 (m, 5H), 2.54-2.46 (m, 1H), 2.34 (t, J = 11.2 Hz, 2H), 2.22-1.63 (m, 22H). Compound A53. 5-(4-((4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione ne-1-

carboxylate (Intermediate 3) [0522] To a solution of 5'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (200 mg, 1 eq, 714 μmol) in 1,4-dioxane (10 mL) and water (1 mL) were added K2CO3 (296 mg, 3 eq, 2.14 mmol), tert- butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (461 mg, 2 eq, 1.43 mmol) and PdCl2(dppf) (52.2 mg, 0.1 eq, 71.4 μmol). The mixture was stirred at 100 °C for 16 h under N2. LCMS indicated completion of reaction. The resulting mixture was concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 30% of EA in PE) to afford tert-butyl 4-((2'-oxospiro[cyclohexane-1,3'-indolin]- 5'-yl)methylene)piperidine-1-carboxylate (250 mg, 630 μmol, 88.3%) as a yellow solid. LC purity (0.1% FA): 78.63% (UV at 254 nm)/MS: 397.2 [M+H]; Retention time: 1.76 min. Synthesis of tert-butyl 4-((2'-oxospiro[cyclohexane-1,3'-indolin]-4'-yl)methyl)piperidine-1- carboxylate (Intermediate 4) [0523] To a solution of tert-butyl 4-((2'-oxospiro[cyclohexane-1,3'-indolin]-4'- yl)methylene)piperidine-1-carboxylate (250 mg, 1 eq, 630 μmol) in MeOH (50 mL) was added Pd/C (67.1 mg, 1 eq, 630 μmol). The mixture was stirred at 25 °C for 5 h under H2. LCMS indicated completion of reaction. The resulting mixture was filtered and concentrated under vacuum to afford tert-butyl 4-((2'-oxospiro[cyclohexane-1,3'-indolin]-4'-yl)methyl)piperidine-1- carboxylate (230 mg, 577 μmol, 91.5%) as a yellow solid. LC purity (0.1% FA): 87.10% (UV at 254 nm)/MS: 399.4 [M+H]; Retention time: 1.75 min. Synthesis of tert-butyl 4-((1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'-indolin]-4'- yl)methyl)piperidine-1-carboxylate (Intermediate 7) [0524] To a solution of tert-butyl 4-((2'-oxospiro[cyclohexane-1,3'-indolin]-4'- yl)methyl)piperidine-1-carboxylate (230 mg, 1 eq, 577 μmol) in acetonitrile (100 mL) were added cesium carbonate (564 mg, 3 eq, 1.73 mmol) and 2-chloro-6-fluorobenzonitrile (180 mg, 2 eq, 1.15 mmol). The mixture was stirred at 80 °C for 16 h. LCMS indicated completion of reaction. The resulting mixture was extracted with EA (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100- 200 mesh silica gel, 30% of EA in PE) to afford tert-butyl 4-((1'-(3-chloro-2-cyanophenyl)-2'- oxospiro[cyclohexane-1,3'-indolin]-4'-yl)methyl)piperidine-1-carboxylate (200 mg, 374 μmol, 64.9%) as a yellow solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 534.2 [M+H]; Retention time: 1.93 min. Synthesis of tert-butyl 4-((1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-5'-yl)methyl)piperidine-1-carboxylate (Intermediate 8) [0525] To a solution of tert-butyl 4-((1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-5'-yl)methyl)piperidine-1-carboxylate (6.80 g, 1 eq, 12.7 mmol) in DMSO (100 mL) were added K2CO3 (4.40 g, 2.5 eq, 31.8 mmol) and H2O2 (77.7 g, 70 mL, 179 eq, 2.28 mol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The resulting mixture was extracted with EA (50 mL) and the organic layers were washed with water (50 mL X 2) and brine (50 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 30% of EA in PE) to afford tert-butyl 4-((1'-(2-carbamoyl-3-chlorophenyl)-2'- oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)piperidine-1-carboxylate (5.00 g, 9.06 mmol, 71.1%) as a yellow solid. LC purity (0.1% FA): 77.26% (UV at 254 nm)/MS: 552.2 [M+H]; Retention time: 1.77 min. Synthesis of 4'-chloro-9'-(piperidin-4-ylmethyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 9) [0526] To a solution of tert-butyl 4-((1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane- 1,3'-indolin]-5'-yl)methyl)piperidine-1-carboxylate (4.80 g, 1 eq, 8.69 mmol) in toluene (80 mL) was added 4-methylbenzenesulfonic acid (7.49 g, 5 eq, 43.5 mmol). The mixture was stirred at 120 °C for 24 h. LCMS indicated completion of reaction. The resulting mixture was extracted with DCM:MeOH=10:1 (50 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford 4'-chloro-9'-(piperidin-4-ylmethyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (3.70 g, 8.53 mmol, 98.1%) as a yellow solid. LC purity (0.1% FA): 85.93% (UV at 254 nm)/MS: 434.2 [M+H]; Retention time: 1.24 min. Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 11) [0527] To a solution of 4'-chloro-9'-(piperidin-4-ylmethyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (150 mg, 1 eq, 346 μmol) in MeOH (6.00 mL) were added triethylamine (175 mg, 5 eq, 1.73 mmol) and sodium cyanotrihydroborate (43.4 mg, 2 eq, 691 μmol). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The resulting mixture was extracted with DCM (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (150 mg, 249 μmol, 71.9%) as a yellow solid. LC purity (0.1% FA): 85.33% (UV at 254 nm)/MS: 631.4 [M+H]; Retention time: 1.41 min. Synthesis of 4'-chloro-9'-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 12) [0528] A solution of tert-butyl 4-((4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (150 mg, 1 eq, 238 μmol) in HCl/EA (3 mL, 4 N) was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 4'-chloro-9'-((1-(piperidin-4- ylmethyl)piperidin-4-yl)methyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (120 mg, 226 μmol, 95.1%) as a white solid. LC purity (0.1% FA): 70.65% (UV at 254 nm)/MS: 531.4 [M+H]; Retention time: 1.17 min. Synthesis of 5-(4-((4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0529] To a solution of 4'-chloro-9'-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (120 mg, 1 eq, 226 μmol) in DMSO (3 mL) were added DIEA (146 mg, 5 eq, 1.13 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5- fluoroisoindoline-1,3-dione (125 mg, 2 eq, 452 μmol). The mixture was stirred at 120 °C for 2 h. LCMS indicated completion of reaction. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1%FA) to afford 5-(4-((4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (59.2 mg, 74.8 μmol, 33.1%) as a yellow solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 787.4 [M+H]; Retention time: 1.36 min.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.59-7.71 (m, 3H), 7.30 (dd, J = 28.5, 8.2 Hz, 3H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.08 (d, J = 12.5 Hz, 2H), 2.90 (dt, J = 38.2, 20.8 Hz, 8H), 2.68 (d, J = 5.9 Hz, 2H), 2.59 (d, J = 17.0 Hz, 2H), 1.98-2.19 (m, 5H), 1.87 (d, J = 14.6 Hz, 5H), 1.73 (dd, J = 42.6, 19.6 Hz, 10H), 1.18-1.36 (m, 2H). Compound A56. (S)-3-(1'-(7-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 2) [0530] To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 1 eq, 418 μmol) in DMSO (3 mL) were added sodium triacetoxyborohydride (177 mg, 2 eq, 835 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6- dione (148 mg, 1 eq, 418 μmol) and potassium acetate (82.0 mg, 2 eq, 835 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EA in PE) to get tert-butyl (S)-2-(7-(2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)- 7-azaspiro[3.5]nonane-7-carboxylate (70 mg, 121 μmol, 28.9%) as a yellow solid. LC purity (0.1% FA): 20.57 % (UV at 254 nm)/MS: 579.4 [M+H]; Retention time: 1.20 min. Synthesis of (S)-3-(6-oxo-1'-(7-azaspiro[3.5]nonan-2-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 3) [0531] To a solution of tert-butyl (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 1 eq, 346 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to get (S)- 3-(6-oxo-1'-(7-azaspiro[3.5]nonan-2-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (160 mg, 334 μmol, 96.7 %) as a yellow oil. LC purity (0.1%TFA): 75.55% (UV at 254 nm)/MS: 479.4 [M+ H]; Retention time: 1.02 min. Synthesis of (S)-3-(1'-(7-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0532] To a solution of (S)-3-(6-oxo-1'-(7-azaspiro[3.5]nonan-2-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (35.0 mg, 1 eq, 73.1 μmol) in DMF (3 mL) were added sodium bicarbonate (123 mg, 20 eq, 1.46 mmol) and 4'-chloro- 10'-(1-(2-chloroethyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (35.3 mg, 1 eq, 73.1 μmol) and KI (12.1 mg, 1 eq, 73.1 μmol). The mixture was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by Prep-HPLC (0.1% FA in CH3CN and H2O) to get (S)-3-(1'-(7-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.00 mg, 1.08 μmol, 1.47 %) as a white solid. LC purity (0.1% FA): 97.66% (UV at 254 nm)/MS: 924.5 [M+H]; Retention time: 1.10 min.1H NMR (400 MHz, MeOD-d4) δ 8.46 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H), 7.93-7.78 (m, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.47-7.28 (m, 3H), 5.16-5.09 (m, 2H), 4.70 (s, 3H), 4.44 (d, J = 12.6 Hz, 2H), 3.84 (d, J = 20.3 Hz, 3H), 3.70 (s, 4H), 3.59 (d, J = 13.3 Hz, 3H), 3.19-3.11 (m, 2H), 3.04-2.84 (m, 4H), 2.78 (d, J = 15.3 Hz, 1H), 2.50 (d, J = 8.3 Hz, 2H), 2.36 (d, J = 12.8 Hz, 6H), 2.23 (d, J = 12.9 Hz, 3H), 2.11 (t, J = 20 Hz, 10H), 1.86 (s, 3H), 1.76 (d, J = 6.3 Hz, 3H), 1.48-1.35 (m, 1H), 1.29 (d, J = 4.2 Hz, 1H), 0.95 (t, J = 7.4 Hz, 1H). [0533] The following compounds were prepared in a manner analogous to Compound A56. Compound A65. (S)-3-(1'-(1-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 856.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.42 (m, 1H), 7.96 (s, 1H), 7.85 (dd, J = 14.8, 8.0 Hz, 2H), 7.66 (m, 1H), 7.34 (dd, J = 19.2, 8.3 Hz, 3H), 5.15-5.09 (m, 1H), 4.57 (s, 8H), 4.35-4.47 (m, 2H), 3.66 (s, 2H), 3.12 (s, 3H), 3.07 (s, 2H), 2.79-2.87 (m, 6H), 2.49-2.51 (m, 2H), 2.23-2.26 (m, 2H), 2.01- 2.05 (m, 5H), 1.89-1.94 (m, 4H), 1.29 (s, 6H), 0.88-0.90 (m, 2H). Compound A113. (S)-3-(1'-(1-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 869.6 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.54-7.20 (m, 3H), 4.56 (d, J = 9.4 Hz, 2H), 4.41 (d, J = 11.9 Hz, 1H), 3.52-3.43 (m, 1H), 3.19-3.09 (m, 4H), 3.04 (d, J = 11.6 Hz, 2H), 2.94-2.86 (m, 1H), 2.82-2.72 (m, 2H), 2.60 (d, J = 40.1 Hz, 4H), 2.42-2.21 (m, 6H), 2.13 (t, J = 21.4 Hz, 6H), 2.07-1.99 (m, 4H), 1.93-1.74 (m, 12H), 1.71-1.60 (m, 2H), 1.31 (d, J = 18.7 Hz, 2H). Compound A57. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)ethyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and Compound A58. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)ethyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

nol (Intermediate 2) [0534] To a solution of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- carboxylate (1.80 g, 1 eq, 6.42 mmol) in THF (4 mL) and MeOH (1 mL) was added LiBH4 (840 mg, 6 eq, 38.5 mmol) at 0 °C. The mixture was stirred at 60 °C for 16 h. TLC indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to give (4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanol (1.10 g, 4.2 mmol, 65%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 6.44 (d, J = 2.0 Hz, 1H), 4.48-4.36 (m, 1H), 3.28 -3.14 (m, 2H), 2.20-2.04 (m, 2H), 2.01-1.86 (m, 1H), 1.81-1.62 (m, 2H), 1.64-1.50 (m, 1H), 1.23 -1.13 (m, 12H). Synthesis of 6-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-3,3-dimethylindolin-2-one (Intermediate 4) [0535] To a solution of 6-bromo-3,3-dimethylindolin-2-one (300 mg, 1 eq, 1.25 mmol) and (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanol (446 mg, 1.5 eq, 1.87 mmol) in 1,4-dioxane (40 mL) and H2O (4 mL) was added and PdCl2(dppf) (91.4 mg, 0.1 eq, 125 μmol). The mixture was stirred at 100 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EA in PE) to get 6-(4- (hydroxymethyl)cyclohex-1-en-1-yl)-3,3-dimethylindolin-2-one (270 mg, 0.83 mmol, 66%) as a yellow solid. LC purity (0.1% FA): 82.86% (UV at 254 nm)/MS: 272.2 [M+H]; Retention time: 1.35 min. Synthesis of 6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethylindolin-2-one (Intermediate 5) [0536] To a solution of 6-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-3,3-dimethylindolin-2-one (900 mg, 1 eq, 3.32 mmol) in chlorobenzene (5 mL) was added Pd/C (176.48 mg, 0.5 eq, 1.6583 mmol) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C under H2 for 16 h. TLC (petroleum ether/ethyl acetate=2:1) or LCMS indicated completion of reaction. The reaction mixture was filtered and the filter was concentrated to give 6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethylindolin-2-one (870 mg, 2.9 mmol, 86%) as a yellow solid. LC purity (0.1%FA): 100.0% (UV at 254 nm)/MS: 274.2 [M+ H]; Retention time: 1.37 min. Synthesis of 2-chloro-6-(6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethyl-2-oxoindolin-1- yl)benzonitrile (Intermediate 6) [0537] To a solution of 6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethylindolin-2-one (900 mg, 1 eq, 3.29 mmol) in MeCN (4 mL) were added Cs2CO3 (3.22 g, 3 eq, 9.88 mmol) and 2-chloro-6- fluorobenzonitrile (1.02 g, 2 eq, 6.58 mmol). The mixture was stirred at 80 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EA in PE) to get 2-chloro-6-(6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethyl-2- oxoindolin-1-yl)benzonitrile (670 mg, 1.64 mmol, 49.8%) as a white solid. LC purity (0.1% FA): 55.96% (UV at 254 nm)/MS: 409.2 [M+H]; Retention time: 1.60 min. Synthesis of 2-chloro-6-(6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethyl-2-oxoindolin-1- yl)benzamide (Intermediate 7) [0538] To a solution of 2-chloro-6-(6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethyl-2- oxoindolin-1-yl)benzonitrile (670 mg, 1 eq, 1.64 mmol) in DMSO (6 mL) were added K2CO3 (566 mg, 2.5 eq, 4.10 mmol) and H2O2 (3.50 mL). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EA in PE) to get 2-chloro-6-(6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethyl-2- oxoindolin-1-yl)benzamide (590 mg, 1.2 mmol, 76%) as a yellow solid. LC purity (0.1% FA): 92.50% (UV at 254 nm)/MS: 427.2 [M+H]; Retention time: 1.41 min. Synthesis of 4-chloro-10-(4-(hydroxymethyl)cyclohexyl)-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one (Intermediate 8) [0539] To a solution of 2-chloro-6-(6-(4-(hydroxymethyl)cyclohexyl)-3,3-dimethyl-2- oxoindolin-1-yl)benzamide (590 mg, 1 eq, 1.38 mmol) in toluene (5 mL) was added p- toluenesulfonic acid (1.19 g, 5 eq, 6.91 mmol). The mixture was stirred at 120 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to get 4-chloro-10-(4-(hydroxymethyl)cyclohexyl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (540 mg, 1.32 mmol, 95.6%) as a yellow solid. LC purity (0.03%TFA): 26.99% (UV at 254 nm)/MS: 409.2 [M+H]; Retention time: 1.70 min. Synthesis of 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)cyclohexane-1-carbaldehyde (Intermediate 9) [0540] To a solution of 4-chloro-10-(4-(hydroxymethyl)cyclohexyl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (100 mg, 1 eq, 245 μmol) in DCM (6 mL) was added 3-oxo-1l5- benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (207 mg, 2 eq, 489 μmol). The mixture was stirred at 25 °C for 2 h. TLC indicated completion of reaction. The reaction was quenched with water (30 mL), washed with DCM (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EA in PE) to get 4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)cyclohexane-1-carbaldehyde (30 mg, 73.7 μmol, 30.1%) as a white solid. LC purity (0.1% FA): 28.11% (UV at 254 nm)/MS: 407.2 [M+H]; Retention time: 1.59 min. Synthesis of (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(2-(2-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)-7- azaspiro[3.5]nonan-7-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0541] To a solution of 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)cyclohexane-1-carbaldehyde (15.0 mg, 1 eq, 36.9 μmol) in were added potassium acetate (7.24 mg, 2 eq, 73.7 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (13.1 mg, 1 eq, 36.9 μmol) and sodium cyanoborohydride (4.63 mg, 2 eq, 73.7 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by Prep-HPLC, eluted with CH3CN in H2O (0.1%NH4HCO3) from 30% to 62% to get (S)-3-(1'-((4- (4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)cyclohexyl)methyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (8.73 mg, 10.5 μmol, 28.6%) as a white solid and (S)-3-(1'-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (8.73 mg, 10.5 μmol, 28.6%, 90.06% purity) as a white solid. [0542] P1: LC purity (0.03% TFA): 100.00% (UV at 254 nm)/MS: 746.5 [M+H]; Retention time: 1.34 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.88-7.75 (m, 1H), 7.75-7.52 (m, 2H), 7.39 (s, 1H), 7.33-7.18 (m, 2H), 5.14-4.98 (m, 1H), 4.56 (s, 2H), 4.45-4.32 (m, 1H), 4.27-4.10 (m, 1H), 2.97-2.83 (m, 2H), 2.79- 2.64 (m, 1H), 2.64-2.53 (m, 1H), 2.40-2.28 (m, 1H), 2.22 (s, 2H), 2.06-1.85 (m, 8H), 1.85-1.57 (m, 6H), 1.50 (s, 6H), 1.19- 0.97 (m, 2H). [0543] P2: LC purity (0.03% TFA): 100.00% (UV at 254 nm)/MS: 746.5 [M+H]; Retention time: 1.34 min.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.60-8.32 (m, 1H), 7.95 (s, 1H), 7.93- 7.76 (m, 1H), 7.76-7.51 (m, 2H), 7.51-7.40 (m, 1H), 7.38-7.17 (m, 2H), 5.30-4.92 (m, 1H), 4.66- 4.48 (m, 2H), 4.48-4.31 (m, 1H), 4.22 (d, J = 17.1 Hz, 1H), 2.93 (d, J = 11.8 Hz, 2H), 2.86-2.68 (m, 2H), 2.70-2.58 (m, 2H), 2.47-2.35 (m, 3H), 2.17-1.79 (m, 8H), 1.73-1.61 (m, 6H), 1.51 (s, 6H), 1.28-1.17 (m, 2H). Compound A59. (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

10- yl)piperidin-1-yl)propanoate (Intermediate 3) [0544] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (150 mg, 1 eq, 0.395 mmol) in DMF (2 mL) were added Cs2CO3 (386 mg, 3 eq, 1.18 mmol) and tert-butyl 3-bromopropanoate, then was added tert-butyl 3-bromopropanoate (124 mg, 1.5 eq, 0.592 mmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to get tert-butyl 3-(4-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)propanoate (111 mg, 0.218 mmol, 55.3%) as white solid. LC purity (0.1% FA):98.36% (UV at 254 nm)/MS: 508.2 [M +H]; Retention time: 1.120 min. Synthesis of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)propanoic acid (Intermediate 4) [0545] A solution of tert-butyl 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)propanoate (60 mg, 1 eq, 0.118 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 30 min. LCMS indicated completion of reaction. The mixture was concentrated to afford a crude product with DCM three times. The product 3-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)propanoic acid (69.0 mg, 153 μmol, 129%) was obtained as white solid. LC purity (0.1% FA): 64.88% (UV at 254 nm)/MS: 452.2 [M+H]; Retention time: 1.015 min. Synthesis of (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0546] To a solution of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)propanoic acid (10 mg, 1 eq, 22.1 μmol) in DMF (1 mL) were added (S)-3- (6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (9.4 mg, 1.2 eq, 26.6 μmol) and DIEA (28.6 mg, 38.5 μL, 10 eq, 221 μmol), after 10 min, was added BOP (7.83 mg, 0.8 eq, 17.7 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The crude product was dissolved in DMF and purified by prep-HPLC. The product (S)-3-(1'-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (6.0 mg, 7.51 μmol, 33.9%, 98.78% Purity) was obtained as white solid. LC purity (0.1% FA): 98.78% (UV at 254 nm)/MS: 790.1 [M+H]; Retention time: 4.267 min.1H NMR (400 MHz, MeOD) δ 8.43 (dd, J = 8.3, 4.6 Hz, 1H), 7.99 (s, 1H), 7.86 (t, J = 7.5 Hz, 1H), 7.64 (dd, J = 21.5, 7.9 Hz, 2H), 7.41 ^ 7.32 (m, 3H), 5.14 (dd, J = 12.0, 6.3 Hz, 1H), 4.70 (s, 2H), 4.57 (d, J = 14.1 Hz, 1H), 4.44 (dt, J = 26.8, 10.9 Hz, 2H), 4.01 (d, J = 13.1 Hz, 1H), 3.62 (s, 2H), 3.21 ^ 2.65 (m, 10H), 2.51 (d, J = 12.3 Hz, 1H), 2.25 ^ 1.78 (m, 10H), 1.60 (s, 6H). Compound A60.5-(4-(((1R,5S,6s)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

y - y , - - - - - , - y - - - , - y 1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 3) [0547] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (400 mg, 1 eq, 1.05 mmol) in MeOH (4 mL) were added tert-butyl (1R,5S)-6-formyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (245 mg, 1.1 eq, 1.16 mmol), TEA (320 mg, 3 eq, 3.16 mmol) and NaBH3CN (132 mg, 2 eq, 2.11 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum, and purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) to afford tert-butyl (1R,5S)-6-((4- (4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)- 3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 348 μmol, 33.0%) as a white oil. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 575.1 [M+H]; Retention time: 1.35 min. Synthesis of 10-(1-(((1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 4) [0548] A solution of tert-butyl (1R,5S)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (150 mg, 1 eq, 261 μmol) in DCM (2 mL) and TFA (2 mL) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 10-(1-(((1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (150 mg, 0.19 mmol, 73%) as a yellow oil. LC purity (0.1%FA): 59.79% (UV at 254 nm)/MS: 538.1 [M+H]; Retention time: 0.881 min. Synthesis of tert-butyl 4-(((1R,5S)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1- carboxylate (Intermediate 6) [0549] To a solution 10-(1-(((1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperidin-4-yl)-4- chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 1 eq, 211 μmol) in MeOH (2 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (49.4 mg, 1.1 eq, 232 μmol), triethylamine (63.9 mg, 3 eq, 632 μmol) and tert-butyl 4-formylpiperidine-1-carboxylate (49.4 mg, 1.1 eq, 232 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) to afford tert-butyl 4-(((1R,5S)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)piperidine-1-carboxylate (70 mg, 99 μmol, 47 %) as a yellow oil. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 672.3 [M+H]; Retention time: 1.181 min. Synthesis of 4-chloro-7,7-dimethyl-10-(1-(((1R,5S)-3-(piperidin-4-ylmethyl)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)-one (Intermediate 7) [0550] A solution of tert-butyl 4-(((1R,5S)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)piperidine-1-carboxylate (50 mg, 1 eq, 74.4 μmol) in DCM (2 mL) and TFA (2 mL) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 10-(1-(((1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperidin-4-yl)-4- chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (150 mg, 0.19 mmol, 73%) as a yellow oil. LC purity (0.1%FA): 75.51% (UV at 254 nm)/MS: 572.2 [M+H]; Retention time: 0.858 min. Synthesis of 5-(4-(((1R,5S,6s)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0551] To a solution of 4-chloro-7,7-dimethyl-10-(1-(((1R,5S,6s)-3-(piperidin-4-ylmethyl)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)-one (50 mg, 1 eq, 87.4 μmol) in DMF (2 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- dione (24.1 mg, 1 eq, 87.4 μmol) and DIEA (45.2 mg, 4 eq, 350 μmol). The mixture was stirred at 120 °C for 4 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA/H2O) from 14% to 24% to afford 5-(4-(((1R,5S,6s)-6-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (6.71 mg, 7.96 μmol, 9.11%) as a yellow solid. LC purity (0.1%FA): 100.00% (UV at 254 nm)/MS: 828.4 [M+H]; Retention time: 1.130 min.1H NMR (400 MHz, MeOD-d4) δ 8.43 (d, J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.88-7.84 (m, 1H), 7.68-7.60 (m, 3H), 7..36-7.31 (m,2H), 7.20-7.17 (m,1H), 5.08-5.04 (m, 1H), 4.04-4.01 (m, 2H), 3.60 (d, J = 11.2 Hz, 2H), 3.18-3.13 (m,2H), 3.02-2.82 (m, 8H), 2.77-2.67 (m, 2H), 2.50-2.42 (m,4H), 2.18- 2.03 (m, 5H), 1.87 (d, J = 13.2 Hz, 2H), 1.77 (s, 1H), 1.58 (d, J = 15.2 Hz, 8H), 1.50-1.48 (m, 1H), 1.28-1.25 (m, 2H). Compound A61. (S)-3-(l '-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1 ,2- a]quinazolin-10-yI)piperidin-l-yl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2, 6-dione

Synthesis of tert-butyl 2-(4-(4-chloro-7, 7-dimethyl-5-oxo-5, 7-dihydroindolo[l,2-a]quinazolin-10- yl)piperidin-l-yl)acetate (Intermediate 3)

[0552] A solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[l,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 pmol), tert-butyl 2-bromoacetate (51.3 mg, 1 eq, 263 pmol) and K2CO3 (36.4 mg, 1 eq, 263 pmol) in DMF (2.00 mL) was stirred at 60 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (20 mL X 2), dried over Na2SO4, concentrated. The residue was purified by prep-TLC (4% of MeOH in DCM ether) to afford tert-butyl 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[l,2-a]quinazolin- 10-yl)piperidin-l-yl)acetate (60 mg, 121 pmol, 46.1%) as yellow solid. LC purity (0.1% FA): 89.99% (UV at 254 nm)/MS: 494.2 [M +H]; Retention time: 1.128 min.

[0553] Synthesis of 2-(4-(4-chloro-7, 7-dimethyl-5-oxo-5, 7-dihydroindolo[l,2-a]quinazolin-10- yl)piperidin-l -yl)acetic acid (Intermediate 4)

[0554] To a solution of tert-butyl 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[l,2- a]quinazolin-10-yl)piperidin-l-yl)acetate (50 mg, 1 eq, 101 pmol) in DCM (3.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[l,2-a]quinazolin-10-yl)piperidin-l-yl)acetic acid (40 mg, 91.3 pmol, 90.3%) as a yellow oil. LC purity (0.1%TFA): 96.39% (UV at 254 nm)/MS: 438.1 [M +H]; Retention time: 1.148 min. [0555] Synthesis of (S)-3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0556] A solution of 2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)acetic acid (30 mg, 1 eq, 68.5 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (29.2 mg, 1.2 eq, 82.2 μmol), HATU (39.1 mg, 1.5 eq, 103 μmol) and DIEA (53.1 mg, 71.6 μL, 6 eq, 411 μmol) in DMF (2.00 mL) was stirred at 25 °C for 16 h. The reaction was monitored by LCMS. LCMS found 55% product. The mixture was quenched with H2O, extracted with EA, dried over Na2SO4, concentrated. The resulting residue was purified by reverse-phase chromatography to afford (S)- 3-(1'-(2-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (24.4 mg, 31.3 μmol, 45.8%, 99.36% Purity) as a white solid. LC purity (0.1%FA): 99.36% (UV at 254 nm)/MS: 775.3 [M+H]; Retention time: 0.924 min. 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 7.7 Hz, 2H), 7.38 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 7.3 Hz, 2H), 5.09 (d, J = 20.1 Hz, 1H), 4.72 ^ 4.61 (m, 2H), 4.39 (t, J = 12.9 Hz, 2H), 4.24 (d, J = 17.2 Hz, 1H), 4.14 (d, J = 18.1 Hz, 1H), 3.27 (s, 1H), 3.24 (s, 1H), 3.20 (s, 1H), 2.95 (dd, J = 50.1, 19.5 Hz, 4H), 2.76 (s, 2H), 2.60 (d, J = 17.9 Hz, 1H), 2.19 (t, J = 12.5 Hz, 2H), 1.98 (s, 2H), 1.85 ^ 1.70 (m, 6H), 1.50 (s, 6H), 1.24 (s, 1H). [0557] The following compounds were prepared in a manner analogous to Compound A61. Compound A62. (S)-3-(1'-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 804.6 [M+H]; 1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.36 (s, 2H), 5.13 (d, J = 13.0 Hz, 1H), 4.68 (s, 2H), 4.56 (d, J = 12.9 Hz, 1H), 4.42 (d, J = 11.8 Hz, 2H), 4.03 (d, J = 14.6 Hz, 1H), 3.51 (d, J = 9.8 Hz, 2H), 2.91 (t, J = 13.2 Hz, 6H), 2.80 (s, 3H), 2.63 (d, J = 6.8 Hz, 2H), 2.51 (d, J = 13.0 Hz, 1H), 2.13 (d, J = 14.0 Hz, 4H), 2.05 ^ 2.00 (m, 4H), 1.87 (d, J = 13.9 Hz, 4H), 1.59 (s, 6H). Compound A68. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 938.6 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 5.9 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.4 Hz, 2H), 5.09 (dd, J = 13.3, 4.9 Hz, 1H), 4.52 (s, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.88 (d, J = 22.6 Hz, 3H), 2.85-3.08 (m, 9H), 2.72 (s, 2H), 2.30 (d, J = 12.2 Hz, 3H), 2.20 (s, 2H), 2.06 (d, J = 17.0 Hz, 3H), 1.68-1.94 (m, 20H), 1.46 (s, 2H), 1.31 (s, 2H). Compound A75. (S)-3-(1'-(1-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 870.5 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 4.99-5.18 (m, 1H), 4.55 (s, 2H), 4.32 (dd, J = 50.7, 15.5 Hz, 3H), 4.00 (d, J = 69.9 Hz, 3H), 3.72 (s, 3H), 3.17 (s, 1H), 2.83 (s, 2H), 2.34 (s, 1H), 2.19 (s, 2H), 1.97-2.11 (m, 5H), 1.93 (s, 4H), 1.71-1.83 (m, 10H), 1.24 (s, 6H). Compound A79. (S)-3-(1'-(1-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 900.2 [M+H]; 1H NMR (400 MHz, DMSO-d6) 10.96 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 5.08 (d, J = 8.3 Hz, 1H), 4.50 (s, 2H), 4.31-4.45 (m, 2H), 4.18 (dd, J = 22.7, 14.7 Hz, 2H), 3.27 (s, 1H), 3.10 (d, J = 13.8 Hz, 1H), 2.97 (s, 3H), 2.87 (s, 2H), 2.71 (d, J = 23.2 Hz, 2H), 2.61 (s, 4H), 2.42 (d, J = 13.1 Hz, 1H), 2.13-2.28 (m, 4H), 2.01 (s, 4H), 1.86 (s, 6H), 1.73 (d, J = 10.4 Hz, 10H), 1.50 (d, J = 9.1 Hz, 1H), 1.26 (d, J = 11.6 Hz, 1H). Compound A97. (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 815.5 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J = 5.9 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.81-7.72 (m, 1H), 7.67-7.59 (m, 1H), 7.35 (d, J = 4.3 Hz, 2H), 5.19-5.09 (m, 1H), 4.75-4.64 (m, 2H), 4.55 (d, J = 12.7 Hz, 1H), 4.50-4.35 (m, 2H), 4.06 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 41.4 Hz, 2H), 3.38 (d, J = 12.3 Hz, 2H), 3.00-2.78 (m, 4H), 2.73 (d, J = 27.2 Hz, 2H), 2.51 (d, J = 11.4 Hz, 1H), 2.15 (d, J = 25.5 Hz, 2H), 2.11-1.98 (m, 8H), 1.96-1.79 (m, 6H), 1.75 (s, 2H). Compound A115. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 830.4 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.56-8.35 (m, 1H), 7.94 (s, 1H), 7.88-7.73 (m, 2H), 7.68-7.58 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.33-7.17 (m, 2H), 5.14-5.01 (m, 1H), 4.77-4.58 (m, 2H), 4.47-4.35 (m, 2H), 4.23 (d, J = 17.1 Hz, 1H), 3.95 (d, J = 14.0 Hz, 1H), 3.18 (d, J = 11.8 Hz, 2H), 3.08 (d, J = 10.6 Hz, 2H), 2.93-2.85 (m, 1H), 2.78-2.71 (m, 2H), 2.67-2.56 (m, 6H), 2.40 (d, J = 13.0 Hz, 1H), 2.12 (d, J = 10.5 Hz, 2H), 2.00 (d, J = 17.8 Hz, 3H), 1.90-1.68 (m, 14H). Compound A122. (S)-3-(1'-(5-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)pentanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 857.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.45 (t, J = 10.1 Hz, 1H), 8.04 (d, J = 10.4 Hz, 1H), 7.87 (dd, J = 16.3, 8.1 Hz, 2H), 7.66 (d, J = 7.3 Hz, 1H), 7.45-7.30 (m, 3H), 5.13 (dt, J = 13.1, 5.3 Hz, 1H), 4.70 (d, J = 9.8 Hz, 2H), 4.56 (d, J = 13.6 Hz, 1H), 4.46-4.34 (m, 2H), 4.03 (d, J = 14.0 Hz, 1H), 3.77 (d, J = 12.8 Hz, 2H), 3.34 (s, 4H), 3.28-3.22 (m, 3H), 3.14 (dd, J = 6.9, 5.3 Hz, 2H), 2.96-2.84 (m, 2H), 2.81-2.72 (m, 1H), 2.60 (dd, J = 10.9, 6.8 Hz, 2H), 2.27 (d, J = 13.4 Hz, 2H), 2.21-2.11 (m, 4H), 2.09-2.00 (m, 3H), 1.88 (d, J = 13.8 Hz, 8H), 1.80-1.73 (m, 4H). Compound A127. (S)-3-(1'-(7-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 938.7 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.86- 7.81 (m, 1H), 7.61 (s, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 5.19-5.09 (m, 1H), 4.50 -4.37 (m, 2H), 3.78 (d, J = 11.6 Hz, 2H), 3.63-3.68 (m, 4H), 3.41 (d, J = 27.0 Hz, 2H), 3.28 (s, 2H), 3.13-3.06 (m, 2H), 2.96-2.84 (m, 2H), 2.72-2.78 (m, 2H), 2.62-2.63 (m, 2H), 2.47-2.56 (m, 1H), 2.35-2.44 (m, 2H), 2.20-2.26 (m, 2H), 2.01-2.19 (m, 10H), 1.80-1.99 (m, 8H), 1.60-1.79 (m, 6H). Compound A130. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)butanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 843.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.90-7.80 (m, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.36 (q, J = 8.1 Hz, 3H), 5.16-5.09 (m, 1H), 4.67 (d, J = 10.7 Hz, 2H), 4.58 (s, 6H), 4.48-4.35 (m, 2H), 4.02 (d, J = 14.0 Hz, 1H), 3.60 (d, J = 11.3 Hz, 2H), 3.13-2.98 (m, 3H), 2.98-2.84 (m, 4H), 2.71-2.59 (m, 2H), 2.56-2.42 (m, 1H), 2.26-2.13 (m, 3H), 2.10-2.02 (m, 6H), 1.97-1.80 (m, 6H), 1.80-1.71 (m, 3H). Compound A148. (S)-3-(1'-(6-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)hexanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 871.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.85 (dd, J = 14.9, 8.1 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.36 (dt, J = 8.1, 5.8 Hz, 3H), 5.17-5.09 (m, 1H), 4.67 (s, 2H), 4.58 (s, 8H), 4.41 (dt, J = 17.1, 10.9 Hz, 2H), 4.03 (d, J = 14.6 Hz, 1H), 3.69 (d, J = 14.3 Hz, 2H), 3.13 (s, 5H), 2.83 (dd, J = 44.4, 13.8 Hz, 3H), 2.52 (dd, J = 15.4, 8.8 Hz, 3H), 2.23 (d, J = 12.4 Hz, 2H), 2.09 (d, J = 11.7 Hz, 4H), 2.03 (s, 2H), 1.87 (d, J = 11.2 Hz, 6H), 1.76-1.70 (m, 3H), 1.51 (dd, J = 14.9, 7.5 Hz, 2H). Compound A63. (S)-3-(1'-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y - y - - - , - y - - - , - y , - q n-10- yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 3) [0558] To a mixture of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (100 mg, 1 eq, 263 μmol), tert-butyl 4-oxopiperidine-1-carboxylate (52.4 mg, 1 eq, 263 μmol) and TEA (79.8 mg, 3 eq, 790 μmol) in DCE (7.0 mL) was added NaBH(OAc)3 (167.0 mg, 3 eq, 790 μmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give crude product. The residue was purified by column chromatography on silica gel (DCM: MeOH=50:1-20:1) to afford tert-butyl 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidine]-1'-carboxylate (103 mg, 183 μmol, 69.5%) as a white solid. LC purity (0.1% FA): 97.48% (UV at 254 nm)/MS: 563.4 [M +H]; Retention time: 0.977 min. Synthesis of 10-([1,4'-bipiperidin]-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)- one (Intermediate 4) [0559] A mixture of tert-butyl 4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidine]-1'-carboxylate (103.0 mg, 1 eq, 183 μmol) in DCM (3.0 mL) was added 2,2,2-trifluoroacetic acid (20.9 mg, 1.00 mL, 1 eq, 183 μmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated to afford 10-([1,4'-bipiperidin]- 4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (81.0 mg, 175 μmol, 95.6%) as a white solid. LC purity (0.1% FA): 91.16% (UV at 254 nm)/MS: 463.3 [M +H]; Retention time: 0.644 min. Synthesis of (S)-3-(1'-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0560] To a mixture of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (30.7 mg, 1 eq, 86.4 μmol) and TEA (26.2 mg, 3 eq, 259 μmol) in DCM (10 mL) was added triphosgene (25.7 mg, 1 eq, 86.4 μmol) and stirred at 25 °C for 0.5 h.10-([1,4'-bipiperidin]-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 1 eq, 86.4 μmol) was added and the mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction was concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EA=100:1-10:1) to afford (S)-3-(1'-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)-[1,4'-bipiperidine]-1'-carbonyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (20.1 mg, 23.8 μmol, 27.6%) as a white solid. LC purity (0.1% FA): 99.14% (UV at 254 nm)/MS: 844.8 [M +H]; Retention time: 4.304 min.1H NMR (400 MHz, MeOD) δ 8.41 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.65 (dd, J = 15.1, 7.8 Hz, 2H), 7.42 ^ 7.32 (m, 3H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 (s, 2H), 4.42 (q, J = 16.9 Hz, 2H), 3.94 (d, J = 13.6 Hz, 2H), 3.81 ^ 3.70 (m, 4H), 3.55 ^ 3.47 (m, 1H), 3.26 (d, J = 12.6 Hz, 1H), 3.20 ^ 2.84 (m, 7H), 2.83 ^ 2.74 (m, 1H), 2.56 ^ 2.44 (m, 1H), 2.30 (d, J = 14.0 Hz, 2H), 2.15 (dd, J = 22.1, 11.2 Hz, 5H), 2.01 (t, J = 12.3 Hz, 2H), 1.83 (dd, J = 19.0, 12.2 Hz, 4H), 1.59 (s, 6H). Compound A64. (S)-3-(1'-(((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

cid (Intermediate 2) [0561] To a solution of (1s,4s)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid (4.00 g, 1 eq, 25.3 mmol) and 1H-imidazole (3.44 g, 2 Eq, 50.6 mmol) in DMF (80 mL) was added tert- butylchlorodimethylsilane (4.19 g, 1.1 eq, 27.8 mmol). The solution was stirred at 25 °C for 16 h. TLC indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 5 g SepaFlash Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 60 mL/min). (1s,4s)-4- (((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid (5.00 g, 18.4 mmol, 72.6%) was obtained as a colorless oil. Synthesis of ((1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methano(Intermediate 3) [0562] To a solution of (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid (5.0 g, 1 eq, 18.4 mmol) in THF (50 mL) was added LiAlH4 (766.0 mg, 1.1 eq, 20.2 mmol). The solution was stirred at 25 °C for 16 h. TLC indicated the starting material was consumed completely. The reaction mixture was quenched with addition H2O (200 mL), and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 50 g SepaFlash Silica Flash Column, Eluent of 0~40% ethyl acetate/petroleum ether gradient @ 60 mL/min). ((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (3.40 g, 13.2 mmol, 71.7 %) was obtained as a colorless oil. Synthesis of (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (Intermediate 4) [0563] To a solution of ((1s,4s)-4(((tertbutyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (1.00 g, 1 eq, 3.87 mmol) in acetonitrile (10 mL) was added IBX (2.00 g, 1 eq, 3.87 mmol). The solution was stirred at 70 °C for 1 h. TLC indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (20 mL), and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 5 g SepaFlash Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 60 mL/min). (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1- carbaldehyde (900 mg, 3.51 mmol, 90.7 %) was obtained as a colorless oil. Synthesis of 10-(1-(((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 5) [0564] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (500 mg, 1 eq, 1.32 mmol) and (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane- 1-carbaldehyde (338 mg, 1 eq, 1.32 mmol) in MeOH (5.0 mL) was added NaBH3CN (165.0 mg, 2 eq, 2.63 mmol). The solution was stirred at 25 °C for 2 h. LC-MS indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (20 mL), and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 5 g SepaFlash Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 60 mL/min).10-(1-(((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (707 mg, 1.14 mmol, 86.6%) was obtained as a white solid. LCMS: Rt:1.508min; MS m/z (ESI):620.4[M+H]. Synthesis of 4-chloro-10-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 6) [0565] To a solution of 10-(1-(((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (707.0 mg, 1 eq, 1.14 mmol) in MeOH (5.0 mL) was added hydrogen chloride (416.0 mg, 10 eq, 11.4 mmol). The solution was stirred at 25 °C for 2 h. LC-MS indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (20 mL), and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 5 g SepaFlash Silica Flash Column, Eluent of 0~40% ethyl acetate/petroleum ether gradient @ 60 mL/min).4-chloro- 10-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (242 mg, 478 μmol, 42.0%) was obtained as a yellow oil. CMS: Rt:1.078min; MS m/z (ESI):506.2[M+H]. Synthesis of (1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (Intermediate 7) [0566] To a solution of 4-chloro-10-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (220 mg, 1 eq, 435 μmol) in DCM (5.0 mL) was added DMP (400 mg, 1 eq, 435 μmol). The solution was stirred at 25 °C for 16 h. LC-MS indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 5 g SepaFlash Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 60 mL/min). (1s,4s)-4-((4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)cyclohexane-1-carbaldehyde (150 mg, 298 μmol, 68.5%) was obtained as a yellow solid. LCMS: Rt:1.203min; MS m/z (ESI):604.5[M+H]. Synthesis of (S)-3-(1'-(((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0567] To a solution of (1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (50 mg, 1 eq, 99.2 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (35.3 mg, 1 eq, 99.2 μmol) in MeOH (5.0 mL) was added NaBH3CN (12.5 mg, 2 eq, 198 μmol). The solution was stirred at 25 °C for 2 h. LC-MS indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (20 mL), and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 5 g SepaFlash Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 60 mL/min). (S)-3-(1'-(((1s,4R)-4-((4-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (10 mg, 11.9 μmol, 12.0%) was obtained as a white solid. LCMS: Rt:0.895min; MS m/z (ESI):843.4[M+H]; 1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.3 Hz, 1H), 7.98 (s, 1H), 7.87 (t, J = 8.3 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.42 ^ 7.32 (m, 3H), 5.13 (dd, J = 13.3, 5.3 Hz, 1H), 4.58 (s, 2H), 4.41 (q, J = 17.0 Hz, 2H), 3.63 (s, 1H), 3.48 (s, 2H), 3.08 (d, J = 38.6 Hz, 2H), 2.90 (s, 2H), 2.77 (d, J = 16.6 Hz, 2H), 2.64 (s, 3H), 2.52 (s, 1H), 2.36 (s, 2H), 2.13 (s, 4H), 2.07 (d, J = 17.2 Hz, 5H), 1.96 (s, 3H), 1.83 (s, 2H), 1.60 (s, 6H), 1.51 (s, 2H), 1.08 (d, J = 8.1 Hz, 2H). Compound A78. (S)-3-(1'-(((1r,4S)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0568] Compound A78 was prepared in a manner analogous to Compound A64. MS m/z (ESI):843.4 [M+H]; 1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 5.17 ^ 5.10 (m, 1H), 4.70 (s, 2H), 4.44 (q, J = 16.9 Hz, 2H), 3.71 (dd, J = 43.1, 14.2 Hz, 6H), 3.11 (d, J = 12.7 Hz, 10H), 2.95 ^ 2.77 (m, 2H), 2.28 (d, J = 53.1 Hz, 8H), 2.05 (d, J = 43.8 Hz, 9H), 1.60 (s, 6H). Compound A66. (S)-3-(1'-(1-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0569] Synthesis of 4'-chloro-10'-(1-(3-hydroxypropyl)piperidin-4-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0570] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (150 mg, 1 eq, 0.36 mmol) in DMF (5 mL) was added sodium bicarbonate (300.1 mg, 10 eq, 3.57 mmol) and the reaction was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EA in PE) to afford 4'-chloro-10'-(1-(3- hydroxypropyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (150 mg, 0.31 mmol, 87.9%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 478.2 [M+H]; Retention time: 1.25 min. [0571] Synthesis of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidin-1-yl)propyl methanesulfonate (Intermediate 4) [0572] To a solution of 4'-chloro-10'-(1-(3-hydroxypropyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 0.06 mmol) in DCM (3 mL) was added methanesulfonyl chloride (10.8 mg, 1.5 eq, 0.09 mmol) at 0 ℃, triethylamine (19.1 mg, 3 eq, 0.19 mmol). The mixture was stirred at 0 °C for 1 h. LCMS indicated completion of reaction. The reaction was poured into H20 (10 mL) and extracted with EA (20 mL), then washed brine and dried over Na2SO4, filtered and concentrated to get 3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)propyl methanesulfonate (30 mg, 0.05 mmol, 78.3%) as a yellow oil. LC purity (0.1% FA): 82.10% (UV at 254 nm)/MS:556.2 [M+H]; Retention time:1.59 min. [0573] Synthesis of (S)-3-(1'-(1-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0574] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propyl methanesulfonate (30 mg, 1 eq, 0.054 mmol) in DMF (2 mL) were added (S)-3-(6-oxo-1'-(piperidin-4-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (23.7 mg, 1 eq, 0.05 mmol)， sodium hydrogen carbonate (45.3 mg, 10 eq, 0.54 mmol). The mixture was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified prep- HPLC, eluted with MeCN in H2O (0.1% FA/H2O) from 10% to 20% to afford (S)-3-(1'-(1-(3-(4- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)propyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.00 mg, 1.10 μmol, 2.04%, 99.05% Purity) as a white solid. LC purity (0.1% FA): 88.87% (UV at 254 nm)/MS: 898.4 [M+H]; Retention time: 1.18 min.1H NMR (400 MHz, MeOD-d4) δ 8.40-8.43 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.83-7.85(m, 2H), 7.65-7.67 (d, J = 7.6 Hz, 1H), 7.29-7.39 (m, 3H), 5.12-5.15 (m, 4H), 4.47-4.50 (m, 2H), 4.41 (s, 2H), 3.48 (s, 1H), 3.39 (s, 2H), 3.34 (s, 2H), 3.02 (s, 2H), 2.81 (s, 2H), 2.76 (s, 2H), 2.57 (s, 4H), 2.41 (s, 4H), 2.15 (s, 2H), 1.90-1.98 (m, 14H), 1.74-1.78 (d, J = 13.2 Hz, 8H). Compound A67. (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Sy

