Targeted protein degradation of PARP14 used in therapy

Abstract

The present invention relates to quinazolinones and related compounds that can degrade PARP14 and are useful, for example, in the treatment of cancer and inflammatory diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to quinazolinones and related compounds that cause intracellular proteolysis of PARP14 and are useful in the treatment of cancer and inflammatory diseases. Background Art

[0002] Poly (ADP-ribose) polymerase (PARP) is a member of a family of seventeen enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, and various cellular stress responses (Vyas S et al., Nat Rev Cancer., 2014 Jun 5; 14(7): 502-509). The ability of cancer cells to survive stress is a fundamental cancer mechanism and an emerging approach for new therapies. PARP1 is a member of the PARP family, and studies have shown that it is an effective cancer target associated with cellular stress induced by DNA damage, which is induced by genetic mutations or cytotoxic chemotherapy. Currently, three drugs have been approved for clinical use, and several more are in late-stage development (Ohmoto A et al., OncoTargets and Therapy., 2017; Vol. 10: 5195).

[0003] Seventeen members of the PARP family have been identified in the human genome based on homology within the catalytic domain (Vyas S et al., Nat Commun., 2013 Aug 7;4:2240). However, their catalytic activities fall into three distinct categories. Most PARP family members catalyze the transfer of a single ADP-ribose unit to their substrate (mono-ART), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units to their substrate (poly-ART). Finally, PARP13 is the only PARP for which catalytic activity has not been demonstrated to date either in vitro or in vivo.

[0004] PARP14 is both a cytoplasmic and nuclear single ART. It was originally identified as BAL2 (B aggressive lymphoma 2), a gene associated with poor outcomes in diffuse large B-cell lymphoma (DLBCL) along with two other single ARTs (PARP9 or BAL1 and PARP15 or BAL3) (Aguiar RC et al., Blood., December 9, 2000; 96(13): 4328-4334 and Juszczynski P et al., Mol Cell Biol., July 1, 2006; 26(14): 5348-5359). PARP14, PARP9 and PARP15 are also referred to as macro-PARPs because of the presence of a macro-domain at their N-termini. The genes for these three macro-PARPs are located in the same genomic locus, indicating the presence of co-regulation. In fact, gene expression of PARP14 and PARP9 is highly correlated in normal tissues and cancer types. PARP14 is overexpressed in tumors compared to normal tissues, including in established cancer cell lines compared to their normal counterparts. Literature examples of cancers with high PARP14 expression include: DLBCL (Aguiar RCT et al., J Biol Chem., 2005 Aug 1; 280(40): 33756-33765), multiple myeloma (MM) (Barbarulo A et al., Oncogene., 2012 Oct 8; 32(36): 4231-4242) and hepatocellular carcinoma (HCC) (Iansante V et al., Nat Commun., 2015 Aug 10; 6: 7882). In MM and HCC cell lines, RNA interference (RNAi)-mediated knockdown of PARP14 inhibited cell proliferation and survival. Other studies have shown that the enzymatic activity of PARP14 is required for the survival of prostate cancer cell lines in vitro (Bachmann SB et al., Mol Cancer., 2014 May 27;13:125).

[0005] PARP14 is an interferon-stimulated gene, whose mRNA is increased by stimulation of various cellular systems with all types of interferons (I, II, and III; www.interferome.org). PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling, affecting the downstream transcription of STAT1 (in the case of IFN-γ) (Iwata H et al., Nat Commun., 2016 Oct 31;7:12849) or STAT6 (in the case of IL-4) (Goenka S et al., Proc Natl Acad Sci USA., 2006 Mar 6;103(11):4210-4215; Goenka S et al., J Biol Chem., 2007 May 3;282(26):18732-18739; and Mehrotra P et al., J Biol Chem., 2010 Nov 16;286(3):1767-1776). Parp14- / - knockout (KO) mice have reduced marginal zone B cells, and the ability of IL-4 to confer B cell survival in vitro is also reduced in the Parp14 KO environment (Cho SH et al., Blood., 2009 Jan 15;113(11):2416-2425). This reduced survival signaling is mechanistically related to the reduced ability of Parp14 KO B cells to maintain metabolic fitness and increased Mcl-1 expression. Parp14 KO can prolong survival in the Eμ-Myc lymphoma model, indicating a role for PARP14 in Myc-driven lymphomagenesis (Cho SH et al., Proc Natl Acad Sci USA., 2011 Sep 12;108(38):15972-15977). Gene expression data also point to a role for PARP14 in human B cell lymphoma. BAL proteins, including PARP14, are highly expressed in host response (HR) DLBCL, a genomically defined subtype of B-cell lymphoma characterized by inflammatory infiltration of T cells and dendritic cells and the presence of an IFN-γ gene signature (Molecular analysis of diffuse large B-cell lymphoma identifies robust subtypes, including one characterized by a host inflammatory response. Monti S et al., Blood., 2005;105(5):1851).

[0006] Due to its role in the IL-4 and IFN-γ signaling pathways downstream, PARP14 is associated with T helper cell and macrophage differentiation. Genetic PARP14 inactivation in macrophages tends to form a pro-inflammatory M1 phenotype associated with anti-tumor immunity, while reducing the pro-tumor M2 phenotype. In human and mouse macrophage models, PARP14 knockout or knockdown found that the expression of M1 genes downstream of IFN-γ was increased, while the expression of M2 genes downstream of IL-4 was reduced. Similarly, studies have shown that genetic PARP14 knockout reduces the Th2T helper cell phenotype in the context of skin and airway inflammation, which is related to the regulatory role of PARP14 in IL-4 signaling (Mehrotra P et al., J Allergy Clin Immunol., 2012 Jul 25; 131(2): 521 and Krishnamurthy P et al., Immunology., 2017 Jul 27; 152(3): 451-461).

[0007] PARP14 promotes signaling of type 2 helper T cells (TH2) and type 17 helper T cells (TH17) cytokines by acting as a coactivator of STAT6-driven and STAT3-driven transcription (Goenka et al., 2006 PMID 16537510; Mehrotra et al., 2015 PMID 26222149). PARP14 is upregulated in tissues with inflammatory diseases, such as skin lesions of patients with atopic dermatitis or psoriasis (He et al., 2021 PMID: 32709423) or endobronchial biopsies from patients with mild atopic asthma (Yick et al., 2013 PMID: 23314903). Studies have shown that genetic deletion or catalytic inhibition of PARP14 blocks IL-4 / STAT6 signaling in macrophages in vitro (Iwata et al., 2016 PMID 27796300; Schenkel et al., 2021 PMID: 33705687) and suppresses pathogenic changes associated with allergic airway disease in mouse models (Cho et al., 2013 PMID: 23956424; Mehrotra et al., 2013 PMID: 22841009; Eddie et al., 2022 PMID: 35817532). Antibodies and small molecules that inhibit TH2 / TH17 cytokine signaling and alarmins have been approved or are being studied for the treatment of a variety of inflammatory diseases, such as atopic dermatitis, asthma, chronic sinusitis, and eosinophilic esophagitis (Sastre et al., 2018, PMID: 29939132; Lyly et al., 2020 PMID: 33322143; Ahn et al., 2021 PMID: 33911806; Ahn et al., 2021 PMID: 33935450). Considering the upregulation of PARP14 in inflammatory disease tissues, the key role of PARP14 in TH2-driven and TH17-driven cytokine signaling, and the common underlying biology of many inflammatory diseases, small molecules targeting PARP14 may be promising therapeutic agents for a wide range of inflammatory diseases.

[0008] Most of the drugs used clinically are based on the inhibition of protein function by small molecules. However, alternative methods that provide protein degradation rather than inhibition also have the potential to provide clinical efficacy. Therefore, targeted protein degradation by ubiquitinating protein targets has become an effective strategy in drug development. Studies have shown that heterobifunctional small molecules that simultaneously bind to target proteins and recruit ubiquitin ligases (such as ubiquitin E3 ligases) can lead to ubiquitination and degradation of target proteins (Bondeson, DP et al., Nat Chem Biol. 201511 (8): 611-617). Examples of these small molecules that can bind to both PARP14 and ubiquitin E3 ligases have been described in PCT Patent Publication WO 2020 / 257416.

[0009] There is a need to develop new drugs, such as small molecules that can bind to both PARP14 and ubiquitin E3 ligase to cause PARP14 degradation, which can be used to treat various diseases, including cancer and inflammatory diseases. Summary of the Invention

[0010] The present invention relates to compounds of formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined as follows.

[0013] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0014] The present invention also relates to a method for degrading PARP14, which comprises contacting the compound of formula (I) or a pharmaceutically acceptable salt thereof with PARP14.

[0015] The present invention also relates to a method for treating a disease or disorder in a patient in need of treatment, wherein the disease or disorder is characterized by overexpression or increased activity of PARP14, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0016] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0017] The present invention also relates to a method of treating an inflammatory disease in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0018] The present invention also provides the use of a compound described herein in the preparation of a medicament for use in therapy. The present disclosure also provides a compound described herein for use in therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is a graph showing the dose-dependent reduction of Alternaria-induced cell infiltration in BALF after treatment with compound 64.

[0020] Figure 2A This figure demonstrates that compound 64 significantly reduced eosinophils in BALF in a dose-dependent manner starting from 100 mg / kg.

[0021] Figure 2B This figure demonstrates that compound 64 significantly reduces the cytokine IL-33 in BALF in a dose-dependent manner starting from 100 mg / kg.

[0022] Figure 2C This figure demonstrates that compound 64 significantly reduces the cytokine IL-4 in BALF in a dose-dependent manner starting from 100 mg / kg.

[0023] Figure 2D This figure demonstrates that compound 64 significantly reduces the cytokine IL-5 in BALF in a dose-dependent manner starting from 100 mg / kg. DETAILED DESCRIPTION

[0024] The present disclosure provides, inter alia, compounds of formula (I):

[0025]

[0026] or a pharmaceutically acceptable salt thereof, wherein:

[0027] W is CR W or N;

[0028] X is CR X or N;

[0029] Z is CR Z or N; and

[0030] Among them, at most two of W, X and Z are N at the same time;

[0031] Y 1 Selected from-NR 3 -、-CR 4 R 5 -, -O- and -(C 2-4 Alkynyl)-;

[0032] Y 2Selected from bond, -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-;

[0033] Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace;

[0034] Ring B is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace;

[0035] R 1 and R 2 are each independently selected from H and methyl;

[0036] R 3 Selected from H and C 1-4 alkyl;

[0037] R 4 and R 5 Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 dialkylamino groups;

[0038] R 6 and R 7 Each independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 dialkylamino groups;

[0039] Each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 1 、Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ;

[0040] Each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 、Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0041] R W 、R X and R Z Each independently selected from H, halo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W 、R X or R Z The C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 3 、Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3and S(O)2NR c3 R d3 ;

[0042] Each Cy 1 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1R d1 ;

[0043] Each Cy 2 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0044] Each Cy 3 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0045] Each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、R b3 、R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、R b3 、R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 4 、Cy 4 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0046] Each Cy 4 is C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl: halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0047] R a4 、R b4 、R c4 and R d4 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0048] or R c1 and R d1 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0049] or Rc2 and R d2 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0050] or R c3 and R d3 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)Rb4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0051] Each R e1 、R e2 、R e3 and R e4 Independently selected from H, C 1-4 Alkyl and CN;

[0052] m is 0, 1, or 2;

[0053] E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and

[0054] L 1 is a linker covalently attached to moiety Q and moiety E;

[0055] wherein any of the aforementioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S;

[0056] wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group are optionally substituted with an oxo (=O) group; and

[0057] wherein one or more ring-forming S atoms of any aforementioned heterocycloalkyl group are optionally substituted by one or two oxo (=O) groups.

[0058] The present disclosure provides, inter alia, compounds of formula (I):

[0059]

[0060] or a pharmaceutically acceptable salt thereof, wherein:

[0061] W is CR W or N;

[0062] X is CR X or N;

[0063] Z is CR Z or N; and

[0064] Among them, at most two of W, X and Z are N at the same time;

[0065] Y 1 Selected from-NR 3 -、-CR 4 R 5 -and-O-;

[0066] Y 2 Selected from bond, -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-;

[0067] Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace;

[0068] Ring B is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace;

[0069] R 1 and R 2 are each independently selected from H and methyl;

[0070] R 3 Selected from H and C 1-4 alkyl;

[0071] R 4 and R 5 Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C1-4 Alkylamino and C 2-8 dialkylamino groups;

[0072] R 6 and R 7 Each independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 dialkylamino groups;

[0073] Each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NRc1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 1 、Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ;

[0074] Each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NRc2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 、Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)Rb2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0075] R W 、R X and R Z Each independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W 、R X or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 3 、Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 Rd3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0076] Each Cy 1 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NRc1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ;

[0077] Each Cy 2 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NRe2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0078] Each Cy 3 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NRc3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0079] Each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、R b3 、R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、Rb3 、R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 4 、Cy 4 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NRc4 R d4 and S(O)2NR c4 R d4 ;

[0080] Each Cy 4 is C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl: halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0081] R a4 、R b4 、R c4 and R d4 Independently selected from H, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0082] or R c1 and R d1 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NRc4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0083] or R c2 and R d2 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2Rb4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0084] or R c3 and R d3 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0085] Each R e1 、R e2 、R e3 and R e4 Independently selected from H, C1-4 Alkyl and CN;

[0086] m is 0, 1, or 2;

[0087] E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and

[0088] L 1 is a linker covalently attached to moiety Q and moiety E;

[0089] wherein any of the aforementioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S;

[0090] wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group are optionally substituted with an oxo (=O) group; and

[0091] wherein one or more ring-forming S atoms of any aforementioned heterocycloalkyl group are optionally substituted by one or two oxo (=O) groups.

[0092] The present disclosure provides, inter alia, compounds of formula (I):

[0093]

[0094] or a pharmaceutically acceptable salt thereof, wherein:

[0095] W is CR W or N;

[0096] X is CR X or N;

[0097] Z is CR Z or N; and

[0098] Among them, at most two of W, X and Z are N at the same time;

[0099] Y 1 Selected from-NR 3 -、-CR 4 R 5 -and-O-;

[0100] Y 2 Selected from -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-;

[0101] Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 3-14Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace;

[0102] Ring B is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace;

[0103] R 1 and R 2 are each independently selected from H and methyl;

[0104] R 3 Selected from H and C 1-4 alkyl;

[0105] R 4 and R 5 Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 dialkylamino groups;

[0106] R 6 and R 7 Each independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 dialkylamino groups;

[0107] Each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 1 、Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ;

[0108] Each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SRa2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 、Cy 2 -C 1-4Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0109] R W 、R X and R Z Each independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W 、R X or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 3 、Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0110] Each Cy 1 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ;

[0111] Each Cy 2 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0112] Each Cy 3 independently selected from C, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ;

[0113] Each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、R b3 、R c3and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、R b3 、R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 4 、Cy 4 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 Rd4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0114] Each Cy 4 is C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl: halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0115] R a4 、R b4 、R c4 and R d4 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6haloalkoxy;

[0116] or R c1 and R d1 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0117] or R c2 and R d2 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 Rd4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0118] or R c3 and R d3 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0119] Each R e1 、R e2 、R e3 and R e4 Independently selected from H, C 1-4 Alkyl and CN;

[0120] m is 0, 1, or 2;

[0121] E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and

[0122] L 1 is a linker covalently attached to moiety Q and moiety E;

[0123] wherein any of the aforementioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S;

[0124] wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group are optionally substituted with an oxo (=O) group; and

[0125] wherein one or more ring-forming S atoms of any aforementioned heterocycloalkyl group are optionally substituted by one or two oxo (=O) groups.

[0126] In some embodiments, W is CR W In some embodiments, W is N.

[0127] In some embodiments, X is CR X In some embodiments, X is N.

[0128] In some embodiments, Z is CR Z In some embodiments, Z is N.

[0129] In some embodiments, Y 1 In some embodiments, Y 1 -CR 4 R 5 -. In some embodiments, Y 1 -NR 3 -. In some embodiments, Y 1 -O- or -CR 4 R 5 -. In some embodiments, Y 1 -O- or -NR 3 -.

[0130] In some embodiments, Y 1 For-(C 2-4 In some embodiments, Y 1 In some embodiments, Y 1 -O-, -NR 3 -or-(C 2-4 In some embodiments, Y 1 -O-, -NR 3 -or -(C2 alkynyl)-.

[0131] In some embodiments, Y 2 is S. In some embodiments, Y 2 In some embodiments, Y 1 In some embodiments, Y 2 Selected from -S-, -S(O)-, -S(O)2-, -CH2-, -O- and -N(R 3 )-. In some embodiments, Y 2 Selected from -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-. In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 2 It is a bond, -S-, -CH2- or -O-.

[0132] In some embodiments, Ring A is a 4- to 18-membered heterocycloalkyl, wherein Ring A is optionally substituted by 1, 2, 3, or 4 R A replace.

[0133] In some embodiments, Ring A is a 4- to 7-membered heterocycloalkyl, wherein Ring A is optionally substituted by 1, 2, 3, or 4 R AIn some embodiments, Ring A is a 4- to 7-membered heterocycloalkyl group, wherein Ring A is optionally substituted with 1 or 2 R A In some embodiments, Ring A is a 4- to 7-membered heterocycloalkyl.

[0134] In some embodiments, Ring A is each optionally substituted with 1, 2, 3, or 4 R A In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A In some embodiments, ring A is each optionally substituted with 1 or 2 R A In some embodiments, ring A is optionally substituted with 1 or 2 R A In some embodiments, ring A is optionally substituted with R A Substituted piperidinyl.

[0135] In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl or 1-methylpiperidin-4-yl. In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl. In some embodiments, Ring A is 1-methylpiperidin-4-yl. In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, or 1-(2,2,2-trifluoroethyl)piperidin-4-yl.

[0136] In some embodiments, Ring A is C 3-14 Cycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A In some embodiments, Ring A is cyclohexyl, wherein Ring A is optionally substituted with 1, 2, 3, or 4 R A In some embodiments, Ring A is 4-hydroxycyclohexyl. In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein Ring A is optionally substituted with 1, 2, 3 or 4 R A In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, or hydroxycyclohexyl.

[0137] In some embodiments, Ring A is a 4- to 7-membered heterocycloalkyl or C 3-14 Cycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A In some embodiments, ring A is a 4- to 7-membered heterocycloalkyl or C 3-14 Cycloalkyl, wherein ring A is optionally substituted by 1 or 2 R AIn some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, or 4-hydroxycyclohexyl. In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, or 1-(2,2,2-trifluoroethyl)piperidin-4-yl.

[0138] In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4-hydroxycyclohexyl.

[0139] In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 4-hydroxycyclohexyl.

[0140] In some embodiments, Ring B is C 3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl, wherein ring B is optionally substituted by 1, 2, 3 or 4 R B In some embodiments, Ring B is C 3-7 Cycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B In some embodiments, Ring B is a 4- to 7-membered heterocycloalkyl group, wherein Ring B is optionally substituted with 1, 2, 3, or 4 R B In some embodiments, Ring B is each optionally substituted with 1, 2, 3, or 4 R B In some embodiments, Ring B is piperidinyl, cyclobutyl or cyclohexyl.

[0141] In some embodiments, Ring B is C 3-7 Cycloalkyl or 4 to 7 membered heterocycloalkyl, wherein ring B is optionally substituted by 1 or 2 R B In some embodiments, Ring B is C 3-7 Cycloalkyl, wherein ring B is optionally substituted by 1 or 2 R B In some embodiments, Ring B is a 4- to 7-membered heterocycloalkyl group, wherein Ring B is optionally substituted with 1 or 2 R B replace.

[0142] In some embodiments, Ring B is optionally substituted with 1, 2, 3, or 4 R B In some embodiments, ring B is optionally substituted with 1 or 2 R BIn some embodiments, ring B is piperidinyl. In some embodiments, ring B is piperazinyl. In some embodiments, ring B is optionally substituted with 1, 2, 3, or 4 R B substituted piperidinyl or piperazinyl.

[0143] In some embodiments, Ring B is C 3-7 Cycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B In some embodiments, Ring B is cyclobutyl or cyclohexyl. In some embodiments, Ring B is cyclopropyl, cyclobutyl or cyclohexyl.

[0144] In some embodiments, Ring B is each optionally substituted with 1, 2, 3, or 4 R B Substituted cyclobutyl, cyclohexyl, piperidinyl or piperazinyl. In some embodiments, Ring B is cyclobutyl, cyclohexyl, piperidinyl or piperazinyl.

[0145] In some embodiments, Ring B is each optionally substituted with 1, 2, 3, or 4 R B substituted piperidinyl, piperazinyl or azetidinyl.

[0146] In some embodiments, R 1 and R 2 Each is H. In some embodiments, R 1 is H. In some embodiments, R 2 For H.

[0147] In some embodiments, R 4 and R 5 Each is H. In some embodiments, R 4 is H. In some embodiments, R 5 For H.

[0148] In some embodiments, R 6 and R 7 Each is H. In some embodiments, R 6 is H. In some embodiments, R 7 For H.

[0149] In some embodiments, each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Each haloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 1 、Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 Rd1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 .

[0150] In some embodiments, each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NRc1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 .

[0151] In some embodiments, each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 NR c1 R d1 NR c1 C(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 .

[0152] In some embodiments, each R A independently selected from halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, CN, NO2 or OR a1 In some embodiments, each R A C 1-6 In some embodiments, each R A C 1-6 Alkyl or C 1-6 In some embodiments, R A In some embodiments, R Ais methyl, OH or 2,2,2-trifluoroethyl.

[0153] In some embodiments, each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 、Cy 2 -C 1-4Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 .

[0154] In some embodiments, each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 .

[0155] In some embodiments, each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 NR c2 R d2 NR c2 C(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 .

[0156] In some embodiments, each RB independently selected from halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, CN, NO2 or OR a2 In some embodiments, each R B independently selected from halo, C 1-6 Alkyl and C 1-6 In some embodiments, each R B independently selected from halo and C 1-6 In some embodiments, each R B In some embodiments, each R B For F.

[0157] In some embodiments, R W 、R X and R Z Each independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 Rd3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W 、R X or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Each haloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 3 、Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2Rb3 and S(O)2NR c3 R d3 .

