Targeted protein degradation of PARP14 used in therapy

Abstract

The present invention relates to compounds of formula I that 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 a variety of 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 others are in late-stage development (Ohmoto A et al., OncoTargets and Therapy., 2017; Vol. 10: 5195).

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

[0004] PARP14 is both a cytoplasmic single ART and a 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 at the same genomic locus, indicating the presence of co-regulation. In fact, the 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 are as follows: 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 survival of B cells 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] PARP14 has been implicated in T helper cell and macrophage differentiation due to its role downstream of IL-4 and IFN-γ signaling pathways. Genetic PARP14 inactivation in macrophages favors the formation of 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 increased the expression of M1 genes downstream of IFN-γ, while reducing the expression of M2 genes downstream of IL-4. Similarly, studies have shown that genetic PARP14 knockout reduces the Th2T helper cell phenotype in the context of skin and airway inflammation, which in turn 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 ubiquitination of 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 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, which method comprises 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 Example 17.

[0020] Figure 2A It is a graph demonstrating that compound 17 significantly reduced eosinophils in BALF in a dose-dependent manner starting from 100 mg / kg.

[0021] Figure 2B It is a graph demonstrating that compound 17 significantly reduced the cytokine IL-33 in BALF in a dose-dependent manner starting from 100 mg / kg.

[0022] Figure 2C It is a graph demonstrating that compound 17 significantly reduced cytokine IL-4 in BALF in a dose-dependent manner starting from 100 mg / kg.

[0023] Figure 2D It is a graph demonstrating that compound 17 significantly reduced 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 -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 3 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;

[0038] 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;

[0039] Each R A 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, 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 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-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 Haloalkyl, 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 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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 ;

[0041] R W , R X and R Z are independently selected from H, halo, C1-6 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, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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 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 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 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 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 ;

[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 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 ;

[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 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, 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 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 ;

[0047] 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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;

[0054] L 1 Select from the following:

[0055] (i) a bond such that ring A is directly attached to moiety E;

[0056] (ii)-(C 1-4 alkyl)-;

[0057] (iii)-(C 2-4 alkenyl)-;

[0058] (iv)-(C 2-4 Alkynyl)-;

[0059] (v) The following structure:

[0060]

[0061] (vi) The following structure:

[0062]

[0063] 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 -;

[0064] G 2 C 6- 10Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl;

[0065] 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 -;

[0066] G 4 is a 4- to 10-membered heterocycloalkyl group;

[0067] Each R G independently selected from H, methyl and ethyl;

[0068] a is 0 or 1;

[0069] b is 0 or 1;

[0070] c is 0 or 1;

[0071] d is 0 or 1;

[0072] e is 0 or 1;

[0073] f is 0 or 1;

[0074] wherein at least one of b, c, e and f is 1; and

[0075] 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;

[0076] 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

[0077] 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.

[0078] In some embodiments, the compound is not:

[0079] 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide;

[0080] (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetylamino)heptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0081] 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and

[0082] 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide.

[0083] The present disclosure provides, inter alia, compounds of formula (I):

[0084]

[0085] or a pharmaceutically acceptable salt thereof, wherein:

[0086] W is CR W or N;

[0087] X is CR X or N;

[0088] Z is CRZ or N; and

[0089] Among them, at most two of W, X and Z are N at the same time;

[0090] Y 1 Selected from NR 3 , CR 4 R 5 and O;

[0091] 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-;

[0092] Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-14 cycloalkyl and 3 to 18 membered heterocycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace;

[0093] 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;

[0094] R 1 and R 2 are each independently selected from H and methyl;

[0095] R 3 Selected from H and C 1-4 alkyl;

[0096] 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;

[0097] 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;

[0098] Each R A 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, C2-6 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 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 b1and S(O)2NR c1 R d1 ;

[0099] 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)2NRc2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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)Rb2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0100] 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 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, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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 NRc3 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 ;

[0101] 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)Rb1 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 ;

[0102] 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 NRc2 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 ;

[0103] 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)2Rb3 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 ;

[0104] 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-C1-4 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 ;

[0105] 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, C1-6 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 ;

[0106] 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4Alkyl, 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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;

[0107] 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)2Rb4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0108] 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 ;

[0109] or R c3 and R d3Together 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 ;

[0110] Each R e1 , R e2 , R e3 and R e4 Independently selected from H, C 1-4 Alkyl and CN;

[0111] m is 0, 1 or 2;

[0112] E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase;

[0113] L 1 Select from the following:

[0114] (i) a bond such that ring A is directly attached to moiety E;

[0115] (ii)-(C 1-4 alkyl)-;

[0116] (iii)-(C 2-4 alkenyl)-;

[0117] (iv)-(C 2-4 Alkynyl)-;

[0118] (v) The following structure:

[0119]

[0120] (vi) The following structure:

[0121]

[0122] 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 -;

[0123] G 2 C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl;

[0124] 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 -;

[0125] G 4 is a 4- to 10-membered heterocycloalkyl group;

[0126] Each R G independently selected from H, methyl and ethyl;

[0127] a is 0 or 1;

[0128] b is 0 or 1;

[0129] c is 0 or 1;

[0130] d is 0 or 1;

[0131] e is 0 or 1;

[0132] f is 0 or 1;

[0133] wherein at least one of b, c, e and f is 1; and

[0134] 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;

[0135] 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

[0136] 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.

[0137] In some embodiments, the compound is not:

[0138] 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide;

[0139] (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetylamino)heptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0140] 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and

[0141] 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide.

[0142] In some embodiments, W is CR WIn some embodiments, W is N.

[0143] In some embodiments, X is CR X In some embodiments, X is N.

[0144] In some embodiments, Z is CR Z In some embodiments, Z is N.

[0145] In some embodiments, Y 1 In some embodiments, Y 1 For-CR 4 R 5 -. In some embodiments, Y 1 For-NR 3 -. In some embodiments, Y 1 -O- or -NR 3 -.

[0146] In some embodiments, Y 1 For-(C 2-4 In some embodiments, Y 1 In some embodiments, Y 1 For-CR 4 R 5 -or-(C 2-4 In some embodiments, Y 1 For-CR 4 R 5 -or -(C2 alkynyl)-.

[0147] In some embodiments, Y 2 is S. In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 2 is 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 For -O-.

[0148] In some embodiments, 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.

[0149] 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 A In some embodiments, Ring A is a 4- to 7-membered heterocycloalkyl group, wherein Ring A is optionally substituted by 1 or 2 R A In some embodiments, Ring A is a 4- to 7-membered heterocycloalkyl.

[0150] 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 R A In some embodiments, ring A is piperidinyl. In some embodiments, ring A is optionally substituted with R A Substituted piperazinyl.

[0151] In some embodiments, Ring A is 1-methylpiperidin-4-yl.

[0152] In some embodiments, Ring A is piperazinyl.

[0153] 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 C 3-7 Cycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A In some embodiments, Ring A is cyclohexyl.

[0154] 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 by 1, 2, 3, or 4 R B replace.

[0155] 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 by 1 or 2 R B replace.

[0156] In some embodiments, Ring B is C 3-7 In some embodiments, ring B is cyclopentyl or cyclopropyl. In some embodiments, ring B is cyclopentyl. In some embodiments, ring B is cyclopropyl.

[0157] 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 B In some embodiments, ring B is each optionally substituted by R B Substituted piperidinyl or tetrahydro-2H-pyranyl.

[0158] 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 B In some embodiments, ring B is substituted with R B Substituted piperidinyl.

[0159] 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 B Substituted tetrahydro-2H-pyranyl. In some embodiments, Ring B is tetrahydro-2H-pyranyl.

[0160] In some embodiments, Ring B is tetrahydro-2H-pyran-4-yl or 1-acetylpiperidin-4-yl. In some embodiments, Ring B is 1-acetylpiperidin-4-yl.

[0161] In some embodiments, Ring B is piperidinyl, tetrahydro-2H-pyranyl, cyclopentyl or cyclobutyl, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B In some embodiments, ring B is piperidinyl, tetrahydro-2H-pyranyl, cyclopentyl or cyclobutyl, wherein ring B is optionally substituted by 1 or 2 R B In some embodiments, ring B is piperidinyl, tetrahydro-2H-pyranyl, cyclopentyl or cyclobutyl, wherein ring B is optionally substituted by R B In some embodiments, Ring B is tetrahydro-2H-pyran-4-yl, 1-acetylpiperidin-4-yl, cyclobutyl, or cyclopentyl.

[0162] In some embodiments, R 1 and R 2 Each is H. In some embodiments, R 1is H. In some embodiments, R 2 For H.

[0163] In some embodiments, R 3 For H.

[0164] 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.

[0165] 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.

[0166] 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 c1S(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 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)2Rb1 and S(O)2NR c1 R d1 .

[0167] 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 .

[0168] In some embodiments, each R A independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated 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 .

[0169] In some embodiments, each R A independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 It is methyl.

[0170] 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 The haloalkyl 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 Rd2 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 .

[0171] 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 Rd2 、S(O)2R b2 and S(O)2NR c2 R d2 .

[0172] 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 .

[0173] In some embodiments, each R B independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO2, C(O)R b2 OR a2 In some embodiments, each R B independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C(O)R b2 In some embodiments, each R B are independently selected from C(O)R b2 In some embodiments, each R B Independently selected from C(O)CH3.

[0174] In some embodiments, 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 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 ; 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)2R b3 and S(O)2NR c3 R d3 .

[0175] 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 Rd3 、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 .

[0176] In some embodiments, 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 In some embodiments, R W is selected from H, halo and C 1-6 In some embodiments, R W is H or F. In some embodiments, R W is F. In some embodiments, R W For H.

[0177] 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 NRc3 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 .

[0178] In some embodiments, 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 .

[0179] 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 For H.

[0180] In some embodiments, R Z Selected from H, halo, C 1-6 Alkyl, C2-6 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 .

[0181] 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 .

[0182] 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 Z For H.

[0183] 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.

[0184] In some embodiments, L 1 is a bond such that ring A is directly connected to moiety E.

[0185] In some embodiments, L 1 For-(C 1-4 alkyl)-.

[0186] In some embodiments, L 1 For-(C 2-4 alkenyl)-.

[0187] In some embodiments, L 1 For-(C 2-4 Alkynyl)-.

[0188] In some embodiments, L 1 For-(C 2-4 Alkynyl)-(G 3 )-.

[0189] In some embodiments, L 1 Has the following structure:

[0190]

[0191] In some embodiments, L 1 Has the following structure:

[0192]

[0193] In some embodiments, L 1 for

[0194]

[0195] In some embodiments, G 1 For-NR GC(O)- or -C(O)-. In some embodiments, G 1 For-NR G C(O)-. In some embodiments, G 1 In some embodiments, G 1 For-NR G C(O)-, -C(O)-, or -O-. In some embodiments, G1 is -O-.

[0196] In some embodiments, G 2 is a 4- to 10-membered heterocycloalkyl. 2 is piperidinyl, piperazinyl or azetidinyl. In some embodiments, G 2 is piperidinyl or piperazinyl. In some embodiments, G 2 In some embodiments, G 2 In some embodiments, G 2 In some embodiments, G 2 is pyrrolidinyl, piperidinyl, piperazinyl or azetidinyl. In some embodiments, G 2 It is pyrrolidyl.

[0197] In some embodiments, G 2 C 3-7 In some embodiments, G 2 It is cyclobutyl.

[0198] In some embodiments, G 3 For-NR G C(O)-、-NR G - or -C(O)-. In some embodiments, G 3 For-NR G Or -O-. In some embodiments, G 3 For-NR G -. In some embodiments, G 3 For -O-.

[0199] In some embodiments, G 4 is piperidinyl or piperazinyl. In some embodiments, G 4 In some embodiments, G 4 It is piperazinyl.

[0200] In some embodiments, a is 0. In some embodiments, a is 1.

[0201] In some embodiments, b is 0. In some embodiments, b is 1.

[0202] In some embodiments, c is 0. In some embodiments, c is 1.

[0203] In some embodiments, d is 0. In some embodiments, d is 1.

[0204] In some embodiments, e is 0. In some embodiments, e is 1.

[0205] In some embodiments, f is 0. In some embodiments, f is 1.

[0206] In some embodiments, g is 0. In some embodiments, g is 1.

[0207] In some embodiments, R G For H.

[0208] 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.

[0209] In some embodiments, E is a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding portion, an MDM2 E3 ubiquitin ligase binding portion, a cerebellar 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. 50 For 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 a MDM2 E3 ubiquitin ligase binding portion. E can be an IAP E3 ubiquitin ligase binding portion.

[0210] In some embodiments, E is an E3 ubiquitin ligase binding moiety that binds to cerebellum.

[0211] In some embodiments, E comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide.

[0212] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, their analogs, their isosteres, or their derivatives.

[0213] In some embodiments, E is selected from the following:

[0214]

[0215]

[0216] The wavy line indicates the group L 1 connection point.

[0217] In some embodiments, E is selected from:

[0218]

[0219] The wavy line indicates the group L 1 connection point.

[0220] In some embodiments, E is:

[0221]

[0222] The wavy line indicates the group L 1 connection point.

[0223] In some embodiments, E is selected from the following:

[0224]

[0225]

[0226] The wavy line indicates the group L 1 connection point.

[0227] In some embodiments, the compound has Formula II:

[0228]

[0229] or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the compound has Formula IIIa:

[0231]

[0232] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the compound has Formula IIIb:

[0234]

[0235] or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the compound has Formula IIIc:

[0237]

[0238] or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compound is selected from the group consisting of:

[0240] 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0241] 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0242] 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(6-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)hexyl)benzamide;

[0243] 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)butyl)benzamide;

[0244] N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0245] N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0246] N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0247] N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0248] N-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0249] N-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0250] N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0251] N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0252] N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0253] N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0254] N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0255] N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide;

[0256] 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione;

[0257] 3-(3-(4-(1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-2-oxoimidazolidin-1-yl)piperidine-2,6-dione;

[0258] 4-(4-((1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0259] 1-(4-(1-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0260] 4-((2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0261] 4-(4-((4-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0262] 4-(4-((4-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0263] 5-((2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0264] 3-((4-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione;

[0265] 4-(4-((4-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0266] 4-(4-((1-(2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0267] 5-(4-((1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0268] 5-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0269] 5-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0270] 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide;

[0271] 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide;

[0272] 5-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0273] 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0274] 3-(4-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)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;

[0275] 3-(5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)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;

[0276] 1-(4-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0277] 1-(3-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0278] 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

[0279] 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and

[0280] 5-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; or a pharmaceutically acceptable salt of any one of the foregoing.

[0281] In some embodiments, the compound is selected from:

[0282] 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0283] 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0284] 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0285] 3-((4-(4-(2-(4-((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0286] 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0287] 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0288] 3-((4-(4-(3-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0289] 3-(6-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione;

[0290] 3-(5-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0291] 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione;

[0292] 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione;

[0293] 3-((4-(4-((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0294] 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0295] 3-((4-(4-(2-(((1r,4r)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0296] 3-((4-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0297] 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione;

[0298] 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione;

[0299] 3-((4-(3-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)pyrrolidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione;

[0300] 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione;

[0301] 1-(6-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0302] 1-(8-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0303] 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0304] 3-((4-(1'-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[4,4'-bipiperidinyl]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0305] 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0306] 3-((4-(3-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0307] 3-((4-(4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0308] Or a pharmaceutically acceptable salt of any of the foregoing substances.

[0309] 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. On the contrary, for brevity, the various features of the present invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0310] At various places in this specification, substituents of compounds of the invention are disclosed in the form of 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.

[0311] Various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described in various places of this specification. 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 (pyridinyl / pyridyl)" or "pyridine ring" can refer to pyridin-2-yl, pyridin-3-yl or pyridin-4-yl rings.