xane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0575] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (200 mg, 1 eq, 476 μmol) in MeOH (1 mL) were added 3- (hydroxymethyl)cyclobutan-1-one (143 mg, 3 eq, 1.43 mmol)，TEA (145 mg, 3 eq, 1.43 mmol) and NaBH3CN (89.8 mg, 3 eq, 1.43 mmol). The mixture was stirred at 60 °C for 3 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford 4'-chloro-9'-(1-(3- (hydroxymethyl)cyclobutyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (220 mg, 0.39 mmol, 82%) as a yellow solid. The residue was directly used in the next step. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 504.2 [M+H]; Retention time: 1.17 min. Synthesis of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)cyclobutane-1-carbaldehyde (Intermediate 4) [0576] To a solution of 4'-chloro-9'-(1-(3-(hydroxymethyl)cyclobutyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (220 mg, 1 eq, 436 μmol) in DCM (1 mL) was added DMP (222 mg, 1.2 eq, 524 μmol). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 8% of MeOH in DCM) to afford 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carbaldehyde (100 mg, 0.18 mmol, 41%) as a yellow solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 502.1 [M+H]; Retention time: 1.00 min. Synthesis of (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0577] To a mixture of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carbaldehyde (80 mg, 1 eq, 159 μmol)， (S)-3- (6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (84.9 mg, 1.5 eq, 239 μmol)， potassium acetate (46.9 mg, 3 eq, 478 μmol) and sodium triacetoxyborohydride (101 mg, 3 eq, 478 μmol) was added DMF (1 mL). The mixture was stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by prep-HPLC, eluted with CH3CN in H2O (0.1% TFA) from 10% to 95% to afford (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutyl)methyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.07 mg, 2.26 μmol, 1.42%) as a white solid. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 842.4 [M+H]; Retention time: 1.18 min. 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 7.95-7.74 (m, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.59-7.30 (m, 3H), 4.60-4.33 (m, 1H), 4.01-3.57 (m, 6H), 3.55-3.44 (m, 3H), 3.25-2.62 (m, 11H), 2.60-1.98 (m, 17H), 1.97-1.63(m, 6H). Compound A69. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 2-(4-(4-chloro-5-oxo-5H-spiro[cyclohexane-1,7-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetate (Intermediate 2) [0578] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (150 mg, 1 eq, 357 μmol) in DMF (3 mL) were added sodium hydrogen carbonate (300 mg, 10 eq, 3.57 mmol) and tert-butyl 2-bromoacetate (69.7 mg, 1 eq, 357 μmol) at rt. The reaction was stirred 25 °C for 16 h. LCMS indicated messy of reaction. The resulting mixture was extracted with EA (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 50% of EA in PE) to afford tert-butyl 2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)acetate (150 mg, 281 μmol, 78.6%) as a yellow solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 534.2 [M+H]; Retention time: 1.32 min. Synthesis of 2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)acetic acid (Intermediate 3) [0579] To a solution of tert-butyl 2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetate (170 mg, 1 eq, 318 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford 2-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)acetic acid (150 mg, 314 μmol, 98.6%) as a yellow solid. LC purity (0.1% FA): 96.94% (UV at 254 nm)/MS: 478.2 [M+H]; Retention time: 1.29 min. Synthesis of (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0580] To a solution of 2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetic acid (40 mg, 1 eq, 83.7 μmol) in DMF (2 mL) were added DIEA (108 mg, 10 eq, 837 μmol), (S)-3-(6-oxo-1'-(2-azaspiro[3.5]nonan-7-yl)-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (40.1 mg, 1 eq, 83.7 μmol) and BOP (74.0 mg, 2 eq, 167 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H2O(0.1% FA) from 20% to 34% to afford (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (4.44 mg, 4.70 μmol, 5.62%, 99.42% Purity) as a white solid. LC purity (0.1% FA): 91.86% (UV at 254 nm)/MS: 939.4 [M+H]; Retention time: 1.19 min.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.24-7.44 (m, 3H), 5.10 (dd, J = 13.2, 5.0 Hz, 1H), 4.62 (d, J = 50.7 Hz, 2H), 4.40 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.4 Hz, 1H), 3.88 (d, J = 20.6 Hz, 2H), 3.68 (d, J = 24.6 Hz, 2H), 3.52 (s, 5H), 3.18 (d, J = 45.6 Hz, 6H), 2.85-2.99 (m, 2H), 2.54-2.69 (m, 2H), 2.44 (d, J = 12.8 Hz, 1H), 2.25 (s, 2H), 2.01 (dd, J = 46.1, 15.7 Hz, 16H), 1.77 (s, 6H), 1.55 (s, 4H). [0581] The following compounds were prepared in a manner analogous to Compound A69. Compound A76. (S)-3-(1'-(1-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 870.5 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.40 (dd, J = 11.8, 8.5 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 5.09 (dd, J = 13.2, 4.7 Hz, 1H), 4.55 (s, 2H), 4.38 (d, J = 17.1 Hz, 1H), 4.25 (dd, J = 26.3, 12.9 Hz, 2H), 4.09 (s, 1H), 3.88-3.94 (m, 1H), 3.73 (s, 1H), 3.16 (s, 1H), 3.03 (s, 2H), 2.97 (d, J = 9.3 Hz, 2H), 2.82 (s, 2H), 2.67 (s, 1H), 2.59 (d, J = 15.3 Hz, 3H), 2.03-2.19 (m, 4H), 1.95 (dd, J = 15.5, 7.0 Hz, 5H), 1.64-1.89 (m, 14H). Compound A77. (S)-3-(1'-(1-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 898.5 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 9.1 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 5.08 (dd, J = 13.2, 5.0 Hz, 1H), 4.48-4.58 (m, 2H), 4.32-4.44 (m, 2H), 4.12-.25 (m, 2H), 3.09 (d, J = 13.2 Hz, 1H), 2.82-.99 (m, 6H), 2.62 (dd, J = 29.9, 14.7 Hz, 5H), 2.25 (t, J = 11.2 Hz, 2H), 2.07-.19 (m, 4H), 1.95-.00 (m, 1H), 1.84 (d, J = 14.7 Hz, 11H), 1.69 (s, 8H), 1.49 (d, J = 11.2 Hz, 1H), 1.25 (d, J = 12.7 Hz, 1H). Compound A95. (S)-3-(1'-(7-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 938.7 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.86- 7.81 (m, 1H), 7.79 (s, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 5.19-5.09 (m, 1H), 4.69 (s, 2H), 4.50 -4.37 (m, 2H), 4.32 (d, J = 5.8 Hz, 2H), 3.78 (d, J = 11.6 Hz, 2H), 3.70-3.53 (m, 4H), 3.41 (d, J = 27.0 Hz, 2H), 3.28 (s, 2H), 3.13-3.06 (m, 1H), 2.97 (d, J = 15.4 Hz, 1H), 2.96-2.84 (m, 2H), 2.82 -2.71 (m, 1H), 2.56-2.47 (m, 1H), 2.44 (d, J = 9.4 Hz, 2H), 2.26 (s, 2H), 2.23-2.11 (m, 10H), 2.10 -1.90 (m, 4H), 1.90-1.65 (m, 10H). Compound A96. (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 815.5 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.43-8.37 (m, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.86-7.80 (m, 1H), 7.76 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.41-7.32 (m, 2H), 5.20-5.08 (m, 1H), 4.74-4.65 (m, 2H), 4.54 (d, J = 13.9 Hz, 1H), 4.50-4.36 (m, 2H), 4.00 (d, J = 13.6 Hz, 1H), 3.97-3.71 (m, 2H), 3.50- 3.40 (m, 2H), 3.03-2.83 (m, 4H), 2.82-2.72 (m, 2H), 2.51 (d, J = 12.6 Hz, 1H), 2.25-2.09 (m, 4H), 2.09-1.91 (m, 8H), 1.91-1.66 (m, 8H). Compound A114. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 829.5 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.35 (t, J = 15.1 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.72-7.59 (m, 2H), 7.47-7.21 (m, 3H), 5.15-4.98 (m, 1H), 4.72-4.54 (m, 2H), 4.44-4.35 (m, 2H), 4.25-4.18 (m, 1H), 3.95 (d, J = 13.5 Hz, 2H), 3.06 (d, J = 10.7 Hz, 3H), 2.94-2.83 (m, 1H), 2.77-2.70 (m, 1H), 2.70-2.54 (m, 6H), 2.20 -2.05 (m, 4H), 1.96-1.53 (m, 17H). Compound A121. (S)-3-(1'-(5-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)pentanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 857.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.39 (t, J = 13.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.95-7.74 (m, 2H), 7.66 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 8.6, 1.6 Hz, 1H), 7.37-7.20 (m, 2H), 5.22-5.03 (m, 1H), 4.76-4.63 (m, 2H), 4.63-4.51 (m, 1H), 4.47-4.36 (m, 2H), 4.03 (d, J = 13.6 Hz, 1H), 3.76 (d, J = 11.6 Hz, 2H), 3.22- 3.01 (m, 4H), 3.16-3.03 (m, 2H), 2.98-2.83 (m, 2H), 2.81-2.73 (m, 1H), 2.60 (d, J = 3.2 Hz, 2H), 2.51-2.37 (m, 1H), 2.31-2.13 (m, 5H), 2.12-1.96 (m, 5H), 1.95-1.79 (m, 10H), 1.79-1.63 (m, 3H). Compound A142. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)butanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 843.3 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.38 (d, J = 8.7 Hz, 1H), 8.12 (t, J = 9.2 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.70-7.60 (m, 2H), 7.44-7.26 (m, 3H), 5.09 (d, J = 13.5 Hz, 1H), 4.72-4.60 (m, 2H), 4.42 (dd, J = 12.9, 9.7 Hz, 2H), 4.23 (dd, J = 17.1, 5.7 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.62 (d, J = 22.2 Hz, 2H), 3.22-3.05 (m, 6H), 2.95 (dd, J = 16.9, 11.5 Hz, 1H), 2.78 (d, J = 9.1 Hz, 1H), 2.60 (d, J = 17.3 Hz, 1H), 2.36-2.24 (m, 1H), 2.13 (d, J = 13.4 Hz, 4H), 1.94 (dd, J = 12.7, 6.7 Hz, 9H), 1.76 (dd, J = 20.9, 13.8 Hz, 10H). Compound A158. (S)-3-(1'-(6-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)hexanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 871.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.37 (q, J = 7.8 Hz, 2H), 5.13 (s, 1H), 4.68 (t, J = 10.1 Hz, 4H), 4.58 (s, 6H), 4.45-4.38 (m, 2H), 4.03 (d, J = 14.5 Hz, 1H), 3.67 (d, J = 13.0 Hz, 2H), 3.09 (dd, J = 25.8, 7.2 Hz, 5H), 2.95-2.83 (m, 3H), 2.53 (t, J = 7.0 Hz, 3H), 2.16 (s, 4H), 2.09-2.00 (m, 5H), 1.83 (s, 6H), 1.75-1.70 (m, 2H), 1.36 (t, J = 6.3 Hz, 2H). Compound A71. (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-(4-chloro-5-oxo-5 -spiro[cyclohexane- ,7-indolo[ , -a]quinazolin]-10'- yl)cyclohexane-1-carbaldehyde (Intermediate 2) [0582] To a solution of 4'-chloro-10'-(4-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (80 mg, 1 eq, 178 μmol) in DCM (6 mL) was added 3-oxo-1l5- benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (151 mg, 2 eq, 356 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with DCM (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to get 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexane-1-carbaldehyde (50 mg, 89 μmol, 50%, 80% Purity) as a white solid. LC purity (0.1% FA): 73.10% (UV at 254 nm)/MS: 447.2 [M +H]; Retention time: 1.759 min. Synthesis of (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione [0583] To a solution of 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclohexane-1-carbaldehyde (80 mg, 1 eq, 179 μmol) in were added potassium acetate (35.1 mg, 2 eq, 358 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (63.6 mg, 1 eq, 179 μmol) and sodium cyanoborohydride (22.5 mg, 2 eq, 358 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to get the crude. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.03% FA) from 20% to 30% to afford (S)-3-(1'-((4- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (3.06 mg, 3.87 μmol, 2.16%) as a white solid. LC purity (0.1% FA): 92.08% (UV at 254 nm)/MS: 786.5 [M+H]; Retention time: 1.457 min. 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 10.7 Hz, 1H), 7.89-7.78 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.39-7.25 (m, 2H), 5.20-5.08 (m, 1H), 4.72 (s, 2H), 4.45 (q, J = 17.0 Hz, 2H), 3.73 (d, J = 14.2 Hz, 2H), 3.51-3.39 (m, 1H), 3.23-3.11 (m, 4H), 2.93-2.76 (m, 3H), 2.53- 2.45 (m, 1H), 2.31 (d, J = 13.9 Hz, 2H), 2.20-2.02 (m, 11H), 1.93-1.71 (m, 9H), 1.37 (d, J = 11.6 Hz, 1H). Compound A72. (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 4'-chloro-9'-(1-((3-oxocyclobutyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0584] To a solution of 3-(bromomethyl)cyclobutan-1-one (155 mg, 2 eq, 952 μmol) in DMF (2 mL) were added K2CO3 (197 mg, 3 eq, 1.43 mmol), 4'-chloro-9'-(piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 476 μmol). The reaction was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 4'-chloro-9'-(1-((3-oxocyclobutyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (170 mg, 0.30 mmol, 63%) as a yellow solid. LC purity (0.1% FA): 89% (UV at 254 nm)/MS: 502.05 [M+H]; Retention time: 1.126 min. Synthesis of tert-butyl (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0585] To a solution of 4'-chloro-9'-(1-((3-oxocyclobutyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 59.8 μmol) in DMF (3 mL) were added potassium acetate (11.7 mg, 2 eq, 120 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (42.5 mg, 2 eq, 120 μmol) and sodium cyanoborohydride (3.76 mg, 1 eq, 59.8 μmol). The reaction was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.05%TFA) from 27% to 30% to afford (S)- 3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (2.00 mg, 2.25 μmol, 3.76%) as a white solid. LC purity (0.1% FA): 94.5% (UV at 254 nm)/MS: 841.3 [M+H]; Retention time: 1.216 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.48-7.42 (m, 2H), 7.36 (d, J = 7.2 Hz, 1H), 5.14 (dd, J = 13.4, 5.2 Hz, 1H), 4.69 (s, 1H), 4.44 (q, J = 17.1 Hz, 2H), 3.64 (dd, J = 41.3, 11.3 Hz, 4H), 3.50-3.44 (m, 1H), 3.36 (s, 2H), 3.20 (t, J = 12.0 Hz, 2H), 3.12-2.88 (m, 4H), 2.81 -2.62 (m, 4H), 2.50 (dt, J = 18.1, 11.0 Hz, 2H), 2.30-2.01 (m, 15H), 1.85 (d, J = 17.4 Hz, 6H). Compound A73. (S)-3-(1'-(1-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propanoyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y y , 1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propanoyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0586] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propanoic acid (50 mg, 1 eq, 102 μmol) in DMF (2 mL) were added (S)-3-(1'-(azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (41.7 mg, 1 eq, 102 μmol) and DIEA (65.7 mg, 5 eq, 508 μmol) and BOP (89.9 mg, 2 eq, 203 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by Prep-HPLC (0.1% FA in CH3CN and H2O) to get (S)-3-(1'-(1-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)propanoyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (13.1 mg, 14.1 μmol, 13.9%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 884.4 [M+H]; Retention time: 1.14 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.42 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.89-7.65 (m, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.39-7.07 (m, 3H), 5.18-4.99 (m, 1H), 4.54 (s, 2H), 4.38 (d, J = 17.5 Hz, 1H), 4.21 (d, J = 17.3 Hz, 2H), 4.03 (s, 1H), 3.90 (t, J = 8.2 Hz, 1H), 3.73 (s, 1H), 2.98-2.75 (m, 7H), 2.64 (d, J = 23.6 Hz, 1H), 2.37 (d, J = 32.5 Hz, 3H), 2.15-1.84 (m, 14H), 1.74 (d, J = 13.0 Hz, 10H), 1.23 (s, 1H). [0587] Compound A74 was prepared in a manner analogous to Compound A73. Compound A74. (S)-3-(1'-(1-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)propanoyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 912.2 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.92-7.75 (m, 2H), 7.74 -7.59 (m, 1H), 7.38-7.24 (m, 3H), 5.19-5.02 (m, 1H), 4.75-4.64 (m, 2H), 4.45-4.34 (m, 1H), 4.27 -4.18 (m, 1H), 4.04 (s, 1H), 3.68 (s, 2H), 3.54 (s, 2H), 3.03 (d, J = 56.8 Hz, 9H), 2.97- 2.81 (m, 4H), 2.69- 2.57 (m, 3H), 2.30 (d, J = 21.1 Hz, 1H), 2.14-1.99 (m, 10H), 1.90 (s, 2H), 1.81- 1.64 (m, 8H), 1.24 (s, 2H). Compound A80. (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 2) [0588] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (427 mg, 3 eq, 2.14 mmol) in MeOH (3 mL) were added 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (300 mg, 1 eq, 714 μmol)， TEA (217 mg, 3 eq, 2.14 mmol) andNaCNBH4CN (135 mg, 3 eq, 2.14 mmol). The mixture was stirred at 60 °C for 3 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 80% of EA in PE) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (270 mg, 448 μmol, 62.7 %) as a yellow oil. LC purity (0.1% FA): 93.09% (UV at 254 nm)/MS: 603.4 [M+H]; Retention time: 1.35 min. Synthesis of 9'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 3) [0589] To a solution of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (270 mg, 1 eq, 448 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 9'-([1,4'-bipiperidin]-4-yl)-4'- chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (220 mg, 437 μmol, 97.7 %) as a yellow solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 503.2 [M+H]; Retention time: 1.04 min. Synthesis of (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0590] To a solution of 9'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (50 mg, 1 eq, 99.4 μmol) in DMF (2 mL) were added N-ethyl-N- isopropylpropan-2-amine (64.2 mg, 5 eq, 497 μmol), (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo- 7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)acetic acid (41.1 mg, 1 eq, 99.4 μmol) and ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (87.9 mg, 2 eq, 199 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 25% to 39% to afford (S)-3-(1'-(2-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-1'-yl)-2-oxoethyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (9.20 mg, 9.70 μmol, 9.76%) as a white solid. LC purity (0.1% FA): 94.20% (UV at 254 nm)/MS: 899.6 [M+H]; Retention time: 1.19 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.81 (t, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 6.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 8.9 Hz, 1H), 4.54 (s, 2H), 4.39 (d, J = 17.1 Hz, 2H), 4.11-4.26 (m, 3H), 3.09-3.18 (m, 2H), 3.01 (s, 3H), 2.91 (s, 1H), 2.86 (s, 2H), 2.68 (s, 1H), 2.61 (s, 2H), 2.33 (s, 2H), 2.08 (s, 4H), 1.99 (s, 1H), 1.82 (s, 10H), 1.70 (s, 9H), 1.52 (s, 1H), 1.30 (s, 1H). Compound A81. (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synth

dolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 3) [0591] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (500 mg, 1 eq, 1.19 mmol) in MeOH (3.00 mL) were added TEA (602 mg, 5 eq, 5.95 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (245 mg, 1.2 eq, 1.43 mmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (112 mg, 1.5 eq, 1.79 mmol) was added to above mixture. The mixture was stirred at 60 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with DCM (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 60% of EA in PE) to afford tert- butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)azetidine-1-carboxylate (350 mg, 609 μmol, 51.1%) as a yellow oil. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 575.2 [M+H]; Retention time: 1.33 min. Synthesis of 10'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate4 ) [0592] To a solution of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidine-1-carboxylate (400 mg, 1 eq, 695 μmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated to get 10'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (320 mg, 674 μmol, 96.9%) as a yellow oil. LC purity (0.1% FA): 94.79% (UV at 254 nm)/MS: 475.2 [M+H]; Retention time: 0.23 min. Synthesis of (S)-3-(1'-(4-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0593] To a solution of (S)-3-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)propanoic acid (30 mg, 1 eq, 70.2 μmol) in DMF (2 mL) were added 10'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (33.3 mg, 1 eq, 70.2 μmol), DIEA (45.4 mg, 5 eq, 351 μmol) and BOP (46.6 mg, 1.5 eq, 105 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1% FA) from 24% to 46% to afford (S)-3- (1'-(3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)azetidin-1-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (14.53 mg, 15.8 μmol, 22.5%) as a white solid. LC purity (0.1% FA): 96.3% (UV at 254 nm)/MS: 884.5 [M+H]; Retention time: 1.26 min. 1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.89-7.77 (m, 2H), 7.64 (s, 1H), 7.34-7.21 (m, 3H), 5.11 (dd, J = 12.9, 5.6 Hz, 1H), 4.60 (s, 2H), 4.49-4.31 (m, 3H), 4.12 (dd, J = 21.0, 10.4 Hz, 2H), 3.90 (dd, J = 9.9, 5.2 Hz, 1H), 3.34 (s, 4H), 3.14-2.98 (m, 5H), 2.99- 2.72 (m, 5H), 2.59-2.33 (m, 5H), 2.27-2.04 (m, 8H), 1.94 (s, 1H), 1.89-1.67 (m, 6H), 1.78 (s, 2H). [0594] The following compounds were prepared in a manner analogous to Compound A81. Compound A82. (S)-3-(1'-(2-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 870.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.43 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J = 15.9, 8.0 Hz, 2H), 7.65 (s, 1H), 7.43 (s, 2H), 7.34 (s, 1H), 5.14 (s, 1H), 4.77-4.56 (m, 4H), 4.48-4.31 (m, 4H), 4.12 (s, 3H), 3.63-3.42 (m, 4H), 3.12 (dd, J = 6.2, 4.4 Hz, 2H), 3.04-2.84 (m, 3H), 2.78 (dd, J = 13.2, 2.4 Hz, 1H), 2.50-2.41 (m, 1H), 2.35-2.12 (m, 2H), 2.18-2.01 (m, 5H), 2.14-1.96 (m, 7H), 1.87-1.65 (m, 3H), 1.75-1.52 (m, 3H). Compound A85. (S)-3-(1'-(2-(7-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-2-oxoethyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 938.8 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40-8.42 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.83- 7.85 (d, J = 8.4 Hz, 2H), 7.64-7.66 (d, J = 8.0 Hz, 1H), 7.38 (s, 2H), 7.31-7.33 (d, J = 8.8 Hz, 1H), 5.08-5.15 (m, 2H), 4.56-4.58 (d, J = 6.0 Hz, 8H), 4.42 (s, 1H), 4.39 (s, 1H), 4.05 (s, 1H), 3.97 (s, 1H), 3.76 (s, 1H), 3.67 (s, 1H), 3.13-3.15 (d, J = 8.4 Hz, 2H), 2.95 (s, 2H), 2.85-2.88 (d, J = 4.8 Hz, 1H), 2.79 (s, 1H), 2.65 (s, 2H), 2.48-2.51 (m, 1H), 2.26 (s, 2H), 2.15 (s, 1H), 1.97-2.10 (m, 12H), 1.87-1.89 (d, J = 9.2 Hz, 3H), 1.78 (s, 4H), 1.62 (s, 2H), 1.47 (s, 2H). Compound A92. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-oxoethyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 939.0 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.45-8.42 (m, 1H), 7.99 (d, J = 3.3 Hz, 1H), 7.82 (t, J = 9.0 Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.44-7.18 (m, 3H), 5.12-5.08 (m, 1H), 4.66-4.60(m, 2H), 4.45-4.16 (m, 4H), 3.86-3.70 (m, 1H), 3.62-3.43 (m, 6H), 3.22-2.99 (m, 3H), 2.91-2.81 (m, 3H), 2.72-2.55 (m, 1H), 2.37-2.19 (m, 4H), 2.18-1.83 (m, 14H), 1.82-1.45 (m, 11H), 1.28-1.23 (m, 1H). Compound A83. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A84. (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 4-chloro-10-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 3) [0595] To a solution of 4-chloro-7,7-dimethyl-10-(piperazin-1-yl) indolo[1,2-a]quinazolin-5(7H)- one (500 mg, 1 eq, 1.31 mmol) in MeOH (5 mL) were added sodium cyanoborohydride (247 mg, 3 eq, 3.94 mmol), 4-(hydroxymethyl)cyclohexan-1-one (505 mg, 3 eq, 3.94 mmol) and TEA (664 mg, 5 eq, 6.56 mmol), the reaction was stirred at 60 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 4-chloro-10-(4-(4- (hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (260 mg, 0.45 mmol, 35%) as a yellow solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 493.3 [M +H]; Retention time: 1.151 min. Synthesis of tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4) [0596] To a solution of 4-chloro-10-(4-(4-(hydroxymethyl)cyclohexyl)piperazin-1-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (120 mg, 1 eq, 243 μmol) in DCM (6 mL) was added DMP (309 mg, 3 eq, 730 μmol), and the reaction was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction was filtered and the filtrated wan concentrated and purified by silica gel column chromatography (100-200 mesh silica gel, 5% MeOH in DCM ) to afford 4- (4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1- yl)cyclohexane-1-carbaldehyde (120 mg, 0.21 mmol, 85%) as a yellow solid. LC purity (0.1%TFA): 85.53% (UV at 254 nm)/MS: 491.2 [M+ H]; Retention time: 1.178 min. Synthesis of tert-butyl (S)-3-(1'-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0597] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperazin-1-yl)cyclohexane-1-carbaldehyde (260 mg, 1 eq, 529 μmol) in MeOH (3 mL) were added potassium acetate (104 mg, 2 eq, 1.06 mmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (376 mg, 2 eq, 1.06 mmol) and sodium cyanoborohydride (66.5 mg, 2 eq, 1.06 mmol), the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1%FA) 15% to 18% to afford (S)-3-(1'-((4- (4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (6.59 mg, 7.80 μmol, 1.47 %) as a yellow solid and (S)-3-(1'-((4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (8.97 mg, 9.99 μmol, 1.89%) as a yellow solid. [0598] P1 (A83): LC purity (0.03%FA): 85.68% (UV at 254 nm)/MS: 830.1 [M+H]; Retention time: 1.159 min.1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.5 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.68-7.61 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.43-7.34 (m, 2H), 7.04 (d, J = 7.1 Hz, 1H), 5.49 (s, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (s, 2H), 4.43 (q, J = 17.0 Hz, 2H), 3.52 (s, 4H), 3.39 (d, J = 12.0 Hz, 2H), 3.34 (d, J = 8.3 Hz, 6H), 3.27 (s, 3H), 2.98-2.86 (m, 2H), 2.78 (d, J = 7.7 Hz, 4H), 2.61-2.48 (m, 1H), 2.23 (d, J = 12.5 Hz, 3H), 2.09 (d, J = 12.7 Hz, 2H), 1.96 (d, J = 12.9 Hz, 2H), 1.57 (s, 7H), 1.20 (d, J = 12.4 Hz, 2H). [0599] P2 (A84): 1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.2 Hz, 1H), 7.70- 7.62 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.41 (t, J = 5.3 Hz, 2H), 7.05 (d, J = 7.3 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 2H), 4.66 (s, 3H), 4.43 (q, J = 17.1 Hz, 3H), 3.52 (s, 4H), 3.34 (d, J = 7.7 Hz, 10H), 3.26 (s, 3H), 3.02 (s, 1H), 2.95 (s, 1H), 2.88 (dd, J = 13.3, 5.2 Hz, 2H), 2.78 (d, J = 15.4 Hz, 1H), 2.50 (dd, J = 12.9, 4.5 Hz, 1H), 2.27 (s, 1H), 2.17 (d, J = 10.2 Hz, 3H), 1.99 (d, J = 14.8 Hz, 4H), 1.79 (s, 2H), 1.76 (s, 3H). Compound A86. (S)-3-(1'-(3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

o[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)propanoate (Intermediate 3) [0600] To a mixture 10'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (50 mg, 1 eq, 105 μmol in MeCN (3 mL) were added DBU (32.0 mg, 2 eq, 211 μmol) and tert-butyl acrylate (20.2 mg, 1.5 eq, 158 μmol). The mixture was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (50 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-80% of ethyl acetate in petroleum ether) to afford tert-butyl 3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidin-1-yl)azetidin-1-yl)propanoate (50 mg, 66 μmol, 63%) as a colorless oil. LC purity (0.1% FA): 95.13% (UV at 254 nm)/MS: 603.4 [M+H]; Retention time: 1.349 min. Synthesis of 3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)azetidin-1-yl)propanoic acid (Intermediate 4) [0601] To a solution of tert-butyl 3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)propanoate (100 mg, 1 eq, 166 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to give 3-(3-(4-(4'-chloro-5'- oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1- yl)propanoic acid (80 mg, 146 μmol, 88.2%) as a yellow solid. LC purity (0.1%TFA): 77.99% (UV at 254 nm)/MS: 547.2 [M+H]; Retention time: 1.195 min. Synthesis of (S)-3-(1'-(3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0602] To a solution of 3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)azetidin-1-yl)propanoic acid (50 mg, 1 eq, 91.4 μmol) in DMF (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (32.5 mg, 1 eq, 91.4 μmol), HATU (52.1 mg, 1.5 eq, 137 μmol) and DIEA (35.4 mg, 3 eq, 274 μmol). The solution was stirred at 25 °C for 5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 10% to 35% to afford (S)-3- (1'-(3-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)azetidin-1-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.94 mg, 4.36 μmol, 4.77 %) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 884.5 [M+H]; Retention time: 1.389 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.88-7.77 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.44-7.28 (m, 3H), 5.19-5.07 (m, 1H), 4.93 (s, 1H), 4.59 (s, 5H), 4.40 (t, J = 14.7 Hz, 2H), 4.01 (d, J = 19.7 Hz, 2H), 3.66 (s, 1H), 3.26-3.15 (m, 2H), 3.02 (d, J = 10.7 Hz, 2H), 2.91 -2.72 (m, 5H), 2.51 (d, J = 13.3 Hz, 1H), 2.22-1.65 (m, 21H). Compound A87. (S)-3-(1'-(2-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synt

hesis of tert-butyl 3-(4-(4-chloro-5-oxo-5H-spiro[cyclohexane-1,7-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 3) [0603] To a mixture of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (200 mg, 1 eq, 476 μmol) in MeOH (5 mL) were added TEA (482 mg, 10 eq, 4.76 mmol), sodium cyanoborohydride (150 mg, 5 eq, 2.38 mmol) and tert-butyl 3-oxoazetidine- 1-carboxylate (163 mg, 2 eq, 952 μmol). The mixture was stirred at 60 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with DCM (50 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100- 200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford tert-butyl 3-(4-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1- carboxylate (100 mg, 163 μmol, 34.5%) as a white solid. LC purity (0.1% FA): 71.48% (UV at 254 nm)/MS: 575.4 [M +H]; Retention time: 1.312 min. Synthesis of 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 4) [0604] A solution of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carboxylate (200 mg, 1 eq, 348 μmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated to get 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (150 mg, 316 μmol, 90.7 %) as a yellow oil. LC purity (0.1% FA): 76.17 % (UV at 254 nm)/MS: 475.2 [M+H]; Retention time: 1.100 min. Synthesis of (S)-3-(1'-(2-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0605] To a solution of (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)acetic acid (26.1 mg, 1 eq, 63.2 μmol) in DCM (3 mL) were added 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 63.2 μmol), BOP (41.9 mg, 1.5 eq, 94.7 μmol) and DIEA (24.5 mg, 3 eq, 189 μmol). The solution was stirred at 25 °C for 5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O from (0.1% FA) from 10% to 35% to afford (S)-3-(1'-(2-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)-2-oxoethyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (6.06 mg, 6.93 μmol, 11.0%) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 870.4 [M+H]; Retention time: 0.834 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.51-7.37 (m, 3H), 5.16-5.10 (m, 1H), 4.68 (s, 2H), 4.57 (d, J = 7.4 Hz, 2H), 4.48-4.32 (m, 4H), 4.09 (s, 3H), 3.62 (d, J = 31.9 Hz, 4H), 3.33 (s, 1H), 3.08 (d, J = 37.7 Hz, 1H), 2.98-2.77 (m, 4H), 2.56-2.45 (m, 1H), 2.33 (d, J = 11.8 Hz, 2H), 2.24-1.95 (m, 12H), 1.84 (d, J = 10.9 Hz, 7H). [0606] The following compounds were prepared in a manner analogous to Compound A87. Compound A89. (S)-3-(1'-(2-(7-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-2-oxoethyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 938.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.50-7.38 (m, 3H), 5.14 (dd, J = 13.1, 5.1 Hz, 2H), 4.70 (s, 2H), 4.41 (dt, J = 44.3, 22.1 Hz, 4H), 3.81-3.74 (m, 1H), 3.68 (s, 5H), 3.59-3.52 (m, 1H), 3.48 (s, 3H), 3.13 (s, 2H), 2.95 (d, J = 35.3 Hz, 4H), 2.84 (d, J = 28.7 Hz, 1H), 2.45 (s, 6H), 2.29-2.03 (m, 15H), 1.83 (s, 13H). Compound A90. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-oxoethyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 938.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.38 (s, 2H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.58 (s, 2H), 4.41 (q, J = 16.9 Hz, 2H), 4.08 (s, 1H), 4.00 (s, 1H), 3.79 (s, 1H), 3.68 (dd, J = 27.0, 10.6 Hz, 3H), 3.23 (d, J = 7.4 Hz, 4H), 3.01 (d, J = 15.9 Hz, 3H), 2.92-2.84 (m, 1H), 2.77 (d, J = 15.2 Hz, 1H), 2.55-2.48 (m, 1H), 2.44-1.89 (m, 18H), 1.84 (d, J = 11.3 Hz, 6H), 1.65 (dd, J = 24.8, 12.7 Hz, 4H), 1.36 (t, J = 6.3 Hz, 2H). Compound A91. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)-3-oxopropyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 912.2 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.90-7.78 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.48-7.30 (m, 3H), 5.16-5.12 (m, 1H), 4.71 (s, 2H), 4.50-4.38 (m, 2H), 4.20-4.07 (m, 1H), 3.73 (d, J = 9.9 Hz, 3H), 3.61-3.47 (m, 3H), 3.24-3.09 (m, 4H), 3.08-3.01 (m, 2H), 2.99 (s, 2H), 2.96-2.89 (m, 1H), 2.86 (s, 2H), 2.82-3.71 (m, 2H), 2.60-2.42 (m, 1H), 2.38-1.98 (m, 15H), 1.95-1.65 (m, 8H). Compound A93. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

yn es s of e - u y - - -c o o- -oxo- -sp o cyc o exane- , -n o o[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)propanoate (Intermediate 2) [0607] To a solution of 10'-([1,4'-bipiperidin]-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (40 mg, 1 eq, 79.5 μmol) in DMF (1 mL) were added sodium bicarbonate (20 mg, 3 eq, 239 μmol)，tert-butyl 3-bromopropanoate (24.9 mg, 1.5 eq, 119 μmol). The mixture was stirred at 65 °C for 16 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 8% of MeOH in DCM) to afford tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)- [1,4'-bipiperidin]-1'-yl)propanoate (30 mg, 43 μmol, 54%) as a yellow oil. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 631.0 [M+H]; Retention time: 1.09 min. Synthesis of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)- [1,4'-bipiperidin]-1'-yl)propanoic acid (Intermediate 3) [0608] A mixture of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)propanoate (30 mg, 1 eq, 47.5 μmol) in DCM (1 mL) was added TFA (3 mL), the mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 8% of MeOH in DCM) to afford 3-(4-(4'-chloro-5'-oxo- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)propanoic acid (20 mg, 31 μmol, 66%) as a white solid. LC purity (0.1% FA): 97.70% (UV at 254 nm)/MS: 575.4 [M+H]; Retention time: 1.12 min. Synthesis of (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0609] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)propanoic acid (15.0 mg, 1 eq, 26.1 μmol) in DMF (1 mL) were added DIEA (20.2 mg, 6 eq, 156 μmol) and BOP (17.3 mg, 1.5 eq, 39.1 μmol). The mixture was stirred at 25 °C for 10 mins, and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (10.2 mg, 1.1 eq, 28.7 μmol) was added in the mixture and stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by prep-HPLC, eluted with MeCN in H2O (0.05%TFA) from 26% to 31% to afford (S)-3-(1'-(3-(4-(4'-chloro-5'- oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'- yl)propanoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (4.29 mg, 4.45 μmol, 17.1%) as a white solid. LC purity (0.1% FA): 99.99% (UV at 254 nm)/MS: 912.4 [M+H]; Retention time: 1.14 min. 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.89-7.83 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.40-7.34 (m, 3H), 5.14 (d, J = 12.9 Hz, 1H), 4.69 (s, 2H), 4.58-4.36 (m, 3H), 4.04-3.82 (m, 3H), 3.77 (d, J = 11.0 Hz, 2H), 3.69-3.57 (m, 1H), 3.53-3.42 (m, 2H), 3.24-3.08 (m, 4H), 3.09-2.73 (m, 6H), 2.50 (d, J = 12.5 Hz, 3H), 2.35-1.98 (m, 13H), 1.95-1.78 (m, 9H). Compound A94. (S)-3-(1'-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 5'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (Intermediate 2) [0610] To a solution of 5-bromoindolin-2-one (20 g, 1 eq, 94.3 mmol) in THF (80 mL) was added lithium bis(trimethylsilyl)amide solution (225 mL, 12 eq, 1.13 mol) slowly at -78 °C. The mixture was stirred at -78 °C for 30 mins. After that, 1,5-dibromopentane (21.7 g, 1 eq, 94.3 mmol) was added. The mixture was stirred at 25 °C for 2 h. Then the mixture was stirred at 60 °C for 4 h. LCMS indicated completion of reaction. The mixture was quenched with NH4Cl solution (80 mL). The resulting mixture was extracted with EA (200 mL X 3) and the organic layers were washed with water (200 mL X 2) and brine (200 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 25% of EA in PE) to afford 5'-bromospiro[cyclohexane-1,3'- indolin]-2'-one (20.9 g, 68 mmol, 72%) as a yellow solid. LC purity (0.03% TFA): 53.25% (UV at 254 nm)/MS: 280.2 [M+H]; Retention time: 1.91 min. Synthesis of 5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)spiro[cyclohexane-1,3'- indolin]-2'-one (Intermediate 4) [0611] To a solution of 5'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (7.0 g, 1 eq, 24.98 mmol) in 1,4-dioxane (20 mL) were added Pd2(dba)3 (2.29 g, 0.1 eq, 2.50 mmol), dicyclohexyl(2',4',6'- triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (1.19 g, 0.1 eq, 2.50 mmol), 4-(((tert- butyldimethylsilyl)oxy)methyl)piperidine (8.58 g, 1.5 eq, 37.5 mmol) and sodium 2- methylpropan-2-olate (4.80 g, 2 eq, 49.96 mmol). The mixture was stirred at 110 °C for 2 h under microwave. LCMS indicated completion of reaction. Filtered and concentrated under vacuum and the resultant residue was purified by silica gel column (EA in PE, 0~10%) to get 5'-(4-(((tert- butyldimethylsilyl)oxy)methyl)piperidin-1-yl)spiro[cyclohexane-1,3'-indolin]-2'-one (6.00 g, 14.0 mmol, 56.04%) as a yellow solid. LC purity (0.1% FA): 67.15% (UV at 254 nm)/MS: 429.3 [M+H]; Retention time: 1.60 min. Synthesis of 2-(5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzonitrile (Intermediate 6) [0612] To a solution of 5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1- yl)spiro[cyclohexane-1,3'-indolin]-2'-one (6.0 g, 1 eq, 14.0 mmol) in MeCN (80 mL) were added Cs2CO3 (7.220 g, 2.5 eq, 35 mmol) and 2-chloro-6-fluorobenzonitrile (2.62 g, 1.2 eq, 16.8 mmol) at rt. The reaction was stirred 80 °C for 12 h. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum. The resulting residue was purified by silica gel column (PE to EA/PE=1/15) to get 2-(5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)- 2'-oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzonitrile (4.90 g, 8.69 mmol, 62.1% Purity) as a yellow solid. LC purity (0.1% FA): 67.42% (UV at 254 nm)/MS: 564.3 [M+H]; Retention time: 1.49 min. Synthesis of 2-(5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzamide (Intermediate 7) [0613] To a solution of 2-(5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzonitrile (4.90 g, 1 eq, 8.69 mmol) in DMSO (300 mL) were added K2CO3 (2.41 g, 2 eq, 17.38 mmol) and H2O2 (30 mL) stirred at 25 °C for 0.5 h. The reaction was stirred at 50 °C for 16 h. LCMS indicated completion of reaction. The mixture was added water, extracted with EA (300 mL X 2), dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column (100-200 mesh silica gel, MeOH/DCM=1/15) to get 2-(5'-(4-(((tert- butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2'-oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6- chlorobenzamide (4.0 g, 7.0 mmol, 80.55%) as a yellow oil. LC purity (0.1% FA): 53.46% (UV at 254 nm)/MS: 582.3 [M+H]; Retention time: 1.72 min. Synthesis of 4'-chloro-9'-(4-(hydroxymethyl)piperidin-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 8) [0614] To a solution of 2-(5'-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzamide (4.0 g, 1 eq, 7.0 mmol) in toluene (50 mL) was added Ts-OH (4.0 g, 3 eq, 0.02 mol) at rt. The reaction was stirred 120 °C for 16 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum, added DCM: Me=10: 1 (100 mL), then washed with NaHCO3 aqueous (40 mL), dried with Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column (100-200 mesh silica gel, PE to EA/PE=1/1) to get 4'-chloro-9'-(4-(hydroxymethyl)piperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (1.10 g, 2.44 mmol, 34.86%) as a yellow solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 450.2 [M+H]; Retention time: 1.37 min. Synthesis of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidine-4-carbaldehyde (Intermediate 9) [0615] To a solution of 4'-chloro-9'-(4-(hydroxymethyl)piperidin-1-yl)-10',11'-dihydro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 0.44 mmol) in DCM (3 mL) was added DMP (469 mg, 2.5 eq, 1.11 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was added saturated sodium thiosulfate solution (30 mL), extracted with DCM (30 mL), dried over Na2SO4 and concentrated under vacuum to get 1-(4'-chloro-5'-oxo-10',11'-dihydro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidine-4-carbaldehyde (150 mg, 0.33 mmol, 75.3%) as a yellow solid. LC purity (0.1% FA): 32.88% (UV at 254 nm)/MS: 448.2 [M+H]; Retention time: 1.54 min. Synthesis of (S)-3-(1'-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)piperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0616] To a solution of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)piperidine-4-carbaldehyde (176 mg, 2 eq, 0.39 mmol) in MeOH (3 mL) were added potassium acetate (38.7 mg, 2 eq, 0.39 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (70 mg, 1 eq, 0.20 mmol) and NaBH3CN (24.8 mg, 2 eq, 0.39 mmol). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with DCM (30 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by prep- HPLC (0.01%NH4HCO3) to afford (S)-3-(1'-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (27.15 mg, 34.14 μmol, 17.3%) as a yellow solid. LC purity (0.1% FA):100% (UV at 254 nm)/MS: 787.4 [M+H]; Retention time: 1.27 min. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.34-8.32 (d, J = 8.4 Hz, 1H), 7.97-7.95 (d, J = 8.4 Hz, 1H), 7.80-7.78 (t, J = 8.0 Hz, 1H), 7.61-7.59 (d, J = 7.6 Hz, 1H), 7.42-7.40 (d, J = 7.6 Hz, 1H), 7.33 (s, 1H), 7.29-7.27 (d, J = 7.6 Hz, 1H), 6.99-6.97 (d, J = 8.8 Hz, 1H), 5.11-5.07 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 4.41-4.36(d, J = 17.2 Hz, 1H), 4.24-4.20 (d, J = 17.2 Hz, 1H), 3.80-3.77 (d, J = 12.0 Hz, 2H), 2.95-2.85 (m, 3H), 2.78-2.72 (t, J = 12.0 Hz, 2H), 2.62-2.57 (d, J = 17.6 Hz, 1H), 2.44-2.42 (m, 1H), 2.24-2.22 (d, J = 6.8 Hz, 2H), 2.16 (s, 2H), 2.03-1.92 (m, 5H), 1.85 (s, 6H), 1.70 (s, 7H), 1.31-1.24 (d, J = 10.7 Hz, 2H). Compound A98. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetate (Intermediate 3) [0617] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (120 mg, 1 eq, 0.29 mmol) in DMF (3 mL) were added sodium bicarbonate (480 mg, 20 eq, 5.71 mmol) and tert-butyl 2-(2-bromoethoxy)acetate (342 mg, 5 eq, 1.43 mmol). The mixture was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-10% of methanol in dichloromethane) to afford tert-butyl 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetate (90 mg, 156 mmol, 54.5%) as a yellow solid. LC purity (0.1% FA): 96.33% (UV at 254 nm)/MS: 578.3 [M+H]; Retention time: 1.40 min. Synthesis of 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)ethoxy)acetic acid (Intermediate 3) [0618] To a solution of tert-butyl 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetate (45 mg, 1 eq, 0.08 mmol) in EA (3 mL) was added hydrogen chloride (918 mg, 323 eq, 25.2 mmol). The reaction was stirred 25 °C for 4 h. LCMS showed reaction worked. Filtered and concentrated under vacuum to get 2-(2-(4- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)ethoxy)acetic acid (40 mg, 0.077 mmol, 98.4%) as a white solid. LC purity (0.1% FA): 94.50% (UV at 254 nm)/MS: 522.2 [M+H]; Retention time: 1.31 min. Synthesis of (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0619] To a solution of 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetic acid (40 mg, 1 eq, 0.077 mmol) in DMF (3 mL) were added BOP (67.8 mg, 2 eq, 0.15 mmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (35.4 mg, 1.3 eq, 0.10 mmol) and DIEA (49.5 mg, 5 eq, 0.38 mmol). The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. Filtered and concentrated under vacuum. The resulting residue was purified by prep- HPLC (0.1% FA) to afford (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)ethoxy)acetyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (27.54 mg, 0.031 mmol, 40%) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 859.4 [M+H]; Retention time: 1.35 min. 1H NMR (400 MHz, MeOD-d4) δ 8.39 (m, 1H), 8.07 (m, 1H), 7.83 (m, 1H), 7.76 (s, 1H), 7.63 (m, 1H), 7.44 (m, 1H), 7.35-7.37 (m, 2H), 5.11 (m, 1H), 4.68 (s, 2H), 4.59 (s, 2H), 4.46 (s, 1H), 4.35-4.40 (m, 3H), 3.83-3.88 (m, 3H), 3.51 (d, J = 21.2 Hz, 2H), 3.25 (m, 1H), 3.15 (s, 2H), 2.72-3.00 (m, 6H), 2.49 (q, J = 13.2 Hz, 1H), 2.03-2.15 (m, 11H), 1.85 (d, J = 12.4 Hz, 8H). Compound A99. (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

o[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetate (Intermediate 2) [0620] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.24 mmol) in DMF (3 mL) were added sodium bicarbonate (400 mg, 0.19 mL, 20 eq, 4.76 mmol) and tert-butyl 2-(2-bromoethoxy)acetate (285 mg, 5 eq, 1.19 mmol). The mixture was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-10% of methanol in dichloromethane) to afford tert-butyl 2-(2-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetate (100 mg, 0.17 mmol, 72.6%) as a yellow solid. LC purity (0.1% FA): 95.82% (UV at 254 nm)/MS: 578.4 [M+H]; Retention time: 1.40 min. Synthesis of 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)ethoxy)acetic acid (Intermediate 3) [0621] To a solution of tert-butyl 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetate (55 mg, 1 eq, 0.10 mmol) in EA (3 mL) was added hydrogen chloride (918 mg, 265 eq, 25.2 mmol). The reaction was stirred 25 °C for 4 h. LCMS indicated completion of reaction. Filtered and concentrated under vacuum to get 2- (2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)ethoxy)acetic acid (49.0 mg, 93.9 μmol, 98.7 %) as a white solid. LC purity (0.1% FA): 95.7% (UV at 254 nm)/MS: 522.2 [M+H]; Retention time: 1.32 min. Synthesis of (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0622] To a solution of 2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetic acid (50 mg, 1 eq, 0.10 mmol) in DMF (3 mL) were added BOP (84.7 mg, 2 eq, 0.19 mmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (44.3 mg, 1.3 eq, 0.13 mmol) and DIEA (61.9 mg, 5 eq, 0.48 mmol). The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. Filtered and concentrated under vacuum. The resulting residue was purified by prep- HPLC (0.1%NH4HCO3) to afford (S)-3-(1'-(2-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)ethoxy)acetyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.08 mg, 0.003 mmol, 3.69%) as a white solid. LC purity (0.03% TFA): 100% (UV at 254 nm)/MS: 859.5 [M+H]; Retention time: 1.368 min.1H NMR (400 MHz, MeOD-d4) δ 8.36 (m, 1H), 7.93 (m, 1H), 7.77- 7.85 (m, 2H), 7.63 (m, 1H), 7.28-7.39 (m, 3H), 5.11 (d, J = 12.8 Hz, 1H), 4.55-4.67 (m, 2H), 4.51 (d, J = 13.6 Hz, 1H), 4.35-4.39 (m, 3H), 4.27 (m, 1H), 3.96 (s, 1H), 3.77-3.79 (m, 2H), 3.48 (s, 1H), 3.23-3.27 (m, 1H), 2.75-2.94 (m, 6H), 2.33-2.54 (m, 3H), 2.00-2.14 (m, 6H), 1.86-1.97 (m, 10H), 1.78 (s, 3H), 1.28 (s, 1H). Compound A100. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and Compound A101. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

10'- yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 3) [0623] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (50 mg, 1 eq, 119 μmol) in MeOH (1 mL) were added potassium acetate (35.1 mg, 3 eq, 357 μmol), 4-oxocyclohexane-1-carboxylic acid (25.4 mg, 1.5 eq, 179 μmol) and NaBH3CN (22.4 mg, 3 eq, 357 μmol). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 8% of MeOH in DCM) to afford 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (30 mg, 54.9 μmol, 46.1%) as a yellow oil. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 564.2 [M+H]; Retention time: 1.30 min. Synthesis of (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0624] To a solution of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (30 mg, 1 eq, 54.9 μmol) in DMF (1 mL) were added DIEA (42.6 mg, 57.4 μL, 6 eq, 330 μmol) and HATU (25.1 mg, 1.2 eq, 65.9 μmol). The mixture was stirred at 25 °C for 10 mins, and (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (23.4 mg, 1.2 eq, 65.9 μmol) was added in the mixture and stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by prep-HPLC, eluted with MeCN in H2O (10mmol/L NH4HCO3) from 46% to 56% to afford (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (6.56 mg, 6.57 μmol, 12.0%) and (S)-3-(1'-(4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione (4.31 mg, 4.43 μmol, 8.06%) as a white solid. [0625] P1 (A100): LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 884.3 [M+H]; Retention time: 1.313 min; 1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.92-7.76 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.44-7.25 (m, 3H), 5.13 (d, J = 12.8 Hz, 1H), 4.68 (s, 2H), 4.54 (d, J = 14.3 Hz, 1H), 4.49-4.37 (m, 2H), 4.17-4.06 (m, 1H), 3.26-3.18 (m, 2H), 3.13 (s, 1H), 2.95-2.79 (m, 4H), 2.77-2.69 (m, 2H), 2.67-2.56 (m, 2H), 2.54-2.43 (m, 1H), 2.20-1.82 (m, 20H), 1.80-1.63 (m, 4H), 1.62-1.46 (m, 3H); [0626] P2 (A101): LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 884.4 [M+H]; Retention time: 1.335 min.1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.91-7.76 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.40-7.32 (m, 3H), 5.23-5.07(m, 1H), 4.68(s, 1H), 4.61-4.50 (m, 2H), 4.48-4.37 (m, 2H), 4.02 (s, 1H), 3.13 (s, 1H), 3.02 (s, 1H), 2.98-2.60 (m, 7H), 2.53-2.41 (m, 1H), 2.21-1.64 (m, 28H). Compound A102. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A103. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione -9'-

yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 3) [0627] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (50 mg, 1 eq, 119 μmol) in MeOH (1 mL) were added 4-oxocyclohexane-1- carboxylic acid (25.4 mg, 1.5 eq, 179 μmol)，potassium acetate (35.1 mg, 3 eq, 357 μmol) and sodium triacetoxyborohydride (75.7 mg, 3 eq, 357 μmol). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 8% of MeOH in DCM) to afford 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (25.0 mg, 41 μmol, 35%) as a yellow oil. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 546.1 [M+H]; Retention time: 1.29 min. Synthesis of (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0628] To a solution of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (25.0 mg, 1 eq, 45.8 μmol) in DMF (1 mL) were added DIEA (35.5 mg, 6 eq, 275 μmol) and HATU (20.9 mg, 1.2 eq, 54.9 μmol). The mixture was stirred at 25 °C for 10 mins, and (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (19.5 mg, 1.2 eq, 54.9 μmol) was added in the mixture and stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L NH4HCO3/H2O) from 45% to 55% to afford (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.74 mg, 2.62 μmol, 5.72%) and (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.62 mg, 2.35 μmol, 5.14%) as a withe solid. [0629] P1 (A102): LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 884.4 [M+H]; Retention time: 1.299min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.50-7.33 (m, 3H), 5.20-5.09 (m, 1H), 4.69 (s, 2H), 4.60-4.50 (m, 1H), 4.45 (t, J = 15.4 Hz, 2H), 4.19-4.05 (m, 1H), 3.25-3.18 (m, 2H), 3.15-3.09 (m, 1H), 2.98-2.84 (m, 2H), 2.83-2.68 (m, 4H), 2.67-2.50 (m, 3H), 2.22-1.78 (m, 23H), 1.67-1.48 (m, 4H); [0630] P2 (A103): LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 884.4 [M+H]; Retention time: 1.334 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.50-7.33 (m, 3H), 5.19-5.09 (m, 1H), 4.68 (s, 2H), 4.61-4.50 (m, 1H), 4.48-4.37 (m, 2H), 4.11-3.95 (m, 1H), 3.13 (s, 1H), 3.07- 2.97 (s, 1H), 2.97-2.40 (m, 9H), 2.21-1.65 (m, 28H). Compound A105. (S)-3-(1'-((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A136. (R)-3-(1'-((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0631] The mixture of ethyl 4-hydroxycyclohexane-1-carboxylate (2.0 g, 1 eq, 11.6 mmol) in dichloromethane (3.00 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (493.0 mg, 0.1 eq, 1.16 mmol) and stirred at 0 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was quenched with H2O/NH4Cl (10 mL), then extracted with DCM (10 mL X2) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford ethyl 4-oxocyclohexane-1-carboxylate (800 mg, 4.70 mmol, 40.5%) as a yellow oily. 1H NMR (400 MHz, CDCl3) δ 4.16 (dq, J = 18.6, 7.2 Hz, 2H), 2.75 (ddd, J = 13.6, 9.6, 3.9 Hz, 1H), 2.48 (dt, J = 14.3, 5.1 Hz, 1H), 2.40 ^ 2.33 (m, 1H), 2.26 ^ 2.16 (m, 1H), 2.07 ^ 1.93 (m, 2H), 1.76 ^ 1.59 (m, 3H), 1.34 ^ 1.21 (m, 3H). Synthesis of ethyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carboxylate (Intermediate 4) [0632] To a solution of ethyl 4-oxocyclohexane-1-carboxylate (298 mg, 3 eq, 1.75 mmol) and 4- chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)-one (222 mg, 1 eq, 584 μmol) in MeOH (5.00 mL) was added titanium isopropoxide (332 mg, 2 eq, 1.17 mmol). The mixture was stirred at 80 °C for 0.5 h. Then, mixture of NaBH3CN (110 mg, 3 eq, 1.75 mmol) was added at 80 °C for 0.5 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of DCM in MeOH) to afford ethyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carboxylate (150 mg, 281 μmol, 48.1%) as a yellow solid. LC purity (0.1%TFA): 70.53% (UV at 254 nm)/MS: 534.2 [M+H]; Retention time: 0.943 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 5) [0633] To a solution of ethyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carboxylate (150 mg, 1 eq, 281 μmol) in 1,4- dioxane hydrochloride (3.50 g, 7.02 mL, 4.00 molar, 100 eq, 28.1 mmol) and stirred at 90 °C for 2 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carboxylic acid (80 mg, 158 μmol, 56.3%) as a white solid.. LC purity (0.1%TFA): 76.53% (UV at 254 nm)/MS: 506.3 [M+H]; Retention time: 0.813 min. Synthesis of (S)-3-(1'-((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate S-3012-P1) and (R)-3-(1'-((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0634] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (44.0 mg, 1 eq, 86.9 μmol) and (S)-3-(6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (30.9 mg, 1 eq, 86.9 μmol) in DMF (3.00 mL) were added N-ethyl-N-isopropylpropan-2-amine (89.9 mg, 8 eq, 696 μmol), HATU (49.6 mg, 1.5 eq, 130 μmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The residue was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to afford both enantiomers as a white solid. (S)-3- (1'-((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (4.25 mg, 5.04 μmol, 5.80%). LC purity (0.1% FA): 90.71% (UV at 254 nm)/MS: 844.4 [M+H]; Retention time: 4.367 min. 1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.38 (s, 3H), 5.13 (s, 1H), 4.68 (s, 2H), 4.42 (d, J = 16.3 Hz, 2H), 4.11 (d, J = 13.7 Hz, 1H), 3.66 ^ 3.55 (m, 4H), 3.12 (dd, J = 25.6, 14.0 Hz, 6H), 2.82 (dd, J = 42.8, 16.3 Hz, 6H), 2.21 (d, J = 17.6 Hz, 6H), 1.89 (d, J = 18.7 Hz, 4H), 1.70 (d, J = 9.5 Hz, 4H), 1.59 (s, 6H). [0635] (R)-3-(1'-((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (6.46 mg, 7.66 μmol, 6.00%) as a white solid. LC purity (0.1% FA): 90.71% (UV at 254 nm)/MS: 844.4 [M+H]; Retention time: 4.367 min.1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.5 Hz, 1H), 7.99 (s, 1H), 7.86 (t, J = 8.3 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 11.9 Hz, 3H), 5.13 (d, J = 12.2 Hz, 1H), 4.68 (s, 2H), 4.54 (d, J = 14.0 Hz, 1H), 4.43 (q, J = 17.1 Hz, 2H), 4.01 (d, J = 12.8 Hz, 1H), 3.62 (d, J = 11.2 Hz, 2H), 3.12 (d, J = 19.2 Hz, 4H), 2.93 ^ 2.72 (m, 4H), 2.57 ^ 2.44 (m, 1H), 2.25 ^ 1.96 (m, 15H), 1.86 (s, 2H), 1.77 (s, 1H), 1.60 (s, 6H). Compound A106. (S)-3-(1'-((1'-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