[0158] In some embodiments, R W Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0159] In some embodiments, R W Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2 and ORa3 In some embodiments, R W Selected from H, halo and C 1-6 In some embodiments, R W For F.

[0160] In some embodiments, R X Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0161] In some embodiments, R X Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the C 6-10Aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a3 and SR a3 .

[0162] In some embodiments, R X Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a3 and C 6-10 In some embodiments, R X is H. In some embodiments, R X In some embodiments, R X is H or F. In some embodiments, R X For F.

[0163] In some embodiments, R Z Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 Rd3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 .

[0164] In some embodiments, R Z Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the C 6-10 Aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a3 and SR a3 .

[0165] In some embodiments, R Z Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a3 and C 6-10 In some embodiments, R X For H.

[0166] In some embodiments, m is 1. In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2.

[0167] In some embodiments, L 1 It is linked to ring B via a covalent bond to ring B.

[0168] In some embodiments, L 1 is a chain having 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10 or 1 to 5 chain atoms, which is optionally substituted by 1 to 3 R q Substituent substituted, and wherein L 1One or more chain carbon atoms of can be oxidized to form a carbonyl group (C=O), and one or more N and S chain atoms can each optionally be oxidized to form an amine oxide, sulfoxide, or sulfonyl group; and

[0169] Each R q Independently selected from OH, CN, -COOH, NH2, halo, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl, NH(C 1-6 alkyl) and N(C 1-6 alkyl)2, wherein R q C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with halo, OH, CN, -COOH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, phenyl, C 3-10 In some embodiments, R q Independently selected from OH, CN, -COOH, NH2, halo, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2.

[0170] In some embodiments, L 1 Select from the following:

[0171] (i) a bond such that ring B is directly connected to moiety E;

[0172] (ii)-(C 1-4 alkyl)-;

[0173] (iii)-(C 2-4 alkenyl)-;

[0174] (iv)-(C 2-4 Alkynyl)-;

[0175] (v)-(C 2-4 Alkynyl)-(G3 )-;

[0176] (vi) The following structure:

[0177]

[0178] (vii) The following structure:

[0179]

[0180] (viii) The following structure:

[0181]

[0182] Among them G 1 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -;

[0183] G 2 C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl;

[0184] G 3 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -;

[0185] G 4 For optionally C 1-6 Alkyl, hydroxyl, C 1-6 4- to 10-membered heterocycloalkyl substituted with an alkoxy group or a halo group;

[0186] Each R G independently selected from H, methyl and ethyl;

[0187] a is 0 or 1;

[0188] b is 0 or 1;

[0189] c is 0 or 1;

[0190] d is 0 or 1;

[0191] e is 0 or 1;

[0192] f is 0 or 1;

[0193] g is 0, 1, or 2;

[0194] wherein at least one of b, c, e and f is 1.

[0195] In some embodiments, L 1 Select from the following:

[0196] (i) a bond such that ring B is directly connected to moiety E;

[0197] (ii)-(C 1-4 alkyl)-;

[0198] (iii)-(C 2-4 alkenyl)-;

[0199] (iv)-(C 2-4 Alkynyl)-;

[0200] (v)-(C 2-4 Alkynyl)-(G 3 )-;

[0201] (vi) The following structure:

[0202]

[0203] (vii) The following structure:

[0204]

[0205] (viii) The following structure:

[0206]

[0207] Among them G 1 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -;

[0208] G 2 are each optionally substituted with a halo group, a C 1-6 Alkyl or C 1-6 Haloalkyl substituted C 6-10 Aryl, C3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl;

[0209] G 3 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -;

[0210] G 4 is a 4- to 10-membered heterocycloalkyl group;

[0211] Each R G independently selected from H, methyl and ethyl;

[0212] a is 0 or 1;

[0213] b is 0 or 1;

[0214] c is 0 or 1;

[0215] d is 0 or 1;

[0216] e is 0 or 1;

[0217] f is 0 or 1;

[0218] g is 0, 1, or 2;

[0219] wherein at least one of b, c, e and f is 1.

[0220] In some embodiments, L 1 Select from the following:

[0221] (viii) a bond such that ring B is directly connected to moiety E;

[0222] (ix)-(C 1-4 alkyl)-;

[0223] (x)-(C 2-4 alkenyl)-;

[0224] (xi)-(C 2-4 alkynyl);

[0225] (xii)-(C 2-4 Alkynyl)-(G 3 )-;

[0226] (xiii) The following structure:

[0227]

[0228] (xiv) The following structure:

[0229]

[0230] (viii) The following structure:

[0231]

[0232] Among them G 1 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -;

[0233] G 2 C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl;

[0234] G 3 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -;

[0235] G 4 is a 4- to 10-membered heterocycloalkyl group;

[0236] Each R G independently selected from H, methyl and ethyl;

[0237] a is 0 or 1;

[0238] b is 0 or 1;

[0239] c is 0 or 1;

[0240] d is 0 or 1;

[0241] e is 0 or 1;

[0242] f is 0 or 1;

[0243] g is 0, 1, or 2;

[0244] wherein at least one of b, c, e and f is 1.

[0245] In some embodiments, L 1 Select from the following:

[0246] (i) a bond such that ring B is directly connected to moiety E;

[0247] (ii)-(C 1-4 alkyl)-;

[0248] (iii)-(C 2-4 alkenyl)-;

[0249] (iv)-(C 2-4 Alkynyl)-;

[0250] (v)-(C 2-4 Alkynyl)-(G 3 )-;

[0251] (vi) The following structure:

[0252]

[0253] (vii) The following structure:

[0254]

[0255] In some embodiments, L 1 is a bond such that ring B is directly connected to moiety E.

[0256] In some embodiments, L 1 For-(C 1-4 alkyl)-.

[0257] In some embodiments, L 1 For-(C 2-4 alkenyl)-.

[0258] In some embodiments, L 1 For-(C 2-4 Alkynyl)-.

[0259] In some embodiments, L 1 For-(C 2-4 Alkynyl)-(G 3 )-.

[0260] In some embodiments, L 1 Has the following structure:

[0261]

[0262] In some embodiments, L 1 for

[0263]

[0264] In some embodiments, G 1 -NR G C(O)- or -C(O)-. In some embodiments, G 1 -NR G C(O)-. In some embodiments, G 1 In some embodiments, G 1 -NR G C(O)-, -C(O)-, or -O-. In some embodiments, G 1 It is -O-.

[0265] In some embodiments, G 2 is optionally substituted with halogen or C 1-6 In some embodiments, G is a 4- to 10-membered heterocycloalkyl substituted with a haloalkyl group. 2 For optionally C 1-6 In some embodiments, G is a 4- to 10-membered heterocycloalkyl substituted with a haloalkyl group. 2 is a 4- to 10-membered heterocycloalkyl. 2 In some embodiments, G is piperidinyl, piperazinyl or azetidinyl. 2 In some embodiments, G 2 In some embodiments, G 2 In some embodiments, G 2 In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptyl or 3,4-dihydroquinazolin-7-yl.

[0266] In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, pyridinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8,2-azaspiro[3.5]nonyl or 7-azaspiro[3.5]nonyl. In some embodiments, G 2is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8,2-azaspiro[3.5]nonyl or 7-azaspiro[3.5]nonyl. In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl, 3,8-diazabicyclo[3.2.1]octyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8,2-azaspiro[3.5]nonyl or 7-azaspiro[3.5]nonyl. In some embodiments, G 2 is cyclobutyl or cyclohexyl.

[0267] In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, pyridinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8,2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl or pyrrolidinyl.

[0268] In some embodiments, G 2 C 3-7 In some embodiments, G 2 It is cyclobutyl.

[0269] In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl or cyclobutyl.

[0270] In some embodiments, G 3 -NR G Or -O-. In some embodiments, G 3 -NR G -. In some embodiments, G 3 It is -O-.

[0271] In some embodiments, G 4 In some embodiments, G 4 In some embodiments, G4 In some embodiments, G 4 In some embodiments, G 4 is azetidinyl, piperidinyl or piperazinyl.

[0272] In some embodiments, a is 0. In some embodiments, a is 1.

[0273] In some embodiments, b is 0. In some embodiments, b is 1.

[0274] In some embodiments, c is 0. In some embodiments, c is 1.

[0275] In some embodiments, d is 0. In some embodiments, d is 1.

[0276] In some embodiments, e is 0. In some embodiments, e is 1.

[0277] In some embodiments, f is 0. In some embodiments, f is 1.

[0278] In some embodiments, g is 0. In some embodiments, g is 1.

[0279] In some embodiments, R G is H. In some embodiments, R G It is a methyl group.

[0280] Ubiquitin ligase binding moieties and linkers are known and well described in the art, for example: Bondeson, Bondeson, DP et al., Nat Chem Biol., 2015 11(8):611-617; An S et al., EBio Medicine, 2018 36:553-562; Paiva SL. et al., Curr. Op. in Chem. Bio., 2010, 50:111-119; and International Patent Application Publication No. WO 2017 / 197056, each of which is incorporated herein by reference in its entirety.

[0281] In some embodiments, E is a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding portion, an MDM2 E3 ubiquitin ligase binding portion, a cerebellum E3 ubiquitin ligase binding portion, or an inhibitor of apoptosis protein (IAP) E3 ubiquitin ligase binding portion, each of which has an IC of less than about 10 μM as determined in a binding assay. 50For example, E is a cerebellar E3 ubiquitin ligase binding portion. E can be a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding portion. E can be an MDM2 E3 ubiquitin ligase binding portion. E can be an IAP E3 ubiquitin ligase binding portion.

[0282] In some embodiments, E is an E3 ubiquitin ligase binding moiety that binds to cerebellum.

[0283] In some embodiments, E comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide.

[0284] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof.

[0285] In some embodiments, E is selected from the group consisting of:

[0286]

[0287]

[0288] In some embodiments, E is selected from the group consisting of:

[0289]

[0290]

[0291] The wavy line represents the group L 1 connection point.

[0292] In some embodiments, E is selected from:

[0293]

[0294] The wavy line represents the group L 1 connection point.

[0295] In some embodiments, E is:

[0296]

[0297] The wavy line represents the group L 1 connection point.

[0298] In some embodiments, E is:

[0299]

[0300] The wavy line represents the group L 1 connection point.

[0301] In some embodiments, E is:

[0302]

[0303] The wavy line represents the group L 1 connection point.

[0304] In some embodiments, E is:

[0305]

[0306] The wavy line represents the group L 1 connection point.

[0307] In some embodiments, E is:

[0308]

[0309] The wavy line represents the group L 1 connection point.

[0310] In some embodiments, E is:

[0311]

[0312] The wavy line represents the group L 1 connection point.

[0313] In some embodiments, E is selected from the group consisting of:

[0314] The wavy line represents the group L 1 connection point.

[0315] In some embodiments, E is selected from the group consisting of:

[0316]

[0317]

[0318]

[0319] The wavy line represents the group L 1 connection point.

[0320] In some embodiments, E is selected from the group consisting of:

[0321] The wavy line represents the group L 1 connection point.

[0322] In some embodiments, E is selected from the group consisting of:

[0323] The wavy line represents the group L 1 connection point.

[0324] In some embodiments, E is selected from the group consisting of:

[0325]

[0326] The wavy line represents the group L 1 connection point.

[0327] In some embodiments, E is:

[0328]

[0329] The wavy line represents the group L 1 connection point.

[0330] In some embodiments, E is:

[0331]

[0332] The wavy line represents the group L 1 connection point.

[0333] In some embodiments, E is:

[0334]

[0335] The wavy line represents the group L 1 connection point.

[0336] In some embodiments, the compound has Formula IA:

[0337]

[0338] or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the compound has Formula IA:

[0340]

[0341] or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the compound has Formula II:

[0343]

[0344] or a pharmaceutically acceptable salt thereof.

[0345] In some embodiments, the compound has Formula IIa:

[0346]

[0347] or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the compound has Formula III:

[0349]

[0350] or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the compound is selected from the group consisting of:

[0352] N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0353] N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0354] N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0355] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione;

[0356] 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione;

[0357] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione;

[0358] N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0359] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0360] 2-(2,6-dioxopiperidin-3-yl)-4-((9-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-9-oxononyl)amino)isoindoline-1,3-dione;

[0361] 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)propyl)amino)isoindoline-1,3-dione;

[0362] 2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione;

[0363] 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione;

[0364] N-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0365] 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione;

[0366] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0367] 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione;

[0368] 3-(4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0369] 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione;

[0370] 1-(4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0371] 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione;

[0372] 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0373] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethoxy)ethyl)amino)isoindoline-1,3-dione;

[0374] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione;

[0375] 2-(2,6-dioxopiperidin-3-yl)-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione;

[0376] N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0377] N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide;

[0378] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione;

[0379] 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione;

[0380] 3-(5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0381] 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0382] 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione;

[0383] 1-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0384] 1-(3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0385] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione;

[0386] 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione;

[0387] 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione;

[0388] 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione;

[0389] 3-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0390] 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0391] 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione;

[0392] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione;

[0393] 5-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0394] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-en-1-yl)isoindoline-1,3-dione;

[0395] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione;

[0396] 3-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-yl)amino)phenyl)piperidine-2,6-dione;

[0397] 3-((4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutyl)methoxy)phenyl)amino)piperidine-2,6-dione;

[0398] 3-({4-[3-({4-[({5-fluoro-2-[(oxan-4-ylsulfanyl)methyl]-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}methyl)cyclobutyloxy]phenyl}amino)piperidine-2,6-dione;

[0399] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0400] 3-((4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione;

[0401] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione;

[0402] 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0403] 3-((4-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0404] 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; and

[0405] 1-(3-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0406] or a pharmaceutically acceptable salt of any one of the foregoing.

[0407] In some embodiments, the compound is selected from the group consisting of:

[0408] 3-((4-(4-(2-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0409] 3-((4-(4-(3-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclobutyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0410] 7-(((1s,3s)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0411] 7-(((1r,3r)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0412] 5-fluoro-3-(4-methoxybenzyl)-7-((1-(2-(4-nitrophenoxy)ethyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0413] (S)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0414] (R)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0415] 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0416] 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0417] 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione;

[0418] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione;

[0419] 3-((3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0420] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0421] 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione;

[0422] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione;

[0423] 3-((3-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione;

[0424] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0425] 3-((6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione;

[0426] 1-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0427] 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)phenyl)amino)piperidine-2,6-dione;

[0428] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)ethynyl)isoindoline-1,3-dione;

[0429] 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)phenyl)amino)piperidine-2,6-dione;

[0430] 1-(6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0431] 1-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0432] 3-((4-(((3aR,5r,6aS)-2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione;

[0433] 1-(4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0434] 3-(5-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione;

[0435] 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione;

[0436] 2-(2,6-dioxopiperidin-3-yl)-5-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione;

[0437] 2-(2,6-dioxopiperidin-3-yl)-4-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione;

[0438] 2-(2,6-dioxopiperidin-3-yl)-4-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione;

[0439] 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione;

[0440] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0441] 3-((4-(4-(2-(4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0442] 3-((4-((4-(((5-Fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)methyl)phenyl)amino)piperidine-2,6-dione;

[0443] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)methyl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione;

[0444] 3-((4-(4-(4-(2-(5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0445] 3-((4-((1-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione;

[0446] 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0447] 3-((4-(4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; and

[0448] 3-((4-(3-((4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione,

[0449] or a pharmaceutically acceptable salt of any one of the foregoing.

[0450] In some embodiments, the compound is selected from:

[0451] 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione;

[0452] 3-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)isoindolin-5-yl)amino)piperidine-2,6-dione;

[0453] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)benzamide;

[0454] 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)amino)phenyl)amino)piperidine-2,6-dione;

[0455] 3-((4-(8-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)piperidine-2,6-dione;

[0456] 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0457] 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0458] 3-((3,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0459] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0460] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0461] 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0462] 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione;

[0463] 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione;

[0464] 3-((4-fluoro-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0465] 3-((4-(4-(2-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0466] 3-((4-(4-(2-(4-(((2-(cyclobutylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0467] 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0468] 3-((5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione;

[0469] 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione;

[0470] 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione;

[0471] 3-((4-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclohexyl)oxy)phenyl)amino)piperidine-2,6-dione;

[0472] 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0473] 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0474] 3-((4-(4-(((5-Fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0475] 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0476] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0477] 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0478] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0479] 3-((5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)piperidine-2,6-dione;

[0480] 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione;

[0481] 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)amino)piperidine-2,6-dione;

[0482] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0483] 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)(methyl)amino)phenyl)amino)piperidine-2,6-dione;

[0484] 3-((4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0485] 3-((4-(4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0486] 3-((3-fluoro-4-(4-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0487] 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0488] 3-((4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione;

[0489] 3-((4-(4-(2-(4-(((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0490] 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0491] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)phenyl)amino)piperidine-2,6-dione;

[0492] 3-((4-(5-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-2-yl)phenyl)amino)piperidine-2,6-dione;

[0493] 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-3-yl)phenyl)amino)piperidine-2,6-dione;

[0494] N-(2,6-dioxopiperidin-3-yl)-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxamide;

[0495] 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0496] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0497] 3-((3-chloro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0498] 3-((4-(7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)piperidine-2,6-dione;

[0499] 3-((5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione;

[0500] 3-((5-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione;

[0501] 3-((2,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0502] 3-((3-chloro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0503] 3-((3-fluoro-4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione;

[0504] 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0505] 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0506] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0507] 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)(methyl)amino)phenyl)amino)piperidine-2,6-dione;

[0508] 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-[1,3'-diazetidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; and

[0509] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin-1'-yl)benzamide,

[0510] or a pharmaceutically acceptable salt of any one of the foregoing.

[0511] In some embodiments, the compound is selected from the group consisting of:

[0512] 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)amino)phenyl)amino)piperidine-2,6-dione;

[0513] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)benzamide;

[0514] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0515] 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0516] 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0517] 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0518] 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione;

[0519] 1-(3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0520] 1-(3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0521] 1-(7-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0522] 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0523] 1-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0524] 1-(8-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0525] 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0526] 1-(5-fluoro-6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0527] 1-(4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0528] 1-(5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0529] 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0530] 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0531] 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione;

[0532] 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0533] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0534] 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0535] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0536] 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0537] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrrolidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0538] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0539] 3-((4-(4-(3-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0540] 3-((3-fluoro-4-(4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0541] 1-(3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0542] 1-(6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0543] 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0544] 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0545] 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0546] 1-(5-fluoro-6-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0547] 1-(6-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0548] 1-(6-(1'-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0549] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazine-1-carbonyl)phenyl)amino)piperidine-2,6-dione;

[0550] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0551] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)isoindoline-1,3-dione;

[0552] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)isoindoline-1,3-dione;

[0553] 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0554] 3-((3-fluoro-4-(4-(2-(3-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0555] 3-({4-[4-(2-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl)piperazin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione;

[0556] 3-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione;

[0557] 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0558] 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0559] 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0560] (3S)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide;

[0561] (3R)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide;

[0562] N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidine-4-carboxamide;

[0563] N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-N-methylpiperidine-4-carboxamide;

[0564] 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0565] 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0566] 1-(7-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0567] 3-((3-fluoro-4-(4-(2-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0568] 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0569] 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0570] 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0571] 1-(8-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0572] 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0573] 1-(5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0574] 3-((3-fluoro-4-(4-((1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0575] 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-2-oxo-[1,4′:1′,4″-terpiperidinyl]-1″-yl)phenyl)amino)piperidine-2,6-dione;

[0576] 3-((3-fluoro-4-(9-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)piperidine-2,6-dione;

[0577] 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0578] 3-((3-fluoro-4-(4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0579] 3-((2,5-difluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0580] 3-((4-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0581] 3-((3-fluoro-4-(4-((4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0582] 3-((2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0583] 3-((2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0584] 3-((3-fluoro-4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0585] 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0586] 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0587] 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0588] 3-((3-fluoro-4-(6-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-2-azaspiro[3.3]hept-2-yl)phenyl)amino)piperidine-2,6-dione;

[0589] 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4′:1′,4″-terpiperidinyl]-1″-yl)phenyl)amino)piperidine-2,6-dione;

[0590] 3-((5-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione;

[0591] 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione;

[0592] 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0593] 3-((3-fluoro-4-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0594] 3-((3-fluoro-4-(4-(3-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0595] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3-oxopiperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0596] 3-((3-fluoro-4-(4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0597] 3-((4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0598] 3-({4-[4-(3-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}azetidin-1-yl)piperidin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione,

[0599] or a pharmaceutically acceptable salt of any one of the foregoing.

[0600] It should also be understood that, for clarity, certain features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the present invention described in the context of a single embodiment may also be provided individually or in any suitable subcombination.

[0601] At various places in this specification, substituents of compounds of the invention are disclosed in groups or ranges. The present invention is specifically intended to include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to disclose individually methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0602] Throughout this specification, various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described. Unless otherwise indicated, these rings can be connected to the rest of the molecule at any ring member where valence allows. For example, the term "pyridyl" or "pyridyl ring" can refer to a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl ring.

[0603] The term "n-membered," where "n" is an integer, generally describes the number of ring atoms in a moiety, where the number of ring atoms is "n." For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0604] Throughout this specification, variables defining a divalent linking group may be described. It is specifically intended that each linking substituent include both the forward and reverse forms of the linking substituent. For example, -C(O)NR G -Including -C(O)NR G and -NR G C(O)-, and each of these forms is intended to be disclosed separately. When a structure requires a linking group, the Markush variable listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" refers to a linking alkylene group or arylene group, respectively.

[0605] For compounds of the invention in which a variable occurs more than once, each variable can be a different portion of a group independently selected from the group defining that variable. For example, when describing a structure having two R groups simultaneously present on the same compound, the two R groups can represent different portions of a group independently selected from the group defining R.

[0606] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0607] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

[0608] As used herein, the term "C i-j ", where i and j are integers representing the range of carbon atoms in the chemical group, and ij defines the range. For example, C 1-6 Alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0609] As used herein, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be straight or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, etc. In some embodiments, the alkyl group is methyl, ethyl, or propyl. The term "alkylene" refers to a connecting alkyl group.