[0312] 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, pyridinyl 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.

[0313] At various places in this specification, variables defining a divalent linking group may be described. It is specifically intended that each linking substituent includes 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 the "alkyl" or "aryl" refers to a linking alkylene group or arylene group, respectively.

[0314] For compounds of the invention in which a variable occurs more than once, each variable may be a different portion of a group independently selected to define the variable. For example, when describing a structure with two R groups present simultaneously on the same compound, the two R groups may represent different portions of a group independently selected to define R.

[0315] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0316] 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 valency.

[0317] 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.

[0318] 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.

[0319] 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, etc.

[0320] 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.

[0321] As used herein, "halo" or "halogen," used alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0322] 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 CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc.

[0323] As used herein, the term "alkoxy" used alone or in combination with other terms refers to a group of formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0324] 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.

[0325] As used herein, "amino," employed alone or in combination with other terms, refers to NH2.

[0326] As used herein, the term "alkylamino" used alone or in combination with other terms refers to a group of 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), etc.

[0327] As used herein, the term "dialkylamino" used alone or in combination with other terms refers to a group of formula -N(alkyl)2. 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.

[0328] As used herein, the term "cycloalkyl" used alone or in combination with other terms refers to non-aromatic cyclic hydrocarbons including alkyl and alkenyl groups of cyclization.Cycloalkyl groups may include monocyclic or polycyclic (e.g., 2, 3 or 4 fused rings, bridged rings or spiro) 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., having a common key) to a cycloalkyl ring, such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, or pyrido derivatives of cyclopentane or cyclohexane.The ring-forming carbon atoms of the cycloalkyl group may be optionally substituted by oxo groups.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, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0329] 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 atom. In some embodiments, the alkyl moiety is methylene. 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.

[0330] 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 spiro heterocycloalkyl 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]decane-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 bonds), or the nitrogen atom may be quaternized. 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, an azetidine ring or a tetrahydrofuran ring.

[0331] 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 moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the heterocycloalkyl moiety 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 moiety is monocyclic. In some embodiments, the heterocycloalkyl moiety is C 2-7 A monocyclic heterocycloalkyl group.

[0332] 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.

[0333] 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 atom. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the aryl moiety is a phenyl group. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is a benzyl group.

[0334] As used herein, the term "heteroaryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen, monocyclic or polycyclic (e.g., fused ring system). 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, quinolyl, isoquinolyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. The 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 bond), 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-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0335] 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.

[0336] The compounds described herein may be asymmetric (e.g., have 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 olefins, 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. The cis and trans geometric isomers of the compounds of the present invention can be separated as a mixture of isomers or as individual isomeric forms.

[0337] Compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of single bonds with adjacent double bonds 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 heterocyclic ring systems, 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 locked into one form in space.

[0338] Compounds of the present invention also include all isotopes of atoms present in 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, compounds of the present invention include at least one deuterium atom.

[0339] Unless otherwise stated, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

[0340] 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.

[0341] 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 the compound is formed or detected. Partial separation can include, for example, a composition rich in the compounds of the present invention. Substantially separating 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 separating compounds and their salts are conventional in the art.

[0342] 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 the activity of PARP14, wherein DC 50 Less than 1 μM in an enzyme assay (see, eg, Example A).

[0343] 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.

[0344] The phrase "pharmaceutically acceptable" as used herein 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 problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0345] 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 the acid or base moiety present into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic 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 a parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or 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.

[0346] synthesis

[0347] 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.

[0348] The reaction of preparing the compounds of this invention can be carried out in a suitable solvent, and the technician in the field of organic synthesis can easily select these suitable solvents. Suitable solvents can be substantially not reacted with raw materials (reactants), intermediates or products at a temperature for reacting, and the temperature can be, for example, in the range of the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or in a mixture of more than one solvent. According to specific reactions steps, those skilled in the art can select a suitable solvent for specific reactions steps.

[0349] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The demand 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.

[0350] 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.

[0351] The compounds of the present invention can be prepared according to a variety of preparation routes known in the literature. Exemplary synthetic methods for preparing compounds of the present invention are provided in the following schemes.

[0352] Solution 1

[0353]

[0354] Scheme 1 shows the general synthesis of quinazolinone compounds of the present disclosure. Formula (1-A) compounds (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) compounds (many of which are known in the art and described in, for example, U.S. Patent No. 10,562,891). The coupling can be carried out under Pd coupling conditions (for example, in the presence of Pd reagents such as [Pd(allyl)Cl]2), and obtain formula (1-C) compounds.

[0355] Solution 2

[0356]

[0357] Scheme 2 shows a general synthesis of certain compounds of the invention. Compounds of formula (2-A) can be prepared according to the pathway provided in Scheme 1 or according to the methods disclosed in, for example, U.S. Patent No. 10,562,891. The N atom of the A ring of the compound of formula (2-A) can be treated with tert-butyl 2-bromoacetate to obtain a compound of formula (2-B). The compound of formula (2-B) can be treated with an acid (e.g., trifluoroacetic acid) to obtain a compound of formula (2-C). The compound of formula (2-C) can be coupled with a compound of formula (2-D) wherein the group L 2 refers to the linker moiety L as defined herein1 The internal part of the formula (2-D) compound is commercially available and is also known in the art. The coupling of the formula (2-C) and the formula (2-D) compound can be carried out under peptide coupling conditions (e.g., EDCI, HOBt and DIPEA; or HATU, DIPEA) to obtain the formula (2-E) compound. The "-CH2-C(O)-L 2 The "-" group corresponds to L as defined herein. 1 Group.

[0358] Solution 3

[0359]

[0360] Scheme 3 shows the general synthesis of certain compounds of the present invention. Compounds of formula (3-A) can be prepared according to the pathway provided in Scheme 1. 2 refers to the linker moiety L as defined herein 1 The internal portion of the compound of formula (3-B) can be oxidized (e.g., with Dess-Martin periodinane) to provide an aldehyde intermediate in situ (not shown). The resulting reaction mixture is treated with a compound of formula (3-A) and then with a hydride reducing agent (e.g., NaBH(OAc)3) to provide a compound of formula (3-C). The "-CH2-L 2 The "-" group corresponds to L as defined herein. 1 Group.

[0361] How to use

[0362] 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 includes contacting the cells with the compound, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, provided herein is a method for degrading PARP14 in a patient, wherein the method includes 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 down PARP14 into multiple peptides or amino acid fragments.

[0363] 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).

[0364] Other cancers that may be treated by administration of 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, gastric 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.

[0365] 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.

[0366] The compounds of the 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.

[0367] In some embodiments, the compounds of the present invention can be used to treat inflammatory diseases. It has been 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)) protects 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), inhibits the infiltration of immune cells such as eosinophils and neutrophils into the lungs, and reduces 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 inhalation of an 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).

[0368] 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 main producers of downstream cytokines (e.g., IL-4, IL-5, and IL-13).

[0369] 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.

[0370] The present invention particularly relates to a method for treating or preventing an inflammatory disease in a patient, the method 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 that can be treated 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.

[0371] Other exemplary inflammatory diseases that can be treated 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.

[0372] In some embodiments, the inflammatory disease is irritable bowel syndrome.

[0373] Eosinophilic disorders that can be treated 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.

[0374] 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.

[0375] In some embodiments, 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. 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.

[0376] 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.

[0377] The present invention also relates particularly to methods of treating or preventing chronic obstructive pulmonary disease (COPD), emphysema and chronic bronchitis.

[0378] The present invention also relates particularly to methods of treating or preventing inflammatory diseases of the skin such as atopic dermatitis or rosacea.

[0379] The present invention also provides a method of achieving the following in a patient:

[0380] (a) reduce the level of airway mucus in lung tissue,

[0381] (b) reduce serum IgE,

[0382] (c) reduce immune cell infiltration and activation in bronchoalveolar fluid,

[0383] (d) reducing the level of one or more inflammatory cytokines in bronchoalveolar fluid or lung tissue, or

[0384] (e) reducing the level of one or more alarmins in bronchoalveolar fluid or lung tissue,

[0385] The method comprises administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0386] In some embodiments, the invention provides methods of reducing airway mucus levels in lung tissue of a patient.

[0387] In some embodiments, the present invention provides a method of 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.

[0388] In some embodiments, the present invention provides a method of reducing one or more inflammatory cytokines in the 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.

[0389] In some embodiments, the present invention provides a method of reducing an alarmin in bronchoalveolar fluid or lung tissue of a patient. In some embodiments, the alarmin is IL-25, IL-33, or TSLP.

[0390] 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 part of a tissue sample excised 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.

[0391] 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, having PARP14, and, for example, introducing the compound of the present invention into a sample containing cells or a purified preparation containing PARP14.

[0392] As used herein, the terms "subject" or "patient" are used interchangeably to refer to a mammal, particularly a human.

[0393] 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.

[0394] As used herein, the term "treating" refers to 1) inhibiting a disease in a subject who is experiencing or exhibiting 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 pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms).

[0395] As used herein, the term "preventing" is the prevention of a disease in an individual who may be susceptible to the disease but who does not yet experience or display the pathology or symptoms of the disease.

[0396] As used herein, the term "reduction" is relative to the level of the patient 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.

[0397] Combination therapy

[0398] One or more additional agents or treatment methods 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 kinases (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.

[0399] Suitable agents for treating cancer in combination with the compounds of the present invention include chemotherapeutic agents, targeted cancer therapy, 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), progesterone (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 leuprolide, goserelin, triptorelin and histrelin), LHRH antagonists (such as degarelix), androgen receptor blockers (such as enzalutamide) and agents (such as abiraterone) that inhibit androgen production.

[0400] Combinations of 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.

[0401] 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, triethylene-melamine, triethylenethio-phosphamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide.

[0402] Other anticancer agents include antibody therapeutics against co-stimulatory 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.

[0403] The safe and effective application methods of most of these chemotherapeutics are known to those skilled in the art. In addition, the use of these chemotherapeutics is described in standard documents. For example, the use of many chemotherapeutics is described in "Physicians' Desk Reference" (PDR, for example, 1996 edition, Medical Economics, Inc., Montville, New Jersey), the disclosure of which is incorporated herein by reference, as if its entirety were set forth.

[0404] Suitable agents for use in combination with the compounds of the 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., avolimumab); T cell modulators (e.g., rigerimod); abatacept; anticoagulants (e.g., heparin, warfarin); and vitamin D supplements.

[0405] 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.

[0406] 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, tromborumab, leblikizumab, etanercept, golimumab, budalumab, and tezetuzumab.

[0407] Drug preparations and dosage forms

[0408] When used as a drug, 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 known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. 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.

[0409] The present invention also includes pharmaceutical compositions containing one or more of the above-mentioned compounds of the present invention as active ingredients in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient or encapsulated in a carrier in the form of, for example, a capsule, a sachet, 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. Therefore, 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 active compounds, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0410] These compositions may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit 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.

[0411] The active compound can be effective within a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered is generally determined by a 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.

[0412] 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 unit dosage forms of the above type, which contain, for example, 0.1 mg to about 500 mg of the active ingredient of the present invention.

[0413] Tablets or pills of the present invention can be coated or otherwise compounded to obtain dosage forms with the advantage of prolonged action. For example, tablets or pills can comprise inner dosage components and outer dosage components, the latter covering the former in the form of a film coating. These two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. Various materials can be used for such enteric layers or coatings, and such materials include a mixture of multiple polymeric acids and polymeric acids and such materials such as shellac, cetyl alcohol and cellulose acetate.

[0414] Liquid forms into which the compounds and compositions of the invention may be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oil suspensions and flavored emulsions containing edible oils (such as cottonseed oil, sesame oil, coconut oil or peanut oil), as well as elixirs and similar pharmaceutically acceptable vehicles.

[0415] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, these compositions are administered by oral or nasal respiratory route to obtain local or systemic effects. The compositions may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be connected to a mask tent or an intermittent pressurized ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device for delivering the formulation in an appropriate manner.

[0416] The amount of the compound or composition administered to the patient will vary depending on the substance being administered, the purpose of the administration (such as prevention or treatment), the patient's state, the mode of administration, etc. 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.

[0417] The composition can be administered to a patient in the form of the above-mentioned pharmaceutical composition. These compositions can be sterilized by conventional sterilization techniques, or can be aseptically filtered. The aqueous solution can be packaged for use as is, or used after lyophilization, and the lyophilized preparation is mixed with a sterile aqueous carrier before administration.

[0418] The therapeutic dose of the compounds of the present invention may 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 may 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 may be provided in an aqueous physiological buffer solution 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 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / 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 extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0419] 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.

[0420] Example

[0421] Equipment: Recorded at 300MHz or 400MHz using AVANCE 300MHz / 400MHz spectrometer 1H NMR spectra. NMR interpretation was performed using Bruker Topspin software to assign chemical shifts and multiplicities. In cases where two adjacent peaks of equal or unequal heights were observed, the two peaks could be labeled as a multiplet or doublet. In the case of a doublet, coupling constants could be assigned using the software. In any given example, one or more protons may not be observed due to obscuration by water and / or solvent peaks. The LCMS equipment and conditions were as follows:

[0422] 1.LC (alkaline conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-packscepter C1833×3.0 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. Schedule:

[0423] T(minutes) A(％) B(％) 0.01 90 10 1.20 5 95 1.80 5 95 1.82 90 10

[0424] 2.LC (alkaline conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-packscepter C1833×3.0 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. Schedule:

[0425] T(minutes) A(％) B(％) 0.01 90 10 1.20 5 95 1.80 5 95 1.82 90 10

[0426] 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. Detector: 190 nm to 400 nm. Gradient stop time, 2.0 min. Schedule:

[0427] T(minutes) A(％) B(％) 0.01 90 5 1.20 5 100 1.80 5 100 1.82 90 5

[0428] 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. Detector: 190 nm to 400 nm. Gradient stop time, 3.0 min. Schedule:

[0429] T(minutes) A(％) B(％) 0.01 90 5 1.20 5 100 1.80 5 100 1.82 90 5

[0430] 5. The MS detector was configured with electrospray ionization as an ionizable source. Acquisition mode: scan; nebulizer gas flow: 1.5 L / min; dry gas flow: 15 L / min; detector voltage: 0.95 kv to 1.25 kv; DL temperature: 250°C; heating block temperature: 250°C; scan range: 90.00 m / z to 900.00 m / z.

[0431] 6. Sample preparation: Dissolve the sample in ACN or methanol at 1 mg / mL to 10 mg / mL, and then filter through a 0.22 μm filter membrane. Injection volume: 1 μL to 3 μL.

[0432] definition :

[0433] ACN (acetonitrile); AcOH (acetic acid); B2(OH)4 (tetrahydroxydiboron); Boc2O (di-tert-butyl dicarbonate); t-BuOK (potassium tert-butoxide); t-BuONa (sodium tert-butoxide); Cs2CO3 (cesium carbonate); CH3CN (acetonitrile); CuI (copper (I) iodide); DCM (dichloromethane); DIEA (N,N-diisopropylethylamine); DMA (N,N-dimethylacetamide); DMF (N,N-dimethylformamide); DMAP (4-dimethylaminopyridine); DMP (Dess-Martin periodinane); DMSO (dimethyl sulfoxide); D MSO-d6 (deuterated dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); equiv (equivalent); ESI (electrospray ionization); EtOAc (ethyl acetate); Et2O (diethyl ether); EtOH (ethanol); FA (formic acid); Fe (iron); FeCl3 (iron (III) chloride); FeCl3.6H2O (iron (III) chloride hexahydrate); g (gram); h (hour); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide); 1HNMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); HOBT (1-hydroxybenzotriazole); Hz (hertz); K2CO3 (potassium carbonate); KI (potassium iodide); KOH (potassium hydroxide); K3PO4 (tripotassium phosphate); L (liter); LCMS (liquid chromatography-mass spectrometry); M (mole); MeCN (acetonitrile); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter), mmol (millimole); NaBH3CN (sodium cyanoborohydride); NaBH( OAc)3 (sodium triacetoxyborohydride); Na2CO3 (sodium carbonate); NaH (sodium hydride); NH4Cl (ammonium chloride); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); Na2SO4 (sodium sulfate); (NH4)HCO3 (ammonium bicarbonate); nm (nano), NMP (N-methylpyrrolidone); PBS (phosphate buffered saline); Pd / C (palladium / carbon); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)); Pd-PEPPSI-IPentCl 2-Methylpyridine (o-methylpyridine) ((SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium); Pd(PPh3)2Cl2 (trans-dichlorobis(triphenylphosphine)palladium(II)); PE (petroleum ether); preparative HPLC (preparative high performance liquid chromatography); ppm (million fraction); STAB (sodium triacetoxyborohydride); TBAB (tetrabutylammonium bromide); TBAF (tetrabutylammonium fluoride); TBHP (tert-butyl hydroperoxide); TEA (triethylamine); TFA (trifluoroacetic acid); TfOH (trifluoromethanesulfonic acid); THF (tetrahydrofuran); RT (retention time); UV (ultraviolet light); Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl).