,2- a]quinazolin]-5'-one (Intermediate 2) [0636] To a solution of 4'-chloro-9'-(4-hydroxypiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (300 mg, 1 eq, 0.69 mmol) in DCM (4 mL) was added DMP (729 mg, 2.5 eq, 1.72 mmol) at 0 °C. The reaction was stirred 25 °C for 4 h. LCMS indicated completion of reaction. The mixture was added saturated sodium thiosulfate solution stirred 0.5 h and added saturated ammonium chloride solution stirred 0.5 h, added DCM (30 mL), extracted with water, dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column (EA:PE=1:1) to get 4'-chloro-9'-(4-oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (90 mg, 0.21 mmol, 30.1%) as a yellow solid. LC purity (0.1% FA): 35% (UV at 254 nm)/MS: 434.2 [M+H]; Retention time: 1.58 min. Synthesis of (S)-3-(1'-((1'-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidin]-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0637] To a solution of (S)-3-(6-oxo-1'-(piperidin-4-ylmethyl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (32.0 mg, 1 eq, 0.071 mmol) in DMF (3 mL) were added potassium acetate (13.9 mg, 2 eq, 0.14 mmol), 4'-chloro-9'-(4- oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (18.4 mg, 0.6 eq, 0.04 mmol), sodium cyanoborohydride (26.7 mg, 6 eq, 0.42 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA/) from 26% to 35% to afford (S)-3-(1'-((1'-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-[1,4'- bipiperidin]-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (3.36 mg, 0.004 mmol, 5.34%) as a yellow solid. LC purity (0.1% FA): 85.40% (UV at 254 nm)/MS: 870.2 [M+H]; Retention time: 1.23 min. 1H NMR (400 MHz, MeOD-d4) δ 8.36 (m, 1H), 8.00 (m, 1H), 7.82 (m, 1H), 7.63 (m, 1H), 7.33-7.42 (m, 3H), 7.11 (m, 1H), 5.11-5.17 (m 2H), 4.58 (s, 13H), 4.41 (m, 1H), 3.93 (m, 1H), 3.43-3.50 (m, 2H), 2.80-3.00 (m, 7H), 2.48 (m, 1H), 2.35-2.36 (m, 2H), 2.15-2.23 (m, 6H), 2.02-2.09 (m, 4H), 1.80-1.84 (m, 8H). Compound A107. (S)-3-(1'-(((1r,3S)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (1r,3r)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)cyclobutane-1-carbaldehyde (Intermediate 6) [0638] To a solution of 4-chloro-10-(1-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)methyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (90 mg, 1.0 eq, 188.7 μmol) in DCM (5.00 mL) was added Dess-Martin periodinane (399.9 mg, 18.8 μL, 5.0 eq, 943.4 μmol). The reaction mixture was stirred at 25 °C for 16 h in N2. The mixture was extracted with DCM (3 x 30 mL) and diluted with water (20 mL x 7). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to get (1r,3r)-3-((4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutane-1- carbaldehyde (25.0 mg, 50.7 μmol, 83.7 %) as a white solid.no need purified and used next step directly.LC purity (0.1% FA): 23.5% (UV at 254 nm)/MS: 476.3 [M +H]; Retention time: 0.823 min. Synthesis of (S)-3-(1'-(((1r,3S)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0639] To a solution of (1r,3r)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutane-1-carbaldehyde (30 mg, 1.0 eq, 63.0 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (24.6 mg, 1.1 eq, 69.3 μmol) in DMF (2.0 mL), The reaction was stirred at rt for 30 min then were added potassium acetate (18.6 mg, 3.0 eq, 189 μmol) and sodium triacetoxyhydroborate (40.1 mg, 3.0 eq, 189 μmol) at 25 °C, The reaction mixture was stirred at 25 °C for 2 h in N2. The reaction was extracted with MeOH/DCM (1/10) (v/v, 30 mL) and diluted with water (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give(S)-3-(1'-(((1r,3S)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (6.65 mg, 7.94 μmol, 12.6%, 97.3% Purity) as a white solid. LC purity (0.1% FA): 97.31% (UV at 254 nm)/MS: 408.8 [M+H]; Retention time: 2.047 min and 3.917 min.1H NMR (400 MHz, MeOD- d4) δ 8.42-8.43 (m, 1H), 7.98 (s, 1H), 7.84-7.88 (m, 1H), 7.60-7.68 (m, 2H), 7.33-7.40 (m, 3H), 5.11-5.16 (m, 1H), 4.59 (s, 2H), 4.35-4.50 (m, 2H), 3.40-3.73 (m, 5H), 2.87-3.13 (m, 6H), 2.62- 2.79 (m, 6H), 2.32-2.51 (m, 3H), 1.99-2.18 (m, 7H), 1.83-1.87 (m, 2H), 1.57-1.60 (m, 7H). Compound A108. (S)-3-(1'-(((1s,3R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y , - - - - - , - y - - - , - y , - q -10- yl)piperidin-1-yl)methyl)cyclobutane-1-carbaldehyde (Intermediate 6) [0640] To a solution of 4-chloro-10-(1-(((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (90 mg, 1.0 eq, 188.7 μmol) in DCM (5.00 mL) was added Dess-Martin periodinane (399.9 mg, 18.8 μL, 5.0 eq, 943.4 μmol). The reaction mixture was stirred at 25 °C for 16 h in N2. The mixture was extracted with DCM (3 x 30 mL) and diluted with water (20 mL x 7). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to get (1s,3s)-3-((4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutane-1- carbaldehyde (25.0 mg, 50.7 μmol, 83.7 %) as a white solid. no need purified and used next step directly.LC purity (0.1% FA): 35.3% (UV at 254 nm)/MS: 476.2 [M +H]; Retention time: 0.803 min. Synthesis of (S)-3-(1'-(((1s,3R)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0641] A solution of (1s,3s)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutane-1-carbaldehyde (30 mg, 1.0 eq, 63.0 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (24.6 mg, 1.1 eq, 69.3 μmol) in DMF (2.0 mL) was stirred at rt for 30 min. Then were added potassium acetate (18.6 mg, 3.0 eq, 189 μmol) and sodium triacetoxyhydroborate (40.1 mg, 3.0 eq, 189 μmol) at 250 °C. The reaction mixture was stirred at 250 °C for 2 h in N2. The reaction was extracted with MeOH/DCM (1/10) (v/v, 30 mL) and diluted with water (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give(S)-3-(1'-(((1r,3S)-3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclobutyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (4.60 mg, 5.36 μmol, 8.51%, 95.1% Purity) as a white solid. LC purity (0.1% FA): 85.1% (UV at 254 nm)/MS: 816.7 [M+H]; Retention time: 2.037 min.1H NMR (400 MHz, MeOD-d4) δ 8.42-8.44 (m, 1H), 8.00 (s, 1H), 7.84-7.88 (m, 1H), 7.62-7.68 (m, 2H), 7.33-7.44 (m, 3H), 5.12-5.17 (m, 1H), 4.70 (s, 1H), 4.42-4.45 (m, 2H), 3.59-3.69 (m, 4H), 3.38-3.41 (m, 2H),3.10-3.28 (m,7H), 2.79- 2.80 (m, 4H), 2.52-2.56 (m, 2H), 2.03-2.28 (m, 13H), 1.59 (s, 7H). Compound A109. (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A110. (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y - - - - - - - - p y - , - , - q -10'- yl)piperidin-1-yl)cyclohexyl)acetic acid (Intermediate 3) [0642] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.24 mmol) in CH3OH (3 mL) were added 2-(4- oxocyclohexyl)acetic acid (55.8 mg, 1.5 eq, 0.36 mmol), potassium acetate (46.7 mg, 2 eq, 0.48 mmol), sodium cyanotrihydroborate (44.9 mg, 3 eq, 0.71 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL), then washed brine and dried over Na2SO4, filtered and concentrated to purification (CH3OH/DCM=10/1) to get 2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetic acid (50 mg, 0.087 mmol, 36.4%) as white solid. LC purity (0.1% FA): 97.01% (UV at 254 nm)/MS: 560.4 [M+H]; Retention time:1.31 min. Synthesis of (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0643] To a solution of 2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetic acid (50 mg, 1 eq, 0.09 mmol) in DMF (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (38 mg, 1.2 eq, 0.11 mmol), DIEA (115 mg, 10 eq, 0.89 mmol), BOP (79 mg, 2 eq, 0.18 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified prep-HPLC, eluted with MeCN in H2O (0.1% FA/) from 25% to 35% to afford (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.44 mg, 2.71 μmol, 3.03%) and (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.46 mg, 1.62 μmol, 1.81%) as a white solid. [0644] P1 (A109): LC purity (0.03% TFA): 100.00% (UV at 254 nm)/MS: 897.6 [M+H]; Retention time: 1.365 min.1H NMR (400 MHz, MeOD-d4) δ 8.40-8.43 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.81-7.88 (m, 2H), 7.65-7.67 (d, J = 7.6 Hz, 1H), 7.32-7.38 (m, 3H), 4.68 (s, 3H), 4.58 (s, 10H), 4.39-4.45 (m, 2H), 4.02 (s, 1H),2.83-2.93 (m, 4H), 2.38-2.39 (d, J = 6.8 Hz, 2H), 2.07-2.18 (m, 8H), 2.03 (s, 6H), 1.87-1.89 (d, J = 11.2 Hz, 6H), 1.54-1.56 (d, J = 12.0 Hz, 1H), 1.30-1.32 (d, J = 18.4 Hz, 4H), 1.17 (s, 1H). [0645] P2 (A110): LC purity (0.03% TFA): 99.95% (UV at 254 nm)/MS: 897.6 [M+H]; Retention time: 1.365 min. 1H NMR (400 MHz, MeOD-d4) δ 8.40-8.43 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.84-7.86 (t, J = 7.2 Hz, 2H), 7.64 (s, 1H), 7.34-7.38 (m, 3H), 4.68 (s, 3H), 4.58 (s, 10H), 4.38- 4.45 (m, 2H), 4.06-4.08 (d, J = 14.4 Hz, 1H), 2.84 (d, J = 30 Hz, 4H), 2.56 (d, J = 7.6 Hz, 2H), 1.99-2.15 (m, 8H), 1.83-1.89 (m, 6H), 1.75-1.79 (m, 6H), 1.30-1.35 (d, J = 17.2 Hz, 6H). Compound A111. (S)-3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0646] To a solution of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)piperidine-4-carbaldehyde (40 mg, 1 eq, 0.09 mmol) in DMF (3 mL) were added potassium acetate (17 mg, 2 eq, 0.18 mmol), (S)-3-(6-oxo-1'-(piperidin-4-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (39 mg, 1 eq, 0.09 mmol) and NaCNBH3 (11.2 mg, 2 eq, 0.18 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified prep- HPLC, eluted with MeCN in H2O (10 mmol/L NH4HCO3/H2O) from 49% to 59% to afford (S)- 3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.90 mg, 2.03 μmol, 2.27 %) as a yellow solid. LC purity (0.03% TFA): 96.78% (UV at 254 nm)/MS: 870.5 [M+H]; Retention time: 0.801 min.1H NMR (400 MHz, DMSO-d6) δ 10.93-11.01 (m, 1H), 8.32-8.35 (d, J = 9.2 Hz, 1H), 7.94-7.96 (d, J = 8.4 Hz, 1H), 7.77-7.79 (d, J = 8.0 Hz, 1H), 7.57-7.59 (d, J = 7.6 Hz, 1H), 7.38-7.41 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.24-7.28 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 5.03-5.12 (m, 1H), 4.52 (s, 2H), 4.36 (s, 1H), 4.23 (s, 1H), 3.75 (s, 2H), 2.89 (s, 4H), 2.67 (s, 2H), 2.33 (s, 2H), 2.17-2.19 (d, J = 17.2 Hz, 8H), 1.82-1.89 (s, 10H), 1.65-1.70 (m, 10H), 1.24 (s, 4H). [0647] The following compounds were prepared in a manner analogous to Compound A111. Compound A118. (S)-3-(1'-(2-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 910.4 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.33-8.31 (d, J = 8.8 Hz, 1H), 7.96-7.93 (d, J = 9.2 Hz, 1H), 7.82-7.77 (t, J = 8.4 Hz, 1H), 7.60-7.58 (d, J = 7.6 Hz, 1H), 7.40-7.37 (d, J = 7.6 Hz, 1H), 7.32-7.31 (d, J = 2.4 Hz, 1H), 7.27-7.25 (d, J = 7.6 Hz, 1H), 6.97-6.94 (dd, J = 9.2, 2.4 Hz, 1H), 5.10-5.06 (dd, J = 13.2, 5.2 Hz, 1H), 4.54-4.47 (m, 2H), 4.39-4.39 (d, J = 17.2 Hz, 1H), 4.23-4.19 (d, J = 17.2 Hz, 1H), 3.76-3.73 (d, J = 12.4 Hz, 2H), 2.93-2.90 (m, 3H), 2.88-2.80 (m, 4H), 2.70-2.65 (m, 2H), 2.61-2.56 (m, 1H), 2.44-2.39 (m, 1H), 2.33-2.31 (m, 3H), 2.25-2.18 (m, 3H), 2.16-2.13 (m, 2H), 2.00-1.95 (m, 1H), 1.91-1.76 (m, 10H), 1.70-64 (m, 8H), 1.43-1.34 (m, 2H), 1.28-1.20 (m, 4H). Compound A120. (S)-3-(1'-(7-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 910.4 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.33-8.31 (d, J = 8.8 Hz, 1H), 7.96-7.94 (d, J = 9.2 Hz, 1H), 7.82-7.78 (t, J = 8.2 Hz, 1H), 7.60-7.58 (d, J = 7.6 Hz, 1H), 7.42- 7.40 (d, J = 7.6 Hz, 1H), 7.32-7.31 (d, J = 2.4 Hz, 1H), 7.27-7.25 (d, J = 7.6 Hz, 1H), 6.98-6.95 (dd, J = 9.2, 2.4 Hz, 1H), 5.11-5.06 (dd, J = 13.2, 5.2 Hz, 1H), 4.54-4.47 (m, 2H), 4.40-4.35 (d, J = 17.2 Hz, 1H), 4.23-4.19 (d, J = 17.2 Hz, 1H), 3.78-3.75 (d, J = 12.0 Hz, 2H), 2.95-2.85 (m, 1H), 2.83-2.58 (m, 7H), 2.44-2.39 (m, 1H), 2.34-2.32 (m, 2H), 2.23-2.17 (m, 2H), 2.14-2.11 (m, 3H), 2.00-1.74 (m, 13H), 1.70-1.64 (m, 7H), 1.59-1.44 (m, 6H), 1.24-1.17 (m, 2H). Compound A135. (S)-3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)methyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 842.4 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.25-7.35 (m, 2H), 6.97 (d, J = 8.7 Hz, 1H), 5.03-5.13 (m, 1H), 4.52 (s, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.3 Hz, 1H), 3.75 (d, J = 10.6 Hz, 2H), 2.86-2.93 (m, 2H), 2.79 (s, 2H), 2.70 (d, J = 9.6 Hz, 4H), 2.61 (s, 1H), 2.55 (s, 2H), 2.42 (d, J = 12.7 Hz, 1H), 2.33 (s, 2H), 2.16 (s, 2H), 1.99 (s, 1H), 1.77-1.91 (m, 10H), 1.68 (s, 6H), 1.45 (s, 1H), 1.26 (d, J = 9.5 Hz, 2H). Compound A112. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclopentane-1-carboxylic acid (Intermediate 3) [0648] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (50 mg, 1 eq, 119 μmol) in MeOH (2 mL) were added sodium cyanoborohydride (22.4 mg， 3 eq, 357 μmol)， 3-oxocyclopentane-1-carboxylic acid (18.3 mg, 1.2 eq, 143 μmol) and potassium acetate (35.1 mg, 22.3 μL, 3 eq, 357 μmol), the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclopentane-1-carboxylic acid (50 mg, 80 μmol, 67 %, 85% Purity) as a yellow solid.LC purity (0.1% FA):86% (UV at 254 nm)/MS: 532 [M+H]; Retention time: 1.281 min. Synthesis of tert-butyl (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0649] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclopentane-1-carboxylic acid (50 mg, 1 eq, 94.0 μmol) in DMF (2 mL) were added HATU (42.9 mg, 1.2 eq, 113 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (33.4 mg, 1 eq, 94.0 μmol) and DIEA (48.6 mg, 4 eq, 376 μmol), the reaction was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 25% to 40% to afford (3S)-3-(1'-(3-(4-(4'-chloro-5'- oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclopentane-1- carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (11.36 mg, 12.33 μmol, 13.1%) as a white solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 869 [M+H]; Retention time: 1.367 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.85 (t, J = 8.2 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 5.09 (d, J = 13.1 Hz, 1H), 4.64 (s, 2H), 4.40 (d, J = 17.1 Hz, 2H), 4.23 (d, J = 13.7 Hz, 1H), 3.97 (d, J = 11.6 Hz, 1H), 3.15 (d, J = 31.1 Hz, 5H), 2.91 (t, J = 12.8 Hz, 2H), 2.65 (dd, J = 45.2, 21.9 Hz, 4H), 2.02 (d, J = 30.8 Hz, 6H), 1.86 (d, J = 27.2 Hz, 8H), 1.75 (s, 12H), 1.49 (d, J = 7.6 Hz, 1H). [0650] The following compounds were prepared in a manner analogous to Compound A121. Compound A132. (S)-3-(1'-(6-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)spiro[3.3]heptane-2-carbonyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 895.6 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.83 (t, J = 7.3 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.1 Hz, 1H), 7.26 (dd, J = 20.0, 7.8 Hz, 2H), 5.09 (d, J = 13.8 Hz, 1H), 4.70-4.58 (m, 2H), 4.43-4.32 (m, 2H), 4.23 (dd, J = 17.4, 8.1 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.64 (d, J = 7.1 Hz, 1H), 3.45 (s, 3H), 3.13- 3.03 (m, 2H), 2.87 (s, 3H), 2.73 (s, 1H), 2.65 (d, J = 21.8 Hz, 1H), 2.58 (s, 1H), 2.39 (d, J = 12.9 Hz, 1H), 2.27 (dd, J = 25.3, 15.8 Hz, 5H), 2.15 (d, J = 13.7 Hz, 4H), 2.06 (d, J = 12.1 Hz, 3H), 1.89 (d, J = 8.9 Hz, 4H), 1.74 (s, 10H). Compound A137. (S)-3-(1'-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carbonyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 842.4 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.41-8.44 (m, 1H), 8.00 (s, 1H), 8.84-8.88 (m, 1H), 7.63-7.69 (m, 2H), 7.35-7.41 (m, 3H), 5.10-5.20 (m, 1H), 4.69 (s, 2H), 4.21-4.52 (m, 3H), 3.73-3.83 (m, 2H), 3.39-3.49 (m, 4H), 2.75-3.20(m, 6H), 2.36-2.42 (m, 7H), 1.82-2.24 (m, 9H), 1.60 (s, 6H). Compound A116. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A117. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y - y - - - - - - - p y - , - 1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclopentane-1-carboxylic acid (Intermediate 3) [0651] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (50 mg, 1 eq, 119 μmol) in MeOH (2 mL) were added sodium cyanoborohydride (22.4 mg, 3 eq, 357 μmol), 3-oxocyclopentane-1-carboxylic acid (18.3 mg, 1.2 eq, 143 μmol) and potassium acetate (35.1 mg, 3 eq, 357 μmol), the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)cyclopentane-1-carboxylic acid (50 mg, 75 μmol, 63%) as a white solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 532 [M+H]; Retention time: 1.309 min. Synthesis of tert-butyl (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0652] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclopentane-1-carboxylic acid (50 mg, 1 eq, 94.0 μmol) in DMF (2 mL) was added HATU (42.9 mg, 1.2 eq, 113 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (33.4 mg, 1 eq, 94.0 μmol) and DIEA (48.6 mg, 4 eq, 376 μmol). The reaction was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L%NH4HCO) from 44% to 54% to afford (3S)-3-(1'-(3-(4- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (1.12 mg, 1.09 μmol, 1.15%) as a white solid and (3S)-3-(1'- (3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)cyclopentane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (4.38 mg, 4.23 μmol, 4.50%) as a white solid. [0653] P1 (A116): LC purity (0.1% FA): 90.87 % (UV at 254 nm)/MS: 883 [M+H]; Retention time: 1.659 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.38 (s, 2H), 5.13 (d, J = 13.6 Hz, 1H), 4.69 (s, 2H), 4.55 (s, 1H), 4.48-4.36 (m, 2H), 4.09 (s, 1H), 3.13 (s, 1H), 2.89 (s, 4H), 2.79 (s, 2H), 2.49 (s, 1H), 2.36 (s, 2H), 2.14 (s, 5H), 2.06 (s, 3H), 1.97 (s, 3H), 1.88 (d, J = 11.7 Hz, 13H), 1.61 (s, 1H), 1.29 (s, 1H). [0654] P2 (A117): LC purity (0.1% FA): 90.87 % (UV at 254 nm)/MS: 883 [M+H]; Retention time: 1.607 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.38 (s, 2H), 5.13 (d, J = 13.2 Hz, 1H), 4.89 (d, J = 8.0 Hz, 1H), 4.69 (s, 2H), 4.55 (d, J = 14.2 Hz, 1H), 4.43 (d, J = 10.6 Hz, 2H), 4.10 (d, J = 12.0 Hz, 1H), 3.19 (dd, J = 32.7, 15.5 Hz, 2H), 2.87 (d, J = 13.6 Hz, 3H), 2.78 (d, J = 15.8 Hz, 2H), 2.50 (d, J = 13.7 Hz, 1H), 2.39 (s, 2H), 2.26 (s, 1H), 2.16 (s, 3H), 2.09-2.01 (m, 4H), 1.96 (s, 5H), 1.93-1.74 (m, 13H). Compound A123. (S)-3-(1'-((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(1'-((1s,4R)-4-(hydroxymethyl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 2) [0655] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (150 mg, 1.0 eq, 422 μmol) and (1s,4s)-4- (hydroxymethyl)cyclohexane-1-carboxylic acid (81.0 mg, 1.21 eq, 512 μmol) in DMF (2.00 mL) were added DIPEA (557.0 mg, 10.2 eq, 4.31 mmol) and benzotriazol-1- yloxy)tris(diethylamino)phosphonium hexafluorophosphate (150 mg, 0.8 eq, 339 μmol). The reaction mixture was stirred at 25 °C for 1 h in N2. The mixture was diluted with water (10 mL), extracted with EtOAc (20 x 3 mL), dried over Na2SO4, concentrated. The residue was purified by prep-TLC (developing agent: DCM/MeOH=3/1 ) to give(S)-3-(1'-((1s,4R)-4- (hydroxymethyl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (110 mg, 222 μmol, 52.6%) as a white solid. LC purity (0.1% FA): 71.38% (UV at 254 nm)/MS: 496.2 [M +H]; Retention time: 1.180 min. Synthesis of (1R,4s)-4-(7-((S)-2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidine]-1'-carbonyl)cyclohexane-1-carbaldehyde (Intermediate 3) [0656] To a solution of (S)-3-(1'-((1s,4R)-4-(hydroxymethyl)cyclohexane-1-carbonyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (110 mg, 1.0 eq, 222 μmol) in DCM (2.00 mL) was added Dess-Martin periodinane (471 mg, 5.0 eq, 1.11 mmol). The reaction mixture was stirred at rt for 1 h in N2. The mixture was diluted with water (10 mL), extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to give (1R,4s)-4-(7-((S)-2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'- carbonyl)cyclohexane-1-carbaldehyde (50 mg, crude) as a white solid.no need purified and used next step directly. LC purity (0.1% FA): 52.77 % (UV at 254 nm)/MS: 494.2 [M +H]; Retention time: 1.257 min. Synthesis of (S)-3-(1'-((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0657] To a solution of (1R,4s)-4-(7-((S)-2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carbonyl)cyclohexane-1-carbaldehyde (40 mg, 1.0 eq, 81.0 μmol) and 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)-one (21.0 mg, 0.7 eq, 55.3 μmol) in THF (2.00 mL) was added sodium triacetoxyborohydride (90 mg, 5.2 eq, 425 μmol). The reaction was stirred at rt for 30 min then was added trimethylamine (82.0 mg, 10 eq, 810 μmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h in N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give (S)-3-(1'-((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.55 mg, 8.02 μmol, 9.90%, 91.11% Purity) as a white solid. LC purity (0.1% FA): 91.11% (UV at 254 nm)/MS: 857.7 [M+H]; Retention time: 4.557 min.1H NMR (400 MHz, MeOD-d4) δ 8.70-8.72 (m, 1H), 8.26 (s, 1H), 8.03-8.06 (m, 1H), 7.70-7.82 (m, 2H), 7.48-7.50 (m, 1H), 7.37 (s, 2H) 5.11- 5.15 (m, 2H), 4.68 (s, 2H), 4.37-4.55 (m, 3H), 4.06-4.09 (m, 1H), 3.77-3.79 (m, 1H), 3.20-3.23 (m, 4H), 2.76-2.94 (m, 4H), 2.17-2.53 (m, 7H), 1.71-1.99(m, 17H), 1.28-1.33 (m, 2H). Compound A124. (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A125. (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0658] To a solution of 3-(bromomethyl)cyclobutan-1-one (155 mg, 2 eq, 952 μmol) in DMF (2 mL) were added K2CO3 (197 mg, 3 eq, 1.43 mmol) and 4'-chloro-9'-(piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 476 μmol). The reaction was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 4'-chloro-9'-(1-((3-oxocyclobutyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (170 mg, 0.30 mmol, 63%) as a yellow solid. LC purity (0.1% FA): 89% (UV at 254 nm)/MS: 502.05 [M+H]; Retention time: 1.126 min. Synthesis of tert-butyl (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0659] To a solution of 4'-chloro-9'-(1-((3-oxocyclobutyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 59.8 μmol) in potassium acetate (11.7 mg, 2 eq, 120 μmol) (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (42.5 mg, 2 eq, 120 μmol) was added sodium cyanoborohydride (3.76 mg, 1 eq, 59.8 μmol), the reaction was stirred at 65 °C for 16 h. The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 27% to 30% to afford (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.00 mg, 2.25 μmol, 3.76%) as a white solid and (S)-3-(1'-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)methyl)cyclobutyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.01 mg, 2.19 μmol, 3.67 %, 91.78% Purity) as a white solid. [0660] P1 (A124): LC purity (0.1% FA): 94.5% (UV at 254 nm)/MS: 841.4 [M+H]; Retention time: 1.216 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.48-7.42 (m, 2H), 7.36 (d, J = 7.2 Hz, 1H), 5.14 (dd, J = 13.4, 5.2 Hz, 1H), 4.69 (s, 1H), 4.44 (q, J = 17.1 Hz, 2H), 3.64 (dd, J = 41.3, 11.3 Hz, 4H), 3.50-3.44 (m, 1H), 3.36 (s, 2H), 3.20 (t, J = 12.0 Hz, 2H), 3.12-2.88 (m, 4H), 2.81-2.62 (m, 4H), 2.50 (dt, J = 18.1, 11.0 Hz, 2H), 2.30-2.01 (m, 15H), 1.85 (d, J = 17.4 Hz, 6H). [0661] P2 (A125): LC purity (0.1% FA): 91.78% (UV at 254 nm)/MS: 841.4 [M+H]; Retention time: 1.684 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.37 (q, J = 7.7 Hz, 2H), 5.13 (dd, J = 13.4, 5.2 Hz, 1H), 4.57 (s, 2H), 4.41 (q, J = 17.0 Hz, 2H), 3.12 (d, J = 9.0 Hz, 3H), 3.01-2.85 (m, 4H), 2.79 (s, 1H), 2.75 (s, 1H), 2.70-2.62 (m, 2H), 2.51 (dd, J = 23.0, 9.8 Hz, 2H), 2.31-2.20 (m, 3H), 2.17 (d, J = 7.6 Hz, 3H), 2.06-1.98 (m, 5H), 1.96-1.88 (m, 6H), 1.31 (d, J = 18.2 Hz, 1H). Compound A126. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione ompound A153. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione in]-10'-

yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 3) [0662] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.24 mmol) in MeOH (2 mL) were added potassium acetate (46 mg, 2 eq, 0.47 mmol), 3-oxocyclohexane-1-carboxylic acid (44 mg, 1.3 eq, 0.31 mmol) and NaCNBH3 (30 mg, 2 eq, 0.47 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L%NH4HCO) from 40% to 54% to get 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (40 mg, 0.07 mmol, 29%) as a yellow solid. LC purity (0.03% TFA): 94.11% (UV at 254 nm)/MS: 546.2 [M+H]; Retention time: 1.286 min. Synthesis of (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (3S)-3-(1'-(3-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0663] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (40 mg, 1 eq, 0.07 mmol) in DMF (1 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (26 mg, 1 eq, 0.07 mmol), DIEA (28.4 mg, 3.0 eq, 0.22 mmol) and HATU (55.7 mg, 2.0 eq, 0.15 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 20% to 35% (0.1% TFA) to get P1 (A126) (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)- 6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.53 mg, 0.003 mmol, 4.70%) as a white solid. LC purity (0.1% FA): 100.0% (UV at 254 nm)/MS: 883.40 [M+H]; Retention time: 1.381 min.1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 8.9 Hz, 1H), 7.97 (s, 1H), 7.89-7.81 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 3.0 Hz, 2H), 7.32 (d, J = 8.5 Hz, 1H), 5.12 (s, 1H), 4.69 (s, 2H), 4.53 (d, J = 36.6 Hz, 2H), 4.43 (d, J = 13.1 Hz, 2H), 4.09 (s, 1H), 3.19 (s, 2H), 2.87 (s, 4H), 2.80 (s, 4H), 2.52 (s, 1H), 2.17 (s, 1H), 2.13-2.01 (m, 8H), 1.89 (d, J = 16.0 Hz, 12H), 1.78-1.63 (m, 4H), 1.48 (s, 2H). and P2 (A153) (3S)-3-(1'-(3-(4-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1- carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (1.09 mg, 1.17 μmol, 1.60%) as a white solid. LC purity (0.1% FA): 100.0% (UV at 254 nm)/MS: 883.4 [M+H]; Retention time: 1.381 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.90-7.80 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.43-7.31 (m, 3H), 5.12 (d, J = 4.2 Hz, 1H), 4.68 (s, 2H), 4.58 (s, 2H), 4.43 (d, J = 12.3 Hz, 2H), 4.02 (d, J = 14.2 Hz, 2H), 3.58 (s, 2H), 3.47 (d, J = 9.4 Hz, 1H), 3.38 (s, 2H), 3.12 (d, J = 10.1 Hz, 1H), 3.06 (s, 2H), 2.92- 2.85 (m, 2H), 2.78 (d, J = 15.6 Hz, 2H), 2.66 (s, 1H), 2.55-2.40 (m, 2H), 2.18 (s, 4H), 2.11-2.02 (m, 6H), 1.87 (s, 6H), 1.78-1.68 (m, 4H), 1.61 (d, J = 12.0 Hz, 2H). Compound A128. (S)-3-(1'-(2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

ne- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 2) [0664] To a solution of 10'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (200 mg, 1 eq, 0.48 mmol) in 1,4-dioxane (2 mL) were added potassium acetate (94.4 mg, 2 eq, 0.96 mmol), bis(pinacolato)diborane (183 mg, 1.5 eq, 0.72 mmol) and PdCl2(dppf) (35.2 mg, 0.1 eq, 0.048 mmol). The mixture was stirred at 90 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to get 4'-chloro-10'-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (110 mg, 0.19 mmol, 40%) as a white oil. LC purity (0.03% TFA): 37.69% (UV at 254 nm)/MS: 463.3 [M+H]; Retention time: 2.156 min. Synthesis of (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)boronic acid (Intermediate 3) [0665] To a solution of 4'-chloro-10'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (20 mg, 1 eq, 0.043 mmol) in Acetone (0.5 mL) and water (0.5 mL) were added acetamide (3.83 mg, 1.5 eq, 0.065 mmol), sodium metaperiodate (13.9 mg, 1.5 eq, 0.065 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to get (4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-10'-yl)boronic acid (6.00 mg, 15.8 μmol, 36.5%) as a white solid. LC purity (0.03% TFA): 52.51% (UV at 254 nm)/MS: 381.0 [M+H]; Retention time: 1.460 min. Synthesis of 4'-chloro-10'-(4-(2-hydroxyethyl)piperidin-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 5) [0666] To a solution of (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)boronic acid (156 mg, 1 eq, 409 μmol) in DCM (1 mL) were added copper diacetate (111 mg, 1.5 eq, 614 μmol), 2-(piperidin-4-yl)ethan-1-ol (105 mg, 2 eq, 819 μmol), pyridine (64.8 mg, 2 eq, 819 μmol) and TEA (82.9 mg, 2 eq, 819 μmol). The mixture was stirred at 25 °C for 1 h under air. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 50% of EA in petroleum ether) to afford 4'-chloro-10'-(4-(2-hydroxyethyl)piperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (54 mg, 0.11 mmol, 27 %) as a yellow solid. LC purity (0.03% TFA): 43.88% (UV at 254 nm)/MS: 464.2 [M+H]; Retention time: 1.535 min. Synthesis of 2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-4-yl)acetaldehyde (Intermediate 6) [0667] To a solution of 4'-chloro-10'-(4-(2-hydroxyethyl)piperidin-1-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (50 mg, 1 eq, 0.11 mmol) in DCM (2 mL) was added DMP (91.4 mg, 2 eq, 0.22 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction was poured into H2O (20 mL) and extracted with EA(20 X 2 mL), then washed brine and dried over Na2SO4, filtered and concentrated under vacuum to get 2- (1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-4- yl)acetaldehyde (40 mg, 82 μmol, 76%) as a yellow solid. LC purity (0.03% TFA): 52.52% (UV at 254 nm)/MS: 462.2 [M+H]; Retention time: 1.674 min. [0668] Synthesis of (S)-3-(1'-(2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0669] To a solution of 2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)acetaldehyde (50 mg, 1 eq, 0.11 mmol) in MeOH (1 mL) were added potassium acetate (31.9 mg, 3 eq, 0.33 mmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (38.5 mg, 1 eq, 0.11 mmol), NaCNBH3 (13.6 mg, 2 eq, 0.22 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (10 mL) and extracted with EA (25 mL), then washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L%NH4HCO) from 40% to 50% to get (S)-3-(1'-(2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)ethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.24 mg, 0.006 mmol, 5.79%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 801.4 [M+H]. Retention time: 1.394 min. 1H NMR (400 MHz, MeOD-d4) δ 8.35 (d, J = 8.5 Hz, 1H), 7.88-7.81 (m, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.44-7.35 (m, 2H), 7.06-6.95 (m, 1H), 5.16- 5.09 (m, 2H), 4.65-4.56 (m, 6H), 4.49-4.35 (m, 2H), 3.83 (d, J = 12.3 Hz, 2H), 2.92-2.83 (m, 4H), 2.81-2.74 (m, 1H), 2.68-2.54 (m, 2H), 2.52-2.43 (m, 1H), 2.19-2.13 (m, 2H), 2.11-2.03 (m, 4H), 1.98 (d, J = 20.6 Hz, 2H), 1.94-1.83 (m, 6H), 1.75-1.66 (m, 4H), 1.53 -1.41 (m, 2H). Compound A129. (S)-3-(1'-(2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(1'-(2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0670] To a solution of (S)-3-(6-oxo-1'-(2-azaspiro[3.5]nonan-7-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (10 mg, 1 eq, 0.021 mmol) in DMF (3 mL) were added potassium acetate (4.10 mg, 2 eq, 0.042 mmol), 4'-chloro-9'-(4- oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (7.25 mg, 0.8 eq, 0.017 mmol) and sodium cyanoborohydride (2.63 mg, 2 eq, 0.042 mmol) at room temperature. The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. The reaction concentrated under vacuum, added DMF (0.5 mL), filtered after adjusted PH to 7-8. The residue was purified by silica gel prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 20% to 34% (0.1 FA%) to afford (S)-3-(1'-(2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.99 mg, 0.006 mmol, 31.1%) as a yellow solid. LC purity (0.1% FA): 96.31% (UV at 254 nm)/MS: 897.3 [M+H]; Retention time: 1.22 min.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.32 (m, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.81 (m, 1H), 7.61 (m, 1H), 7.35-7.37 (m, 2H), 7.29 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.06-5.14 (m, 1H), 4.67 (s, 1H), 4.39 (m, 1H), 4.24 (m, 1H), 3.97 (s, 4H), 3.51 (s, 2H), 3.42 (s, 1H), 3.37 (s, 6H), 3.27-3.31 (m, 4H), 2.90 (m, 1H), 2.78 (s, 2H), 2.67 (s, 1H), 2.63 (s, 1H), 2.33 (s, 1H), 2.19 (s, 6H), 1.99-2.01 (m, 8H), 1.85 (s, 4H), 1.67 (s, 2H), 1.57 (s, 2H). Compound A131. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and Compound A133. (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperazin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

10'- yl)piperazin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 3) [0671] To a solution of 4'-chloro-10'-(piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (150 mg, 1 eq, 356 μmol) in MeOH (3 mL) were added potassium acetate (140 mg, 4 eq, 1.43 mmol), 4-oxocyclohexane-1-carboxylic acid (60.8 mg, 1.2 eq, 428 μmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (44.8 mg, 2 eq, 713 μmol) was added to above mixture. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with DCM (50 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-20% of MeOH in DCM) to afford 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carboxylic acid (100 mg, 0.15 mmol, 41%) as a yellow oil. LC purity (0.1% FA): 82.51% (UV at 254 nm)/MS: 547.4 [M+H]; Retention time: 1.257 min. Synthesis of (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperazin-1- yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0672] To a solution of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carboxylic acid (100 mg, 1 eq, 182 μmol) in DMF (10 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (77.9 mg, 1.2 eq, 219 μmol), HATU (104 mg, 1.5 eq, 274 μmol) and DIEA (70.8 mg, 3 eq, 548 μmol). The solution was stirred at 25 °C for 5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O from 90: 10 to 5: 95, (0.1% FA) to afford (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.00 mg, 7.34 μmol, 4.02%) as a white solid and (S)-3-(1'-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperazin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.00 mg, 7.15 μmol, 3.91%) as a white solid. [0673] P1 (A131): LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 884.5 [M+H]; Retention time: 1.362 min.1H NMR (400 MHz, MeOD-d4) δ 8.37 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 9.7 Hz, 2H), 7.72-7.58 (m, 2H), 7.38 (t, J = 5.1 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 5.14 (s, 1H), 4.69 (s, 2H), 4.56-4.38 (m, 3H), 4.06 (d, J = 13.2 Hz, 3H), 3.69 (s, 2H), 3.45 (d, J = 20.6 Hz, 4H), 3.16 (d, J = 24.5 Hz, 3H), 2.93-2.75 (m, 4H), 2.52 (s, 1H), 2.31 (s, 2H), 2.04 (d, J = 20.6 Hz, 6H), 1.87 (s, 7H), 1.72 (d, J = 11.8 Hz, 6H). [0674] P2 (A133): LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 884.6 [M+H]; Retention time: 1.384 min.1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J = 8.5 Hz, 1H), 7.89-7.77 (m, 2H), 7.73- 7.63 (m, 2H), 7.48-7.33 (m, 2H), 7.10-6.97 (m, 1H), 5.13 (d, J = 13.7 Hz, 1H), 4.67 (d, J = 10.9 Hz, 2H), 4.55-4.36 (m, 3H), 4.05 (d, J = 12.7 Hz, 3H), 3.73 (d, J = 12.5 Hz, 2H), 3.54-3.36 (m, 4H), 3.26-3.05 (m, 4H), 2.93-2.74 (m, 3H), 2.51 (d, J = 13.1 Hz, 1H), 2.17 (d, J = 5.0 Hz, 2H), 2.11-1.93 (m, 9H), 1.88 (s, 6H), 1.75 (s, 5H). Compound A134. (S)-3-(1'-(6-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)spiro[3.3]heptane-2-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

n]- 9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 3) [0675] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (60 mg, 1 eq, 143 μmol) in MeOH (3 mL) were added 6- oxospiro[3.3]heptane-2-carboxylic acid (33.0 mg, 1.5 eq, 214 μmol)，potassium acetate (28.0 mg, 2 eq, 286 μmol) and NaBH3CN (26.9 mg, 3 eq, 429 μmol). The mixture was stirred at 25 °C for 5 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-1'-carboxylate (30 mg, 49.7 μmol, 34.8%) as a yellow oil. LC purity (0.1% FA): 94.01% (UV at 254 nm)/MS: 558.3 [M+H]; Retention time: 1.27 min. Synthesis of (S)-3-(1'-(6-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)spiro[3.3]heptane-2-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0676] To a solution of 6-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxylic acid (30 mg, 1 eq, 53.8 μmol) in DMF (2 mL) were added DIEA (34.7 mg, 5 eq, 269 μmol), (S)-3-(6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (28.7 mg, 1.5 eq, 80.6 μmol) and HATU (40.9 mg, 2 eq, 108 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 28% to 40% to afford (S)-3-(1'-(6-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)spiro[3.3]heptane-2- carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (30.43 mg, 32.49 μmol, 60.4%) as a white solid. LC purity (0.1% FA): 97.45% (UV at 254 nm)/MS: 896.4 [M+H]; Retention time: 1.33 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.81 (t, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 21.0, 7.9 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 4.63 (s, 2H), 4.38 (t, J = 16.0 Hz, 2H), 4.20-4.28 (m, 1H), 3.11 (d, J = 12.6 Hz, 2H), 2.94 (s, 3H), 2.60-2.70 (m, 4H), 2.20-2.34 (m, 4H), 2.06 (s, 6H), 1.88 (d, J = 8.5 Hz, 5H), 1.85-1.64 (m, 16H). Compound A138. (S)-3-(1'-(7-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(1'-(7-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0677] To a solution of (S)-3-(6-oxo-1'-(7-azaspiro[3.5]nonan-2-yl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (30 mg, 1 eq, 0.063 mmol) in DMF (3 mL) were added potassium acetate (12.3 mg, 2 eq, 0.13 mmol), 4'-chloro-9'-(4- oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (21.8 mg, 0.8 eq, 0.05 mmol) and sodium cyanoborohydride (7.88 mg, 2 eq, 0.13 mmol) at rt. The reaction was stirred 25 °C for 16 h. LCMS indicated completion of reaction. Filtered and concentrated under vacuum to get the crude. The crude was purified by prep-HPLC (0.1% FA in CH3CN and H2O) from 20% to 34% to get (S)-3-(1'-(7-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.13 mg, 0.0023 mmol, 3.61%) as a yellow solid. LC purity (0.1% FA): 95.10% (UV at 254 nm)/MS: 896.4 [M+H]; Retention time: 1.23 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32 (m, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 7.59 (m, 1H), 7.41 (m, 1H), 7.32 (s, 1H), 7.26 (m, 1H), 6.97 (m, 1H), 5.08 (m, 1H), 4.51 (s, 2H), 4.38 (m, 1H), 4.21 (m, 1H), 3.80-3.83 (m, 3H), 2.78 (s, 3H), 2.67-2.72 (m, 4H), 2.33-2.40 (m, 6H), 2.16 (s, 3H), 1.84 (s, 8H), 1.68 (s, 8H), 1.43-1.60 (m, 9H). Compound A139. (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and Compound A140. (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione

-9'- yl)piperidin-1-yl)cyclohexyl)acetic acid (Intermediate 3) [0678] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.24 mmol) in CH3OH (3 mL) were added 2-(4- oxocyclohexyl)acetic acid (74.4 mg, 2 eq, 0.48 mmol), potassium acetate (46.7 mg, 2 eq, 0.48 mmol), sodium cyanotrihydroborate (44.9 mg, 3 eq, 0.72 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (15 mL) and extracted with EA (30 mL), then washed brine and dried over Na2SO4, filtered and concentrated to purification (CH3OH:DCM=10:1) to get 2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetic acid (60 mg, 0.11 mmol, 44.7 %) as a white solid. LC purity (0.03%TFA): 99.37% (UV at 254 nm)/MS: 560.4 [M+H]; Retention time: 0.89 min. Synthesis of (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0679] To a solution of 2-(4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetic acid (60 mg, 1 eq, 0.11mmol) in DMF (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (45.7 mg, 1.2 eq, 0.13 mmol), DIEA (138 mg, 10 eq, 1.07 mmol), BOP (94.8 mg, 2 eq, 0.21 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum and purified prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 24% to 34% to afford P1 (A139) (S)-3-(1'-(2-(4-(4-(4'-chloro-5'- oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetyl)- 6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.00 mg, 1.10 μmol, 1.03%) as a white solid and P2 (A140) (S)-3-(1'-(2-(4-(4-(4'-chloro-5'-oxo- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexyl)acetyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.00 mg, 1.11 μmol, 1.04%) as a white solid. [0680] P1 (A139): LC purity (0.03% TFA): 100.00% (UV at 254 nm)/MS: 897.6 [M+H]; Retention time: 1.393 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.36-8.39 (d, J = 8.8 Hz, 1H), 8.03-8.05 (d, J = 8.4 Hz, 1H), 7.80-7.82 (t, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.60-7.63 (d, J = 7.6 Hz, 1H), 7.35-7.39 (m, 2H), 7.27-7.29 (d, J = 7.6 Hz, 1H), 5.07-5.10 (d, J = 9.2 Hz, 1H), 4.64 (s, 2H), 4.40-4.42 (d, J = 17.2 Hz, 3H), 4.25 (s, 2H), 3.17 (s, 4H), 2.95 (s, 4H), 2.66-2.69 (m, 4H), 2.62 (s, 2H), 2.32-2.35(m, 4H), 2.09 (s, 2H), 2.07 (s, 1H), 2.00-2.02 (d, J = 9.2 Hz, 2H), 1.80- 1.83 (d, J = 10.4 Hz, 8H), 1.74-1.76 (d, J = 5.4 Hz, 2H), 1.24 (s, 6H), 0.85 (s, 1H). [0681] P2 (A140): LC purity (0.03% TFA): 100.00% (UV at 254 nm)/MS: 897.6 [M+H]; Retention time: 1.387 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.37-8.39 (d, J = 9.2 Hz, 1H), 8.03-8.05 (d, J = 8.8 Hz, 1H), 7.80-7.82 (t, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.60-7.63 (d, J = 8.0 Hz, 1H), 7.35-7.39 (m, 2H), 7.27-7.29 (d, J = 7.6 Hz, 1H), 5.07 (s, 1H), 4.64 (s, 2H), 4.40- 4.42 (d, J = 17.6 Hz, 2H), 4.24 (s, 1H), 3.95 (s, 2H), 3.07-3.13 (m, 4H), 2.67 (s, 2H), 2.61 (s, 2H), 2.56 (s, 2H), 2.33 (s, 2H), 2.23 (s, 1H), 2.07-2.09 (d, J = 4.4 Hz, 2H), 1.99 (s, 1H), 1.84 (s, 6H), 1.72-1.75 (d, J = 22.6 Hz, 12H), 1.55 (s, 4H), 1.24 (s, 2H). Compound A141. (S)-3-(1'-(1'-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-4-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carbonyl)piperidine-1-carboxylate (Intermediate 2) [0682] To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50 mg, 1 eq, 218 μmol) in DMF (2 mL) were added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (166 mg, 2 eq, 436 μmol) and (S)-3-(6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (77.5 mg, 1 eq, 218 μmol) and N-ethyl-N-isopropylpropan-2-amine (141 mg, 5 eq, 1.09 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The resulting mixture was extracted with EA (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to get tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro- 2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carbonyl)piperidine-1-carboxylate (60 mg, 106 μmol, 48.6%) as a yellow solid. LC purity (0.1% FA): 52.56% (UV at 254 nm)/MS: 567.4 [M+H]; Retention time: 1.39 min. Synthesis of (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidine]-1'-carbonyl)piperidine-1-carboxylic acid (Intermediate 3) [0683] A mixture of tert-butyl (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carbonyl)piperidine-1-carboxylate (60 mg, 1 eq, 106 μmol) and HCl in EA (3 mL, 4 N) was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuo to get (S)-4-(7-(2,6-dioxopiperidin-3-yl)-6- oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carbonyl)piperidine-1- carboxylic acid (50 mg, 97.9 μmol, 92.5%) as a yellow oil. LC purity (0.1%FA): 97.56% (UV at 254 nm)/MS: 467.2 [M+ H]; Retention time: 0.90 min. Synthesis of (S)-3-(1'-(1'-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-[1,4'-bipiperidine]-4-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0684] To a solution of (S)-3-(6-oxo-1'-(piperidine-4-carbonyl)-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (30 mg, 1 eq, 64.3 μmol) in DMF (2 mL) were added potassium acetate (18.9 mg, 3 eq, 193 μmol), 4'-chloro-9'-(4- oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (27.9 mg, 1 eq, 64.3 μmol) and sodium cyanoborohydride (8.08 mg, 2 eq, 129 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 15% to 30% to get (S)-3-(1'-(1'-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-[1,4'-bipiperidine]-4-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.02 mg, 1.15 μmol, 1.78%) as a yellow solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 884.3 [M+H]; Retention time: 1.23 min. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.48-7.24 (m, 3H), 7.10-6.95 (m, 1H), 5.17-5.01 (m, 1H), 4.79-4.56 (m, 2H), 4.45-4.31 (m, 2H), 4.31-4.14 (m, 1H), 3.99 (d, J = 12.5 Hz, 3H), 3.55 (d, J = 11.0 Hz, 2H), 3.11 (d, J = 11.6 Hz, 3H), 2.80 (t, J = 12.0 Hz, 3H), 2.68-2.58 (m, 2H), 2.36-2.29 (m, 1H), 2.20-2.08 (m, 4H), 1.97 (d, J = 7.6 Hz, 3H), 1.93-1.44 (m, 18H). [0685] The following compounds were prepared in a manner analogous to Compound A141. Compound A150. (S)-3-(1'-(1-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)azetidine-3-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 856.3 [M+H]; 1H NMR (400 MHz, MeOD-d4) δ 8.37 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.41-7.33 (m, 3H), 7.10 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 13.4 Hz, 2H), 4.70- 4.41 (m, 8H), 3.90-3.47 (m, 10H), 2.94-2.78 (m, 5H), 2.50 (d, J = 13.1 Hz, 2H), 2.18 (s, 3H), 1.83 (d, J = 5.8 Hz, 9H), 1.48 (d, J = 7.7 Hz, 2H). Compound A143. (S)-3-(1'-(1-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (S)-3-(1'-(1-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0686] To a solution of 4'-chloro-9'-(4-oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (30 mg, 1 eq, 69.1 μmol) in DMF (2 mL) were added potassium acetate (13.6 mg, 8.64 μL, 2 eq, 138 μmol)，(S)-3-(1'-(azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (40 mg, 1.41 eq, 97.4 μmol) and NaCNBH3 (8.69 mg, 2 eq, 138 μmol). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction was purified by prep-HPLC, eluted with MeCN in H2O (0.1% NH4HCO3) from 44% to 54% to afford (S)-3-(1'-(1-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-4-yl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.07 mg, 1.14 μmol, 1.66%) as a green solid. LC purity (0.1% NH4HCO3): 100% (UV at 254 nm)/MS: 828.3 [M+H]; Retention time: 1.559 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 13.5, 4.9 Hz, 1H), 4.52 (s, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 16.9 Hz, 1H), 3.60 (s, 2H), 2.85 (dd, J = 26.7, 6.9 Hz, 6H), 2.73 (s, 2H), 2.67 (s, 1H), 2.33 (s, 1H), 2.17 (s, 4H), 1.86 (d, J = 14.8 Hz, 8H), 1.76 (s, 2H), 1.69 (s, 6H), 1.19-1.41 (m, 4H). Compound A144. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A147. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

-9'- yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (Intermediate 3) [0687] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 238 μmol) in MeOH (3 mL) were added potassium acetate (93.5 mg, 59.5 μL, 4 eq, 952 μmol), 3-oxocyclobutane-1-carboxylic acid (32.6 mg, 1.2 eq, 286 μmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (29.9 mg, 27.7 μL, 2 eq, 476 μmol) was added to above mixture. The mixture was stirred at 60 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with DCM (50 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-70% of ethyl acetate in petroleum ether) to afford 3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (90 mg, 174 μmol, 73.0%). LC purity (0.1% FA): 93.93% (UV at 254 nm)/MS: 518.2 [M+H]; Retention time: 1.227 min. Synthesis of (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (S)-3-(1'-(3-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)cyclobutane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0688] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (70 mg, 1 eq, 135 μmol) in DMF (3 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (57.6 mg, 1.2 eq, 162 μmol), HATU (77.1 mg, 1.5 eq, 203 μmol) and DIEA (52.4 mg, 3 eq, 405 μmol). The solution was stirred at 25 °C for 5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 20% to 35% to afford P1(A144) (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)piperidin-1-yl)cyclobutane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.00 mg, 5.81 μmol, 4.30%). and P2(A147) (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)cyclobutane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (5.00 mg, 5.79 μmol, 4.29%,) as a white solid. [0689] P1(A144): LC purity (0.1% FA): 93.93% (UV at 254 nm)/MS: 855.5 [M+H]; Retention time: 1.359 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.38 (s, 2H), 5.17-5.08 (m, 1H), 4.88 (s, 1H), 4.68 (s, 2H), 4.57 (s, 1H), 4.50-4.34 (m, 2H), 3.82 (d, J = 12.9 Hz, 1H), 3.45 (d, J = 21.1 Hz, 2H), 3.28-3.21 (m, 1H), 2.98-2.75 (m, 4H), 2.67-2.33 (m, 7H), 2.11 (d, J = 44.3 Hz, 8H), 1.99- 1.65 (m, 12H). [0690] P2(A147): LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 855.5 [M+H]; Retention time: 1.017 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.37 (q, J = 7.6 Hz, 2H), 5.13 (t, J = 10.5 Hz, 1H), 4.88 (s, 1H), 4.69 (s, 2H), 4.51 (d, J = 18.6 Hz, 1H), 4.41 (dd, J = 18.2, 13.4 Hz, 2H), 3.93 (d, J = 14.2 Hz, 1H), 3.71 (d, J = 14.1 Hz, 2H), 3.50-3.38 (m, 1H), 3.08 (dt, J = 25.0, 6.7 Hz, 4H), 2.93-2.68 (m, 5H), 2.58-2.43 (m, 3H), 2.33-1.76 (m, 21H). Compound A149. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carbonyl)-5-methyl-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Synt

olo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carbonyl)-5-methyl-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0691] To a solution of 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (100 mg, 1 eq, 210 μmol) in DCM (3 mL) were added N-ethyl-N- isopropylpropan-2-amine (81.6 mg, 3 eq, 631 μmol) and bis(trichloromethyl) carbonate (93.7 mg, 1.5 eq, 315 μmol) at 0 °C for 1 h. Then room temperature with (S)-3-(5-methyl-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (116 mg, 1.5 eq, 316 μmol) for 4 h. LCMS indicated completion of reaction. The reaction mixture was poured into water (20 mL), extracted with DCM (20 mL X 3). The combined organic layers were washed with brine (30 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 20% to 38% to afford (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)azetidine-1-carbonyl)-5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.00 mg, 3.17 μmol, 1.50%) as a white solid.LC purity (0.1% FA): 80.65% (UV at 254 nm)/MS: 870.6 [M+H]; Retention time: 1.371 min.1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.19 (s, 1H), 4.56 (s, 2H), 4.31 (d, J = 16.9 Hz, 1H), 4.15 (d, J = 17.2 Hz, 1H), 3.97 (s, 2H), 3.76 (d, J = 16.2 Hz, 3H), 3.06 (s, 2H), 2.90 (d, J = 9.7 Hz, 5H), 2.67 (s, 2H), 2.33 (s, 2H), 2.10 (s, 3H), 1.96-1.62 (m, 20H), 1.23 (s, 1H). Compound A151. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A152. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