[0610] As used herein, "alkenyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0611] As used herein, "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0612] As used herein, "halo" or "halogen," employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0613] As used herein, the term "haloalkyl" used alone or in combination with other terms refers to an alkyl group having up to a full valence halogen atom substituent, which halogen atom substituents may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF , C F , CHF , CCl , CHCl , C Cl , etc.

[0614] As used herein, the term "alkoxy" used alone or in combination with other terms refers to a group of the formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0615] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy group is -OCF3.

[0616] As used herein, "amino," employed alone or in combination with other terms, refers to NH2.

[0617] As used herein, the term "alkylamino" used alone or in combination with other terms refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0618] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of the formula -N(alkyl). Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0619] As used herein, the term "cycloalkyl" used alone or in combination with other terms refers to the non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups.Cycloalkyl groups can include monocyclic or polycyclic (e.g., with 2, 3, or 4 fused rings, bridged rings, or spirocyclic) ring systems.The definition of cycloalkyl also includes a portion having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., with a common key) to a cycloalkyl ring, such as a benzo derivative of cyclopentane, cyclohexene, cyclohexane, or a pyrido derivative of cyclopentane or cyclohexane. The ring-forming carbon atoms of the cycloalkyl group can optionally be substituted with an oxo group.Cycloalkyl groups also include cycloalkylene groups.The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantane-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane, etc.). In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7 Monocyclic cycloalkyl groups. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, tetrahydronaphthyl, octahydronaphthyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0620] As used herein, the term "cycloalkylalkyl" used alone or in combination with other terms refers to a group of the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the cycloalkyl moiety has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 A monocyclic cycloalkyl group.

[0621] As used herein, the term "heterocycloalkyl" used alone or in combination with other terms refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of a ring structure having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus. The heterocycloalkyl group may include a monocyclic or polycyclic ring system (e.g., having 2, 3 or 4 fused rings, bridged rings or spirocycles). In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. The definition of heterocycloalkyl also includes a portion having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to a non-aromatic heterocycloalkyl ring (i.e., having a common bond), such as 1,2,3,4-tetrahydro-quinoline, etc. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadamantan-1-yl, etc.) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]dec-N-yl], etc.). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring of the heterocycloalkyl group may be oxidized to form a carbonyl, N-oxide or sulfonyl group (or other oxidized bond), or the nitrogen atom may be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7 Monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0622] As used herein, the term "heterocycloalkylalkyl" used alone or in combination with other terms refers to a group of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is a methylene group. In some embodiments, the heterocycloalkyl portion has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is C 2-7 Monocyclic heterocycloalkyl groups.

[0623] As used herein, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon portion of a monocyclic or polycyclic (e.g., fused ring system), such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, etc. In some embodiments, the aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[0624] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is a methylene moiety. In some embodiments, the aryl moiety is a phenyl moiety. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is a benzyl group.

[0625] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. Carbon atoms or heteroatoms in the ring of the heteroaryl group may be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized linkage), or the nitrogen atom may be quaternized, provided that the aromatic nature of the ring is retained. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0626] As used herein, the term "heteroarylalkyl" used alone or in combination with other terms refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

[0627] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically inert raw materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are within the contemplation of the present invention. Cis and trans geometric isomers of the compounds of the present invention can be separated as mixtures of isomers or as individual isomeric forms.

[0628] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imide pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be balanced by appropriate substitution or sterically locked into one form.

[0629] The compounds of the present invention also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom.

[0630] Unless otherwise indicated, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

[0631] All compounds and pharmaceutically acceptable salts thereof may exist together with other substances such as water and solvents (eg, in the form of hydrates and solvates), or may be isolated.

[0632] In some embodiments, the compounds of the present invention, or their salts, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation can include, for example, a composition enriched with the compounds of the present invention. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present invention, or their salts. Methods for isolating compounds and their salts are conventional in the art.

[0633] The term "small molecule PARP14 targeting moiety" refers to a chemical group that binds to PARP14. The small molecule PARP14 targeting moiety can be a group derived from a compound that inhibits PARP14 activity. In some embodiments, the small molecule PARP14 targeting moiety inhibits PARP14 activity, wherein DC 50 Less than 1 μM in an enzyme assay (see, eg, Example A).

[0634] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting the substrate proteins for degradation.

[0635] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0636] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Lists of suitable salts are found in "Remington's Pharmaceutical Sciences," 17th ed., Mack Publishing Co., Easton, Pa., 1985, p. 1418 and in Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0637] synthesis

[0638] The compounds of the present invention (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

[0639] The reaction of preparing the compounds of this invention can be carried out in a suitable solvent, and those skilled in the art of organic synthesis can easily select these suitable solvents. Suitable solvent can be substantially not reacted with raw material (reactant), intermediate or product at the temperature of reacting, and this temperature can be in the range of the freezing temperature of solvent to the boiling temperature of solvent for example. Given reaction can be carried out in a solvent or in a mixture of more than a solvent. According to specific reactions steps, those skilled in the art can select the suitable solvent for specific reactions steps.

[0640] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley & Sons, New York (1999), which is incorporated herein by reference in its entirety.

[0641] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography.

[0642] The compounds of the present invention can be prepared according to a variety of preparative routes known in the literature. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0643] Solution 1

[0644]

[0645] Scheme 1 shows the general synthesis of quinazolinone compounds of the present disclosure. Formula (1-A) compound (many of which are commercially available or can be prepared via approaches known to those skilled in the art) can be coupled with formula (1-B) compound wherein "Hal" is a halogen (e.g., Br). Many formula (1-B) compounds are known in the art and are described in, for example, U.S. Patent number 10,562,891. The coupling can be carried out under Pd coupling conditions (e.g., at Pd reagents such as [Pd (allyl) Cl] 2 in the presence of), and obtain formula (1-C) compound.

[0646] Option 2

[0647]

[0648] Scheme 2 shows a general synthesis of certain compounds of the present invention. The compound of formula (2-A) can be prepared according to the route provided in Scheme 1 or according to the method described in, for example, U.S. Patent No. 10,562,891. The N atom of the B ring of the compound of formula (2-A) can be coupled with the compound of formula (2-B) under peptide coupling conditions (e.g., EDCI, HOBt and DIPEA; or HATU, DIPEA) to obtain the compound of formula (2-C), wherein "PG" refers to a protecting group (e.g., a Boc group). Group L2 refers to the linker moiety L as defined herein 1 The internal part of the compound of formula (2-C) can be deprotected (for example, by treating with an acid) to obtain a compound of formula (2-D). The compound of formula (2-D) can be coupled with a compound of formula (2-E) in which "Hal" is a halogen atom to obtain a compound of formula (2-F). The compound of formula (2-E) is commercially available and is also known in the art. When "Hal" is F, the coupling of the compound of formula (2-D) with the compound of formula (2-E) can be carried out, for example, in the presence of a base (for example, triethylamine) under heating (for example, 100°C) to obtain a compound of formula (2-F). The "-NH-L 2 The "-C(O)-" group corresponds to L as defined herein. 1 group.

[0649] Option 3

[0650]

[0651] Scheme 3 shows a general synthesis of compounds of the present invention. The compound of formula (3-A) prepared according to Scheme 1 can be treated with tert-butyl 2-bromoacetate to obtain a compound of formula (3-B). The compound of formula (3-B) can be deprotected (e.g., by treatment with an acid) to obtain a compound of formula (3-C). The compound of formula (3-C) can be coupled with a compound of formula (3-D) known in the art. The coupling can be carried out under peptide coupling conditions (e.g., EDCI, HOBt, and DIPEA; or HATU, DIPEA) to obtain a compound of formula (3-E). The "-L" of the compound of formula (3-E) 2 -N(H)-C(O)-CH2-" group corresponds to L as defined herein 1 group.

[0652] Option 4

[0653]

[0654] Scheme 4 shows the general synthesis of compounds of the present invention. The nucleophilic N atom of the B ring of the compound of formula (4-A) prepared according to Scheme 1 can be reacted with an electrophilic compound of formula (4-B), many of which are commercially available and known in the art. The reaction gives a compound of formula (4-C), wherein "PG" refers to a protecting group (e.g., an alcohol protecting group, such as a silyl ether). The compound of formula (4-C) can be deprotected (e.g., by treating with a fluoride source such as HF) to give a compound of formula (4-D). The compound of formula (4-D) can be halogenated (e.g., by treating with 3-nitrobenzenesulfonyl chloride) to give a compound of formula (4-E), wherein "hal" is a halogen (e.g., Cl). The compound of formula (4-E) can be reacted with a nucleophilic compound of formula (4-F), many of which are commercially available or known in the art, wherein R is selected from H, C 1-6 Alkyl, 4 to 6 membered heterocycloalkyl and C 1-6 Substituents of cycloalkyl; to obtain a compound of formula (4-G). The "-L" of the compound of formula (4-G) 1 '-N(H)-(C 1-6 alkyl)-" group corresponds to L as defined herein 1 group.

[0655] How to use

[0656] The compounds disclosed herein can bind to both PARP14 and ubiquitin E3 ligase to cause PARP14 degradation, and the compounds can be used to treat various diseases, including cancer. In some embodiments, the compounds provided herein can degrade PARP14 in cells, which comprises contacting the cells with the compound, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, provided herein are methods for degrading PARP14 in a patient, wherein the method comprises administering to the patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof. "Degrading PARP14" refers to inactivating PARP14 by, for example, changing its structure or breaking it down into multiple peptides or amino acid fragments.

[0657] The compounds of the present invention can be used to treat various diseases associated with abnormal expression or activity of PARP14. For example, the compounds of the present invention can be used to treat cancer. In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies, such as leukemias and lymphomas. Exemplary lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Exemplary leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0658] Other cancers that may be treated by administering the compounds of the invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, stomach cancer, gastrointestinal tumors, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0659] In some embodiments, the cancer treatable by administration of the compounds of the invention is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer, or melanoma.

[0660] The compounds of the present invention may also have therapeutic utility in PARP14-related disorders in disease areas such as cardiology, virology, neurodegenerative diseases, inflammation and pain, particularly when these diseases are characterized by overexpression or increased activity of PARP14.

[0661] In some embodiments, the compounds of the present invention can be used to treat inflammatory diseases. It was found that genetic inactivation of poly (ADP-ribose) polymerase family member 14 (PARP14) (also known as ADP-ribosyltransferase diphtheria toxin-like 8 (ARTD8) or B aggressive lymphoma protein (BAL2)) protected mice from allergen-induced airway disease (Mehrothra et al., J Allergy Clin Immunol, July 25, 2012, 131 (2): 521-531; and Cho et al., Proc Natl Acad Sci USA, September 20, 2011, 108 (38): 15972-15977), inhibited the infiltration of immune cells such as eosinophils and neutrophils into the lungs, and reduced the release of inflammatory Th2 cytokines. Furthermore, treatment with a PARP14 inhibitor protected mice from a severe asthma model induced by sensitization and recall challenge with an inhaled Alternaria extract (Eddie et al., PMID 35817532). Animals treated with a PARP14 inhibitor showed reduced levels of airway mucus, serum IgE, immune cells (eosinophils, neutrophils, and lymphocytes), Th2 cytokines (IL-4, IL-5, and IL-13), and alarmins (IL-33 and TSLP) (Eddie et al., PMID 35817532 and Ribon internal data).

[0662] While not being bound by theory, studies have shown that PARP14 affects STAT6 signaling and STAT3 signaling, signaling induced by Th2 cytokines and Th17 cytokines, M1 / M2 macrophage polarization, and lymphocyte signaling. Studies have also shown that PARP14 is a regulator of Th2 / Th17 / THF T cell development, is involved in B cell development, and is involved in eosinophil / neutrophil recruitment / activation. It is believed that lymphocytes may be ILCs (e.g., ILC2 and ILC3) activated by alarmins (e.g., TSLP and IL-33) and are the primary producers of downstream cytokines (e.g., IL-4, IL-5, and IL-13).

[0663] Studies have shown that PARP14 inhibition not only affects the asthma phenotype at the level of secondary cytokines (e.g., IL-4, IL-5, and IL-13) and signaling to myeloid cells, but also suppresses the alarmins TSLP and IL-33, which are key upstream drivers of asthma released in response to allergens.

[0664] The present invention particularly relates to a method for treating or preventing an inflammatory disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Exemplary inflammatory diseases treatable by the disclosed methods include, for example, asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloids, eosinophilic disorders, pulmonary fibrosis, and other type 2 cytokine pathologies. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0665] Other exemplary inflammatory diseases treatable by the disclosed methods include inflammatory bowel disease ("IBD"), including ulcerative colitis ("UC" or "colitis") and Crohn's disease. In some embodiments, the inflammatory disease is inflammatory bowel disease. In some embodiments, the inflammatory disease is ulcerative colitis. In some embodiments, the inflammatory disease is Crohn's disease.

[0666] In some embodiments, the inflammatory disease is irritable bowel syndrome.

[0667] Eosinophilic disorders treatable by the disclosed methods include, for example, eosinophilic esophagitis (esophageal EoE), eosinophilic gastritis (gastric EG), eosinophilic gastroenteritis (gastric and small intestine EGE), eosinophilic enteritis (small intestine EE), eosinophilic colitis (large intestine EC), and eosinophilic chronic sinusitis.

[0668] The present invention is also particularly directed to a method of treating or preventing asthma in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0669] In some embodiments, the asthma is steroid-resistant asthma, steroid-refractory asthma, steroid-resistant asthma, atopic asthma, nonspecific asthma, persistent asthma, severe asthma, or steroid-refractory severe asthma. In some embodiments, the severe asthma is T2 high endotype, T2 low endotype, or non-T2 endotype. In some embodiments, the severe asthma is T2 high endotype. In some embodiments, the severe asthma is T2 low endotype or non-T2 endotype. In some embodiments, the severe asthma is T2 low endotype. In some embodiments, the severe asthma is non-T2 endotype.

[0670] The present invention also relates in particular to methods for treating or preventing fibrotic diseases, such as, but not limited to, pulmonary fibrosis, renal fibrosis, liver fibrosis (e.g., NASH and NAFLD), systemic fibrosis, and idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is systemic fibrosis.

[0671] The present invention also relates particularly to methods of treating or preventing chronic obstructive pulmonary disease (COPD), emphysema and chronic bronchitis.

[0672] The present invention also relates particularly to methods of treating or preventing inflammatory diseases of the skin such as atopic dermatitis or rosacea.

[0673] The present invention also provides a method of achieving the following in a patient:

[0674] (a) reduce the level of airway mucus in lung tissue,

[0675] (b) reduce serum IgE,

[0676] (c) reduce immune cell infiltration and activation in bronchoalveolar fluid,

[0677] (d) reducing the level of one or more inflammatory cytokines in bronchoalveolar fluid or lung tissue, or

[0678] (e) reducing the level of one or more alarmins in bronchoalveolar fluid or lung tissue, wherein the method comprises administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0679] In some embodiments, the present invention provides methods of reducing airway mucus levels in lung tissue of a patient.

[0680] In some embodiments, the present invention provides a method for reducing immune cell infiltration and activation in bronchoalveolar fluid of a patient. In some embodiments, the immune cell is an eosinophil, a neutrophil, or a lymphocyte.

[0681] In some embodiments, the present invention provides a method for reducing one or more inflammatory cytokines in bronchoalveolar fluid or lung tissue of a patient. In some embodiments, the inflammatory cytokine is a Th2 cytokine or a Th17 cytokine. In some embodiments, the inflammatory cytokine is a Th2 cytokine. In some embodiments, the inflammatory cytokine is IL-4, IL-5, IL-13, or IL-17A. In some embodiments, the inflammatory cytokine is IL-4, IL-5, or IL-13.

[0682] In some embodiments, the present invention provides a method for reducing an alarmin in bronchoalveolar fluid or lung tissue of a patient. In some embodiments, the alarmin is IL-25, IL-33, or TSLP.

[0683] As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a portion of a tissue sample removed from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that survives in an organism such as a mammal.

[0684] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" PARP14 or "contacting" cells with a compound of the present invention includes administering the compound of the present invention to an individual or patient, such as a human, who has PARP14, as well as, for example, introducing the compound of the present invention into a sample containing cells or a purified preparation containing PARP14.

[0685] As used herein, the terms "subject" or "patient" are used interchangeably to refer to a mammal, particularly a human.

[0686] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response in a tissue, system, animal, individual or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0687] As used herein, the terms "treating" and "treatment" refer to 1) inhibiting a disease in a subject who is experiencing or exhibiting the pathology or symptoms of the disease (i.e., preventing further development of the pathology and / or symptoms, or 2) ameliorating a disease in a subject who is experiencing or exhibiting the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms).

[0688] As used herein, the terms "preventing" and "prevention" are used to prevent a disease in an individual who may be susceptible to the disease but who does not yet experience or exhibit the pathology or symptoms of the disease.

[0689] As used herein, the term "reduction" is relative to the patient's level before administration. More specifically, when a biomarker or symptom in a patient is reduced, the reduction is relative to the level or severity of the biomarker or symptom in the patient before administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0690] Combination therapy

[0691] One or more additional agents or treatments such as chemotherapeutic agents or other anticancer agents, immunopotentiators, immunosuppressants, immunotherapy, radiation, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.) and / or kinase (tyrosine or serine / threonine), epigenetics or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be combined with the compounds of the present invention into a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0692] Suitable agents for treating cancer in combination with the compounds of the present invention include chemotherapeutic agents, targeted cancer therapies, immunotherapy, or radiotherapy. The compounds of the present invention can be effectively treated with anti-hormonal agents in combination with breast cancer and other tumors. Suitable examples are anti-estrogen agents (including but not limited to tamoxifen and toremifene), aromatase inhibitors (including but not limited to letrozole, anastrozole, and exemestane), adrenocortical steroids (such as prednisone), progestogens (such as megestrol acetate), and estrogen receptor antagonists (such as fulvestrant). Suitable anti-hormonal agents for treating prostate cancer and other cancers can also be combined with the compounds of the present invention. These suitable anti-hormonal agents include anti-androgens (including but not limited to flutamide, bicalutamide, and nilutamide), luteinizing hormone-releasing hormone (LHRH) analogs (including leuprorelin, goserelin, triptorelin, and histrelin), LHRH antagonists (such as degarelix), androgen receptor blockers (such as enzalutamide), and agents that inhibit androgen production (such as abiraterone).

[0693] Combining angiogenesis inhibitors with FGFR inhibitors may be effective for some tumors. These angiogenesis inhibitors include antibodies against VEGF or VEGFR or VEGFR kinase inhibitors. Anti-VEGF antibodies or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0694] Suitable chemotherapeutic or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide, TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenetriamine, triethylenethio-phosphamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide.

[0695] Other anticancer agents include antibody therapeutics against costimulatory molecules such as CTLA-4, 4-1BB, PD-1, and PD-L1, or antibodies against cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab, and rituximab.

[0696] The safe and effective application method of most of these chemotherapeutics is well known to those skilled in the art. In addition, the use of these chemotherapeutics is described in the standard literature. For example, the use of many chemotherapeutics is described in " U.S. Physician's Desk Reference " (PDR, for example 1996 editions, Medical Economics, Inc., Montville, New Jersey), the disclosure of which is incorporated herein by reference, as if its full content is set forth.

[0697] Suitable agents for use in combination with the compounds of the present invention for treating inflammatory diseases include, but are not limited to, corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone); disease-modifying antirheumatic drugs ("DMARDs," e.g., immunosuppressants or anti-inflammatory agents); antimalarials (e.g., hydroxychloroquine and chloroquine); immunosuppressants (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate); anti-inflammatory agents (e.g., aspirin, NSAIDs (e.g., ibuprofen, naproxen, indomethacin, nabumetone, celecoxib); antihypertensives (e.g., calcium channel blockers (e.g., ammonia); clodipine, nifedipine) and diuretics (e.g., furosemide); statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin); anti-B cell agents (e.g., anti-CD20 (e.g., rituximab), anti-CD22); anti-B lymphocyte stimulators ("anti-BLyS," e.g., belimumab, briximumab); type 1 interferon receptor antagonists (e.g., avolumab); T cell modulators (e.g., rigerimod); abatacept; anticoagulants (e.g., heparin, warfarin); and vitamin D supplements.

[0698] Additional suitable agents for use in combination with the present invention for treating inflammatory diseases include, but are not limited to, sulfonylureas, meglitinides, biguanides, α-glucosidase inhibitors, peroxisome proliferator-activated receptor-γ (i.e., PPAR-γ) agonists, insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (e.g., fibrates, including fenofibrate, bezafibrate, gemfibrozil, clofibrate; bile acid sequestrants, including cholestyramine, colestipol, etc.; niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists, including clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and adiponectin.

[0699] Suitable agents for use in combination with the compounds of the present invention in the treatment of asthma include, but are not limited to, beclomethasone (Qvar TM ), budesonide (Pulmicort Flexhaler TM ), budesonide / formoterol (Symbicort TM ), Ciclesonide (Alvesco TM ), Flunisolide (Aerospan TM ), Fluticasone (Flovent Diskus TM Flovent HFA TM 、Arnuity Ellipta TM ), fluticasone / salmeterol (Advair TM ), mometasone (Asmanex TM ), mometasone / formoterol (Dulera TM ), albuterol sulfate (VoSpireER TM ), Formoterol Fumarate (Aerolizer TM ), Serevent TM ), Formoterol tartrate (Brovana TM ), Odaterol (Striverdi TM ), fluticasone furoate / vilanterol (Breo Ellipta TM ), Fluticasone Furoate / Umeclidinium / Vilanterol (Trelegy Ellipta TM ), Fluticasone Propionate / Salmeterol (AirDuo TM ), glycopyrrolate / formoterol fumarate (Bevespi Aerosphere TM ), Indacaterol / Glycopyrrolate (Utibron Neohaler TM ), Tiotropium / olodaterol (Stiolto RespimatTM ), Umeclidinium / Vilanterol (Anoro Ellipta TM ), Omalizumab (Xolair TM ), mepolizumab (NUCALA TM ), benralizumab (Fasenra TM ), reslizumab (Cinqair TM ), dupilumab, trombopag, lebrikizumab, etanercept, golimumab, budalumab, and tezetuzumab.

[0700] Drug preparations and dosage forms

[0701] When used as a medicine, the compounds of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a compound of the present invention, or a combination of a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local treatment or systemic treatment and the area to be treated are needed. Administration can be oral, topical (including ocular and mucosal administration, including intranasal, vaginal and rectal delivery), pulmonary administration (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular or parenteral.