[0434] Intermediate A1: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole Synthesis of 1,3-Phenyline-Dione

[0435]

[0436] Step A

[0437] 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] + .

[0438] Step B

[0439] A solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (4.2 g, 7.8 mmol, 1.0 equiv) in TFA (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 aqueous Na2CO3. 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)isoindolin-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] + .

[0440] Intermediates A1-a to A1-e were synthesized according to the process described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazine-1-yl)isoindoline-1,3-dione using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0441]

[0442]

[0443] Intermediate A2: N-(6-aminohexyl)-3-(2,4-dioxo-1,3-diazin-1-yl)benzamide hydrochloride synthesis

[0444]

[0445] Step A

[0446] To a solution of 3-(2,4-dioxo-1,3-diazin-1-yl)benzoic acid (170 mg, 0.72 mmol, 1.0 eq) and tert-butyl N-(6-aminohexyl)carbamate (157 mg, 0.72 mmol, 1.0 eq) in DMF (2 mL) was added DIEA (281 mg, 2.18 mmol, 3.0 eq) and HATU (414 mg, 1.09 mmol, 1.5 eq). The resulting mixture was stirred for 1 hour. The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient 0% to 40% in 20 minutes; detector: UV 254 nm to give tert-butyl N-(6-{[3-(2,4-dioxo-1,3-diazin-1-yl)phenyl]formamido}hexyl)carbamate (256 mg, 82% yield) as a white solid. LCMS (ESI, m / z): 433.24 [M+H] + .

[0447] Step B

[0448] A solution of tert-butyl N-(6-{[3-(2,4-dioxo-1,3-diazin-1-yl)phenyl]formamido}hexyl)carbamate (100 mg, 0.23 mmol, 1.0 equiv) and 1,4-dioxane (1 mL, 4M) in HCl in 1,4-dioxane (1 mL) was stirred for 2 hours. The resulting mixture was concentrated in vacuo to give N-(6-aminohexyl)-3-(2,4-dioxo-1,3-diazin-1-yl)benzamide (71 mg, 92% yield) as a white solid. LCMS (ESI, m / z): 333.18 [M+H] + .

[0449] Intermediate A2-a was synthesized according to the process described for the synthesis of N-(6-aminohexyl)-3-(2,4-dioxo-1,3-diazine-1-yl)benzamide using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0450]

[0451] Intermediate A3: 3-((4-(1-(6-aminohexyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride Synthesis

[0452]

[0453] Step A

[0454] A solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.0 g, 3.6 mmol, 1.0 equiv), 3-bromopiperidine-2,6-dione (1.4 g, 7.2 mmol, 2.0 equiv) and DIEA (0.94 g, 7.2 mmol, 2.0 equiv) in 1,4-dioxane was stirred at 80 °C for 24 h. The resulting mixture was concentrated under reduced pressure and dissolved in DMSO (10 mL). The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 0% to 60% gradient in 20 min; UV 254 nm to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.2 g, 86% yield) as a white solid. LCMS (ESI, m / z): 388.22 [M+H] + .

[0455] Step B

[0456] A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.2 g, 3.1 mmol, 1.0 equiv) and HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by trituration with Et2O (50 mL) to give 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (998 mg) as a white crude solid, which was used without further purification. LCMS (ESI, m / z): 288.16 [M+H] + .

[0457] Step C

[0458] A solution of 3-{[4-(4-aminobutan-2-yl)phenyl]amino}piperidine-2,6-dione (350 mg, 1.27 mmol, 1.0 eq), tert-butyl N-(6-bromohexyl)carbamate (410 mg, 1.46 mmol, 1.2 eq) and KCO (337 mg, 2.43 mmol, 2.0 eq) in DMF (5 mL) was stirred at 60° C. for 4 h. The mixture was acidified to pH 5 with citric acid. The mixture was directly purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 0% to 50% gradient in 20 minutes; detector: UV 254nm to give tert-butyl (6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)carbamate (254 mg, 43% yield) as a green solid. LCMS (ESI, m / z): 487.32 [M+H] + .

[0459] Step D

[0460] A solution of tert-butyl N-[6-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)hexyl]carbamate (150 mg, 0.31 mmol, 1.0 equiv) and HCl in 1,4-dioxane (1.5 mL, 4M) was stirred for 6 hours. The resulting mixture was concentrated under reduced pressure to give 3-((4-(1-(6-aminohexyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (256 mg) as a green crude solid, which was used in the next step without further purification. LCMS (ESI, m / z): 387.25 [M+H] + .

[0461] Intermediates A3-a to A3-d were synthesized according to the process described for the synthesis of 3-((4-(1-(6-aminohexyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0462]

[0463] Intermediate A4: 3-((4-(1-(6-aminohexanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride Salt synthesis

[0464]

[0465] Step A

[0466] To a stirred solution of 3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione (300 mg, 1.04 mmol, 1.5 eq) and 6-[(tert-butoxycarbonyl)amino]hexanoic acid (161 mg, 0.70 mmol, 1.0 eq) in DMF (5 mL) was added HATU (317 mg, 0.835 mmol, 1.2 eq) and DIEA (270 mg, 2.09 mmol, 3.0 eq). The resulting mixture was stirred for 4 h. The mixture was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient 0% to 46% in 20 minutes; detector: UV 254nm to give tert-butyl (6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)carbamate (219 mg, 63% yield) as a white solid. LCMS (ESI, m / z): 501.30 [M+H] + .

[0467] Step B

[0468] A solution of tert-butyl (6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)carbamate (169 mg, 0.338 mmol, 1.0 equiv) in HCl in 1,4-dioxane (2.5 mL, 4M) was stirred for 6 hours. The resulting mixture was concentrated under reduced pressure to give 3-((4-(1-(6-aminohexanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (238 mg) as a green crude solid. LCMS (ESI, m / z): 401.25 [M+H] + .

[0469] Intermediates A4-a to A4-e were synthesized according to the process described for the synthesis of 3-((4-(1-(6-aminohexanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0470]

[0471]

[0472] Intermediate A5: 3-((4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride Synthesis

[0473]

[0474] Step A

[0475] A solution of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (250mg, 0.77mmol, 1.0 equivalent), tert-butyl (2-oxoethyl)carbamate (184mg, 1.16mmol, 1.5 equivalents) and NaBH3CN (97mg, 1.5mmol, 2.0 equivalents) in MeOH (10mL) was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (9:1) to give tert-butyl (2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate (200mg, 48% yield) as a white solid. LCMS (ESI, m / z): 431.25[M+H] + .

[0476] Step B

[0477] A solution of tert-butyl (2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)carbamate (200 mg, 0.465 mmol, 1.0 equiv) in HCl in 1,4-dioxane (11 mL, 4M) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give 3-((4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (240 mg) as a crude white solid. The crude product was used without further purification. LCMS (ESI, m / z): 331.25 [M+H] + .

[0478] Intermediate A5-a was synthesized according to the process described for the synthesis of 3-((4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0479]

[0480] Intermediate A6: 2-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetyl Synthesis of amines

[0481]

[0482] At 0°C, bromoacetyl chloride (1.44 g, 9.15 mmol, 2.5 equiv) was added to a solution of pomalidomide (1.0 g, 3.7 mmol, 1.0 equiv) in THF (20 mL). The resulting mixture was stirred at 70°C for 2 hours. The resulting mixture was concentrated in vacuo. The crude product was dissolved in ether and then stirred for 20 minutes. The precipitated solid was collected by filtration and washed with 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): 412.95 [M+H] + .

[0483] Intermediate A6-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 using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0484]

[0485] Intermediate A7: 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dihydropyrimidine Synthesis of Ketones

[0486]

[0487] Step A

[0488] A solution of 1-[4-(piperidin-4-yl)phenyl]-1,3-diazine-2,4-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 (120 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, filtered, and the filtrate was concentrated under reduced pressure. 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 NH4HCO3), 5% to 95% gradient in 35 minutes; detector: UV254nm to give 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] +.

[0489] Step B

[0490] 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 min. The 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 yellow crude solid which was used directly in the next step without further purification. LCMS (ESI, m / z): 371.10 [M+H] + .

[0491] Intermediate A8: 3-(2-oxo-3-(4-(piperidin-4-yl)phenyl)imidazolin-1-yl)piperidine-2,6-dione hydrochloride Salt synthesis

[0492]

[0493] Step A

[0494] To a solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.0 g, 7.2 mmol, 1.0 equiv) in DCM (10 mL) was added 1-chloro-2-ethyl isocyanate (916 mg, 8.68 mmol, 1.2 equiv) in portions at 0 ° C. The solution was stirred at 0 ° C for 1 hour and then concentrated in vacuo to give tert-butyl 4-(4-(3-(2-chloroethyl)ureido)phenyl)piperidine-1-carboxylate (2.9 g, 99% yield) as a white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 326.25 [M+Ht-Bu] + .

[0495] Step B

[0496] To a solution of tert-butyl 4-(4-(3-(2-chloroethyl)ureido)phenyl)piperidine-1-carboxylate (2.9 g, 7.6 mmol, 1.0 equiv) in THF (10 mL) was added NaH (220 mg, 9.19 mmol, 1.2 equiv, 60% dispersion in oil) in portions at 0°C. The resulting mixture was stirred at 0°C for 1 hour. Upon completion, water was added and extracted with ethyl acetate (3×100 mL). The combined organic layers were concentrated in vacuo to give tert-butyl 4-(4-(2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (2.74 g, 93% yield) as a white solid. LCMS (ESI, m / z): 346.10 [M+H]+ .

[0497] Step C

[0498] A solution of tert-butyl 4-(4-(2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (500 mg, 1.5 mmol, 1.0 equiv), 2,6-bis(benzyloxy)-3-bromopyridine (536 mg, 1.45 mmol, 1.0 equiv), (1R,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (206 mg, 1.45 mmol, 1.0 equiv), K3PO4 (922 mg, 4.34 mmol, 3.0 equiv) and CuI (28 mg, 0.14 mmol, 0.10 equiv) in toluene (10 mL) was stirred at 120°C for 4 hours. The solution was concentrated in vacuo and applied to a silica gel column and eluted with ethyl acetate / petroleum ether (20:80) to give tert-butyl 4-(4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (720 mg, 63%) as a white solid. LCMS (ESI, m / z): 635.25 [M+H] + .

[0499] Step D

[0500] A solution of tert-butyl 4-(4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (600 mg, 0.95 mmol, 1.0 equiv) and Pd / C (503 mg, 4.72 mmol, 5.0 equiv) in ethyl acetate (10 mL) was stirred under a hydrogen atmosphere for 15 minutes. The resulting mixture was filtered and the filter cake was washed with DCM (3×200 mL). The filtrate was concentrated in vacuo to give tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (360 mg, 75%) as a brown solid. LCMS (ESI, m / z): 457.10 [M+H] + .

[0501] Step E

[0502] A solution of tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (340 mg, 0.745 mmol, 1.0 equiv) in HCl in 1,4-dioxane (5 mL, 4M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to give 3-(2-oxo-3-(4-(piperidin-4-yl)phenyl)imidazolin-1-yl)piperidine-2,6-dione hydrochloride (380 mg) as a brown crude solid which was used without further purification. LCMS (ESI, m / z): 357.30 [M+H] + .

[0503] Intermediate A9: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6- Synthesis of diketones

[0504]

[0505] Step A

[0506] To a stirred solution of 3-bromopiperidine-2,6-dione (5.0 g, 26.0 mmol, 1.0 equiv), PPh3 (10.3 g, 39.1 mmol, 1.5 equiv) and (4-methoxyphenyl)methanol (5.40 g, 39.1 mmol, 1.5 equiv) in THF (50 mL) was added DEAD (6.80 g, 39.1 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred at room temperature for 4 hours. After concentration, the residue was purified by silica gel column eluting with PE / EA (1:1) to give 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (7.3 g, 90% yield) as a yellow solid.

[0507] Step B

[0508] A solution of 7-bromo-1-methyl-3H-1,3-benzodiazol-2-one (1.0 g, 4.4 mmol, 1 eq) in ACN (8 mL) was treated with CsCO (4.30 g, 13.2 mmol, 3.0 eq) at 0 °C for 5 min, followed by the dropwise addition of 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (1.65 g, 5.29 mmol, 1.2 eq) at 0 °C. The resulting solution was stirred at room temperature for 15 h. After concentration, the residue was purified by silica gel column eluting with PE / EA (1:1) to give 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (900 mg, 45% yield) as a white solid. LCMS (ESI, m / z): 458.15 [M+H] + .

[0509] Step C

[0510] A solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1.16 g, 2.53 mmol, 1.0 equiv) in methanesulfonic acid (4 mL) and toluene (8 mL) was stirred at 120 ° C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding ice water (20 mL). The precipitated solid was collected by filtration and washed with water. The crude product was purified by silica gel chromatography eluted with PE / EA (1:3) to give 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (800 mg, 93% yield) as a gray solid. LCMS (ESI, m / z): 337.80 [M+H] + .

[0511] Intermediate A9-a was synthesized according to the process described for the synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, using appropriate building blocks and adjusting reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0512]

[0513] Intermediate A10: 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-diol Synthesis of Ketones

[0514]

[0515] A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.55 mmol, 1 eq), piperidin-4-ylmethanol (178 mg, 1.55 mmol, 1 eq), Pd-PEPPSI-IPentCl2-methylpyridine (o-methylpyridine) (67 mg, 0.077 mmol, 0.05 eq) and Cs2CO3 (1008 mg, 3.09 mmol, 2 eq) in dioxane (5 mL) was stirred at 100° 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 (1:1) to give 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (240 mg, 43%) as a yellow solid. LCMS (ESI, m / z): 358.25 [M+H] + .

[0516] Intermediate A11: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one

[0517]

[0518] A solution of piperidin-4-one hydrochloride (6.0 g, 44 mmol, 1 eq.), 1,2-difluoro-4-nitrobenzene (7.04 g, 44.3 mmol, 1 eq.) and TEA (13.4 g, 133 mmol, 3 eq.) in DMF (40 mL) was stirred at 80 °C overnight. The product was precipitated by adding water. The precipitated solid was collected by filtration and washed with water (3×80 mL) to give 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (9 g, 85%) as a yellow solid. LCMS (ESI, m / z): 239.10 [M+H] + .