-9'- yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 3) [0692] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.24 mmol) in MeOH (2 mL) were added potassium acetate (46.7 mg, 2 eq, 0.47 mmol), 3-oxocyclohexane-1-carboxylic acid (44.0 mg, 1.3 eq, 0.31 mmol) and NaCNBH3 (29.9 mg, 2 eq, 0.47 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (0.1% FA) to get 3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (50 mg, 0.055 mmol, 23%) as a yellow solid. LC purity (0.03% TFA): 94.11% (UV at 254 nm)/MS: 546.2 [M+H]; Retention time: 1.286 min. Synthesis of (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione and (3S)-3-(1'-(3-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1- yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0693] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (40 mg, 1 eq, 0.073 mmol) in DMF (1 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (26.0 mg, 1 eq, 0.073 mmol), DIEA (28.4 mg, 3 eq, 0.220 mmol) and HATU (55.7 mg, 2 eq, 0.146 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (0.1% TFA) to get (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.15 mg, 1.22 μmol, 1.67 %) as a white solid, and (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)cyclohexane-1-carbonyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.04 mg, 2.29 μmol, 3.13%)as white solid. [0694] P1 (A151): LC purity (0.03% TFA): 97.66% (UV at 254 nm)/MS: 883.4 [M+H]; Retention time: 1.326 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.87-7.80 (m, 1H), 7.77 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.42-7.34 (m, 2H), 5.14 (s, 1H), 4.69 (d, J = 2.1 Hz, 2H), 4.56 (d, J = 13.0 Hz, 2H), 4.43 (d, J = 13.6 Hz, 2H), 4.09 (d, J = 14.4 Hz, 1H), 3.68 (s, 2H), 3.44 (s, 1H), 3.16-3.09 (m, 2H), 2.97 (d, J = 15.7 Hz, 2H), 2.91-2.85 (m, 2H), 2.78 (d, J = 13.0 Hz, 1H), 2.51 (d, J = 12.8 Hz, 2H), 2.26 (d, J = 13.6 Hz, 2H), 2.22-2.14 (m, 6H), 2.09-2.03 (m, 4H), 1.88 (s, 6H), 1.82-1.74 (m, 4H), 1.63 (d, J = 10 Hz, 2H), 1.31 (d, J = 18.7 Hz, 2H) [0695] P2 (A152): LC purity (0.03% TFA): 100.0% (UV at 254 nm)/MS: 883.4 [M+H]; Retention time: 1.326 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 5.6 Hz, 1H).5.14 (s, 1H), 4.69 (d, J = 2.1 Hz, 2H), 4.56 (d, J = 13.0 Hz, 2H), 4.43 (d, J = 13.6 Hz, 2H), 4.09 (d, J = 14.4 Hz, 1H), 3.68 (s, 2H), 3.44 (s, 1H), 3.16 ^ 3.09 (m, 2H), 2.97 (d, J = 15.7 Hz, 2H), 2.91-2.85 (m, 2H), 2.78 (d, J = 13.0 Hz, 1H), 2.51 (d, J = 12.8 Hz, 2H), 2.26 (d, J = 13.6 Hz, 2H), 2.22-2.14 (m, 6H), 2.09-2.03 (m, 4H), 1.88 (s, 6H), 1.82 -1.74 (m, 4H), 1.63 (d, J = 10 Hz, 2H), 1.31 (d, J = 18.7 Hz, 2H). Compound A155. (S)-3-(1'-((3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0696] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (250 mg, 1.0 eq, 660 μmol) and methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (123.0 mg, 1.21 eq, 798 μmol) in DMF (2.00 mL) were added DIPEA (815.4 mg, 10 eq, 6.60 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (223.8 mg, 0.8 eq, 528 μmol). The reaction mixture was stirred at 25 °C for 1 h in N2. The mixture was diluted with water (10 mL), extracted with EtOAc (20 x 3 mL), dried over Na2SO4, concentrated to give methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (500 mg, crude) as a yellow oil. no need purified and used next step directly.1H NMR (400 MHz, DMSO-d6) δ 12.11-12.66 (m, 1H), 3.60-3.64 (m, 3H), 2.22-2.64 (m, 6H). Synthesis of methyl 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (Intermediate4) [0697] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (250 mg, 1.0 eq, 660 μmol) and methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (123.0 mg, 1.21 eq, 798 μmol) in DMF (2.00 mL) were added DIPEA (815.4 mg, 10 eq, 6.60 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (223.8 mg, 0.8 eq, 528 μmol). The reaction mixture was stirred at 25 °C for 1 h in N2. The mixture was diluted with water (10 mL), extracted with EtOAc (20 x 3 mL), dried over Na2SO4, concentrated. The residue was purified by prep-TLC (developing agent: DCM/MeOH=30/1 ) to give methyl 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (250 mg, 482 μmol, 73.0%) as a white solid. LC purity (0.1% FA): 90.44% (UV at 254 nm)/MS: 518.3 [M +H]; Retention time: 0.863 min. Synthesis of 4-chloro-9-(1-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidin-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate5) [0698] To a solution of methyl 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (250 mg, 1.0 eq, 482 μmol) in MeOH (20.00 mL) was added NaBH4 (55.1 mg, 3.0 eq, 1.45 mmol) at 0 °C. The reaction mixture was stirred at 70 °C for 1.5 h in N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 x 3 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give 4-chloro-9-(1-((3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (200 mg, 409 μmol, 84.9%) as a yellow oil. LC purity (0.1% FA): 11.4% (UV at 254 nm)/MS: 490.3 [M +H]; Retention time: 0.823 min. Synthesis of (3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (Intermediate 6) [0699] To a solution of 4-chloro-9-(1-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1- yl)methyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 1.0 eq, 204 μmol) and TEA(10.8 mg, 5.0 eq, 1.06 mmol) in DCM (2.00 mL) was added MsCl (120.8 mg, 5.0 eq, 1.06 mmol). The reaction mixture was stirred at rt for 1 h in N2. The mixture was diluted with water (10 mL), extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to give (3-((4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (120 mg, crude) as a white solid.no need purified and used next step directly. LC purity (0.1% FA): 55.07 % (UV at 254 nm)/MS: 596.4 [M +H2O]; Retention time: 0.933 min. Synthesis of (S)-3-(1'-((3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Compound S-3008) [0700] To a solution of (3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (30 mg, 1.0 eq, 52.8 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (22.5 mg, 1.2 eq, 63.4 μmol) in DMF (5.00 mL) were added sodium bicarbonate (22.2 mg, 5.0 eq, 264 μmol) and potassium iodide (4.4 mg, 0.5 eq, 26.4 μmol). The reaction mixture was stirred at 105 °C for 16 h in N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 x 3 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum, The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give (S)-3-(1'-((3-((4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (0.69 mg, 0.76 μmol, 1.4%, 91% Purity) as a white solid. LC purity (0.1% FA): 91.00% (UV at 254 nm)/MS: 827.5 [M+H]; Retention time: 10.82 min.1H NMR (400 MHz, MeOD-d4) δ 8.43-8.45 (m, 1H), 7.98-8.00 (m, 1H), 8.85-8.89 (m, 1H), 7.62-7.69 (m, 3H), 7.35-7.43 (m, 1H), 5.30-5.38 (m, 4H), 3.59-3.70 (m, 22H), 3.46-3.49 (m, 4H), 3.10-3.14 (m, 4H), 2.15-2.22 (m, 11H). Compound A156. (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione O O O Cl Cl O ^Cl N N B N Boc N O N O Pd/C N N 2 N TFA Br NH O

Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 3) [0701] To a mixture of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (180 mg, 1 eq, 433 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (161 mg, 1.2 eq, 520 μmol) and K2CO3 (179 mg, 3 eq, 1.30 mmol) in 1,4-dioxane (10 mL) and H2O (1.00 mL) was added Pd(dppf)Cl2 (31.7 mg, 0.1 eq, 43.3 μmol) at 20 °C, then heated to 100 °C and stirred for 16 h to give yellow solution. LCMS showed the reaction was completed. The reaction was cooled to 20 °C and concentrated under vacuum. The residue was purified by column chromatography on silica gel(PE:EA=100:1-10:1) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)- 3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 328 μmol, 75.8%) as a yellow solid. LC purity (0.1% FA): 58.37% (UV at 254 nm)/MS: 518.3 [M +H]; Retention time: 1.546 min. Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)piperidine-1-carboxylate (Intermediate 4) [0702] To a mixture of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 1 eq, 328 μmol) and ZnBr2 (14.8 mg, 0.2 eq, 65.6 μmol) in THF (10 mL) was added Pd/C (60 mg, 1 eq, 328 μmol). The mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction was concentrated under vacuum to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidine-1-carboxylate (159 mg, 306 μmol, 93.2%) as a white solid. LC purity (0.1% FA): 78.66% (UV at 254 nm)/MS: 520.3 [M +H]; Retention time: 2.012 min. Synthesis of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (Intermediate 5) [0703] A mixture of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidine-1-carboxylate (150 mg, 1 eq, 288 μmol) in DCM (6.0 mL) was added 2,2,2-trifluoroacetic acid (32.9 mg, 2.0 mL, 288 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to afford 4'-chloro-9'-(piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (91.0 mg, 217 μmol, 75.1%)as a white solid. LC purity (0.1% FA): 66.62% (UV at 254 nm)/MS: 420.2 [M +H]; Retention time: 0.892 min. Synthesis of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate 7) [0704] To a mixture of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 238 μmol), tert-butyl 3-oxoazetidine-1-carboxylate (81.5 mg, 2 eq, 476 μmol) and TEA (72.2 mg, 3 eq, 714 μmol) in DCE (5.0 mL) was added NaBH(OAc)3 (252.0 mg, 5 eq, 1.19 mmol) and stirred at 25 °C for 16 h to give white solution. The mixture was concentrated to give crude product. The residue was purified by column chromatography on silica gel(DCM: MeOH=50:1-20:1) to afford tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carboxylate (70 mg, 122 μmol, 51.1%) as a white solid. LC purity (0.1% FA): 41.35% (UV at 254 nm)/MS: 575.4 [M +H]; Retention time: 1.035 min. Synthesis of 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 8) [0705] A mixture of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidine-1-carboxylate (31.0 mg, 1 eq, 53.9 μmol) in DCM (3.0 mL) was added 2,2,2-trifluoroacetic acid (1.00 mL, 1 eq, 53.9 μmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated to afford 9'-(1-(azetidin-3-yl)piperidin- 4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (23.0 mg, 48.4 μmol, 89.8%) as a white solid. LC purity (0.1% FA): 49.34% (UV at 254 nm)/MS: 475.3 [M +H]; Retention time: 0.794 min. Synthesis of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate 12) [0706] A mixture of 1,1'-sulfonylbis(1H-imidazole) (1.00 g, 1 eq, 5.05 mmol) in DCM (20 mL) was added methyl trifluoromethanesulfonate (1.08 g, 1.3 eq, 6.56 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated to afford 1-((1H-imidazol-1- yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (360 mg, 994 μmol, 19.7 %) as a white solid. LC purity (0.1% FA): 45.31% (UV at 254 nm)/MS: 213.2 [M +H]; Retention time: 0.428 min. Synthesis of (S)-3-(1'-((1H-imidazol-1-yl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 13) [0707] To a mixture of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (100 mg, 1 eq, 281 μmol) and 1-((1H-imidazol-1- yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (102.0 mg, 1 eq, 281 μmol) in CH3CN (10 mL) was added NaHCO3 (47.3 mg, 2 eq, 563 μmol). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, concentrated under vacuum to give a crude product. The residue was purified by column chromatography on silica gel(PE:EA=100:1-6:1) to afford (S)-3-(1'-((1H- imidazol-1-yl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (44.0 mg, 90.6 μmol, 32.2%) as a white solid. LC purity (0.1% FA): 59.65% (UV at 254 nm)/MS: 486.0 [M +H]; Retention time: 1.203 min. Synthesis of (S)-1-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate 9) [0708] A mixture of (S)-3-(1'-((1H-imidazol-1-yl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (44.0 mg, 1 eq, 90.6 μmol) in DCM (5.0 mL) was added methyl trifluoromethanesulfonate (14.9 mg, 1 eq, 90.6 μmol). The mixture was stirred at 0 °C for 3 h. The mixture was concentrated to afford (S)-1-((7-(2,6- dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'- yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate(41.0 mg, 81.2%) as a white solid. LC purity (0.1% FA): 88.15% (UV at 254 nm)/MS: 500.2 [M +H]; Retention time: 0.325 min. Synthesis of (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0709] To a mixture of 9'-(1-(azetidin-3-yl)piperidin-4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (20 mg, 1 eq, 42.1 μmol) and (S)-1-((7-(2,6-dioxopiperidin-3-yl)- 6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)sulfonyl)-3-methyl- 1H-imidazol-3-ium trifluoromethanesulfonate (27.4 mg, 1 eq, 42.1 μmol) in CH3CN (5.0 mL) was added NaHCO3 (7.1 mg, 2 eq, 84.2 μmol) at 20 °C. The mixture was stirred at 25 °C for 16 h to give yellow solution. LCMS showed the reaction was completed. The reaction was concentrated under vacuum. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1-20:1) to afford (S)-3-(1'-((3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)azetidin-1-yl)sulfonyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (4.64 mg, 5.20 μmol, 12.3%) as a white solid. LC purity (0.1% FA): 88.03% (UV at 254 nm)/MS: 892.6 [M +H]; Retention time: 5.382 min.1H NMR (400 MHz, MeOD) δ 8.41 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 10 Hz, 1H), 7.38 (d, J = 11.1 Hz, 2H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.61 (d, J = 20.6 Hz, 2H), 4.45 ^ 4.36 (m, 2H), 4.07 (d, J = 6.1 Hz, 4H), 3.77 (d, J = 13.0 Hz, 2H), 3.64 (d, J = 12.0 Hz, 1H), 3.07 ^ 2.84 (m, 5H), 2.73 (dd, J = 36.4, 12.7 Hz, 3H), 2.50 (dt, J = 13.4, 10.5 Hz, 2H), 2.19 ^ 2.02 (m, 10H), 1.92 ^ 1.76 (m, 9H). Compound A161. (S)-3-(1'-((2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)methyl)-2-azaspiro[3.5]nonane-2-carboxylate (Intermediate 3) [0710] To a solution of tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 1 eq, 0.39 mmol) in MeOH (3 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (112 mg, 0.8 eq, 0.32 mmol) and sodium cyanoborohydride (49.6 mg, 2.0 eq, 0.79 mmol) and potassium acetate (77.5 mg, 2 eq, 0.79 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EA in PE) to get tert-butyl (S)-7- ((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-1'-yl)methyl)-2-azaspiro[3.5]nonane-2-carboxylate (115 mg, 0.18 mmol, 46%) as a white solid. LC purity (0.03% TFA): 82.02% (UV at 254 nm)/MS: 593.4 [M+H]; Retention time:1.228 min. Synthesis of (S)-3-(1'-((2-azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 4) [0711] To a solution of tert-butyl (S)-7-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)methyl)-2-azaspiro[3.5]nonane-2-carboxylate (60 mg, 1 eq, 0.10 mmol) in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated to get (S)-3-(1'-((2- azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (60 mg, 0.12 mmol, 100%) as a yellow oil. LC purity (0.03% TFA): 89.16% (UV at 254 nm)/MS: 493.4 [M+H]; Retention time: 0.266 min. Synthesis of (S)-3-(1'-((2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0712] To a solution of (S)-3-(1'-((2-azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 0.10 mmol) in MeOH (2 mL) were added 4'-chloro-9'-(4-oxopiperidin-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (44.0 mg, 1.0 eq, 0.10 mmol), sodium cyanoborohydride (12.8 mg, 2.0 eq, 0.20 mmol) and potassium acetate (29.9 mg, 3.0 eq, 0.30 mmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with EA (50 mL), then washed brine and dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 25% to 40% to get (S)-3-(1'-((2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.63 mg, 1.70 μmol, 1.68%) as a yellow solid. LC purity (0.03% TFA): 100.0% (UV at 254 nm)/MS: 910.4 [M+H]; Retention time: 0.921 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.85-7.73 (m, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 11.8 Hz, 2H), 7.29 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.15-5.04 (m, 1H), 4.62 (d, J = 31.1 Hz, 2H), 4.39 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.2 Hz, 1H), 3.95 (s, 4H), 3.84 (s, 2H), 3.55 (s, 4H), 3.05 (s, 2H), 2.90 (d, J = 13.2 Hz, 2H), 2.80-2.73 (m, 2H), 2.69-2.58 (m, 4H), 2.43 (d, J = 13.5 Hz, 1H), 2.30 (d, J = 21.5 Hz, 1H), 2.18 (s, 2H), 1.98 (d, J = 10.6 Hz, 8H), 1.85 (s, 4H), 1.71 (s, 6H), 1.49 (s, 4H). Compound A162. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-1H-pyrazol-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0713] To a solution of 4'-chloro-10'-(1H-pyrazol-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (20 mg, 1 eq, 49.6 μmol) in DMSO (5 mL) was added KOH (27.9 mg, 10 eq, 496 μmol). The mixture was stirred at 25 °C for 2 h. And 1,3-dibromopropane (15.0 mg, 1.5 eq, 74.5 μmol) was added. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was poured into H2O (30 mL) and extracted with ethyl acetate (30 mL X 2). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 10'-(1-(3-bromopropyl)-1H-pyrazol-4-yl)-4'- chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (20 mg, 38.2 μmol, 76.9%) as a yellow solid. LC purity (0.1% FA): 17.38% (UV at 254 nm)/MS: 523.2 [M+H]; Retention time: 1.65 min. Synthesis of (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-1H-pyrazol-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0714] To a solution of 10'-(1-(3-bromopropyl)-1H-pyrazol-4-yl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (35.0 mg, 1 eq, 66.8 μmol) in DMF (2 mL) were added sodium bicarbonate (56.1 mg, 26.0 μL, 10 eq, 668 μmol) and (S)-3-(6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (23.7 mg, 1 eq, 66.8 μmol) was added. The mixture was stirred at 65 °C for 16 h. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 20% to 36% to afford (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-1H-pyrazol-1-yl)propyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.01 mg, 1.23 μmol, 1.85%) as a yellow solid. LC purity (0.1% FA): 89.68% (UV at 254 nm)/MS: 798.4 [M+H]; Retention time: 1.35 min. 1H NMR (400 MHz, MeOD-d4) δ 8.46 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.86 (t, J = 8.5 Hz, 2H), 7.63 (dd, J = 20.1, 7.9 Hz, 2H), 7.40 (s, 2H), 4.60 (s, 5H), 4.40 (s, 2H), 3.56 (s, 2H), 3.13 (s, 2H), 3.02 (s, 1H), 2.88 (d, J = 13.7 Hz, 1H), 2.79 (s, 1H), 2.40 (s, 2H), 2.15 (dd, J = 57.3, 12.6 Hz, 10H), 1.85 (d, J = 24.4 Hz, 7H). Compound A163. (S)-3-(1'-(((1s,4R)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-chloro-10-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 2) [0715] The product 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (398 mg, 1 eq, 809 μmol) was purified by SFC (supercritical CO2/EtOH as eluent) to afford 4-chloro-10-(1-((1s,4s)-4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 203 μmol, 25.1%) as a yellow solid. LC purity (0.1%TFA): 92.53% (UV at 254 nm)/MS: 492.7 [M+H]; Retention time: 0.553 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 3) [0716] To a mixture of 4-chloro-10-(1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 1 eq, 81.3 μmol) in dry DCM (6.00 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (19.0 mg, 1 eq, 44.7 μmol) at 0 °C. The mixture was stirred for 3 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford (1s,4s)-4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (20 mg, 40.8 μmol, 91.3%) as a yellow solid. LC purity (0.1%TFA): 74.53% (UV at 254 nm)/MS: 490.2 [M+H]; Retention time: 0.853 min. Synthesis of (R)-3-(1'-(((1s,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0717] To a mixture of (R)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (25.4 mg, 1 eq, 71.4 μmol) in dry DCM (4.00 mL) was added triethylamine (361 μg, 0.05 Eq, 3.57 μmol) at 25 °C stirred for 0.5 h. Then, a solution of (1s,4s)- 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (35.0 mg, 1 eq, 71.4 μmol) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was added (1s,4s)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (35.0 mg, 1 eq, 71.4 μmol) and stirred at 25 °C for 16 h. The mixture was concentrated under vacuum, The resulting residue was purified by reverse-phase chromatography to afford (R)-3-(1'-(((1s,4S)-4-(4- (4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (2.25 mg, 2.55 μmol, 3.57 %, 93.89% Purity) as a white solid.LC purity (0.1% FA): 91.41% (UV at 254 nm)/MS: 830.6 [M+H]; Retention time: 3.777 min.1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.87 (t, J = 8.2 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 5.14 (dd, J = 13.3, 4.8 Hz, 2H), 4.71 (s, 2H), 4.44 (q, J = 16.9 Hz, 2H), 3.74 (d, J = 12.3 Hz, 4H), 3.64 (s, 1H), 3.14 (d, J = 9.6 Hz, 4H), 2.94 ^ 2.84 (m, 1H), 2.78 (d, J = 18.7 Hz, 1H), 2.51 (d, J = 13.7 Hz, 1H), 2.38 (s, 4H), 2.24 (s, 5H), 2.10 (d, J = 19.1 Hz, 5H), 1.99 (s, 2H), 1.86 (s, 4H), 1.60 (s, 6H). Compound A164. (S)-3-(1'-(((1r,4S)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

,2- a]quinazolin-5(7H)-one (Intermediate 3) [0718] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (650 mg, 1 eq, 1.71 mmol) in dry DCM (10.00 mL) was added triethylamine (17.3 mg, 0.1 eq, 171 μmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then, a solution of NaBH3CN (312 mg, 3 eq, 5.13 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford 4-chloro-10-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (300 mg, 610 μmol, 35.6%) as a yellow solid. LC purity (0.1% FA): 77.33% (UV at 254 nm)/MS: 492.4 [M +H]; Retention time: 0.803 min. Synthesis of 4-chloro-10-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 4) [0719] The product 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (398 mg, 1 eq, 809 μmol) was purified by SFC (supercritical CO2/EtOH as eluent) to afford 4-chloro-10-(1-((1r,4r)-4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 203 μmol, 25.1%) as a yellow solid. LC purity (0.1%TFA): 92.53% (UV at 254 nm)/MS: 492.7 [M+H]; Retention time: 0.553 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 5) [0720] To a mixture of 4-chloro-10-(1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (22.0 mg, 1 eq, 44.7 μmol) in dry DCM (6.00 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (19.0 mg, 1 eq, 44.7 μmol) at 0 °C. The mixture was stirred for 3 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford (1r,4r)-4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (20 mg, 40.8 μmol, 91.3%). as a yellow solid. LC purity (0.1%TFA): 74.53% (UV at 254 nm)/MS: 490.2 [M+H]; Retention time: 0.853 min. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine- 1-carboxylate (Intermediate 7) [0721] To a mixture of (R)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (14.5 mg, 1 eq, 40.8 μmol) in dry DCM (4.00 mL) was added triethylamine (250 μg, 0.05 eq, 2.47 μmol) at 25 °C stirred for 0.5 h. Then, a solution of (1r,4r)-4- (4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (20 mg, 1 eq, 40.8 μmol) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was added NaBH3CN (7.45 mg, 3 eq, 122 μmol) and stirred at 25 °C for 16 h. The mixture was concentrated under vacuum, The resulting residue was purified by reverse-phase chromatography to afford (R)-3-(1'-(((1r,4R)-4-(4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.01 mg, 2.22 μmol, 5.43%, 91.42% Purity) as a white solid.LC purity (0.1% FA): 91.41% (UV at 254 nm)/MS: 830.6 [M+H]; Retention time: 3.777 min.1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.7 Hz, 1H), 8.00 (s, 1H), 7.86 (t, J = 8.2 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 9.1 Hz, 2H), 5.14 (dd, J = 13.9, 6.0 Hz, 2H), 4.70 (s, 2H), 4.46 (t, J = 13.3 Hz, 2H), 3.68 (d, J = 12.7 Hz, 4H), 3.63 (s, 2H), 3.12 (s, 4H), 2.83 (dd, J = 41.0, 15.4 Hz, 2H), 2.25 (d, J = 12.4 Hz, 5H), 2.13 (d, J = 19.6 Hz, 10H), 1.74 (d, J = 19.8 Hz, 2H), 1.60 (s, 6H), 1.31 (d, J = 16.1 Hz, 3H). Compound A165. (S)-3-(1'-((4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

ynt es s of met y -(((tert- uty met y s y )oxy)met y ) cyc o[ . . ] eptane- -car oxylate (Intermediate2) [0722] To a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate (900 mg, 1.0 eq, 4.88 mmol) and Imidazole (998 mg, 3.0 eq, 14.7 mmol) in DCM (2.00 mL) was added tert- butyldimethylchlorosilane (1.47 g, 1.63 mL, 2.0 eq, 9.77 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 15 h in N2. TLC showed work. The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptane-1-carboxylate (760 mg, 2.5 mmol, 51%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 3.57-3.58 (m, 5H), 1.81-1.85 (m, 2H), 1.54-1.59 (m, 4H), 1.42 (s, 2H), 1.23-1.27 (m, 2H), 0.81 (s, 9H), -0.022--0.085 (m, 6H). Synthesis of (4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptan-1-yl)methanol (Intermediate3) [0723] To a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptane-1- carboxylate (500 mg, 1.0 eq, 1.68 mmol) in THF (20.00 mL) was added aluminum lithium hydride (63.6 mg, 1.0 eq, 1.68 mmol) at 25 °C, The reaction mixture was stirred at 50 °C for 1.5 h in N2. TLC showed work. The reaction was purified by column chromatography on silica gel (100-200 mesh size) using petroleum ether/EtOAc (50:1-20:1) as eluent to give (4-(((tert- butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptan-1-yl)methanol (310 mg, 1.15 mmol, 68.4%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.29-4.31 (m, 2H), 3.24-3.44 (m, 7H), 1.50- 1.52 (m, 3H), 0.83-0.84 (m, 12H), 0.08-0.19 (m, 6H). Synthesis of 10-(1-((4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptan-1- yl)methyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate5) [0724] To a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptan-1- yl)methanol (320 mg, 1.0 eq, 1.18 mmol) in DCM (20.00 mL) was added Dess-Martin periodinane (502 mg, 1.0 eq, 1.18 mmol) at 25 °C, The reaction mixture was stirred at 25 °C for 1.5 h in N2. TLC showed work. The reaction was filtered and concentrated to give 4-(((tert- butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptane-1-carbaldehyde (636 mg crude), The crude dissolve in MeOH (2.00 mL) were added 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2- a]quinazolin-5(7H)-one (300 mg, 1.0 eq, 790 μmol) and sodium cyanoborohydride (149 mg, 3.0 eq, 2.37 mmol) at 25 °C, The reaction mixture was stirred at 25 °C for 1.5 h in N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give (200 mg, 316.3 μmol, 40%) as a yellow oil. LC purity (0.1% FA): 44.39% (UV at 254 nm)/MS: 649.3 [M + OH]; Retention time: 1.313 min. Synthesis of 4-chloro-10-(1-((4-(hydroxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)piperidin-4- yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate6) [0725] To a solution of 10-(1-((4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.2.1]heptan-1- yl)methyl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (200 mg, 1.0 eq, 349 μmol) in MeOH (2.00 mL) was added 2.0 M HCl (2.0 mL). The reaction mixture was stirred at 25 °C for 1 h in N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give 4-chloro-10-(1-((4- (hydroxymethyl)bicyclo[2.2.1]heptan-1-yl)methyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (110 mg, 212 μmol, 60.7 %) as a white solid. LC purity (0.1% FA): 47.89% (UV at 254 nm)/MS: 518.2 [M +H]; Retention time: 1.692 min. Synthesis of (4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)methyl methanesulfonate (Intermediate 7) [0726] To a solution of 4-chloro-10-(1-((4-(hydroxymethyl)bicyclo[2.2.1]heptan-1- yl)methyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (110 mg, 1.0 eq, 212 μmol) and TEA(10.8.8 mg, 5.0 eq, 1.06 mmol) in DCM (2.00 mL) was added MsCl (120.8 mg, 5.0 eq, 1.06 mmol). The reaction mixture was stirred at rt for 1 h in N2. The mixture was diluted with water (10 mL), extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to give 4-((4-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)bicyclo[2.2.1]heptane-1-carbaldehyde (143.0 mg, crude) as a white solid.no need purified and used next step directly. LC purity (0.1% FA): 27.77 % (UV at 254 nm)/MS: 536.3 [M-MsCl+Cl]; Retention time: 1.023 min. Synthesis of (S)-3-(1'-((4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate S-3007) [0727] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (143 mg, 1.2 eq, 403 μmol) and (4-((4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)bicyclo[2.2.1]heptan-1-yl)methyl methanesulfonate (200 mg, 1.0 eq, 335 μmol) in DMF (5.00 mL). potassium iodide (55.7 mg, 1.0 eq, 335 μmol) and sodium bicarbonate (141 mg, 5.0 eq, 1.68 mmol) were added. The reaction mixture was stirred at 110 °C for 16.0 h in N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 x 3 mL), The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give (S)-3-(1'-((4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)methyl)- 6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.98 mg, 4.53 μmol, 1.35%, 97.45% Purity), as a white solid. LC purity (0.1% FA): 97.45% (UV at 254 nm)/MS: 855.4 [M+H]; Retention time: 9.23 min.1H NMR (400 MHz, MeOD-d4) δ 8.42- 8.44 (m, 1H), 7.97 (s, 1H), 7.84-7.89 (m, 1H), 7.58-7.68 (m, 2H), 7.34-7.39 (m, 3H), 5.11-5.15 (m, 1H), 4.58 (s, 2H), 4.39-4.42 (m, 1H), 3.62-3.63 (m, 1H), 3.47-3.48 (m, 1H), 2.78-3.13 (m,8H), 1.98-2.64 (m, 14H), 1.73-1.79(m, 6H), 1.51-1.59 (m, 10H), 1.40 (s, 2H). Compound A166. (S)-3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0728] To a solution of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidine-4-carbaldehyde (20 mg, 1 eq, 0.04 mmol) in MeOH (1 mL) were added potassium acetate (13.1 mg, 3 eq, 0.134 mmol), (S)-3-(1'-(azetidin-3-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (18.3 mg, 1.0 eq, 0.045 mmol), NaCNBH3 (4.21 mg, 1.5 eq, 0.067 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The crude product was purified by prep-HPLC (0.1% TFA in CH3CN and H2O) from 22% to 35% to get (S)-3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-4-yl)methyl)azetidin-3-yl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.04 mg, 0.002 mmol, 4.39%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 842.5 [M+H]. Retention time: 0.902 min. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.68-7.60 (m, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.09 (d, J = 8.8 Hz, 1H), 4.56 (s, 2H), 4.38 (d, J = 17.1 Hz, 2H), 4.22 (d, J = 17.1 Hz, 2H), 3.84 (s, 2H), 3.19 (s, 2H), 2.91 (s, 2H), 2.75 (d, J = 10.2 Hz, 2H), 2.67 (s, 1H), 2.60 (d, J = 10.6 Hz, 2H), 2.43-2.36 (m, 1H), 2.01 (s, 4H), 1.90 (s, 4H), 1.79 (s, 8H), 1.72 (s, 6H), 1.37 (d, J = 11.0 Hz, 2H). Compound A167. (S)-3-(1'-(1-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)azetidine-3-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[1,2- a]quinazolin]-5'-one (Intermediate 2) [0729] To a solution of 4'-chloro-9'-(4-hydroxycyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (36.0 mg, 1 eq, 82.8 μ mol) in DCM (5mL) was added DMP (176.0 mg, 5 eq, 414 μmol). The mixture was stirred at 0 °C for 2 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The crude product was purified by Prep-TLC (DCM:MeOH=10:1). The product4'-chloro- 9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (12.0 mg, 27.7 μmol, 33.5%) was obtained as yellow solid. LC purity (0.1% FA): 44.77 % (UV at 254 nm)/MS: 433.2 [M +H]; Retention time: 1.623 min. Synthesis of (S)-3-(1'-(1-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)azetidine-3-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0730] To a solution of (S)-3-(1'-(azetidine-3-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (18.2 mg, 1.5 eq, 41.6 μmol) in MeOH (1 mL) was added TEA (8.4 mg, 11.6 μL, 3 eq, 83.2 μmol) after 20 min, was added 4'- chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (12.0 mg, 1 eq, 27.7 μmol). After 20min, NaBH3CN (5.2 mg, 3 eq, 83.2 μmol) was added. The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was extracted with DCM:MeOH= 10:1, dried over Na2SO4, concentrated. The crude product was purified by Prep-HPLC. The product (S)-3-(1'-(1-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)azetidine-3-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.0 mg, 1.08 μmol, 3.91%, 92.71% Purity) was obtained as white solid. LC purity (0.1% FA): 92.71% (UV at 254 nm)/MS: 855.6 [M+H]; Retention time: 5.087 min.1H NMR (400 MHz, MeOD) δ 8.40 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.74 (d, J = 16.0 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.51 ^ 7.33 (m, 3H), 5.14 (m, J = 6.1 Hz, 3H), 4.68 (s, 2H), 4.47 ^ 4.39 (m, 3H), 3.61 (m, J = 22.0 Hz, 2H), 3.48 (m, J = 1.7 Hz, 1H), 2.90 (m, 3H), 2.77 (d, J = 19.4 Hz, 1H), 2.65 ^ 2.15 (m, 6H), 2.02 (m, J = 6.3 Hz, 6H), 1.78 (dd, J = 62.9, 16.3 Hz, 12H), 1.37 (m, J = 64.0 Hz, 3H). Compound A168. (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Compound A169. (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3-P1 and Intermediate 3- P2 ) [0731] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (1.00 g, 1 eq, 2.38 mmol) in MeOH (10 mL) were added 4- (hydroxymethyl)cyclohexan-1-one (916 mg, 3 eq, 7.14 mmol), triethylamine (723 mg, 3 eq, 7.14 mmol) and sodium cyanotrihydroborate (299 mg, 2 eq, 4.76 mmol). The mixture was stirred at 60 °C for 16 h. LCMS indicated completion of reaction. The mixture was added H2O (50 mL), extracted with EA (40 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 4'-chloro-10'-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (700 mg, 1.32 mmol, 55.2%) as white oil. After purification by SFC, 4'- chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (3-P1, 150 mg, 0.28 mmol) as white oil and 4'-chloro-10'-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (3-P2, 150 mg, 0.28 mmol) as white oil were obtained. Synthesis of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4-P1 and Intermediate 4-P2) [0732] To a solution of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (150 mg, 1 eq, 0.28 mmol) in DCM (5 mL) was added DMP (179 mg, 1.5 eq, 423 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to afford 4-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (4-P1, 135 mg, 0.25 mmol, 90%) as white solid. LC purity (0.03%TFA): 94.79% (UV at 254 nm)/MS: 530.4 [M+H]; Retention time: 1.283 min. [0733] 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (128 mg, 0.24 mmol, 85.1%) (4-P2) was prepared according to the same method as 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (4-P1). LC purity (0.03%TFA): 96.62% (UV at 254 nm)/MS: 530.4 [M+H]; Retention time: 1.239 min. Synthesis of (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0734] To a mixture of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (4-P2, 40 mg, 1 eq, 75.5 μmol) ， (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (32.2 mg, 1.2 eq, 90.5 μmol) in DMF (3 mL) was potassium acetate (22.2 mg, 3 eq, 226 μmol) and NaCNBH3 (9.48 mg, 2 eq, 151 μmol). then stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1% FA) from 15% to 30% to afford (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (A168, 25.0 mg, 27.7 μmol, 36.7 %) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 869.4 [M+H]; Retention time: 1.232 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 7.86-7.77 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.41-7.18 (m, 3H), 5.13-5.08 (m, 5.1 Hz, 1H), 4.66 (s, 2H), 4.42-4.22 (m, 2H), 3.29-2.85 (m, 11H), 2.28-1.52 (m, 29H), 1.29-1.04 (m, 3H). Synthesis of (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0735] To a mixture of 4-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (135 mg, 1 eq, 0.25 mmol)， (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6- dione (121 mg, 1.3 eq, 0.34 mmol) in DMF (3 mL) were added potassium acetate (83.3 mg, 3.3 eq, 0.86 mmol) and NaCNBH3 (35.6 mg, 2.2 eq, 0.56 mmol), then stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 15% to 30% to afford (S)-3-(1'-((4-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (A169, 30 mg, 32.9 μmol, 11.6%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 869.4 [M+H]; Retention time: 1.167 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.44 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.87-7.72 (m, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 5.11-5.06 (m, 1H), 4.53 (s, 2H), 4.40-4.19 (m, 2H), 3.17-3.05 (m, 3H), 2.96-2.79 (m, 3H), 2.76-2.55 (m, 2H), 2.44-2.21 (m, 6H), 2.10-1.40 (m, 27H), 1.23 (s, 2H). Compound A170. (3S)-3-(1'-((4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y - p y - , - - - [0736] To a mixture of 6-bromoindolin-2-one (9.00 g, 1 eq, 42.4 mmol) in THF (100 mL) was added LiHMDS (23.40 g, 140 mL, 1.00 molar, 3.3 eq, 140 mmol) at -78 °C for 30 min. After adding 1,5-dibromopentane (9.76 g, 5.78 mL, 1 eq, 42.4 mmol) for another 30 min at -78 °C. The solution was stirred at 25 °C for 16 h. LCMS indicated finished. After completion, the reaction mixture was quenched with sat. NH4Cl solution and extracted with ethyl acetate (3 X 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @100 mL/min). Compound 6'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (10 g, 30.7 mmol, 72.4%) was obtained as a yellow solid. LC purity (0.1% FA): 86.12% (UV at 254 nm)/MS: 282.0 [M+H]; Retention time: 1.815 min. Synthesis of tert-butyl 5-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (Intermediate 5) [0737] To a mixture of 6'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (2.00 g, 1 eq, 7.14 mmol) in 1,4-dioxane (25.0 mL) and water (3.00 mL) were added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.65 g, 1.2 eq, 8.57 mmol) and potassium phosphate, tribasic (3.03 g, 1.18 mL, 2 eq, 14.3 mmol) and PdCl2(dppf) (522 mg, 0.1 eq, 714 μmol). The solution was stirred at 80 °C for 4 h. LCMS indicated finished. The reaction mixture was poured by addition H2O (100 mL), and extracted with DCM (3 X 50 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~17% ethyl acetate/petroleum ether gradient @60 mL/min). Compound tert-butyl 5-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)-3,6- dihydropyridine-1(2H)-carboxylate (2.70 g, 6.18 mmol, 86.6%) was obtained as a red oil. LC purity (0.1%FA): 87.57% (UV at 254 nm)/MS: 383.2 [M+H]; Retention time: 2.005 min. Synthesis of tert-butyl 3-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (Intermediate 6) [0738] To a mixture of tert-butyl 5-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.00 g, 1 eq, 2.61 mmol) in MeOH (15.0 mL) was added Pd/C (2.78 g, 10% Wt, 1 eq, 2.61 mmol). The solution was stirred at 25 °C for 16 h under H2 atmosphere. LCMS indicated finished. The reaction mixture was filtered and concentrated under reduced pressure. tert-Butyl 3-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine-1-carboxylate (1.00 g, 2.47 mmol, 94.4%) was obtained as a yellow oil. LC purity (0.1%FA): 94.88% (UV at 254 nm)/MS: 383.2 [M-H]; Retention time: 2.006 min. Synthesis of tert-butyl 3-(1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'-indolin]-6'- yl)piperidine-1-carboxylate (Intermediate 8) [0739] To a mixture of tert-butyl 3-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine-1- carboxylate (1.00 g, 1 eq, 2.60 mmol) in ACN (15.0 mL) were added 2-chloro-6-fluorobenzonitrile (809 mg, 2 eq, 5.20 mmol) and Cs2CO3 (1.69 g, 2 eq, 5.20 mmol). The solution was stirred at 95 °C for 5 h. LCMS indicated finished. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @60 mL/min). Compound tert-butyl 3-(1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-6'-yl)piperidine-1-carboxylate (800 mg, 1.52 mmol, 58.3%) was obtained as a yellow oil. LC purity (0.1%FA): 98.52% (UV at 254 nm)/MS: 464.2 [M+H-56]; Retention time: 2.156 min. Synthesis of tert-butyl 3-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-6'-yl)piperidine-1-carboxylate (Intermediate 9) [0740] To a mixture of tert-butyl 3-(1'-(3-chloro-2-cyanophenyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-6'-yl)piperidine-1-carboxylate (800 mg, 1 eq, 1.54 mmol) in DMSO (10 mL) were added K2CO3 (425 mg, 2 eq, 3.08 mmol) and H2O2 (2.22 g, 2 mL, 42.4 eq, 65.3 mmol). The solution was stirred at 60 °C for 3 h. LCMS indicated finished. The reaction mixture was poured by addition H2O (150 mL), and extracted with DCM (3 X 30 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @60 mL/min). Compound tert- butyl 3-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl)piperidine- 1-carboxylate (689 mg, 1.19 mmol, 77.1%) was obtained as a white solid. LC purity (0.1%FA): 92.6% (UV at 254 nm)/MS: 538.2 [M+H]; Retention time: 1.744 min. Synthesis of tert-butyl 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidine-1-carboxylate (Intermediate 10) [0741] To a mixture of tert-butyl 3-(1'-(2-carbamoyl-3-chlorophenyl)-2'-oxospiro[cyclohexane- 1,3'-indolin]-6'-yl)piperidine-1-carboxylate (689 mg, 1 eq, 1.28 mmol) in toluene (15 mL) was added TsOH (731 mg, 3 eq, 3.84 mmol). The solution was stirred at 145 °C for 16 h under Ar atmosphere. LCMS indicated finished. The reaction mixture was poured by addition aqueous solution of NaHCO3 (15 mL x 3) and extracted with DCM (3 X 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/DCM gradient @60 mL/min). Compound tert-butyl 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidine-1-carboxylate (500 mg, 961 μmol, 75.1%) was obtained as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.89 – 7.81 (m, 2H), 7.65 (dd, J = 7.9, 0.8 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 3.21 ^ 3.09 (m, 2H), 2.75 (ddd, J = 18.0, 15.2, 7.3 Hz, 2H), 2.04 (dd, J = 17.3, 7.7 Hz, 5H), 1.88 (dd, J = 23.9, 11.1 Hz, 5H), 1.75 (dt, J = 19.0, 8.1 Hz, 5H). Synthesis of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 12) [0742] To a mixture of 4'-chloro-10'-(piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (430 mg, 1 eq, 1.024 mmol) in MeOH (10 mL) were added 4- (hydroxymethyl)cyclohexan-1-one (196.9 mg, 1.5 eq, 1.536 mmol) and tetraisopropyl titanate (2.00 mL) at 100 °C under microwave for 50 min. After adding sodium cyanoborohydride (193.0 mg, 179 μL, 3 eq, 3.072 mmol). The solution was stirred at 100 °C under microwave for another 30 min. LCMS indicated finished. The reaction mixture was poured by sat. NaHCO3 solution (50 mL) and extracted with DCM (3 X 15 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~13% MeOH/DCM gradient @50 mL/min). Compound 4'-chloro-10'-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (160 mg, 295 μmol, 28.8%) was obtained as a yellow solid. LC purity (0.1%FA): 98.06% (UV at 254 nm)/MS: 532.3 [M+H]; Retention time: 0.992 min. Synthesis of 4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 13) [0743] To a mixture of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (167.00 mg, 1 eq, 313.83 μmol) in DCM (10 mL) was added DMP (1.33 g, 10 eq, 3.1383 mmol). The solution was stirred at 0 °C for 1 h. LCMS indicated finished. The reaction mixture was poured by addition NH4Cl aqueous solution (20 mL), and extracted with DCM (3 X 5 mL). The combined organic layers were washed with brine (15.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC( DCM : MeOH = 10 : 1). Compound 4-(3-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1- carbaldehyde (100 mg, 158 μmol, 50.2%) was obtained as a yellow solid. LC purity (0.1%FA): 83.55% (UV at 254 nm)/MS: 530.3 [M+H]; Retention time: 0.968 min. Synthesis of (3S)-3-(1'-((4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0744] A mixture of 4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (60 mg, 1 eq, 113 μmol) in MeOH (5.00 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (60.3 mg, 1.5 eq, 170 μmol) and TEA (0.10 mL) and HOAc (0.20 mL) for 30 min. After added sodium cyanoborohydride (21.3 mg, 19.8 μL, 3 eq, 340 μmol). The solution was stirred at 25 °C for 16 h. LCMS indicated finished. The reaction mixture was concentrated under reduced pressure. Purified by prep-HPLC to afford compound (3S)-3-(1'-((4-(3-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (21.44 mg, 24.57 μmol, 21.7 %) was obtained as a white solid. LC purity (0.1%FA): 99.63% (UV at 254 nm)/MS: 869.7 [M+H]; Retention time: 4.244 min.1H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.01 (s, 1H), 7.89 – 7.81 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.37 (dd, J = 7.7, 4.2 Hz, 2H), 7.33 (t, J = 6.6 Hz, 1H), 5.12 (dd, J = 13.2, 5.2 Hz, 1H), 4.56 (s, 2H), 4.40 (d, J = 12.0 Hz, 1H), 3.53 (dd, J = 23.0, 14.0 Hz, 2H), 3.26 ^ 3.11 (m, 3H), 3.08 ^ 2.97 (m, 3H), 2.95 ^ 2.84 (m, 1H), 2.81 ^ 2.73 (m, 1H), 2.49 (dd, J = 13.0, 4.6 Hz, 1H), 2.33 (d, J = 6.9 Hz, 1H), 2.09 (ddd, J = 42.6, 20.7, 11.4 Hz, 16H), 1.94 ^ 1.60 (m, 15H), 1.13 (t, J = 12.3 Hz, 1H). Compound A171. 4-(4-((1r,4S)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)piperazin-1-yl)-N-((S)- 2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

1,2-

a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylate (Intermediate 3) [0745] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (309 mg, 1 eq, 814 μmol) in MeOH (2 mL) was added TEA (247 mg, 340 μL, 3 eq, 2.44 mmol). After 20 min, was added ethyl (1r,4r)-4-formylcyclohexane-1-carboxylate (150 mg, 1 eq, 814 μmol). After 20 min, NaBH3CN (153 mg, 3 eq, 2.44 mmol) was added. The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was extracted with DCM:MeOH= 10:1, dried over Na2SO4, concentrated. The crude product was purified by Prep- TLC (DCM:MeOH= 10:1 ). The product ethyl (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylate (301 mg, 549 μmol, 67.5%) was obtained as yellow solid. LC purity (0.1% FA): 81.04% (UV at 254 nm)/MS: 548.4 [M +H]; Retention time: 0.960 min. Synthesis of (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylic acid (Intermediate 4) [0746] To a solution of ethyl (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylate (50 mg, 1 eq, 91.2 μmol) in 1,4-dioxane (1 mL) was added HCl (0.05 mL). The mixture was stirred at 90 °C for 16 h. LCMS indicated completion of reaction. The mixture was concentrated to afford a crude product. The product (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylic acid (47.0 mg, 90.4 μmol, 99.1%) was obtained as white solid. LC purity (0.1% FA): 63.50%. (UV at 254 nm)/MS: 520.3 [M +H]; Retention time: 1.030 min. Synthesis of 4-(4-((1r,4S)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)piperazin-1-yl)-N-((S)-2,6- dioxopiperidin-3-yl)-2-fluorobenzamide [0747] To a solution of (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylic acid (25.0 mg, 1 eq, 48.1 μmol) in DMF (1 mL) were added (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1- yl)benzamide (19.3 mg, 1.2 eq, 57.7 μmol) and DIEA (62.1 mg, 83.7 μL, 10 eq, 481 μmol), after 10 min was added BOP (17.0 mg, 0.8 eq, 38.5 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was extracted with EA, dried over Na2SO4, concentrated. The crude product was purified by Prep-HPLC. The product4-(4-((1r,4S)-4-((4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)cyclohexane-1-carbonyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2- fluorobenzamide (9.02 mg, 10.3 μmol, 21.3%, 95.08% Purity) was obtained as yellow solid.LC purity (0.1% FA): 95.08%,(UV at 254 nm)/MS: 836.6 [M+H]; Retention time: 4.427 min. 1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.90 – 7.83 (m, 1H), 7.78 (t, J = 9.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 6.85 (dd, J = 8.9, 2.5 Hz, 1H), 6.74 (dd, J = 15.5, 2.3 Hz, 1H), 4.79 (dd, J = 13.3, 5.9 Hz, 2H), 3.87 (s, 1H), 3.75 (m, J = 4.7 Hz, 4H), 3.39 (d, J = 21.1 Hz, 4H), 3.10 ^ 2.53 (m, 6H), 2.46 (s, 3H), 2.33 ^ 2.16 (m, 2H), 2.12 (s, 2H), 2.01 (m, J = 19.1 Hz, 6H), 1.85 (d, J = 13.3 Hz, 2H), 1.59 (s, 6H), 1.13 (d, J = 12.8 Hz, 2H). Compound A172. (S)-3-(1'-(2-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidine-4-carbaldehyde (Intermediate 2) [0748] To a solution of 4'-chloro-10'-(4-(hydroxymethyl)piperidin-1-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (70 mg, 1 eq, 156 μmol) in DCM (2 mL) was added DMP (198 mg, 3 eq, 467 μmol). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (30 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 60 of EtOAc in PE) to afford 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidine-4-carbaldehyde (60 mg, 134 μmol, 86.1%) as a colorless oil. LC purity (0.1% FA): 38.3% (UV at 254 nm)/MS: 448.2 [M+H]; Retention time: 1.65 min. Synthesis of (S)-3-(1'-(2-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0749] To a solution of 1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidine-4-carbaldehyde (30 mg, 1 eq, 67.0 μmol) in MEOH (2 mL) were added (S)-3-(6- oxo-1'-(2-azaspiro[3.5]nonan-7-yl)-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (38.5 mg, 1.2 eq, 80.4 μmol), potassium acetate (19.7 mg, 3 eq, 201 μmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (6.31 mg, 5.85 μL, 1.5 eq, 100 μmol) was added to above mixture. The mixture was stirred at 25 °C for 1 h.. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 15% to 30% to afford (S)-3- (1'-(2-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin- 4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.65 mg, 2.48 μmol, 3.71%) as a white solid. LC purity (0.1% FA): 85.29% (UV at 254 nm)/MS: 910.5 [M+H]; Retention time: 1.11 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 2H), 7.48 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.08-5.01 (m, 1H), 4.52-4.41 (m, 2H), 4.37 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 3.78 (d, J = 11.6 Hz, 3H), 2.98-2.85 (m, 5H), 2.82 (d, J = 10.8 Hz, 2H), 2.73-2.53 (m, 2H), 2.59 (d, J = 16.0 Hz, 1H), 2.42-2.31 (m, 1H), 2.34-2.26 (m, 2H), 2.22-2.01 (m, 3H), 1.99-1.72 (m, 3H), 1.83- 1.78 (m, 8H), 1.76 -1.59 (m, 10H), 1.42-1.33 (m, 2H), 1.26-1.12 (m, 4H). [0750] The following compounds were prepared in a manner analogous to Compound A172. Compound A173. (S)-3-(1'-(7-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 910.5 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.63 (t, J = 6.8 Hz, 2H), 7.48 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.08-5.01 (m, 1H), 4.55-4.45 (m, 2H), 4.38 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 3.79 (d, J = 11.6 Hz, 3H), 2.89-2.79 (m, 1H), 2.76 (t, J = 11.6 Hz, 4H), 2.70-2.58 (m, 2H), 2.25-2.01 (m, 3H), 2.13-1.99 (m, 2H), 1.99-1.82 (m, 3H), 1.94-1.81 (m, 8H), 1.71-1.52 (m, 11H), 1.50-1.32 (m, 7H), 1.23-1.02 (m, 2H). Compound A174. (S)-3-(1'-(1-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 870.6 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.90-7.78 (m, 1H), 7.69- 7.59 (m, 2H), 7.48 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 5.14-5.02 (m, 1H), 4.53 (d, J = 9.8 Hz, 2H), 4.43-4.15 (m, 2H), 3.80 (d, J = 11.6 Hz, 2H), 2.89 (s, 4H), 2.81-2.73 (m, 2H), 2.67 (d, J = 1.7 Hz, 1H), 2.62- 2.54 (m, 1H), 2.33 (s, 1H), 2.22 (d, J = 11.1 Hz, 2H), 2.16 (d, J = 5.9 Hz, 2H), 1.99 (s, 4H), 1.90-1.81 (m, 8H), 1.70 (d, J = 10.6 Hz, 8H), 1.45 (d, J = 9.9 Hz, 2H), 1.24 (s, 4H). Compound A175. (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperazin-1-yl)azetidine-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

ane-

1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 2) [0751] To a solution of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (300 mg, 1.0 eq, 22 μmol) in 1,4-dioxane (4.00 mL) were added 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (165 mg, 0.9 eq, 649 μmol), potassium phosphate, tribasic (460 mg, 179 μL, 3.0 eq, 2.16 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride (52.8 mg, 0.1 eq, 72.2 μmol). The mixture was stirred at 80 °C for 2 h under N2. LCMS showed that target product was found. The mixture was concentrated to afford a crude product. The crude product was dissolved in DMF filtered over celite and concentrated. The crude product was purified by flash chromatography (eluted with CH3CN in H2O (0.1% FA) from 0% to 100% ) to afford 4'-chloro-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (75.0 mg, 0.09 mmol, 13.3%) as a white solid. LC purity (0.1% FA): 59.42% (UV at 254 nm)/MS: 463.2[M+H]; Retention time: 2.099 min. Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)piperazine-1-carboxylate (Intermediate 4) [0752] To a solution 4'-chloro-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (70 mg, 1.0 eq, 151 μmol) in CH3CN (4.00 mL) were added cupric acetate, monohydrate (30.2 mg, 16.1 μL, 1.0 eq, 151 μmol), tert- butyl piperazine-1-carboxylate (56.3 mg, 2.0 eq, 303 μmol) and trimethylamine (45.9 mg, 63.2 μL, 3.0 eq, 454 μmol). The mixture was stirred at 60 °C for 2 h under N2. LCMS showed that target product was found. The mixture was extracted with DCM/MeOH=10:1 (2x30 mL), dried over Na2SO4, concentrated. The crude product was purified by Prep-TLC (PE/EA=2:1) to give tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperazine-1-carboxylate (47.0 mg, 78 μmol, 52% ) as a yellow oil. LC purity (0.1% FA): 87.20% (UV at 254 nm)/MS: 521.1 [M+H]; Retention time: 2.047 min. Synthesis of 4'-chloro-9'-(piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (Intermediate 5) [0753] To a solution of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperazine-1-carboxylate (47.0 mg, 1.0 eq, 90.2 μmol) in DCM (3.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 1 h under N2. LCMS showed that target product was found. The mixture concentrated to give 4'-chloro-9'-(piperazin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (47.0 mg, 0.10 mmol, 120% ) as a yellow oil. LC purity (0.1% FA): 93.30% (UV at 254 nm)/MS: 421.2 [M+H]; Retention time: 0.323 min. Synthesis of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperazin-1-yl)azetidine-1-carboxylate (Intermediate 7) [0754] To a solution of 4'-chloro-9'-(piperazin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (29.0 mg, 1.0 eq, 68.9 μmol) in MeOH (3.00 mL) was added trimethylamine (20.9 mg, 28.8 μL, 3.0 eq, 207 μmol). After 30 min, tert-butyl 3-oxoazetidine-1-carboxylate (70.8 mg, 6.0 eq, 413 μmol) was added. After 15 min, sodium cyanoborohydride (43.3 mg, 40.1 μL, 10 eq, 689 μmol) was added. The mixture was stirred at 25 °C for 6 h under N2. LCMS showed that target product was found. The mixture was extracted with DCM/MeOH=10:1 (2x30 mL), dried over Na2SO4, concentrated. The crude product was purified by Prep-TLC (DCM/MeOH=10:1) to give tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperazin-1-yl)azetidine-1-carboxylate (36.0 mg, 46 μmol, 66% ). LC purity (0.1% FA):73.23% (UV at 254 nm)/MS: 576.1 [M+H]; Retention time: 1.323 min. Synthesis of 9'-(4-(azetidin-3-yl)piperazin-1-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 8) [0755] To a solution of tert-butyl 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperazin-1-yl)azetidine-1-carboxylate (36 mg, 1.0 eq, 62 μmol) in DCM (3.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 1 h under N2. LCMS showed that target product was found. The reaction liquid is directly pulled dry by the oil pump to give 9'- (4-(azetidin-3-yl)piperazin-1-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (36.0 mg, 56 μmol, 90% ). LC purity (0.1% FA):52.56% (UV at 254 nm)/MS:476.3 [M+H]; Retention time: 0.883 min. Synthesis of (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperazin-1-yl)azetidine-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0756] To a solution of 9'-(4-(azetidin-3-yl)piperazin-1-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (20 mg, 1.0 eq, 42.0 μmol) in DCM (5.00 mL) was added trimethylamine (12.8 mg, 17.6 μL, 3.0 eq, 126 μmol). After 30 min, (S)-3-(6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (14.9 mg, 1.0 eq, 42.0 μmol) in trimethylamine (12.8 mg, 17.6 μL, 3.0 eq, 126 μmol) was added. After 15 min, triphosgene (12.5 mg, 7.38 μL, 1.0 eq, 42.0 μmol) was added. The mixture was stirred at 25 °C for 16 h under N2. LCMS showed that target product was found. The mixture was quenched with NH4Cl at 25 °C, extracted with DCM/MeOH=10:1 (20x2 mL), dried over Na2SO4, concentrated. The crude product was purified by Prep-HPLC to give (S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)piperazin-1-yl)azetidine-1-carbonyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.82 mg, 3.29 μmol, 7.83%) as a white solid. LC purity (0.03% TFA in H2O, 0.03% TFA in ACN): 95.05% (UV at 254 nm)/MS: 857.4 [M+H]; Retention time: 1.033 min. 1H NMR (400 MHz, MeOD) δ 8.37 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.42 ^ 7.32 (m, 3H), 7.15 (d, J = 11.0 Hz, 1H), 5.34 (s, 1H), 5.13 (d, J = 13.4 Hz, 2H), 4.66 (s, 2H), 4.51 ^ 4.25 (m, 4H), 4.22 (s, 2H), 3.91 (d, J = 14.6 Hz, 2H), 3.63 (s, 2H), 3.48 (s, 2H), 3.19 (s, 4H), 3.05 (s, 2H), 2.83 (d, J = 25.4 Hz, 2H), 2.51 (d, J = 13.6 Hz, 1H), 2.23 ^ 2.14 (m, 4H), 1.94 (d, J = 8.4 Hz, 4H), 1.83 (s, 4H), 1.60 (s, 2H). Compound A176. (3S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3'-fluoro-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-

spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 4-(4-chloro-5-oxo-5H-spiro[cyclohexane-1,7-indolo[1,2-a]quinazolin]- 9'-yl)-3'-hydroxy-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 3) [0757] To a mixture of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (500 mg, 1 eq, 1.19 mmol) and K2CO3 (493.0 mg, 3 eq, 3.57 mmol) in DMF (10 mL) was added tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (2.4 g, 10 eq, 11.9 mmol) at 0 °C, then heated to 100 °C and stirred for 16 h. LCMS showed the reaction was completed. The reaction was quenched with water and extracted with EA. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1-12:1) to afford tert-butyl 4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-3'-hydroxy-[1,4'- bipiperidine]-1'-carboxylate (480 mg, 775 μmol, 65.1%) as an oil liquid. LC purity (0.1% FA): 46.29% (UV at 254 nm)/MS: 619.4 [M +H]; Retention time: 1.015 min. Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-3'-fluoro-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 4) [0758] To a -78°C solution of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)-3'-hydroxy-[1,4'-bipiperidine]-1'-carboxylate (210 mg, 1 eq, 339 μmol) in DCM (10 mL) was added DAST (76.4 mg, 1.4 eq, 475 μmol). The solution was stirred at room temperature for 16 h. The mixture was quenched with saturated NaHCO3 solution and exacted with DCM. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1-15:1) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-9'-yl)-3'-fluoro-[1,4'-bipiperidine]-1'-carboxylate (170 mg, 274 μmol, 80.7 %) as an oil liquid. LC purity (0.1% FA): 80.34% (UV at 254 nm)/MS: 621.3 [M +H]; Retention time: 1.229 min. Synthesis of 4'-chloro-9'-(3'-fluoro-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 5) [0759] A mixture of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3'-fluoro-[1,4'-bipiperidine]-1'-carboxylate (170 mg, 1 eq, 274 μmol) in DCM (5.0 mL) was added 2,2,2-trifluoroacetic acid (1.5 mL, 274 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to afford 4'-chloro-9'-(3'-fluoro-[1,4'-bipiperidin]-4-yl)- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (130 mg, 249 μmol, 91.2%) as a white solid. LC purity (0.1% FA): 50.87% (UV at 254 nm)/MS: 521.3 [M +H]; Retention time: 0.867 min. Synthesis of (3S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3'-fluoro-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0760] To a mixture of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (27.3 mg, 1 eq, 76.8 μmol) and TEA (23.3 mg, 3 eq, 230 μmol) in DCM (10 mL) was added triphosgene (22.8 mg, 1 eq, 76.8 μmol) and stirred for 0.5 h.4'- chloro-9'-(3'-fluoro-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (40 mg, 1 eq, 76.8 μmol) was added to the mixture and stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction was concentrated under vacuum. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1-10:1) to afford (3S)-3- (1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-3'-fluoro- [1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (11.99 mg, 13.29 μmol, 17.3%) as a white solid. LC purity (0.1% FA): 91.27% (UV at 254 nm)/MS: 902.6 [M +H]; Retention time: 5.319 min.1H NMR (400 MHz, MeOD) δ 8.40 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.82 (dd, J = 18.9, 10.5 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.41 ^ 7.35 (m, 2H), 5.14 (dd, J = 13.1, 5.1 Hz, 2H), 4.69 ^ 4.62 (m, 2H), 4.43 (q, J = 17.0 Hz, 2H), 4.19 (dd, J = 10.2, 4.7 Hz, 1H), 3.88 ^ 3.68 (m, 6H), 3.53 (dt, J = 22.4, 9.4 Hz, 3H), 3.11 (dd, J = 21.4, 10.4 Hz, 5H), 2.95 ^ 2.85 (m, 1H), 2.78 (d, J = 15.5 Hz, 1H), 2.52 (t, J = 11.6 Hz, 1H), 2.28 ^ 2.13 (m, 7H), 2.05 (dd, J = 14.8, 6.2 Hz, 4H), 1.85 (dd, J = 22.0, 10.4 Hz, 9H). Compound A177. (R)-3-(1'-((1-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)azetidin-3-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.90 mg, 3.38 μmol, 4.19%, 98.07% Purity) Synth

es s of ( )- -( -(( -( -( -c oro- -oxo- -sp ro[cyc o exane- , - ndolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)azetidin-3-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0761] To a mixture of (R)-3-(1'-(azetidin-3-ylmethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (34.2 mg, 1 eq, 80.7 μmol) in DMF (3.00 mL) was added triethylamine (4.08 mg, 5.62 μL, 0.5 eq, 40.3 μmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then, a solution of 4'-chloro-10'-(4-oxopiperidin-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (35.0 mg, 1 eq, 80.7 μmol) was added at 25 °C for 16 h. The mixture was added NaBH3CN (14.7 mg, 3 eq, 242 μmol) and stirred at 25 °C for 0.5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated. The resulting residue was purified by reverse-phase chromatography to afford (R)-3-(1'-((1-(1-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-4- yl)azetidin-3-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (2.90 mg, 3.38 μmol, 4.19%, 98.07% Purity) as a white solid. LC purity (0.1% FA): 98.09% (UV at 254 nm)/MS: 842.9 [M+H]; Retention time: 0.893 min.1H NMR (400 MHz, MeOD) δ 8.35 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.1 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 5.15 ^ 5.10 (m, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.49 ^ 4.37 (m, 4H), 4.22 (d, J = 8.2 Hz, 2H), 3.96 (d, J = 12.3 Hz, 2H), 3.73 ^ 3.56 (m, 6H), 3.47 (s, 1H), 2.96 ^ 2.78 (m, 4H), 2.31 (d, J = 13.2 Hz, 2H), 2.16 (d, J = 11.8 Hz, 3H), 2.04 (dd, J = 23.1, 12.7 Hz, 7H), 1.86 (d, J = 7.8 Hz, 4H), 1.70 (s, 5H). [0762] The following compounds were prepared in a manner analogous to Compound A177. Compound A181. (S)-3-(1'-((7-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 910.3 [M+H]; 1H NMR (400 MHz, MeOD) δ 8.35 (d, J = 8.9 Hz, 1H), 7.82 (m, J = 8.3 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.64 (m, J = 12.1 Hz, 2H), 7.42 (d, 1H), 7.35 (d, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.13 (m, J = 12.5 Hz, 3H), 4.69 (s, 1H), 4.44 (d, J = 13.2 Hz, 2H), 4.00 (d, 2H), 3.58 (m, 9H), 3.11 (m, 3H), 2.97 ^ 2.73 (m, 6H), 2.55 ^ 2.42 (m, 1H), 2.36 (m, 1H), 2.24 (s, 5H), 2.06 (m, 6H), 1.87 (m, 8H), 1.75 ^ 1.68 (m, 3H), 1.34 ^ 1.25 (m, 1H). Compound A182. (S)-3-(1'-(7-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 897.5 [M+H]; 1H NMR (400 MHz, MeOD) δ 8.36 (d, J = 8.7 Hz, 1H), 7.83 (t, J = 8.2 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 ^ 7.58 (m, 2H), 7.37 (dd, J = 20.5, 7.7 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.17 ^ 5.11 (m, 1H), 4.57 (s, 2H), 4.41 (q, J = 16.9 Hz, 2H), 3.98 (d, J = 13.3 Hz, 2H), 3.64 (m, 2H), 3.48 (s, 1H), 3.14 ^ 2.79 (m, 12H), 2.49 (dd, J = 13.3, 4.8 Hz, 1H), 2.17 (s, 6H), 2.05 (d, J = 10.2 Hz, 6H), 1.85 (m, J = 15.7 Hz, 12H), 1.73 (m, 2H). Compound A184. (S)-3-(1'-((2-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 911.7 [M+H]; 1H NMR (400 MHz, MeOD) δ = 8.33 (s, 1H), 8.26 (d, J=8.4, 1H), 7.74 (t, J=8.4, 1H), 7.66 (d, J=8.4, 1H), 7.56 ^ 7.50 (m, 2H), 7.29 (q, J=7.6, 2H), 6.91 (d, J=6.8, 1H), 5.04 (dd, J=13.2, 4.8, 2H), 4.51 (d, J=14.8, 8H), 4.33 (q, J=17.2, 2H), 3.92 ^ 3.75 (m, 6H), 2.81 (t, J=12.8, 3H), 2.68 (d, J=13.2, 1H), 2.59 (s, 4H), 2.11 ^ 1.92 (m, 11H), 1.77 (d, J=8.8, 5H), 1.65 ^ 1.47 (m, 9H). Compound A195. (R)-3-(1'-(1-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)azetidin-3-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione. MS: 829.3 [M+H]; 1H NMR (400 MHz, MeOD) δ 8.36 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.36 (dd, J = 20.1, 7.6 Hz, 2H), 7.00 (d, J = 8.9 Hz, 1H), 5.13 (dd, J = 13.4, 5.3 Hz, 1H), 4.57 (s, 2H), 4.41 (q, J = 16.8 Hz, 2H), 3.84 (d, J = 12.4 Hz, 2H), 3.75 (t, J = 7.4 Hz, 2H), 3.63 (s, 1H), 3.25 (s, 2H), 3.12 (s, 1H), 2.95 ^ 2.83 (m, 6H), 2.78 (d, J = 17.9 Hz, 1H), 2.52 (dd, J = 17.7, 12.8 Hz, 2H), 2.17 (s, 1H), 2.07 ^ 1.99 (m, 11H), 1.89 ^ 1.81 (m, 4H), 1.71 (d, J = 15.1 Hz, 2H), 1.50 (d, J = 9.1 Hz, 2H). Compound A198. (S)-3-(1'-(1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-4-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione. MS: 773.3 [M+H]; 1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.92 (t, J = 8.3 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.49 ^ 7.38 (m, 3H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.74 (s, 1H), 4.45 (q, J = 17.2 Hz, 2H), 4.03 (d, J = 12.3 Hz, 2H), 3.78 (d, J = 11.8 Hz, 2H), 3.69 ^ 3.61 (m, 2H), 3.01 ^ 2.75 (m, 3H), 2.48 (ddd, J = 41.0, 20.7, 11.4 Hz, 6H), 2.16 (ddd, J = 34.4, 19.8, 10.4 Hz, 11H), 1.99 ^ 1.86 (m, 5H), 1.69 (d, J = 59.1 Hz, 2H). Compound A178. (S)-4-(4-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidin]-1'-yl)propanoyl)piperazin-1-yl)-N-(2,6- dioxopiperidin-3-yl)-2-fluorobenzamide Syn

y , y , y , q zolin-10- yl)-[1,4'-bipiperidin]-1'-yl)propanoate (Intermediate 3) [0763] The mixture of 10-([1,4'-bipiperidin]-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one (40 mg, 1 eq, 86.4 μmol), tert-butyl 3-bromopropanoate (21.7 mg, 1.2 eq, 104 μmol) and K2CO3 (35.8 mg, 3 eq, 259 μmol) in DMF (3.00 mL) was stirred at 60 °C for 16 h. The mixture was filtered to afford tert-butyl 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidin]-1'-yl)propanoate (30 mg, 50.7 μmol, 58.7 %) and used directly for the next step. LC purity (0.1% FA): 88.26% (UV at 254 nm)/MS: 591.4 [M+H]; Retention time: 0.353 min. Synthesis of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)-[1,4'- bipiperidin]-1'-yl)propanoic acid (Intermediate 4) [0764] To a solution of tert-butyl 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidin]-1'-yl)propanoate (30 mg, 1 eq, 50.7 μmol) was added TFA (1.50 mL) and stirred at 25 °C for 4 h. LCMS showed reaction was completed. The mixture was concentrated in vacuum to afford 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidin]-1'-yl)propanoic acid (25.0 mg, 46.7 μmol, 92.1%) as a light yellow solid. LC purity (0.1% FA): 98.16% (UV at 254 nm)/MS: 535.3 [M+H]; Retention time: 0.793 min. Synthesis of (S)-4-(4-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)-[1,4'-bipiperidin]-1'-yl)propanoyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2- fluorobenzamide [0765] To a mixture of (R)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (20.6 mg, 1.1 eq, 61.7 μmol), 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)-[1,4'-bipiperidin]-1'-yl)propanoic acid (30 mg, 1 eq, 56.1 μmol),2-(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (32.0 mg, 1.5 eq, 84.1 μmol), n-ethyl-N-isopropylpropan-2-amine (58.0 mg, 8 eq, 449 μmol) in DMF (3.00 mL) was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was concentrated. The resulting residue was purified by reverse-phase chromatography to afford (S)-4-(4-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)- [1,4'-bipiperidin]-1'-yl)propanoyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2- fluorobenzamide (3.50 mg, 4.11 μmol, 7.33%) as a white solid. LC purity (0.1% FA): 94.62% (UV at 254 nm)/MS: 738.6 [M+H]; Retention time: 1.697 min.1H NMR (400 MHz, MeOD) δ 8.46 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.81 (t, J = 8.6 Hz, 1H), 7.67 (dd, J = 17.5, 7.5 Hz, 2H), 7.38 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 16.3 Hz, 1H), 3.90 (d, J = 12.6 Hz, 2H), 3.79 (d, J = 5.6 Hz, 4H), 3.69 (d, J = 24.9 Hz, 4H), 3.51 (d, J = 19.5 Hz, 4H), 3.42 (s, 2H), 3.37 (s, 1H), 3.20 (d, J = 25.2 Hz, 6H), 3.05 (s, 2H), 2.82 (dd, J = 12.8, 5.3 Hz, 1H), 2.73 (d, J = 18.6 Hz, 1H), 2.51 (d, J = 11.1 Hz, 2H), 2.21 (dd, J = 31.8, 14.6 Hz, 11H), 1.62 (s, 6H), 1.33 (d, J = 17.2 Hz, 1H). Compound A179. (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of ethyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohex-3-ene-1-carboxylate (Intermediate 3) [0766] To a mixture of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (621.0 mg, 1 eq, 1.49 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (121.2 mg, 0.1 eq, 0.15mmol), potassium phosphate (636.0 mg, 2.0 eq, 2.99 mmol), ethyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (460 mg, 1.5 eq, 1.64 mmol). The mixture was stirred at 80 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (50*2 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-25% of ethyl acetate in petroleum ether) to afford ethyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohex-3-ene-1-carboxylate (584 mg, 0.899 mmol, 60.2%) as a yellow solid. LC purity (0.1%TFA): 75.33% (UV at 254 nm)/MS: 489.1 [M +H]; Retention time: 2.034 min. Synthesis of ethyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexane-1-carboxylate (Intermediate 4) [0767] To a mixture of ethyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohex-3-ene-1-carboxylat (320 mg, 1 eq, 0.654 mmol) in tetrahydrofuran (30 mL) was added 10% Pd/C (32 mg, 0.046 eq, 30 umol), followed by zinc bromide (73.7 mg, 0.5 eq, 0.277 mmol). The mixture was stirred at 25 °C for 4 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum, the residue was purified by Prep-TLC (30% of ethyl acetate in petroleum ether) to afford ethyl 4- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)cyclohexane-1- carboxylate (124 mg, 0.19 mmol, 29.0%) as a yellow solid. LC purity (0.1%TFA): 75.1% (UV at 254 nm)/MS: 491.3 [M+ H]; Retention time: 1.890 min. Synthesis of tert-butyl 4-(3,3-dimethyl-2-oxoindolin-5-yl)piperidine-1-carboxylate (Intermediate 5) [0768] To a mixture of ethyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexane-1-carboxylate (124 mg, 1 eq, 253 umol) in HCl/dioxane (4 M) (5 mL) in a sealed-tube was added conc. HCl (0.5 mL). The reaction mixture was heated at 80 °C for 16 h, cooled down to room temperature, LCMS indicated completion of reaction. The mixture was concentrated under vacuum and the residue was purified by purified by ChemFlash (eluted with CH3CN in H2O (0.1% FA) from 0% to 100%) to afford 4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)cyclohexane-1-carboxylic acid (68.2 mg, 147 µmol, 58.3%) as a white solid. LC purity (0.1%TFA): 99.22% (UV at 254 nm)/MS: 463.2 [M +H]; Retention time: 1.574 min. Synthesis of (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0769] To a solution of 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)cyclohexane-1-carboxylic acid (25.0 mg, 54.0 μmol, 1 eq) in N,N-Dimethylformamide (5.00 mL) were added N,N-diisopropylethylamine (27.9 mg, 216 μmol, 4.0 eq), O-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.7 mg, 64.8 μmol, 1.2 eq) and (S)-3- (6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (21.1 mg, 59.4 μmol, 1.1 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was purified by pre-HPLC. (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to give (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexane-1-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (21.2 mg, 25.5 µmol, 47.3% yield) as a white solid. LC purity (0.1%TFA): 96.4% (UV at 254 nm)/MS: 800.6 [M+H]; Retention time: 9.236 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.66-7.11 (m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.37 (s, 2H), 5.14-5.09 (m, 1H), 4.71-4.66 (m, 2H), 4.59-4.54 (m, 1H), 4.48-4.36 (m, 2H), 4.20-4.05 (m, 2H), 3.12-3.08 (m, 1H), 2.94-2.74 (m, 4H), 2.55-2.45 (m, 1H), 2.20-2.12 (m, 4H), 2.06-1.98 (m, 4H), 1.89-1.80 (m, 9H), 1.35-1.25 (m, 6H). Compound A180. (S)-3-(1'-(((1s,4R)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

cid (Intermediate 2) [0770] To a solution of (1s,4s)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid (2.00 g, 1 eq, 12.6 mmol) in DMF (20 mL) were added imidazole (3.44 g, 4 eq, 50.6 mmol) and TBS-Cl (5.72 g, 3 eq, 37.9 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (30 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, PE:EA=8:1) to afford (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid (4 g, 14.7 mmol, 116%) as a yellow oil. LC purity (0.1% FA): 61.23% (UV at 254 nm)/MS: 273.5 [M+H]; Retention time: 1.822 min. Synthesis of ((1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (Intermediate 3) [0771] To a solution of (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid (4.00 g, 1 eq, 14.7 mmol) in THF (50 mL) was added LiAlH4 (2.79 g, 5 eq, 73.4 mmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to afford ((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (1.70 g, 6.58 mmol, 44.8%)as a yellow solid. LC purity (0.1%FA): 80.89% (UV at 254 nm)/MS: 259.4 [M+H]; Retention time: 1.827 min. Synthesis of (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (Intermediate 4) [0772] To a solution ((1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (1.50 g, 1 eq, 5.80 mmol) in DCM (20 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)- triyl triacetate (4.92 g, 2 eq, 11.6 mmol). The mixture was stirred at 25 °C for 4 h. TLC indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (1.50 g, 4.7 mmol, 81%, 80% Purity) as a yellow oil. Synthesis of 10'-(1-(((1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin- 4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 6) [0773] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (500 mg, 1 eq, 1.19 mmol) in DMF (2 mL) were added (1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (458 mg, 1.5 eq, 1.78 mmol), potassium acetate (350 mg, 3 eq, 3.57 mmol) and sodium cyanotrihydroborate (149 mg, 2 eq, 2.38 mmol). The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 15% of MeOH in DCM) to afford 10'-(1-(((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 0.15 mmol, 13%) as a yellow solid. LC purity (0.1%FA): 51.67% (UV at 254 nm)/MS: 660.4 [M+H]; Retention time: 1.557 min. Synthesis of 4'-chloro-10'-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 7) [0774] 10'-(1-(((1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4- yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 303 μmol) in HCl/EA (4 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford 4'-chloro-10'-(1-(((1s,4s)-4- (hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (40 mg, 4.7 mmol, 20%) as a yellow oil. LC purity (0.1%FA): 80.00% (UV at 254 nm)/MS: 546.1 [M+H]; Retention time: 1.328 min. Synthesis of ((1s,4s)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (Intermediate 8) [0775] To a solution 4'-chloro-10'-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4- yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (10 mg, 1 eq, 18.3 μmol) in DCM (2 mL) was added DMP (7.77 mg, 1.00 eq, 18.3 μmol). The mixture was stirred at 25 °C for 10 min. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford (1s,4s)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (10 mg, 13 μmol, 70%) as a yellow solid. LC purity (0.1%FA): 70.37% (UV at 254 nm)/MS: 544.14 [M+H]; Retention time: 1.289 min. Synthesis of (S)-3-(1'-(((1s,4R)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0776] To a solution of (1s,4s)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (30 mg, 1 eq, 55.1 μmol) in MeOH (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (19.6 mg, 1 eq, 55.1 μmol), potassium acetate (10.8 mg, 2 eq, 110 μmol) and NaBH3CN (6.93 mg, 2 eq, 110 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 14% to 24% to afford (S)-3-(1'-(((1s,4R)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (2.18 mg, 2.43 μmol, 4.40%) as a white solid. LC purity (0.1%FA): 100.00% (UV at 254 nm)/MS: 883.53 [M+H]; Retention time: 1.183 min.1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.88-7.82 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.44-7.42 (m,1H), 7.35-7.33(m,2H), 5.16-5.12 (m, 1H), 4.70 (s, 2H), 4.53-4.38 (m, 2H), 3.80 -3.72 (m, 2H), 3.70-3.65 (m, 1H), 3.25-3.13 (m, 4H), 3.11-3.08 (m, 3H), 2.91-2.86 (m, 1H), 2.81-2.74 (m, 1H), 2.52-2.46 (m, 1H), 2.42-2.36 (m, 2H), 2.25-2.17 (m,5H), 2.10 -2.04 (m, 5H), 2.01-1.99 (m, 4H), 1.90-1.84 (m, 3H), 1.79-1.73 (m, 4H), 1.62-1.58 (m, 2H), 1.34-1.29 (m, 4H), 1.26-1.23 (m, 2H), 0.91-1.88 (m, 1H). Compound A183. (3S)-3-(1'-((4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)pyrrolidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synth

esis of 4-(3-(4-chloro-5-oxo-5H-spiro[cyclohexane-1,7-indolo[1,2-a]quinazolin]-10'- yl)pyrrolidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 2) [0777] To a solution of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)pyrrolidin-3-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (50 mg, 1 eq, 96.5 μmol) in DCM (5 mL) was added DMP (123.0 mg, 3 eq, 290 μmol). The mixture was stirred at 0 °C for 2 h. LCMS indicated completion of reaction. The crude product was purified by Prep-TLC (DCM:MeOH=10:1). The product 4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)pyrrolidin-1-yl)cyclohexane-1-carbaldehyde (56.0 mg, 109 μmol, 112%) was obtained as white solid. LC purity (0.1% FA): 79.23% (UV at 254 nm)/MS: 516.5 [M +H]; Retention time: 0.923 min. Synthesis of (3S)-3-(1'-((4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)pyrrolidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0778] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (17.9 mg, 1 eq, 50.4 μmol) in MeOH (1 mL) was added TEA (15.3 mg, 21.1 μL, 3 eq, 151 μmol). After 20 min, was added 4-(3-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)pyrrolidin-1-yl)cyclohexane-1- carbaldehyde (26.0 mg, 1 eq, 50.4 μmol). After 20 min NaBH3CN (9.50 mg, 3 eq, 151 μmol) was added. The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The crude product was purified by Prep-HPLC. The product (3S)-3-(1'-((4-(3-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)pyrrolidin-1-yl)cyclohexyl)methyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione was obtained as white solid. LC purity (0.1% FA): 94.72% (UV at 254 nm)/MS: 855.2 [M+H]; Retention time: 0.970 min.1H NMR (400 MHz, MeOD) δ 8.57 (dd, J = 47.6, 8.5 Hz, 1H), 8.18 (d, J = 50.3 Hz, 1H), 7.95 ^ 7.89 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.48 ^ 7.38 (m, 3H), 5.14 (dd, J = 13.4, 5.1 Hz, 1H), 4.70 (s, 1H), 4.53 ^ 4.37 (m, 2H), 3.90 (m, 3H), 3.74 (m, 1H), 3.64 (m, 1H), 3.58 (s, 2H), 3.18 ^ 3.09 (m, 3H), 2.89 (d, J = 13.1 Hz, 1H), 2.80 (m, 1H), 2.57 (d, J = 33.9 Hz, 2H), 2.35 (m, 6H), 2.18 (m, 3H), 2.08 (m, J = 7.5 Hz, 12H), 1.80 (m, 6H), 1.29 (s, 2H). Compound A185. (S)-3-(1'-(((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

10- yl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (Intermediate 2) [0779] To a solution of 4-chloro-10-(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin- 1-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (30 mg, 1 eq, 59.2 μmol) in DCM (2 mL) was added DMP (50.2 mg, 2 eq, 118 μmol). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1s,4s)-4-((4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1-yl)methyl)cyclohexane-1- carbaldehyde (30 mg, 55 μmol, 92%) as a white solid. LC purity (0.1% FA): 92.51% (UV at 254 nm)/MS: 505.2 [M+H]; Retention time: 1.148 min. Synthesis of (S)-3-(1'-(((1s,4R)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0780] To a solution of (1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (30 mg, 1 eq, 59.4 μmol) in MeOH (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (31.7 mg, 1.5 eq, 89.1 μmol), potassium acetate (11.7 mg, 2 eq, 119 μmol) and NaBH3CN (7.47 mg, 2 eq, 119 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 20% to 30% to afford (S)-3-(1'-(((1s,4R)-4-((4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperazin-1- yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (1.65 mg, 1.93 μmol, 3.26%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 844.4 [M+H]; Retention time: 1.016 min. 1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.6 Hz, 1H), 7.86-7.82 (m, 1H), 7.71-7.63 (m, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.44-7.42 (m, 1H), 7.37-7.34 (m, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.16-5.12 (m, 1H), 4.70 (s, 2H), 4.57-4.38 (m,2H), 3.99-3.85 (m, 1H), 3.72-3.65 (m, 3H), 3.34-3.32 (m, 3H), 3.28- 3.26 ( m,3H), 3.21-3.06 (m, 5H), 2.95-2.74 (m, 2H), 2.56 -2.45 (m, 1H), 2.39-2.32 (m, 2H), 2.23- 1.91 (m, 8H), 1.85-1.75 (m, 2H), 1.60-1.59 (m, 1H), 1.57 (s, 6H), 1.33-1.19 (m, 3H). Compound A186. (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-9'-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0781] To a mixture 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'- one (0.20 g, 1 eq, 0.48 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added (4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanol (0.14 g, 1.2 eq, 0.58 mmol), potassium phosphate, tribasic (0.20 g, 2 eq, 0.96 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.04 g, 0.1 eq, 0.05 mmol). The mixture was stirred at 80 °C for 2 h under argon atmosphere. LCMS indicated completion of reaction. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford compound 4'-chloro-9'-(4- (hydroxymethyl)cyclohex-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (0.11 g, 0.24 mmol, 49%) as a yellow solid. LC purity (0.1% FA): 95.86% (UV at 254 nm)/MS: 447.2 [M+H]; Retention time: 1.675 min. Synthesis of 4'-chloro-9'-(4-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 4) [0782] To a mixture of4'-chloro-9'-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (0.11 g, 1 eq, 0.24 mmol) in tetrahydrofuran (5 mL) was added 10% Pd/C (0.05 g, 2.1 eq, 0.42 mmol). The mixture was stirred at 25 °C for 3 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford 4'-chloro-9'-(4- (hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (0.08 g, 0.18 mmol, 72.7 %) as a yellow solid. LC purity (0.1%TFA): 91.14% (UV at 254 nm)/MS: 449.2 [M +H]; Retention time: 1.675 min. Synthesis of 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexane-1-carbaldehyde (Intermediate 5) [0783] To a mixture of 4'-chloro-9'-(4-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (0.08 g, 1 eq, 0.18 mmol) in tetrahydrofuran (5 mL) was added pyridinium chlorochromate (0.08 mg, 2 Eq, 0.37 mmol). The mixture was stirred at 25 °C for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-100% of ethyl acetate in petroleum ether) to afford compound 4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)cyclohexane-1-carbaldehyde (0.04 g, 0.09 mmol, 50.6%) as a yellow oil. LC purity (0.1% FA): 56.18% (UV at 254 nm)/MS: 447.2 [M+H]; Retention time: 1.840 min. Synthesis of (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0784] A mixture of 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexane-1-carbaldehyde (15.0 mg, 1 eq, 33.6 μmol) in DCE (3 mL) were added (S)-3-(6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (18.0 mg, 1.5 eq, 50.3 μmol), TEA (3.4 mg, 1 eq, 33.6 μmol) at 25 °C, after 1 h. sodium triacetoxyborohydride (21.0 mg, 3 eq, 101 μmol) was added then stirred at 25 °C for 16 h. [0785] LCMS indicated completion of reaction. The crude product was purified by prep-HPLC to afford (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (2.56 mg, 3.14 μmol, 9.36%) as a white solid. LC purity (0.1% FA): 96.456% (UV at 254 nm)/MS: 786.6 [M+H]; Retention time: 5.307 min. 1H NMR (400 MHz, MeOD) δ 8.36 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.77 (t, J = 8.2 Hz, 1H), 7.68 (d, J = 6.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.45 ^ 7.27 (m, 3H), 5.24 (t, J = 4.8 Hz, 1H), 5.05 (dd, J = 13.3, 5.0 Hz, 2H), 4.63 (s, 1H), 4.35 (q, J = 17.2 Hz, 2H), 3.66 (t, J = 13.2 Hz, 2H), 3.54 (s, 2H), 3.31 (d, J = 6.8 Hz, 1H), 3.10 ^ 3.03 (m, 2H), 2.82 ^ 2.65 (m, 3H), 2.49 ^ 2.25 (m, 4H), 2.09 (dd, J = 16.8, 9.5 Hz, 4H), 1.95 (d, J = 13.2 Hz, 4H), 1.77 (dd, J = 20.5, 10.6 Hz, 8H), 1.63 ^ 1.46 (m, 3H). Compound A187. (3S)-3-(1'-((1R)-3-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-

piperidin]-7-yl)piperidine-2,6-dione

H)- one (Intermediate 3) [0786] To a mixture of 4-chloro-7,7-dimethyl-9-(3-oxocyclohex-1-en-1-yl) indolo[1,2- a]quinazolin-5(7H)-one (748 mg, 1 eq, 2.0 mmol) in 1,4-dioxane (20 mL) and water (4 mL) were added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (162 mg, 0.1 eq, 0.2 mmol), potassium phosphate (848.0 mg, 2.0 eq, 4.0 mmol), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-2-en-1-one (488.6 mg, 1.1 eq, 2.20 mmol). The mixture was stirred at 80 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (60*2 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford 4-chloro-7,7-dimethyl-9-(3-oxocyclohex-1-en-1-yl) indolo[1,2-a]quinazolin-5(7H)-one (621 mg, 1.35 mmol, 67.76%) as a yellow solid. LC purity (0.1%TFA): 97.49% (UV at 254 nm)/MS: 433.3 [M +H]; Retention time: 1.117 min. Synthesis of 4-chloro-7,7-dimethyl-9-(3-oxocyclohexyl) indolo[1,2-a]quinazolin-5(7H)-one (Intermediate 4) [0787] To a mixture of 4-chloro-7,7-dimethyl-9-(3-oxocyclohex-1-en-1-yl) indolo[1,2- a]quinazolin-5(7H)-one (240 mg, 1 eq, 0.62 mmol) in tetrahydrofuran (50 mL) was added 10% Pd/C (192.0 mg, 0.292 eq, 181 umol), followed by zinc bromide (83.8 mg, 0.6 eq, 0.372 mmol). The mixture was stirred at 25 °C for 2 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum, the residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-70% of ethyl acetate in petroleum ether) to afford 4-chloro-7,7-dimethyl-9-(3-oxocyclohexyl) indolo[1,2-a]quinazolin-5(7H)-one (13 mg, 33.2 umol, 5.34%) as a yellow solid. LC purity (0.1%TFA): 97.92% (UV at 254 nm)/MS: 393.1 [M+ H]; Retention time: 1.338 min. Synthesis of (3S)-3-(1'-((1R)-3-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0788] To a solution of 4-chloro-7,7-dimethyl-9-(3-oxocyclohexyl) indolo[1,2-a]quinazolin- 5(7H)-one (13.0 mg, 1 eq, 33.2 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (14.3 mg, 1.1 eq, 36.5 μmol) in ethanol (5.00 mL) was added tetraethoxytitanium (37.9 mg, 5.0 eq, 166 μmol). The reaction mixture was stirred at 60 °C for 4 h, then sodium cyanoborohydride (10.4 mg, 5.0 eq, 166 umol) was added. The reaction mixture was stirred at 60 °C for 1 h, cooled down to 25 °C, 8 mL of water was added, ethanol was removed under reduced pressure, extracted with DCM (10 mL*3). The combined organic layers were dried over Na2SO4, filtered, the filtrate was evaporated. The residue was purified by pre-HPLC. (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to afford (3S)- 3-(1'-((1R)-3-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (3.01 mg, 4.11 μmol, 12.4%) as white solid. LC purity (0.1%TFA): 100% (UV at 254 nm)/MS: 732.6 [M+H]; Retention time: 3.377 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41-7.37 (m, 2H), 5.35-5.31 (m, 1H), 5.15-5.00 (m, 1H), 4.63-4.57 (m, 3H), 4.47-4.36 (m, 1H), 4.20-4.11 (m, 4H), 2.93-2.69 (m, 2H), 2.52-2.35 (m, 2H), 2.20-2.14 (m, 3H), 1.93-1.89 (m, 2H), 1.61 (s, 6H), 1.35-1.31 (m, 8H). Compound A188. (3S)-3-(1'-((1S)-3-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione

H)- one (Intermediate 3) [0789] To a mixture of 4-chloro-7,7-dimethyl-9-(3-oxocyclohex-1-en-1-yl) indolo[1,2- a]quinazolin-5(7H)-one (748 mg, 1 eq, 2.0 mmol) in 1,4-dioxane (20 mL) and water (4 mL) were added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (162 mg, 0.1 eq, 0.2 mmol), potassium phosphate (848 mg, 2.0 eq, 4.0 mmol), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-2-en-1-one (488 mg, 1.1 eq, 2.20 mmol). The mixture was stirred at 80 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (60*2 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford 4-chloro-7,7-dimethyl-9-(3-oxocyclohex-1-en-1-yl) indolo[1,2-a]quinazolin-5(7H)-one (621 mg, 1.35 mmol, 67.76%) as a yellow solid. LC purity (0.1%TFA): 97.49% (UV at 254 nm)/MS: 433.3 [M +H]; Retention time: 1.117 min. Synthesis of 4-chloro-7,7-dimethyl-9-(3-oxocyclohexyl) indolo[1,2-a]quinazolin-5(7H)-one (Intermediate 4) [0790] To a mixture of 4-chloro-7,7-dimethyl-9-(3-oxocyclohex-1-en-1-yl) indolo[1,2- a]quinazolin-5(7H)-one (240 mg, 1 eq, 0.62 mmol) in tetrahydrofuran (50 mL) was added 10% Pd/C (192 mg, 0.292 eq, 181 umol), followed by zinc bromide (83.8 mg, 0.6 eq, 0.372 mmol). The mixture was stirred at 25 °C for 2 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum, the residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-70% of ethyl acetate in petroleum ether) to afford 4-chloro-7,7-dimethyl-9-(3-oxocyclohexyl) indolo[1,2-a]quinazolin-5(7H)-one (13 mg, 33.2 umol, 5.34%) as a yellow solid. LC purity (0.1%TFA): 97.92% (UV at 254 nm)/MS: 393.1 [M+ H]; Retention time: 1.338 min. Synthesis of (3S)-3-(1'-((1S)-3-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0791] To a solution of 4-chloro-7,7-dimethyl-9-(3-oxocyclohexyl) indolo[1,2-a]quinazolin- 5(7H)-one (13.0 mg, 1 eq, 33.2 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (14.3 mg, 1.1 eq, 36.5 μmol) in ethanol (5.00 mL) was added tetraethoxytitanium (37.9 mg, 5.0 eq, 166 μmol). The reaction mixture was stirred at 60 °C for 4 h, then sodium cyanoborohydride (10.4 mg, 5.0 eq, 166 umol) was added. The reaction mixture was stirred at 60 °C for 1 h, cooled down to 25 °C, 8 mL of water was added, ethanol was removed under reduced pressure, extracted with DCM (10 mL*3). The combined organic layers were dried over Na2SO4, filtered, the filtrate was evaporated. The residue was purified by pre-HPLC. (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to afford (3S)- 3-(1'-((1R)-3-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.71 mg, 4.11 μmol, 7.04%) as white solid. LC purity (0.1%TFA): 100% (UV at 254 nm)/MS: 732.6 [M+H]; Retention time: 3.394 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.45-7.43 (m, 1H), 7.39-7.33 (m, 2H), 5.34 (t, J = 4.8 Hz, 1H), 5.14-5.10 (m, 1H), 4.59-4.57 (m, 2H), 4.46-4.35 (m, 2H), 4.20-4.12 (m, 3H), 3.63-3.62 (m, 1H), 3.25-3.12 (m, 2H), 2.90-2.79 (m, 2H), 2.20-2.16 (m, 3H), 1.95-1.85 (m, 2H), 1.93-1.89 (m, 2H), 1.61 (s, 6H), 1.37-1.31 (m, 8H). [0792] Compound A190. (S)-3-(1'-(5-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)pyrimidin-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

y - - - , - p p - -y - - - , - y - , - p 2,3- e]isoindole-3,4'-piperidin]-1'-yl)pyrimidine-5-carbaldehyde (Intermediate 2) [0793] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (100 mg, 1 eq, 281.4 μmol) in THF (2 mL) were added 2- chloropyrimidine-5-carbaldehyde (48.13 mg, 1.2 eq, 337.7 μmol) and DIEA (72.74 mg, 2 eq, 562.8 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (50 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 45% of EtOAc in PE) to afford (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)pyrimidine-5-carbaldehyde as a colorless oil. LC purity (0.1% FA): 85.3% (UV at 254 nm)/MS: 462.2 [M +H]; Retention time: 1.30 min. Synthesis of (S)-3-(1'-(5-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)pyrimidin-2-yl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0794] To a solution of (S)-2-(7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)pyrimidine-5-carbaldehyde (30 mg, 1 eq, 65.0 μmol) in DMF (2 mL) were added potassium acetate (12.8 mg, 2 eq, 130 μmol), 4'-chloro-10'- (piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (30 mg, 1.1 eq, 71.5 μmol) and sodium cyanoborohydride (6.13 mg, 1.5 eq, 97.5 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) to afford (S)-3-(1'-(5- ((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)methyl)pyrimidin-2-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione (1.30 mg, 1.50 μmol, 2.31%) as a white solid. LC purity (0.1% FA): 99.27 % (UV at 254 nm)/MS: 865.4 [M +H]; Retention time: 1.02 min. 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.2 Hz, 1H), 8.35-8.21 (m, 2H), 7.96 (s, 1H), 7.84 (dd, J = 15.8, 7.6 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 17.3, 8.0 Hz, 3H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.49- 4.40 (m, 2H), 3.49-3.31 (m, 2H), 3.14-2.98 (m, 5H), 2.94-2.85 (m, 1H), 2.78 (d, J = 11.2 Hz, 2H), 2.50 (dd, J = 13.2, 4.8 Hz, 1H), 2.23-2.01 (m, 3H), 2.03-1.86 (m, 5H), 1.97-1.84 (m, 9H), 1.76- 1.52 (m, 4H), 1.28-1.01 (m, 3H). Compound A191. (S)-3-(1'-(4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 10'-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4'-chloro-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0795] To a mixture of 10'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (400 mg, 1 eq, 962 μmol), 2-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (270 mg, 1 eq, 962 μmol) and K2CO3 (398.0 mg, 3 eq, 2.89 mmol) in 1,4-dioxane (10 mL) and H2O (1.00 mL) was added Pd(dppf)Cl2 (70.3 mg, 0.1 eq, 96.2 μmol) at 20 °C, then heated to 80 °C and stirred for 2 h to give yellow solution. LCMS showed the reaction was completed. The reaction was cooled to 20 °C and concentrated under vacuum. The residue was purified by column chromatography on silica gel(PE:EA=100:1-5:1) to afford 10'- ((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (390 mg, 798 μmol, 82.9%) as a white solid. LC purity (0.1% FA): 98.55% (UV at 254 nm)/MS: 489.2 [M +H]; Retention time: 1.975 min. Synthesis of 10'-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 4) [0796] To a mixture of 10'-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 409.0 μmol) and ZnBr2 (104.3 mg, 1 eq, 409.0 μmol) in THF (55.0 mL) was added Pd/C (60 mg, 3 eq, 1.227 mmol) and stirred at 25 °C for 30 min. LCMS showed the reaction was completed. The reaction was filtered and concentrated to afford 10'-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (156 mg, 318 μmol, 77.7 %) as a white solid. LC purity (0.1% FA): 77.92% (UV at 254 nm)/MS: 491.3 [M +H]; Retention time: 1.790 min. Synthesis of 4'-chloro-10'-((4-oxocyclohexyl)methyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 5) [0797] A mixture of 10'-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (156.0 mg, 1 eq, 318 μmol) in Formic Acid (5.0 mL) was stirred at 25 °C for 2 h. The mixture was concentrated to afford 4'-chloro-10'- ((4-oxocyclohexyl)methyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (78.0 mg, 175 μmol, 54.9%) as an oil liquid. LC purity (0.1% FA): 59.41% (UV at 254 nm)/MS: 447.2 [M +H]; Retention time: 1.526 min. Synthesis of (S)-3-(1'-(4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione [0798] To a mixture of 4'-chloro-10'-((4-oxocyclohexyl)methyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 67.1 μmol), KOAc (19.7 mg, 3 eq, 201 μmol) and (R)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (23.9 mg, 1 eq, 67.1 μmol) in DMF (3.0 mL) was added NaBH3CN (12.7 mg, 3 eq, 201 μmol) and stirred at 25 °C for 4 h. 6% of product was monitored by LCMS. The residue was purified by column chromatography on silica gel(DCM: MeOH=50:1-20:1) to afford (R)-3-(1'-(4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (4.42 mg, 5.42 μmol, 8.07 %) as a white solid. LC purity (0.1% FA): 96.37% (UV at 254 nm)/MS: 786.6 [M +H]; Retention time: 5.497 min. 1H NMR (400 MHz, MeOD) δ 8.45 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 13.1 Hz, 1H), 7.86 (dd, J = 14.1, 6.3 Hz, 2H), 7.67 (d, J = 6.8 Hz, 1H), 7.44 (t, J = 9.8 Hz, 1H), 7.38 ^ 7.25 (m, 2H), 5.16 ^ 5.11 (m, 1H), 4.70 (d, J = 19.4 Hz, 1H), 4.51 ^ 4.37 (m, 2H), 3.73 (d, J = 11.5 Hz, 1H), 3.61 (d, J = 11.8 Hz, 2H), 3.19 (dd, J = 26.5, 15.1 Hz, 3H), 2.93 (d, J = 8.1 Hz, 1H), 2.87 (s, 1H), 2.77 (d, J = 11.1 Hz, 2H), 2.21 ^ 1.99 (m, 13H), 1.81 (d, J = 43.2 Hz, 8H), 1.46 (s, 4H). Compound A193. (S)-3-(1'-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzoyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Sy

, o[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzoate (Intermediate 3) [0799] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 238 μmol) in DMF (3 mL) were added tert-butyl 4- formylbenzoate (98.2 mg, 2 eq, 476 μmol), potassium acetate (23.4 mg, 1 eq, 238 μmol) and NaCNBH4 (29.9 mg, 2 eq, 476 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford tert-butyl 4-((4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)methyl)benzoate (50 mg, 79 μmol, 33%) as a yellow solid. LC purity (0.1% FA): 96.85% (UV at 254 nm)/MS: 610.4 [M+H]; Retention time: 1.407 min. Synthesis of 4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)methyl)benzoic acid (Intermediate 4) [0800] To a solution of tert-butyl 4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzoate (50 mg, 1 eq, 81.9 μmol) in DCM (2 mL) and TFA (2 mL). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford 4-((4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzoic acid (10 mg, 16 μmol, 19%) as a yellow oil. LC purity (0.1%FA): 87.46% (UV at 254 nm)/MS: 554.2 [M+H]; Retention time: 1.235 min. Synthesis of (S)-3-(1'-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0801] To a solution 4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzoic acid (40 mg, 1 eq, 72.2 μmol) in DMF (2 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (38.5 mg, 1.5 eq, 108 μmol), DIEA (37.3 mg, 4 eq, 289 μmol) and HATU (54.9 mg, 2 eq, 144 μmol). The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (10 mmol/L%NH4HCO) from 57% to 67% to afford (S)- 3-(1'-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)methyl)benzoyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (13.6 mg, 14.1 μmol, 19.5%) as a white solid. LC purity (0.1% FA): 100.00% (UV at 254 nm)/MS: 891.4 [M+H]; Retention time: 1.297 min. 1H NMR (400 MHz, MeOD-d4) δ 8.40 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.86-7.79 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.55-7.49 (m, 4H), 7.46-7.30 (m,3H), 5.15-5.11 (m, 1H), 4.70-4.61 (m, 3H), 4.58-4.34 (m, 2H), 3.79-3.74 (m, 3H), 3.15-3.13 (m, 3H), 2.90-2.79 (m, 2H), 2.52-2.28 (m, 3H), 2.10-1.99 (m, 6H), 1.92-1.86 (m, 8H), 1.78-1.60 (m, 4H), 1.33-1.28 (m, 2H). Compound A194. (S)-3-(1'-((2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethyl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

,4'- piperidin]-7-yl)piperidine-2,6-dione (Intermediate 2) [0802] To a solution of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (200 mg, 1 eq, 563 μmol) in DCM (3 mL) were added DIEA (364 mg, 5 eq, 2.81 mmol) and 2-chloroethane-1-sulfonyl chloride (138 mg, 1.5 eq, 844 μmol) under N2. The mixture was stirred at 0 °C for 1 h. LCMS indicated completion of reaction. The resulting mixture was extracted with EA (20 mL) and the organic layers were washed with water (20 mL X 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 10% of MeOH in DCM) to get (S)-3-(6-oxo-1'-(vinylsulfonyl)-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (20 mg, 44.9 μmol, 7.98%) as a yellow solid. LC purity (0.1% FA): 92.86% (UV at 254 nm)/MS: 562.3 [M+H]; Retention time: 1.31 min. Synthesis of (S)-3-(1'-((2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethyl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione) [0803] To a solution of (S)-3-(6-oxo-1'-(vinylsulfonyl)-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (20 mg, 1 eq, 44.9 μmol) in DCM (2 mL) were added 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'- one (18.9 mg, 1 eq, 44.9 μmol) and DIEA (29.0 mg, 5 eq, 224 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by Prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 15% to 30% to get (S)-3-(1'-((2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)ethyl)sulfonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (9.97 mg, 11.4 μmol, 25.4%) as a white solid. LC purity (0.1%FA): 99.42% (UV at 254 nm)/MS: 865.4 [M+ H]; Retention time: 1.20 min. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.81 (t, J = 8.2 Hz, 1H), 7.66-7.51 (m, 2H), 7.47-7.14 (m, 3H), 5.09 (d, J = 12.9 Hz, 1H), 4.74- 4.60 (m, 2H), 4.38 (s, 1H), 4.30-4.20 (m, 1H), 3.95 (d, J = 10.5 Hz, 2H), 3.31-2.97 (m, 6H), 2.95 -2.54 (m, 4H), 2.36-2.12 (m, 4H), 2.02 (d, J = 32.5 Hz, 4H), 1.86 (s, 8H), 1.78-1.58 (m, 6H). Compound A196. (S)-4-(4-(2-(6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)acetyl)piperazin-1-yl)-N-(2,6- dioxopiperidin-3-yl)-2-fluorobenzamide