[0702] The present invention also includes pharmaceutical compositions containing one or more of the compounds of the present invention described above as active ingredients in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in a carrier in the form of, for example, a capsule, pouch, paper, or other container. When an excipient is used as a diluent, it can be a solid, semisolid, or liquid material that acts as a solvent, carrier, or medium for the active ingredient. Thus, these compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0703] These compositions may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0704] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the actual amount of compound administered is generally determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0705] In order to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a uniform mixture of the compounds of this invention. When these preformulation compositions are referred to as uniform, the active ingredient is usually evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preformulation is then subdivided into the unit dosage form of the above type, which contains, for example, 0.1 mg to about 500 mg of the active ingredient of the present invention.

[0706] Tablet of the present invention or pill can be coated or otherwise compounded, to obtain the dosage form with the advantage of prolonged effect.For example, tablet or pill can comprise interior dosage component and exterior dosage component, and the latter covers the former with film-coated form.These two kinds of components can be separated by enteric layer, and this enteric layer is used to prevent disintegration in stomach and allows inner component to enter duodenum or delay release intactly.Multiple materials can be used for this type of enteric layer or coating, and this type of material comprises the mixture of multiple polymeric acid and polymeric acid and this type of material such as shellac, cetyl alcohol and cellulose acetate.

[0707] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutically acceptable vehicles.

[0708] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, these compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions can be aerosolized using an inert gas. Nebulized solutions can be inhaled directly from the aerosolizing device, or the aerosolizing device can be connected to a mask tent or intermittent pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0709] The amount of compound or composition administered to a patient will vary depending on the substance being administered, the purpose of administration (such as prevention or treatment), the patient's condition, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition to be treated and the judgment of the attending clinician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0710] The compositions can be administered to patients in the form of the above-mentioned pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The aqueous solutions can be packaged for use as is or lyophilized, and the lyophilized formulations can be mixed with a sterile aqueous carrier before administration.

[0711] The therapeutic dose of the compounds of the present invention can vary according to, for example, the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in the pharmaceutical composition can vary according to a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in aqueous physiological buffer solutions containing about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1g / kg body weight per day. In some embodiments, the dosage range is about 0.01mg / kg to about 100mg / kg body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or disorder, the overall health of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be obtained by extrapolating the dose-response curve derived from an in vitro or animal model test system.

[0712] The compounds of the present invention may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent such as antiviral agents, anticancer agents, vaccines, antibodies, immunopotentiators, immunosuppressants, anti-inflammatory agents, and the like.

[0713] Example

[0714] Equipment: Recorded at 300MHz or 400MHz using an AVANCE 300MHz / 400MHz spectrometer 1H NMR spectra. NMR interpretation was performed using Bruker Topspin software to assign chemical shifts and multiplicities. Where two adjacent peaks of equal or unequal height were observed, the peaks were labeled as a multiplet or doublet. In the case of a doublet, coupling constants were assigned using the software. In any given sample, one or more protons may not be observed due to obscuration by water and / or solvent peaks. LCMS equipment and conditions were as follows:

[0715] 1. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-packscepter C183 3×3.0 mm, 3.0 μm. Mobile phase: A: water / 6.5 mM (NH₄)HCO₃; B: acetonitrile. Flow rate: 1.5 mL / min, 40°C. Detector: 190 nm to 400 nm. Gradient stop time: 2.0 min. Timetable:

[0716] T (minutes) A(％) B(％) 0.01 90 10 1.20 5 95 1.80 5 95 1.82 90 10

[0717] 2. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-packscepter C183 3×3.0 mm, 3.0 μm. Mobile phase: A: water / 5 mM (NH₄)HCO₃; B: acetonitrile. Flow rate: 1.5 mL / min, 40°C. Detector: 190 nm to 400 nm. Gradient stop time: 2.0 min. Timetable:

[0718] T (minutes) A(％) B(％) 0.01 90 10 1.20 5 95 1.80 5 95 1.82 90 10

[0719] 3. LC (acidic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Halo C18, 30 × 3.0 mm, 2.0 μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min, 40°C. Detection: 190 nm to 400 nm. Gradient stop time: 2.0 min. Timetable:

[0720]

[0721]

[0722] 4. LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Halo C18, 30 × 3.0 mm, 2.0 μm. Mobile phase A: water / 0.1% FA; B: acetonitrile / 0.1% FA. Flow rate: 1.5 mL / min, 40°C. Detection: 190 nm to 400 nm. Gradient stop time: 3.0 min. Timetable:

[0723] T (minutes) A(％) B(％) 0.01 90 5 1.20 5 100 1.80 5 100 1.82 90 5

[0724] 5. The MS detector was equipped with electrospray ionization as the ionizable source. Acquisition mode: Scan; Nebulizer gas flow: 1.5 L / min; Drying gas flow: 15 L / min; Detector voltage: 0.95 kV to 1.25 kV; DL temperature: 250°C; Heat block temperature: 250°C; Scan range: 90.00 m / z to 900.00 m / z.

[0725] 6. Sample Preparation: Dissolve the sample in ACN or methanol at a concentration of 1 mg / mL to 10 mg / mL and filter through a 0.22 μm filter. Injection volume: 1 μL to 3 μL.

[0726] definition :

[0727] ACN (acetonitrile); Ac2O (acetic anhydride); BALF (bronchoalveolar lavage fluid); B2(OH)4 (tetrahydroxydiboron); BINAP ((±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc2O (di-tert-butyl dicarbonate); CaCl2 (calcium chloride); CH3CN (acetonitrile); Cs2CO3 (cesium carbonate); CsF (cesium fluoride); CuI (copper(I) iodide); Cu(OAc)2( Copper(II) acetate); DCE (1,2-dichloroethane); DCM or CH2Cl2 (dichloromethane); DEAD (diisopropyl azodicarboxylate); DIBAL-H (diisobutylaluminum hydride); DIEA (N,N-diisopropylethylamine)(DiMeIHeptCl)Pd(cinnamyl)Cl2([1,3-bis[2,6-bis[3-methyl-1-(2-methylpropyl)butyl]phenyl]-4,5-dichloro-1,3 -dihydro-2H-imidazol-2-ylidene]chloro[(1,2,3-η)-1-phenyl-2-propen-1-yl]-palladium); DMF (N,N-dimethylformamide); DMAP (4-dimethylaminopyridine); DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); dtbpy (4,4'-di-tert-butyl-2 ,2'-bipyridine); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); equiv (equivalent); ESI (electrospray ionization); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); Fe (iron); g (gram); h (hour); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide) 1H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); HOAc (acetic acid); HOBT (1-hydroxybenzotriazole hydrate); Hz (hertz); K2CO3 (potassium carbonate); KI (potassium iodide); K3PO4 (tripotassium phosphate); L (liter); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylamide); LiAlH4 (lithium aluminum hydride); LiCl (lithium chloride); LiHMDS (lithium bis(trimethylsilyl)amide); M (mole); MeCN (acetonitrile); MeI (methyl iodide); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter), mmol (millimolar); NaBH4 (sodium borohydride); NaBH3CN (sodium cyanoborohydride); Na2C O3 (sodium carbonate); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); NaOCN (sodium cyanate); NaOH (sodium hydroxide); Na2SO4 (sodium sulfate); Na2SO4·10H2O (sodium sulfate decahydrate); NH3 (ammonia); NH4Cl (ammonium chloride); (NH4)HCO3 (ammonium bicarbonate); nm (nanometer); NiBr2.glyme (nickel(II) bromide glycol dimethyl ether complex); NMI (N-methylimidazole); NMP (N-methylpyrrolidone); PBS (phosphate-buffered saline); [Pd(allyl)Cl]2 (bis(allyl)dichloropalladium); Pd / C (palladium on carbon); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)); Pd2(dba)3.CHCl3 (tris(dibenzylideneacetone)dipalladium-chloroform adduct); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Pd(OAc)2 (palladium(II) acetate); PdPEPPSI IPentCl (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl](3-chloropyridyl)palladium(II)); Pd(PPh3)4(tetrakis(triphenylphosphine)palladium(0)); Pd(PPh3)2Cl2(trans-dichlorobis(triphenylphosphine)palladium(II)); PE (petroleum ether); PPh3 (triphenylphosphine); preparative HPLC (preparative high-performance liquid chromatography); ppm (parts per million); RockPhos (di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine); RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl); RuPhos-PdCl-2nd Palladium(II) chloride; RuPhos Pd G3 (palladium(II) methanesulfonate); SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride); STAB (sodium triacetoxyborohydride); TBAB (tetrabutylammonium bromide); TBAF (tetrabutylammonium fluoride); TBDPSCl (tert-butyldiphenylchlorosilane); t-BuBrettPhos (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethylthiophene); oxy-1,1'-biphenyl); t-BuOK (potassium tert-butoxide); t-BuONa (sodium tert-butoxide); TCFH (chloro-N,N,N',N'-tetramethylformamidine hexafluorophosphate); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); TfOH (trifluoromethanesulfonic acid); THF (tetrahydrofuran); T3P (propylphosphonic anhydride); TsCl (p-toluenesulfonyl chloride); RT (retention time); UV (ultraviolet light); and XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

[0728] Intermediate A1: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole Synthesis of 1,3-Phenyline-Dione

[0729]

[0730] Step A

[0731] A solution of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (8.90 g, 31.4 mmol, 1.2 eq) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (7.23 g, 26.2 mmol, 1.0 eq) and TEA (7.95 g, 78.6 mmol, 3.0 eq) in NMP (70 mL) was stirred at 70° C. for 3 hours. The resulting mixture was diluted with brine (200 mL) and EtOAc (300 mL). The precipitated solid was collected by filtration and washed with EtOAc (30 mL) to give tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (4.2 g, 30% yield) as a yellow solid. LCMS (ESI, m / z): 540.05 [M+H] + .

[0732] Step B

[0733] A solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (4.2 g, 7.8 mmol, 1.0 equivalent) in trifluoroacetic acid (30 mL) and DCM (90 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and then diluted with DCM (60 mL) and water (50 mL). The mixture was neutralized to pH 7 with saturated Na2CO3 aqueous solution. The resulting mixture was concentrated in vacuo to remove DCM. The precipitated solid was collected by filtration to give 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazine-1-yl)isoindoline-1,3-dione (3.9 g) as a yellow crude solid. The product was used without further purification. LCMS (ESI, m / z): 440.10 [M+H] + .

[0734] Intermediates A1-a to A1-p were prepared according to the procedure described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (Intermediate A1), using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0735]

[0736]

[0737]

[0738]

[0739] Intermediate A2: 2-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetyl Synthesis of amines

[0740]

[0741] At 0 ° C, bromoacetyl chloride (1.44 g, 9.15 mmol, 2.5 equivalents) was added to a solution of pomalidomide (1.0 g, 3.7 mmol, 1.0 equivalents) in THF (20 mL). The resulting mixture was stirred at 70 ° C for 2 hours and then concentrated in vacuo. The crude product was dissolved in diethyl ether and stirred for 20 minutes. The precipitated solid was collected by filtration and washed with diethyl ether (3×20 mL) to give 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (1.2 g, 83% yield) as a yellow solid. LCMS (ESI, m / z): 393.95, 395.95 [M+H] + .

[0742] Intermediate A2-a was synthesized according to the process described for the synthesis of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Intermediate A2) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0743]

[0744] Intermediate A3: 3-((4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride Salt synthesis

[0745]

[0746] Step A

[0747] To a solution of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (600mg, 2.09mmol, 1.0 equivalent) and tert-butyl 4-formylpiperidine-1-carboxylate (668mg, 3.13mmol, 1.5 equivalents) in MeOH (20mL) was added NaBHCN (262mg, 4.18mmol, 2.0 equivalents) in batches. The resulting solution was stirred for 4 hours. The mixture was concentrated under reduced pressure and directly purified by silica gel column chromatography, eluted with DCM / MeOH (9: 1) to give tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (639mg, 63% yield) as a yellow solid. LCMS(ESI,m / z):485.30[M+H] + .

[0748] Step B

[0749] A solution of tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (639 mg, 1.32 mmol, 1.0 equiv) in HCl in 1,4-dioxane (20 mL, 4 M) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 3-((4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (969 mg) as a white crude solid which was used without further purification. LCMS (ESI, m / z): 385.30 [M+H] + .

[0750] Intermediate A4: 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dihydropyrimidine Synthesis of ketones

[0751]

[0752] Step A

[0753] A solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (500 mg, 1.8 mmol, 1.0 equiv) and acrylic acid (196 mg, 2.71 mmol, 1.5 equiv) in toluene (50 mL) was stirred at 120 ° C for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (8: 1) to give 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)propanoic acid (252 mg, 40% yield) as a yellow solid. LCMS (ESI, m / z): 347.25 [MH] - .

[0754] Step B

[0755] A solution of 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)propanoic acid (240 mg, 0.69 mmol, 1 equiv) and urea (83 mg, 1.4 mmol, 2 equiv) in HOAc (25 mL) was stirred at 120° C. for 3 hours. The mixture was neutralized to pH 7 with saturated aqueous NaHCO₃. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH₄HCO₃), gradient from 5% to 95% over 20 minutes; detector, UV 254 nm to afford 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (95 mg, 50% yield) as a yellow oil. LCMS (ESI, m / z): 274.15 [M+H] + .

[0756] Step C

[0757] A solution of 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (85 mg, 0.31 mmol, 1.0 equiv), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (130 mg, 0.47 mmol, 1.5 equiv) and DIEA (121 mg, 0.93 mmol, 3.0 equiv) in NMP (5 mL) was stirred at 120 ° C for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×35 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 5% to 95% over 35 minutes; detector, UV 254 nm, to afford tert-butyl 4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (35 mg, 24% yield) as a yellow solid. LCMS (ESI, m / z): 471.35 [M+H] + .

[0758] Step D

[0759] A solution of tert-butyl 4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (35 mg, 0.074 mmol, 1.0 equiv) and TFA (1 mL) in DCM (1 mL) was stirred for 50 minutes. The resulting mixture was concentrated in vacuo to afford 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (28 mg) as a crude yellow solid which was used without further purification. LCMS (ESI, m / z): 371.10 [M+H] + .

[0760] Intermediate A4-a was synthesized according to the procedure described for the synthesis of 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)dione (Intermediate A4) hydrochloride, using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0761]

[0762] Intermediate A4-b was synthesized according to the process described for the synthesis of 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)dione hydrochloride (Intermediate A4) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0763]

[0764] Intermediate A5: Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride become

[0765]

[0766] Step A

[0767] A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.55 mmol, 1.0 equiv), tert-butyl piperazine-1-carboxylate (288 mg, 1.55 mmol, 1.0 equiv), PdPEPPSIIPentCl (133 mg, 0.16 mmol, 0.1 equiv), and CsCO (1008 mg, 3.09 mmol, 2.0 equiv) in 1,4-dioxane (5 mL) was stirred at 100° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (400 mg, 60%) as a white solid. LCMS (ESI, m / z): 429.15 [M+H] + .

[0768] Step B

[0769] A solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (400 mg, 0.93 mmol, 1.0 equiv) in HCl in 1,4-dioxane (5 mL, 4 M) was stirred for 1 hour. The resulting mixture was concentrated in vacuo to give 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (425 mg) as a yellow crude solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 329.10 [M+H] + .

[0770] Intermediates A5-a to A5-c were synthesized according to the process described for the synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (intermediate A5) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0771]

[0772]

[0773] Intermediates A5-d and A5-e were synthesized according to the process described for the synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (intermediate A5) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0774]

[0775]

[0776] Intermediate A6: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)cyclobutyloxy)isoindoline-1,3- Synthesis of diketones

[0777]

[0778] Step A

[0779] To a stirred solution of 3-(hydroxymethyl)cyclobutan-1-ol (2.0 g, 19.6 mmol, 1.0 equiv), TEA (5.94 g, 58.7 mmol, 3.0 equiv) and DMAP (0.24 g, 1.96 mmol, 0.1 equiv) in DCM (5 mL) was added TBDPSCl (5.38 g, 19.6 mmol, 1.0 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (13 / 7) to give 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-ol (3 g, 45% yield) as a colorless oil. LCMS (ESI, m / z): 341.20 [M+H] + .

[0780] Step B

[0781] To a stirred solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-ol (300 mg, 0.88 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (362 mg, 1.32 mmol, 1.5 equiv), and PPh (347 mg, 1.32 mmol, 1.5 equiv) in THF (5 mL) was added DEAD (230 mg, 1.32 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at 50°C for 4 hours. After concentration, the residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 80% over 20 minutes; detector, UV 254 nm. 5-(3-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobutyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (400 mg, 76% yield) was obtained as a white solid. LCMS (ESI, m / z): 597.23 [M+H].

[0782] Step C

[0783] To a stirred solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (365 mg, 0.61 mmol, 1.0 equiv) in THF (5 mL) was added TBAF (320 mg, 1.22 mmol, 2.0 equiv) portionwise. The resulting mixture was stirred for 1 hour. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 20% gradient over 20 minutes; detector, UV 254 nm. 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)cyclobutoxy)isoindoline-1,3-dione (165 mg, 75% yield) was obtained as a white solid. LCMS (ESI, m / z): 359.12 [M+H] + .

[0784] Intermediate A6-a was synthesized according to the process described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)cyclobutyloxy)-isoindoline-1,3-dione (Intermediate A6) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0785]

[0786] Intermediate A7: 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride Synthesis

[0787]

[0788] Step A

[0789] A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (1.0 g, 3.62 mmol, 1.0 equiv), tert-butyl piperazine-1-carboxylate (0.74 g, 3.98 mmol, 1.1 equiv) and DIEA (1.40 g, 10.9 mmol, 3.0 equiv) in NMP (5 mL) was stirred at 120 ° C for 2 hours. The mixture was allowed to cool to room temperature and then diluted with water (25 mL). The precipitated solid was collected by filtration and washed with water (3×10 mL) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate (1.02 g, 64% yield) as a yellow crude solid. LCMS (ESI, m / z): 443.10[M+H] + .

[0790] Step B

[0791] A solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate (1.0 g, 2.26 mmol, 1.0 equiv) in HCl in 1,4-dioxane (50 mL, 4 M) was stirred for 50 minutes. The resulting mixture was concentrated in vacuo to give 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindolin-1,3-dione hydrochloride (1.1 g) as a yellow crude solid. The crude product was used directly in the next step without any further purification. LCMS (ESI, m / z): 343.15 [M+H] + .

[0792] Intermediates A7-a to A7-d were synthesized according to the process described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (intermediate A7) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0793]

[0794] Intermediate A8: Synthesis of 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione hydrochloride

[0795]

[0796] Step A

[0797] To a solution of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (1.0 g, 3.59 mmol, 1.0 equiv) in DMF (2 mL) was added NaH (0.17 g, 7.19 mmol, 2.0 equiv) at 0 ° C. The resulting mixture was stirred at 0 ° C for 15 minutes. 3-bromopiperidine-2,6-dione (0.83 g, 4.31 mmol, 1.2 equiv) was then added, and the mixture was stirred for 12 hours. The reaction was quenched with water at 0 ° C and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 7 mL), dried over anhydrous Na2SO4 and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (300 mg, 21% yield) as a white solid. LCMS (ESI, m / z): 390.25 [M+H] + .

[0798] Step B

[0799] A mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (300 mg, 0.77 mmol, 1.0 equiv) in 1,4-dioxane (5 mL, 4 M) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione hydrochloride (250 mg, 99% yield) as a crude yellow solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 290.15 [M+H] + .

[0800] Intermediate A9: Synthesis of 3-(methyl(4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0801]

[0802] Step A

[0803] A solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (3.0 g, 10.8 mmol, 1.0 equiv), TFAA (2.73 g, 13.0 mmol, 1.2 equiv) and TEA (2.19 g, 21.6 mmol, 2.0 equiv) in DCM (20 mL) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give tert-butyl 4-(4-(2,2,2-trifluoroacetylamino)phenyl)piperazine-1-carboxylate (8.3 g) as a brown crude solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 374.15 [M+H] + .

[0804] Step B

[0805] A solution of tert-butyl 4-(4-(2,2,2-trifluoroacetylamino)phenyl)piperazine-1-carboxylate (8.3 g, 22.2 mmol, 1.0 equiv), MeI (3.16 g, 22.2 mmol, 1.0 equiv) and K2CO3 (6.14 g, 44.4 mmol, 2.0 equiv) in DMF (10 mL) was stirred at 60 ° C overnight. The product was precipitated by adding water. The solid was collected by filtration. Tert-butyl 4-(4-(2,2,2-trifluoro-N-methylacetylamino)phenyl)piperazine-1-carboxylate (3.6 g, 42% yield) was obtained as a black solid. LCMS (ESI, m / z): 388.15 [M + H] + .

[0806] Step C

[0807] A solution of tert-butyl 4-(4-(2,2,2-trifluoro-N-methylacetylamino)phenyl)piperazine-1-carboxylate (3.6 g, 9.29 mmol, 1.0 equiv) and K2CO3 (2.57 g, 18.6 mmol, 2.0 equiv) in water (5 mL) and MeOH (20 mL) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (57:43) to give tert-butyl 4-(4-(methylamino)phenyl)piperazine-1-carboxylate (2.5 g, 92% yield) as a white solid. LCMS (ESI, m / z): 292.15 [M+H] + .

[0808] Step D

[0809] A solution of tert-butyl 4-(4-(methylamino)phenyl)piperazine-1-carboxylate (1.5 g, 5.15 mmol, 1.0 equiv), 3-bromopiperidine-2,6-dione (1.19 g, 6.18 mmol, 1.2 equiv) and NaHCO3 (0.86 g, 10.3 mmol, 2.0 equiv) in ACN (50 mL) was stirred at 90 ° C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (30:70) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazine-1-carboxylate (1.6 g, 77% yield) as a light yellow powder. LCMS (ESI, m / z): 403.15 [M+H] + .

[0810] Step E

[0811] A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazine-1-carboxylate (1.6 g, 3.98 mmol, 1.0 equiv) in HCl in 1,4-dioxane (30 mL, 4 M) was stirred for 50 minutes. The resulting mixture was concentrated under reduced pressure to afford 3-(methyl(4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (2.1 g) as a light green solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 303.15 [M+H] + .