[0519] Intermediate A12: 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione Synthesis of hydrochloride

[0520]

[0521] Step A

[0522] To a stirred solution of 6-bromobenz[cd]indol-2(1H)-one (2.0 g, 8.1 mmol, 1 eq) and THF (150 mL) was added NaH (1.61 g, 40.3 mmol, 5 eq, 60% dispersion in oil) in portions at 0°C. The mixture was stirred at room temperature for 1 hour. A solution of 3-bromopiperidine-2,6-dione (3.87 g, 20.2 mmol, 2.5 eq) in THF (10 mL) was added dropwise at 0°C. The mixture was stirred at 60°C overnight. The reaction was quenched by slowly adding saturated aqueous NH4Cl solution (80 mL) at 0°C. The mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was titrated with DCM (10 mL) to give 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (940 mg, 33%) as a yellow-green solid. LCMS (ESI, m / z): 359.18 [M+H] + .

[0523] Step B

[0524] A solution of 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (400 mg, 1.11 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (311 mg, 1.67 mmol, 1.5 eq), Pd-PEPPSI-IPentCl 2-methylpyridine (o-methylpyridine) (94 mg, 0.111 mmol, 0.1 eq) and Cs2CO3 (544 mg, 1.67 mmol, 1.5 eq) in dioxane (10 mL) was stirred at 100° C. under nitrogen atmosphere 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-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (361 mg, 70%) as a yellow solid. LCMS (ESI, m / z): 465.52 [M+H] + .

[0525] Step C

[0526] A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (341 mg, 0.73 mmol, 1 eq) and HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 30 minutes. The mixture was concentrated to give 3-(2-oxo-6-(piperazine-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (335 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI,m / z):365.41[M+H] + .

[0527] Intermediate A13: 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione synthesis

[0528]

[0529] Step A

[0530] 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 (1135 mg, 3.48 mmol, 2 eq) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-methylpyridine) (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] + .

[0531] Step B

[0532] 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] + .

[0533] Intermediate A14: 3-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione Synthesis .

[0534]

[0535] Step A

[0536] A solution of tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (2.0 g, 7.4 mmol, 1 eq.), 1,2-difluoro-4-nitrobenzene (1.18 g, 7.42 mmol, 1 eq.) and TEA (2.25 g, 22.3 mmol, 3 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 PE / EtOAc (5:1) to give tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.2 g, 72%) as a brown solid. LCMS (ESI, m / z): 409.30 [M+H] + .

[0537] Step B

[0538] A solution of tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.2 g, 5.39 mmol, 1 eq.), NH4Cl (0.86 g, 16 mmol, 3 eq.) and Fe (1.50 g, 26.9 mmol, 5 eq.) in EtOH (50 mL) and water (10 mL) was stirred at 80 °C for 1 hour. The mixture was concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (1:4) to give tert-butyl 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.9 g, 99%) as a brown solid. LCMS (ESI, m / z): 379.30 [M+H] + .

[0539] Step C

[0540] A solution of tert-butyl 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.9 g, 5.02 mmol, 1 eq.), 3-bromopiperidine-2,6-dione (4.82 g, 25.1 mmol, 5 eq.) and NaHCO3 (2.11 g, 25.1 mmol, 5 eq.) in ACN (50 mL) was stirred at 90 °C overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (2:3) to give tert-butyl 4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.7 g, 69%) as a brown solid. LCMS (ESI, m / z): 490.25 [M+H] + .

[0541] Step D

[0542] A solution of tert-butyl 4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.7 g, 3.5 mmol, 1 equivalent) in HCl in 1,4-dioxane (30 mL, 4 M) was stirred for 1 hour. The mixture was concentrated to give 3-((3-fluoro-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (2.2 g) as a brown solid. The crude product was used directly in the next step without further purification. LCMS(ESI,m / z):390.20[M+H] + .

[0543] Intermediate A15: 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4-(1H, Synthesis of 3H)-dione

[0544]

[0545] Step A

[0546] A solution of 6-bromo-1-methyl-1H-indazol-3-amine (30 g, 132 mmol, 1 eq.), acrylic acid (14.3 g, 199 mmol, 1.5 eq.) and TBAB (4.28 g, 13.3 mmol, 0.1 eq.) in 2M HCl (1.2 L) was stirred at 100 °C overnight. The mixture was neutralized to pH 7 with aqueous NaOH (4 M). The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The resulting solid was dried under infrared to give 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (35.9 g, 77%) as a gray solid. LCMS (ESI, m / z): 300.10 [M+H] + .

[0547] Step B

[0548] A solution of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (10 g, 34 mmol, 1 eq.) in AcOH (150 mL) was treated with sodium cyanate (6.54 g, 101 mmol, 3 eq.) at 80 °C for 12 h, followed by dropwise addition of HCl (150 mL, 4 M) at room temperature. The solution was then stirred at 80 °C overnight. The precipitated solid was collected by filtration and washed with water (3 x 30 mL). The resulting solid was dried under infrared to give 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (4.28 g, 40%) as a white solid. LCMS (ESI, m / z): 325.00 [M+H] + .

[0549] Step C

[0550] A solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 3.7 mmol, 1 eq), piperidin-4-one (0.55 g, 5.6 mmol, 1.5 eq), Cs2CO3 (3.63 g, 11.1 mmol, 3 eq) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-methylpyridine) (0.31 g, 0.37 mmol, 0.1 eq) in dioxane (8 mL) was stirred at 85 °C overnight. After concentration, the residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (480 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 342.10 [M+H] + .

[0551] Intermediate A16: 3-((4-([4,4'-bipiperidinyl]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione hydrochloride Salt synthesis

[0552]

[0553] Step A

[0554] A mixture of [4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (2.0 g, 7.5 mmol, 1 eq.), 1,2-difluoro-4-nitrobenzene (1.78 g, 11.2 mmol, 1.5 eq.) and NaHCO3 (2.50 g, 29.8 mmol, 4 eq.) in ACN (5 mL) was stirred at 90 ° C for 4 hours. After concentration, the residue was purified by silica gel column chromatography eluted with PE / EtOAc (4:1) to give 1'-(2-fluoro-4-nitrophenyl)-[4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (2.7 g, 89%) as a yellow solid. LCMS (ESI, m / z): 408.35 [M+H] + .

[0555] Step B

[0556] A mixture of tert-butyl 1'-(2-fluoro-4-nitrophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.7 g, 6.6 mmol, 1 eq.), Fe (1.85 g, 33.1 mmol, 5 eq.) and NH4Cl (0.71 g, 13 mmol, 2 eq.) in EtOH (4 mL) and water (1 mL) was stirred at 80 °C for 4 hours. After concentration, the residue was purified by silica gel column chromatography eluted with PE / EtOAc (3:7) to give tert-butyl 1'-(4-amino-2-fluorophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.34 g, 94%) as a yellow solid. LCMS (ESI, m / z): 378.15 [M+H] + .

[0557] Step C

[0558] A mixture of tert-butyl 1'-(4-amino-2-fluorophenyl)-[4,4'-bipiperidin]-1-carboxylate (2.3 g, 6.09 mmol, 1 eq.), 3-bromopiperidine-2,6-dione (3.51 g, 18.3 mmol, 3 eq.) and NaHCO3 (2.56 g, 30.5 mmol, 5 eq.) in ACN (6 mL) was stirred at 90 °C overnight. After concentration, the residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:1) to give tert-butyl 1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[4,4'-bipiperidin]-1-carboxylate (2.6 g, 87%) as a green solid. LCMS (ESI, m / z): 487.25 [MH] - .

[0559] Step D

[0560] A mixture of 1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[4,4'-bipiperidin]-1-carboxylic acid tert-butyl ester (2.6 g, 5.3 mmol, 1 equivalent) in 1,4-dioxane (8 mL, 4M) was stirred for 3 hours. The mixture was concentrated to give 3-((4-([4,4'-bipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione hydrochloride (2.8 g) as a white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 389.20 [M+H] + .

[0561] Intermediate A17: 1-(8-(piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride Synthesis

[0562]

[0563] Step A

[0564] A solution of 8-bromoisoquinoline (5 g, 24.0 mmol, 1 eq.), I2 (12.2 g, 48.1 mmol, 2 eq.) and TBHP (6.50 g, 72.1 mmol, 3 eq., 70% aqueous solution) in DCE (50 mL) was stirred at 120 °C overnight. The reaction was quenched with aqueous sodium sulfite at room temperature. The aqueous layer was extracted with DCM (3×20 mL). The resulting mixture was concentrated under reduced pressure to give 8-bromo-4-iodoisoquinoline (5.3 g, 66%) as a red solid. LCMS (ESI, m / z): 333.80 [M+H] + .

[0565] Step B

[0566] A solution of 8-bromo-4-iodoisoquinoline (1 g, 3.0 mmol, 1 eq), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.91 g, 3.89 mmol, 1.3 eq), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.21 g, 1.50 mmol, 0.5 eq), Cs2CO3 (1.95 g, 6.0 mmol, 2 eq) and CuI (0.23 g, 1.20 mmol, 0.4 eq) in dioxane (6 mL) was stirred at 65 °C under nitrogen atmosphere overnight. The resulting 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] + .

[0567] Step C

[0568] A solution of 1-(8-bromoisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.6 g, 3.63 mmol, 1 equiv) in TFA (5 mL) and TfOH (1 mL) was stirred for 4 hours. The residue was diluted with EtOAc (4 mL) and then basified to pH 8 with TEA. The precipitated solid was collected by filtration and washed with water (3×5 mL). 1-(8-bromoisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.5 g) was obtained as a yellow solid. The crude product was used directly in the next step without further purification, LCMS (ESI, m / z): 320.00 [M+H] +.

[0569] Step D

[0570] A solution of 1-(8-bromoisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.56 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (436 mg, 2.34 mmol, 1.5 eq), Pd-PEPPSI-IPentCl2-methylpyridine (o-methylpyridine) (131 mg, 0.16 mmol, 0.1 eq) and Cs2CO3 (1018 mg, 3.12 mmol, 2 eq) in dioxane (4 mL) was stirred at 85 °C under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / EtOH (92:8) to give tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-8-yl)piperazine-1-carboxylate (377 mg, 57%) as a yellow solid. LCMS (ESI, m / z): 426.21 [M+H] + .

[0571] Step E

[0572] A solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-8-yl)piperazine-1-carboxylate (367 mg, 0.86 mmol, 1 equiv) in HCl in 1,4-dioxane (5 mL, 4M) was stirred for 1 hour. The mixture was concentrated to dryness to give 1-(8-(piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 326.15 [M+H] + .

[0573] Intermediate B1: 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl) Synthesis of 1-(2-thio)piperidin-1-yl)acetic acid

[0574]

[0575] Step A

[0576] A solution of tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (5.0 g, 10.5 mmol, 1.0 equiv) in HCl in 1,4-dioxane (60 mL, 4M) was stirred at 40 °C for 2 hours. The resulting mixture was concentrated in vacuo. The mixture was diluted with ethyl acetate (60 mL) and the precipitated solid was collected by filtration to give the HCl salt of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (5.0 g) as a gray solid. The crude product mixture was used directly without further purification. LCMS (ESI, m / z): 377.15 [M+H] + .

[0577] Step B

[0578] A solution of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (4.28 g, 11.4 mmol, 1.0 equiv), tert-butyl 2-bromoacetate (1.69 g, 8.65 mmol, 0.76 equiv) and KCO (6.28 g, 45.5 mmol, 4.0 equiv) in DMF (45 mL) was stirred at 70° C. for 3 hours. The resulting mixture was diluted with brine (30 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by trituration with EtOAc (20 mL) to give tert-butyl 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (2.6 g, 47%) as an off-white solid. LCMS (ESI, m / z): 491.15 [M+H] + .

[0579] Step C

[0580] A solution of tert-butyl 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)thio)piperidin-1-yl)acetate (2.6g, 5.3mmol, 1.0 equivalent) in trifluoroacetic acid (20mL) and DCM (40mL) was stirred for 16 hours. The resulting mixture was concentrated in vacuo and then diluted with DCM (20mL) and water (20mL). The mixture was neutralized to pH 6.0 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-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)thio)piperidin-1-yl)acetic acid (1.4g, 61%) as a white solid. LCMS (ESI, m / z): 435.10 [M+H] + .

[0581] Intermediate B2: 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinoline Synthesis of (2-oxazoline-2-yl)methyl)thio)piperidin-1-yl)acetic acid

[0582]

[0583] Step A

[0584] To a solution of NaOH (0.37 g, 9.2 mmol, 3.0 equiv) in water (10 mL) was added 2-(chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (1.0 g, 3.0 mmol, 1.0 equiv) and tert-butyl 4-mercaptopiperidine-1-carboxylate (0.80 g, 3.7 mmol, 1.2 equiv) at room temperature. The solution was stirred for 4 hours and then acidified to pH 6 with aqueous HCl. The precipitated solid was collected by filtration and washed with water (3×10 mL) to give tert-butyl 4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1.47 g, 95% yield) as a white solid. LCMS (ESI, m / z): 508.30 [M+H] + .

[0585] Step B

[0586] A solution of tert-butyl 4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1.46 g, 2.88 mmol, 1.0 equiv) in HCl in 1,4-dioxane (10 mL, 4M) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to give 5-fluoro-2-((piperidin-4-ylthio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.52 g) as a white crude solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 408.19 [M+H] + .

[0587] Step C

[0588] A solution of 5-fluoro-2-((piperidin-4-ylthio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.51 g, 3.40 mmol, 1.0 equiv), KCO (0.94 g, 6.8 mmol, 2.0 equiv) and tert-butyl 2-bromoacetate (0.66 g, 3.4 mmol, 1.0 equiv) in ACN (20 mL) was stirred at 70° C. for 16 hours. The organics were removed in vacuo. The precipitated solid was collected by filtration and washed with water (3×10 mL). The resulting solid was dried in an oven to give tert-butyl 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (1.1 g, 62% yield) as a white solid. LCMS (ESI, m / z): 522.25 [M+H] + .

[0589] Step D

[0590] A solution of tert-butyl 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (1.15 g, 2.20 mmol, 1.0 equiv) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated in vacuo to give 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid (15.8 g) as a brown crude oil. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 466.20 [M+H]+ .

[0591] Intermediate B3 was synthesized according to the process described for the synthesis of 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid, using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0592]

[0593] Intermediate B4: 2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydro Synthesis of (quinazolin-2-yl)ethyl)piperidin-1-yl)acetic acid

[0594]

[0595] Step A

[0596] To a solution of methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (2.0 g, 6.2 mmol, 1.0 equiv) in MeOH (18 mL) was added a solution of KOH (3.46 g, 61.7 mmol, 10.0 equiv) in water (6 mL). The resulting mixture was stirred at 40 ° C overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with MeOH / DCM (1: 9) to give 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid (1.12 g, 59% yield) as a yellow solid. LCMS (ESI, m / z): 311.15 [M+H] + .

[0597] Step B

[0598] To a solution of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid (580 mg, 1.87 mmol, 1.0 equiv) and NH4Cl (200 mg, 3.74 mmol, 2.0 equiv) in DMF (4 mL) at room temperature were added DIEA (725 mg, 5.61 mmol, 3.0 equiv) and HATU (1066 mg, 2.804 mmol, 1.5 equiv) portionwise. The resulting mixture was stirred for 1 hour and then directly 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 50% gradient in 10 minutes; detector: UV 254 nm) to give 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzamide (428 mg, 72% yield) as a yellow solid. LCMS (ESI, m / z): 310.15 [M+H] + .

[0599] Step C

[0600] To a stirred solution of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzamide (569 mg, 1.84 mmol, 1.0 equiv) and tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (882 mg, 3.66 mmol, 2.0 equiv) in water (10 mL) was added FeCl (594 mg, 3.65 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred at 100 ° C for 1 hour, then the solution was cooled to room temperature and the pH was adjusted to pH 7 with saturated aqueous NaHCO. The resulting mixture was filtered and the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (4:1) to give impure 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (529 mg) as a brown oil. LCMS (ESI, m / z): 431.25 [M+H] + .