-10- yl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 3) [0804] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)- one (200 mg, 1 eq, 526 μmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (334 mg, 3 eq, 1.58 mmol), TEA (320 mg, 440 μL, 6 eq, 3.16 mmol) and NaBH3CN (99.2 mg, 3 Eq, 1.58 mmol) in MeOH (5.00 mL) was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (20 mL X 2), dried over Na2SO4, concentrated. The residue was purified by Prep-TLC (4% of MeOH in DCM ether) to afford tert- butyl 6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)-2-azaspiro[3.3]heptane-2-carboxylate as a white solid. LC purity (0.1% FA): 60.71% (UV at 254 nm)/MS: 575.4 [M +H]; Retention time: 0.943 min. Synthesis of 10-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (Intermediate 4) [0805] To a solution of tert-butyl 6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (220 mg, 1 eq, 383 μmol) in DCM (3.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford 10-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin- 5(7H)-one (180 mg, 379 μmol, 99.1%) was obtained as a yellow oil. LC purity (0.1%TFA): 60.92% (UV at 254 nm)/MS: 475.3 [M +H]; Retention time: 0.633 min. Synthesis of 2-(6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)acetic acid (Intermediate 5) [0806] To a solution of 10-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (50 mg, 1 eq, 105 μmol), TEA (63.9 mg, 88.0 μL, 6 eq, 632 μmol), (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (35.1 mg, 1 eq, 105 μmol) and NaBH3CN (13.2 mg, 2 eq, 211 μmol) in MeOH (3.00 mL) was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The residue was purified by Prep-TLC (10% of MeOH in DCM ether) to afford 2-(6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)acetic acid (30 mg, 56.3 μmol, 53.5%) as a yellow solid. LC purity (0.1%FA): 98.98% (UV at 254 nm)/MS: 533.4 [M +H]; Retention time: 3.507 min. Synthesis of (S)-4-(4-(2-(6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)acetyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3- yl)-2-fluorobenzamide. [0807] To a solution of 2-(6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)acetic acid (20 mg, 1 eq, 37.5 μmol), (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (15.1 mg, 1.2 eq, 45.0 μmol), ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (24.9 mg, 1.5 eq, 56.3 μmol) and N-ethyl-N-isopropylpropan-2-amine (29.1 mg, 6 eq, 225 μmol) in DMF (2.00 mL) was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The resulting residue was purified by reverse-phase chromatography to afford (S)-4-(4-(2-(6-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)acetyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)- 2-fluorobenzamide (19.0 mg, 22.3 μmol, 59.4%, 99.45% Purity) as a white solid. LC purity (0.1%FA): 99.45% (UV at 254 nm)/MS: 849.7 [M +H]; Retention time: 3.633 min.1H NMR (400 MHz, DMSO) δ 7.54 (d, J = 8.6 Hz, 1H), 7.11 (s, 1H), 6.95 (t, J = 8.3 Hz, 1H), 6.87 (t, J = 9.0 Hz, 1H), 6.73 (dd, J = 16.7, 7.8 Hz, 2H), 6.45 (d, J = 7.7 Hz, 1H), 5.94 (d, J = 8.9 Hz, 1H), 5.84 (d, J = 15.5 Hz, 1H), 3.52 (s, 3H), 3.41 (s, 2H), 2.85 ^ 2.69 (m, 6H), 2.65 (s, 2H), 2.54 (d, J = 16.9 Hz, 5H), 2.21 (s, 1H), 2.07 (s, 2H), 1.96 ^ 1.79 (m, 6H), 1.36 (d, J = 41.2 Hz, 7H), 0.69 (s, 6H). Compound A197. (3S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3',3'-difluoro-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-3'-oxo-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 2) [0808] To a solution of (COCl)2 (267.0 mg, 5 eq, 2.10 mmol) in DCM (10 mL) were added dropwise a mixture of DMSO (328.0 mg, 10 eq, 4.20 mmol) and 1 mL methylene chloride at - 78°C for 5 min. After the resultant solution was stirred for 30 min, a solution of above tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-3'-hydroxy-[1,4'- bipiperidine]-1'-carboxylate (260. mg, 1 eq, 420 μmol) in 1 mL methylene chloride was added dropwise. After the addition the solution was allowed to -78°C, and then the stirring was continued for 1 h. To this solution was added 5 mL triethylamine before it was warmed to 0 °C. After 20 mL saturated NaHCO3 was added, the organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. Concentration and column flash chromatography (DCM:MeOH=100:1-15:1) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-3'-oxo-[1,4'- bipiperidine]-1'-carboxylate (86.0 mg, 139 μmol, 33.2%) as an oil liquid. LC purity (0.1% FA): 70.71% (UV at 254 nm)/MS: 617.3 [M +H]; Retention time: 1.099 min. Synthesis of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-3',3'-difluoro-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 3) [0809] To a mixture of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3'-oxo-[1,4'-bipiperidine]-1'-carboxylate (150 mg, 1 eq, 243 μmol) in DCM (7.0 mL) was added DAST (39.1 mg, 1.50 mL, 1 eq, 243 μmol) at 78°C. The mixture was stirred at room temperature for 4 h. LCMS showed the reaction was completed. The reaction was quenched with water and extracted with DCM. The residue was purified by column chromatography on silica gel(DCM:MeOH=20:1) to afford tert-butyl 4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-3',3'-difluoro-[1,4'-bipiperidine]-1'- carboxylate (52.0 mg, 81.4 μmol, 33.5%) as an oil liquid. LC purity (0.1% FA): 83.43% (UV at 254 nm)/MS: 639.3 [M +H]; Retention time: 1.878 min. Synthesis of 4'-chloro-9'-(3',3'-difluoro-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 4) [0810] A mixture of tert-butyl 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3',3'-difluoro-[1,4'-bipiperidine]-1'-carboxylate (52.0 mg, 1 eq, 81.4 μmol) in DCM (3.0 mL) was added 2,2,2-trifluoroacetic acid (1.0 mL, 81.4 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to afford 4'-chloro-9'-(3',3'-difluoro-[1,4'- bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (40 mg, 74.2 μmol, 91.2%) as a white solid. LC purity (0.1% FA): 77.64% (UV at 254 nm)/MS: 539.3 [M +H]; Retention time: 1.032 min. Synthesis of (3S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-3',3'-difluoro-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0811] To a mixture of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (26.4 mg, 1 eq, 74.2 μmol) and TEA (0.02 mL, 3 eq, 223 μmol) in DCM (5.0 mL) was added triphosgene (22.0 mg, 1 eq, 74.2 μmol) and stirred for 0.5 h.4'-chloro-9'-(3',3'-difluoro-[1,4'-bipiperidin]-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (40 mg, 1 eq, 74.2 μmol) was added to the mixture and stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction was concentrated under vacuum. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1-10:1) to afford (3S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)- 3',3'-difluoro-[1,4'-bipiperidine]-1'-carbonyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (17.48 mg, 18.99 μmol, 25.6%) as a white solid. LC purity (0.1% FA): 94.19% (UV at 254 nm)/MS: 920.6 [M +H]; Retention time: 6.883 min.1H NMR (400 MHz, MeOD) δ 8.40 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.82 (dd, J = 18.0, 9.6 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.41 ^ 7.35 (m, 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.70 ^ 4.62 (m, 2H), 4.43 (q, J = 16.9 Hz, 2H), 4.27 (d, J = 12.5 Hz, 1H), 3.94 ^ 3.73 (m, 5H), 3.65 ^ 3.47 (m, 2H), 3.36 (d, J = 11.8 Hz, 1H), 3.12 (dt, J = 23.5, 12.7 Hz, 4H), 2.96 ^ 2.84 (m, 1H), 2.83 ^ 2.74 (m, 1H), 2.56 ^ 2.43 (m, 1H), 2.38 ^ 2.28 (m, 1H), 2.27 ^ 2.12 (m, 8H), 2.11 ^ 1.92 (m, 5H), 1.91 ^ 1.74 (m, 8H). Compound A199. (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-9'-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 2) [0812] To a mixture of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (1 g, 1 eq, 2.41 mmol) in 1,4-dioxane (20 mL) and water (3 mL) were added 4,4,5,5- tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (448 mg, 0.7 eq, 1.68 mmol) and potassium phosphate, tribasic (1.02 g, 398 μL, 2 eq, 4.81 mmol) andPdCl2(dppf) (176 mg, 0.1 eq, 241 μmol). The solution was stirred at 80 °C for 2 h under Ar atmosphere. LCMS indicated finished. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~67% ethyl acetate/petroleum ether gradient @60 mL/min). Compound 4'- chloro-9'-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (700 mg, 1.2 mmol, 49%) was obtained as a yellow solid. LC purity (0.1%FA): 80% (UV at 254 nm)/MS: 475.2 [M+H]; Retention time: 2.001 min. Synthesis of 4'-chloro-9'-(1,4-dioxaspiro[4.5]decan-8-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 3) [0813] To a mixture of 4'-chloro-9'-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (460 mg, 1 eq, 968 μmol) in THF (50 mL) were added Pd(OH)2 (680 mg, 10% Wt, 0.5 eq, 484 μmol) and zinc bromide (21.8 mg, 5.16 μL, 0.1 eq, 96.8 μmol). The solution was stirred at 25 °C for 24 h under H2 atmosphere. LCMS indicated finished. The reaction mixture was filtered and concentrated under reduced pressure. Used directly for next step. LC purity (0.1%FA): 77 % (UV at 254 nm)/MS: 477.1 [M+H]; Retention time: 1.944 min. Synthesis of 4'-chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 5) [0814] To a mixture of 4'-chloro-9'-(1,4-dioxaspiro[4.5]decan-8-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (400 mg, 1 eq, 839 μmol) in THF (6 mL) was added HCl (6 mL). The solution was stirred at 25 °C for 1 h. LCMS indicated finished. The reaction mixture was concentrated under reduced pressure. Purified by prep-flash (0~70% ACN) to afford compound 4'-chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (110 mg, 248 μmol, 29.6%) was obtained as a yellow solid. LC purity (0.1%FA): 97.64% (UV at 254 nm)/MS: 433.2 [M+H]; Retention time: 1.640 min. Synthesis of (S)-3-(1'-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0815] To a mixture of 4'-chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (20 mg, 1 eq, 46.2 μmol) in DMF (1 mL) was added (S)-3-(6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (24.6 mg, 1.5 eq, 69.3 μmol). After 1h, sodium cyanoborohydride (14.5 mg, 13.4 μL, 5 eq, 231 μmol) was added. The solution was stirred at 25 °C for 16 h. LCMS indicated ok. The reaction mixture was concentrated under reduced pressure. Purified by prep-flash to afford compound (S)-3-(1'-(4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)cyclohexyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.08 mg, 1.31 μmol, 2.84%) was obtained as a grey solid. LC purity (0.1%FA): 93.94% (UV at 254 nm)/MS: 772.6 [M+H]; Retention time: 7.967 min.1H NMR (400 MHz, MeOD) δ 8.40 (d, J = 8.7 Hz, 1H), 8.06 (dd, J = 8.6, 2.7 Hz, 1H), 7.87 ^ 7.72 (m, 2H), 7.65 (dd, J = 7.8, 3.8 Hz, 1H), 7.55 ^ 7.35 (m, 3H), 5.14 (dt, J = 13.1, 5.0 Hz, 1H), 4.67 (d, J = 18.1 Hz, 1H), 4.43 (qd, J = 17.1, 7.6 Hz, 2H), 3.56 (d, J = 11.4 Hz, 2H), 3.10 (d, J = 12.2 Hz, 2H), 2.83 (dd, J = 41.6, 14.5 Hz, 3H), 2.58 ^ 2.45 (m, 1H), 2.32 ^ 1.76 (m, 25H) Compound A200. (S)-3-(1'-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)azetidin-3-yl)methyl)-6-oxospiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7(2H,6H,8H)-yl)piperidine-2,6-dione

,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0816] To a solution of 4'-chloro-10'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (80 mg, 1 eq, 173 μmol) and azetidin-3- ylmethanol, HCl (107 mg, 5 eq, 864 μmol) in DCM (1.00 mL) were added trimethylamine (140 mg, 193 μL, 8 eq, 1.38 mmol) and cupric acetate, monohydrate (51.8 mg, 27.6 μL, 1.5 eq, 259 μmol). The reaction was stirred at 25 °C for 16 h under nitrogen protection. The crude was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: DCM) to get 4'-chloro-10'-(3- (hydroxymethyl)azetidin-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (26.0 mg, 61.6 μmol, 35.6%) as a yellow solid. LC purity (0.1% FA): 51.74% (UV at 254 nm)/MS: 422.2 [M+H+]; Retention time: 1.510 min. Synthesis of (1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)azetidin-3-yl)methyl methanesulfonate (Intermediate 4) [0817] To a solution of 4'-chloro-10'-(3-(hydroxymethyl)azetidin-1-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (10 mg, 1 eq, 23.7 μmol) in DCM (1.00 mL) were added trimethylamine (7.0 mg, 9.64 μL, 2.92 eq, 69.2 μmol) and methanesulfonyl chloride (5.0 mg, 3.38 μL, 1.84 eq, 43.7 μmol). The reaction was stirred at 25 °C for 2 h under nitrogen protection. [0818] The reaction was monitored by LCMS. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to get a crude (1-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)azetidin-3-yl)methyl methanesulfonate (12.0 mg, 19 μmol, 81%, 80% Purity) as a yellow solid. LC purity (0.1%FA): 58.42% (UV at 254 nm)/MS: 500 [M+H+]; Retention time: 1.747 min. Synthesis of (S)-3-(1'-((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)azetidin-3-yl)methyl)-6-oxospiro[furo[2,3-e]isoindole-3,4'-piperidin]-7(2H,6H,8H)- yl)piperidine-2,6-dione [0819] To a solution of (1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)azetidin-3-yl)methyl methanesulfonate (12.0 mg, 1 eq, 24.0 μmol) and (S)-3-(6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (13.0 mg, 1.52 eq, 36.6 μmol) in DMF (2.00 mL) were added potassium iodide (80 mg, 36.4 μL, 20.1 eq, 482 μmol) and sodium bicarbonate (159 mg, 73.6 μL, 78.9 eq, 1.89 mmol). The reaction was stirred at 100 °C for 16 h under nitrogen protection. The reaction was monitored by LCMS. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 10), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Method: FA) to get (S)-3-(1'- ((1-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)azetidin-3- yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (5.50 mg, 6.56 μmol, 27.3%, 90.52% Purity) as a white solid. LC purity (0.1% FA): 88.51% (UV at 254 nm)/MS: 759.2 [M+H+]; Retention time: 0.958 min. 1H NMR (400 MHz, DMSO-d6) 8.36 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 12.0 Hz, 1H), 7.71-7.63 (m, 2H), 7.41-7.37 (m, 2H), 7.05 (s, 1H), 7.47 (d, J = 10 Hz, 1H), 5.36-5.32 (m, 2H), 4.58 (s, 4H), 4.42 (dd, J = 13.2 Hz, 25.6 Hz, 3H), 4.17 (t, J = 7.2 Hz, 2H), 3.71-3.61 (m, 2H), 3.14-3.09 (m, 2H), 3.05-2.99 (m, 2H), 2.89-2.83 (m, 2H), 2.69 (s, 1H), 2.94-3.06 (m, 3H), 2.32-2.18 (m, 2H), 2.06-2.00 (m, 4H), 1.87- 1.82 (m, 4H), 1.72-1.69 (m, 1H), 1.34-31.28 (m, 3H). Compound A201. (S)-3-(1'-(4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 9-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4-chloro-5H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0820] To a mixture of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (0.770 g, 1 eq, 1.85 mmol) in 1,4-dioxane (20 mL) and water (2.00 mL) were added PdCl2(dppf) (0.136 g, 0.1 eq, 185 μmol) and 2-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.623 g, 1.2 eq, 2.22 mmol) and potassium phosphate, tribasic (0.786 g, 307 μL, 2 eq, 3.70 mmol). The solution was stirred at 80 °C for 2 h under argon atmosphere. LCMS indicated finished. The reaction mixture was poured by water (100 mL), and extracted with DCM (3 X 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford compound 9'-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (727 mg, 1.49 mmol, 80.3%) was obtained as a white solid. LC purity (0.1% FA): 91.29% (UV at 254 nm)/MS: 489.2 [M+H]; Retention time: 1.735 min. Synthesis of 9'-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 4) [0821] To a solution of 9'-((1,4-dioxaspiro[4.5]decan-8-ylidene)methyl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (20 mg, 1 eq, 40.9 μmol) in THF (5.00 mL) were added Pd/C (34.8 mg, 10% Wt, 0.8 eq, 32.7 μmol) and zinc bromide (4.61 mg, 1.09 μL, 0.5 eq, 20.4 μmol). The solution was stirred at 25 °C for 2 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford 9'-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-4'-chloro-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (16.0 mg, 32.6 μmol, 72.1%) was obtained as a yellow solid. LC purity (0.1%TFA): 91.14% (UV at 254 nm)/MS: 491.2 [M +H]; Retention time: 1.713 min. Synthesis of 4'-chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 5) [0822] To a mixture of 4'-chloro-9'-(1,4-dioxaspiro[4.5]decan-8-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (85.0 mg, 1 eq, 178 μmol) in THF (2.00 mL) was added HCl (2.00 mL). The solution was stirred at 25 °C for 2 h. LCMS indicated finished. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-100% of ethyl acetate in petroleum ether) to afford compound 4'-chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (35.0 mg, 80.3 μmol, 45.0%, 99.3% Purity) was obtained as a yellow solid. LC purity (0.1% FA): 54.98% (UV at 254 nm)/MS: 433.0 [M+H]; Retention time: 1.361 min. Synthesis of (S)-3-(1'-(4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0823] To a solution of 4'-chloro-9'-((4-oxocyclohexyl)methyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (40 mg, 1 eq, 89.5 μmol) in DMF (2.00 mL) were added TEA (73.0 mg, 0.10 mL, 8.0 eq, 0.72 mmol) and acetic acid (0.11 g, 0.11 mL, 21 Eq, 1.9 mmol). After 1h, sodium cyanoborohydride (28.1 mg, 26.0 μL, 5 eq, 447 μmol) was added. The solution was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford (S)- 3-(1'-(4-((4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)methyl)cyclohexyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (7.83 mg, 9.53 μmol, 10.6%) as a white solid. LC purity (0.1% FA): 95.69% (UV at 254 nm)/MS: 786.7 [M+H]; Retention time: 5.317 min. 1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 7.8 Hz, 1H), 8.13 (dd, J = 7.7, 4.3 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.74 (dd, J = 24.5, 15.0 Hz, 2H), 7.50 ^ 7.35 (m, 3H), 5.16 ^ 5.11 (m, 1H), 4.74 ^ 4.68 (m, 1H), 4.44 (dd, J = 12.7, 7.7 Hz, 1H), 3.69 (d, J = 42.3 Hz, 3H), 3.13 (s, 1H), 2.95 ^ 2.84 (m, 2H), 2.81 ^ 2.70 (m, 2H), 2.53 ^ 2.34 (m, 3H), 2.15 ^ 2.01 (m, 9H), 1.88 (dd, J = 40.6, 15.3 Hz, 7H), 1.75 ^ 1.58 (m, 4H), 1.31 (d, J = 19.0 Hz, 5H). Compound A202. (S)-3-(1'-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Syn

exane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0824] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 238 μmol) in MeOH (3 mL) was added potassium acetate (93.5 mg, 4 eq, 952 μmol) and stirred at 25 °C for 0.5 h. Then sodium cyanoborohydride (29.9 mg, 2 eq, 476 μmol) was added to above mixture. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-50% of ethyl acetate in petroleum ether) to afford 4'-chloro-10'-(1-(4- (hydroxymethyl)benzyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'- one (100 mg, 0.15 mmol, 62%) as a yellow solid. LC purity (0.1% FA): 57.33% (UV at 254 nm)/MS: 540.3 [M+H]; Retention time: 1.246 min. Synthesis of 4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)methyl)benzaldehyde (Intermediate 4) [0825] To a solution of 4'-chloro-10'-(1-(4-(hydroxymethyl)benzyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (70 mg, 1 eq, 130 μmol) in DCM (6 mL) was added 3-oxo-1l5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (82.5 mg, 1.5 eq, 194 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 mL), washed with DCM (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EA in PE) to get 4-((4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)methyl)benzaldehyde (60 mg, 112 μmol, 86.0%) as a white solid. LC purity (0.1%TFA): 27.36% (UV at 254 nm)/MS: 538.1 [M+H]; Retention time: 0.906 min. Synthesis of (S)-3-(1'-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0826] To a solution of 4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)benzaldehyde (40 mg, 1 eq, 74.3 μmol) in MeOH (3 mL) were added potassium acetate (29.2 mg, 4 eq, 297 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (26.4 mg, 1 eq, 74.3 μmol) and stirred at 25 °C for 0.5 h. Then the sodium cyanoborohydride (9.34 mg, 2 eq, 149 μmol) was added to above mixture. The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The resulting mixture was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 25% to 40% to afford (S)-3-(1'-(4-((4- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)methyl)benzyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (1.71 mg, 1.80 μmol, 2.42%) as a white solid. LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 877.5 [M+H]; Retention time: 1.471 min.1H NMR (400 MHz, MeOD-d4) δ 8.38 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.87-7.74 (m, 2H), 7.64 (d, J = 8.6 Hz, 5H), 7.45-7.23 (m, 3H), 5.20-5.07 (m, 2H), 4.65 (s, 4H), 4.49-4.34 (m, 5H), 4.17 (s, 2H), 3.60 (d, J = 11.1 Hz, 2H), 3.21-3.02 (m, 4H), 2.96-2.62 (m, 5H), 2.56-2.42 (m, 1H), 2.13 (d, J = 30 Hz, 8H), 1.78 (d, J = 46.7 Hz, 6H). Compound A203. (S)-3-(1'-(((1r,4S)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

ynt esis of ( r, r)- -(((tert- uty imet y si y )oxy)met y )cyc o exane- -car a e yde (Intermediate 2) [0827] To a solution of ((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (200 mg, 1 eq, 774 μmol) in DCM (2 mL) was added DMP (656 mg, 2 eq, 1.55 mmol). The mixture was stirred at 25 °C for 16 h. TLC showed the reaction was completed. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (200 mg, 0.35 mmol, 45%) as a white solid. Synthesis of 10'-(1-(((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin- 4-yl)-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 4) [0828] To a solution of 4'-chloro-10'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 238 μmol) in DMF (2 mL) were added (1r,4r)-4-(tert- butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (122 mg, 2 eq, 476 μmol), potassium acetate (46.7 mg, 2 eq, 476 μmol) and NaBH3CN (29.9 mg, 2 eq, 476 μmol). The mixture was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of PE in EA) to afford 10'-(1-(((1r,4r)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (60 mg, 90.9 μmol, 38.2%) as a yellow solid. LC purity (0.1%FA): 97.53% (UV at 254 nm)/MS: 660.4 [M+H]; Retention time: 1.615 min. Synthesis of 4'-chloro-10'-(1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 5) [0829] To a solution of 10'-(1-(((1r,4r)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4'-chloro-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (60 mg, 1 eq, 90.9 μmol) in HCl/EA (2 mL). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 4'-chloro-10'-(1-(((1r,4r)-4- (hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (60 mg, 89 μmol, 98%) as a yellow solid. LC purity (0.1% FA): 81.37 % (UV at 254 nm)/MS: 546.4 [M+H]; Retention time: 1.255 min. Synthesis of (1r,4r)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (Intermediate 6) [0830] To a solution of 4'-chloro-10'-(1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin- 4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (20 mg, 1 eq, 36.6 μmol) in DCM (2 mL) was added DMP (31.1 mg, 2 eq, 73.2 μmol). The mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1r,4r)-4-((4-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)methyl)cyclohexane-1-carbaldehyde (20 mg, 17 μmol, 47 %) as a white solid. LC purity (0.1% FA): 78.20% (UV at 254 nm)/MS: 544.4 [M+H]; Retention time: 1.284 min. Synthesis of (S)-3-(1'-(((1r,4S)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0831] To a solution of (1r,4r)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (20 mg, 1 eq, 36.8 μmol) in DMF (2mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (19.6 mg, 1.5 eq, 55.1 μmol), potassium acetate (7.21 mg, 2 eq, 73.5 μmol) and NaCNBH3 (4.62 mg, 2 eq, 73.5 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The reaction was concentrated under vacuum and purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 16% to 26% to afford (S)-3-(1'-(((1r,4S)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.40 mg, 1.50 μmol, 4.08%) as a white solid. LC purity (0.1%FA): 94.66% (UV at 254 nm)/MS: 885.5 [M+H]; Retention time: 1.204 min.1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.87-7.83 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.41-7.33 (m, 3H), 5.16-5.11 (m, 1H), 4.48-4.36 (m, 2H), 3.55-3.48 (m,2H), 3.15-3.13 (m, 2H), 3.03-2.73 (m, 7H), 2.55-2.45 (m, 3H), 2.39-2.37 (m, 2H), 2.18-2.03 (m, 11H), 1.96-1.93 (m, 4H), 1.89-1.64 (m, 10H), 1.33-1.29 (m, 2H), 1.18-1.05 (m, 4H). Compound A204. (S)-3-(1'-((1-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-4-fluoropiperidin-4-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (Intermediate 2) [0832] To a solution of oxalyl chloride (653 mg, 2 eq, 5.14 mmol) in DCM (2 mL) were added at -78 °C under N2 DMSO (602.9 mg, 3 eq, 7.716 mmol) and tert-butyl 4-fluoro-4- (hydroxymethyl)piperidine-1-carboxylate (600 mg, 1 eq, 2.572 mmol. The reaction was stirred at -78 °C for 2 h, then DIEA (2.327 g, 3.14 mL, 7 eq, 18.00 mmol) was added.1H NMR indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford tert-butyl 4-fluoro-4- formylpiperidine-1-carboxylate (420 mg, 1.6 mmol, 64%) as a white oil. 1H NMR (400 MHz, CDCl3-d) δ 9.74 (d, J = 4.9 Hz, 1H), 4.03 (d, J = 11.3 Hz, 2H), 3.12 (t, J = 10.1 Hz, 2H), 1.77 (ddd, J = 19.2, 16.3, 4.5 Hz, 4H), 1.47 (s, 9H). Synthesis of tert-butyl (S)-4-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)methyl)-4-fluoropiperidine-1-carboxylate (Intermediate 4) [0833] To a solution of tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (50 mg, 1 eq, 216 μmol) in DMF (2 mL) were added potassium acetate (42.4 mg, 2 eq, 432 μmol), (S)-3-(6-oxo-6,8- dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (76.8 mg, 1 eq, 216 μmol) and sodium cyanoborohydride (27.2 mg, 2 eq, 432 μmol), the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford tert-butyl (S)-4-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-1'-yl)methyl)-4-fluoropiperidine-1-carboxylate (50 mg, 79 μmol, 36%) as a yellow solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 570 [M+H]; Retention time: 1.21 min. Synthesis of tert-butyl(S)-3-(1'-((4-fluoropiperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 5) [0834] To a solution of tert-butyl (S)-4-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)methyl)-4-fluoropiperidine-1-carboxylate (50 mg, 1 eq, 87.6 μmol) in DCM (2 mL) was added TFA (2 mL) at rt. The reaction was stirred 25 °C for 2 h. LCMS showed reaction worked. The mixture was added DCM (20 mL) and concentrated, repeated three times to get (S)-3-(1'-((4-fluoropiperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 96 μmol, 110%) as a yellow solid. Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine- 1-carboxylate [0835] To a solution of (S)-3-(1'-((4-fluoropiperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (50 mg, 1 eq, 106 μmol) in DMF (2 mL) were added potassium acetate (20.9 mg, 2 eq, 213 μmol), 4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)cyclohexane-1-carbaldehyde (47.5 mg, 1 eq, 106 μmol) and sodium cyanoborohydride (13.4 mg, 2 eq, 213 μmol) and the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford (S)-3-(1'-((1-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-4-fluoropiperidin-4-yl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (4.77 mg, 5.12 μmol, 4.82%) as a white solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 901.2 [M+H]; Retention time: 1.354 min.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.44 (d, J = 9.1 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.4 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 18.7, 10.4 Hz, 3H), 5.10 (d, J = 8.6 Hz, 1H), 4.68 (s, 1H), 4.40 (d, J = 17.1 Hz, 1H), 4.24 (d, J = 16.3 Hz, 1H), 3.61 (s, 4H), 3.08 (s, 4H), 2.92 (s, 2H), 2.81-2.55 (m, 5H), 2.37 (d, J = 30.9 Hz, 4H), 1.98 (d, J = 60.7 Hz, 11H), 1.74 (d, J = 9.2 Hz, 12H), 1.24 (s, 2H). Compound A205. (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclopentyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of tert-butyl ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-ene-1-carboxylate (Intermediate 2) [0836] To a solution of ethyl 3-oxocyclopentane-1-carboxylate (5.00 g, 1 eq, 32.0 mmol) in DCE (5 mL) were added 2,6-di-tert-butylpyridine (9.19 g, 1.5 eq, 48.0 mmol) and Tf2O (11.7 g, 1.3 eq, 41.6 mmol) at 0 °C, the reaction was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The reaction concentrated under vacuum. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was used directly in the next step. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 289.2 [M+H]; Retention time: 1.465 min. Synthesis of tert-butyl ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-ene-1- carboxylate (Intermediate 3) [0837] To a solution of ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-ene-1-carboxylate (5.00 g, 1 eq, 17.3 mmol) in 1,4-dioxane (5 mL) were added potassium acetate (3.40 g, 2 eq, 34.7 mmol), bis(pinacolato)diborane (6.61 g, 1.5 eq, 26.0 mmol) and PdCl2(dppf) (635 mg, 0.05 eq, 867 μmol) and the reaction was stirred at 90 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100- 200 mesh silica gel, 5% of EtOAc in PE) to afford ethyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclopent-2-ene-1-carboxylate (5.00 g, 17 mmol, 97 %) as a yellow oil. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 267 [M+H]; Retention time: 1.6 min. Synthesis of tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1- yl)methanol (Intermediate 4) [0838] To a solution of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-ene- 1-carboxylate (2.50 g, 1 eq, 9.92 mmol) in THF (3 mL) was added diisobutylaluminum hydride (2.82 g, 2 eq, 19.8 mmol) at 0 °C. The reaction was stirred 0 °C for 1 h. LCMS indicated completion of reaction. The mixture was added water, extracted with EA (30 mL), dried over Na2SO4 and concentrated. The crude product was purified by silica gel column (PE to EA:PE=1:10) to get (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1- yl)methanol (1.00 g, 4.0 mmol, 40%) as a yellow oil. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 224.2 [M+H]; Retention time: 1.465 min. Synthesis of tert-butyl 4'-chloro-10'-(3-(hydroxymethyl)cyclopent-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 6) [0839] To a solution of 10'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (2.23 g, 1.2 eq, 5.35 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) were added PdCl2(dppf) (326 mg, 0.1 eq, 446 μmol), (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopent-3-en-1-yl)methanol (1.00 g, 1 eq, 4.46 mmol) and K2CO3 (1.23 g, 2 eq, 8.92 mmol), the reaction was stirred at 100 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 50% of EtOAc in PE) to afford 4'-chloro-10'-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (1.00 g, 2.0 mmol, 45%, 90% Purity) as a yellow solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 434.2 [M+H]; Retention time: 1.627 min. Synthesis of tert-butyl 4'-chloro-10'-(3-(hydroxymethyl)cyclopentyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 7) [0840] To a solution of 4'-chloro-10'-(3-(hydroxymethyl)cyclopent-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 462 μmol) in EA (2 mL) was added Pd/C (10 mg, 0.2 eq, 94.0 μmol) and the reaction was stirred at 25 °C for 3 h under H2. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of EtOAc in PE) to afford 4'-chloro-10'-(3-(hydroxymethyl)cyclopentyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 0.14 mmol, 30%) as a yellow solid. LC purity (0.1% FA): 60% (UV at 254 nm)/MS:435 [M+H]; Retention time: 1.632 min Synthesis of tert-butyl 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclopentane-1-carbaldehyde (Intermediate 8) [0841] To a solution of 4'-chloro-10'-(3-(hydroxymethyl)cyclopentyl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (300 mg, 1 eq, 689 μmol) in DCM (3 mL) was added DMP (877 mg, 3 eq, 2.06 mmol) and the reaction was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 3-(4'-chloro-5'-oxo- 5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)cyclopentane-1-carbaldehyde (50 mg, 0.10 mmol, 15%) as a white solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 433.2 [M+H]; Retention time: 1.699 min. Synthesis of (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclopentyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0842] To a solution of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclopentane-1-carbaldehyde (50 mg, 1 eq, 115 μmol) in DMF (2 mL) were added potassium acetate (22.7 mg, 2 eq, 231 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (41.0 mg, 1 eq, 115 μmol) and sodium cyanoborohydride (14.5 mg, 2 eq, 231 μmol) and the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL X 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)cyclopentyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (20.1 mg, 25.5 μmol, 22.1%) as a white solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 772.2 [M+H]; Retention time: 1.465 min.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 30.8, 7.7 Hz, 3H), 5.14-5.07 (m, 1H), 4.63 (d, J = 33.5 Hz, 2H), 4.40 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 3.58 (s, 2H), 3.25-3.15 (m, 2H), 3.11 (s, 2H), 2.98-2.86 (m, 1H), 2.60 (d, J = 16.5 Hz, 2H), 2.37 (d, J = 34.8 Hz, 3H), 2.17 (s, 2H), 2.10-1.77 (m, 11H), 1.68 (dd, J = 67.5, 47.2 Hz, 9H). Compound A206. (S)-3-(1'-((4-((S)-3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

, 1,2- a]quinazolin]-5'-one and (S)-4'-chloro-10'-(piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 1-Fr1, 1-Fr2) [0843] SFC separation was carried out for compound 1 (1 g). [0844] The SFC separation information are shown as following: [0845] Analytical separation method: [0846] SFC condition: Rt: 4.019 min, 5.215 min. [0847] Instrument: waters UPCC (CA-119), Column: DAICELCHIRALPAK®AD, 100 × 3.0 mm, 3.0µm, Mobile phase: A for CO2 and B for IPA (0.1%DEA), Gradient: B 0-35%, Flow rate: 1.5 mL/min, Back pressure: 1800 psi, Column temperature: 35 °C, Wavelength: 214 nm [0848] Preparative separation method: [0849] Instrument: waters SFC 150, Column: DAICELCHIRALCEL®AD, 250*30 mm 10 ^m, Mobile phase: Supercritical CO2, and B for IPA (+0.1% 7.0mol/l Ammonia in MEOH), Gradient: B 40%, Flow rate: 120 ml /min, Back pressure: 100 bar, Column temperature: RT, Wavelength: 214 nm, Cycle time: 7.4 min, Sample preparation: Compound was dissolved in 55 mL methanol, Injection: 0.9 ml per injection. [0850] Compd 1-Fr1 (S or R) (470 mg, 47 %, 84.96% ee) was obtained as a yellow solid. [0851] LC purity (0.1%FA): 96.37% (UV at 254 nm)/MS: 420.2 [M+H]; Retention time: 0.888 min. [0852] Compd 1-Fr2 (S or R) (430 mg, 43%, 84.76% ee) was obtained as a yellow solid. [0853] LC purity (0.1%FA): 96.35% (UV at 254 nm)/MS: 420.2 [M+H]; Retention time: 0.890 min Synthesis of (S)-4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0854] To a mixture of (S)-4'-chloro-10'-(piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 238 μmol) in MeOH (5 mL) were added 4- (hydroxymethyl)cyclohexan-1-one (33.6 mg, 1.1 eq, 262 μmol) and tetraisopropyl titanate (1.00 mL) at 100 °C under microwave for 50 min. After adding NaBH3CN (44.9 mg, 3 eq, 714 μmol). The solution was stirred at 100 °C under microwave for 30 min. LCMS indicated finished. The reaction mixture was poured by sat. NaHCO3 solution (10 mL), and extracted with DCM (3 X 5 mL). The combined organic layers were washed with brine (15.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~13% MeOH/DCM gradient @50 mL/min). Compound (S)-4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin- 3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (76.0 mg, 143 μmol, 60%) was obtained as a yellow solid. LC purity (0.1%FA): 60% (UV at 254 nm)/MS: 532.2 [M+H]; Retention time: 0.909 min. Synthesis of 4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4) [0855] To a mixture of 4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (76 mg, 1 eq, 142.8 μmol) in DCM (5.00 mL) was added DMP (605.8 mg, 10 eq, 1.428 mmol). The solution was stirred at 0 °C for 1 h. LCMS indicated finished. The reaction mixture was poured by addition NH4Cl aqueous solution (20 mL), and extracted with DCM (3 X 5 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC ( DCM : MeOH = 10 : 1). Compound 4-(3-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1- carbaldehyde (70 mg, 110 μmol, 77.2%) was obtained as a yellow solid. LC purity (0.1%FA): 83.55% (UV at 254 nm)/MS: 530.3 [M+H]; Retention time: 0.968 min. Synthesis of (S)-3-(1'-((4-((S)-3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0856] To a mixture of (S)-4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (40 mg, 1 eq, 75.5 μmol) in MeOH (5 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (40.2 mg, 1.5 eq, 113 μmol) and TEA (0.10 mL) and HOAc (0.20 mL) for 30 min. After adding sodium cyanoborohydride (14.2 mg, 13.2 μL, 3 eq, 226 μmol). The solution was stirred at 25 °C for 16 h. LCMS indicated finished. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford compound (S)-3-(1'-((4-((S)-3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (9.24 mg, 10.3 μmol, 13.6%, Purity) as a white solid. LC purity (0.1%FA): 96.66% (UV at 254 nm)/MS: 869.7 [M+H]; Retention time: 4.297 min.1H NMR (400 MHz, MeOD) δ 8.42 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.84 (dd, J = 12.2, 7.9 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.34 (dt, J = 16.2, 7.6 Hz, 3H), 5.12 (dd, J = 13.3, 4.9 Hz, 1H), 4.56 (d, J = 4.3 Hz, 2H), 4.40 (q, J = 16.9 Hz, 2H), 3.57 (dd, J = 27.8, 16.5 Hz, 3H), 3.24 ^ 3.16 (m, 2H), 3.14 ^ 3.00 (m, 3H), 2.94 ^ 2.84 (m, 1H), 2.77 (d, J = 15.9 Hz, 1H), 2.58 ^ 2.46 (m, 1H), 2.39 (d, J = 6.2 Hz, 1H), 2.30 ^ 2.03 (m, 13H), 2.01 ^ 1.89 (m, 5H), 1.73 (dt, J = 29.0, 14.2 Hz, 11H), 1.33 ^ 1.28 (m, 1H), 1.12 (d, J = 11.8 Hz, 1H). Compound A207. (S)-3-(1'-((4-((R)-3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0857] To a mixture of (R)-4'-chloro-10'-(piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (100 mg, 1 eq, 0.24 mmol) in Methanol (5.0 mL) and tetraisopropyl titanate (1 mL) was added 4-(hydroxymethyl)cyclohexan-1-one (45.8 mg, 1.5 eq, 0.36 mmol) at 100 °C under microwave for 50 min. sodium cyanoborohydride (44.9 mg, 3 eq, 0.71 mmol) was added. The mixture was stirred at 100 °C under microwave for 30 min. LCMS indicated completion of reaction. The mixture was poured into saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 0~10% of MeOH in DCM) to afford (R)-4'-chloro-10'-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (85.0 mg, 0.13 mmol, 55.5%) as a colorless oil. LC purity (0.1%FA): 82.68% (UV at 254 nm)/MS: 532.3 [M+ H]; Retention time: 1.120 min. Synthesis of (R)-4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4) [0858] To a mixture of (R)-4'-chloro-10'-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-3-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (65 mg, 1 eq,.012 mmol) in DCM (2 mL) was added Dess-Martin periodinane (518 mg, 10 eq, 1.22 mmol). The mixture was stirred at 0 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into saturated ammonium chloride solution (20 mL), extracted with dichloromethane (10 mL X 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (R)-4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (40 mg, 75.5 µmol, 61.8%) as a white solid. LC purity (0.1% FA): 77.25% (UV at 254 nm)/MS: 530.2 [M+H]; Retention time: 0.913 min. Synthesis of (S)-3-(1'-((4-((R)-3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0859] A mixture of (R)-4-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (32 mg, 1 eq, 60.4 μmol) in methanol (2.0 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (32 mg, 1.5 eq, 90.5 μmol), TEA (0.2 mL) at 25 °C after 10 min. Acetic acid (0.5 mL) was added then stirred at 25 °C for 30 min. sodium cyanotrihydroborate (11 mg, 3 eq, 181 μmol) was added then stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The crude product was purified by prep-HPLC to afford (S)-3-(1'-((4-((R)-3-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1- yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (9.39 mg, 10.8 μmol, 17.8%,) as a white solid. LC purity (0.1% FA): 99.71% (UV at 254 nm)/MS: 869.7 [M+H]; Retention time: 4.217 min. 1H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.89 – 7.84 (m, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.41 ^ 7.30 (m, 3H), 5.15 ^ 5.10 (m, 1H), 4.57 (s, 2H), 4.40 (q, J = 17.1 Hz, 1H), 3.57 ^ 3.47 (m, 3H), 3.15 ^ 3.11 (m, 1H), 3.07 ^ 2.96 (m, 2H), 2.95 ^ 2.74 (m, 2H), 2.49 (dt, J = 13.7, 8.3 Hz, 2H), 2.26 ^ 2.00 (m, 15H), 1.99 ^ 1.72 (m, 13H), 1.71 ^ 1.54 (m, 4H), 1.33 ^ 1.27 (m, 1H), 1.14 ^ 1.06 (m, 1H). Compound A208. (R)-3-(1'-((1-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)azetidin-3-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione Sy

dolin-5- yl)piperidine-1-carboxylate (Intermediate 3) [0860] To a mixture of (R)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (100 mg, 1 eq, 281 μmol) in DMF (3.00 mL) was added triethylamine (1.42 mg, 1.96 μL, 0.05 eq, 14.1 μmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (96.3 mg, 2 eq, 563 μmol) was added at 25 °C for 16 h. The mixture was added NaBH3CN (51.3 mg, 3 eq, 844 μmol) and stirred at 25 °C for 0.5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated. The resulting residue was purified by reverse-phase chromatography to afford tert-butyl (R)-3-(7- (2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'- yl)azetidine-1-carboxylate (50 mg, 97.9 μmol, 34.8%) as a white solid. LC purity (0.1% FA): 88.26% (UV at 254 nm)/MS: 511.4 [M+H]; Retention time: 0.553 min. Synthesis of (R)-3-(1'-(azetidin-3-ylmethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate C1) [0861] To a solution of tert-butyl (R)-3-((7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-yl)methyl)azetidine-1-carboxylate (30 mg, 1 eq, 57.2 μmol) in DCM (3.00 mL) was added TFA (0.20 mL) and stirred at 25 °C for 2h. LCMS showed reaction was completed. The mixture was concentrated in vacuum to afford (R)-3-(1'-(azetidin-3- ylmethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine- 2,6-dione (25.0 mg, 58.9 μmol, 103%) as a white solid. LC purity (0.1% FA): 85.62% (UV at 254 nm)/MS: 425.1 [M+Na]; Retention time: 0.303 min. Synthesis of (R)-3-(1'-((1-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)azetidin-3-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0862] To a mixture of 4'-chloro-9'-(4-oxocyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (30 mg, 2 eq, 69.3 μmol) in DMF (3.00 mL) was added triethylamine (1.8 mg, 0.5 eq, 17.3 μmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then, a solution of (R)- 3-(1'-(azetidin-3-ylmethyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione (14.7 mg, 1 eq, 34.6 μmol) was added at 25 °C for 16 h. The mixture was added NaBH3CN (6.32 mg, 3 eq, 104 μmol) and stirred at 25 °C for 0.5 h. LCMS indicated completion of reaction. The reaction mixture was concentrated. The resulting residue was purified by reverse-phase chromatography to afford (R)-3-(1'-((1-(4-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)cyclohexyl)azetidin-3-yl)methyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.27 mg, 1.48 μmol, 4.28%, 98.26% Purity) as a white solid. LC purity (0.1% FA): 98.26% (UV at 254 nm)/MS: 842.4 [M+H]; Retention time: 0.353 min.1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.87 (dd, J = 15.1, 9.7 Hz, 2H), 7.75 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 7.7 Hz, 2H), 4.46 (dd, J = 24.1, 10.7 Hz, 2H), 4.16 (dd, J = 16.1, 10.7 Hz, 2H), 3.66 (s, 7H), 2.17 (ddd, J = 42.1, 27.3, 13.1 Hz, 11H), 1.96 ^ 1.59 (m, 8H), 1.41 (dd, J = 59.6, 16.0 Hz, 14H). Compound A209. 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)propyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro- 2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

,7'-

indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0863] To a solution of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (0.10 g, 1 eq, 0.24 mmol) and 3-bromopropan-1-ol (66 mg, 2 eq, 0.48 mmol) in DMF (3.00 mL) was added K2CO3 (99 mg, 3 eq, 0.71 mmol) at 25 ℃. The mixture was stirred at 60 ℃ for 2.5 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford 4'-chloro-9'-(1-(3-hydroxypropyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (0.10 g, 0.21 mmol, 88%) as a white solid. LC purity (0.1% FA): 77.33% (UV at 254 nm)/MS: 487.3 [M+H]; Retention time: 0.883 min. Synthesis of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)propyl (4-nitrophenyl) carbonate (Intermediate 5) [0864] To a solution of 4-nitrophenyl carbonochloridate (0.01 g, 1.5 eq, 0.06 mmol) in DCM (10 mL) was added TEA (6 mg, 9 μL, 1.5 eq, 0.06 mmol) at 0 ℃. The mixture was stirred at 25 ℃ for 0.5 h. Then, 4'-chloro-9'-(1-(3-hydroxypropyl)piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (0.02 g, 1 eq, 0.04 mmol) was added at 25 ℃. The mixture was stirred at 25 ℃ for 2 h. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)propyl (4-nitrophenyl) carbonate (20 mg, 31.1 μmol, 70%) as a white solid. LC purity (0.1%TFA): 85.53% (UV at 254 nm)/MS: 642.22 [M+H]; Retention time: 1.093 min. Synthesis of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)piperidin-1-yl)propyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate [0865] To a solution of 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)propyl (4-nitrophenyl) carbonate (15.0 mg, 1 eq, 23 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6- dione (8.3 mg, 1 eq, 23 μmol) in DMF (8.00 mL) were added NaHCO3 (2.0 mg, 1 eq, 23 μmol) and TEA (0.24 mg, 0.33 μL, 0.1 eq, 2.3 μmol) at 25 ℃. The mixture was stirred at 25 ℃ for 3 h. The reaction was monitored by LCMS. LCMS showed 28% of product. The residue was purified by Prep-TLC(DCM:MEOH=20:1) to afford 3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)propyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (3.93 mg, 4.49 μmol, 19%, 98.18% Purity) as a white solid. LC purity (0.03%FA): 85.68% (UV at 254 nm)/MS: 858.35[M+H]; Retention time: 1.103 min.1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 8.7 Hz, 1H), 8.00 (s, 1H), 7.86 (t, J = 8.2 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 9.1 Hz, 2H), 5.14 (dd, J = 13.9, 6.0 Hz, 2H), 4.70 (s, 2H), 4.46 (t, J = 13.3 Hz, 2H), 3.68 (d, J = 12.7 Hz, 4H), 3.63 (s, 2H), 3.12 (s, 4H), 2.83 (dd, J = 41.0, 15.4 Hz, 2H), 2.25 (d, J = 12.4 Hz, 5H), 2.13 (d, J = 19.6 Hz, 10H), 1.74 (d, J = 19.8 Hz, 2H), 1.60 (s, 6H), 1.31 (d, J = 16.1 Hz, 3H). Compound A210. (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclopentyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4'-chloro-9'-(3-(hydroxymethyl)cyclopent-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0866] To a mixture of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (840 mg, 1 eq, 2.02 mmol) in 1,4-dioxane (25 mL) and water (5 mL) were added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (164 mg, 0.1 eq, 202 umol), potassium phosphate (862.0 mg, 2.0 eq, 4.04 mmol), (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopent-2-en-1-yl)methanol (498 mg, 1.1 eq, 2.22 mmol). The mixture was stirred at 80 °C for 4 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (60*2 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-80% of ethyl acetate in petroleum ether) to afford 4'- chloro-9'-(3-(hydroxymethyl)cyclopent-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (437.3 mg, 958 umol, 47.4%) as a yellow solid. LC purity (0.1%TFA): 94.8% (UV at 254 nm)/MS: 433.3 [M +H]; Retention time: 1.360 min. Synthesis of 4'-chloro-9'-(3-(hydroxymethyl)cyclopentyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 4) [0867] To a mixture of 4'-chloro-9'-(3-(hydroxymethyl)cyclopent-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (240 mg, 1 eq, 0.554 mmol) in tetrahydrofuran (50 mL) was added 10% Pd/C (120 mg, 0.2 eq, 113 umol), followed by zinc bromide (62.4 mg, 0.5 eq, 0.277 mmol). The mixture was stirred at 25 °C for 16 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum, the residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-80% of ethyl acetate in petroleum ether) to afford 4'-chloro-9'-(3- (hydroxymethyl)cyclopentyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (64.1 mg, 0.147 mmol, 26.6%) as a yellow solid. LC purity (0.1%TFA): 100% (UV at 254 nm)/MS: 435.3 [M+ H]; Retention time: 1.360 min. Synthesis of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclopentane-1-carbaldehyde (Intermediate 5) [0868] To a mixture of 4'-chloro-9'-(3-(hydroxymethyl)cyclopentyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (90 mg, 1 eq, 207 umol) in dichloromethane (8 mL) was added Dess-Martin periodinane (175.8 mg, 2 eq, 414 umol). The reaction mixture was stirred at 25 °C for 1 h, LCMS indicated completion of reaction.8 mL of sat NaHCO3 solution and 8 mL of sat Na2S2O3 solution was added. The mixture was stirred at 25 °C for 30 min, extracted with dichloromethane (20 mL*2). The combined organic layers was dried over Na2SO4, filtered, the filtrate was concentrated under vacuum and the residue was purified by purified by silica gel column chromatography (100-200 mesh silica gel, 0-60% of ethyl acetate in petroleum ether) to afford 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclopentane-1-carbaldehyde (50.6 mg, 111 µmol, 53.8%) as a white solid. LC purity (0. 1%TFA): 95.19% (UV at 254 nm)/MS: 433.3 [M +H]; Retention time: 1.546 min. Synthesis of (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclopentyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0869] To a solution of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)cyclopentane-1-carbaldehyde (25.0 mg, 1 eq, 57.7 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (24.6 mg, 1.2 Eq, 69.3 μmol) in ethanol (8.00 mL) was added tetraethoxytitanium (65.9 mg, 5.0 Eq, 289 μmol). The reaction mixture was stirred at 25 °C for 1 h, then sodium cyanoborohydride (14.7 mg, 4.0 Eq, 234 umol) was added. The reaction mixture was stirred at 25 °C for 1 h, 8 mL of water was added. Ethanol was removed under reduced pressure, and the mixture was extracted with DCM (15 mL*3). The combined organic layers was dried over Na2SO4, filtered, the filtrate was evaporated, The residue was purified by ChemFlash (eluted with CH3CN in H2O (0.1% FA) from 0% to 100%) to afford (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclopentyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (7.35 mg, 9.38 μmol, 16.2%, 98.52% Purity) as white solid. LC purity (0.1%TFA): 98.52% (UV at 254 nm)/MS: 772.7 [M+H]; Retention time: 1.766 min. 1H NMR (400 MHz, MeOD-d4) δ 8.39 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.40-7.37 (m, 2H), 5.15-5.11 (m, 1H), 4.61 (s, 3H), 4.47-4.35 (m, 2H), 3.30-3.21 (m, 2H), 2.95-2.85 (m, 1H), 2.79-2.70 (m, 3H), 2.55-2.39 (m, 3H), 2.21-2.07 (m, 6H), 2.06-1.95 (m, 3H), 1.85-1.71 (m, 9H), 1.64-1.44 (m, 2H), 1.32-1.28 (m, 2H). Compound A211. (S)-3-(1'-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanol (Intermediate 2) [0870] To a mixture of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- carboxylate (3.0 g, 1.0 eq, 10.7 mmol) in THF (30 mL) at 0 °C was added LiBH4 (943 mg, 4.0 eq, 42.9 mmol) slowly at 0 °C, after 30 min, the reaction was stirred at 60 °C for 16 h. The mixture was poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanol (2.2g, 9.24 mol, 86.3%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ4.56-4.89 (m, 2H), 3.59 (s, 6H), 3.32-3.38 (m, 4H), 1.85 (s, 12H) Synthesis of 6'-(4-(hydroxymethyl)cyclohex-1-en-1-yl)spiro[cyclohexane-1,3'-indolin]-2'-one (Intermediate 4) [0871] To a mixture (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1- yl)methanol (2.2 g, 1 eq, 9.24 mmol) in 1,4-dioxane (30 mL) and water (3 mL) were added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (671 mg, 0.1 eq, 0.924 mmol), sodium carbonate (2.9 g, 3 eq, 27.72 mmol), 6'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (3.87 g, 1.5 eq, 13.85 mmol). The mixture was stirred at 90 °C for 12 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-30% of ethyl acetate in petroleum ether) to afford 6'-(4-(hydroxymethyl)cyclohex-1-en-1- yl)spiro[cyclohexane-1,3'-indolin]-2'-one (1.2 g, 3.86 mmol, 41.7%) as a yellow solid. LC purity (0.1%NH4HCO3): 80.8% (UV at ELSD)/MS: 312.9 [M +H]; Retention time: 0.682 min. Synthesis of 6'-(4-(hydroxymethyl)cyclohexyl)spiro[cyclohexane-1,3'-indolin]-2'-one (Intermediate 5) [0872] To a mixture of 6'-(4-(hydroxymethyl)cyclohex-1-en-1-yl)spiro[cyclohexane-1,3'- indolin]-2'-one (1.2 g, 1 eq, 3.86 mmol) in methanol (50 mL) was added 10% Pd/C (240 mg, 0.06 eq, 0.23 mmol). The mixture was stirred at 20 °C for 12 h under hydrogen atmosphere. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford 6'-(4-(hydroxymethyl)cyclohexyl)spiro[cyclohexane-1,3'-indolin]-2'-one (1.1 g, 3.51 mmol,90.9%) as a yellow solid. LC purity (0.1%FA): 13.23% (UV at 254 nm)/MS: 312.2 [M- H]; Retention time: 1.529 min. Synthesis of 2-bromo-6-(6'-(4-(hydroxymethyl)cyclohexyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-1'-yl)benzonitrile (Intermediate 7) [0873] To a mixture of 6'-(4-(hydroxymethyl)cyclohexyl)spiro[cyclohexane-1,3'-indolin]-2'-one (1.1 g, 1 eq, 3.51 mmol) in acetonitrile (50 mL) were added cesium carbonate (142 mg, 3 eq, 10.53 mmol) and 2-bromo-6-fluorobenzonitrile (838 mg, 1.2 eq, 4.21 µmol). The mixture was stirred at 80 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL X 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 2-bromo-6-(6'-(4-(hydroxymethyl)cyclohexyl)-2'-oxospiro[cyclohexane-1,3'-indolin]- 1'-yl)benzonitrile (936 mg, 1.90 mmol, 54.2%) as a white solid. LC purity (0.1% FA): 20.1% (UV at 254 nm)/MS: 493.2 [M+H]; Retention time: 1.873 min. Synthesis of 2-bromo-6-(6'-(4-(hydroxymethyl)cyclohexyl)-2'-oxospiro[cyclohexane-1,3'- indolin]-1'-yl)benzamide (Intermediate 8) [0874] To a mixture of 2-bromo-6-(6'-(4-(hydroxymethyl)cyclohexyl)-2'-oxospiro[cyclohexane- 1,3'-indolin]-1'-yl)benzonitrile (936 mg, 1 eq, 1.90 mmol) in DMSO (20 mL) was added potassium carbonate (786.6 mg, 3 eq, 5.7 µmol) at 0 °C then added hydrogen peroxide (646 mg, 10 eq, 19.0 mmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford 2-bromo-6-(6'-(4- (hydroxymethyl)cyclohexyl)-2'-oxospiro[cyclohexane-1,3'-indolin]-1'-yl)benzamide (470 mg, 921 µmol, 48.4%) as a white solid. LC purity (0.1% FA): 32.17 % (UV at 254 nm)/MS: 513.3 [M(Br)+H]; Retention time: 1.503 min. Synthesis of 4'-bromo-10'-(4-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (Intermediate 9) [0875] To a mixture of 2-bromo-6-(6'-(4-(hydroxymethyl)cyclohexyl)-2'-oxospiro[cyclohexane- 1,3'-indolin]-1'-yl)benzamide (390 mg, 1.0 eq, 764 µmol) in toluene (30.00 mL) was added p- toluenesulfonic acid (394 mg, 3.0 eq, 2.29 mmol). The reaction mixture was stirred at 140 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into H2O (50 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by reverse-phase chromatography to afford 4'-bromo-10'-(4- (hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (114 mg, 232 µmol, 30.3%) as a white solid. LC purity (0.1% FA): 25.38% (UV at 254 nm)/MS: 495.1 [M(Br)+ H]; Retention time: 1.738 min. Synthesis of 4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)cyclohexane-1-carbaldehyde (Intermediate10) [0876] A mixture of 4'-bromo-10'-(4-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (50 mg, 1 eq, 0.1 mmol) in DCM (10 mL) was added Dess-Martin periodinane (129 mg, 3.0 eq, 0.3 μmol). The solution was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was poured into H2O (50 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give 4-chloro-7,7-dimethyl-9-(piperidin-4-yl) indolo[1,2-a]quinazolin-5(7H)-one (42 mg, crude) as a white solid. no need purified and used next step directly.LC purity (0.1% FA): 20% (UV at 254 nm)/MS: 509.2 [M(Br)+H2O]; Retention time: 1.713 min. Synthesis of (S)-3-(1'-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl)piperidine-2,6-dione(S-3229) [0877] To a solution of 4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)cyclohexane-1-carbaldehyde (10 mg, 1 Eq, 20.3 μmol) and (S)-3-(6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (7.23 mg, 1.0 eq, 20.3 μmol) in MeOH (2.00 mL) was added NaBH3CN (1.28 mg, 1.0 eq, 20.3 μmol). The solution was stirred at 25 °C for 30 min.LC-MS indicated the starting material was consumed completely. The reaction mixture was poured by addition H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluting with H2O:CH3CN (neutral conditions) from 90:10 to 5:95 to give (S)-3-(1'-((4-(4'-bromo-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.77 mg, 2.13 μmol, 10.5%) as a white solid.LC purity (0.1% FA): 100% (UV at 254 nm)/MS: 832.2 [M+H]; Retention time: 1.225 min.1H NMR (400 MHz, MeOD-d4) δ 8.46 (s, 1H), 7.97 (s, 1H), 7.88-7.91 (m, 1H), 7.75-7.82 (m, 2H), 7.37-7.43 (m, 3H), 5.33-5.35 (m, 2H), 5.12-5.17 (m, 2H), 4.72 (s, 1H), 4.43- 4.46 (m, 2H), 3.40-3.69 (m, 3H), 2.80-3.13 (m, 6H), 2.02-2.34 (m, 7H), 1.60-1.90 (m, 8H),1.58- 1.59 (m, 4H), 1.28-1.33 (m, 4H). Compound A212. (S)-3-(1'-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)prop-2-yn-1-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of 4-chloro-10-(3-hydroxyprop-1-yn-1-yl)-5H-spiro[cyclohexane-1,7-indolo[1,2- a]quinazolin]-5'-one (Intermediate 3) [0878] To a solution of 10'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (200 mg, 1 eq, 481 μmol) in toluene (1 mL) were added CuI (9.2 mg, 0.1 eq, 48.1 μmol), prop-2-yn-1-ol (80.9 mg, 3 eq, 1.44 mmol) and PdCl2(dppf) (17.6 mg, 0.05 eq, 24.1 μmol) and TEA (243 mg, 335 μL, 5 eq, 2.41 mmol). The mixture was stirred at 80 °C for 4 h. LCMS indicated completion of reaction. The crude product was purified by Prep-TLC (PE:EA= 3:1). The product4'-chloro-10'-(3-hydroxyprop-1-yn-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (178 mg, 455 μmol, 94.7 %) was obtained as brown solid. LC purity (0.1% FA):77.73% (UV at 254 nm)/MS: 391.2 [M +H]; Retention time: 1.183 min. Synthesis of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)prop-2-yn-1-yl methanesulfonate (Intermediate 4) [0879] To a solution of 4'-chloro-10'-(3-hydroxyprop-1-yn-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (18.0 mg, 1 eq, 46.1 μmol) in DCM (2 mL) was added TEA (14.0 mg, 19.3 μL, 3 eq, 138 μmol), after 20min was added methanesulfonyl chloride (10.5 mg, 2 eq, 92.1 μmol). The mixture was stirred at 0 °C for 1 h. LCMS indicated completion of reaction The crude product was purified by Prep-TLC (PE:EA=2:1). The product3-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)prop-2-yn-1-yl methanesulfonate (15.0 mg, 32.0 μmol, 69.5%) was obtained as white solid.LC purity (0.1% FA): 81.32% (UV at 254 nm)/MS: 469.1 [M+H]; Retention time: 1.373 min. Synthesis of (S)-3-(1'-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)prop-2-yn-1-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione [0880] To a solution of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)prop-2-yn-1-yl methanesulfonate (15.0 mg, 1 eq, 32.0 μmol) in DMF (2.00 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6- dione (11.4 mg, 1 eq, 32.0 μmol), KI (15.9 mg, 3 eq, 96.0 μmol) and sodium bicarbonate (8.06 mg, 3.73 μL, 3 eq, 96.0 μmol). The mixture was stirred at 100 °C for 2 h. LCMS indicated completion of reaction. The crude product was purified by Prep-HPLC. The product(S)-3-(1'-(3- (4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)prop-2-yn-1-yl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (3.57 mg, 4.90 μmol, 15.3%) was obtained as white solid.LC purity (0.1% FA): 98.27 % (UV at 254 nm)/MS: 728.3 [M+H]; Retention time: 1.013 min.1H NMR (400 MHz, MeOD) δ 8.38 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.91 ^ 7.82 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.40 (q, J = 7.7 Hz, 2H), 5.15 ^ 5.09 (m, 1H), 4.64 (s, 1H), 4.42 (q, J = 17.0 Hz, 2H), 3.86 (s, 2H), 3.70 ^ 3.45 (m, 2H), 2.95 ^ 2.85 (m, 1H), 2.72 (dd, J = 30.1, 18.4 Hz, 3H), 2.50 (dt, J = 13.2, 8.5 Hz, 1H), 2.20 ^ 1.75 (m, 16H). Compound A213. (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-2-ene-1-carboxylate (Intermediate 2) [0881] To a mixture of ethyl 3-oxocyclohexane-1-carboxylate (2.00 g, 1 eq, 11.8 mmol) in THF (30 mL) at -78 °C was added lithium diisopropylamide solution (1.89 g, 1.5 eq, 17.6 mmol) dropwise slowly at -78 °C, after 30 min, Trifluoromethanesulfonic anhydride (4.31 g, 1.3 eq, 15.3 mmol) was added then stirred at 25 °C for 4 h. TLC (petroleum ether : ethyl acetate = 5 : 1, Rf = 0.8) indicated compound I was consumed completely and a new spot formed. The mixture was poured into saturated ammonium chloride solution (60 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-2-ene-1-carboxylate (820 mg, 2.71 mmol, 23.1%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 5.82 (dd, J = 27.6, 25.7 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.71 ^ 2.41 (m, 2H), 2.30 ^ 2.16 (m, 2H), 1.98 ^ 1.60 (m, 3H), 1.21 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, CDCl3) δ -73.83 (s), -73.96 (s). Synthesis of ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-ene-1-carboxylate (Intermediate 3) 513 [0882] To a mixture of ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-2-ene-1-carboxylate (820 mg, 1 eq, 2.71 mmol) in 1,4-dioxane (10 mL) were added bis(pinacolato)diborane (1.03 g, 1.5 eq, 4.07 mmol), potassium acetate (799 mg, 3 eq, 8.14 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium(II) dichloride (199 mg, 0.1 eq, 0.27 mmol). The mixture was stirred at 80 °C for 16 h under argon atmosphere. TLC (petroleum ether: ethyl acetate = 10 : 1, Rf = 0.6) indicated compound I was consumed completely and a new spot formed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford ethyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-ene-1-carboxylate (476 mg, 1.70 mmol, 62.6%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 4.12 – 4.01 (m, 2H), 2.44 – 2.35 (m, 1H), 2.24 ^ 2.02 (m, 3H), 1.99 ^ 1.87 (m, 1H), 1.84 ^ 1.66 (m, 1H), 1.63 ^ 1.51 (m, 1H), 1.22 ^ 1.17 (m, 15H). Synthesis of (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl)methanol (Intermediate 4) [0883] To a mixture of ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-ene-1- carboxylate (376 mg, 1 eq, 1.34 mmol) in THF (5 mL) was added diisobutylaluminium hydride (2.68 mL, 3 eq, 4.03 mmol) was added then stirred at 0 °C for 1 h. The mixture was poured into saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (10 mL X 2). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2- en-1-yl)methanol (277 mg, 1.16 mmol, 86.7%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.51 (d, J = 52.7 Hz, 1H), 3.63 ^ 3.47 (m, 2H), 2.32 ^ 2.09 (m, 3H), 1.86 ^ 1.71 (m, 3H), 1.57 (s, 1H), 1.26 (s, 12H). Synthesis of 4'-chloro-9'-(3-(hydroxymethyl)cyclohex-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 7) [0884] To a mixture of 9'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (150 mg, 1 eq, 368.0 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) were added (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl)methanol (129 mg, 1.5 eq, 0.54 mmol), potassium phosphate, tribasic (153 mg, 2 eq, 0.72 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.1 eq, 0.04 mmol). The mixture was stirred at 80 °C for 2 h under argon atmosphere. LCMS indicated completion of reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of EtOAc in PE) to afford 4'-chloro-9'-(3- (hydroxymethyl)cyclohex-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (189 mg, 0.39 mmol, 87.9%) as a yellow oil. LC purity (0.1% FA): 98.68% (UV at 254 nm)/MS: 447.2 [M+H]; Retention time: 1.663 min. Synthesis of tert-butyl 4'-chloro-9'-(3-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 8) [0885] To a mixture of 4'-chloro-9'-(3-(hydroxymethyl)cyclohex-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (53.0 mg, 1 eq, 119 µmol) in THF (12 mL) were added zinc bromide (8.01 mg, 0.3 eq, 36 µmol), 10% Pd(OH)2 (20 mg, 1.2 eq, 142 µmol) at 25 °C for 2 h under hydrogen atmosphere. LCMS indicated completion of reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH=20:1) to afford compound 4'-chloro-9'-(3-(hydroxymethyl)cyclohexyl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (50 mg, 108 µmol, 91.2%) as a colorless oil. LC purity (0.1% FA): 97.13% (UV at 254 nm)/MS: 449.1 [M+H]; Retention time: 1.665 min. Synthesis of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexane-1-carbaldehyde (Intermediate 9) [0886] To a mixture of 4'-chloro-9'-(3-(hydroxymethyl)cyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (45 mg, 1 eq, 100.2 μmol) in dichloromethane (1 mL) was added Dess-Martin periodinane (212 mg, 5 eq, 501.1 μmol). The reaction mixture was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with dichloromethane (10 mL X 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 100% of EtOAc in PE) to afford 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexane-1-carbaldehyde (30 mg, 58.7 µmol, 58.5%) as a colorless oil. LC purity (0.1% FA): 87.41% (UV at 254 nm)/MS: 447.0 [M+H]; Retention time: 1.937 min. Synthesis of (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole- 3,4'-piperidin]-7-yl)piperidine-2,6-dione [0887] A mixture of 3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'- yl)cyclohexane-1-carbaldehyde (10 mg, 1 eq, 22.4 μmol) in methanol (2 mL) were added (S)-3- (6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (10 mg, 1.2 eq, 26.8 µmol), TEA (0.02mL). The mixture was stirred at 25 °C for 10 min. Acetic acid (0.05 mL) was added then stirred at 25 °C for 10 min. sodium cyanoborohydride (4.2 mg, 3 eq, 195 μmol) was added then stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The crude product was purified by prep-HPLC to afford (3S)-3-(1'-((3-(4'-chloro-5'-oxo-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)cyclohexyl)methyl)-6-oxo-6,8-dihydro- 2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (1.65 mg, 1.9 μmol, 8.5%,) as a white solid. LC purity (0.1% FA): 90.96% (UV at 254 nm)/MS: 786.7 [M+H]; Retention time: 5.407 min.1H NMR (400 MHz, MeOD) δ 8.48 (s, 2H), 8.40 (d, J = 9.0 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.69 (dd, J = 24.8, 6.9 Hz, 1H), 7.43 ^ 7.32 (m, 2H), 5.13 (dd, J = 14.1, 5.5 Hz, 1H), 4.64 (s, 1H), 4.42 (q, J = 17.1 Hz, 1H), 3.66 ^ 3.52 (m, 1H), 2.95 ^ 2.57 (m, 6H), 2.28 ^ 2.08 (m, 6H), 1.89 (ddd, J = 42.9, 30.1, 14.8 Hz, 13H), 1.63 ^ 1.52 (m, 2H), 1.34 ^ 1.28 (m, 8H). Compound A214. (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-1-methylcyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