[0812] Intermediate A10: Synthesis of 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

[0813]

[0814] Step A

[0815] A solution of tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (2.0 g, 7.23 mmol, 1.0 equiv), 2,6-bis(benzyloxy)-3-bromopyridine (2.68 g, 7.24 mmol, 1.0 equiv), t-BuONa (1.04 g, 10.9 mmol, 1.5 equiv), Pd(dba)·CHCl (0.75 g, 0.72 mmol, 0.1 equiv), and XantPhos (0.42 g, 0.72 mmol, 0.1 equiv) in toluene (30 mL) was stirred at 100°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 40 minutes; detector, UV 254 nm. Tert-butyl 4-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidine-1-carboxylate (3.2 g, 78%) was obtained as a brown solid. LCMS (ESI, m / z): 566.25 [M+H] + .

[0816] Step B

[0817] A solution of tert-butyl 4-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidine-1-carboxylate (3.2 g, 5.66 mmol, 1.0 equiv) and Pd / C (3.0 g) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 30 minutes. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (3×20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (2.2 g, 96%) as a dark green solid. LCMS (ESI, m / z): 386.25 [MH] - .

[0818] Step C

[0819] A solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (2.3 g, 5.94 mmol, 1.0 equiv) in HCl in 1,4-dioxane (20 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure to give 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (2.4 g) as a dark green crude powder. The product was used in the next step without further purification. LCMS (ESI, m / z): 288.15 [M+H] + .

[0820] Intermediate A11: Synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride

[0821]

[0822] Step A

[0823] A solution of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol, 1.0 equiv), tert-butyl piperazine-1-carboxylate (7.0 g, 37.9 mmol, 1.2 equiv) and K2CO3 (8.71 g, 63.1 mmol, 2.0 equiv) in DMF (10 mL) was stirred at 80 ° C for 5 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with water (3×10 mL). The solid was dried in an oven to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (9.6 g, 98%) as a yellow solid. LCMS (ESI, m / z): 309.15 [M+H] + .

[0824] Step B

[0825] A solution of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (9.6 g, 31.1 mmol, 1.0 equiv), Fe (10.4 g, 187 mmol, 6.0 equiv) and NHCl (3.33 g, 62.3 mmol, 2.0 equiv) in water (10 mL) and EtOH (10 mL) was stirred at 80 ° C overnight. The resulting mixture was filtered and the filter cake was washed with EtOH (10×10 mL). The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:1) to give tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (8 g, 92%) as a red oil. LCMS (ESI, m / z): 279.20 [M+H] + .

[0826] Step C

[0827] A solution of tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (2.0 g, 7.19 mmol, 1.0 equiv), 3-bromopiperidine-2,6-dione (1.66 g, 8.62 mmol, 1.2 equiv) and NaHCO3 (1.81 g, 21.6 mmol, 3.0 equiv) in ACN (5 mL) was stirred at 90 ° C overnight. The mixture was cooled to 0 ° C. The precipitated solid was collected by filtration and washed with water (2×8 mL). The solid was dried in an oven to give tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (1.5 g, 54%) as a green solid. LCMS (ESI, m / z): 390.20 [M+H] + .

[0828] Step D

[0829] A solution of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (1.5 g, 3.85 mmol, 1.0 equiv) in HCl in 1,4-dioxane (6 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to afford 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride (1.0 g, 90%) as a crude purple solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 290.15 [M+H] + .

[0830] Intermediates A11-a and A11-b were synthesized according to the process described for the synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride (intermediate A11) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0831]

[0832] Intermediate A12: 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-ylethynyl)isoindoline-1,3-dioxopiperidin-3-yl)-5-(piperidin-4-ylethynyl)isoindoline Synthesis of Ketone Hydrochloride

[0833]

[0834] Step A

[0835] A mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.58 g, 4.70 mmol, 1.0 equiv), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.00 g, 4.79 mmol, 1.0 equiv), Pd(PPh3)2Cl2 (329 mg, 0.47 mmol, 0.1 equiv) and TEA (1.42 g, 14.1 mmol, 3.0 equiv) in DMSO (7 mL) was stirred at 80° C. for 5 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DMSO (2 mL), and the filtrate was purified by C18 reverse phase chromatography, eluting with water (10 mmol / L NH4HCO3) / ACN (55:45) to afford tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate (1.28 g, 59%) as a tan solid. LCMS (ESI, m / z): 410.15 [M+Ht-Bu] + .

[0836] Step B

[0837] A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate (981 mg, 2.11 mmol) in HCl in 1,4-dioxane (30 mL, 4 M) was stirred for 1.5 hours. The resulting mixture was concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-ylethynyl)isoindolin-1,3-dione hydrochloride (815 mg, 96%) as a white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 366.15 [M+H] + .

[0838] Intermediate A13: Synthesis of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazine-2,4-dione

[0839]

[0840] Step A

[0841] A solution of 6-bromo-1-methylindazol-3-amine (10 g, 44.2 mmol, 1.0 equiv), acrylic acid (3.2 g, 44.4 mmol, 1.0 equiv) and HOAc (6.8 g, 113 mmol, 2.56 equiv) in water (100 mL) was stirred at 100 ° C overnight. NaOH (17.7 g, 443 mmol, 10 equiv) was then added. The resulting mixture was extracted with EtOAc. The pH value of the aqueous layer was adjusted to 3-4 with aqueous HCl solution. The precipitated solid was collected by filtration and washed with water to give 3-[(6-bromo-1-methylindazol-3-yl)amino]propionic acid (8 g, 61%) as an off-white solid. LCMS (ESI, m / z): 298.15 [M + H] + .

[0842] Step B

[0843] A solution of 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoic acid (4.0 g, 13.4 mmol, 1.0 equiv) and urea (3.0 g, 50.0 mmol, 3.72 equiv) in HOAc (30 mL) was stirred at 120° C. overnight. After concentration, the residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% HCl), gradient from 0% to 40% over 15 minutes; detector, UV 254 nm. 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazine-2,4-dione (1.2 g, 14%) was obtained as a pink solid. LCMS (ESI, m / z): 323.15 [M+H] + .

[0844] Step C

[0845] 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazine-2,4-dione (800 mg, 2.48 mmol, 1.0 equivalent), tert-butyl 4-bromopiperidine-1-carboxylate (684 mg, 2.59 mmol, 1.05 equivalent), NiBr2 .A solution of glyme (153 mg, 0.50 mmol, 0.20 equiv), dtbpy (133 mg, 0.5 mmol, 0.20 equiv), Mn (545 mg, 9.92 mmol, 4.01 equiv), NaI (372 mg, 2.48 mmol, 1.00 equiv) and pyridine (196 mg, 2.48 mmol, 1.00 equiv) in DMPU (15 mL) was stirred at 70° C. under a nitrogen atmosphere overnight. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), gradient from 10% to 52% in 15 minutes; detector, UV 254 nm. Tert-butyl 4-[3-(2,4-dioxo-1,3-diazin-1-yl)-1-methylindazol-6-yl]piperidine-1-carboxylate (230 mg, 22%) was obtained as a light yellow oil. LCMS (ESI, m / z): 428.50 [M+H] + .

[0846] Step D

[0847] A solution of tert-butyl 4-[3-(2,4-dioxo-1,3-diazine-1-yl)-1-methylindazol-6-yl]piperidine-1-carboxylate (230 mg, 0.54 mmol, 1.0 equiv) in TFA (5 mL) and DCM (5 mL) was stirred for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 42% B, 42% B in 9 minutes; wavelength: 254 / 220 nm; RT1 (min): 8.9). 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazine-2,4-dione (110 mg, 62%) was obtained as a white solid. LCMS (ESI, m / z): 328.39 [M+H] + .

[0848] Intermediate A13-a was synthesized according to the process described for the synthesis of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazine-2,4-dione (intermediate A13) using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0849]

[0850] Intermediate A14: 3-((4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amine Synthesis of 2,6-dione (1,2-dione)piperidine hydrochloride

[0851]

[0852] Step A

[0853] A solution of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1000 mg, 4.40 mmol, 1.0 equiv), 1-fluoro-4-nitrobenzene (931 mg, 6.6 mmol, 1.5 equiv) and t-BuOK (987 mg, 8.8 mmol, 2.0 equiv) in DMSO (6 mL) was stirred for 1 hour. The mixture was cooled to 0°C. The product was precipitated by the addition of water. The precipitated solid was collected by filtration and washed with water (3×10 mL) to give tert-butyl (3aR,5r,6aS)-5-(4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.2 g, 78%) as a brown oil. LCMS (ESI, m / z): 349.15 [M+H] + .

[0854] Step B

[0855] A solution of tert-butyl (3aR,5r,6aS)-5-(4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1100 mg, 3.16 mmol, 1.0 equiv), Fe (882 mg, 15.8 mmol, 5.0 equiv) and NHCl (338 mg, 6.31 mmol, 2.0 equiv) in EtOH (4 mL) and water (4 mL) was stirred at 80 °C for 3 hours. The resulting mixture was filtered and the filter cake was washed with EtOH (10 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl (3aR,5r,6aS)-5-(4-aminophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (825 mg, 82%) as a blue solid. LCMS (ESI, m / z): 319.20 [M+H] + .

[0856] Step C

[0857] A solution of tert-butyl (3aR,5r,6aS)-5-(4-aminophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (810 mg, 2.54 mmol, 1.0 equiv), 3-bromopiperidine-2,6-dione (733 mg, 3.82 mmol, 1.5 equiv) and NaHCO (641 mg, 7.63 mmol, 3.0 equiv) in ACN (5 mL) was stirred overnight at 90° C. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl (3aR,5r,6aS)-5-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (804 mg, 74%) as a blue solid. LCMS (ESI, m / z): 429.23 [M+H] + .

[0858] Step D

[0859] A solution of tert-butyl (3aR,5r,6aS)-5-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (816 mg, 3.85 mmol, 1.0 equiv) in HCl in 1,4-dioxane (6 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to afford 3-((4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione hydrochloride (804 mg, 90%) as a grey crude solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 330.17 [M+H] + .

[0860] Intermediate A15: Synthesis of 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)dione hydrochloride

[0861]

[0862] Step A

[0863] A solution of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.86 mmol, 1.0 equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (689 mg, 2.23 mmol, 1.2 equiv), Pd(dppf)Cl2CH2Cl2 (151 mg, 0.19 mmol, 0.1 equiv), K3PO4 (789 mg, 3.72 mmol, 2.0 equiv) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 80°C for 1 hour. After concentration, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 94%) as a white solid. LCMS (ESI, m / z): 370.10 [MH] - .

[0864] Step B

[0865] A solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 1.75 mmol, 1.0 equiv) and Pd / C (186 mg) in EA (5 mL) was stirred under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×9 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-1-carboxylate (620 mg, 95%) as a white solid. LCMS (ESI, m / z): 372.15 [MH] - .

[0866] Step C

[0867] A solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-1-carboxylate (600 mg, 1.61 mmol, 1.0 equiv) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 1 hour. The solution was concentrated to give 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg) as a white crude solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 274.05 [M+H] + .

[0868] Intermediates A15-a to A15-d were synthesized according to the process described for the synthesis of 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (intermediate A15) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0869]

[0870]

[0871] Intermediate A16: 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-1- Synthesis of 2,6-dione (1,2-dione)piperidine hydrochloride

[0872]

[0873] Step A

[0874] A solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g, 2.9 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.82 g, 5.91 mmol, 2.0 equiv), K 3 PO 4 (1.88 g, 8.87 mmol, 3.0 equiv) and Pd(dppf)Cl 2 C H 2 Cl 2 (241 mg, 0.296 mmol, 0.1 equiv) in dioxane (8 mL) was stirred at 80° C. for 2 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (567 mg, 43%) as a white solid. LCMS (ESI, m / z): 441.15 [M+H] + .

[0875] Step B

[0876] A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (413 mg, 0.938 mmol, 1.0 equiv) and 10% Pd / C (2 g) in 7 mL EtOAc was stirred under a hydrogen atmosphere for 1 hour. The solution was filtered through celite and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (243 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 443.15 [M+H] + .

[0877] Step C

[0878] A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (210 mg, 0.475 mmol, 1.0 equiv) in hydrochloric acid in 1,4-dioxane (10 mL, 4 M) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloric acid (224 mg) as a brown crude oil. The crude product was used directly in the next step without further purification. LCMS(ESI,m / z):343.15[M+H] + .

[0879] Intermediate A17: 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1- Synthesis of 2,6-dione (1,2-dione)piperidine hydrochloride

[0880]

[0881] Step A

[0882] A solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, 1 eq) and tert-butyl piperazine-1-carboxylate (413 mg, 2.2 mmol, 1.5 eq), RuPhos-PdCl-2nd G (115 mg, 0.15 mmol, 0.1 eq), RuPhos (69.1 mg, 0.15 mmol, 0.1 eq) and LiHMDS (2.9 mL, 2.9 mmol, 2 eq, 1 M in THF) in toluene (5 mL) was stirred at 80° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 25% over 20 minutes; detector, UV 254 nm. Tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (220 mg, 33% yield) was obtained as a gray solid. LCMS (ESI, m / z): 444.20 [M+H] + .

[0883] Step B

[0884] A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (220 mg, 0.50 mmol, 1 equiv) in HCl in 1,4-dioxane (5 mL, 4 M) was stirred for 1 hour. The resulting mixture was concentrated in vacuo to give crude 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (240 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 344.15 [M+H] + .

[0885] Intermediate A18: Synthesis of 3-(isoindolin-5-ylamino)piperidine-2,6-dione

[0886]

[0887] Step A

[0888] A solution of tert-butyl 5-aminoisoindoline-2-carboxylate (3.0 g, 12.8 mmol, 1 eq), 3-bromopiperidine-2,6-dione (4.92 g, 25.6 mmol, 2 eq) and NaHCO 3 (5.38 g, 64.0 mmol, 5 eq) in ACN (20 mL) was stirred at 90° C. for 2 days. The solution was concentrated in vacuo and the residue was applied to a silica gel column and eluted with EtOAc / PE (50:50) to give tert-butyl 5-((2,6-dioxopiperidin-3-yl)amino)isoindoline-2-carboxylate (5 g, 90%) as a dark blue solid. LCMS (ESI, m / z): 346.25 [M+H] + .

[0889] Step B

[0890] A solution of tert-butyl 5-((2,6-dioxopiperidin-3-yl)amino)isoindoline-2-carboxylate (5.0 g, 14.5 mmol, 1 equiv) in HCl in 1,4-dioxane (40 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to afford 3-(isoindolin-5-ylamino)piperidine-2,6-dione (3.4 g, 96%) as a brown solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 246.20 [M+H] + .

[0891] Intermediate A18-b was synthesized according to the process described for the synthesis of 3-(isoindolin-5-ylamino)piperidine-2,6-dione hydrochloride (intermediate A18) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0892]

[0893] Intermediate A19: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide

[0894]

[0895] Step A

[0896] A solution of methyl 4-bromo-2-fluorobenzoate (5.0 g, 21.5 mmol, 1 eq) in dioxane (20 mL) was treated with tert-butyl piperazine-1-carboxylate (4.80 g, 25.7 mmol, 1.2 eq), Pd(OAc)2 (0.48 g, 2.15 mmol, 0.1 eq) and BINAP (1.34 g, 2.15 mmol, 0.1 eq) at 100 ° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (72:28) to give tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (6 g, 83%) as a yellow solid. LCMS (ESI, m / z): 339.16 [M + H] + .

[0897] Step B

[0898] A solution of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.0 g, 5.91 mmol, 1 equiv) in MeOH (5 mL) was treated with a solution of NaOH (4.73 g, 118 mmol, 20 equiv) in water (15 mL) for 3 hours. The mixture was acidified to pH 7 with concentrated HCl, and the precipitated solid was collected by filtration. 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (1.9 g, 99%) was obtained as a white solid. LCMS (ESI, m / z): 325.15 [M+H] + .

[0899] Step C

[0900] A solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (1.9 g, 5.86 mmol, 1.0 equiv) in DMF (15 mL) was treated with 3-aminopiperidine-2,6-dione (0.90 g, 7.03 mmol, 1.2 equiv), DIEA (2.27 g, 17.6 mmol, 3.0 equiv), HOBT (1.19 g, 8.79 mmol, 1.5 equiv) and EDCI (1.68 g, 8.79 mmol, 1.5 equiv) overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 40% over 15 minutes; detector, UV 254 nm, to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (1.29 g, 50%) as a gray solid. LCMS (ESI, m / z): 435.20 [M+H] + .

[0901] Step D

[0902] A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (1.28 g, 2.94 mmol, 1 equivalent) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (1.35 g) as an off-white solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 335.14 [M+H] + .

[0903] Intermediate A20: Synthesis of N-methyl-N-(4-nitrophenyl)piperidin-4-amine

[0904]

[0905] Step A

[0906] A solution of tert-butyl 4-((4-nitrophenyl)amino)piperidine-1-carboxylate (4.0 g, 12.4 mmol, 1 equiv.) in THF (25 mL) was treated with NaH (0.90 g, 37.3 mmol, 3 equiv.) at 0 ° C. for 30 minutes, followed by dropwise addition of iodomethane (3.53 g, 24.9 mmol, 2 equiv.) at room temperature. The solution was stirred at room temperature for 4 hours. The reaction was quenched with water at 0 ° C. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were concentrated under reduced pressure. Tert-butyl 4-(methyl(4-nitrophenyl)amino)piperidine-1-carboxylate (4 g, 96%) was obtained as a yellow solid. LCMS (ESI, m / z): 336.15 [M + H] + .

[0907] Step B

[0908] A solution of tert-butyl 4-(methyl(4-nitrophenyl)amino)piperidine-1-carboxylate (4.8 g, 14.3 mmol, 1 equivalent) in 1,4-dioxane (20 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure. N-methyl-N-(4-nitrophenyl)piperidin-4-amine (4 g) was obtained as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 236.20 [M+H] + .

[0909] Intermediate A21: Synthesis of 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0910]

[0911] Step A

[0912] A solution of 2,4-difluoro-1-nitrobenzene (5.0 g, 31.4 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (5.85 g, 31.4 mmol, 1 eq) and TEA (9.54 g, 94.3 mmol, 3 eq) in DMF (20 mL) was stirred at 80 ° C for 5 hours. The reaction was quenched with water and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a mixture of positional isomers. The residue was purified by C18 reverse phase chromatography eluting with water / MeCN (40:60) to give the desired isomer, tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (5 g, 48%), as a light yellow solid. LCMS (ESI, m / z): 326.15 [M+H] + .

[0913] Step B

[0914] A solution of tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (5 g, 15.1 mmol, 1 eq), Fe (4.21 g, 75.3 mmol, 5 eq) and NHCl (1.61 g, 30.1 mmol, 2 eq) in EtOH (10 mL) and water (10 mL) was stirred at 80° C. for 3 hours. The resulting mixture was concentrated in vacuo and applied to a silica gel column with MeOH / DCM (10:90) to give tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (3.3 g, 88%) as a black oil. LCMS (ESI, m / z): 296.15 [M+H] + .

[0915] Step C

[0916] A solution of tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (800 mg, 2.71 mmol, 1 eq), 3-bromopiperidine-2,6-dione (1.56 g, 10.2 mmol, 2 eq) and NaHCO 3 (1.13 g, 25.4 mmol, 5 eq) in ACN (5 mL) was stirred at 90 ° C for 2 days. The resulting mixture was concentrated in vacuo and the residue was purified by C18 reverse phase chromatography eluting with water / ACN (33:67) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (800 mg, 73%). LCMS (ESI, m / z): 407.20 [M + H] + .

[0917] Step D

[0918] A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (800 mg, 1.23 mmol, 1 equiv) in 1,4-dioxane (5 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to afford 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (800 mg) as a black solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 307.10 [M+H] +

[0919] Intermediate A22: Synthesis of 2-(4-(1-(4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol

[0920]

[0921] A solution of 1-(4-nitrophenyl)piperidin-4-one (1.0 g, 4.54 mmol, 1 eq), 2-(piperazin-1-yl)ethan-1-ol (0.59 g, 4.54 mmol, 1 eq), and STAB (1.92 g, 9.08 mmol, 2 eq) in DCE (30 mL) was stirred for 2 hours. After concentration, the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 50% over 40 minutes; detector, UV 254 nm. 2-(4-(1-(4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol (455 mg, 30%) was obtained as a yellow oil. LCMS (ESI, m / z): 335.20 [M+H] + .

[0922] Intermediate A23: Synthesis of 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione .

[0923]

[0924] Step A

[0925] A mixture of 1,2,3-trifluoro-5-nitrobenzene (5.0 g, 28.2 mmol, 1 equiv), tert-butyl piperazine-1-carboxylate (5.25 g, 28.2 mmol, 1.0 equiv) and TEA (8.56 g, 84.6 mmol, 3.0 equiv) in DMF (8 mL) was stirred at 80 ° C for 1 hour. After adding water, the precipitated solid was collected by filtration and washed with water to give tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (9.4 g, 97%) as a yellow solid. LCMS (ESI, m / z): 344.20 [M + H] + .

[0926] Step B

[0927] A mixture of tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (4.5 g, 13.1 mmol, 1 equiv), Fe (3.6 g, 64.5 mmol, 4.9 equiv) and NHCl (2.1 g, 39.3 mmol, 3.0 equiv) in EtOH (20 mL) and water (5 mL) was stirred at 80 ° C overnight. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography, eluting with water (10 mmol / L NH4HCO3) / ACN (30:70). The resulting mixture was in tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (3 g, 73%) as a purple solid. LCMS (ESI, m / z): 314.15 [M+H] + .

[0928] Step C

[0929] A mixture of tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (1.5 g, 4.79 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (7.3 g, 38.0 mmol, 7.94 equiv) and NaHCO3 (3.6 g, 42.9 mmol, 8.95 equiv) in ACN (40 mL) was stirred at 90 ° C for 2 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (4: 1) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (3.45 g) as a white solid. LCMS (ESI, m / z): 425.10 [M + H] + .

[0930] Step D

[0931] A mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (1.0 g, 2.36 mmol, 1 equiv) and HCl in 1,4-dioxane (30 mL, 4 M) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (990 mg, crude product) as a white solid. LCMS (ESI, m / z): 325.20 [M+H] + .

[0932] Intermediate A24: Synthesis of 2-(4-(1-(4-nitrophenyl)azetidin-3-yl)piperazin-1-yl)ethan-1-ol

[0933]

[0934] Step A

[0935] A mixture of 2-(piperazin-1-yl)ethan-1-ol (5 g, 38.4 mmol, 1 eq), tert-butyl 3-oxoazetidine-1-carboxylate (16.4 g, 96.0 mmol, 2.5 eq) and STAB (16.3 g, 76.8 mmol, 2 eq) in DCE (20 mL) was stirred for 2 hours. The residue was concentrated and purified by silica gel column chromatography eluting with DCM / MeOH (92:8) to give tert-butyl 3-(4-(2-hydroxyethyl)piperazin-1-yl)azetidine-1-carboxylate (10.3 g, 94%) as a yellow oil. LCMS (ESI, m / z): 286.15 [M+H] + .

[0936] Step B

[0937] A solution of tert-butyl 3-(4-(2-hydroxyethyl)piperazin-1-yl)azetidine-1-carboxylate (5 g, 17.5 mmol, 1 equivalent) in 1,4-dioxane (15 mL, 4 M) was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure to give 2-(4-(azetidine-3-yl)piperazin-1-yl)ethan-1-ol (4.8 g) as a yellow oil. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 186.15 [M+H] + .

[0938] Step C

[0939] A solution of 2-(4-(azetidin-3-yl)piperazin-1-yl)ethan-1-ol (3.8 g, 20.5 mmol, 1 eq), K2CO3 (8.50 g, 61.5 mmol, 3 eq) and 1-fluoro-4-nitrobenzene (5.79 g, 41.0 mmol, 2 eq) in DMF (20 mL) was stirred at 80 ° C overnight. After cooling to room temperature, the mixture was quenched with water (40 mL). The precipitated solid was collected by filtration and washed with water. The solid was triturated with diethyl ether (30 mL). After filtration, 2-(4-(1-(4-nitrophenyl)azetidin-3-yl)piperazin-1-yl)ethan-1-ol (2.4 g, 39%) was isolated as a yellow solid. LCMS (ESI, m / z): 307.10 [M+H] + .

[0940] Intermediate A25: Synthesis of 3-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]piperidine-2,6-dione

[0941]

[0942] Step A

[0943] Under a nitrogen atmosphere, to a mixture of 6-bromo-3-iodo-1H-indazole (500 mg, 1.54 mmol, 1.0 equiv) and NaH (111 mg, 4.64 mmol, 3.0 equiv) in DMF (2 mL) was added MeI (330 mg, 2.32 mmol, 1.5 equiv) at 0 ° C. The resulting mixture was stirred for 2 hours, then quenched with water at 0 ° C. and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (5: 1) to give 6-bromo-3-iodo-1-methylindazole (275 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 336.8 [M+H] + .

[0944] Step B

[0945] A solution of 6-bromo-3-iodo-1-methylindazole (500 mg, 1.48 mmol, 1.0 equiv) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (929 mg, 2.23 mmol, 1.5 equiv) and KCO (615 mg, 4.45 mmol, 3.0 equiv) in dioxane (2 mL) and water (1 mL) was stirred at 80 ° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methylindazole (490 mg, 66%) as a yellow oil. LCMS (ESI, m / z): 500.1 [M+H] + .

[0946] Step C

[0947] A solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methylindazole (1.7 g, 3.48 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (1.0 g, 5.21 mmol, 1.5 equiv), Cs2CO3 (3.4 g, 10.4 mmol, 3.0 equiv), Ruphos (160 mg, 0.34 mmol, 0.1 equiv) and RuPhos Pd G3 (291 mg, 0.34 mmol, 0.1 equiv) in 1,4-dioxane (10 ml) was stirred at 90 ° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}piperazine-1-carboxylate (1.1 g, 52%) as a yellow oil. LCMS (ESI, m / z): 606.3 [M+H] + .

[0948] Step D

[0949] To a mixture of tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}piperazine-1-carboxylate (3.5 g, 5.78 mmol, 1.0 equiv) in MeOH (250 mL) was added Pd / C (500 mg, 4.70 mmol, 0.8 equiv). The resulting mixture was stirred under a hydrogen atmosphere for 3 days. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 90% over 30 minutes; detector, UV 254 nm. Tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperazine-1-carboxylate (624 mg, 25%) was obtained as a purple solid. LCMS (ESI, m / z): 428.2 [M+H] + .

[0950] Step E

[0951] A solution of tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperazine-1-carboxylate (400 mg, 0.94 mmol, 1.0 equiv) in dioxane (2 mL) was treated with a 1,4-dioxane solution of HCl (2 mL, 4 M) and then stirred for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by trituration with diethyl ether (50 mL) to give 3-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]piperidine-2,6-dione (180 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 328.15 [M+H] + .

[0952] Intermediate A25-b was synthesized according to the process described in steps AD for the synthesis of 3-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]piperidine-2,6-dione (intermediate A25) using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0953]

[0954]

[0955] Intermediate A26: (4-(4-((tert-Butoxycarbonyl)amino)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate Synthesis

[0956]

[0957] Step A

[0958] To a solution of tert-butyl (4-hydroxyphenyl)carbamate (5.6 g, 26.8 mmol, 1.0 equiv), methyl 4-hydroxycyclohexane-1-carboxylate (6.35 g, 40.1 mmol, 1.5 equiv) and PPh3 (10.5 g, 40.1 mmol, 1.5 equiv) in THF (50 mL) was added DEAD (6.99 g, 40.1 mmol, 1.5 equiv) in portions over 10 minutes at 0 ° C. The resulting mixture was stirred at 50 ° C for 4 hours. The solution was concentrated in vacuo and applied to a silica gel column and eluted with EtOAc / PE (30:70) to give methyl 4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexane-1-carboxylate (4.4 g, 47%) as a brown oil. LCMS (ESI, m / z): 350.20 [M+H] + .

[0959] Step B

[0960] A solution of methyl 4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexane-1-carboxylate (4.4 g, 12.6 mmol, 1 eq) in THF (20 mL) was treated with LiAlH4 (0.96 g, 25.2 mmol, 2 eq) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water at 0°C and extracted with EtOAc (3×100 mL). The combined organic extracts were concentrated in vacuo to give tert-butyl (4-((4-(hydroxymethyl)cyclohexyl)oxy)phenyl)carbamate (3.7 g, 91%) as a crude brown oil. LCMS (ESI, m / z): 322.20 [M+H] + .

[0961] Step C

[0962] A solution of tert-butyl (4-((4-(hydroxymethyl)cyclohexyl)oxy)phenyl)carbamate (500 mg, 1.56 mmol, 1 eq) in DCM (10 mL) was treated with TEA (472 mg, 4.67 mmol, 3 eq) at room temperature for 5 minutes, followed by the addition of 4-methylbenzenesulfonyl chloride (356 mg, 1.87 mmol, 1.2 eq) in portions at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and purified on a silica gel column eluted with ethyl acetate / petroleum ether (20:80) to give (4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate (550 mg, 74%) as a brown oil. LCMS (ESI, m / z): 476.20 [M+H] + .

[0963] Intermediate A27: 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Synthesis of hydrochloride

[0964]

[0965] Step A

[0966] To a solution of 6-bromobenz[cd]indol-2(1H)-one (1 g, 4.03 mmol, 1 eq) in THF (30 mL) was added NaH (0.48 g, 20.2 mmol, 5 eq) in portions at 0°C. The resulting mixture was stirred at room temperature for 1 hour. To the above mixture was added 3-bromopiperidine-2,6-dione (1.93 g, 10.1 mmol, 2.5 eq) at 0°C. The resulting mixture was stirred at 60°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (169 mg, 12%) as a yellow solid. LCMS (ESI, m / z): 359.00, 361.00 [M+H] +

[0967] Step B

[0968] A solution of 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (149 mg, 0.42 mmol, 1 eq) and tert-butyl piperazine-1-carboxylate (115.9 mg, 0.622 mmol, 1.5 eq), PdPEPPSIIPentCl (36 mg, 0.042 mmol, 0.1 eq) and CsCO (203 mg, 0.622 mmol, 1.50 eq) in dioxane (5 mL) was stirred at 90° C. for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (162 mg, 84%) as a yellow solid. LCMS (ESI, m / z): 465.25 [M+H] + .

[0969] Step C

[0970] A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (152 mg, 0.327 mmol, 1 equiv) in HCl in 1,4-dioxane (5 mL, 4 M) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give crude 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (153 mg) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 365.30 [M+H]+ .

[0971] Intermediate A28: Synthesis of 2-(6-(4-nitrophenyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate

[0972]

[0973] Step A

[0974] A solution of methyl 2-(6-chloropyridin-3-yl)acetate (3.0 g, 16.2 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (4.02 g, 16.2 mmol, 1 eq), CsF (4.91 g, 32.3 mmol, 2 eq) and Pd(PPh3)2Cl2 (1.13 g, 1.62 mmol, 0.1 eq) in water (6 mL) and EtOH (18 mL) was stirred at 100 ° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give methyl 2-(6-(4-nitrophenyl)pyridin-3-yl)acetate (3.1 g, 70%) as a yellow oil. LCMS (ESI, m / z): 273.25 [M+H] + .

[0975] Step B

[0976] A solution of methyl 2-(6-(4-nitrophenyl)pyridin-3-yl)acetate (1.5 g, 5.51 mmol, 1 eq), CaCl2 (1.22 g, 11.0 mmol, 2 eq) and NaBH4 (0.417 g, 11.0 mmol, 2 eq) in EtOH (10 mL) was stirred at 0 ° C for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5: 1) to give 2-(6-(4-nitrophenyl)pyridin-3-yl)ethan-1-ol (900 mg, 67%) as a white solid. LCMS (ESI, m / z): 245.10 [M + H] + .

[0977] Step C

[0978] A solution of 2-(6-(4-nitrophenyl)pyridin-3-yl)ethan-1-ol (500 mg, 2.05 mmol, 1 eq), TEA (621 mg, 6.14 mmol, 3 eq), TsCl (390 mg, 2.04 mmol, 1 eq) and DMAP (25.0 mg, 0.205 mmol, 0.1 eq) in DCM (5 mL) was stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give 2-(6-(4-nitrophenyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (450 mg, 55%) as a yellow solid. LCMS (ESI, m / z): 399.20 [M+H] + .

[0979] Intermediate A28-a was synthesized according to the process described for the synthesis of 2-(6-(4-nitrophenyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (intermediate A28) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0980]

[0981] Intermediate A29: Synthesis of 2-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)ethan-1-ol

[0982]

[0983] Step A

[0984] A solution of tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (5 g, 18.6 mmol, 1 equiv), 2-bromoethan-1-ol (4.64 g, 37.1 mmol, 2 equiv) and K2CO3 (7.70 g, 55.7 mmol, 3 equiv) in DMF (25 mL) was stirred at 80 ° C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EtOAc (4×50 mL). The combined organic layers were concentrated under reduced pressure to give tert-butyl 4-(1-(2-hydroxyethyl)piperidin-4-yl)piperazine-1-carboxylate (8 g) as a yellow crude solid. LCMS (ESI, m / z): 314.25 [M+H] + .

[0985] Step B

[0986] A solution of tert-butyl 4-(1-(2-hydroxyethyl)piperidin-4-yl)piperazine-1-carboxylate (8 g, 25.5 mmol, 1 equivalent) in HCl in 1,4-dioxane (50 ml, 4 M) was stirred for 1 hour. The precipitated solid was collected by filtration and washed with PE (2×10 mL). The resulting solid was dried in an oven to give 2-(4-(piperazin-1-yl)piperidin-1-yl)ethan-1-ol hydrochloride (7 g) as a white crude solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 214.20 [M+H] + .

[0987] Step C

[0988] A solution of 2-(4-(piperazin-1-yl)piperidin-1-yl)ethan-1-ol hydrochloride (6 g, 28 mmol, 1 eq) and 1,2-difluoro-4-nitrobenzene (4.47 g, 28.2 mmol, 1 eq) and NaHCO (11.8 g, 140.6 mmol, 5 eq) in ACN (50 mL) was stirred at 80° C. for 1 hour. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give 2-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)ethan-1-ol (3.64 g, 37%) as a yellow solid. LCMS (ESI, m / z): 353.20 [M+H] + .

[0989] Intermediate A30: Synthesis of 3-((4-fluoro-3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0990]

[0991] Step A

[0992] A solution of 2-bromo-1-fluoro-4-nitrobenzene (5 g, 22.7 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (4.23 g, 22.7 mmol, 1 eq), Pd(OAc)2 (510 mg, 2.27 mmol, 0.1 eq), XantPhos (1.32 g, 2.27 mmol, 0.1 eq) and Cs2CO3 (14.8 g, 45.5 mmol, 2 eq) in 1,4-dioxane (50 mL) was stirred at 110 ° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give tert-butyl 4-(2-fluoro-5-nitrophenyl)piperazine-1-carboxylate (3.7 g, 50%) as a yellow solid. LCMS (ESI, m / z): 326.14 [M+H] + .

[0993] Step B

[0994] A solution of tert-butyl 4-(2-fluoro-5-nitrophenyl)piperazine-1-carboxylate (2 g, 6.15 mmol, 1 equiv), Fe (1.72 g, 30.7 mmol, 5 equiv) and NHCl (0.66 g, 12.3 mmol, 2 equiv) in EtOH (30 mL) and water (10 mL) was stirred at 80 ° C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (8: 1) to give tert-butyl 4-(5-amino-2-fluorophenyl)piperazine-1-carboxylate (1.62 g, 89%) as a brown solid. LCMS (ESI, m / z): 296.17 [M + H] + .

[0995] Step C

[0996] A solution of tert-butyl 4-(5-amino-2-fluorophenyl)piperazine-1-carboxylate (790 mg, 2.68 mmol, 1 eq), 3-bromopiperidine-2,6-dione (1541 mg, 8.03 mmol, 3 eq) and NaHCO3 (449.4 mg, 5.35 mmol, 2 eq) in ACN (15 mL) was stirred at 90 ° C for 2 days. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE / EA (1: 1) to give tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1.35 g, quantitative) as a light blue solid. LCMS (ESI, m / z): 407.20 [M + H] + .

[0997] Step D

[0998] A solution of tert-butyl 4-{5-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1-carboxylate (1.3 g, 3.2 mmol, 1 equiv) and HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 14 hours. The precipitated solid was collected by filtration and washed with PE (3×5 mL) to give 3-((4-fluoro-3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (822 mg, 75%) as a light green solid. LCMS (ESI, m / z): 307.15 [M+H] + .

[0999] Intermediate A31: (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methyl 4-methylbenzenesulfonate synthesis

[1000]

[1001] Step A

[1002] A solution of methyl 3-aminocyclobutane-1-carboxylate (4.9 g, 37.9 mmol, 1 equivalent), 1,2-difluoro-4-nitrobenzene (5.43 g, 34.1 mmol, 0.9 equivalent) and DIEA (14.7 g, 114 mmol, 3 equivalents) in NMP (30 mL) was stirred at 80 ° C for 2 hours. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 25 minutes; detector, UV 254 nm, to afford methyl 3-((2-fluoro-4-nitrophenyl)amino)cyclobutane-1-carboxylate (7.5 g, 74%) as a yellow solid. LCMS (ESI, m / z): 269.10 [M+H] + .

[1003] Step B

[1004] To a stirred solution of 3-((2-fluoro-4-nitrophenyl)amino)cyclobutane-1-carboxylic acid methyl ester (4.5 g, 16.8 mmol, 1 eq) and Cs2CO3 (10.9 g, 33.6 mmol, 2 eq) in DMF (30 mL) was added iodomethane (4.76 g, 33.6 mmol, 2 eq) at room temperature. The resulting mixture was stirred for 2 hours. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with PE / EA (41:9) to give 3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutane-1-carboxylic acid methyl ester (4.1 g, 87%) as an orange oil. LCMS (ESI, m / z): 283.30 [M+H]+.

[1005] Step C

[1006] Under a nitrogen atmosphere, DIBAL-H (7.9 mL, 38.9 mmol, 11 equiv) was added dropwise to a solution of methyl 3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutane-1-carboxylate (1.0 g, 3.54 mmol, 1 equiv) in DCM (20 mL) at -65 ° C. The resulting mixture was stirred at -65 ° C for 15 minutes and then diluted with cold ether (20 mL). The mixture was heated to 0 ° C. The reaction was quenched with water (1 mL) and 15% NaOH (1 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 15 minutes. Anhydrous MgSO4 was added to the mixture in portions at room temperature. The resulting mixture was stirred for 15 minutes and then filtered, and the filter cake was washed with water (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (71:29) to give (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methanol (513 mg, 57%) as an orange oil. LCMS (ESI, m / z): 255.25 [M+H] + .

[1007] Step D

[1008] A solution of (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methanol (593 mg, 2.33 mmol, 1 eq) in DCM (12 mL) was treated with TEA (472 mg, 4.66 mmol, 2 eq) at room temperature, followed by the addition of p-toluenesulfonyl chloride (667 mg, 3.5 mmol, 1.5 eq) in portions at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (19:6) to give (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methyl 4-methylbenzenesulfonate (792 mg, 83%) as a yellow solid. LCMS (ESI, m / z): 409.75 [M + H] + .

[1009] Intermediate A32: 3-((5-Fluoro-6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione dione hydrochloride Salt synthesis

[1010]

[1011] Step A

[1012] A solution of tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol, 1 equivalent) and 2,3-difluoro-5-nitropyridine (430 mg, 2.68 mmol, 1 equivalent) and TEA (815 mg, 8.05 mmol, 3 equivalents) in DMF (3 mL) was stirred at 80 ° C for 2 hours. The product was precipitated by adding water. The precipitated solid was collected by filtration and washed with water (2×10 mL). The resulting solid was dried in an oven to give tert-butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (300 mg, 34%) as a yellow solid. LCMS (ESI, m / z): 327.15 [M+H] + .

[1013] Step B

[1014] A solution of tert-butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (780 mg, 2.39 mmol, 1 eq) and Pd / C (254 mg, 2.39 mmol, 1 eq) in EtOAc (6 mL) was stirred under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×6 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(5-amino-3-fluoropyridin-2-yl)piperazine-1-carboxylate (625 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 297.15 [M+H] + .

[1015] Step C

[1016] A solution of tert-butyl 4-(5-amino-3-fluoropyridin-2-yl)piperazine-1-carboxylate (600 mg, 2.03 mmol, 1 eq) and 2,6-bis(benzyloxy)-3-bromopyridine (750 mg, 2.03 mmol, 1 eq), t-BuONa (584 mg, 6.08 mmol, 3 eq), Pd2(dba)3CHCl3 (210 mg, 0.20 mmol, 0.1 eq) and XantPhos (117 mg, 0.20 mmol, 0.1 eq) in toluene (10 mL) was stirred at 100° C. under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl 4-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (1 g, 84%) as a yellow solid. LCMS (ESI, m / z): 586.30 [M+H] + .

[1017] Step D

[1018] A solution of tert-butyl 4-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (500 mg, 0.854 mmol, 1 eq) in EtOAc (15 mL) was treated with Pd / C (91 mg, 0.85 mmol, 1 eq) at room temperature under a hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with EtOAc (2×10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (330 mg, 95%) as a yellow solid. LCMS (ESI, m / z): 408.20 [M+H] + .

[1019] Step E

[1020] A solution of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (350 mg, 0.86 mmol, 1 equivalent) in HCl in 1,4-dioxane (5 mL, 4 M) was stirred for 3 hours. The resulting mixture was concentrated under reduced pressure to give 3-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride (650 mg) as a dark green crude solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 308.15 [M+H] + .

[1021] Intermediate A33: 2-(4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-ol Synthesis

[1022]

[1023] Step A

[1024] A solution of 1,2-difluoro-4-nitrobenzene (5.0 g, 31.4 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (5.85 g, 31.4 mmol, 1 eq) and NaHCO 3 (7.92 g, 94.3 mmol, 3 eq) in ACN (120 mL) was stirred at 90° C. overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (8.7 g, 85%) as a yellow solid. LCMS (ESI, m / z): 326.20 [M+H] + .

[1025] Step B

[1026] A solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (8.7 g, 27 mmol, 1 equivalent) in 1,4-dioxane (120 mL, 4 M) was stirred for 2 hours. The mixture was concentrated in vacuo to give 1-(2-fluoro-4-nitrophenyl)piperazine (7.0 g) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 226.20 [M+H] + .

[1027] Step C

[1028] A solution of 1-(2-fluoro-4-nitrophenyl)piperazine (4.0 g, 18 mmol, 1 eq), tert-butyl 4-formylpiperidine-1-carboxylate (4.55 g, 21.3 mmol, 1.2 eq) and STAB (7.53 g, 35.5 mmol, 2 eq) in DCE (120 mL) was stirred for 2 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (7.9 g) as a crude yellow solid which was used without further purification. LCMS (ESI, m / z): 423.15 [M+H] + .

[1029] Step D

[1030] A solution of tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (7.9 g, 19 mmol, 1 equiv) in HCl in 1,4-dioxane (150 mL, 4 M) was stirred for 2 hours. The mixture was concentrated in vacuo to give 1-(2-fluoro-4-nitrophenyl)-4-(piperidin-4-ylmethyl)piperazine (7.0 g) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 323.30 [M+H] + .

[1031] Step E

[1032] A solution of 1-(2-fluoro-4-nitrophenyl)-4-(piperidin-4-ylmethyl)piperazine (2.5 g, 7.8 mmol, 1 eq), 2-bromoethan-1-ol (0.97 g, 7.8 mmol, 1 eq) and KCO (4.29 g, 31.0 mmol, 4 eq) in ACN (120 mL) was stirred at 80° C. for 6 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (5:1) to give 2-(4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-ol (1.3 g, 46%) as a yellow oil. LCMS (ESI, m / z): 367.20 [M+H] + .

[1033] Intermediate A34: Synthesis of methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate

[1034]

[1035] Step A

[1036] A solution of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.6 mmol, 1 eq), 1,4-dioxa-8-azaspiro[4.5]decane (1.11 g, 7.72 mmol, 0.9 eq), Pd2(dba)3·CHCl3 (0.89 g, 0.86 mmol, 0.1 eq), XantPhos (0.50 g, 0.86 mmol, 0.1 eq) and Cs2CO3 (5.59 g, 17.2 mmol, 2 eq) in toluene (10 mL) was stirred at 80°C under nitrogen atmosphere overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (88:12) to give methyl 2-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzoate (988 mg, 39%) as a yellow solid. LCMS (ESI, m / z): 296.12 [M+H] + .

[1037] Step B

[1038] A solution of methyl 2-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzoate (978 mg, 3.31 mmol, 1 equiv) and HCl (5 mL, 2 M) in THF (5 mL) was stirred at 70 ° C for 1 hour. The mixture was neutralized to pH 7 with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×20 mL). The mixture was concentrated to dryness to give methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate (822 mg, 99%) as a yellow oil. The crude product was used without further purification. LCMS (ESI, m / z): 252.10 [M+H] + .

[1039] Intermediate A34-a was synthesized according to the process described for the synthesis of methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate (intermediate A34) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[1040]

[1041] Intermediate A35: Synthesis of 1-(3-fluoro-4-nitrophenyl)piperidin-4-one

[1042]

[1043] A solution of 4-piperidone (5.0 g, 50.4 mmol, 1 equiv), TEA (15.3 g, 151 mmol, 3 equiv) and 2,4-difluoro-1-nitrobenzene (12.0 g, 75.7 mmol, 1.5 equiv) in DMF (20 mL) was stirred at 80 ° C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (85:15) to give 1- (3-fluoro-4-nitrophenyl) piperidin-4-one (3.38 g, 28%) as a yellow solid. LCMS (ESI, m / z): 239.25 [M + H] + .

[1044] Intermediate A36: 3-(5-Fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride Salt synthesis

[1045]

[1046] Step A

[1047] A solution of 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.5 g, 4.23 mmol, 1 eq), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.76 g, 4.23 mmol, 1 eq), Pd(dppf)Cl2 (0.31 g, 0.42 mmol, 0.1 eq) and K2CO3 (1.17 g, 8.45 mmol, 2 eq) in dioxane (8 mL) and water (4 mL) was stirred at 80°C under nitrogen atmosphere for 1 hour. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1.0 g, 46%) as a yellow solid. LCMS (ESI, m / z): 518.35 [M+H] + .

[1048] Step B

[1049] A solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1.0 g, 1.93 mmol, 1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (597 mg, 1.93 mmol, 1 eq), Pd(dppf)Cl2 (141 mg, 0.193 mmol, 0.1 eq) and K2CO3 (533 mg, 3.86 mmol, 2 eq) in dioxane (0.8 mL) and water (0.4 mL) was stirred at 80°C under nitrogen atmosphere for 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (7:1) to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 84%) as a yellow solid. LCMS (ESI, m / z): 621.15 [M+H] + .

[1050] Step C

[1051] A solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 1.6 mmol, 1 equiv) and 10% Pd / C (200 mg) in MeOH (60 mL) was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered and the filter cake was washed with MeOH (4×25 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (653 mg, 91%) as a gray solid. LCMS (ESI, m / z): 445.25 [M+H] + .

[1052] Step D

[1053] A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazole-6-yl)piperidine-1-carboxylate (640 mg, 1.44 mmol, 1 equivalent) and HCl in 1,4-dioxane (20 mL, 4 M) was stirred for 1 hour. The mixture was concentrated to dryness to give 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazole-3-yl)piperidine-2,6-dione hydrochloride (600 mg) as a gray solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 345.25[M+H] + .

[1054] Intermediate A37: 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione synthesis

[1055]

[1056] Step A

[1057] A solution of 1-(4-bromo-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.74 mmol, 1 eq), 1,4-dioxa-8-azaspiro[4.5]decane (374 mg, 2.61 mmol, 1.5 eq), Cs2CO3 (1.14 g, 3.48 mmol, 2 eq) and PdPEPPSIIPentCl (147 mg, 0.174 mmol, 0.1 eq) in dioxane (8 mL) was stirred at 85°C under nitrogen atmosphere for 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:3) to give 1-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (520 mg, 85%) as a white solid. LCMS (ESI, m / z): 350.35 [M+H] + .

[1058] Step B

[1059] A solution of 1-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (510 mg, 1.46 mmol, 1 equiv) and HCl (10 mL, 6 M) in THF (10 mL) was stirred overnight. The mixture was neutralized to pH 7 with saturated aqueous NaHCO₃. The mixture was extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (460 mg) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 306.15 [M+H] + .

[1060] Intermediates A37-a to A37-c were synthesized according to the process described for the synthesis of 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (intermediate A37) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[1061]

[1062] Intermediate A38: Synthesis of 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[1063]

[1064] Step A

[1065] A solution of tert-butyl acetate (0.63 g, 5.42 mmol, 1 equivalent) in THF (10 mL) was treated with LDA (2 M THF solution) (1.16 g, 10.8 mmol, 2 equivalents) at -78 ° C under a nitrogen atmosphere for 15 minutes, followed by the addition of 1- (3-fluoro-4-nitrophenyl) piperidin-4-one (1.49 g, 6.2 mmol, 1.15 equivalents) at -78 ° C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated NH4Cl aqueous solution (10 mL) at room temperature. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with water (3 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (958 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 355.15 [M+H] + .

[1066] Step B

[1067] A mixture of tert-butyl 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (940 mg, 2.65 mmol, 1 equiv) in HCl in 1,4-dioxane (3 mL, 4 M) was stirred for 2 hours. The mixture was concentrated to dryness to give 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetic acid (716 mg, 91%) as a yellow solid, which was used without further purification. LCMS (ESI, m / z): 299.15 [M+H] + .

[1068] Intermediate A39: (3S)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pyrrolidine-3-carboxylate Synthesis of amides

[1069]

[1070] Step A

[1071] A solution of 2-fluoro-4-nitroaniline (2.0 g, 13 mmol, 1 eq) in DMF (10 mL) was treated with (3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.76 g, 12.8 mmol, 1 eq) and DIEA (4.97 g, 38.4 mmol, 3 eq), followed by the dropwise addition of T3P (16.3 g, 51.2 mmol, 4 eq). The mixture was stirred at 80° C. overnight. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 65% over 35 minutes; detector, UV 254 nm, to afford tert-butyl (S)-3-((2-fluoro-4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate (3.04 g, 67%) as an orange solid. LCMS (ESI, m / z): 352.10 [MH] - .

[1072] Step B

[1073] A solution of (3S)-tert-butyl 3-[(2-fluoro-4-nitrophenyl)carbamoyl]pyrrolidine-1-carboxylate (3.02 g, 8.55 mmol, 1 eq) in EtOH (28 mL) was treated with a solution of NHCl (0.91 g, 17 mmol, 2 eq) in water (7 mL), followed by the addition of Fe (2.39 g, 42.7 mmol, 5 eq) in portions at 80 °C. The mixture was stirred at 80 °C for 2 hours and then concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (93:7) to give (S)-tert-butyl 3-((4-amino-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate (2.6 g, 94%) as an orange solid. LCMS (ESI, m / z): 322.25 [MH] - .

[1074] Step C

[1075] A solution of (3S)-tert-butyl 3-[(4-amino-2-fluorophenyl)carbamoyl]pyrrolidine-1-carboxylate (800 mg, 2.47 mmol, 1 eq), 3-bromopiperidine-2,6-dione (475 mg, 2.47 mmol, 1 eq) and NaHCO3 (624 mg, 7.42 mmol, 3 eq) in ACN (10 mL) was stirred at 90°C overnight and then concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (19:1) to give (3S)-tert-butyl 3-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate (730 mg, 68%) as a green solid. LCMS (ESI, m / z): 433.30 [MH] - .

[1076] Step D

[1077] A solution of tert-butyl (3S)-3-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate (710 mg, 1.63 mmol, 1 equiv) in TFA (3 mL) and DCM (12 mL) was stirred for 30 minutes. The mixture was concentrated to dryness to give (3S)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pyrrolidine-3-carboxamide trifluoroacetate (1.3 g) as a dark blue solid. The product was used directly in the next step without further purification. LCMS (ESI, m / z): 335.15 [M+H] + .

[1078] Intermediates A39-a and A39-b were synthesized according to the process described for the synthesis of (3S)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pyrrolidine-3-carboxamide trifluoroacetate (intermediate A39) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[1079]

[1080] Intermediate A40: N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-N-methylpiperidin-4-carboxylate Synthesis of amides

[1081]

[1082] Step A

[1083] A solution of tert-butyl 4-[(2-fluoro-4-nitrophenyl)carbamoyl]piperidine-1-carboxylate (4 g, 10.9 mmol, 1 equivalent) in DMF (10 mL) was treated with NaH (0.87 g, 21.8 mmol, 2 equivalents, 60% dispersion in oil) and stirred at 0° C. for 15 minutes under a nitrogen atmosphere. Iodomethane (1.55 g, 10.9 mmol, 1 equivalent) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hour. The reactant was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-((2-fluoro-4-nitrophenyl) (methyl)carbamoyl)piperidine-1-carboxylate (2.79 g, 67%) as a white solid. LCMS (ESI, m / z): 382.2 [M+H] + .

[1084] Step B

[1085] A solution of tert-butyl 4-[(2-fluoro-4-nitrophenyl)(methyl)carbamoyl]piperidine-1-carboxylate (2.79 g, 7.31 mmol, 1 equiv) and 10% Pd / C (0.78 g) in MeOH (10 mL) was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered and washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-((4-amino-2-fluorophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.65 g) as a white solid, which was used without further purification. LCMS (ESI, m / z): 352.2 [M+H] + .

[1086] Step C

[1087] A solution of tert-butyl 4-[(4-amino-2-fluorophenyl)(methyl)carbamoyl]piperidine-1-carboxylate (2.0 g, 5.69 mmol, 1 eq), 3-bromopiperidine-2,6-dione (1.31 g, 6.83 mmol, 1.2 eq) and NaHCO3 (1.43 g, 17.1 mmol, 3 eq) in ACN (40 mL) was stirred at 90°C for 3 days. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.5 g, 95%) as a white solid. LCMS (ESI, m / z): 463.3 [M+H] + .

[1088] Step D

[1089] A solution of tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (500 mg, 1.08 mmol, 1 equiv) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 1 hour. The mixture was concentrated to dryness to give N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-N-methylpiperidine-4-carboxamide (440 mg) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 363.3 [M+H] + .

[1090] Intermediate A41: 1"-(2-fluoro-4-nitrophenyl)-4-(hydroxymethyl)-[1,4':1',4"-terpiperidinyl]-2-one Synthesis

[1091]

[1092] Step A

[1093] A solution of methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (1.35 g, 8.82 mmol, 1 eq), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (3.00 g, 13.2 mmol, 1.5 eq), Cu(OAc)2 (0.48 g, 2.7 mmol, 0.3 eq) and pyridine (4.18 g, 52.9 mmol, 6 eq) in THF (10 mL) was stirred at 50 °C in air for 15 h. After concentration, the residue was purified by silica gel column chromatography using PE / EtOAc (2:3) as eluent to give 1'-(tert-butyl)4-methyl 2-oxo-3',6'-dihydro-2H-[1,4'-bipyridine]-1',4(2'H)-dicarboxylate (1.4 g, 47%) as a white solid. LCMS (ESI, m / z): 335.10 [M+H] + .

[1094] Step B

[1095] A mixture of 1'-(tert-butyl) 4-methyl 2-oxo-3',6'-dihydro-2H-[1,4'-bipyridine]-1',4(2'H)-dicarboxylate (1.4 g, 4.2 mmol, 1 equivalent) and 10% Pd / C (0.14 g) in EtOAc (5 mL) was stirred overnight under a hydrogen atmosphere. The mixture was filtered and washed with EtOAc (3×5 mL). The filtrate was concentrated under reduced pressure to give 1'-(tert-butyl) 4-methyl 2-oxo-[1,4'-bipiperidine]-1',4-dicarboxylate (1.2 g, 84%) as a white solid. LCMS (ESI, m / z): 339.20 [MH] - .

[1096] Step C

[1097] A mixture of 1'-(tert-butyl)4-methyl 2-oxo-[1,4'-bipiperidine]-1',4-dicarboxylate (1.2 g, 3.5 mmol, 1 equiv) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 4 hours. The mixture was concentrated to dryness to give methyl 2-oxo-[1,4'-bipiperidine]-4-carboxylate hydrochloride (1.4 g) as a white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 241.10 [M+H] + .

[1098] Step D

[1099] A mixture of methyl 2-oxo-[1,4'-bipiperidine]-4-carboxylate hydrochloride (1.4 g, 5.8 mmol, 1 equiv), 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (2.36 g, 9.90 mmol, 1.7 equiv), and STAB (2.47 g, 11.7 mmol, 2 equiv) in DCE (5 mL) was stirred for 2 days. The solution was concentrated, and the residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 15 minutes; detector, UV 254 nm, to afford methyl 1"-(2-fluoro-4-nitrophenyl)-2-oxo-[1,4':1',4"-terpiperidine]-4-carboxylate (900 mg, 33%) as a yellow solid. LCMS (ESI, m / z): 463.20 [M+H] + .

[1100] Step E

[1101] A mixture of methyl 1″-(2-fluoro-4-nitrophenyl)-2-oxo-[1,4′:1′,4″-terpiperidine]-4-carboxylate (900 mg, 1.95 mmol, 1 eq), NaBH4 (110 mg, 2.92 mmol, 1.5 eq) and CaCl2 (432 mg, 3.89 mmol, 2 eq) in EtOH (3 mL) was stirred overnight. The reaction was quenched with water at 0°C. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (8:1) to give 1″-(2-fluoro-4-nitrophenyl)-4-(hydroxymethyl)-[1,4′:1′,4″-terpiperidine]-2-one (400 mg, 47%) as a yellow solid. LCMS (ESI, m / z): 435.20 [M+H] + .

[1102] Intermediate A42: Synthesis of 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetic acid become

[1103]

[1104] Step A

[1105] A mixture of tert-butyl 2-(azetidin-3-yl)acetate hydrochloride (2.05 g, 9.86 mmol, 1 eq) and 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (3.52 g, 14.8 mmol, 1.5 eq) in DCE (20 mL) was stirred for 1 hour. STAB (6.27 g, 29.6 mmol, 3 eq) was added to the above mixture and the mixture was stirred for 1 hour. After concentration, the residue was purified by silica gel column chromatography eluted with CHCl / MeOH (4:1) to give tert-butyl 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetate (2.4 g, 54%) as an orange oil. LCMS (ESI, m / z): 394.3 [M+H] + .

[1106] Step B

[1107] A mixture of tert-butyl 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetate (2.38 g, 6.05 mmol, 1 equiv) and TFA (5 mL) in DCM (25 mL) was stirred for 2 hours. The mixture was concentrated to give 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetic acid (3.5 g) as an orange oil. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 338.1 [M+H]+ .

[1108] Intermediate A43: Synthesis of 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetaldehyde

[1109]

[1110] Step A

[1111] A solution of piperazin-2-one (5.0 g, 50 mmol, 1 eq), 1,2-difluoro-4-nitrobenzene (11.9 g, 74.9 mmol, 1.5 eq) and NaHCO (12.6 g, 150 mmol, 3 eq) in ACN (60 mL) was stirred at 80° C. overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with CH Cl / MeOH (12:1) to give 4-(2-fluoro-4-nitrophenyl)piperazin-2-one (6.44 g, 54%) as a yellow solid. LCMS (ESI, m / z): 239.10 [M + H] + .

[1112] Step B

[1113] To a solution of 4-(2-fluoro-4-nitrophenyl)piperazin-2-one (5.25 g, 21.9 mmol, 1 eq) in THF (20 mL) was added portionwise NaH (1.05 g, 26.3 mmol, 1.2 eq, 60% dispersion in oil) at 0°C. The mixture was stirred at 0°C for 20 minutes. Ethyl bromoacetate (9.16 g, 54.9 mmol, 2.5 eq) was added dropwise and the mixture was stirred at 0°C for 1 hour. Water (10 mL) was added at 0°C, and the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were concentrated to dryness to give ethyl 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetate (8.37 g) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 325.10 [M+H] + .

[1114] Step C

[1115] A solution of ethyl 2-[4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl]acetate (8.37 g, 25.7 mmol, 1 eq) and NaOH (3.09 g, 77.2 mmol, 3 eq) in MeOH (10 mL) and water (40 mL) was stirred for 2 hours. The product was precipitated by adjusting to pH 6 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3×5 mL). The solid was dried under infrared light to give 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetic acid (6 g, 78%) as a yellow solid. LCMS (ESI, m / z): 297.10 [M+H] + .

[1116] Step D

[1117] A solution of 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetic acid (2.29 g, 7.70 mmol, 1 eq), benzyl bromide (1.58 g, 9.25 mmol, 1.2 eq) and KCO (2.13 g, 15.4 mmol, 2 eq) in DMF (10 mL) was stirred overnight. The product was precipitated by the addition of water. The precipitated solid was collected by filtration and washed with water (3×5 mL) to give benzyl 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetate (1.98 g, 66%) as a yellow solid. LCMS (ESI, m / z): 387.10 [M+H] + .

[1118] Step E

[1119] To a stirred solution of 2-[4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl]benzyl acetate (516 mg, 1.33 mmol, 1 eq) and LiCl (113 mg, 2.66 mmol, 2 eq) in EtOH (6 mL) and THF (6 mL) was added NaBH4 (101 mg, 2.66 mmol, 2 eq) in portions at 0°C. The mixture was stirred at room temperature for 1 hour. The solution was cooled to 0°C and water was added. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give 4-(2-fluoro-4-nitrophenyl)-1-(2-hydroxyethyl)piperazin-2-one (278 mg, 74%) as a yellow solid. LCMS (ESI, m / z): 283.10 [M+H] + .

[1120] Step F

[1121] A solution of 4-(2-fluoro-4-nitrophenyl)-1-(2-hydroxyethyl)piperazin-2-one (278 mg, 0.981 mmol, 1 eq) and Dess-Martin periodinane (624 mg, 1.47 mmol, 1.5 eq) in DCM (5 mL) was stirred for 3 hours. The solution was cooled to 0°C and saturated aqueous NaHCO3 (10 mL) was added. The mixture was extracted with CHCl (3×15 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetaldehyde (153 mg, 55%) as a yellow oil. LCMS (ESI, m / z): 281.10 [M+H] + .

[1122] Intermediate A44: Synthesis of 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylic acid

[1123]

[1124] Step A

[1125] A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.5 g, 7.5 mmol, 1 eq) in DCE (15 mL) was treated with methyl azetidine-3-carboxylate hydrochloride (1.30 g, 11.3 mmol, 1.5 eq) and STAB (3.19 g, 15.1 mmol, 2 eq) at 40 ° C. for 3 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (55:45) to give tert-butyl 4-(3-(methoxycarbonyl)azetidin-1-yl)piperidine-1-carboxylate (2.21 g, 98%) as a white solid. LCMS (ESI, m / z): 299.10 [M+H] + .

[1126] Step B

[1127] A solution of tert-butyl 4-(3-(methoxycarbonyl)azetidine-1-yl)piperidine-1-carboxylate (2.4 g, 8.0 mmol, 1 equivalent) in HCl in 1,4-dioxane (25 mL, 4 M) was stirred for 1 hour. The mixture was concentrated to dryness to give methyl 1-(piperidin-4-yl)azetidine-3-carboxylate (2.05 g) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 199.15 [M+H] + .

[1128] Step C

[1129] A solution of methyl 1-(piperidin-4-yl)azetidine-3-carboxylate (2.05 g, 10.1 mmol, 1 eq) in ACN (15 mL) was treated with 1,2-difluoro-4-nitrobenzene (3.21 g, 20.2 mmol, 2 eq) and NaHCO (2.54 g, 30.3 mmol, 3 eq) at 80 °C for 2 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with CHCl / MeOH (95:5) to give methyl 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylate (2.27 g, 67%) as a yellow solid. LCMS (ESI, m / z): 338.15 [M+H] + .

[1130] Step D

[1131] A solution of methyl 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylate (2.25 g, 6.66 mmol, 1 eq) in MeOH (3 mL) was treated with NaOH (1.07 g, 26.6 mmol, 4 eq) and water (15 mL) for 1 hour. The mixture was adjusted to pH 6 with aqueous HCl. The precipitated solid was collected by filtration to give 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylic acid (2.13 g, 99%) as a yellow solid. LCMS (ESI, m / z): 324.15 [M+H] + .

[1132] Intermediate A45: 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4-(1H, Synthesis of 3H)-dione

[1133]

[1134] Step A

[1135] A mixture of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (1.6 g, 5.4 mmol, 1 eq) and NaOCN (697 mg, 10.7 mmol, 2 eq) in HOAc (19 mL) was stirred at 60 ° C under nitrogen overnight. HCl (19 mL, 2 M) was added dropwise to the mixture. The mixture was stirred at 60 ° C for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by trituration with water (130 mL) to give 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.19 g, 66%) as an off-white solid after filtration. LCMS (ESI, m / z): 324.95 [M+H] + .

[1136] Step B

[1137] A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (360 mg, 1.11 mmol, 1 eq), piperidin-4-one hydrochloride (151 mg, 1.11 mmol, 1 eq), PdPEPPSI IPentCl (94 mg, 0.11 mmol, 0.1 eq) and CsCO (726 mg, 2.23 mmol, 2 eq) in 1,4-dioxane (4 mL) was stirred at 85° C. under a nitrogen atmosphere overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 20 minutes; detector, UV 254 nm, to afford 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 47%) as an orange solid. LCMS (ESI, m / z): 342.10 [M+H] + .

[1138] Intermediate A45-a was synthesized according to the process described for the synthesis of 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (intermediate A45) using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[1139]

[1140] Intermediate A46: 1-(5-Fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4-(1H, Synthesis of 3H)-diketone hydrochloride

[1141]

[1142] Step A

[1143] A solution of 4-bromo-2,5-difluorobenzonitrile (3.0 g, 14 mmol, 1 eq), methylhydrazine sulfate (9.92 g, 68.8 mmol, 5 eq) and K2CO3 (9.51 g, 68.8 mmol, 5 eq) in n-BuOH (100 mL) was stirred at 100°C for 5 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 6-bromo-5-fluoro-1-methyl-1H-indazol-3-amine (1.7 g, 51%) as a yellow solid. LCMS (ESI, m / z): 243.98 [M+H] + .

[1144] Step B

[1145] A solution of 6-bromo-5-fluoro-1-methyl-1H-indazol-3-amine (1.7 g, 6.97 mmol, 1 equivalent) and acrylic acid (3.01 g, 41.8 mmol, 6 equivalents) in toluene (50 mL) was stirred overnight. The mixture was concentrated and the residue was diluted with water (5 mL). The mixture was neutralized to pH 7 with saturated aqueous NaHCO3. The mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 20% gradient in 10 minutes; detector, UV 254 nm to give 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl) amino) propanoic acid (998 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 316.00 [M+H] + .

[1146] Step C

[1147] A solution of 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propanoic acid (988 mg, 3.13 mmol, 1 eq) and NaOCN (406 mg, 6.25 mmol, 2 eq) in HOAc (6 mL) was stirred at 60 ° C overnight. HCl (6 mL, 2 M) was then added dropwise at room temperature over 1 minute. The mixture was stirred at 60 ° C for 3 hours. The solution was diluted with water (15 mL) and concentrated to remove volatiles. The precipitated solid was collected by filtration and washed with water (30 mL) to give 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (688 mg, 65%) as an off-white solid. LCMS (ESI, m / z): 341.00 [M+H] + .

[1148] Step D

[1149] A solution of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (688 mg, 2.02 mmol, 1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (748 mg, 2.42 mmol, 1.2 eq), Pd(dppf)Cl2·CH2Cl2 (164 mg, 0.202 mmol, 0.1 eq), K2CO3 (558 mg, 4.03 mmol, 2 eq) in water (2 mL) and dioxane (20 mL) was stirred at 80°C for 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:99) to give tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (715 mg, 80%) as an off-white solid. LCMS (ESI, m / z): 444.20 [M+H] + .

[1150] Step E

[1151] A solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (705 mg, 1.59 mmol, 1 equivalent) and 10% Pd / C (508 mg) in EtOAc (20 mL) was stirred under a hydrogen atmosphere for 30 minutes. After filtration, the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated to give tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (320 mg, 45%) as an off-white solid. LCMS (ESI, m / z): 446.21[M+H] + .

[1152] Step F

[1153] A solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (310 mg, 0.70 mmol, 1 equiv) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 1 hour. The mixture was concentrated to dryness to give 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (255 mg, 96%) as an off-white solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 346.10 [M+H] + .

[1154] Intermediate A47: 1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- Synthesis of diketones .

[1155]

[1156] Step A

[1157] A solution of 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.17 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (325 mg, 1.75 mmol, 1.5 eq) and CsCO (38.0 mg, 0.117 mmol, 0.1 eq) in dioxane (5 mL) was treated with PdPEPPSIIPentCl (98.0 mg, 0.117 mmol, 0.1 eq) under a nitrogen atmosphere. The mixture was stirred at 90° C. for 4 hours. After concentration, the crude product was purified by silica gel chromatography eluting with DCM / MeOH (95:5) to give tert-butyl 4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)piperazine-1-carboxylate (576 mg, 93%) as a yellow-green solid. LCMS (ESI, m / z): 535.25 [M+H] + .

[1158] Step B

[1159] A solution of tert-butyl 4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)piperazine-1-carboxylate (250 mg, 0.468 mmol, 1 equiv) and TFA (10 mL) in DCM (30 mL) was stirred for 1 hour. The mixture was concentrated to dryness to give 3-(4-methoxybenzyl)-1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (230 mg) as a dark green solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 435.30 [M+H] + .

[1160] Step C

[1161] A solution of 3-(4-methoxybenzyl)-1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (230 mg, 0.529 mmol, 1 equiv) and TfOH (5 mL) in TFA (25 mL) was stirred for 3 hours. The solution was adjusted to pH 7 with saturated aqueous NaHCO3. The mixture was concentrated to dryness and the residue was purified on a silica gel column eluted with DCM / MeOH (90:10) to give 1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (170 mg, crude) as a dark green solid. LCMS (ESI, m / z): 315.05 [M+H] + .

[1162] Intermediate A48: 1-(8-(piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride Synthesis

[1163]

[1164] Step A :

[1165] A solution of 8-bromo-4-iodoisoquinoline (1.00 g, 2.99 mmol, 1 equiv), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.91 g, 3.89 mmol, 1.3 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.21 g, 1.50 mmol, 0.5 equiv), Cs2CO3 (1.95 g, 6.0 mmol, 2 equiv) and CuI (0.23 g, 1.20 mmol, 0.4 equiv) in dioxane (6 mL) was stirred at 65°C under nitrogen atmosphere overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (45:55) to give 1-(8-bromoisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (730 mg, 55%) as a yellow solid. LCMS (ESI, m / z): 440.05 [M+H] + .

[1166] Step B

[1167] A solution of 1-(8-bromoisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.6 g, 3.6 mmol, 1 equivalent) in TFA (5 mL) and TfOH (1 mL) was stirred for 4 hours. The solution was diluted with EtOAc (4 mL). The mixture was basified to pH 8 with TEA. The precipitated solid was collected by filtration and washed with water (3×5 mL) to give 1-(8-bro...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: W is CR W or N; X is CR X or N; Z is CR Z or N; and Among them, at most two of W, X and Z are N at the same time; Y 1 Selected from -NR 3 -、-CR 4 R 5 -, -O- and -(C 2-4 Alkynyl)-; Y 2 is selected from a bond, -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-; Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace; R 1 and R 2 are each independently selected from H and methyl; R 3 Selected from H and C 1-4 alkyl; R 4 and R 5 Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 Dialkylamino; R 6 and R 7 are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 Dialkylamino; Each R A are independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; Each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; R W , R X and R Z are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W , R X or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 3 , Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 和S(O)2NR c3 R d3 ; Each Cy 1 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; Each Cy 2 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; Each Cy 3 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 4 , Cy 4 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; Each Cy 4 is C each optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl: halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; R a4 , R b4 , R c4 and R d4 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R c1 and R d1 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; or R c2 and R d2 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 , NR c4 C(O)R b4 、NR c4 C(O)NR c4 R d4 、NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 、 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 、 NR c4 S(O)2R b4 、NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; or R c3 and R d3 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 , NR c4 C(O)R b4 、NR c4 C(O)NR c4 R d4 、NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 、 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 、 NR c4 S(O)2R b4 、NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; Each R e1 , R e2 , R e3 and R e4 Independently selected from H, C 1-4 Alkyl and CN; m is 0, 1 or 2; E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and L 1 is a linker covalently linked to moiety Q and moiety E; wherein any of the aforementioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; wherein one or more ring-forming C or N atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with an oxo (=O) group; and wherein one or more ring-forming S atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups.

2. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: W is CR W or N; X is CR X or N; Z is CR Z or N; and Among them, at most two of W, X and Z are N at the same time; Y 1 Selected from -NR 3 -、-CR 4 R 5 - and -O-; Y 2 is selected from a bond, -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-; Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace; R 1 and R 2 are each independently selected from H and methyl; R 3 Selected from H and C 1-4 alkyl; R 4 and R 5 Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 Dialkylamino; R 6 and R 7 are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 Dialkylamino; Each R A are independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; Each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; R W , R X and R Z are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W , R X or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 3 , Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; Each Cy 1 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; Each Cy 2 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; Each Cy 3 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 4 , Cy 4 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; Each Cy 4 is C each optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl: halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; R a4 , R b4 , R c4 and R d4 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R c1 and R d1 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; or R c2 and R d2 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; or R c3 and R d3 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; Each R e1 , R e2 , R e3 and R e4 Independently selected from H, C 1-4 Alkyl and CN; m is 0, 1 or 2; E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and L 1 is a linker covalently linked to moiety Q and moiety E; wherein any of the aforementioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; wherein one or more ring-forming C or N atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with an oxo (=O) group; and wherein one or more ring-forming S atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups.

3. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: W is CR W or N; X is CR X or N; Z is CR Z or N; and Among them, at most two of W, X and Z are N at the same time; Y 1 Selected from -NR 3 -、-CR 4 R 5 - and -O-; Y 2 Selected from -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-; Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 Cycloalkyl and 4 to 18 membered heterocycloalkyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace; R 1 and R 2 are each independently selected from H and methyl; R 3 Selected from H and C 1-4 alkyl; R 4 and R 5 Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 Dialkylamino; R 6 and R 7 are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 Dialkylamino; Each R A are independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; Each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; R W , R X and R Z are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; where R W , R X or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 3 , Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、 S(O)NR c3 R d3 、 S(O)2R b3 和 S(O)2NR c3 R d3 ; Each Cy 1 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; Each Cy 2 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; Each Cy 3 independently selected from C each optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: Cy 4 , Cy 4 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; Each Cy 4 is C each optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl: halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; R a4 , R b4 , R c4 and R d4 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R c1 and R d1 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 、 NR c4 S(O)2R b4 、NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; or R c2 and R d2 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 , NR c4 C(O)R b4 、NR c4 C(O)NR c4 R d4 、NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 、 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 、 NR c4 S(O)2R b4 、NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ; or R c3 and R d3 Together with the N atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , SR a4 、C(O)R b4 、C(O)NR c4 R d4 、C(O)OR a4 、OC(O)R b4 、OC(O)NR c4 R d4 NR c4 R d4 , NR c4 C(O)R b4 、NR c4 C(O)NR c4 R d4 、NR c4 C(O)OR a4 、C(=NR e4 )NR c4 R d4 、 NR c4 C(=NR e4 )NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 、 NR c4 S(O)2R b4 、NR c4 S(O)2NR c4 R d4 和S(O)2NR c4 R d4 ; Each R e1 , R e2 , R e3 and R e4 Independently selected from H, C 1-4 Alkyl and CN; m is 0, 1 or 2; E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and L 1 is a linker covalently attached to moiety Q and moiety E; wherein any of the aforementioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; wherein one or more ring-forming C or N atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with an oxo (=O) group; and wherein one or more ring-forming S atoms of any of the aforementioned heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein W is CR W .

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is CR X .

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Z is CR Z .

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y 1 For -O-.

8. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y 1 For-CR 4 R 5 -.

9. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y 1 For-NR 3 -.

10. A compound according to any one of claims 1 and 4 to 6, or a pharmaceutically acceptable salt thereof, wherein Y 1 For-(C 2-4 Alkynyl)-.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y 2 For -S-.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y 2 It is -CH2-.

13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y 2 For -O-.

14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y 2 is the key.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 4- to 18-membered heterocycloalkyl group, wherein Ring A is optionally substituted by 1, 2, 3 or 4 R A replace.

16. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 4- to 7-membered heterocycloalkyl group, wherein Ring A is optionally substituted by 1, 2, 3 or 4 R A replace.

17. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is each optionally substituted by 1, 2, 3 or 4 R A Substituted tetrahydro-2H-pyranyl or piperidinyl.

18. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is tetrahydro-2H-pyran-4-yl or 1-methylpiperidin-4-yl.

19. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl or 1-(2,2,2-trifluoroethyl)piperidin-4-yl.

20. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is C 3-14 cycloalkyl, and wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace.

21. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 4-hydroxycyclohexyl.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is C 3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl, wherein ring B is optionally substituted by 1, 2, 3 or 4 R B replace.

23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 4- to 7-membered heterocycloalkyl group, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace.

24. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted with 1, 2, 3 or 4 R B Substituted piperidinyl.

25. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is piperidinyl.

26. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is each optionally substituted by 1, 2, 3 or 4 R B substituted piperidinyl, piperazinyl or azetidinyl.

27. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is C 3-7 cycloalkyl, and wherein ring B is optionally substituted by 1, 2, 3 or 4 R B replace.

28. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclopropyl, cyclobutyl or cyclohexyl.

29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is H.

30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Each is H.

31. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 Each is H.

32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein each R A are independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 , NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 、 NR c1 C(=NR e1 )NR c1 R d1 、NO c1 SOUTH b1 、NO c1 S(O)2R b1 、 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 和S(O)2NR c1 R d1 。 33. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein each R A are independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO2 or OR a1 .

34. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein each R A C 1-6 alkyl.

35. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R A It is methyl.

36. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R A is methyl, OH or 2,2,2-trifluoroethyl.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R B are independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 , NR c2 C(O)R b2 、NR c2 C(O)OR a2 、NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、 C(=NR e2 )NR c2 R d2 、NO c2 C(=NR e2 )NR c2 R d2 、NO c2 SOUTH b2 、 NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 和S(O)2NR c2 R d2 。 38. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R B are independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO2 or OR a2 .

39. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R B are independently selected from halo.

40. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R B For F.

41. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R W Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a3 , SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 , NR c3 C(O)OR a3 、NR c3 C(O)NR c3 R d3 、C(=NR e3 )R b3 、C(=NR e3 )NR c3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、NO c3 SOUTH b3 、NO c3 S(O)2R b3 、 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 和S(O)2NR c3 R d3 。 42. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R W Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl halides, CN, NO2 and OR a3 .

43. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R W is selected from H, halo and C 1-6 Halogenated alkyl.

44. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R W For F.

45. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R X Selected from C 6-10 Aryl and 5 to 10 membered heteroaryl, wherein the C 6-10 Aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a3 and SR a3 .

46. ​​A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R X Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a3 and C 6-10 Aryl.

47. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R X For H.

48. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R X It is H or F.

49. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R Z Selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl halides, CN, NO2 and OR a3 .

50. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R Z For H.

51. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein m is 2.

52. The compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein m is 1.

53. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein m is 0.

54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein L 1 Select from the following: (i) a bond such that ring B is directly attached to moiety E; (ii)-(C 1-4 alkyl)-; (iii)-(C 2-4 alkenyl)-; (iv)-(C 2-4 Alkynyl)-; (v)-(C 2-4 Alkynyl)-(G 3 )-; (vi) The following structure: (vii) The following structure: and (viii) The following structure: Among them G 1 Selected from -C(O)-, -NR G C(O)-、-NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -、-NR G C(O)NR G -, -S(O2)- and -S(O)NR G -; G 2 C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl; G 3 selected from -C(O)-, -NR G C(O)-, -NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -, -NR G C(O)NR G -, -S(O2)- and -S(O)NR G -; G 4 For optionally C 1-6 Alkyl, hydroxyl, C 1-6 4- to 10-membered heterocycloalkyl substituted with alkoxy or halo; Each R G independently selected from H, methyl and ethyl; a is 0 or 1; b is 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1; g is 0, 1, or 2; At least one of b, c, e and f is 1.

55. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond such that ring B is directly connected to moiety E.

56. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 For-(C 1-4 alkyl)-.

57. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 For-(C 2-4 alkenyl)-.

58. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 For-(C 2-4 Alkynyl)-.

59. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 For-(C 2-4 Alkynyl)-(G 3 )-.

60. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 Has the following structure:

61. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein L 1 for 62. A compound according to any one of claims 54 to 61, or a pharmaceutically acceptable salt thereof, wherein G 1 For-NR G C(O)- or -C(O)-.

63. A compound according to any one of claims 54 to 61, or a pharmaceutically acceptable salt thereof, wherein G 1 For-NR G C(O)-, -C(O)-, or -O-.

64. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 is a 4- to 10-membered heterocycloalkyl group.

65. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 is piperidinyl, piperazinyl or azetidinyl.

66. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 It is an azetidinyl group.

67. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl or cyclobutyl.

68. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 It is piperidinyl, piperazinyl, azetidinyl, pyridinyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8,2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl or pyrrolidinyl.

69. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 C 3-7 Cycloalkyl.

70. A compound according to any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein G 2 It is cyclobutyl.

71. A compound according to any one of claims 54 to 70, or a pharmaceutically acceptable salt thereof, wherein G 3 For-NR G or -O-.

72. A compound according to any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein G 4 It is piperidinyl or piperazinyl.

73. A compound according to any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein G 4 is azetidinyl, piperidinyl or piperazinyl.

74. A compound according to any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein G 4 It is piperazinyl.

75. A compound according to any one of claims 54 to 74, or a pharmaceutically acceptable salt thereof, wherein a is 0.

76. A compound according to any one of claims 54 to 74, or a pharmaceutically acceptable salt thereof, wherein a is 1.

77. A compound according to any one of claims 54 to 76, or a pharmaceutically acceptable salt thereof, wherein b is 0.

78. A compound according to any one of claims 54 to 76, or a pharmaceutically acceptable salt thereof, wherein b is 1.

79. A compound according to any one of claims 54 to 78, or a pharmaceutically acceptable salt thereof, wherein c is 0.

80. The compound of any one of claims 54 to 78, or a pharmaceutically acceptable salt thereof, wherein c is 1.

81. A compound according to any one of claims 54 to 80, or a pharmaceutically acceptable salt thereof, wherein d is 0.

82. A compound according to any one of claims 54 to 80, or a pharmaceutically acceptable salt thereof, wherein d is 1.

83. A compound according to any one of claims 54 to 82, or a pharmaceutically acceptable salt thereof, wherein e is 0.

84. A compound according to any one of claims 54 to 82, or a pharmaceutically acceptable salt thereof, wherein e is 1.

85. A compound according to any one of claims 54 to 84, or a pharmaceutically acceptable salt thereof, wherein f is 0.

86. A compound according to any one of claims 54 to 84, or a pharmaceutically acceptable salt thereof, wherein f is 1.

87. A compound according to any one of claims 54 to 86, or a pharmaceutically acceptable salt thereof, wherein g is 0.

88. A compound according to any one of claims 54 to 86, or a pharmaceutically acceptable salt thereof, wherein g is 1.

89. A compound according to any one of claims 54 to 88, or a pharmaceutically acceptable salt thereof, wherein R G For H.

90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is an E3 ubiquitin ligase binding moiety that binds to the cerebellum.

91. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

92. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

93. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

94. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is:

95. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

96. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

97. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

98. A compound according to any one of claims 1 to 97, wherein the compound has Formula II: or a pharmaceutically acceptable salt thereof.

99. A compound according to any one of claims 1 to 97, wherein the compound has formula III: or a pharmaceutically acceptable salt thereof.

100. The compound according to any one of claims 1 to 3, wherein the compound is selected from the following: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-4-((9-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-9-oxononyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)propyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione; N-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 3-(4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 1-(4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione; 3-(5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione; 3-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione; 5-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-en-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; 3-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-yl)amino)phenyl)piperidine-2,6-dione; 3-((4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutyl)methoxy)phenyl)amino)piperidine-2,6-dione; 3-({4-[3-({4-[({5-fluoro-2-[(oxan-4-ylsulfanyl)methyl]-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}methyl)cyclobutyloxy]phenyl}amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; and 1-(3-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; Or a pharmaceutically acceptable salt of any of the foregoing substances.

101. A compound according to any one of claims 1 to 3, wherein the compound is selected from the following: 3-((4-(4-(2-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclobutyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 7-(((1s,3s)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((1r,3r)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-3-(4-methoxybenzyl)-7-((1-(2-(4-nitrophenoxy)ethyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (S)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; (R)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; 3-((3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione; 3-((3-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione; 1-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)ethynyl)isoindoline-1,3-dione; 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(((3aR,5r,6aS)-2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione; 1-(4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)isoindoline-1,3-dione; 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)methyl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)methyl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione; 3-((4-(4-(4-(2-(5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((1-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; and 3-((4-(3-((4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione, Or a pharmaceutically acceptable salt of any of the foregoing substances.

102. The compound according to claim 1 or 2, wherein the compound is selected from: 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)isoindolin-5-yl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)benzamide; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)amino)phenyl)amino)piperidine-2,6-dione; 3-((4-(8-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-((4-fluoro-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclobutylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyloxy)phenyl)amino)piperidine-2,6-dione; 3-((4-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclohexyl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)piperidine-2,6-dione; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)(methyl)amino)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)phenyl)amino)piperidine-2,6-dione; 3-((4-(5-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-3-yl)phenyl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxamide; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-chloro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((2,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-chloro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)(methyl)amino)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-[1,3'-diazetidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; and N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)benzamide, Or a pharmaceutically acceptable salt of any of the foregoing substances.

103. The compound of claim 1, wherein the compound is selected from: 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)amino)phenyl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)benzamide; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 1-(3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrrolidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1'-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)isoindoline-1,3-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(3-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-({4-[4-(2-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl)piperazin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione; 3-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (3S)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide; (3R)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide; N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidine-4-carboxamide; N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-N-methylpiperidine-4-carboxamide; 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((3-fluoro-4-(4-(2-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((3-fluoro-4-(4-((1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-2-oxo-[1,4':1',4"-terpiperidinyl]-1"-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(9-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2,5-difluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(6-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-2-azaspiro[3.3]hept-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4':1',4"-terpiperidinyl]-1"-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidinyl]-1'-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3-oxopiperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-({4-[4-(3-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}azetidin-1-yl)piperidin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione, Or a pharmaceutically acceptable salt of any of the foregoing substances.

104. A pharmaceutical composition comprising a compound according to any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

105. A method for degrading PARP14, the method comprising contacting the compound according to any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof, with the PARP14.

106. A method of treating cancer in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof.

107. A method of treating cancer in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof, in combination with an additional therapy or therapeutic agent.

108. The method of claim 106 or 107, wherein the cancer is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer, or melanoma.

109. A method of treating an inflammatory disease in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof.

110. The method of claim 109, wherein the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloids, eosinophilic disorders, pulmonary fibrosis, and type 2 cytokine pathology.

111. The method of claim 109, wherein the inflammatory disease is atopic dermatitis.

112. The method of claim 109, wherein the inflammatory disease is systemic sclerosis.

113. The method of claim 110, wherein the asthma is steroid-insensitive asthma, steroid-refractory asthma, steroid-resistant asthma, atopic asthma, nonspecific asthma, persistent asthma, severe asthma, or steroid-refractory severe asthma.

114. The method of claim 113, wherein the severe asthma is T2 high endotype, T2 low endotype, or non-T2 endotype.

115. The method of claim 113, wherein the severe asthma is T2 low endotype or non-T2 endotype.

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