[0601] Step D

[0602] A solution of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (339 mg, 0.787 mmol, 1.0 equiv), DIEA (305 mg, 2.36 mmol, 3.0 equiv) and tert-butyl 2-bromoacetate (461 mg, 2.36 mmol, 3.0 equiv) in NMP (3 mL) was stirred at room temperature for 2 h. The solution was directly 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 50% gradient in 10 minutes; detector: UV 254 nm) to give tert-butyl 2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetate (240 mg, 51% yield) as a colorless oil. LCMS (ESI, m / z): 545.30 [M+H] + .

[0603] Step E

[0604] A solution of tert-butyl 2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetate (224 mg, 0.411 mmol, 1.0 equiv) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to give 2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetic acid as a colorless oil. The crude product was used without further purification. LCMS (ESI, m / z): 489.30 [M+H] + .

[0605] Intermediate B5: 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((1-(prop-2-yn-1-yl) ... Synthesis of (4-pyridin-4-yl)thio)methyl)quinazolin-4(3H)-one

[0606]

[0607] A solution of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (500 mg, 1.03 mmol, 1.0 equiv), DIEA (400 mg, 3.09 mmol, 3.0 equiv) and 3-bromoprop-1-yne (172 mg, 1.44 mmol, 1.4 equiv) in DMSO (2 mL) was stirred at room temperature for 1 hour. The residue was purified by reverse phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), gradient 0% to 35% in 20 minutes; detector, UV 254nm) to give 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((1-(prop-2-yn-1-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (200 mg, 40% yield) as a white solid. LCMS (ESI, m / z): 487.20 [M+H] + .

[0608] Intermediate B6: 7-(Cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one Synthesis of hydrochloride

[0609]

[0610] Step A

[0611] A solution of 2-(chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazoline-4(3H)-one (3 g, 10.6 mmol, 1.0 equiv), tert-butyl 4-(acetylthio)piperidine-1-carboxylate (2.78 g, 10.7 mmol, 1.01 equiv) and NaOH (1.27 g, 31.8 mmol, 3.0 equiv) in H2O (30 mL) was stirred at room temperature for 1.5 hours. The mixture was acidified to pH 3 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3×5 mL). The solid was dried under infrared to give the title compound (4.8 g, 97% yield) as a white solid. LCMS (ESI, m / z): 464.19 [M+H] + .

[0612] Step B

[0613] A solution of tert-butyl 4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (2.5 g, 5.4 mmol, 1.0 equiv) and HCl in 1,4-dioxane (10 mL, 4 M) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give the title compound (2.09 g, 97% yield) as a white solid. LCMS (ESI, m / z): 364.14 [M+H] + .

[0614] Intermediate B7: 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoro Synthesis of Quinazolin-4(3H)-One

[0615]

[0616] Step A

[0617] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (230 mg, 0.63 mmol, 1 eq) in NMP (5 mL) was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (167 mg, 0.70 mmol, 1.1 eq) and DIEA (245 mg, 1.90 mmol, 3 eq) and then stirred at 80° C. overnight. Water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and 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 NH4HCO3), gradient 10% to 72% in 20 minutes; detector, UV 254 nm to give 2-(((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (97 mg, 29%) as a brown solid. LCMS (ESI, m / z): 522.25 [M+H] + .

[0618] Step B

[0619] A solution of 2-(((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (97 mg, 0.19 mmol, 1 equiv) was treated with a solution of HCl in 1,4-dioxane (15 mL, 4M) for 3 h. The resulting mixture was concentrated to dryness to afford 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (118 mg) as a brown solid which was used directly in the next step without further purification. LCMS (ESI, m / z): 408.15 [M+H] + .

[0620] Step C

[0621] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (100 mg, 0.25 mmol, 1 eq) in DCM (2 mL) was treated with 3-nitrobenzenesulfonyl chloride (54 mg, 0.25 mmol, 1 eq) and TEA (75 mg, 0.74 mmol, 3 eq) and stirred for 2 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (1 / 9) to give 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (30 mg, 29%) as a yellow solid. LCMS (ESI, m / z): 426.15 [M+H] + .

[0622] Intermediate B8: 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran- Synthesis of 4-(4-yl)methoxy)quinazolin-4(3H)-one

[0623]

[0624] A solution of 5-fluoro-7-(oxan-4-ylmethoxy)-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (500 mg, 1.23 mmol, 1 eq), aqueous chloroacetaldehyde (239 mg, 1.23 mmol, 1 eq, 40 wt%) and STAB (520 mg, 2.45 mmol, 2 eq) in DCM (5 mL) was stirred for 1 h. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (200 mg, 35%) as a white solid. LCMS (ESI, m / z): 470.20 [M+H] + .

[0625] Intermediate B9: 2-(((1-(azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro- Synthesis of 2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[0626]

[0627] Step A

[0628] A solution of 5-fluoro-2-((piperidin-4-ylthio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (2.0 g, 4.9 mmol, 1 eq), tert-butyl 3-oxoazetidine-1-carboxylate (1.54 g, 9.01 mmol, 2 eq) and STAB (1.91 g, 9.01 mmol, 2 eq) in DCM (7 mL) was stirred for 3 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (97:3) to give tert-butyl 3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidine-1-carboxylate (1.17 g, 46%) as a yellow solid. LCMS (ESI, m / z): 563.26 [M+H] + .

[0629] Step B

[0630] A solution of tert-butyl 3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidine-1-carboxylate (1.17 g, 2.08 mmol, 1 eq) in HCl in 1,4-dioxane (7 mL, 4M) was stirred for 30 minutes. The mixture was concentrated to dryness to give 2-(((1-(azetidine-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.06 g) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI,m / z):463.21[M+H] + .

[0631] Intermediates B9-a to B9-c were synthesized according to the process described for the synthesis of 2-(((1-(azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride, using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0632]

[0633]

[0634] Intermediate B10: 2-(((1-(2-chloroethyl)piperidin-4-yl)oxy)methyl)-5-fluoro-7-((tetrahydro-2H-pyridine Synthesis of (4-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[0635]

[0636] Step A

[0637] A solution of 2-(chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (2.0 g, 6.1 mmol, 1 eq), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.97 g, 9.79 mmol, 1.6 eq) and t-BuOK (2.06 g, 18.4 mmol, 3 eq) in DMA (10 mL) was stirred at 40 °C for 5 h. 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 NH4HCO3), 10% to 50% gradient over 25 minutes; detector, UV 254 nm to give tert-butyl 4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidine-1-carboxylate (2 g, 59%) as a light pink solid. LCMS (ESI, m / z): 492.10 [M+H] + .

[0638] Step B

[0639] A solution of tert-butyl 4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidine-1-carboxylate (1.99 g, 4.05 mmol, 1 equiv) in HCl in 1,4-dioxane (20 mL, 4M) was stirred for 1 hour. The mixture was concentrated in vacuo to give 5-fluoro-2-((piperidin-4-yloxy)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (2 g) as a light brown solid, which was used directly in the next step without further purification. LCMS (ESI, m / z): 392.15 [M+H] + .

[0640] Step C

[0641] A solution of 5-fluoro-2-((piperidin-4-yloxy)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (500 mg, 1.28 mmol, 1 eq), 2-chloroacetaldehyde (501 mg, 2.55 mmol, 2.0 eq, 40 wt%) and STAB (541 mg, 2.55 mmol, 2 eq) in DCE (2 mL) was stirred for 1 h. The mixture was purified by silica gel column chromatography eluting with DCM / MeOH (12:1) to give 2-(((1-(2-chloroethyl)piperidin-4-yl)oxy)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (180 mg, 31%) as a white solid. LCMS (ESI, m / z): 454.25 [M+H] + .

[0642] Intermediate B11: Synthesis of 2-(2-chloroethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one .

[0643]

[0644] A solution of methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate (300 mg, 1.2 mmol, 1 eq) and acrylonitrile (332 mg, 6.27 mmol, 5 eq) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred for 1 hour. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 2-(2-chloroethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (250 mg, 67%) as a brown oil. LCMS (ESI, m / z): 297.10 [M+H] + .

[0645] Intermediate B12: 2-(2-([1,4'-bipiperidinyl]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazoline- Synthesis of 4(3H)-Keto Hydrochloride

[0646]

[0647] Step A

[0648] A solution of methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate (2 g, 8.36 mmol, 1 eq) and KOH (3.75 g, 66.9 mmol, 8 eq) in MeOH (40 mL) and water (10 mL) was stirred at 60 °C overnight. The mixture was concentrated and then acidified to pH 4 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3 x 100 mL) to give 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoic acid (1.8 g, 96%) as a light yellow solid. LCMS (ESI, m / z): 226.0 [M+H] + .

[0649] Step B

[0650] A solution of 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoic acid (1.8 g, 7.99 mmol, 1 eq.), NH4Cl (0.43 g, 7.99 mmol, 1 eq.), DIEA (4.13 g, 32.0 mmol, 4 eq.) and HATU (4.56 g, 12.0 mmol, 1.5 eq.) in DMF (10 mL) was stirred for 1 hour. The mixture was 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 50% gradient in 10 minutes; detector, UV 254 nm. 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzamide (1.5 g, 84%) was obtained as a white solid. LCMS (ESI, m / z): 225.01 [M+H] + .

[0651] Step C

[0652] A solution of 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzamide (0.50 g, 2.23 mmol, 1 eq.), tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (1.08 g, 4.46 mmol, 2 eq.) and FeCl3.6H2O (1.21 g, 4.46 mmol, 2 eq.) in water (7 mL) was stirred at 100 °C for 1 hour. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give the crude compound (300 mg) as a yellow solid. 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), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. 7-(Cyclopropylmethoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (155 mg, 20%) was obtained as a white solid. LCMS (ESI, m / z): 346.01 [M+H] + .

[0653] Step D

[0654] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (135 mg, 0.391 mmol, 1 eq), tert-butyl 4-oxopiperidine-1-carboxylate (156 mg, 0.782 mmol, 2 eq) and STAB (166 mg, 0.782 mmol, 2 eq) in DCE (13.5 mL) was stirred overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give tert-butyl 4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidine]-1'-carboxylate (80 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 529.3 [M+H] + .

[0655] Step E

[0656] A solution of tert-butyl 4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidine]-1'-carboxylate (80 mg, 0.151 mmol, 1 eq) and HCl in 1,4-dioxane (10 mL, 4M) was stirred for 1 hour. The mixture was concentrated to dryness to give 2-(2-([1,4'-bipiperidine]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride (100 mg) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 429.16 [M+H] + .

[0657] Example 1: 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazoline- 2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin- Synthesis of 3-amino-1,3-isoindoline-1,3-dione

[0658]

[0659] A solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (1.31 g, 3.00 mmol, 1.0 equiv), 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid (1.37 g, 3.15 mmol, 1.05 equiv), HOBT (608 mg, 4.50 mmol, 1.5 equiv), EDCI (863 mg, 4.50 mmol, 1.5 equiv) and DIEA (1.55 g, 12.0 mmol, 4.0 equiv) in DMF (12 mL) and DCM (9 mL) was stirred at 45 °C for 5 h. The resulting mixture was diluted with brine (100 mL) and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by trituration with ethyl acetate (20 mL×3), ethanol (20 mL×3), and MeCN (20 mL×3) to give 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.28 g, 50% yield) as a yellow solid. LCMS (ESI, m / z): 856.45 [M+H] +.1H NMR (300MHz, DMSO-d6) δ11.66(s,1H),11.10(s,1H),7.71(t,J=9.01H),7.35(t,J=9.0Hz,2H),6.84(d,J=6.5Hz, 1H),6.42(dd,J=13.9,2.1Hz,1H),6.36(d,J=2.1Hz,1H),5.10(dd,J=12.7,5.4Hz,1H),4.31(d,J=12.8Hz,1H),4. 03(d,J=12.9Hz,1H),3.85-3.74(m,1H),3.53(s,2H),3.38-3.30(m,4H),3.24-3.15(m,1H),3.03-2.69(m,6H),2. 67-2.53(m,5H),2.25-2.16(m,2H),2.14-2.00(m,3H),1.99-1.85(m,4H),1.84-1.30(m,12H),1.19-0.81(m,3H).

[0660] Examples 2-29 were synthesized according to the process described for the synthesis of 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676] Example 30: 5-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinoline Synthesis of (2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) (2-(2,6-dioxopiperidin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0677]

[0678] A solution of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (200 mg, 0.45 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (123 mg, 0.45 mmol, 1.0 equiv), DIEA (230 mg, 1.78 mmol, 4.0 equiv) in NMP (5 mL) was stirred at 120 °C for 12 hours. The residue was directly 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 70% gradient in 15 minutes; detector, UV 254 nm) to give 5-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (47 mg, 15%) as a green solid. LCMS (ES, m / z): 705.35 [M+H] + . 11H NMR (300 MHz, methanol-d4) δ 7.66 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 6.96 - 6.90 (m, 1H), 6.84 (dd, J = 12.5, 2.4 Hz, 1H), 5.08 (dd, J = 12.3, 5.4 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 4.04 - 3.88 (m, 5H), 3.72 (d, J = 4.8 Hz, 1H), 3.26 - 3.04 (m, 4H), 2.97 - 2.63 (m, 4H), 2.21 - 2.01 (m, 7H), 2.00 - 1.81 (m, 2H), 1.77 - 1.56 (m, 2H), 1.47 - 1.20 (m, 3H).

[0679] Example 31: 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinoline (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- Synthesis of 4-amino)acetamide

[0680]

[0681] A solution of 7-[(1-acetylpiperidin-4-yl)methoxy]-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (100 mg, 0.223 mmol, 1.0 equiv), 2-bromo-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]acetamide (83 mg, 0.21 mmol, 0.95 equiv) and K2CO3 (62 mg, 0.45 mmol, 2.0 equiv) in DMF (2 mL) was stirred at 70°C for 2 h. The residue was directly purified by reverse phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 5% to 95% gradient in 25 minutes; detector, UV254nm), and further purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 42% B, 42% B in 9 minutes; wavelength: 254 / 220 nm; RT (min): 8.9), to give 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (12 mg, 7%) as a white solid. LCMS (ESI, m / z): 762.25 [M+H] + ; 1 HNMR (300MHz, DMSO-d6) δ11.12(s,1H),11.01(s,1H),8.79(d,J=9.0Hz,1H),8.22(s,1H),7.85(t,J=9 .0Hz,1H),7.59(d,J=6.0Hz,1H),6.95-6.82(m,2H),5.22-5.10(m,1H),4.39(d,J=12.0Hz,1H),4.00(d ,J=6.0Hz,2H),3.91-3.71(m,2H),3.62(s,2H),3.21(d,J=9.0Hz,2H),3.11-2.99(m,1H),2.98-2.81( m,4H),2.68-2.52(m,2H),2.39-2.28(m,2H),2.12-1.85(m,7H),1.82-1.61(m,4H),1.32-1.05(m,2H).

[0682] Example 32 was synthesized according to the process described for the synthesis of 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide, using appropriate building blocks and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0683]

[0684] Example 33: 5-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dimethoxy (2-(2,6-dioxopiperidin-3-yl)isoindolyl) Synthesis of Indoline-1,3-dione

[0685]

[0686] A solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-(hydroxymethyl)piperidin-1-yl]isoindoline-1,3-dione (200 mg, 0.54 mmol, 1.0 eq) and Dess-Martin periodinane (251 mg, 0.59 mmol, 1.1 eq) in DCM (3 mL) was stirred for 2 hours. 7-[(1-acetylpiperidin-4-yl)methoxy]-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (241 mg, 0.539 mmol, 1 eq) was added dropwise to the mixture. The resulting mixture was stirred for 2 hours, then NaBH(OAc)3 (5716 mg, 2.69 mmol, 5.0 eq) was added, and then stirred for 16 hours. The mixture was concentrated in vacuo and 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 NH4HCO3), gradient 0% to 43% in 25 min; detector, UV 254 nm). The crude product was further 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: 15% B to 45% B, 45% B in 7 minutes; wavelength: 254 / 220 nm; RT (min): 5.5) to give 5-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4.2 mg, 1%) as a yellow solid. LCMS (ES, m / z): 802.33 [M+H] + ; 1 HNMR(300MHz,DMSO-d6)δ12.14(s,1H),11.06(s,1H),7.63(d,J=8.5Hz,1H),7.28(d ,J=2.1Hz,1H),7.21(d,J=8.6Hz,1H),6.93-6.82(m,2H),5.11-5.05(m,1H),4.38(d, J=12.7Hz,1H),4.08-3.95(m,4H),3.83(d,J=13.8Hz,1H),3.58(s,2H),3.05-2.74( m,6H),2.59-2.51(m,1H),2.09-1.69(m,17H),1.51-1.48(m,2H),1.29-1.05(m,5H).

[0687] Example 34: 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dimethoxy (2-(2,6-dioxopiperidin-3-yl)-1-( ...2-(2,6-dioxopiperidin-3-yl)-1-(2,6-dioxopiperidin-2-yl)-2-(2,6-dioxopiperidin-3-yl)-1-(2,6

[0688] Synthesis of Isoindoline-1,3-dione

[0689]

[0690] A solution of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((1-(prop-2-yn-1-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (200 mg, 0.41 mmol, 1.0 equiv), 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (139 mg, 0.41 mmol, 1.0 equiv), TEA (83 mg, 0.82 mmol, 2.0 equiv) and Pd(PPh3)2Cl2 (29 mg, 0.041 mmol, 0.10 equiv) in DMSO (2 mL) was stirred at 80°C for 2 hours. After concentration, the residue was purified by C18 reverse phase chromatography, eluting with water / CH3CN (56:44), and further purified by preparative HPLC under the following conditions: (column: XSelect CSH Fluoro Phenyl, 30*150mm, 5μm; mobile phase A: water (10mmol / LNH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 28% B to 49% B in 9.5 minutes; detector: 254 / 220nm; RT (min): 8.55), to give 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (24mg, 8% yield) as a white solid. LCMS (ESI, m / z): 743.30[M+H] +;1HNMR(400MHz,DMSO-d6)δ12.16(s,1H),11.15(s,1H),7.89-7.75(m,2H),7.88(s,1H),6.89(s, 1H),6.87(s,1H),5.17(dd,J=12.9,5.6Hz,1H),4.38(d,J=13.0Hz,1H),3.97(d,J=6.5Hz,2H),3. 80-3.70(m,1H),3.60(d,J=16.0Hz,4H),3.01-2.89(m,1H),2.84-2.68(m,4H),2.61-2.54(m,2H) ,2.28-2.19(m,2H),2.01-1.75(m,8H),1.76-1.59(m,2H),1.54-1.30(m,2H),1.22-1.10(m,2H).

[0691] Examples 35-38 were synthesized according to the process described for the synthesis of 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0692]

[0693]

[0694] Example 39: 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dimethoxy (2-(2,6-dioxopiperidin-3-yl)isoindolyl) Synthesis of Indoline-1,3-dione

[0695]

[0696] Step A

[0697] A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (5.0 g, 18 mmol, 1.0 equiv), piperidin-4-ylmethanol (2.50 g, 21.7 mmol, 1.2 equiv) and DIEA (7.02 g, 54.3 mmol, 3.0 equiv) in NMP (100 mL) was stirred at 120 ° C for 4 hours. The resulting mixture was diluted with water and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to give 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (6.7 g, 99%) as a yellow oil. LCMS (ESI, m / z): 372.15 [M+H] + .

[0698] Step B

[0699] A solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindole-1,3-dione (500 mg, 1.35 mmol, 1.0 equiv), p-toluenesulfonyl chloride (308 mg, 1.25 mmol, 1.2 equiv), TEA (409 mg, 4.04 mmol, 3.0 equiv) and DMAP (82 mg, 0.67 mmol, 0.5 equiv) in DCM (40 mL) was stirred for 16 h. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (620 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 526.15 [M+H] + .

[0700] Step C

[0701] A solution of (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (100 mg, 0.19 mmol, 1.0 equiv), 7-[(1-acetylpiperidin-4-yl)methoxy]-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (85 mg, 0.19 mmol, 1.0 equiv), KI (16 mg, 0.095 mmol, 0.5 equiv) and DIEA (74 mg, 0.57 mmol, 3.0 equiv) in ACN (5 mL) was stirred at 60 °C for 1 h. The resulting mixture was concentrated in vacuo, and 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 NH4HCO3), 5% to 95% gradient in 20 minutes; detector, UV254nm), and further purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μ m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 45% B in 9.5 min; detector: 254 / 220 nm; RT (min): 9.78) to give 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (17 mg, 11%) as a yellow solid. LCMS (ESI, m / z): 802.35 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ12.15(s,1H),11.05(s,1H),7.56(dd,J=8.6,6.9Hz,1H),7.16-7.04(m,2 H),6.95-6.84(m,2H),5.06(dd,J=12.6,5.6Hz,1H),4.40(d,J=13.0Hz,1H),4.00(d,J=6.3Hz,2H) ,3.84(d,J=13.4Hz,1H),3.74-3.54(m,4H)3.53-3.42(m,1H),3.11-3.00(m,1H)2.94-2.52(m,8H) ,2.39-2.34(m,2H),2.34-2.12(m,1H),2.12-1.68(m,11H),1.63-1.20(m,7H),1.01-0.89(m,1H).

[0702] Example 40 was synthesized according to the process described for the synthesis of 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0703]

[0704] Example 41: 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3, 4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindoline-2-yl Synthesis of 2,6-piperidin-2,6-dione

[0705]

[0706] Step A

[0707] A solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (160 mg, 0.49 mmol, 1.0 eq), azetidin-3-ylmethanol hydrochloride (73 mg, 0.59 mmol, 1.2 eq), Pd-PEPPSI-IPentCl2-methylpyridine (o-methylpyridine) (42 mg, 0.050 mmol, 0.1 eq) and Cs2CO3 (323 mg, 0.99 mmol, 2.0 eq) in dioxane (10 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with DCM (3×30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water, 5% to 20% gradient over 10 minutes; detector, UV 254 nm) to give 3-(4-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95 mg, 58%) as a white solid. LCMS (ESI, m / z): 330.15 [M+H] + .

[0708] Step B

[0709] To a stirred solution of 3-(4-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.27 mmol, 1.0 equiv), TEA (138 mg, 1.37 mmol, 5.0 equiv) and DMAP (17 mg, 0.14 mmol, 0.5 equiv) in DCM (25 mL) was added methanesulfonic anhydride (143 mg, 0.82 mmol, 3.0 equiv) portionwise at 0 °C and then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water, 5% to 30% gradient in 10 minutes; detector, UV 254nm) to give (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)azetidin-3-yl)methyl methanesulfonate (78.2 mg, 70%) as a white solid. LCMS (ESI, m / z): 408.15 [M+H] + .

[0710] Step C

[0711] A mixture of (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)azetidin-3-yl)methyl methanesulfonate (61 mg, 0.15 mmol, 1.0 equiv), 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (67 mg, 0.15 mmol, 1.0 equiv), DIEA (96 mg, 0.75 mmol, 5.0 equiv) and KI (50 mg, 0.29 mmol, 2.0 equiv) in ACN (30 mL) was stirred overnight at 80° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography, eluting with water / CH3CN (67:33), and further purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35% B to 40% B, 40% B in 8 min; wavelength: 254 nm; RT (min): 8), to give 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7 mg, 6%) as a white solid. LCMS (ESI, m / z): 760.30 [M+H] + . 1 HNMR(300MHz,DMSO-d6)δ12.11(s,1H),10.95(s,1H),7.31(t,J=7.7Hz,1H),7.04(d,J=7.3Hz,1H), 6.97-6.80(m,2H),6.54(d,J=7.9Hz,1H),5.08(dd,J=13.1,5.2Hz,1H),4.48-4.23(m,3H),4.21-3.9 4(m,4H),3.91-3.80(m,1H),3.79-3.46(m,5H),2.92-2.72(m,4H),2.67-2.59(m,1H),2.58-2.54(m, 2H),2.10-1.82(m,8H),1.82-1.71(m,2H),1.47-1.36(m,2H),1.32-1.09(m,5H),0.90-0.80(m,1H).

[0712] Example 42: 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazole Synthesis of (1-(4-(2-piperidin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione

[0713]

[0714] A solution of 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (173 mg, 0.406 mmol, 1 eq) in DMSO (5 mL) was treated with 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (117 mg, 0.406 mmol, 1 eq) and DIEA (210 mg, 1.62 mmol, 4 eq) at 80° C. for 3 h. The mixture was concentrated and 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 NH4HCO3), 10% to 41% gradient over 20 min; detector, UV 254 nm. The product (85 mg) was obtained as a brown solid. The 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: 24% B to 34% B, 34% B in 10 minutes; wavelength: 220 / 254 nm; RT (min): 11.80) to give 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (49.2 mg, 18%) as a brown solid. LCMS (ESI, m / z): 678.20 [M+H] + .1HNMR(300MHz,DMSO-d6)δ12.02(br,1H),10.77(s,1H),6.90(s,1H),6.85(s,1H),6.74(d,J =8.5Hz,2H),6.60(d,J=8.5Hz,2H),5.38(d,J=7.2Hz,1H),4.25-4.15(m,1H),3.96(d,J=7.1H z,2H),3.70-3.59(m,5H),2.91(s,3H),2.85-2.65(m,3H),2.62-2.55(m,2H),2.41(s,4H),2. 05-1.84(m,5H),1.51-1.35(m,2H),1.30-1.15(m,2H),0.63-0.52(m,2H),0.41-0.31(m,2H).

[0715] According to the process described in Example 42 for the synthesis of 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, appropriate structural units were used and the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions were adjusted as needed to synthesize Examples 43-49.

[0716]

[0717]

[0718]

[0719]

[0720] Example 50: 3-(5-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazoline- 2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione synthesis

[0721]

[0722] A solution of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, 0.336 mmol, 1 eq) and DMP (285 mg, 0.672 mmol, 2 eq) in DCM (2 mL) was stirred at room temperature for 1 hour. To the above mixture was added 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (123 mg, 0.338 mmol, 1 eq) and NaBH3CN (42.4 mg, 0.68 mmol, 2 eq) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. 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 NH4HCO3), gradient 10% to 45% in 10 minutes; detector, UV 254 nm. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 55% B to 60% B, 60% B in 8 minutes; wavelength: 254 nm; RT (min): 8) to give 3-(5-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28.6 mg, 12%) as a white solid. LCMS (ESI, m / z): 703.30 [M+H] + .1HNMR (400MHz, DMSO-d6) δ12.14(s,1H),10.93(s,1H),7.49(d,J=8.4Hz,1H),7.03(d,J=8.1Hz,2H),6.88(d ,J=15.7Hz,2H),5.04(dd,J=13.3,5.1Hz,1H),4.32-4.19(m,2H),3.96(d,J=7.1Hz,2H),3.85(d,J=12.5Hz,2H ),3.60(s,2H),2.93-2.68(m,6H),2.64-2.54(m,2H),2.40-2.32(m,1H),2.11(d,J=6.6Hz,2H),2.01-1.85(m, 4H),1.79-1.65(m,3H),1.52-1.39(m,2H),1.29-1.06(m,3H),0.70-0.60(d,J=7.8Hz,2H),0.38-0.27(m,2H).

[0723] Example 51: 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methyl oxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl) Synthesis of (amino)piperidine-2,6-dione formate

[0724]

[0725] Step A

[0726] A solution of 2-(((1-(azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.04 g, 2.26 mmol, 1 eq), 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (0.75 g, 3.14 mmol, 1.5 eq) and STAB (0.89 g, 4.18 mmol, 2 eq) in DCM (8 mL) was stirred for 2 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (91:9) to give 5-fluoro-2-(((1-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (733 mg, 51%) as a yellow solid. LCMS (ESI, m / z): 685.29 [M+H] + .

[0727] Step B

[0728] A solution of Fe (295 mg, 5.28 mmol, 5 eq.) and NH4Cl (113 mg, 2.11 mmol, 2 eq.) in EtOH (6 mL) and water (3 mL) was stirred at 80° C. for 10 min, followed by the addition of 5-fluoro-2-(((1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (723 mg, 1.06 mmol, 1 eq.) at 80° C. The final reaction mixture was irradiated with microwave radiation at 80° C. for 30 min. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (91:9) to give 2-(((1-(1-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (669 mg, 97%) as a yellow solid. LCMS (ESI, m / z): 655.32 [M+H] + .

[0729] Step C

[0730] A solution of 2-(((1-(1-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (200 mg, 0.305 mmol, 1 eq), 3-bromopiperidine-2,6-dione (176 mg, 0.915 mmol, 3 eq) and NaHCO3 (180 mg, 2.14 mmol, 7 eq) in ACN (4 mL) was stirred at 90°C overnight. The mixture was concentrated and 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 NH4HCO3), gradient 10% to 50% in 20 minutes; detector, UV 254 nm to give the crude material as a white solid. The crude product was further purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 5% B in 2 minutes, 9% B to 19% B in 10 minutes; wavelength: 254 nm / 220 nm) to give 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione formate (27.8 mg, 12%) as a white solid. LCMS (ESI, m / z): 766.25 [M+H] + .1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.22(s,2H),6.93-6.79(m,3H),6.50(dd,J=15.0,2.6Hz,1H),6.41( dd,J=8.7,2.6Hz,1H),5.79(d,J=7.6Hz,1H),4.30-4.20(m,1H),3.993(d,J=6.4Hz,2H),3.92-3.83(m,2H) ,3.66-3.50(m,4H),3.40-3.28(m,2H),3.11-3.01(m,3H),2.95-2.80(m,2H),2.79-2.70(m,1H),2.68-2.5 8(m,3H),2.57-2.54(m,1H),2.51-2.50(m,3H),2.40-2.30(m,1H),2.11-1.63(m,10H),1.50-1.30(m,6H).

[0731] According to the process described in the synthesis of 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione formate Example 51, appropriate structural units were used and the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions were adjusted as needed to synthesize Examples 52-53.

[0732]

[0733]

[0734] Example 54: 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)- Synthesis of (1,4'-bipiperidinyl)-1'-yl)-3-fluorophenyl)-amino)piperidin-2,6-dione formate

[0735]

[0736] Step A

[0737] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (2 g, 5.50 mmol, 1 eq) in DCE (100 mL) was treated with 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (1.97 g, 8.26 mmol, 1.5 eq) for 3 h, then STAB (2.33 g, 11.0 mmol, 2 eq) was added portionwise. The resulting mixture was stirred for 1 day. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (7:1) to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(2-fluoro-4-nitrophenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (1.4 g, 43%) as a yellow oil. LCMS (ESI, m / z): 586.35 [M+H] + .

[0738] Step B

[0739] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(2-fluoro-4-nitrophenyl)-[1,4'-bipiperidinyl]-4-yl)thio)methyl)quinazolin-4(3H)-one (500 mg, 0.854 mmol, 1 eq), 4,4'-bipyridine (13.3 mg, 0.085 mmol, 0.1 eq) and B2(OH)4 (230 mg, 2.56 mmol, 3 eq) in DMF (10 mL) was stirred for 30 min. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give 2-(((1'-(4-amino-2-fluorophenyl)-[1,4'-bipiperidinyl]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (300 mg, 63%) as a yellow solid. LCMS (ESI, m / z): 556.45 [M+H] + .

[0740] Step C

[0741] A solution of 2-(((1'-(4-amino-2-fluorophenyl)-[1,4'-bipiperidinyl]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (300 mg, 0.54 mmol, 1 eq), 3-bromopiperidine-2,6-dione (1037 mg, 5.4 mmol, 10 eq) and NaHCO3 (453.5 mg, 5.4 mmol, 10 eq) in ACN (30 mL) was stirred at 90°C for 3 days. The resulting mixture was concentrated and the residue was purified by C18 reverse phase chromatography eluting with water / ACN (45:55) and further purified by preparative HPLC under the following conditions (column: Xselect CSHOBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 5% B in 2 minutes, 12% B to 22% B in 10 minutes; wavelength: 254 nm / 220 nm; RT (min): 9.6) to give 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (63.4 mg, 17%) as a grey solid. LCMS (ESI, m / z): 667.25 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.13(s,1H),10.76(s,H),8.18(s,1H),6.93-6.76(m,3H),6.50(dd,J=15.0,2.6Hz, 1H),6.40(dd,J=8.8,2.5Hz,1H),5.77(d,J=7.6Hz,1H),4.30-4.19(m,1H),3.99(d,J=6.8Hz,2H),3.65(s,2H ),3.15(d,J=10.9Hz,2H),2.89-2.76(m,4H),2.76-2.67(m,2H),2.35-2.27(m,1H),2.27-2.23(m,2H),2.13- 2.04(m,1H),2.03-1.74(m,5H),1.57-1.39(m,4H),1.31-1.13(m,2H),0.64-0.54(m,2H),0.40-0.32(m,2H).

[0742] Example 55: 3-((4-(4-(2-(((1r,4r)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6- Synthesis of diketones .

[0743]

[0744] Step A

[0745] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one (1000 mg, 2.64 mmol, 1 eq), (2-bromoethoxy)(tert-butyl)dimethylsilane (759 mg, 3.17 mmol, 1.2 eq) and K2CO3 (1096 mg, 7.93 mmol, 3 eq) in DMF (5 mL) was stirred at 80° C. for 3 h. 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 NH4HCO3), 10% to 90% gradient over 30 min; detector, UV 254 nm. 2-((((1r,4r)-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (870 mg, 61%) was obtained as a white solid. LCMS (ESI, m / z): 537.20 [M+H] + .

[0746] Step B

[0747] A solution of 2-((((1r,4r)-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (820 mg, 1.53 mmol, 1 eq) in HCl in 1,4-dioxane (10 mL, 4M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to give crude 7-(cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one (990 mg) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 423.50 [M+H] + .

[0748] Step C

[0749] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one (990 mg, 2.34 mmol, 1 eq) and TEA (711 mg, 7.03 mmol, 3 eq) in DCM (5 mL) was stirred at room temperature for 1 hour. 3-nitrobenzenesulfonyl chloride (779 mg, 3.51 mmol, 1.5 eq) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred at 40°C for 3 hours. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (8:1) to give 2-((((1r,4r)-4-(2-chloroethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (500 mg, 48%) as a white solid. LCMS (ESI, m / z): 441.90 [M+H] + .

[0750] Step D

[0751] A solution of 2-((((1r,4r)-4-(2-chloroethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (500 mg, 1.13 mmol, 1 eq), 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (521 mg, 1.70 mmol, 1.5 eq), KI (37.7 mg, 0.227 mmol, 0.2 eq) and K2CO3 (313 mg, 2.27 mmol, 2 eq) in ACN (5 mL) was stirred at 80° C. for 3 h. 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 NH4HCO3), gradient 0% to 90% in 30 min; detector, UV 254 nm. The crude product (200 mg) was purified by preparative HPLC under the following conditions (column: Xselect CSHOBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 5% B in 2 minutes, 16% B to 26% B in 10 minutes; wavelength: 254 nm / 220 nm, RT (min): 8.9) to give 3-((4-(4-(2-(((1r,4r)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (76 mg, 9%) as a white solid. LCMS (ESI, m / z): 711.50 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.79(s,1H),7.02-6.78(m,3H),6.58-6.39(m,2H), 6.05-5.79(m,1H),4.58-4.40(m,2H),4.30-4.10(m,2H),4.04-3.94(m,4H), 3.83-3.20(m,3H),3.11-2.79(m,4H),2.79-2.53(m,6H),2.15-1.93(m,3H), 1.93-1.74(m,3H),1.39-1.01(m,5H),0.66-0.54(m,2H),0.42-0.31(m,2H).

[0752] Example 56: 3-((4-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazoline- 2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione formate synthesis

[0753]

[0754] Step A

[0755] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (1 g, 2.75 mmol, 1 eq), tert-butyl 4-formylpiperidine-1-carboxylate (0.88 g, 4.13 mmol, 1.5 eq) and STAB (1.75 g, 8.25 mmol, 3 eq) in DCE (8 mL) was stirred for 1 h. After concentration, the residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give tert-butyl 4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.6 g, 99%) as an orange oil. LCMS (ESI, m / z): 561.30 [M+H] + .

[0756] Step B

[0757] A solution of tert-butyl 4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.6 g, 2.85 mmol, 1 equiv) in HCl in 1,4-dioxane (8 mL, 4M) was stirred for 1 hour. The mixture was concentrated to dryness to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride (1 g, 65%) as a yellow solid. LCMS (ESI, m / z): 461.20 [M+H] + .

[0758] Step C

[0759] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride (1.00 g, 0.022 mmol, 1 eq), 1,2-difluoro-4-nitrobenzene (415 mg, 0.026 mmol, 1.2 eq) and NaHCO3 (547 mg, 0.066 mmol, 3 eq) in ACN (5 mL) was stirred at 90 °C for 5 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:97) to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (580 mg, 39%) as a yellow solid. LCMS (ESI, m / z): 600.30 [M+H] + .

[0760] Step D

[0761] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (550 mg, 0.917 mmol, 1 eq), Fe (256 mg, 0.085 mmol, 5 eq) and NH4Cl (98.1 mg, 1.83 mmol, 2 eq) in EtOH (5 mL) and water (1 mL) was stirred at 80° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH (5×10 mL). The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give 2-(((1-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (487 mg, 93%) as a yellow solid. LCMS (ESI, m / z): 570.15 [M+H] + .

[0762] Step E

[0763] A solution of 2-(((1-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (477 mg, 0.84 mmol, 1 eq), 3-bromopiperidine-2,6-dione (482 mg, 2.51 mmol, 3 eq) and NaHCO3 (352 mg, 4.19 mmol, 5 eq) in ACN (3 mL) was stirred at 90° C. overnight. The mixture was concentrated and the residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 50% over 10 min; detector, UV 254 nm. 3-((4-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (184 mg, 29%) was obtained as a dark blue solid. LCMS (ESI, m / z): 681.25 [M+H] + .1H NMR (400MHz, DMSO-d6) δ12.14(s,1H),10.77(s,1H),8.15(s,1H),6.93-6.77(m,3H),6.49(dd,J=14.9,2.6Hz,1 H),6.41(dd,J=8.8,2.6Hz,1H),5.77(d,J=7.6Hz,1H),4.30-4.19(m,1H),3.97(d,J=7.1Hz,2H),3.60(s,2H),3 .10(d,J=11.1Hz,2H),2.83-2.65(m,4H),2.62-2.53(m,3H),2.15(d,J=7.1Hz,2H),2.12-2.04(m,3H),2.00-1. 78(m,5H),1.73(d,J=12.1Hz,2H),1.64-1.36(m,3H),1.30-1.15(m,3H),0.64-0.55(m,2H),0.40-0.32(m,2H).

[0764] Example 57: 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)- Synthesis of (1,4'-bipiperidinyl)-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidin-2,6-dione

[0765]

[0766] Step A

[0767] A solution of 2-(([1,4'-bipiperidinyl]-4-ylthio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride (600 mg, 1.24 mmol, 1 eq), 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (260 mg, 1.24 mmol, 1 eq) and NaHCO3 (313 mg, 3.73 mmol, 3 eq) in ACN (10 mL) was stirred at 80°C overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(4-nitro-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (420 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 636.10 [M+H] + .

[0768] Step B

[0769] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(4-nitro-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (420 mg, 0.661 mmol, 1 eq), Fe (185 mg, 3.31 mmol, 5 eq) and NH4Cl (70.7 mg, 1.32 mmol, 2 eq) in EtOH (5 mL) and water (1 mL) was stirred at 80 °C for 3 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (7:1) to give 2-(((1'-(4-amino-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidinyl]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (350 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 606.10 [M+H] + .

[0770] Step C

[0771] A solution of 2-(((1'-(4-amino-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (320 mg, 0.528 mmol, 1 eq), 3-bromopiperidine-2,6-dione (304 mg, 1.58 mmol, 3 eq) and NaHCO3 (222 mg, 2.64 mmol, 5 eq) in ACN (5 mL) was stirred at 90° C. overnight. The resulting mixture was concentrated and 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 NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (135 mg, 36%) was obtained as a white solid. LCMS (ESI, m / z): 717.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.79(s,1H),7.27(d,J=8.7Hz,1H),6.94-6.83(m,4H),6.17( d,J=7.8Hz,1H),4.44-4.33(m,1H),3.97(d,J=7.1Hz,2H),3.60(s,2H),2.86-2.79(m,4H),2.77-2.63 (m,3H),2.62-2.55(m,2H),2.32-2.25(m,1H),2.22-2.11(m,2H),2.09-2.03(m,2H),1.96-1.86(m,3H ),1.72(d,J=8.0Hz,2H),1.54-1.42(m,3H),1.29-1.22(m,1H),0.64-0.55(m,2H),0.40-0.33(m,2H).

[0772] According to the process described in Example 57 for the synthesis of 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione, appropriate structural units were used and the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions were adjusted as needed to synthesize Examples 58-59.

[0773]

[0774]

[0775] Example 60: 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl) Synthesis of (1,4'-bipiperidinyl)-1'-yl)-(3-fluorophenyl)-2,4(1H,3H)-dione

[0776]

[0777] A solution of 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (140 mg, 0.46 mmol, 1 eq.), 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (167 mg, 0.46 mmol, 1 eq.) and STAB (194 mg, 0.92 mmol, 2 eq.) in DMF (8 mL) was stirred at 60° C. for 1 hour. The mixture was 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 50% gradient in 10 minutes; detector, UV 254 nm. The crude product 100 mg was obtained as a white solid. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 5% B in 2 minutes, 10% B to 20% B in 10 minutes; wavelength: 254 / 220 nm; RT (min): 9.2) to give 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (49.4 mg, 16%) as a white solid. LCMS (ESI, m / z): 653.30 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ12.25(br,1H),10.45-10.24(m,1H),8.29(d,J=16.3Hz,1H),7.40-6.80(m,4H), 4.06-3.92(m,2H),3.75(dd,J=14.4,7.6Hz,2H),3.62(d,J=11.5Hz,2H),3.42-3.30(m,2H),2.89-2.79(m 3H),2.78-2.54(m,4H),2.40-2.32(m,1H),2.23-2.17(m,2H),2.00-1.90(d,J=15.3Hz,2H),1 .89-1.70(m,2H),1.68-1.34(m,4H),1.32-1.14(m,1H),0.70-0.50(m,2H),0.46-0.26(m,2H).

[0778] According to the process described in Example 60 for the synthesis of 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione, appropriate structural units were used and the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions were adjusted as needed to synthesize Examples 61-62.

[0779]

[0780]

[0781] Example 63: 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazoline- Synthesis of 2-(2-yl)ethyl)piperazine-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate .

[0782]

[0783] A solution of 2-(2-chloroethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (180 mg, 0.607 mmol, 1 eq), 3-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (236 mg, 0.607 mmol, 1 eq), K2CO3 (168 mg, 1.21 mmol, 2 eq) and KI (10.1 mg, 0.061 mmol, 0.1 eq) in ACN (20 mL) was stirred at 60°C for 1 h. The resulting mixture was concentrated and purified by silica gel column chromatography, eluting with DCM / MeOH (8:1), and then purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 16% B to 26% B in 10 minutes; wavelength: 254 / 220 nm; RT (min): 12.8) to give 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (17.6 mg, 4%) as a dark grey solid. LCMS (ESI, m / z): 650.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.15(br,1H),10.76(s,1H),8.27(s,1H),6.93-6.77(m,3H),6.49(dd,J=15.0,2.6Hz ,1H),6.40(dd,J=8.7,2.5Hz,1H),5.78(d,J=7.6Hz,1H),4.30-4.19(m,1H),3.95(d,J=7.0Hz,2H),3.65-3.55( m,3H),3.15(d,J=11.0Hz,2H),2.85-2.76(m,1H),2.81-2.66(m,6H),2.62-2.50(m,4H),2.44-2.30(m,4H),2.2 7-2.19(m,1H),2.13-2.04(m,1H),1.95-1.72(m,4H),1.58-1.46(m,2H),0.64-0.55(m,2H),0.39-0.29(m,2H).

[0784] Example 64 was synthesized according to the process described in the synthesis of 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate Example 63, using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0785]

[0786] Example 65: 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazoline-2- Synthesis of 1,4'-bipiperidinyl-1'-yl)-3-fluorophenyl)amino)piperidin-2,6-dione

[0787]

[0788] Step A

[0789] A solution of 2-(2-([1,4'-bipiperidinyl]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride (90 mg, 0.194 mmol, 1 eq.), 1,2-difluoro-4-nitrobenzene (30.8 mg, 0.194 mmol, 1 eq.) and DIEA (100 mg, 0.776 mmol, 4 eq.) in NMP (4 mL) was stirred at 80° C. for 1 hour. 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 NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. 7-(Cyclopropylmethoxy)-5-fluoro-2-(2-(1'-(2-fluoro-4-nitrophenyl)-[1,4'-bipiperidinyl]-4-yl)ethyl)quinazolin-4(3H)-one (100 mg, 91%) was obtained as a yellow solid. LCMS (ESI, m / z): 568.16 [M+H] + .

[0790] Step B

[0791] A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(2-(1'-(2-fluoro-4-nitrophenyl)-[1,4'-bipiperidinyl]-4-yl)ethyl)quinazolin-4(3H)-one (100 mg, 0.176 mmol, 1 eq), Fe (49.2 mg, 0.880 mmol, 5 eq) and NH4Cl (18.9 mg, 0.352 mmol, 2 eq) in EtOH (5 mL) and water (1 mL) was stirred at 80 °C for 1 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give 2-(2-(1'-(4-amino-2-fluorophenyl)-[1,4'-bipiperidinyl]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (80 mg, 85%) as a white solid. LCMS (ESI, m / z): 538.16 [M+H] + .

[0792] Step C

[0793] A solution of 2-(2-(1'-(4-amino-2-fluorophenyl)-[1,4'-bipiperidin]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (70 mg, 0.13 mmol, 1 eq.), 3-bromopiperidine-2,6-dione (50.0 mg, 0.26 mmol, 2 eq.) and NaHCO3 (43.8 mg, 0.52 mmol, 4 eq.) in ACN (10 mL) was stirred overnight at 90° C. The resulting mixture was concentrated and 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 NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (22.2 mg, 24%) was obtained as a purple solid. LCMS (ESI, m / z): 649.30 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.07(br,1H),10.77(s,1H),8.23(s,2H),6.91-6.76(m,3H),6.50(dd,J=15.0,2.6Hz, 1H), 6.41 (dd, J=8.7, 2.6Hz, 1H), 5.79 (d, J=7.6Hz, 1H), 4.28-4.22 (m, 1H), 3.96 (d, J=7.1Hz, 2H), 3.17 (d, J=11. 0Hz,2H),2.99-2.90(m,2H),2.76-2.65(m,2H),2.61-2.57(m,2H),2.56-2.51(m,3H),2.28-2.15(m,2H),2.10- 2.01(m,1H),1.95-1.80(m,3H),1.72-1.59(m,6H),1.34-1.14(m,4H),0.62-0.56(m,2H),0.36(t,J=5.1Hz,2H).

[0794] Example 66 was synthesized according to the process described in Example 65 for the synthesis of 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, using appropriate structural units and adjusting the reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0795]

[0796] Example 67: 3-((4-(4-(((7-(Cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)- Synthesis of (1,4'-bipiperidinyl)-1'-yl)-3-fluorophenyl)-amino)piperidin-2,6-dione formate

[0797]

[0798] Step A

[0799] A solution of tert-butyl 4-(((7-bromo-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1000 mg, 2.12 mmol, 1 eq), ethynylcyclopropane (420 mg, 6.35 mmol, 3 eq), Pd(PPh3)2Cl2 (149 mg, 0.21 mmol, 0.1 eq), CuI (40.3 mg, 0.21 mmol, 0.1 eq) and TEA (429 mg, 4.23 mmol, 2 eq) in DMSO (10 mL) was stirred at 100°C under nitrogen atmosphere overnight. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:9) to give tert-butyl 4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1.3 g) as a brown oil. The crude product was used directly in the next step without further purification, LCMS (ESI, m / z): 458.10 [M+H] + .

[0800] Step B

[0801] A solution of tert-butyl 4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (260 mg, 0.57 mmol, 1 equiv) in HCl in 1,4-dioxane (5 mL, 4M) was stirred for 1 hour. The mixture was concentrated to dryness to give 7-(cyclopropylethynyl)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (130 mg, 64%) as a white solid. LCMS (ESI, m / z): 358.10 [M+H] + .

[0802] Step C

[0803] A solution of 7-(cyclopropylethynyl)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (100 mg, 0.28 mmol, 1 eq), 3-((3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)amino)piperidine-2,6-dione (179 mg, 0.56 mmol, 2 eq), STAB (119 mg, 0.56 mmol, 2 eq) and TEA (2.83 mg, 0.028 mmol, 0.1 eq) in DCE (1 mL) was stirred for 1 hour. 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 NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. The crude product (100 mg) was further purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 23% B to 33% B in 10 minutes; wavelength: 254 / 220 nm; RT (min): 9) to give 3-((4-(4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (14.3 mg, 8%) as a white solid. LCMS (ESI, m / z): 661.25 [M+H] + .1HNMR (400MHz, DMSO-d6) δ10.77(s,1H),8.21(s,1H),7.34(s,1H),7.20(d,J=11.2Hz,1H),6.82(t,J=9.3 Hz,1H),6.59-6.36(m,2H),5.78(d,J=7.6Hz,1H),4.32-4.18(m,1H),3.61-3.54(m,5H),3.15(d,J=10.7Hz, 3H),2.84-2.65(m,5H),2.62-2.56(m,2H),2.28-2.22(m,3H),2.14-2.02(m,1H),1.94-1.89(m,2H),1.88-1 .81(m,1H),1.77-1.60(m,2H),1.66-1.54(m,3H),1.49-1.39(m,2H),0.97-1.91(m,2H),0.83-0.76(m,2H).

[0804] Example A: NanoLuc Assay for Degradation of PARP14

[0805] NanoLuc Plasmid

[0806] The catalytic domain of human PARP14 (residues 1611 to 1801, GenBank accession number NM_017554) was inserted into the pcDNA3.1(-) vector. The insert also contained a NanoLuc tag at the N-terminus of the PARP14 protein.

[0807] Determination of PARP14 degradation

[0808] The degradation of PARP14 protein was assessed using the measurement of the NanoLuc tag as a surrogate for PARP14 protein. PARP14 with a NanoLuc tag was overexpressed in HEK-293T cells (ATCC) using the plasmids described in Table 1. Plasmid DNA was diluted in empty vector DNA and then added to 1.163 mL of OptiMEM (Thermo Fisher) without phenol red. The concentration of plasmid DNA used in each assay is described in Table 1. The plasmid DNA was mixed with 78.5 μL Fugene HD (Promega) and incubated for 5 minutes.

[0809] Table 1

[0810] Plasmids Plasmid DNA concentration Concentration of empty vector PARP14(pRTX240) 0.0002μg / μL 0.0198μg / μL

[0811] Next, 1.125mL was added to 10 million 293T cells in DMEM (Thermo Fisher) supplemented with 10% FBS (VWR) and 1X Glutamax (Gibco). The transfectants were incubated at 37 degrees for 24 hours in an incubator supplemented with 5% CO2. The cells were then trypsinized and cultured in OptiMEM medium without phenol red. The transfected HEK-293T cells were diluted to 125,000 cells / mL and then added to an assay plate (Corning 3574) using Multidrop (Thermo Fisher) to add 40 μL to each well of a 384-well plate to obtain 5,000 cells / well. Each test compound of a 40nL dose response curve diluted in DMSO was added to the cell plate using Mosquito (TTP Labtech), and the plate was incubated at 37 degrees for 2 hours. The assay plate was brought to room temperature and 20 μL NanoGlo (Promega) was added to the plate per well. Luminescence was measured on an Envision (Perkin Elmer).

[0812] The average DMSO was calculated from 32 wells containing 0.1% DMSO only in columns 12 and 24 of the assay plate. The % DMSO value was calculated as follows:

[0813]

[0814] The % DMSO values ​​were plotted as a function of compound concentration and the DC was derived using the following 4-parameter fit: 50 value:

[0815]

[0816] where top, bottom and Hill coefficient can be floated. Y is the % of DMSO and X is the compound concentration.

[0817] DC of Example Compounds 50 The data are provided in Table 2 below ("+" < 0.1 μM; "++" ≥ 0.1 μM and < 1 μM; and "+++" ≥ 1 μM).

[0818] Example B: HiBiT assay for degradation of PARP14

[0819] HiBiT-tagged PARP14 in Jurkat cells expressing LgBiT

[0820] Jurkat cells stably transfected with LgBiT (Promega) were engineered to contain a HiBiT tag (Genbank accession number: NM_017554) on both alleles of the PARP14 gene via CRISPR / Cas9 editing. The HiBiT tag is an 11 amino acid tag created by Promega that binds to the LgBiT protein to form a Tagging. Clones were isolated and HiBiT tagging was confirmed by Sanger sequencing.

[0821] Determination of PARP14 degradation

[0822] The degradation of PARP14 protein was assessed by measuring the luminescence of the HiBiT tag bound to the LgBiT protein as a surrogate for PARP14 protein.

[0823] Jurkat cells are diluted to 250,000 cells / mL and then added to an assay plate (Corning 3574) using Multidrop (Thermo Fisher) to add 20 μL to each well of a 384-well plate to obtain 5000 cells / well. Each test compound of a 20 nL dose response curve diluted in DMSO is added to the cell plate using Mosquito (TTP Labtech), and the plate is incubated at 37°C for 2 or 24 hours. The assay plate is placed at room temperature, and 5 μL of live cell substrates (Promega) are then added to the plate in each well. Luminescence is measured on Envision (Perkin Elmer).

[0824] The average DMSO was calculated from 32 wells containing 0.1% DMSO only in columns 12 and 24 of the assay plate. The % DMSO value was calculated as follows:

[0825]

[0826] The % DMSO values ​​were plotted as a function of compound concentration and the DC was derived using the following 4-parameter fit: 50 value:

[0827]

[0828] where top, bottom and Hill coefficient can be floated. Y is the % of DMSO and X is the compound concentration.

[0829] DC of Example Compounds 50 The data are provided in Table 2 below ("+" < 0.03 μM; "++" ≥ 0.03 μM).

[0830] Table 2. DC of Example Compounds 50 data

[0831]

[0832]

[0833]

[0834] 1 : "A" refers to the assay described in Example A; "B" refers to the assay described in Example B.

[0835] Example C: Cell counts and expression in BALF and lung homogenates after Alternaria sensitization and treatment with PARP14 degraders Reduction of cytokines .

[0836] The effect of compound 17 was studied in the Alternaria asthma mouse model. On days 1-5, male Balb / c mice under isoflurane anesthesia were attacked by dropping 5 μg (protein weight) of Alternaria in 40 μL PBS into each nostril. Compound 17 was administered two days before Alternaria attack (days were defined as -1 day), and animals were treated with vehicle (10% DMSO / 45% PEG-400 / 45% "20% HP-β-CD" aqueous solution) or compound 17 (30 mg / kg and 100 mg / kg) once a day by subcutaneous injection for 7 days (defined as -1 day to 5 day). Total cell counts and differential cell counts of BALF fluid samples were measured using XT-2000iV analyzer (Sysmex). Cytokine concentrations of BALF supernatants in samples from all groups were measured using ELISA kits (Biotechne, UK). Statistical significance was calculated using one-way ANOVA followed by Dunnett's post-test, comparing treatment groups to vehicle controls (P<0.05). Figure 1 It is shown that starting from the 30 mg / kg dose, compound 17 significantly reduced total cell counts in a dose-dependent manner. Figure 2 shows that starting from 30 mg / kg, compound 17 also significantly reduced eosinophils and cytokines IL-33, IL-4 and IL-5 in BALF in a dose-dependent manner.

[0837] From the foregoing description, in addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications and publications, is incorporated herein by reference in its entirety.

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 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 3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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; L 1 Select from the following: (vii) a bond such that ring A is directly attached to moiety E; (viii)-(C 1-4 alkyl)-; (ix)-(C 2-4 alkenyl)-; (x)-(C 2-4 Alkynyl); (xi) The following structure: and (xii) 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 is a 4- to 10-membered heterocycloalkyl group; 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; wherein at least one of b, c, e and f is 1; and 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; Provided that the compound is not: 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide; (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetylamino)heptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide.

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 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 3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 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; L 1 Select from the following: (xiii) a bond such that ring A is directly attached to moiety E; (xiv)-(C 1-4 alkyl)-; (xv)-(C 2-4 alkenyl)-; (xvi)-(C 2-4 Alkynyl)-; (xvii) The following structure: and (xviii) 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 is a 4- to 10-membered heterocycloalkyl group; 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; wherein at least one of b, c, e and f is 1; and 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; Provided that the compound is not: 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide; (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetylamino)heptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W is CR W .

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is CR X .

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is CR Z .

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y 1 For -O-.

7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y 1 For-NR 3 -.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y 1 For-(C 2-4 Alkynyl)-.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y 2 For -S-.

10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y 2 It is -CH2-.

11. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y 2 For -O-.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is a monocyclic or polycyclic 4 to 18-membered heterocycloalkyl group, wherein Ring A is optionally substituted by 1, 2, 3 or 4 R A replace.

13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is a monocyclic 4- to 7-membered heterocycloalkyl, wherein Ring A is optionally substituted by 1, 2, 3 or 4 R A replace. 14 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl. 15 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is piperazinyl.

16. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is C 3-14 Cycloalkyl, 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 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is C 3-7 Cycloalkyl, wherein ring A is optionally substituted by 1, 2, 3 or 4 R A replace.

18. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is a cyclohexyl group.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 4- to 18-membered heterocycloalkyl group, wherein Ring B is optionally substituted by 1, 2, 3 or 4 R B replace.

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted with 1, 2, 3 or 4 R B Substituted piperidinyl or tetrahydro-2H-pyranyl.

21. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is tetrahydro-2H-pyran-4-yl or 1-acetylpiperidin-4-yl.

22. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is C 3-14 Cycloalkyl, 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 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclopentyl or cyclopropyl.

24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is H.

25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R 3 For H.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Each is H.

27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 Each is H.

28. A compound according to any one of claims 1 to 27, 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 。 29. A compound according to any one of claims 1 to 27, 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 .

30. A compound according to any one of claims 1 to 29, 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 。 31. A compound according to any one of claims 1 to 29, 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, C(O)R b2 OR a2 .

32. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R B It is C(O)CH3.

33. A compound according to any one of claims 1 to 32, 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 。 34. A compound according to any one of claims 1 to 32, 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 .

35. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R W is selected from H, halo and C 1-6 Halogenated alkyl.

36. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R W For F.

37. A compound according to any one of claims 1 to 36, 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 .

38. A compound according to any one of claims 1 to 36, 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.

39. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R X For H.

40. A compound according to any one of claims 1 to 39, 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 .

41. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R Z For H.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein m is 0.

43. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein m is 1.

44. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond such that ring A is directly connected to moiety E.

45. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L 1 For-(C 1-4 alkyl).

46. ​​A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L 1 For-(C 2-4 alkynyl).

47. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L 1 For the following structure:

48. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L 1 For the following structure:

49. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein G 1 For-NR G C(O)- or -C(O)-.

50. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein G 1 For-NR G C(O)-, -C(O)-, or -O-.

51. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein G 2 is a 4- to 10-membered heterocycloalkyl group.

52. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein G 2 is piperidinyl, piperazinyl or azetidinyl.

53. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein G 2 is pyrrolidinyl, piperidinyl, piperazinyl or azetidinyl.

54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein G 3 For-NR G C(O)-、-NR G -or -C(O)-.

55. A compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, wherein G 4 It is piperidinyl or piperazinyl.

56. A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein a is 0.

57. A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein a is 1.

58. A compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein b is 0.

59. A compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein b is 1.

60. The compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein c is 0.

61. A compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein c is 1.

62. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein d is 0.

63. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein d is 1.

64. A compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein e is 0.

65. A compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein e is 1.

66. A compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein f is 0.

67. A compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein f is 1.

68. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein R G For H.

69. The compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein E is an E3 ubiquitin ligase binding moiety that binds to the cerebellum.

70. A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

71. A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein E is selected from the following:

72. A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein E is selected from:

73. A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein E is:

74. A compound according to any one of claims 1 to 73, wherein the compound has formula II: or a pharmaceutically acceptable salt thereof.

75. A compound according to any one of claims 1 to 73, wherein the compound has formula IIIa: or a pharmaceutically acceptable salt thereof.

76. A compound according to any one of claims 1 to 73, wherein the compound has the formula IIIb: or a pharmaceutically acceptable salt thereof.

77. A compound according to any one of claims 1 to 73, wherein the compound has the formula IIIc: or a pharmaceutically acceptable salt thereof.

78. The compound according to claim 1 or 2, wherein the compound is selected from: 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(6-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)hexyl)benzamide; 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)butyl)benzamide; N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-(3-(4-(1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-2-oxoimidazolidin-1-yl)piperidine-2,6-dione; 4-(4-((1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 1-(4-(1-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-((4-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-((4-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-((4-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 4-(4-((4-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-((1-(2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide; 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide; 5-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)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; 3-(5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)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-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and 5-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; Or a pharmaceutically acceptable salt of any of the foregoing substances.

79. The compound of claim 1, wherein the compound is selected from: 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-(6-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-(5-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(((1r,4r)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)pyrrolidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(1'-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[4,4'-bipiperidinyl]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(3-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidinyl]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione Or a pharmaceutically acceptable salt of any of the foregoing substances.

80. A pharmaceutical composition comprising a compound according to any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

81. A method for degrading PARP14, the method comprising contacting the compound according to any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof, with the PARP14.

82. A method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof.

83. 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 79, or a pharmaceutically acceptable salt thereof, in combination with an additional therapy or therapeutic agent.

84. The method of claim 82 or 83, 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.

85. 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 79, or a pharmaceutically acceptable salt thereof.

86. The method of claim 85, 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.

87. The method of claim 85, wherein the inflammatory disease is atopic dermatitis.

88. The method of claim 85, wherein the inflammatory disease is systemic sclerosis.

89. The method of claim 86, 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.

90. The method of claim 89, wherein the severe asthma is T2 high endotype, T2 low endotype, or non-T2 endotype.

91. The method of claim 89, wherein the severe asthma is T2 low endotype or non-T2 endotype.

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