Synthesis of ethyl 1-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (Intermediate 2) [0888] To a solution of ethyl 1-methyl-4-oxocyclohexane-1-carboxylate (2.00 g, 1 eq, 10.9 mmol), 2,6-di-tert-butylpyridine (3.12 g, 1.5 eq, 16.3 mmol) in DCE (15 mL) was added Tf2O (3.98 g, 1.3 eq, 14.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford ethyl 1-methyl- 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1.50 g, 4.74 mmol, 43.7 %) as a white solid. LC purity (0.1% FA): 68.3% (UV at 254 nm)/MS: 317.4 [M +H]; Retention time: 1.22 min. Synthesis of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- carboxylate (Intermediate 3) [0889] To a solution of ethyl 1-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1- carboxylate (3.00 g, 1 eq, 9.48 mmol) in 1,4-dioxane (30 mL) were added bis(pinacolato)diborane (3.61 g, 1.5 eq, 14.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (694 mg, 0.1 eq, 948 μmol) and potassium acetate (1.86 g, 2 eq, 19.0 mmol). The mixture was stirred at 90 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 30% of EtOAc in PE) to afford ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- carboxylate as a white solid.LC purity (0.1% FA): 55.98% (UV at 254 nm)/MS: 295.2 [M+H]; Retention time: 1.78 min. Synthesis of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- carboxylate (Intermediate 4) [0890] To a solution of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex- 3-ene-1-carboxylate (1.20 g, 1 eq, 4.08 mmol) in THF (12 mL) was added diisobutylaluminum hydride (870 mg, 1.5 eq, 6.12 mmol) at 0 °C. The reaction was stirred 0 °C for 1 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to afford ethyl 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1.20 g, 1 eq, 4.08 mmol) as a yellow oil. LC purity (0.1% FA): 46.98% (UV at 254 nm)/MS: 253.2 [M+H]; Retention time: 1.50 min. Synthesis of 4'-chloro-10'-(3-(hydroxymethyl)-3-methylcyclohex-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 6) [0891] To a solution of (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en- 1-yl)methanol (300 mg, 1 eq, 1.19 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) were added 10'-bromo-4'-chloro-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (593 mg, 1.2 eq, 1.43 mmol), K2CO3 (411.0 mg, 2.5 eq, 2.974 mmol) and PdCl2(dppf) (87.1 mg, 0.1 eq, 119 μmol) at rt. The reaction was stirred 100 °C for 3 h under N2. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to afford 4'-chloro-10'-(3-(hydroxymethyl)-3- methylcyclohex-1-en-1-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one as a yellow solid. LC purity (0.1% FA): 81.98% (UV at 254 nm)/MS: 461.2 [M+H]; Retention time: 1.52 min. Synthesis of 4'-chloro-10'-(4-(hydroxymethyl)-4-methylcyclohexyl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 7) [0892] To a solution of 4'-chloro-10'-(4-(hydroxymethyl)-4-methylcyclohex-1-en-1-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (200 mg, 1 eq, 433 μmol) in EA (5.00 mL) was added Pd/C (50.5 mg, 1.09 eq, 475 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The organic phase is filtered with diatomaceous earth. The reaction mixture was concentrated to give 4'-chloro-10'-(4-(hydroxymethyl)-4- methylcyclohexyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one as a colorless oil. LC purity (0.1% FA): 50.98% (UV at 254 nm)/MS: 463.2 [M+H]; Retention time: 1.51min. Synthesis of 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)-1- methylcyclohexane-1-carbaldehyde (Intermediate 8) [0893] To a solution of 4'-chloro-10'-(4-(hydroxymethyl)-4-methylcyclohexyl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (30 mg, 1 eq, 64.8 μmol) in DCM (2 mL) was added DMP (55.0 mg, 2 eq, 130 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to afford 4-(4'-chloro- 5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)-1-methylcyclohexane-1- carbaldehyde (15.0 mg, 32.5 μmol, 50.2%) as a colorless oil. LC purity (0.1% FA): 30.9% (UV at 254 nm)/MS: 461.2 [M+H]; Retention time: 1.61min. Synthesis of (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)-1-methylcyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0894] To a solution of 4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 10'-yl)-1-methylcyclohexane-1-carbaldehyde (10 mg, 1 eq, 21.7 μmol) in DMF (2 mL) were added potassium acetate (2.13 mg, 1 eq, 21.7 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (8.48 mg, 1.1 eq, 23.9 μmol) and sodium cyanoborohydride (1.36 mg, 1 eq, 21.7 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction mixture was extracted with ethyl acetate (100 mL) and concentrated under vacuum. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL X 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC，eluted with MeCN in H2O (0.1% FA) from 15% to 30% to afford (S)-3-(1'-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'- yl)-1-methylcyclohexyl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione (1.00 mg, 1.25 μmol, 5.76%) as a white solid. LC purity (0.1% FA): 96.27% (UV at 254 nm)/MS: 800.4 [M +H]; Retention time: 1.32 min.1H NMR (400 MHz, MeOD-d4) δ 8.51-8.34 (m, 1H), 7.86 (t, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.48 (d, J = 6.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18-7.14 (m, 1H), 5.40-5.35 (m, 1H), 5.15 (d, J = 5.2 Hz, 2H), 4.43 (d, J = 12.8 Hz, 2H), 2.80 (s, 2H), 2.53-2.46 (m, 2H), 2.18 (d, J = 7.2 Hz, 2H), 2.10-1.98 (m, 5H), 1.90-1.72 (m, 4H), 1.81-1.70 (m, 4H), 1.40-1.12 (m, 6H), 1.32- 1.12 (m, 5H), 1.17-1.01 (m, 3H), 0.95-0.86 (m, 3H). Compound A215. (3S)-3-(1'-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclopentyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione

,2- a]quinazolin]-5'-one (Intermediate 2) [0895] To a solution of 4'-chloro-10'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (50 mg, 1 eq, 108 μmol) in water (0.2 mL) and 1,4-dioxane (2 mL) were added TEA (16.4 mg, 1.5 eq, 162 μmol) and cyclopent-2-en-1-one (8.87 mg, 1 eq, 108 μmol) and bis(1,5-cyclooctadiene)dirhodium(I)dichloride (5.33 mg, 0.1 eq, 10.8 μmol) stirred at 100 °C, Then mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was quenched with water (30 ml), washed with EA (20 mL X 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to get 4'-chloro-10'-(3-oxocyclopentyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (15.0 mg, 35.8 μmol, 33.1%) as a yellow solid. LC purity (0.1% FA): 95.73% (UV at 254 nm)/MS: 695.2 [M+H]; Retention time: 1.56 min. Synthesis of (3S)-3-(1'-(3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclopentyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0896] To a solution of 4'-chloro-10'-(3-oxocyclopentyl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (30 mg, 1 eq, 71.6 μmol) in DMF (2 mL) were added sodium cyanoborohydride (9.00 mg, 2 eq, 143 μmol) and (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (25.5 mg, 1 eq, 71.6 μmol) and potassium acetate (14.1 mg, 2 eq, 143 μmol). The mixture was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum. The resulting residue was purified by prep-HPLC, eluted with MeCN in H2O (0.1% FA) from 15% to 30% to get (3S)-3-(1'- (3-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)cyclopentyl)-6- oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (10.26 mg, 13.17 μmol, 18.4%) as a yellow solid. LC purity (0.1%FA): 98.63% (UV at 254 nm)/MS: 758.5 [M+ H]; Retention time: 1.43 min. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.61-8.38 (m, 1H), 8.12-7.94 (m, 1H), 7.92-7.77 (m, 2H), 7.71-7.61 (m, 1H), 7.45-7.19 (m, 3H), 5.17-5.03 (m, 1H), 4.81-4.58 (m, 2H), 4.41 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 17.2 Hz, 1H), 3.93-3.53 (m, 4H), 3.31 (s, 1H), 3.10 (s, 2H), 2.97-2.83 (m, 1H), 2.69-2.56 (m, 2H), 2.44 (d, J = 13.0 Hz, 1H), 2.36-2.25 (m, 2H), 2.34-2.21 (m, 2H), 2.21-2.10 (m, 2H), 2.10-1.82 (m, 8H), 1.82- 1.60 (m, 6H). Compound A216. (S)-3-(1'-((1-((1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

-a] quinazolin-5(7H)-one (Intermediate 3) [0897] To a solution of 4-chloro-7,7-dimethyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolo[1,2-a] quinazolin-5(7H)-one (200 mg, 1.0 eq, 473 μmol) in acetonitrile (10 mL) were added copper(II) acetate hydrate (94.5 mg, 1.0 eq, 473 μmol), 4-(dimethoxymethyl) piperidine (90.4 mg, 1.2 eq, 568 μmol) and triethylamine (47.9 mg, 1.0 eq 473 μmol). The mixture was stirred at 70 °C for 3 h under Ar. The reaction was monitored by LCMS. LCMS showed 32% of product. The mixture was filtered and concentrated to get the crude product. The crude product was purified by pre-TLC (DCM: MeOH=30:1) to get 4-chloro-10-(4-(dimethoxymethyl)piperidin-1-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 220 μmol, 46.6%) as yellow oil. LC purity (0.1% FA): 81.59% (UV at 254 nm)/MS: 454.2 [M+H]; Retention time: 1.243 min. Synthesis of 1-(4-chloro-7,7 -dimethyl-5-oxo-5,7-dihydroindolo[1,2-a] quinazolin-10-yl) piperidine-4-carbaldehyde (Intermediate 4) [0898] To a solution of 4-chloro-10-(4-(dimethoxymethyl) piperidin-1-yl)-7,7- dimethylindolo[1,2-a] quinazolin-5(7H)-one (100 mg, 1.0 eq, 220 μmol) in DCM (4.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 2 h under Ar. The reaction was monitored by LCMS. LCMS showed OK. The mixture was concentrated to get 1-(4-chloro-7,7 - dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidine-4-carbaldehyde (90 mg, 221 μmol, 100%) as yellow oil. LC purity (0.1% FA): 88.23% (UV at 254 nm)/MS: 408.1 [M+H]; Retention time: 1.393 min. Synthesis of 4-chloro-10-(4-((4-(dimethoxymethyl) piperidin-1-yl) methyl) piperidin-1-yl)-7,7- dimethylindolo[1,2-a] quinazolin-5(7H)-one (Intermediate 6) [0899] To a solution of 1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a] quinazolin-10- yl)piperidine-4-carbaldehyde (70 mg, 1.0 eq, 172 μmol) in DMF (5.00 mL) were added 4- (dimethoxymethyl) piperidine (32.8 mg, 1.2 eq, 206 μmol) and potassium acetate (50.5 mg, 3.0 eq 515 μmol). The mixture was stirred at 25 °C for 10 mins, and to the mixture was added sodium triacetoxyhydroborate (109 mg, 3.0 eq, 515 μmol). The mixture was stirred at 25 °C for 1 h under Ar. The reaction was monitored by LCMS. LCMS showed most of product. The mixture was quenched with water and extracted with DCM: MeOH(10:1). The organic phase was concentrated to get the crude product. The crude product was purified by pre- TLC(DCM:MeOH=20:1) to get 4-chloro-10-(4-((4-(dimethoxymethyl)piperidin-1- yl)methyl)piperidin-1-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 72.6 μmol, 42.3%) as yellow oil. LC purity (0.1% FA): 73.10% (UV at 254 nm)/MS: 551.3 [M+H]; Retention time: 1.028 min. Synthesis of 1-((1-(4-chloro-7, 7 -dimethyl-5-oxo-5,7-dihydroindolo[1,2-a] quinazolin-10-yl) piperidin-4-yl) methyl) piperidine-4-carbaldehyde (Intermediate 7) [0900] To a solution of 4-chloro-10-(4-((4-(dimethoxymethyl) piperidin-1-yl) methyl) piperidin- 1-yl)-7,7-dimethylindolo[1,2-a] quinazolin-5(7H)-one (40 mg, 1.0 eq, 72.6 μmol) in DCM (4.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 1 h under Ar. The reaction was monitored by LCMS. The mixture was concentrated to get the crude product.1-((1-(4-chloro- 7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-4-yl)methyl)piperidine- 4-carbaldehyde (36.0 mg, 71.3 μmol, 98.2%) was obtained as yellow oil. LC purity (0.1% FA): 95.86% (UV at 254 nm)/MS: 523.3 [M+H]; Retention time: 0.938 min. Synthesis of (S)-3-(1'-((1-((1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a] quinazolin- 10-yl) piperidin-4-yl) methyl) piperidin-4-yl) methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0901] To a solution of 1-((1-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (20 mg, 1.0 eq, 39.6 μmol) in DMF (2.00 mL) were added (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7- yl)piperidine-2,6-dione (15.5 mg, 1.1 eq, 43.6 μmol) and potassium acetate (11.7 mg, 7.43 μL, 3.0 eq, 119 μmol). The mixture was stirred at 25 °C for 10 mins, and to the mixture was added sodium triacetoxyborohydride (25.2 mg, 17.6 μL, 3.0 eq, 119 μmol). The mixture was stirred at 25 °C for 1 h under Ar. The reaction was monitored by LCMS. LCMS showed most of product. The mixture was quenched with water and extracted with DCM:MeOH(10:1). The organic phase was concentrated to get the crude product. The crude product was purified by pre-HPLC (eluted with CH3CN in H2O (0.1% TFA) from 5.0% to 95%). (S)-3-(1'-((1-((1-(4-chloro-7,7-dimethyl-5-oxo- 5,7-dihydroindolo[1,2-a] quinazolin-10-yl) piperidin-4-yl) methyl) piperidin-4-yl) methyl)-6-oxo- 6,8-dihydro-2H,7H-spiro[furo[2,3-e] isoindole-3,4'-piperidin]-7-yl) piperidine-2,6-dione (6.79 mg, 7.78 μmol, 19.6%, 96.76% Purity) was obtained as faint yellow solid. LC purity (0.1% FA in H2O, 0.1% FA in ACN): 96.76% (UV at 254 nm)/MS: 844.4 [M+H]; Retention time: 0.868 min. 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.37 (d, J = 4.2 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H),7.64 (d, J = 3.8 Hz, 1H), 7.51 (d, J = 4.0 Hz, 2H), 7.36 (d, J = 3.8 Hz, 1H),7.30 (s, 1H),6.98(s, 1H ),5.12- 5.08(m,1H),4.68 (s, 2H),4.38 (s, 1H), 4.24(d, J = 8.6 Hz, 1H), 3.87(d, J = 6.0 Hz, 2H), 3.63 (s, 10H),3.06 (s, 4H), 2.92-2.83(m, 4H), 2.67-2.56(m,2H),2.32-2.22(m,2H),2.01-1.99 (m, 4H),1.99- 1.87(m, 2H),1.55-1.52(m,2H),1.48(s, 6H),1.43-1.34(m,2H). Compound A217. (S)-3-(1'-(7-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

ne- 1,3'-indolin]-2'-one (Intermediate 3) [0902] A mixture of 5'-bromospiro[cyclohexane-1,3'-indolin]-2'-one (300 mg, 1 eq, 1.08 mmol), 2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonane (413.4 mg, 1.5 eq, 1.62 mmol), Ruphos (413.4 mg, 0.3 eq, 1.62 mmol), Ruphos Pd G2 (271 mg, 0.3 eq, 1.62 mmol) and LiHMDS (1 M) (6.5 mL) in toluene (13 mL) in a microwave reactor was heated to 115 °C for 1 h. LCMS indicated completion of reaction. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-20% of ethyl acetate in petroleum ether) to afford 5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7- yl)spiro[cyclohexane-1,3'-indolin]-2'-one (171.5 mg, 312 umol, 29.2%) as a yellow solid. LC purity (0.1%TFA): 82.8% (UV at 254 nm)/MS: 455.3 [M +H]; Retention time: 1.353min. Synthesis of 2-(5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzonitrile (Intermediate 5) [0903] To a mixture of 5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7- yl)spiro[cyclohexane-1,3'-indolin]-2'-one (943.1 mg, 1 eq, 2.08 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.04 g, 2.0 eq, 4.16 mmol), followed by 2-chloro-6-fluorobenzonitrile (832.0 mg, 2.0 eq, 4.16 mmol). The mixture was stirred at 88 °C for 4 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum, the residue was dissolved in ethyl acetate (100 mL), the organic layer was washed with water (20 mL), dried over Na2SO4, filtered, the filtrate was evaporated under reduce pressure, the residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-15% of ethyl acetate in petroleum ether) to afford 2-(5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzonitrile (713 mg, 0.859 mmol, 41.4%) as a yellow solid. LC purity (0.1%TFA): 71.1% (UV at 254 nm)/MS: 590.4 [M+ H]; Retention time: 1.611 min. Synthesis of 2-(5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzamide (Intermediate 6) [0904] To a mixture of 2-(5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzonitrile (713 mg, 1 eq, 1.21 mmol) in dimethyl sulfoxide (20 mL) was added potassium carbonate (334 mg, 2.0 eq, 2.42 mmol), followed by hydrogen peroxide (30%, w/w) (1.29 mL). The mixture was stirred at 60 °C for 2 h. LCMS indicated completion of reaction. The mixture was diluted with 80 mL of water, extracted with ethyl acetate (80 mL*2). The combined organic layers was washed with water (80 mL*2), dried over Na2SO4, filtered, the filtrate was evaporated under reduce pressure, the residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-25% of ethyl acetate in petroleum ether) to afford 2-(5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7-yl)- 2'-oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzamide (477.4 mg, 0.784 mmol, 44.1%) as a yellow solid. LC purity (0.1%TFA): 67.8% (UV at 254 nm)/MS: 608.4 [M+ H]; Retention time: 1.627 min. Synthesis of 4'-chloro-9'-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (Intermediate 8) [0905] A mixture of 2-(5'-(2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonan-7-yl)-2'- oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-6-chlorobenzamide (474 mg, 1 eq, 779 μmol) and 4- methylbenzenesulfonic acid (403 mg, 3.0 eq, 2.34 mmol) in toluene (30 mL) with water knockout vessel was heated to 138 °C for 16 h, LCMS indicated completion of reaction. The reaction mixture was evaporated, the residue was purified by Prep-TLC (dichloromethane:methanol=15:1) to afford 4'-chloro-9'-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (235.6 mg, 0.0.46 mmol, 59.1% ). LC purity (0.1%TFA): 92.9% (UV at 254 nm)/MS: 476.3[M+ H]; Retention time: 1.088 min. [0906] Synthesis of 4'-chloro-9'-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-5'-one (Intermediate 9) [0907] To a solution of 4'-chloro-9'-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (120 mg, 1 eq, 252 μmol) in dimethyl sulfoxide (5.00 mL) was added 2-iodylbenzoic acid (141 mg, 2.0 eq, 504 μmol). The reaction mixture was stirred at 25 °C for 1 h, LCMS indicated completion of reaction.20 mL of water was added, followed by 5 mL of Sat NaHCO3 solution. Extracted with dichloromethane (25mL*3). The combined organic layers was washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered, the filtrate was evaporated, the residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-1% of methanol in dichloromethane) to afford 4'-chloro-9'-(2-oxo-7- azaspiro[3.5]nonan-7-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (80.5 mg, 163 μmol, 64.8%) as a yellow solid. LC purity (0.1%TFA): 92.64% (UV at 254 nm)/MS: 474.3 [M+ H]; Retention time: 1.386 min. Synthesis of ((S)-3-(1'-(7-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 9'-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin]-7-yl)piperidine-2,6-dione [0908] A mixture of 4'-chloro-9'-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-5'-one (15.0 mg, 1 eq, 31.6 μmol), (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (13.5 mg, 1.2 eq, 38.0 μmol) and tetraethoxytitanium (36.1 mg, 5.0 eq, 158 μmol) in ethanol (5.00 mL) was heated to 60 °C for 16 h, cooled down to rt, sodium cyanoborohydride (10 mg, 5.0 eq, 158 umol) was added, stirred at 25 °C for 1 h, 10 mL of water was added, most of ethanol was removed under reduced pressure. The water phase was extracted with dichloromethane (10 mL*3). The combined organic layers were dried over Na2SO4, filtered, the filtrate was evaporated. The residue was purified by pre- HPLC. (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to afford (S)-3-(1'-(7-(4'- chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-9'-yl)-7-azaspiro[3.5]nonan- 2-yl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6- dione (4.18 mg, 5.12 μmol, 16.2%) as a white solid.. LC purity (0.1%TFA): 99.67% (UV at 254 nm)/MS: 813.6 [M+H]; Retention time: 6.699 min.1H NMR (400 MHz, MeOD-d4) δ 8.35 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.81 (t, J = 8.4 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.41- 7.35 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 5.15-5.11 (m, 1H), 4.59 (s, 2H), 4.47-4.35 (m, 2H), 3.22- 3.19 (m, 3H), 3.11-3.08 (m, 3H), 2.90-2.75 (m, 3H), 2.51-2.47 (m, 1H), 2.24-2.18 (m, 7H), 2.10- 1.99 (m, 5H), 1.89-1.80 (m, 11H), 1.33-1.30 (m, 2H). Compound A218. (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)-2-hydroxypropyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione O NH H_N ^N O O N O Br N O N 2 N 1 Cl O b^s NH O -1,7'-

indolo[1,2-a]quinazolin]-5'-one (Intermediate 3) [0909] The mixture of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-5'-one (300 mg, 1.0 eq, 714 μmol) and potassium carbonate (197 mg, 2.0 eq, 1.43 mmol), 2-(bromomethyl)oxirane (196 mg, 2.0 eq, 1.43 mmol) in DMF (3.00 mL) was stirred at 70 °C for 2 h under N2. LCMS indicated completion of reaction. The mixture was filtrated, the residue was purified by flash chromatography (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to get 4'-chloro-9'-(1-(oxiran-2-ylmethyl) piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a] quinazolin]-5'-one (230 mg, 483 μmol,67.6%) as a white solid. LC purity (0.1% FA): 94.18% (UV at 254 nm)/MS: 476.1 [M+MeCN +H]; Retention time: 1.094 min. Synthesis of (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-9'-yl)piperidin-1-yl)-2-hydroxypropyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione [0910] To a solution of 4'-chloro-9'-(1-(oxiran-2-ylmethyl)piperidin-4-yl)-5'H- spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one (30 mg, 1.0 eq, 63.0 μmol) and TEA (31.9 mg, 43.9 μL, 5.0 eq, 315 μmol) in EtOH (1.50 mL) was added (S)-3-(6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (33.6 mg, 1.5 eq, 94.5 μmol) and stirred at 80 °C for 3 h under N2. The reaction was monitored by LCMS, LCMS showed 40% of desired MS. The mixture was concentrated and extracted with EA/water (10 mL/10 mL), concentrated, the crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to get (3S)-3-(1'-(3-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-9'-yl)piperidin-1-yl)-2-hydroxypropyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (11.0 mg, 12.6 μmol, 20%, 95.47% Purity) as a white solid. LC purity (0.1%TFA): 59.78% (UV at 254 nm)/ MS: 831.1 [M+MeCN-H]; Retention time: 0.977 min. 1H NMR (400 MHz, MeOD) δ 8.40 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H), 5.16 ^ 5.11 (m, 1H), 4.70 (s, 2H), 4.44 (q, J = 17.2 Hz, 2H), 3.74 (d, J = 16.4 Hz, 5H), 3.48 (s, 2H), 3.26 ^ 3.19 (m, 2H), 3.11 (d, J = 12.4 Hz, 2H), 2.93 ^ 2.75 (m, 2H), 2.63 ^ 1.68 (m, 23H). Compound A219.3-((4-(1-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione

de (Intermediate 2) [0911] To a solution of ((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (300 mg, 1 eq, 1.16 mmol) in DCM (2 mL) was added DMP (985 mg, 2 eq, 2.32 mmol) and the reaction was stirred at 25 °C for 2 h. TLC indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (150 mg, 585 μmol, 50.4%) as a white solid. Synthesis of 10-(1-(((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin- 4-yl)-4-chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 4) [0912] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (200 mg, 1 eq, 526 μmol) in DMF (3 mL) were added (1r,4r)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (203 mg, 1.5 eq, 790 μmol), potassium acetate (103 mg, 2 eq, 1.05 mmol) and NaCNBH3 (66.2 mg, 2 eq, 1.05 mmol). The reaction was stirred at 25 °C for 4 h. LCMS indicated completion of reaction. The reaction was poured into H2O (130 mL) and extracted with EA (130 mL x 2), then washed brine and dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh size, eluted with PE:EA = 1: 1) to give 10-(1-(((1r,4r)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 0.15 mmol, 29%) as a yellow oil. LC purity (0.1% FA): 97.87% (UV at 254 nm)/MS: 620.3 [M+H]; Retention time: 1.551 min. Synthesis of 4-chloro-10-(1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 5) [0913] A solution of 10-(1-(((1r,4r)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 1 eq, 161 μmol) in EA/HCl (3 mL) was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford 4-chloro-10-(1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 71 μmol, 44%) as a colorless oil. LC purity (0.1% FA): 77.51% (UV at 254 nm)/MS: 506.1 [M+H]; Retention time: 1.14 min. Synthesis of (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (Intermediate 6) [0914] To a solution of 4-chloro-10-(1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (40 mg, 1 eq, 79.0 μmol) in DCM (5 mL) was added DMP (67 mg, 2 eq, 158 μmol) and the reaction was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1r,4r)-4-((4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1- carbaldehyde (40 mg, 40 μmol, 50%) as a white solid. LC purity (0.1% FA): 55% (UV at 254 nm)/MS: 504.1 [M+H]; Retention time: 1.16 min. Synthesis of 3-((4-(1-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione [0915] To a solution of (1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (30 mg, 1 eq, 59.5 μmol) in DMF (2 mL) were added 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (17.1 mg, 1 eq, 59.5 μmol), potassium acetate (11.7 mg, 2 eq, 119 μmol) and NaCNBH3 (7.48 mg, 2 eq, 119 μmol). The reaction was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The reaction was concentrated under vacuum and purified by prep- HPLC (Waters 3767/QdaColumn: SunFire Sunfire C18, 19*250 mm，10 um; Mobile Phase A: 0.1% FA/H2O, B: ACN; flow rate: 20 mL/min; gradient: 25-40% Retention Time: 7.4-7.8 of 17 min) to afford 3-((4-(1-(((1r,4r)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (1.55 mg, 1.89 μmol, 3.18%) as a white solid. LC purity (0.1% FA): 94.75% (UV at 254 nm)/MS: 775.44 [M+H]; Retention time: 1.189 min. ¹H NMR (400 MHz, MeOD-d4) δ 8.43 (d, J = 8.3 Hz, 1H), 7.97 (s, 1H), 7.87 (t, J = 8.3 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 4.31-4.20 (m, 1H), 3.24-3.08 (m, 2H), 2.84-2.55 (m, 6H), 2.43-2.16 (m, 5H), 2.02- 1.82 (m, 12H), 1.59 (s, 6H), 1.31 (d, J = 19.6 Hz, 2H), 1.08 (s, 3H). Compound A220.3-((4-(1-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6- dione

Sy in-10-

yl)piperidin-1-yl)butanoate (Intermediate 3) [0916] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (70 mg, 1 eq, 184 μmol) in DMF (3 mL) were added sodium hydrogen carbonate (155 mg, 10 eq, 1.84 mmol) and tert-butyl 4-bromobutanoate (41.1 mg, 1 eq, 184 μmol) at rt. The reaction was stirred 25 °C for 16 h. LCMS. The resulting mixture was extracted with EA (20 mL) and the organic layers were washed with water (20 mL x 2) and brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was then purified by silica gel column (100-200 mesh silica gel, 30% of EA in PE) to afford tert-butyl 4-(4- (4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)butanoate (70 mg, 134 μmol, 72.8%) as a yellow solid. LC purity (0.1% FA): 82.48% (UV at 254 nm)/MS: 522.2 [M+H]; Retention time: 1.23 min. Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)butanoic acid (Intermediate 4) [0917] To solution of tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)butanoate (90 mg, 1 eq, 172 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated completion of reaction. The reaction was concentrated under vacuum to give 4-(4-(4-chloro-7,7-dimethyl-5-oxo- 5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)butanoic acid (80 mg, 172 μmol, 99.6%) as a yellow oil. LC purity (0.1% FA): 89.02% (UV at 254 nm)/MS: 466.2 [M+H]; Retention time: 1.09 min. Synthesis of 3-((4-(1-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)butanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione [0918] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)butanoic acid (60 mg, 1 eq, 129 μmol) in DMF (2 mL) were added 3-((4- (piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (55.5 mg, 1.5 eq, 193 μmol) and DIEA (83.2 mg, 5 eq, 644 μmol) and HATU (97.9 mg, 2 eq, 258 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was diluted with water (30 mL), washed with EA (20 mL x 3), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by prep-HPLC (TFA 0.03% in CH₃CN and H₂O) to give 3-((4-(1-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)butanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (10.91 mg, 14.27 μmol, 11.1%) as a yellow solid. LC purity (0.1% TFA): 92.88% (UV at 254 nm)/MS: 735.4 [M+H]; Retention time: 1.33 min.¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.41 (d, J = 8.7 Hz, 1H), 7.96 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.73-7.61 (m, 2H), 7.38-7.17 (m, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 4.55 (d, J = 11.0 Hz, 1H), 4.33-4.18 (m, 1H), 3.95 (d, J = 12.9 Hz, 1H), 3.67 (d, J = 11.3 Hz, 3H), 3.24-2.91 (m, 7H), 2.81-2.56 (m, 5H), 2.20-2.04 (m, 3H), 2.04-1.85 (m, 5H), 1.77 (t, J = 12.4 Hz, 2H), 1.52 (s, 6H), 1.42-1.06 (m, 2H). Compound A221. 3-((4-(1-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclobutane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione Synt

, , , zolin-9- yl)piperidin-1-yl)cyclobutane-1-carboxylate(Intermediate 3) [0919] To a solution of 4-chloro-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (150 mg, 1 eq, 395 μmol) and methyl 3-oxocyclobutane-1-carboxylate (304 mg, 6 eq, 2.37 mmol) in DMF (15 mL) was added potassium acetate (116 mg, 74.0 μL, 3 eq, 1.18 mmol) and the reaction was stirred at 25 °C for 30min. Then sodium cyanoborohydride (74.4 mg, 68.9 μL, 3 eq, 1.18 mmol) was added to the mixture. The solution was stirred at 25 °C for 3 h. The mixture was concentrated to give crude product. The residue was purified by silica gel chromatography (100- 200 mesh silica gel, 0-20% of MeOH in DCM) to afford methyl 3-(4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclobutane-1-carboxylate (39 mg, 71 μmol, 18%) as a white solid. LC purity 95% (UV at 254 nm)/MS: 492.3 [M+H]; Retention time: 1.018 min Synthesis of 3-((4-(1-((4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6- dione(Intermediate 4) [0920] A solution of methyl 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclobutane-1-carboxylate (20 mg, 1 eq, 40.6 μmol) in HCl/1,4- dioxane (3 mL) was stirred at 90 °C for 2 h. The reaction was concentrated to afford 3-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclobutane- 1-carboxylic acid (19 mg, 40.6 μmol, 97.8%) as a white solid. Synthesis of 3-((4-(1-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclobutane-1-carbonyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione [0921] To a mixture of 3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (30 mg, 1 eq, 62.8 μmol), 3-((4-(piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (18 mg, 1 eq, 62.8 μmol) and DIEA (64.9 mg, 87.5 μL, 8 eq, 502 μmol) in DMF (8 mL) was added BOP (36.1 mg, 1.3 eq, 81.6 μmol) at 20 ^oC. TLC showed the reaction was completed. The reaction was concentrated under vacuum. The residue was purified by prep-HPLC to afford 3-((4-(1-(3-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclobutane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (12.18 mg, 15.70 μmol, 25%) as a white solid. LC purity (LA 70B30): 97% (UV at 254 nm)/MS: 747.6 [M+H]; Retention time: 4.467 min; ¹H NMR (400 MHz, MeOD) δ 8.42 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.28 (dd, J = 11.8, 4.8 Hz, 1H), 3.68 (t, J = 12.3 Hz, 4H), 3.28 ^ 3.21 (m, 2H), 3.14 ^ 3.08 (m, 2H), 3.06 (d, J = 6.2 Hz, 2H), 2.86 ^ 2.76 (m, 2H), 2.71 (dt, J = 8.2, 4.4 Hz, 1H), 2.35 ^ 2.27 (m, 2H), 2.22 (d, J = 17.5 Hz, 3H), 2.11 (d, J = 13.8 Hz, 4H), 2.07 ^ 1.97 (m, 5H), 1.96 ^ 1.88 (m, 2H), 1.73 (dd, J = 23.6, 11.1 Hz, 2H), 1.61 (s, 6H), 1.29 (d, J = 8.0 Hz, 4H). Compound A222. 3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione Synthesi

uinazolin-9- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde(Intermediate 2) [0922] To a solution of 4-chloro-9-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (30 mg, 1 eq, 61.0 μmol) in ACN (10 mL) was added IBX (34.1 mg, 2 eq, 122 μmol). The solution was stirred at 90 °C for 2 h. The mixture was concentrated to give crude product 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde(18 mg, 36.7 μmol, 60.2%) as a white solid. Synthesis of 3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione [0923] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (7 mg, 1 eq, 14.3 μmol) and 3-((4-(piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (4.10 mg, 1 eq, 14.3 μmol) in DMF (4 mL) was added potassium acetate (4.21 mg, 2.68 μL, 3 eq, 42.9 μmol) and stirred at 25 °C for 30 min. Then sodium cyanoborohydride (2.69 mg, 2.49 μL, 3 eq, 42.9 μmol) was added to the mixture. The solution was stirred at 25 °C for 3 h. The mixture was concentrated to give crude product. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-20% of MeOH in DCM) to afford 3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6- dione (3.07 mg, 3.88 μmol, 27.2%, 96.260% purity) as a white solid. LC purity (LA 70B30): 96% (UV at 254 nm)/MS: 762.6 [M+H]; Retention time: 3.947 min. ¹H NMR (400 MHz, MeOD) δ 8.42 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.28 (dd, J = 11.8, 4.8 Hz, 1H), 3.68 (t, J = 12.3 Hz, 4H), 3.28 ^ 3.21 (m, 2H), 3.14 ^ 3.08 (m, 2H), 3.06 (d, J = 6.2 Hz, 2H), 2.86 ^ 2.76 (m, 2H), 2.71 (dt, J = 8.2, 4.4 Hz, 1H), 2.35 ^ 2.27 (m, 2H), 2.22 (d, J = 17.5 Hz, 3H), 2.11 (d, J = 13.8 Hz, 4H), 2.07 ^ 1.97 (m, 5H), 1.96 ^ 1.88 (m, 2H), 1.73 (dd, J = 23.6, 11.1 Hz, 2H), 1.61 (s, 6H), 1.29 (d, J = 8.0 Hz, 4H). Compound A223 and Compound A224.3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione Synthes

dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 3-P1 and Intermediate 3-P2) [0924] To a solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (300 mg, 1 eq, 790 μmol) in MeOH (5 mL) was added NaCNBH₃ (149 mg, 3 eq, 2.37 mmol), 4-(hydroxymethyl)cyclohexan-1-one (405 mg, 4 eq, 3.16 mmol) and TEA (240 mg, 3 eq, 2.37 mmol). The mixture was stirred at 60 °C for 16 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 6% of MeOH in DCM) to afford 4-chloro-10-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (300 mg, 610 μmol, 77.2%) as a yellow oil. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 492.2[M+H]; Retention time: 1.16 min. [0925] The product was separated by SFC to give 4-chloro-10-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (68 mg, 138 μmol, 45.3%) as a white solid (3-P1) and 4-chloro-10-(1-(4- (hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 138 μmol, 66.7%) as a white solid (3-P2) Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4-P1) [0926] To a solution of 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (68 mg, 1 eq, 138 μmol) in DCM (3 mL) was added DMP (70.3 mg, 1.2 eq, 166 μmol). The mixture was stirred at 25 °C for 1 h under N₂. LCMS indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (60 mg, 122 μmol, 88.6%) as a white solid. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 490.2 [M+H]; Retention time: 1.17 min. Synthesis of 3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (Compound A223) [0927] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (60 mg, 1 eq, 122 μmol) in DMF (1 mL) were added potassium acetate (36 mg, 3 eq, 367 μmol), 3-((4-(piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (70.4 mg, 2 eq, 245 μmol) and NaCNBH4 (15.4 mg, 2 eq, 245 μmol). The mixture was stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (Waters 3767/Qda Column: Sunfire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA/H₂O, B: ACN; flow rate: 20 mL/min; gradient: 12-27% Retention Time:7.3-8.1 min of 17 min) to afford 3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (11.08 mg, 14.02 μmol, 11.4%) as a yellow solid. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 761.4 [M+H]; Retention time: 1.138 min.¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.62 (t, J = 8.1 Hz, 2H), 7.29 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.2 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.64 (d, J = 7.3 Hz, 1H), 4.36- 4.16 (m, 1H), 3.09 (d, J = 11.1 Hz, 2H), 2.93 (d, J = 10.6 Hz, 2H), 2.79-2.65 (m, 2H), 2.61-2.53 (d, J = 17.9 Hz, 1H), 2.37 (d, J = 5.4 Hz, 2H), 2.33-2.26 (m, 2H), 2.24-2.15 (m, 3H), 2.14-2.04 (m, 1H), 2.00-1.35 (m, 25H). Synthesis of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (Intermediate 4-P2) [0928] To a solution of 4-chloro-10-(1-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (110 mg, 1 eq, 224 μmol) in DCM (3 mL) was added DMP (114 mg, 1.2 eq, 268 μmol). The mixture was stirred at 25 °C for 1 h under N₂. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 5% of MeOH in DCM) to afford 4-(4-(4- chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexane-1-carbaldehyde (100 mg, 0.18 mmol, 82%) as a white solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 490.2 [M+H]; Retention time: 1.24 min. Synthesis of 3-((4-(1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (Compound A224) [0929] To a solution of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)cyclohexane-1-carbaldehyde (100 mg, 1 eq, 204 μmol) in DMF (1 mL) were added potassium acetate (60.1 mg, 3 eq, 612 μmol), 3-((4-(piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (117 mg, 2 eq, 408 μmol) and NaCNBH3 (25.6 mg, 2 eq, 408 μmol). The mixture was stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (Waters 3767/Qda Column: Sunfire C18，19*250 mm, 10 um, Mobile Phase A: 0.1% FA/H2O, B: ACN; flow rate: 20 mL/min; gradient: 14-27% Retention Time: 6.2-7.4 min of 17 min) to afford 3-((4- (1-((4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (16.95 mg, 21.40 μmol, 10.5%) as a white oil. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 761.4 [M+H]; Retention time: 1.098 min.¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.47 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.2 Hz, 1H), 7.62 (t, J = 8.2 Hz, 2H), 7.28 (d, J = 7.9 Hz, 1H), 6.95 (d, J =

8.5 Hz, 2H), 6.60 (d, J = 8.5 Hz, 2H), 5.64 (d, J = 7.4 Hz, 1H), 4.32-4.20 (m, 1H), 3.03 (d, J = 10.8 Hz, 2H), 2.91 (d, J = 10.8 Hz, 2H), 2.81-2.66 (m, 2H), 2.62-2.53 (m, 1H), 2.45-2.27 (m, 5H), 2.14-2.06 (m, 3H), 1.99-1.78 (m, 11H), 1.72-1.54 (m, 5H), 1.51 (s, 6H), 1.38-1.19 (m, 2H), 0.95-0.80 (m, 2H). Compound A225.3-((4-(1-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione

[0930] To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1 g, 1 eq, 5.88 mmol) in THF (40 mL) was added BH3^.DMS (5.88 mL, 2 eq, 11.8 mmol). The mixture was stirred at 0 °C for 16 h under N₂. TLC indicated completion of reaction. The reaction mixture was diluted with MeOH (20 mL). The reaction was concentrated. The resulting residue was purified by column chromatography (100-200 mesh silica gel, 50% of EA in PE) to afford methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (0.90 g, 5.2 mmol, 88%) as a yellow oil. Synthesis of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (Intermediate 3) [0931] To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (200 mg, 1 eq, 1.28 mmol) in DCM (2 mL) was added DMP (815 mg, 1.5 eq, 1.92 mmol). The mixture was stirred at 25 °C for 1 h. TLC indicated completion of reaction. The mixture was filtered and concentrated under vacuum to afford methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (200 mg, 1.30 mmol, 101%) as a white solid. Synthesis of methyl 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (Intermediate 5) [0932] To a solution of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (200 mg, 3 eq, 1.30 mmol) in MeOH (2 mL) were added 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2- a]quinazolin-5(7H)-one (164 mg, 1 eq, 432 μmol), TEA (131 mg, 3 eq, 1.30 mmol) and NaCNBH₃ (81.5 mg, 3 eq, 1.30 mmol). The mixture was stirred at 25 °C for 1 h under N₂. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 4% of MeOH in DCM) to afford methyl 3- ((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (90 mg, 0.16 mmol, 36%) as a white solid. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 518.2[M+H]; Retention time: 1.21 min. Synthesis of 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Intermediate 6) [0933] To a solution of methyl 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (41 mg, 1 eq, 79.1 μmol) in THF (2 mL) was added HCl (2 mL, 6 N). The mixture was stirred at 90 °C for 1 h under N₂. LCMS indicated completion of reaction. The mixture was concentrated under vacuum to afford 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10- yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (40 mg, 79.4 mmol, 100%) as a colorless oil. LC purity (0.1% FA): 90% (UV at 254 nm)/MS: 504.2 [M+H]; Retention time: 1.18 min. 539 Synthesis of 3-((4-(1-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione [0934] To a solution of 3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (40 mg, 1 eq, 79.4 μmol) in DMF (2 mL) were added DIEA (61.5 mg, 6 eq, 476 μmol) and 3-((4-(piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (45.6 mg, 2 eq, 159 μmol). The mixture was stirred at 25 °C for 1 h under N2. LCMS indicated completion of reaction. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (Waters 3767/Qda Column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA/H2O, B: ACN; flow rate: 20mL/min; gradient: 25-33% Retention Time:6.8-7.7min of 17 min) to afford 3-((4-(1-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1- carbonyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (3.21 mg, 4.09 μmol, 5.15%) as a white solid. LC purity (0.1% FA): 99% (UV at 254 nm)/MS: 773.4 [M+H]; Retention time: 1.29 min.¹H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.61 (d, J = 8.5 Hz, 2H), 5.67 (d, J = 7.6 Hz, 1H), 4.49-4.37 (m, 1H), 4.32-4.14 (m, 2H), 3.08- 2.97 (m, 2H), 2.72-2.65 (m, 2H), 2.63-2.55 (m, 2H), 2.46-2.42 (m, 3H), 2.34-2.26 (m, 2H), 2.14- 1.97 (m, 9H), 1.90-1.67 (m, 6H), 1.55-1.45 (m, 6H), 1.44-1.28 (m, 2H). Compound A226. 3-((4-(1-(4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione

Synthes inazolin-9-

yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (Intermediate 2) [0935] A solution of tert-butyl 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1-carboxylate (21 mg, 1 eq, 35 μmol) in TFA/DCM=1:3 (9 mL) was stirred at 90 °C for 4 h. LCMS indicated 4-(4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1- carboxylic acid was consumed completely and product detected. The reaction was concentrated under vacuum and used directly. LC purity (0.1% FA): 95% (UV at 254 nm)/MS: 506.3 [M+H]; Retention time: 0.863 min. Synthesis of 3-((4-(1-((1s,4s)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione [0936] To a mixture of 4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9- yl)piperidin-1-yl)cyclohexane-1-carboxylic acid (17 mg, 1 eq, 33.6 μmol), 3-((4-(piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (9.65 mg, 1 eq, 33.6 μmol) and DIEA (34.7 mg, 46.8 μL, 8 eq, 269 μmol) in DMF (5 mL) was added BOP (19.3 mg, 1.3 eq, 43.7 μmol) at 20 ^oC. TLC showed the reaction was completed. The reaction was concentrated under vacuum. The residue was purified by prep-HPLC to afford 3-((4-(1-((1s,4s)-4-(4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)cyclohexane-1-carbonyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione (3.97 mg, 3.73 μmol, 11.1%) as a green solid. LC purity: 93.2% (UV at 254 nm)/MS: 776.1 [M+H]; Retention time: 4.387 min; 1H NMR (400 MHz, MeOD) δ 8.42 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.28 (dd, J = 11.8, 4.8 Hz, 1H), 3.68 (t, J = 12.3 Hz, 4H), 3.28 ^ 3.21 (m, 2H), 3.14 ^ 3.08 (m, 2H), 3.06 (d, J = 6.2 Hz, 2H), 2.86 ^ 2.76 (m, 2H), 2.71 (dt, J = 8.2, 4.4 Hz, 1H), 2.35 ^ 2.27 (m, 2H), 2.22 (d, J = 17.5 Hz, 3H), 2.11 (d, J = 13.8 Hz, 4H), 2.07 ^ 1.97 (m, 5H), 1.96 ^ 1.88 (m, 2H), 1.73 (dd, J = 23.6, 11.1 Hz, 2H), 1.61 (s, 6H), 1.29 (d, J = 8.0 Hz, 4H). Compound A227.3-((4-(1-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7- dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione

-1- carboxylate (Intermediate 3) [0937] To a solution of methyl (1s,4s)-4-(hydroxymethyl)cyclohexane-1-carboxylate (1 g, 1 eq, 5.81 mmol) in DMF (20 mL) were added imidazole (1.58 g, 4 eq, 23.2 mmol) and tert- butyldimethylchlorosilane (2.63 g, 3 eq, 17.4 mmol) and the reaction was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of EtOAc in PE) to afford methyl (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylate (1.60 g, 5.0 mmol, 87%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 3.64 (s, 3H), 3.40 (d, J = 6.4 Hz, 2H), 2.53 (m, J = 4.7 Hz, 1H), 2.02-1.92 (m, 2H), 1.60-1.46 (m, 5H), 1.25-1.16 (m, 2H), 0.85 (s, 9H), 0.00 (d, J = 2.8 Hz, 6H). Synthesis of tert-butyl ((1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (Intermediate 4) [0938] To a solution of methyl (1s,4s)-4-(((tert-butyldimethylsilyl) oxy) methyl) cyclohexane-1- carboxylate (1.60 g, 1 eq, 5.58 mmol) in THF (20 mL) was added LiAlH4 (318 mg, 1.5 eq, 8.38 mmol) dropwise at 0 ^oC. The mixture was stirred at 25 °C for 2 h. TLC (PE:EA=10:1) showed the reaction was completed. The reaction was poured into H2O (20 mL) and extracted with EA (20 mL x 2), then washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give ((1s,4s)-4-(((tert-butyldimethylsilyl) oxy) methyl)cyclohexyl) methanol (1.30 g, 4.0 mmol, 72%) as a yellow oil.¹H NMR (400 MHz, CDCl3) δ 3.51 (d, J = 7.0 Hz, 2H), 3.44 (d, J = 6.9 Hz, 2H), 1.64 (dddd, J = 14.7, 11.0, 7.3, 3.9 Hz, 2H), 1.49-1.43 (m, 3H), 1.41-1.31 (m, 5H), 0.85 (s, 9H), 0.02 (d, J = 12.6 Hz, 6H). Synthesis of tert-butyl (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1- carbaldehyde (Intermediate 5) [0939] To a solution of ((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (300 mg, 1 eq, 1.161 mmol) in DCM (3 mL) was added DMP (985 mg, 2 eq, 2.321 mmol). The mixture was stirred at 25 °C for 2 h under N2. TLC showed the reaction was completed. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (1r,4r)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (290 mg, 1.0 mmol, 88%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.23 (s, 1H), 3.43 (t, J = 16.5 Hz, 2H), 2.61-2.56 (m, 1H), 2.04-1.95 (m, 2H), 1.55 (ddd, J = 14.1, 13.2, 4.2 Hz, 4H), 1.30 -1.19 (m, 3H), 0.89-0.80 (m, 9H), 0.04--0.01 (m, 6H). Synthesis of tert-butyl 4-(1-(3-chloro-2-cyanophenyl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine- 1-carboxylate (Intermediate 7) [0940] A solution of 4-chloro-7,7-dimethyl-10-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)- one (400 mg, 0.9 eq, 1.053 mmol) in DMF (2 mL) was added potassium acetate (230 mg, 2 eq, 2.34 mmol), (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (300 mg, 1 eq, 1.17 mmol) and NaCNBH3 (147 mg, 2 eq, 2.34 mmol) was stirred at 25 °C for 3 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 10% of MeOH in DCM) to afford 10-(1-(((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4- chloro-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (200 mg, 0.23 mmol, 19%) as a yellow solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 620.5 [M+H]; Retention time: 1.601 min. Synthesis of tert-butyl 4-chloro-10-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4- yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (Intermediate 8) [0941] To a solution of 10-(1-(((1s,4s)-4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)piperidin-4-yl)-4-chloro-7,7- dimethylindolo[1,2-a]quinazolin-5(7H)-one (100 mg, 1 eq, 161 μmol) in DCM (2 mL) was added TFA (18.4 mg, 1 eq, 161 μmol) at rt. The reaction was stirred 25 °C for 2 h. The mixture was diluted with DCM (20 mL) and concentrated (repeated three times) to give 4-chloro-10-(1- (((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)-7,7-dimethylindolo[1,2- a]quinazolin-5(7H)-one (60 mg, 59 μmol, 37%) as a yellow solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 506.5 [M+H]; Retention time: 2.071 min. Synthesis of tert-butyl (1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (Intermediate 9) [0942] To a solution of 4-chloro-10-(1-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperidin- 4-yl)-7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (10 mg, 1 eq, 19.8 μmol) in DCM (2 mL) was added DMP (16.8 mg, 2 eq, 39.5 μmol), and the reaction was stirred at 25 °C for 16 h. LCMS indicated completion of reaction. The mixture was poured into water (50 mL), extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (100-200 mesh silica gel, 20% of EtOAc in PE) to afford (1s,4s)-4-((4- (4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-10-yl)piperidin-1- yl)methyl)cyclohexane-1-carbaldehyde (8 mg, 15.9 μmol, 80.3%) as a white solid. LC purity (0.1% FA): 79% (UV at 254 nm)/MS: 504.1 [M+H]; Retention time: 1.244 min. Synthes is of 3-((4-(1-(((1s,4s)-4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione [0943] To a solution of (1r,4r)-4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylic acid (20 mg, 1 eq, 33.1 μmol) in DMF (2 mL) were added 3-(5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione (9.07 mg, 1 eq, 33.1 μmol), DIEA (21.4 mg, 5 eq, 165 μmol) and HATU (18.9 mg, 1.5 eq, 49.6 μmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated completion of reaction. The reaction was poured into H2O (300 mL) and extracted with EA (500 mL), then washed brine, dried over Na2SO4, filtered and concentrated. The reaction was purified by prep-HPLC, eluted with MeCN in H₂O (0.1% FA) to afford 3-(5-(4-((1r,4r)-4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)piperazin-1- yl)pyridin-2-yl)piperidine-2,6-dione (2.66 mg, 2.92 μmol, 8.83%) as a yellow solid. LC purity (0.1% FA): 95.3% (UV at 254 nm)/MS: 862.2 [M+H]; Retention time: 1.228 min.¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.44 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.67 (dd, J = 11.9, 8.1 Hz, 2H), 7.27 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H), 5.76 (s, 1H), 4.28 (s, 1H), 3.61 (d, J = 30.1 Hz, 4H), 3.05 (s, 11H), 2.09 (s, 6H), 1.91 (s, 7H), 1.60 (s, 4H), 1.52 (s, 6H), 1.48-1.40 (m, 3H), 1.05 (s, 1H). Compound A228. 3-((4-(1-((4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione S

in-9- yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde(Intermediate 2) [0944] To a solution of 4-chloro-9-(1-((4-(hydroxymethyl)cyclohexyl)methyl)piperidin-4-yl)- 7,7-dimethylindolo[1,2-a]quinazolin-5(7H)-one (150 mg, 1 eq, 296 μmol) in ACN (9 mL) was added IBX (166 mg, 2 eq, 593 μmol). The solution was stirred at 90 °C for 16 h. LCMS indicated 4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)methyl)cyclohexane-1-carbaldehyde was consumed completely and product was detected. The mixture was concentrated to give crude product. The residue was purified by column chromatography on silica gel (DCM: MeOH=50:1-20:1) to afford 4-((4-(4-chloro-7,7-dimethyl-5- oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (37 mg, 95%) as a white solid. LC purity (0.1% FA): 95% (UV at 254 nm)/MS: 504.3 [M+H]; Retention time: 0.863 min. Synthesis of 3-((4-(1-((4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione [0945] To a solution of 4-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin- 9-yl)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (37 mg, 1 eq, 73.4 μmol) and 3-((4- (piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (21.1 mg, 1 eq, 73.4 μmol) in DMF (5 mL) was added potassium acetate (21.6 mg, 13.8 μL, 3 eq, 220 μmol) and the reaction was stirred at 25 °C for 30 min. Then NaBH3CN (13.8 mg, 3 eq, 220 μmol) was added to the mixture. The solution was stirred at 25 °C for 2 h. The mixture was concentrated to give crude product. The reaction mixture was purified by flash chromatography to give 3-((4-(1-((4-((4-(4-chloro-7,7- dimethyl-5-oxo-5,7-dihydroindolo[1,2-a]quinazolin-9-yl)piperidin-1- yl)methyl)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (11.46 mg, 14.74 μmol, 20.1%) as a white solid. LC purity (0.1% FA): 99.738% (UV at 254 nm)/MS: 776.1 [M+H]; Retention time: 5.687 min.¹H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.98 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 3.61 (dd, J = 22.5, 13.7 Hz, 7H), 2.98 (d, J = 16.4 Hz, 8H), 2.80 ^ 2.65 (m, 2H), 2.59 (d, J = 18.1 Hz, 1H), 2.06 (s, 5H), 1.94 ^ 1.82 (m, 9H), 1.54 (d, J = 6.0 Hz, 6H), 1.24 (s, 2H), 1.05 (s, 4H). Compound B1, 5-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

Synth

[0946] To a solution of 1 (50 mg, 0.12 mmol, 1.0 eq) in DMF (3 mL) was added DIPEA (62 mg, 0.47 mmol, 3.0 eq), and 2 (60 mg, 0.24 mmol, 2.0 eq). the mixture was stirred for 16 h at 90 °C. After reaction, the mixture was diluted by adding EA (20 mL), washed by water twice. After dried by anhydrous Na₂SO₄ and concentrated, the crude product was received and dissolved into DCM (2 mL), then TFA (2 mL) was added. The reaction was stirred for 30 min. After that, the solution was concentrated. The residue was purified by reversal C-18 column chromatography (elution with CH₃CN/H₂O from 10% to 100%, 0.1% TFA) to get product 4 (30 mg, 52%) as a colorless oil. Synthesis of compound B1 [0947] To a solution of 4 (30 mg, 0.061 mmol, 1.0 eq) in DMF (3 mL) was added DIPEA (31 mg, 0.24 mmol, 4.0 eq), and 5 (34 mg, 0.12 mmol, 2.0 eq). the mixture was stirred for 16 h at 100 °C. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product B1 (23 mg, 50%) as a yellow solid. ESI MS m/z: 745.30 [M+H]. Compound B2, 5-(3-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[0948] solid. ESI

MS m/z: 789.22 [M+H]. Compound B3, 5-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione [094

olid. ESI MS m/z: 773.32 [M+H]. Compound B4, 5-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[095 lid. ESI

MS m/z: 817.25 [M+H]. Compound B5, 3-(5-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione [095

, lid. ESI MS m/z: 759.32 [M+H]. Compound B6, 3-(5-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0952] The procedure was the same as the synthesis of Bl, B6 was obtained as a yellow solid. ESI

MS m/z: 803.28 [M+H],

Compound B7, 5-(3-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-9'-yl)piperidin-l-yl)methyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0953] The procedure was the same as the synthesis of Bl, B7 was obtained as a yellow solid. ESI

MS m/z: 789.22 [M+H],

Compound B8, 5-(3-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)pyrrolidin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0954] The procedure was the same as the synthesis of Bl, B8 was obtained as a yellow solid. ESI

MS m/z: 805.25 [M+H],

Compound B9, 5-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2-a]quinazolin]- 10'-yl)-[l,4'-bipiperidin]-l'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

Synthesis of compound 3

[0955] To a solution of 1 (50 mg, 0.11 mmol, 1.0 eq) in DMF/DCE (2/2 mL) was added 2 (64 mg, 0.32 mmol, 3.0 eq), and NaBH(OAc)3 (136 mg, 0.65 mmol, 6 eq), the mixture was stirred for 6 h at 100 °C. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product 3 (32 mg, 46%) as a colorless solid. ESI MS m/z: 647.25 [M+H],

Synthesis of compound 4

[0956] To a solution of 3 (32 mg, 0.049 mmol, 1.0 eq) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred for 30 min at rt. After reaction, the reaction solvent was concentrated and the crude product used in the next step directly. Synthesis of compound B9

[0957] The procedure was the same as the synthesis of Bl, B9 was obtained as a yellow solid. ESI

MS m/z: 647.25 [M+H],

Compound BIO, 5-(4-(2-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)ethyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0958] The procedure was the same as the synthesis of Bl, BIO was obtained as a yellow solid.

ESI MS m/z: 831.28 [M+H],

Compound Bll, 5-(4-(3-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)propyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-

[0959] The procedure was the same as the synthesis of Bl, Bll was obtained as a yellow solid.

ESI MS m/z: 845.30 [M+H], Compound B12, 5-(9-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indoIo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)-3-azaspiro[5.5]undecan-3-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0960] The procedure was the same as the synthesis of B9, B12 was obtained as a yellow solid.

ESI MS m/z: 871.32 [M+H],

Compound B13, 5-(9-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-9'-yl)piperidin-l-yl)-3-azaspiro[5.5]undecan-3-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0961] The procedure was the same as the synthesis of B9, B13 was obtained as a yellow solid.

ESI MS m/z: 871.32 [M+H], Compound B14, 5-(9-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-3-azaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0962] The procedure was the same as the synthesis of Bl, B14 was obtained as a yellow solid.

ESI MS m/z: 885.32 [M+H],

Compound B15, 5-(9-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-9'-yI)piperidin-l-yl)methyI)-3-azaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0963] The procedure was the same as the synthesis of Bl, B15 was obtained as a yellow solid.

ESI MS m/z: 885.32 [M+H], Compound B16, 5-(2-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-9'-yl)piperidin-l-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0964] The procedure was the same as the synthesis of Bl, B16 was obtained as a yellow solid.

ESI MS m/z: 857.30 [M+H],

Compound B17, (lr,4r)-4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-

4-yl)cyclohexane-l-carboxamide

Synthesis of compound 3

[0965] To a solution of 1 (50 mg, 0.11 mmol, 1.0 eq) in DMF/DCE (2/2 mL) was added 2 (34 mg, 0.22 mmol, 3.0 eq), and NaBH(OAc)3 (92 mg, 0.44 mmol, 4.0 eq), the mixture was stirred for 3 h at 100 °C. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product 3 (46 mg, 71%) as a colorless solid. ESI MS m/z: 604.22 [M+H]. Synthesis of compound B17 [0966] To a solution of 3 (40 mg, 0.066mmol, 1.0 eq) in DMF (2 mL) was added 4 (17 mg, 0.066 mmol, 1.0 eq), and HATU (38 mg, 0.099 mmol, 1.5 eq). the mixture was stirred for 1 h at rt. After reaction, the reaction solution was purified by pre-HPLC (elution with CH₃CN/H₂O from 10% to 100%, 0.1% TFA) to get product B17 (39 mg, 70%) as a colorless solid. ESI MS m/z: 845.30 [M+H]. Compound B18, (1r,4r)-4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)cyclohexane-1-carboxamide

[0967] The procedure was the same as the synthesis of B17, B18 was obtained as a colorless solid. ESI MS m/z: 845.30 [M+H]. Compound B19, 3-((R)-7-((1r,4R)-4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexane-1-carbonyl)-1-oxo- 1,3,5,5a,6,7,8,9-octahydro-2H-pyrazino[1',2':4,5][1,4]oxazino[2,3-e]isoindol-2-yl)piperidine- 2,6-dione

[0968] T lorless solid.

ESI MS m/z: 944.35 [M+H]. Compound B20, 3-(5-(4-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione Synthesis

[0969] To a solution of 1 (50 mg, 0.12 mmol, 1.0 eq) in DMF (3 mL) was added DIPEA (62 mg, 0.47 mmol, 3.0 eq), and 2 (33 mg, 0.24 mmol, 2.0 eq). the mixture was stirred for 3 h at 80 °C. After reaction, the mixture was purified by reversal C-18 column chromatography (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product 3 (43 mg, 76%) as a colorless oil. Synthesis of compound B20 [0970] The procedure was the same as the synthesis of B17, B20 was obtained as a colorless solid. ESI MS m/z: 788.32 [M+H]. Compound B21, 3-((R)-7-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)-1-oxo-1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1',2':4,5][1,4]oxazino[2,3-e]isoindol-2-yl)piperidine-2,6-dione orless solid.

ESI MS m/z: 816.32 [M+H]. Compound B22, 3-(6-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol- 2(1H)-yl)piperidine-2,6-dione [

olid. ESI MS m/z: 745.28 [M+H]. Compound B23, 6-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)acetyl)-2-(2,6-dioxopiperidin-3-yl)-6,7- dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione [09

] e proce ure was t e same as t e synt es s o , was o ta ne as a co or ess solid. ESI MS m/z: 759.26 [M+H]. Compound B24, 4-(3-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione [097 ess solid.

ESI MS m/z: 745.28 [M+H]. Compound B25, 4-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione [0975

ess solid. ESI MS m/z: 773.31 [M+H]. Compound B26, 4-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)-[1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione O HN O

[0976] The procedure was the same as the synthesis of Bl, B26 was obtained as a colorless solid.

ESI MS m/z: 805.25 [M+H],

Compound B27, 4-(4-(2-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)ethyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0977] The procedure was the same as the synthesis of Bl, B27 was obtained as a colorless solid.

ESI MS m/z: 787.32 [M+H],

Compound B28, 4-(4-(3-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)propyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0978] The procedure was the same as the synthesis of Bl, B27 was obtained as a colorless solid.

ESI MS m/z: 801.35 [M+H],

Compound B29, 4-(9-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)-3-azaspiro[5.5]undecan-3-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0979] The procedure was the same as the synthesis of Bl, B29 was obtained as a colorless solid.

ESI MS m/z: 871.33 [M+H],

Compound B30, 5-(3-((4-(4-chloro-7,7-dimethyl-5-oxo-5,7-dihydroindolo[l,2-a]quinazolin- 10-yI)piperidin-l-yl)methyI)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0980] The procedure was the same as the synthesis of Bl, B30 was obtained as a colorless solid.

ESI MS m/z: 705.25 [M+H],

Compound B31, 3-(4-(4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)piperidin-l-yl)-3-fluorophenyl)piperidine-2,6- dione

Synth

[0981] To a solution of 1 (3.0 g, 9.97 mmol, 1.0 eq) in dioxane/H2O (90/15 mL) was added 2 (3.34 g, 9.97 mmol, 1.0 eq), Pd(dppf)Cl₂ (730 mg, 0.99 mmol, 0.1 eq) and K₂CO₃ (2.76 g, 19.94 mmol, 2.0 eq). The mixture was refluxed for 3 h. After reaction, the mixture was diluted by adding EA (80 mL), washed by brine once. After dried by anhydrous Na2SO4 and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA/hexane = 1/1) to get product 3 (3.3 g, 71%) as a colorless oil. Synthesis of compound 5 [0982] To a solution of 3 (1.2 g, 2.58 mmol, 1.0 eq) in dioxane (60 mL) was added 4 (450 mg, 3.88 mmol, 1.5 eq), Pd₂(dba)₃ (236 mg, 0.26 mmol, 0.1 eq), Xphos (246 mg, 0.52 mmol, 0.2 eq) and Cs2CO3 (1.68 g, 5.17 mmol, 2.0 eq). The mixture was refluxed for 16 h. After reaction, the mixture was diluted by adding EA (80 mL), washed by brine once. After dried by anhydrous Na₂SO₄ and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA/hexane = 1/1) to get product 3 (860 mg, 67%) as a yellow oil. Synthesis of compound 7 [0983] To a solution of 5 (500 mg, 1.00 mmol, 1.0 eq) in MeOH (60 mL) was added Pd/C (450 mg, 10% Wt, 50% water contained), The mixture was stirred for 16 h under hydrogen atmosphere. After reaction, the mixture was concentrated to get product 6. [0984] The received 6 was dissolved into DMSO, then DMP (638 mg, 1.5 mmol, 1.5 eq) was added. The mixture was stirred for 16 h at rt. the mixture was purified by reversal C-18 column chromatography (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product 7 (110 mg, 34%) as a colorless solid. ESI MS m/z: 319.14 [M+H]. Synthesis of compound B31 [0985] To a solution of 7 (50 mg, 0.16 mmol, 1.0 eq) in DMF/DCE (2/2 mL) was added 8 (65 mg, 0.16 mmol, 1.0 eq), and NaBH(OAc)₃ (44 mg, 0.47 mmol, 3.0 eq). the mixture was stirred for 3 h at rt. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product B31 (63 mg, 56%) as a colorless solid. ESI MS m/z: 722.32 [M+H]. Compound B32, 5-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione Synthesis o

p [0986] To a solution of 1 (100 mg, 0.36 mmol, 1.0 eq) in DMF (4 mL) was NaN3 (47 mg, 0.72 mmol, 2.0 eq), The mixture was stirred for 3 h at 90 °C. After reaction, the mixture was purified by reversal C-18 column chromatography (elution with CH₃CN/H₂O from 10% to 100%, 0.1% TFA) to get product 2 (96 mg, 87%) as a white solid. Synthesis of compound 5 [0987] To a solution of 3 (100 mg, 0.24 mmol, 1.0 eq) in DMF (4 mL) was added 4 (37 mg, 0.31 mmol, 1.3 eq), The mixture was stirred for 3 h at rt. After reaction, the mixture was purified by reversal C-18 column chromatography (elution with CH₃CN/H₂O from 10% to 100%, 0.1% TFA) to get product 5 (89 mg, 82%) as an oil. Synthesis of compound 32 [0988] To a solution of 5 (20 mg, 0.043 mmol, 1.0 eq) and 2 (13 mg, 0.043 mmol, 1.0 eq) in tBuOH/H2O (4/2 mL) was added Cu2SO4 (7.0 mg, 0.043 mmol, 1.0 eq) and sodium ascorbate (18 mg, 0.087 mmol, 2.0 eq). The mixture was stirred for 16 h at rt. After reaction, the mixture was purified by pre-HPLC (elution with CH₃CN/H₂O from 10% to 100%, 0.1% TFA) to get product B32 (15 mg, 43%) as a colorless solid. ESI MS m/z: 801.21 [M+H]. Compound B33, 3-(5-(4-(2-(4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)ethyl)-1H-1,2,3-triazol-1-yl)-1,3-dioxo-2,3-dihydro-1H- inden-2-yl)piperidine-2,6-dione [0989] Th

, olorless solid. ESI MS m/z: 815.22 [M+H]. Compound B34, 3-(5-(4-((1r,4r)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-1,2,3-triazol-1-yl)-1,3- dioxo-2,3-dihydro-1H-inden-2-yl)piperidine-2,6-dione

[0990] The procedure was the same as the synthesis of B32, B34 was obtained as a colorless solid. ESI MS m/z: 838.34 [M+H]. Compound B35, 5-(4-(((1r,4r)-4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione and B36, 5-(4-(((1s,4s)-4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane- 1,7'-indolo[1,2-a]quinazolin]-10'-yl)cyclohexyl)methyl)piperazin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione

Sy

[0991] Under nitrogen protection, to a solution of 1 (10.0 g, 47.16 mmol, 1.0 eq) in dry THF (100 mL) was added LHMDS (155 mL, 115 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred 30 min. After that, 2 (10.84 g, 47.16 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 5 h. After reaction, the mixture was quenched by NH4Cl solution, diluted by ethyl acetate (200 mL). the organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, the residue was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/1) to obtained product 3 (10.2 g, 77%) as a yellow solid. ESI MS m/z: 280.03 [M+H]⁺. Synthesis of 5 [0992] To a solution of 3 (10.0 g, 35.69 mmol, 1.0 eq), Pd(dppf)Cl₂ (2.62 g, 3.57 mmol, 0.1 eq), K₂CO₃ (9.87 g, 71.39 mmol, 2.0 eq) in a mixture solvent of dioxane and water (200 mL and 20 mL) was added 4 (11.4 g, 42.83 mmol, 1.2 eq). The suspension was protected by nitrogen and refluxed for 6 h. LC-MS showed the reaction completed. The reaction mixture was cooled to room temperature. After removing solvent, the residue dissolved into a mixture of EA/H₂O. the organic layers were collected. After dried and removed solvent. The residue was purified by silica-gel column chromatography (ethyl acetate/hexane= 1/1) to obtained product 5 (9.6 g, 79.24%). Synthesis of 7 [0993] To a mixture of 5 (8.0 g, 23.57 mmol, 1.0 eq) in methanol (160 mL) was added 10% Pd/C (2 g). The mixture was stirred for 12 h under hydrogen atmosphere at room temperature. LCMS indicated completion of reaction. The mixture was filtered and concentrated to afford 6 and 7 as a mixture. [0994] The mixture was dissolved into TFA (200 mL). HCl (2N, 50 mL) was added to the mixture. The reaction mixture was stirred for 4 h at rt. After rection, EA was added to the mixture. The organic layer was collected. After dried and removed solvent. The residue was purified by silica- gel column chromatography (ethyl acetate/hexane= 1/1) to get target product 7 (5.3 g, 76%). Synthesis of 9 [0995] To a mixture of 7 (5.00 g, 16.81 mmol, 1.0 eq) in acetonitrile (120 mL) was added cesium carbonate (10.96 g, 33.62 mmol, 2.0 eq,) and 8 (6.73 g, 33.62 mmol, 2.0 eq). The mixture was refluxed for 6 h. The mixture was concentrated. The residue was added into mixture of EA/water. The organic phase was collected. After dried and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane= 1/1) to afford 9 (6.70 g, 83%) as a white solid. Synthesis of 10 [0996] To a mixture of 9 (4.5 g, 9.43 mmol, 1.0 eq) in DMSO (60.00 mL) was added potassium carbonate (2.61 mg, 18.85 mmol, 2.0 eq). then hydrogen peroxide (10 mL) was added. The mixture was stirred at 60 °C for 3 h. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with water (100.0 mL x 2), dried over sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane= 1/1) to afford 10 (3.6 g, 77%) as a white solid. Synthesis of 11 [0997] To a solution of 10 (2.00 g, 4.04 mmol, 1.0 eq) in dry toluene (20 mL) was added TsOH (2.09 G, 12.2, 3.0 eq) under nitrogen protection, the mixture was refluxed overnight. After that, the mixture was concentrated, the residue was purified by C-18 reversal column chromatograpy to recycled starting material (1.0 g). and obtained product 11 (820 mg, 43%). Synthesis of 12 [0998] To a solution of (methoxymethyl)triphenylphosphonium (1.15 g, 3.35 mmol, 2.0 eq) in dry THF (20 mL) was added ^tBuOK (1 M in THF, 3.4 mL, 3.4 mmol, 2.0 eq). The mixture was stirred for 30 min and followed by addition of 11 (800 mg, 1.68 mmol, 1.0 eq). The mixture was stirred for 1h at rt. The reaction was quenched by 2N HCl (8 mL) and stirred for 3 h. After removing solvent, the mixture was subjected to pre-HPLC (25-100% MeCN in H₂O, 0.1 % TFA) to give compound 12 (620 mg, 75 %). Synthesis of B35 and B36 [0999] To a solution of 12 (50 mg, 0.11 mmol, 1.0 eq) in DMF/DCE (2/2 mL) was added 13 (35 mg, 0.11 mmol, 1.0 eq), and NaBH(OAc)3 (29 mg, 0.31 mmol, 3.0 eq). the mixture was stirred for 1 h at rt. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN/H2O from 10% to 100%, 0.1% TFA) to get product B35 (20 mg, 24%) and B36 (26 mg, 31%) as a colorless solid. ESI MS m/z: 817.26 [M+H]. Compound B37, 3-(5-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione

[1000] The procedure was the same as the synthesis of B36, B37 was obtained as a colorless solid.

ESI MS m/z: 803.28 [M+H],

Compound B38, 3-(5-(4-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indoIo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione

Synthesis of 3

[1001] To a solution of 1 (1.2 g, 4.28 mmol, 1.0 eq) in dioxane (60 mL) was added 2 (1.02 mg, 6.42 mmol, 1.5 eq), Pd2(dba).3 (392 mg, 0.43 mmol, 0.1 eq), Xphos (408 mg, 0.86 mmol, 0.2 eq) and Cs₂CO₃ (2.79 g, 8.56 mmol, 2.0 eq). The mixture was refluxed for 16 h. After reaction, the mixture was diluted by adding EA (80 mL), washed by brine once. After dried by anhydrous Na2SO4 and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA/hexane = 1/1) to get product 3 (450 mg, 29%) as a yellow oil. [1002] For the synthesis of synthesis of compound 5, 6, 7, 8, The procedures are the same as the general procedure of preparing B35 and B36. [1003] For the synthesis of synthesis of compound B38, the procedure was the same as the synthesis of B36, B38 was obtained as a colorless solid. ESI MS m/z: 803.28 [M+H]. Compound B39, 5-(4-((1-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione [100

ss solid. ESI MS m/z: 818.26 [M+H]. Compound B40, 7-((1-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)-5,5a,6,7,8,9- hexahydro-1H-pyrazino[1',2':4,5][1,4]oxazino[2,3-e]isoindole-1,3(2H)-dione [1

e p oce u e was e sa e as e sy es s o , was o a e as a co o ess solid. ESI MS m/z: 846.26 [M+H]. Compound B41, 3-(4-(2-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-2,6- difluorophenyl)piperidine-2,6-dione [10

ss solid. ESI MS m/z: 780.34 [M+H]. Compound B42, 3-(4-(2-((4-(4-bromo-7,7-dimethyl-5-oxo-5,7-dihydroindolo[1,2- a]quinazolin-10-yl)piperidin-1-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-2,6- difluorophenyl)piperidine-2,6-dione [10

p y , s solid. ESI MS m/z: 784.26 [M+H]. Compound B43, 3-(4-(4-((1-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2,6-difluorophenyl)piperidine- 2,6-dion [100

ss solid. ESI MS m/z: 741.32 [M+H]. Compound B44, 3-(4-(2-((1-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6- difluorophenyl)piperidine-2,6-dione [10

e poceue was e sa e as e sy ess o , was o a e as a coo ess solid. ESI MS m/z: 781.34 [M+H]. Compound B45, 3-(4-(7-((1-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6- difluorophenyl)piperidine-2,6-dione [10

solid. ESI MS m/z: 781.34 [M+H]. Compound B46, 3-(4-(2-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6- difluorophenyl)piperidine-2,6-dione [1011]

, less solid. ESI MS m/z: 824.29 [M+H]. Compound B47, 3-(4-(7-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6- difluorophenyl)piperidine-2,6-dione

[1012] The procedure was the same as the synthesis of B31, B47 was obtained as a colorless solid.

ESI MS m/z: 824.29 [M+H],

Compound B48, 3-(l'-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

[1013] The procedure was the same as the synthesis of B31, B48 was obtained as a colorless solid.

ESI MS m/z: 776.28 [M+H],

Compound B49, 3-(l'-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-6-fluoro-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

[1014] The procedure was the same as the synthesis of B31, B49 was obtained as a colorless solid.

ESI MS m/z: 794.26 [M+H], Compound B50, 3-(l'-((4-(4'-bromo-5'-oxo-5'H-spiro[cycIohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

[1015] The procedure was the same as the synthesis of B31, B48 was obtained as a colorless solid.

ESI MS m/z: 777.28 [M+H],

Compound B51, 3-(l'-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-fluoro-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

[1016] The procedure was the same as the synthesis of B31, B49 was obtained as a colorless solid.

ESI MS m/z: 793.26 [M+H],

Compound B52, 4-(4-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)piperazin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2- fluorobenzamide

[1017] The procedure was the same as the synthesis of B31, B52 was obtained as a colorless solid.

ESI MS m/z: 810.28 [M+H],

Compound B53, 4-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)piperazin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2- fluor obenzam ide

[1018] The procedure was the same as the synthesis of B31, B53 was obtained as a colorless solid.

ESI MS m/z: 809.27 [M+H],

Compound B54, 3-(4-(8-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-2-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1019] The procedure was the same as the synthesis of B31, B54 was obtained as a colorless solid.

ESI MS m/z: 839.30 [M+H],

Compound B55, 3-(4-(2-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1020] The procedure was the same as the synthesis of B31, B55 was obtained as a colorless solid.

ESI MS m/z: 839.30 [M+H],

Compound B56, 3-(4-(9-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1021] The procedure was the same as the synthesis of B31, B56 was obtained as a colorless solid.

ESI MS m/z: 855.32 [M+H],

Compound B57, 3-(4-(8-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]decan-2-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1022] The procedure was the same as the synthesis of B31, B57 was obtained as a colorless solid.

ESI MS m/z: 838.30 [M+H],

Compound B58, 3-(4-(2-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indoIo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]decan-8-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1023] The procedure was the same as the synthesis of B31, B55 was obtained as a colorless solid.

ESI MS m/z: 838.30 [M+H],

Compound B59, 3-(4-(9-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indoIo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1024] The procedure was the same as the synthesis of B31, B59 was obtained as a colorless solid.

ESI MS m/z: 852.32 [M+H],

Compound B60. 3-(4-(2-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1025] The procedure was the same as the synthesis of B31. B60 was obtained as a colorless solid. ESI MS m/z: 824.30 [M+H],

Compound B61. 3-(4-(7-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-2,6- difluorophenyI)piperidine-2, 6-dione

[1026] The procedure was the same as the synthesis of B31. B61 was obtained as a colorless solid. ESI MS m/z: 780.34 [M+H],

Compound B62. 3-(4-(7-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1027] The procedure was the same as the synthesis of B31. B62 was obtained as a colorless solid. ESI MS m/z: 824.29 [M+H],

Compound B63. 3-(4-(9-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-3-azaspiro[5.5]undecan-3-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1028] The procedure was the same as the synthesis of B31. B63 was obtained as a colorless solid. ESI MS m/z: 808.38 [M+H],

Compound B64. 3-(4-(9-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)-3-azaspiro[5.5]undecan-3-yl)-2,6- difluorophenyl)piperidine-2, 6-dione

[1029] The procedure was the same as the synthesis of B31. B64 was obtained as a colorless solid. ESI MS m/z: 852.32 [M+H],

Compound B65. 3-(4-(4-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)acetyl)piperazin-l-yl)-2,6-difluorophenyl)piperidine-2,6- dione

[1030] The procedure was the same as the synthesis of B17. B65 was obtained as a colorless solid. ESI MS m/z: 769.30 [M+H],

Compound B66. 3-(4-(4-(2-(4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)acetyl)piperazin-l-yl)-2,6-difluorophenyl)piperidine-2,6- dione

[1031] The procedure was the same as the synthesis of B17. B66 was obtained as a colorless solid.

ESI MS m/z: 897.32 [M+H],

Compound B67. 3-(l'-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

Compound B68. 3-(l'-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)-6-fluoro-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

Compound B69. 3-(l'-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

Compound B70. 3-(l'-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)-6-fluoro-3H-spiro[benzofuran-2,4'-piperidin]-5- yl)piperidine-2, 6-dione

[1032] Syntheses of B67, B68, B69, and B70 are similar to B17.

Compound B71. 4-(4-((l-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-4-yl)methyl)piperazin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2- fluorobenzamide

Compound B72. 4-(4-((4-(4'-bromo-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)cyclohexyl)methyl)piperazin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2- fluorobenzamide

[1033] Synthesis of B71 and B72 is the same as B17.

Compound B73. 3-(l'-((lr,4r)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'- indolo[l,2-a]quinazolin]-10'-yl)piperidin-l-yl)methyl)cyclohexane-l-carbonyl)-3H- spiro[benzofuran-2,4'-piperidin]-5-yl)piperidine-2, 6-dione

Compound B74. 3-(l'-((lr,4r)-4-((4-(4'-chIoro-5'-oxo-5'H-spiro[cyclohexane-l,7'- indolo[l,2-a]quinazolin]-10'-yl)piperidin-l-yl)methyl)cyclohexane-l-carbonyl)-4-fluoro-3H- spiro[benzofuran-2,4'-piperidin]-5-yl)piperidine-2, 6-dione Compound B75. 3-(1'-((lr,4r)-4-((4-(4'-chloro-5'-oxo-5'II-spiro[cyclohexane-l,7'- indolo[l,2-a]quinazolin]-10'-yl)piperidin-l-yl)methyl)cyclohexane-l-carbonyl)-6-fluoro-3H- spiro[benzofuran-2,4'-piperidin]-5-yl)piperidine-2, 6-dione

Compound B76. 3-(2-((lr,4r)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-l,7'-indolo[l,2- a]quinazolin]-10'-yl)piperidin-l-yl)methyl)cyclohexane-l-carbonyl)isoindolin-5- yl)piperidine-2, 6-dione

[1034] Synthesis of B73, B74, B75, and B76 are similar to the general procedure of making B17.

II. Biological Activity

For “A ” Series of Compounds

HiBiT Assay for protein degradation: [1035] The HiBit assay was performed using engineered HT1080 CRISPR knock-in cell utilizing the Nano-Glo HiBiT Lytic Detection System from Promega, Cat # N3040. Compounds were transferred, 25 nL DMSO or test compounds (final DMSO @ 0.1%) to intermediate plates (Corning3570) using ECHO550. Cells were seeded onto compounds at 2000 cells/25 uL/well and incubated for 6 hrs in tissue culture incubator at 37^oC and 5% CO2. The LgBiT Protein was diluted at 1:100 and the Nano-Glo® HiBiT Lytic Substrate 1:50 into an appropriate volume of room temperature using the Nano-Glo® HiBiT Lytic Buffer. At end of compound incubation time 15 ul of the detection reagent was added to each well (without LgBiT for negative control wells) using the Thermo Scientific multidrop combi. The plate was shaken for 10 mins at RT using Combi. After brief centrifugation (2000 rpm 1 mins), plate was read on Envision (Ultrasensitive luminescence model). The results of the HiBiT Assay are summarized in Table E1 below. Table E1. SMARCA2 SMARCA4 HT1080 HiBit HT1080 HiBit

SMARCA2 SMARCA4 Compound No. HT1080 HiBit HT1080 HiBit

DC50: A (<10 nM), B (10-100 nM), C (101-500 nM), and D (>500 nM). Dmax: A (>90% degradation), B (70-90% degradation), C (50-69% degradation), and D (<50% degradation). For ^B^ Series of Compounds HiBiT Assays for protein degradation of SMARCA2 and SMARCA4 [1036] Hela cells were genetically modified via CRISPR/Cas9 to fuse HiBiT to the carboxy terminus of SMARCA2 (Promega CS302365) or SMARCA4 (Promega CS3023225). Cells were cultured in DMEM containing 10% FBS and 1% (Vol : Vol) penicillin-streptomycin. At the time of experiment, cells were seeded at a density of 20,000 cells per well in a 96-well plate (Corning Cat. #3903) and treated with serial dilutions of testing compounds for 24 hours. At the end of experiment, levels of SMARCA2 or SMARCA4 expression were assessed with Nano-Glo® HiBiT Lytic Detection Assay (Promega N3050). IC50 was obtained using the GraphPad Prism data analysis software. The results of the HiBiT Assay are summarized in Table E2 below. Table E2. Compound SMARCA 2 SMARCA 2 SMARCA 4 SMARCA 4

Note:

DCso: A (<1O nM), B (10-100 nM), C (101-500 nM), and D (>500 nM).

Dma_X: A (>90% degradation), B (70-90% degradation), C (50-69% degradation), and D (<50% degradation).

INCORPORATION BY REFERENCE

[1037] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

[1038] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.

[1039] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula I T-L-C (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: T is of Formula I-1 1), wherein:

A¹ is CR^A1 or N; A² is CR^A2 or N; A³ is CR^A3 or N; A⁴ is CR^A4 or N; R^A1, R^A2, R^A3, and R^A4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two R^C together form an oxo; or two R^C, together with the carbon atom to which they are attached, form Ring D ; Ring D is C_3-12 carbocycle or 3- to 12-

ocycle; each R^D is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- ₁₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; d is an integer selected from 0 to 10, as valency permits; E¹ is CR^E1 or N; E² is CR^E2 or N; E³ is CR^E3 or N; E⁴ is CR^E4 or N; one of R^E2, R^E3, or R^E4 is ; R^E1, R^E2, and R^E4, R^E1, R^E3, and R^E4, or

R^E3 are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, - NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, - OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; * denotes attachment to L; Ring F is C_3-12 carbocyclyl or 3- to 12-membered heterocycle; each R^F is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and f is an integer selected from 0 to 10, as valency permits; or R^E1, R^E2, R^E3, and R^E4 are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; wherein one of R^E1, R^E2, R^E3, and R^E4 is ; and denotes attachment to L;

L is of Formula I-2 2), wherein:

* denotes attachment to T, and ** denotes attachment to C; each L^ is independently C_1-6 alkylene, C_1-6 heteroalkylene, C_2-6 alkenylene, C_2-6 alkynylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u; each occurrence of R^{L^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and l is an integer selected from 0 to 5, C is of Formula I-3^ ^), wherein:

H² is N or CR^H2; H³ is N or CR^H3; H⁴ is N or CR^H4; H⁵ is N or CR^H5; one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, wherein Ring G is optionally substituted C5- 12 carbocycle or 5- to 16-membered heterocycle; when one of R^H2 and R^H3, R^H3 and R^H4, and R^H4 and R^H5, together with the carbon atoms to which they are bonded, form Ring G which is attached to L, then the remaining R^H4 and R^H5, R^H2 and R^H5, or R^H2 and R^H3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, - S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, -NR^cS(=O)₂OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)2OR^b, -OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is ; denotes attachment to L;

denotes an optional covalent bond between H¹ and J¹; i) when the bond between H¹ and J¹ is present: r is 1; H¹ is C; J¹ is -C(R^J1)2- or -C(=O)-; each R^J1 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; or two R^J1, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u; and J² is N; ii) when the bond between H¹ and J¹ is absent: r is 0 or 1; H¹ is N or CR^H1; R^H1 is hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2- 6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; J¹ is absent; or J¹ is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; J² is absent, N, or O; wherein i) when J² is N, then J¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when J² is absent or O, then J¹ is absent; K¹ is N or CR^K1; R^K1 is hydrogen, deuterium, or C1-6 alkyl optionally substituted with one or more R^u; q is an integer from 0 to 2, each R^K is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and k is an integer selected from 0 to 5, wherein: each R^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R^u, together with the one or more intervening atoms, form C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^z; each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each R^b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; and each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and each R^z is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

2. The compound of claim 1, wherein T is of Formula I-1-i or I-1-ii ii), wherein each

, C_1-6 alkyl, C_1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

3. The compound of claim 1, wherein T is of Formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-ii-1, I-1-ii- 2, I-1-ii-3, I-1-i-7, I-1-i-8, I-1-i-9, I-1-ii-7, or I-1-ii-8, or I-1-ii-9 ), ), 3),

-9), wherein alkyl, C1-6

alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

4. The compound of any one of claims 1-3, wherein R^A1 is hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

5. The compound of any one of claims 1-3, wherein R^A1 is halogen.

6. The compound of claim 1, wherein T is of Formula I-1-i-4, I-1-i-5, I-1-i-6, I-1-ii-4, or I- 1-ii-5, I-1-ii-6, I-1-i-10, I-1-i-11, I-1-i-12, I-1-ii-10, I-1-ii-11, or I-1-ii-12

2), wherei

each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and R^A1 is halogen.

7. The compound of any one of claims 1-6, wherein Ring F is 4- to 6-membered heterocycle or C4-6 carbocycle.

8. The compound of any one of claims 1-7, wherein each R^F is independently oxo, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

9. The compound of any one of claims 1-8, wherein f is 0.

10. The compound of any one of claims 1-9, wherein R^E1, R^E2, and R^E4, R^E1, R^E3, and R^E4, or R^E1, R^E2, and R^E3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

11. The compound of claim 10, wherein each of R^E1, R^E2, and R^E4, each of R^E1, R^E3, and R^E4, or each of R^E1, R^E2, and R^E3 is hydrogen.

12. The compound of any one of claims 1-9, wherein one or two of E¹, E², and E⁴, one or two of E¹, E³, and E⁴, or one or two of E¹, E², and E³ are N.

13. The compound of claim 12, wherein one or two of R^E1, R^E2, and R^E4, one or two of R^E1, R^E3, and R^E4, or one or two of R^E1, R^E2, and R^E3 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

14. The compound of claim 13, wherein one or two of R^E1, R^E2, and R^E4, one or two of R^E1, R^E3, and R^E4, or one or two of R^E1, R^E2, and R^E3 are hydrogen.

15. The compound of any one of claims 1-14, wherein each of R^A2, R^A3, and R^A4 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

16. The compound of any one of claims 1-14, wherein each of R^A2, R^A3, and R^A4 is hydrogen.

17. The compound of any one of claims 1-16, wherein Ring D is C_3-12 carbocycle.

18. The compound of claim 17, wherein Ring D is C5-7 carbocycle.

19. The compound of any one of claims 1-16, wherein Ring D is 3- to 12-membered heterocycle.

20. The compound of claim 19, wherein Ring D is 5- to 7-membered heterocycle.

21. The compound of any one of claims 1-20, wherein each R^D is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

22. The compound of any one of claims 1-21, wherein d is 0.

23. The compound of any one of claims 1-16, wherein each R^C is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

24. The compound of any one of claims 1-16, wherein at least one R^C is C_1-6 alkyl.

25. The compound of any one of claims 1-16, wherein each of R^C is C1-6 alkyl.

26. The compound of any one of claims 1-25, wherein each L^ is independently C1-6 alkylene, C1-6 heteroalkylene, 5- to 10-membered heteroarylene, C6-10 arylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(R^{L^})-, -C(=O)O-, -N(R^{L^})-, -S(=O)₂-, or -O-, wherein the alkylene, heteroalkylene, heteroarylene, arylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u, and l is an integer selected from 0 to 4.

27. The compound of any one of claims 1-25, wherein L is absent, -C(=O)-, C_1-12 alkylene, C_3- 12 carbocyclylene, 3- to 12-membered heterocyclylene, *-(3- to 12-membered heterocyclylene)- (C1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(5- to 10-membered heteroarylene)-, *- (C3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-, *-(C1-6 alkylene)-(C6-10 arylene)-C(=O)-, *-(C1-6 alkylene)-O-C(=O)-, *- (3- to 12-membered heterocyclylene)-S(=O)₂-, *-(C_1-6 alkylene)-S(=O)₂-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)- C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-N(R^{L^})-, *-(3- to 12-membered heterocyclylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-C(=O)-(3- to 12- membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(C1-6 alkylene)-, *- (3- to 12-membered heterocyclylene)-(C1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)- (C_3-12 carbocyclylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, *-(C_1-6 alkylene)- (C_6-10 arylene)-(C_1-6 alkylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-C(=O)-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, C1-12 alkylene, 3- to 12-membered heterocyclylene, *-C_1-12 alkylene-N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-N(R^{L^})- , *-(C1-6 alkylene)-(C3-12 carbocyclylene)-N(R^{L^})-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)- , *-C(=O)-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-C(=O)-(3- to 12-membered heterocyclylene)- (3- to 12-membered heterocyclylene)-, *-C(=O)-(C_3-12 carbocyclylene)-N(R^{L^})-, *-C(=O)-(C_1-6 alkylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-C1-6 alkylene-C(=O)-(3- to 12-membered heterocyclylene)-, *-C1-6 alkylene-C(=O)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)- , *-(C_3-12 carbocyclylene)-N(R^{L^})-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-(5- to 10-membered heteroarylene)-, or *-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, wherein each alkylene, heterocyclylene, heteroarylene, arylene, and carbocyclylene is independently optionally substituted with one or more R^u, and *denotes attachment to T.

28. The compound of claim 27, wherein L is absent, -C(=O)-, C_1-12 alkylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, *-(3- to 12-membered heterocyclylene)-(C1- 6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C1-6 alkylene)-(5- to 10-membered heteroarylene)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-(5- to 10-membered heteroarylene)-, *- (C3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-, *-(C1-6 alkylene)-(C6-10 arylene)-C(=O)-, *-(C1-6 alkylene)-C(=O)-, *- (C_1-6 alkylene)-O-C(=O)-, *-C(=O)-(C_1-6 alkylene)-, *-C(=O)-(C_3-12 carbocyclylene)-NH-, *- C(=O)-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-, *-C(=O)-(3- to 12-membered heterocyclylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-S(=O)2-, *-(C1-6 alkylene)-S(=O)2-, *-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C3-12 carbocyclylene)-NH-, *-(C1- ₆ alkylene)-(C_3-12 carbocyclylene)-C(=O)-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-C(=O)-(3- to 12- membered heterocyclylene)-O-, *-(C3-12 carbocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C_1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-NH-, *-(C1-6 alkylene)- (C_3-12 carbocyclylene)-NH-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-C(=O)-NH-, *-(C_1-6 alkylene)-(C_3-12 carbocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-, *-(3- to 12- membered heterocyclylene)-(C1-6 alkylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)- C(=O)-(C_1-6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-, *-(3- to 12- membered heterocyclylene)-(C3-12 carbocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(C6-10 arylene)-(C1-6 alkylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-(C_1-6 alkylene)-, *-(C_3-12 carbocyclylene)-(C_1-6 alkylene)-C(=O)-, *-(C_3-12 carbocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-(C1-6 alkylene)-(5- to 10-membered heteroarylene)-, or *-(C1-6 alkylene)-(3- to 12- membered heterocyclylene)-, wherein each alkylene, heterocyclylene, heteroarylene, arylene, and carbocyclylene is independently optionally substituted with one or more R^u.

29. The compound of any one of claims 1-28, wherein C is of Formula I-3^-i i).

30. The compound of claim 29, wherein R^H2, R^H3, R^H4, and R^H5 are independently , hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u, wherein one of R^H2, R^H3, R^H4, and R^H5 is .

31. The compound of claim 29, wherein R^H3 is , and each of R^H2, R^H4, and R^H5 is hydrogen.

32. The compound of any one of claims 1-28, wherein C is of Formula I-3^-iii 3^-iii).

33. The compound of claim 32, wherein one of R^H2, R^H3, and R^H4 is ; R^H1, R^H5, and the other two of R^H2, R^H3, and R^H4 are independently hydrogen, halogen, -C

N, -NO₂, -OH, -NH₂, C_1- ₆ alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

34. The compound of claim 32, wherein R^H3 is , R^H1 and R^H5 are independently halogen, and each of R^H2 and R^H4 is hydrogen.

35. The compound of any one of claims 1-28, wherein C is of Formula I-3^-i or I-3^-iii ii).

36. The compound of claim 35, wherein J¹ is CH2, and i) R^H2 and R^H3, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted 5- to 16-membered heterocycle; or ii) R^H3 and R^H4, together with the carbon atoms to which they are bonded, form Ring G attached to L, wherein Ring G is optionally substituted 5- to 16-membered heterocycle.

37. The compound of claim 36, wherein i) H⁴ is CR^H4 and H⁵ is CR^H5, wherein R^H4 and R^H5 are independently hydrogen, halogen, -CN, - NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or ii) H¹ is CR^H1, H² is CR^H2, and H⁵ is CR^H5, wherein R^H1, R^H2, and R^H5 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

38. The compound of claim 37, wherein i) R^H4 and R^H5 are independently hydrogen or halogen; or ii) R^H1 and R^H5 are independently halogen.

39. The compound of any one of claims 35-38, wherein Ring G is optionally substituted 7- to 16-membered spiro heterocycle.

40. The compound of claim 39, wherein Ring G is: , wherein:

** denotes attachment to L; Ring G^II is C4-8 carbocycle or 4- to 8-membered heterocycle; each G¹ is independently -C(R^G1)₂-, -NR^{G1^}-, -O-, -S-, -S(=O)-, or -S(=O)₂-; each G² is independently -C(R^G2)2-, -NR^{G2^}-, -O-, -S-, -S(=O)-, or -S(=O)2-; each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, -S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, - NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, - OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; two geminal R^G1 or two geminal R^G2 together form oxo; or two geminal R^G1 or two geminal R^G2, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more R^u; each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; g' and g'' are independently an integer selected from 0-3, wherein g' and g'' are not both 0; each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 1₀ aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)2R^a, -OS(=O)2OR^b, - OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits.

41. The compound of claim 39, wherein Ring G is: 1) .

42. The compound of claim 40 or 41, wherein each G¹ is independently -C(R^G1)2-, -NR^{G1^}-, or -O-, and each G² is independently -C(R^G2)₂-, -NR^{G2^}-, or -O-.

43. The compound of any one of claims 40-42, wherein each occurrence of R^G1 and R^G2 is independently hydrogen, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and each occurrence of R^{G1^} and R^{G2^} is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

44. The compound of claim 43, wherein each occurrence of R^G1 and R^G2 is hydrogen; and each occurrence of R^{G1^} and R^{G2^} is hydrogen.

45. The compound of claim 39, wherein Ring G is .

46. The compound of any one of claims 35-38, wherein Ring G is optionally substituted 7- to 16-membered fused heterocycle.

47. The compound of claim 46, wherein Ring G is , wherein:

Ring G^III and Ring G^IV are independently C4-8 carbocycle or 4- to 8-membered heterocycle; wherein at least one of Ring G^III and Ring G^IV is 4- to 8-membered heterocycle; G³ and G⁴ are independently C, CR^Gx, or N; R^Gx is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^G is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits, wherein R^A may be present on either Ring G^III or Ring G^IV.

48. The compound of claim 46, wherein Ring G is , wh

R^N is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)₂R^a, -S(=O)₂OR^b, - S(=O)2NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6- 10 aryl, 5- to 10-membered heteroaryl, -SR^b, -S(=O)R^a, -S(=O)2R^a, -S(=O)2OR^b, - S(=O)2NR^cR^d, -NR^cS(=O)2R^a, -NR^cS(=O)R^a, -NR^cS(=O)2OR^b, -NR^cS(=O)2NR^cR^d, - NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -OS(=O)₂R^a, -OS(=O)₂OR^b, - OS(=O)2NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and g is an integer selected from 0 to 8, as valency permits.

49. The compound of claim 48, wherein R^N is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

50. The compound of claim 49, wherein R^N is hydrogen or C1-6 alkyl.

51. The compound of any one of claims 40-45 and 47-50, wherein each R^G is independently oxo, halogen, -CN, -NO₂, -OH, -NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

52. The compound of claim 51, wherein g is 0.

53. The compound of any one of claims 29-52, wherein K¹ is CR^K1.

54. The compound of claim 53, wherein R^K1 is hydrogen.

55. The compound of any one of claims 29-52, wherein K¹ is N.

56. The compound of any one of claims 29-55, wherein q is 1.

57. The compound of any one of claims 29-56, wherein k is 0.

58. A compound selected from the compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

59. A pharmaceutical composition comprising the compound of any one of claims 1 -58, and a pharmaceutically acceptable excipient.

60. A method of degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample comprising contacting said patient or biological sample with a compound of any one of claims 1-58.

61. Use of a compound of any one of claims 1-58 in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample.

62. A compound of any one of claims 1-58 for use in degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample.

63. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound of any one of claims 1-58.

64. Use of a compound of any one of claims 1-58 in the manufacture of a medicament for treating a disease or disorder.

65. A compound of any one of claims 1-58 for use in treating a disease or disorder.

66. The method, use, or compound for use of any one of claims 63-65, wherein the disease or disorder is a SMARCA2 or SMARCA4 protein-mediated disease or disorder.

67. The method, use, or compound for use of any one of claims 63-65, wherein the disease or disorder is cancer.

68. The method, use, or compound for use of claim 67, wherein the cancer is selected from NSCLC adenocarcinoma (LU AD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).

69. The method, use, or compound for use of claim 68, wherein the cancer is selected from NSCLC adenocarcinoma (LU AD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC).