Targeted proteolysis of PARP14 for therapeutic uses

Abstract

The present invention relates to quinazolinones and related compounds that degrade PARP14 and are useful, for example, in the treatment of cancer and inflammatory diseases. TIFF2025526433000377.tif36168

Description

[Technical Field]

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

[0002] Poly(ADP-ribose) polymerase (PARP) is a member of a family of 17 enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, and multiple cellular stress responses (Vyas S et al., Nat Rev Cancer. 2014 Jun 5;14(7):502-509). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and a novel approach to novel therapeutic agents. One member of the PARP family, PARP1, has already been shown to be a valid cancer target for cellular stress induced by DNA damage induced by genetic mutations or cytotoxic chemotherapy, with three clinically approved drugs and several others in late-stage development (Ohmoto A et al., Onco Targets and Therapy. 2017;10:5195).

[0003] Seventeen members of the PARP family have been identified in the human genome based on homology within their catalytic domains (Vyas S et al., Nat Commun. 2013 Aug. 7;4:2240). However, their catalytic activities fall into three distinct categories. Most PARP family members catalyze the transfer of mono-ADP-ribose units onto their substrates (mono-ARTs), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units onto substrates (poly-ARTs). Finally, PARP13 is the only PARP whose catalytic activity has not been demonstrated in vitro or in vivo so far.

[0004] PARP14 is a cytoplasmic and nuclear mono-ART. It was originally identified as BAL2 (B-cell lymphoma 2), a gene associated with poor outcome in diffuse large B-cell lymphoma (DLBCL), along with two other mono-ARTs (PARP9 or BAL1 and PARP15 or BAL3) (Aguiar RC et al., Blood. 2000 December 9;96(13):4328-4334; and Juszczynski P et al., Mol Cell Biol. 2006 July 1;26(14):5348-5359). PARP14, PARP9, and PARP15 are also referred to as macro-PARPs due to the presence of a macrodomain at their N-terminus. The genes for the three macro-PARPs are located at the same genomic locus, suggesting co-regulation. Indeed, gene expression of PARP14 and PARP9 is highly correlated across normal tissues and cancer types. PARP14 is overexpressed in tumors compared to normal tissues, including established cancer cell lines compared to their normal counterparts. Literature examples of cancers with high PARP14 expression include DLBCL (Aguiar RCT et al., J Biol Chem. 2005 Aug. 1; 280(40):33756-33765), multiple myeloma (MM) (Barbarulo A et al., Oncogene. 2012 Oct. 8; 32(36):4231-4242), and hepatocellular carcinoma (HCC) (Iansante V et al., Nat Commun. 2015 Aug. 10; 6:7882). In MM and HCC cell lines, RNA interference (RNAi)-mediated PARP14 knockdown inhibits cell proliferation and survival. Other studies have shown that PARP14 enzymatic activity 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 cell lines with all types of interferon (I, II, and III; www.interferome.org). PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling, affecting transcription downstream 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 promote B cell survival in vitro is similarly reduced in the Parp14 KO setting (Cho SH et al., Blood. 2009 Jan 15;113(11):2416-2425). This reduced survival signaling was mechanistically linked to the impaired ability of Parp14 KO B cells to maintain metabolic fitness and increase Mcl-1 expression. Parp14 KO can extend survival in an Eμ-Myc lymphoma model, suggesting 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 B-cell lymphoma subtype characterized by an inflammatory infiltrate of T cells and dendritic cells and the presence of an IFN-γ gene signature (Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes, including one characterized by host inflammatory response. Monti S et al., Blood. 2005;105(5):1851).

[0006] Through its downstream role in the IL-4 and IFN-γ signaling pathways, PARP14 is involved in T helper cell and macrophage differentiation. Genetic inactivation of PARP14 in macrophages favors the pro-inflammatory M1 phenotype associated with antitumor immunity while attenuating the pro-tumor M2 phenotype. In human and mouse macrophage models, PARP14 knockout or knockdown was found to increase M1 gene expression downstream of IFN-γ while decreasing M2 gene expression downstream of IL-4. Similarly, genetic PARP14 knockout has been shown to reduce the Th2 T helper cell phenotype in the context of skin and airway inflammation, also implicating PARP14's regulatory role 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 by type 2 helper T cell (TH2) and type 17 helper T cell (TH17) cytokines by acting as a coactivator of STAT6- and STAT3-driven transcription (Goenka et al., 2006 PMID16537510; Mehrotra et al., 2015 PMID26222149). PARP14 is upregulated in tissues with inflammatory diseases, such as skin lesions in patients with atopic dermatitis or psoriasis (He et al., 2021 PMID:32709423) or in endobronchial biopsies from patients with mild atopic asthma (Yick et al., 2013 PMID:23314903). Either genetic deletion or catalytic inhibition of PARP14 has been shown to block IL4 / STAT6 signaling in macrophages in vitro (Iwata et al., 2016 PMID:27796300, Schenkel et al., 2021 PMID:33705687) and to suppress 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 under investigation as treatments for several 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). Given the upregulation of PARP14 in tissues with inflammatory diseases, its central role in TH2- and TH17-driven cytokine signaling, and the shared underlying biology of numerous inflammatory diseases, small molecules targeting PARP14 may be promising therapeutic agents for a wide range of inflammatory diseases.

[0008] Most clinically used pharmaceutical agents are based on small molecule inhibition of protein function. However, alternative approaches that result in protein degradation rather than inhibition also have the potential to achieve clinical efficacy. Therefore, targeted protein degradation through ubiquitination of protein targets has emerged as an effective strategy in drug discovery. Heterobifunctional small molecules that simultaneously bind to target proteins and recruit ubiquitin ligases (e.g., ubiquitin E3 ligases) have been shown to result in the ubiquitination and degradation of target proteins (Bondeson, DP et al., Nat Chem Biol. 2015 11(8):611-617). Examples of such small molecules that can bind to both PARP14 and ubiquitin E3 ligases are described in PCT Patent Publication WO2020 / 257416. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2020 / 257416 [Non-patent literature]

[0010] [Non-Patent Document 1] Vyas S et al. Nat Rev Cancer. 2014 June 5;14(7):502-509 [Non-patent document 2] Ohmoto A et al., OncoTargets and Therapy. 2017;10:5195 [Non-patent document 3] Vyas S et al., Nat Commun. 2013 Aug 7;4:2240 [Non-patent document 4] Aguiar RC et al. Blood. 2000 Dec. 9;96(13):4328-4334 [Non-patent document 5] Juszczynski P et al. Mol Cell Biol. 2006 July 1; 26(14): 5348-5359

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[0011] There is a need for the development of new drugs, such as small molecules, that can bind to both PARP14 and ubiquitin E3 ligase, causing degradation of PARP14, and that are useful in the treatment of various diseases, including cancer and inflammatory diseases. [Means for solving the problem]

[0012] (Summary of the Invention) The present invention provides compounds of formula (I):

[0013] [ka] or a pharmaceutically acceptable salt thereof (members of the construct are defined below).

[0014] The present invention is further directed to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0015] The present invention is further directed to a method of degrading PARP14, comprising the step of contacting PARP14 with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] The present invention is further directed to a method of treating a disease or disorder in a patient in need thereof, wherein the disease or disorder is characterized by overexpression or increased activity of PARP14, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] The present invention is further directed to a method of treating cancer in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] The present invention is further directed to a method of treating an inflammatory disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0019] The present invention also provides the use of a compound described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides a compound described herein for use in therapy. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a graph showing dose-dependent attenuation of Alternaria-induced cellular infiltration in BALF after treatment with Compound 64. [Figure 2A] 1 is a graph showing that Compound 64 significantly reduces eosinophils in BALF in a dose-dependent manner, starting at 100 mg / kg. [Figure 2B] 1 is a graph showing that Compound 64 significantly reduces the cytokine IL-33 in BALF in a dose-dependent manner, starting at 100 mg / kg. [Figure 2C] 1 is a graph showing that Compound 64 significantly reduces the cytokine IL-4 in BALF in a dose-dependent manner, starting at 100 mg / kg. [Figure 2D]1 is a graph showing that Compound 64 significantly reduces the cytokine IL-5 in BALF in a dose-dependent manner, starting at 100 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure relates, inter alia, to compounds of formula (I):

[0022] [ka] or a pharmaceutically acceptable salt thereof, W is CR W or N, X is CR X or N, Z is CR Z or N, Three of W, X and Z cannot be N at the same time, Y 1 is -NR 3 -, -CR 4 R 5 -, -O- and -(C 2~4 alkynyl)-, Y 2 represents a bond, -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-, Ring A is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring A is selected from 1, 2, 3, or 4 R A and optionally substituted by Ring B is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring B is selected from 1, 2, 3, or 4 R B and optionally substituted by R 1 and R 2 are each independently selected from H and methyl; R 3 is H and C 1~4 alkyl, R 4 and R 5 is H, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, Amino, C 1~4 Alkylamino and C 2~8 are each independently selected from dialkylamino; R 6 and R 7 H, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, Amino, C 1~4 Alkylamino and C 2~8 are each independently selected from dialkylamino; R A are halo and C, respectively. 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 are independently selected from R A The above 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 Alkyl is Cy 1 , Cy 1 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR 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 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R B are H, halo, and C, respectively. 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, ORa2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 are independently selected from R B The above 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 1~4Alkyl is Cy 2 , Cy 2 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R W , R X and R Z H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 6~10Aryl, 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 are independently selected from R W , R X or R Z The above C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 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 Alkyl is Cy 3 , Cy 3 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2Rb3 and S(O)2NR c3 R d3 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1, S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 2 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2Rb2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 3 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R.c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 are H and C, respectively. 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; 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 above C 1~6 Alkyl, C 2~6Alkenyl, 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 is 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 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NRc4 R d4 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 4 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R a4 , R b4 , Rc4 and R d4 is 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, 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 is OH, CN, amino, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 each optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)ORa4 ,OC(O)R b4 , OC(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)2NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)ORa4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from or R c3 and R d3 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R.c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from R e1 , R e2 , R e3 and R e4 are H and C, respectively. 1~4 independently selected from alkyl and CN; m is 0, 1 or 2; E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and L 1 is a linker covalently connecting moiety Q and moiety E, Any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 heteroatoms forming the ring, independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups is optionally substituted by an oxo (=O) group; One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

[0023] The present disclosure relates, inter alia, to compounds of formula (I):

[0024] [ka] or a pharmaceutically acceptable salt thereof, W is CR W or N, X is CR X or N, Z is CR Z or N, Three of W, X and Z cannot be N at the same time, Y 1 is -NR 3 -, -CR 4 R 5 - and -O-; Y 2 represents a bond, -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 )-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-, Ring A is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring A is selected from 1, 2, 3, or 4 R A and optionally substituted by Ring B is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring B is selected from 1, 2, 3, or 4 R B and optionally substituted by R 1 and R 2 are each independently selected from H and methyl; R 3 is H and C 1~4 alkyl, R 4 and R 5 is H, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, Amino, C 1~4 Alkylamino and C 2~8 are each independently selected from dialkylamino; R 6 and R 7 H, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, Amino, C 1~4 Alkylamino and C 2~8are each independently selected from dialkylamino; R A are halo and C, respectively. 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2Rb1 and S(O)NR c1 R d1 are independently selected from R A The above 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 Alkyl is Cy 1 , Cy 1 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2Rb1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R B are H, halo, and C, respectively. 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NRc2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 are independently selected from R B The above 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 Alkyl is Cy 2 , Cy 2 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R.c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R W , R X and R Z 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, 5-10 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)Rb3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 are independently selected from R W , R X or R Z The above 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 Alkyl is Cy 3 , Cy 3 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R.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 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR 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 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 2 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 3 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 are H and C, respectively. 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; 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 above C 1~6 Alkyl, 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 is 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, S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)2NR c4 R d4 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 4 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)2NR c4 R d4 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R a4 , R b4 , R c4 and R d4 is 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, 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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 is OH, CN, amino, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 each optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2Rb4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from or R c3 and R d3together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)2NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from R e1 , R e2 , R e3 and R e4 are H and C, respectively. 1~4 independently selected from alkyl and CN; m is 0, 1 or 2; E is an E3 ubiquitin ligase binding moiety, which binds to an E3 ubiquitin ligase; L 1is a linker covalently connecting moiety Q and moiety E, Any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 heteroatoms forming the ring, independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups is optionally substituted by an oxo (=O) group; One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

[0025] The present disclosure relates, inter alia, to compounds of formula (I):

[0026] [ka] or a pharmaceutically acceptable salt thereof, W is CR W or N, X is CR X or N, Z is CR Z or N, Three of W, X and Z cannot be N at the same time, Y 1 is -NR 3 -, -CR 4 R 5 - and -O-; Y 2 -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 a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring A is selected from 1, 2, 3, or 4 R A and optionally substituted by Ring B is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring B is selected from 1, 2, 3, or 4 R B and optionally substituted by R 1 and R 2 are each independently selected from H and methyl; R 3 is H and C 1~4 alkyl, R 4 and R 5 is H, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, Amino, C 1~4 Alkylamino and C 2~8 are each independently selected from dialkylamino; R 6 and R 7 H, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, Amino, C 1~4 Alkylamino and C 2~8 are each independently selected from dialkylamino; R A are halo and C, respectively. 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NRc1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 are independently selected from R A The above 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 Alkyl is Cy 1 , Cy 1 -C 1~4Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R B are H, halo, and C, respectively. 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 6~10Aryl-C 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 are independently selected from R B The above C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 6~10 Aryl, C 3~7Cycloalkyl, 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 is Cy 2 , Cy 2 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R W , R X and R Z 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, 5-10 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, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)Rb3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 are independently selected from R W , R X or R Z The above 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 Alkyl is Cy 3 , Cy 3 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NRc3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)Rb1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 2 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2, N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 3 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is 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 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5-10 membered heteroaryl-C 1~4 Alkyl, 4-10 membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , S.R. 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 , N.R.c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 are H and C, respectively. 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; Ra1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 or R d3 The above C 1~6 Alkyl, 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 is 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 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NRe4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)2NR c4 R d4 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 4 are respectively, C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4, N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)2NR c4 R d4 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R a4 , R b4 , R c4 and R d4 is 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, 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 is OH, CN, amino, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 each optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)ORa4 ,OC(O)R b4 , OC(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from or R c3 and R d3 together with the N atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Haloalkyl, CN, OR a4 , S.R. 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 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)ORa4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 and S(O)NR c4 R d4 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from R e1 , R e2 , R e3 and R e4 are H and C, respectively. 1~4 independently selected from alkyl and CN; m is 0, 1 or 2; E is an E3 ubiquitin ligase binding moiety, which binds to an E3 ubiquitin ligase; L 1 is a linker covalently connecting moiety Q and moiety E, Any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 heteroatoms forming the ring, independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups is optionally substituted by an oxo (=O) group; One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

[0027] In some embodiments, W is CR W In some embodiments, W is N.

[0028] In some embodiments, X is CR X In some embodiments, X is N.

[0029] In some embodiments, Z is CR Z In some embodiments, Z is N.

[0030] In some embodiments, Y 1 is —O—. In some embodiments, Y 1 -CR 4 R 5 In some embodiments, Y 1 is -NR 3 In some embodiments, Y 1 is -O- or -CR 4 R 5 In some embodiments, Y 1 is -O- or -NR 3 -It is.

[0031] In some embodiments, Y 1 Ha-(C 2~4 In some embodiments, Y 1 is -(C alkynyl)-. In some embodiments, Y 1 -O-, -NR 3 -or-(C 2~4 In some embodiments, Y 1 -O-, -NR 3 - or -(C2 alkynyl)-.

[0032] In some embodiments, Y 2 is S. In some embodiments, Y 2 is -CH2-. In some embodiments, Y 2 is -S- or CH2-. In some embodiments, Y 2 is -S-, -S(O)-, -S(O)2-, -CH2-, -O- and -N(R 3In some embodiments, Y 2 is -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 )CH2-. In some embodiments, Y 2 is -S-, -CH2-, or -O-. 2 is a bond. In some embodiments, Y 2 is a bond, —S—, —CH2— or —O—.

[0033] In some embodiments, ring A is a 4-18 membered heterocycloalkyl, and ring A contains 1, 2, 3, or 4 R A is optionally replaced by

[0034] In some embodiments, ring A is a 4-7 membered heterocycloalkyl, and ring A contains 1, 2, 3, or 4 R A In some embodiments, ring A is a 4-7 membered heterocycloalkyl, and ring A is optionally substituted with one or two R A In some embodiments, ring A is a 4-7 membered heterocycloalkyl.

[0035] In some embodiments, ring A is tetrahydro-2H-pyranyl or piperidinyl, which each have one, two, three, or four R A In some embodiments, ring A is optionally substituted with 1, 2, 3, or 4 R A In some embodiments, ring A is tetrahydro-2H-pyranyl optionally substituted by one, two, three, or four R A In some embodiments, Ring A is tetrahydro-2H-pyranyl or piperidinyl, each of which is substituted with one or two R A In some embodiments, ring A is optionally substituted with one or two RA In some embodiments, ring A is tetrahydro-2H-pyranyl optionally substituted by R A and piperidinyl optionally substituted by:

[0036] In some embodiments, ring A is tetrahydro-2H-pyran-4-yl or 1-methylpiperidin-4-yl. In some embodiments, ring A is tetrahydro-2H-pyran-4-yl. In some embodiments, ring A is 1-methylpiperidin-4-yl. In some embodiments, ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, or 1-(2,2,2-trifluoroethyl)piperidin-4-yl.

[0037] In some embodiments, ring A is C 3~14 cycloalkyl, and ring A is one, two, three, or four R A In some embodiments, Ring A is cyclohexyl, and Ring A is optionally substituted with 1, 2, 3, or 4 R A In some embodiments, ring A is 4-hydroxycyclohexyl. In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and ring A is optionally substituted with one, two, three, or four R A In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, or hydroxycyclohexyl.

[0038] In some embodiments, ring A is a 4-7 membered heterocycloalkyl or C 3~14 cycloalkyl, and ring A is one, two, three, or four R A In some embodiments, ring A is optionally substituted by a 4-7 membered heterocycloalkyl or C 3~14 cycloalkyl, and ring A is one or two R AIn some embodiments, ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, or 4-hydroxycyclohexyl. In some embodiments, ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, or 1-(2,2,2-trifluoroethyl)piperidin-4-yl.

[0039] In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4-hydroxycyclohexyl.

[0040] In some embodiments, Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 4-hydroxycyclohexyl.

[0041] In some embodiments, ring B is C 3~7 cycloalkyl or 4- to 7-membered heterocycloalkyl, and ring B is one, two, three, or four R B In some embodiments, ring B is optionally substituted by C 3~7 cycloalkyl, and ring B is one, two, three, or four R B In some embodiments, Ring B is a 4-7 membered heterocycloalkyl, and Ring B is optionally substituted with 1, 2, 3, or 4 R B In some embodiments, Ring B is piperidinyl, cyclobutyl, or cyclohexyl, each of which is optionally substituted with 1, 2, 3, or 4 R BIn some embodiments, Ring B is piperidinyl, cyclobutyl, or cyclohexyl.

[0042] In some embodiments, ring B is C 3~7 cycloalkyl or 4- to 7-membered heterocycloalkyl, and ring B is one or two R B In some embodiments, ring B is optionally substituted by C 3~7 cycloalkyl, and ring B is one or two R B In some embodiments, Ring B is a 4-7 membered heterocycloalkyl, and Ring B is optionally substituted with one or two R B is optionally replaced by

[0043] In some embodiments, ring B contains 1, 2, 3, or 4 R B In some embodiments, ring B is piperidinyl optionally substituted by one or two R B In some embodiments, Ring B is piperidinyl optionally substituted by: In some embodiments, Ring B is piperidinyl. In some embodiments, Ring B is piperazinyl. In some embodiments, Ring B is substituted with 1, 2, 3, or 4 R B and piperidinyl or piperazinyl optionally substituted by:

[0044] In some embodiments, ring B is C 3~7 cycloalkyl, and ring B is one, two, three, or four R B In some embodiments, Ring B is cyclobutyl or cyclohexyl. In some embodiments, Ring B is cyclopropyl, cyclobutyl, or cyclohexyl.

[0045] In some embodiments, Ring B is cyclobutyl, cyclohexyl, piperidinyl, or piperazinyl, each of which has one, two, three, or four R BIn some embodiments, Ring B is cyclobutyl, cyclohexyl, piperidinyl, or piperazinyl.

[0046] In some embodiments, Ring B is piperidinyl, piperazinyl, or azetidinyl, each of which has one, two, three, or four R B is optionally replaced by

[0047] In some embodiments, R 1 and R 2 are each H. In some embodiments, R 1 is H. In some embodiments, R 2 is H.

[0048] In some embodiments, R 4 and R 5 are each H. In some embodiments, R 4 is H. In some embodiments, R 5 is H.

[0049] In some embodiments, R 6 and R 7 are each H. In some embodiments, R 6 is H. In some embodiments, R 7 is H.

[0050] In some embodiments, R A are halo and C, respectively. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 are independently selected from R A The above C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Haloalkyl is Cy 1 , Cy 1 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 C(=NR e1)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 Each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0051] In some embodiments, R A are halo and C, respectively. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 Rd1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 are independently selected from

[0052] In some embodiments, R A are halo and C, respectively. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 are independently selected from

[0053] In some embodiments, R A are halo and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, CN, NO2 or OR a1 In some embodiments, R A are respectively, C 1~6 In some embodiments, R A are respectively, C 1~6Alkyl or C 1~6 In some embodiments, R A is methyl. In some embodiments, R A is methyl, OH or 2,2,2-trifluoroethyl.

[0054] In some embodiments, R B are H, halo, and C, respectively. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 are independently selected from R B The above C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Haloalkyl is Cy 2 , Cy 2 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0055] In some embodiments, R B are H, halo, and C, respectively.1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 are independently selected from

[0056] In some embodiments, R B are H, halo, and C, respectively. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NRc2 R d2 , C(O)OR a2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 are independently selected from

[0057] In some embodiments, R B are halo and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, CN, NO2 or OR a2 In some embodiments, R B are halo and C, respectively. 1~6 Alkyl and C 1~6 In some embodiments, R B are halo and C, respectively. 1~6 In some embodiments, R B Each R is independently selected from halo. B are F, respectively.

[0058] In some embodiments, R W , R X and R Z H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)Rb3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 are independently selected from R W , R X or R Z The above C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 Haloalkyl is Cy 3 , Cy 3 -C 1~4 Alkyl, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 C(=NR e3 )NRc3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 Each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0059] In some embodiments, R W H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3, N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is selected from.

[0060] In some embodiments, R W H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2 and OR a3 In some embodiments, R W H, halo and C 1~6 In some embodiments, R is selected from haloalkyl. W is F.

[0061] In some embodiments, R X H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R.c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)NR c3 R d3 is selected from.

[0062] In some embodiments, R X is C 6~10 aryl and 5- to 10-membered heteroaryl, 6~10 Aryl and 5-10 membered heteroaryl are substituted with halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, OR a3 and SR a3 Each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0063] In some embodiments, R X H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, OR a3 and C 6~10 In some embodiments, R X is H. In some embodiments, R Xis H or halo. In some embodiments, R X is H or F. In some embodiments, R X is F.

[0064] In some embodiments, R Z H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , S.R. 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 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is selected from.

[0065] In some embodiments, R Z is C6~10 aryl and 5- to 10-membered heteroaryl, 6~10 Aryl and 5-10 membered heteroaryl are substituted with halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, OR a3 and SR a3 Each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0066] In some embodiments, R Z H, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, OR a3 and C 6~10 In some embodiments, R X is H.

[0067] 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.

[0068] In some embodiments, L 1 is linked to ring B via a covalent bond to ring B.

[0069] In some embodiments, L 1 is a chain consisting of 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10 or 1 to 5 chain atoms, which is q optionally substituted by a substituent; L 1 one or more chain carbon atoms may be oxidized to form a carbonyl (C=O), and one or more N and S chain atoms may be optionally oxidized to form an amine oxide group, a sulfoxide group, or a sulfonyl group, respectively; R q are OH, CN, -COOH, NH2, halo, and C, respectively. 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3~6 Cycloalkyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; R q C 1~6 Alkyl, phenyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are substituted with halo, OH, CN, -COOH, NH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, Phenyl, C 3~10 Each is optionally substituted with cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl. q OH, CN, -COOH, NH2, halo, C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2.

[0070] In some embodiments, L 1 is the following: (i) a bond directly connecting ring B to moiety E (ii) -(C 1~4 alkyl)- (iii) -(C 2~4 alkenyl)- (iv) -(C 2~4 alkynyl) (v) -(C 2~4 alkynyl)-(G 3 )- (vi) the following structure:

[0071] [ka] (vii) a structure of:

[0072] [ka] and (viii) the following structure:

[0073] [ka] [In the formula, G 1 -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 - selected from G 2 is C 6~10 Aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl; G 3 -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 - selected from G 4 is C 1~6 Alkyl, Hydroxyl, C 1~6 a 4-10 membered heterocycloalkyl optionally substituted with alkoxy or halo; R G are each independently selected from H, methyl and ethyl; a is 0 or 1, b is 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1, g is 0, 1 or 2; At least one of b, c, e, and f is 1.] is selected from.

[0074] In some embodiments, L 1 is the following: (i) a bond directly connecting ring B to moiety E (ii) -(C 1~4 alkyl)- (iii) -(C 2~4 alkenyl)- (iv) -(C 2~4 alkynyl) (v) -(C 2~4 alkynyl)-(G 3 )- (vi) the following structure:

[0075] [ka] (vii) a structure of:

[0076] [ka] and (viii) the following structure:

[0077] [ka] [In the formula, G 1 -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 - selected from G 2 is C 6~10 Aryl, C 3~7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; G 3 -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 - selected from G 4 is a 4- to 10-membered heterocycloalkyl; R G are each independently selected from H, methyl and ethyl; a is 0 or 1, b is 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1, g is 0, 1 or 2; At least one of b, c, e, and f is 1.] is selected from.

[0078] In some embodiments, L 1 is the following: (viii) a bond directly connecting ring B to moiety E ( (ix) -(C 1~4 alkyl)- (x) -(C 2~4 alkenyl)- (xi) -(C 2~4 alkynyl) (xii) -(C 2~4alkynyl)-(G 3 )- (xiii) the following structure:

[0079] [ka] (xiv) the structure:

[0080] [ka] and (viii) the following structure:

[0081] [ka] [In the formula, G 1 -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 - selected from G 2 is C 6~10 Aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl; G 3 -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 - selected from G 4 is a 4- to 10-membered heterocycloalkyl; R G are each independently selected from H, methyl and ethyl; a is 0 or 1, b is 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1, g is 0, 1 or 2; At least one of b, c, e, and f is 1.] is selected from.

[0082] In some embodiments, L 1 is the following: (i) a bond directly connecting ring B to moiety E (ii) -(C 1~4 alkyl)- (iii) -(C 2~4 alkenyl)- (iv) -(C 2~4 alkynyl) (v) -(C 2~4 alkynyl)-(G 3 )- (vi) the following structure:

[0083] [ka] and (vii) a structure of:

[0084] [ka] is selected from.

[0085] In some embodiments, L 1 is the bond that directly connects ring B to moiety E.

[0086] In some embodiments, L 1 Ha-(C 1~4 alkyl)-.

[0087] In some embodiments, L 1 Ha-(C 2~4 alkenyl).

[0088] In some embodiments, L 1 Ha-(C 2~4 alkynyl)-.

[0089] In some embodiments, L 1 is -(C 2~4 alkynyl)-(G 3 )-.

[0090] In some embodiments, L 1 has the following structure:

[0091] [ka] It has.

[0092] In some embodiments, L 1 teeth,

[0093] [ka] is.

[0094] In some embodiments, G 1 is -NR G In some embodiments, G is -C(O)- or -C(O)-. 1 is -NR G In some embodiments, G is C(O)-. 1 is —C(O)—. In some embodiments, G 1 is -NR G In some embodiments, G is —C(O)—, —C(O)—, or —O—. 1 is -O-.

[0095] In some embodiments, G 2 is a 4-10 membered heterocycloalkyl, which is selected from halo and C 1~6 In some embodiments, G is optionally substituted with haloalkyl. 2is a 4-10 membered heterocycloalkyl, which is 1~6 In some embodiments, G is optionally substituted with haloalkyl. 2 is a 4-10 membered heterocycloalkyl. 2 is piperidinyl, piperazinyl, or azetidinyl. 2 is piperidinyl or piperazinyl. 2 is piperidinyl. 2 is piperazinyl. In some embodiments, G 2 is azetidinyl. 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptanyl or 3,4-dihydroquinazolin-7-yl.

[0096] In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, pyridinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octanyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonanyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8, 2-azaspiro[3.5]nonanyl, or 7-azaspiro[3.5]nonanyl. In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octanyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonanyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8, 2-azaspiro[3.5]nonanyl, or 7-azaspiro[3.5]nonanyl. In some embodiments, G 2is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,4-dihydroquinazolin-7-yl, 3,8-diazabicyclo[3.2.1]octanyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonanyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8, 2-azaspiro[3.5]nonanyl, or 7-azaspiro[3.5]nonanyl. In some embodiments, G 2 is cyclobutyl or cyclohexyl.

[0097] In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, pyridinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,4-dihydroquinazolin-7-yl, cyclobutyl, 3,8-diazabicyclo[3.2.1]octanyl, cyclohexyl, (trifluoromethyl)piperazinyl, 7-azaspiro[3.5]nonanyl, piperazin-1-yl-2,2,3,3,5,5,6,6-d8, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl or pyrrolidinyl.

[0098] In some embodiments, G 2 is C 3~7 In some embodiments, G is cycloalkyl. 2 is cyclobutyl.

[0099] In some embodiments, G 2 is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,4-dihydroquinazolin-7-yl or cyclobutyl.

[0100] In some embodiments, G 3 is -NR G - or -O-. In some embodiments, G 3 is -NR G In some embodiments, G 3 is -O-.

[0101] In some embodiments, G 4 is piperidinyl or piperazinyl. 4 is piperidinyl. 4 is piperazinyl. In some embodiments, G 4 is azetidinyl. 4 is azetidinyl, piperidinyl or piperazinyl.

[0102] In some embodiments, a is 0. In some embodiments, a is 1.

[0103] In some embodiments, b is 0. In some embodiments, b is 1.

[0104] In some embodiments, c is 0. In some embodiments, c is 1.

[0105] In some embodiments, d is 0. In some embodiments, d is 1.

[0106] In some embodiments, e is 0. In some embodiments, e is 1.

[0107] In some embodiments, f is 0. In some embodiments, f is 1.

[0108] In some embodiments, g is 0. In some embodiments, g is 1.

[0109] In some embodiments, R G is H. In some embodiments, R G is methyl.

[0110] Ubiquitin ligase binding moieties and linkers are known and are fully described in the art, e.g., Bondeson, DP et al., Nat Chem Biol. 2015 11(8):611-617; An S et al., EBioMedicine 2018 36:553-562; Paiva SL. et al., Curr. Op. in Chem. Bio. 2010, 50:111-119; and International Patent Application Publication No. 2017 / 197056, each of which is incorporated by reference in its entirety.

[0111] In some embodiments, E is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety, an MDM2 E3 ubiquitin ligase binding moiety, a cereblon E3 ubiquitin ligase binding moiety, or an inhibitor of apoptosis protein (IAP) E3 ubiquitin ligase binding moiety, each of which has an IC of less than about 10 μM as determined in a binding assay. 50 For example, E can be a cereblon E3 ubiquitin ligase binding moiety. E can be a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety. E can be an MDM2 E3 ubiquitin ligase binding moiety. E can be an IAP E3 ubiquitin ligase binding moiety.

[0112] In some embodiments, E is an E3 ubiquitin ligase binding moiety that binds to cereblon.

[0113] In some embodiments, E comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide.

[0114] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof.

[0115] In some embodiments, E is:

[0116] [ka] Selected from TIFF2025526433000020.tif102167, In some embodiments, E is:

[0117] [ka] TIFF2025526433000022.tif67167, where the wavy line represents the group L 1 Represents a point of attachment to

[0118] In some embodiments, E is

[0119] [ka] wherein the wavy line represents the group L 1 Represents the attachment point to

[0120] In some embodiments, E is

[0121] [ka] where the wavy line represents the group L 1 Represents the attachment point to

[0122] In some embodiments, E is

[0123] [ka] wherein the wavy line represents the group L 1 Represents the attachment point to

[0124] In some embodiments, E is:

[0125] [ka] where the wavy line represents the group L 1 Represents the attachment point to

[0126] In some embodiments, E is:

[0127] [ka] where the wavy line represents the group L 1 Represents a point of attachment to

[0128] In some embodiments, E is:

[0129] [ka] where the wavy line represents the group L 1 Represents a point of attachment to

[0130] In some embodiments, E is:

[0131] [ka] where the wavy line represents the group L 1 Represents a point of attachment to

[0132] In some embodiments, E is:

[0133] [ka] wherein the wavy line represents the group L 1 Represents a point of attachment to

[0134] In some embodiments, E is:

[0135] [ka] TIFF2025526433000032.tif219167TIFF2025526433000033.tif95167, where the wavy line represents the group L 1 Represents a point of attachment to

[0136] In some embodiments, E is:

[0137] [ka] wherein the wavy line represents the group L 1 Represents a point of attachment to

[0138] In some embodiments, E is:

[0139] [ka] wherein the wavy line represents the group L 1 Represents a point of attachment to

[0140] In some embodiments, E is:

[0141] [ka] wherein the wavy line represents the group L 1 Represents a point of attachment to

[0142] In some embodiments, E is:

[0143] [ka] where the wavy line represents the group L 1 Represents a point of attachment to

[0144] In some embodiments, E is:

[0145] [ka] where the wavy line represents the group L 1 Represents a point of attachment to

[0146] In some embodiments, E is:

[0147] [ka] where the wavy line represents the group L 1 Represents a point of attachment to

[0148] In some embodiments, the compound has formula IA:

[0149] [ka] or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound has formula IA:

[0151] [ka] or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound has Formula II:

[0153] [ka] or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the compound has Formula IIa:

[0155] [ka] or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound has Formula III:

[0157] [ka] or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the compound is: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-4-((9-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-9-oxononyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)propyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione; N-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 3-(4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 1-(4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione; 3-(5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione; 3-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione; 5-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-en-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; 3-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-yl)amino)phenyl)piperidine-2,6-dione; 3-((4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutyl)methoxy)phenyl)amino)piperidine-2,6-dione; 3-({4-[3-({4-[({5-fluoro-2-[(oxan-4-ylsulfanyl)methyl]-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}methyl)cyclobutoxy]phenyl}amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione and 1-(3-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt of any of the above.

[0159] In some embodiments, the compound is: 3-((4-(4-(2-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclobutyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 7-(((1s,3s)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((1r,3r)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-3-(4-methoxybenzyl)-7-((1-(2-(4-nitrophenoxy)ethyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (S)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; (R)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; 3-((3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione; 3-((3-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione; 1-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)ethynyl)isoindoline-1,3-dione; 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(((3aR,5r,6aS)-2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione; 1-(4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)methyl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)methyl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione; 3-((4-(4-(4-(2-(5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((1-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)phenyl)amino)piperidine-2,6-dione and 3-((4-(3-((4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione or a pharmaceutically acceptable salt of any of the above.

[0160] In some embodiments, the compound is: 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)isoindolin-5-yl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)benzamide; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)amino)phenyl)amino)piperidine-2,6-dione; 3-((4-(8-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-((4-fluoro-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclobutylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione; 3-((4-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclohexyl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)piperidine-2,6-dione; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)(methyl)amino)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)phenyl)amino)piperidine-2,6-dione; 3-((4-(5-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-3-yl)phenyl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxamide; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-chloro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((2,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-chloro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)(methyl)amino)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)phenyl)amino)piperidine-2,6-dione and N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)benzamide or a pharmaceutically acceptable salt of any of the above.

[0161] In some embodiments, the compound is: 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)amino)phenyl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)benzamide; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 1-(3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrrolidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1'-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)isoindoline-1,3-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(3-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-({4-[4-(2-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl)piperazin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione; 3-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (3S)—N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide; (3R)—N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide; N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidine-4-carboxamide; N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-N-methylpiperidine-4-carboxamide; 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((3-fluoro-4-(4-(2-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((3-fluoro-4-(4-((1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-2-oxo-[1,4':1',4''-terpiperidine]-1''-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(9-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2,5-difluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-[1,4'-bipiperidin]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(6-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4':1',4''-terpiperidine]-1''-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3-oxopiperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-({4-[4-(3-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}azetidin-1-yl)piperidin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione or a pharmaceutically acceptable salt of any of the above.

[0162] It is further understood that certain features of the invention, which are, for clarity, described in the context of individual embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0163] Substituents for compounds of the invention are disclosed in various places herein in groups or in ranges. It is specifically intended that the invention include all individual subcombinations of the members of such groups and ranges. For example, the term "C 1~6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0164] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places herein. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member, if allowed by valence. For example, the term "pyridinyl," "pyridyl," or "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0165] The term "n-membered" (where "n" is an integer) generally describes the number of atoms that form a ring in a moiety, with "n" being the number of atoms that form the ring. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0166] At various places herein, variables defining divalent bridging groups may be described. Each linking substituent is specifically intended to include both the forward and backward forms of the linking substituent. For example, —C(O)NR G - is -C(O)NR G -and-NR G C(O)- are included, and each form is intended to be disclosed individually. When a structure requires a linking group, the Markush variable recited for that group is understood to be the linking group. For example, when a structure requires a linking group and a Markush group, the definition for that variable recites "alkyl" or "aryl," and then "alkyl" or "aryl" is understood to represent a linking alkylene group or a linking arylene group, respectively.

[0167] For compounds of the invention in which a variable occurs more than once, each variable may be a different moiety independently selected from the group defining that variable. For example, when a structure is depicted having two R groups co-occurring in the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0168] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0169] As used herein, the term "substituted" means that a hydrogen atom has been replaced with a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

[0170] As used herein, the term "C" when used in combination with a chemical group i~j " (where i and j are integers) represents a range of carbon atoms in a chemical group, and i to j define that range. For example, C 1~6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0171] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained 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, and n-heptyl. In some embodiments, the alkyl group is methyl, ethyl, or propyl. The term "alkylene" refers to a linking alkyl group.

[0172] As used herein, the term "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. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0173] As used herein, the term "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of 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.

[0174] 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.

[0175] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having halogen atom substituents, which may be the same or different, up to the total valence. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF, C2F, CHF, CCl, CHCl, C2Cl, and the like.

[0176] As used herein, the term "alkoxy," used alone or in combination with other terms, refers to a group of formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0177] 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 example of a haloalkoxy group is -OCF.

[0178] As used herein, "amino," used alone or in combination with other terms, refers to NH2.

[0179] 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, alkylamino groups have 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0180] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of formula -N(alkyl). Examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, the alkyl groups each independently have 1 to 6 or 1 to 4 carbon atoms.

[0181] As used herein, the term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having two, three, or four fused, bridged, or spiro rings) ring systems. Similarly, moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., having a bond in common with) a cycloalkyl ring, e.g., a benzo derivative such as cyclopentane, cyclohexene, or cyclohexane, or a pyrido derivative of cyclopentane or cyclohexane, are also included in the definition of cycloalkyl. The ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-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). In some embodiments, cycloalkyl groups have 3 to 10 ring members or 3 to 7 ring members. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are C 3~7 Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0182] As used herein, the term "cycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is 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 It is a monocyclic cycloalkyl group.

[0183] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having two, three, or four fused, bridged, or spirocyclic) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, and oxygen. Similarly, moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., having a bond in common with) a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydroquinoline, are also included in the definition of heterocycloalkyl. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom such as azaadmantan-1-yl) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused at a single atom such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl]). In some embodiments, heterocycloalkyl groups have 3 to 10 atoms forming the ring, 4 to 10 atoms forming the ring, or about 3 to 8 atoms forming the ring. In some embodiments, heterocycloalkyl groups have 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, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Carbon atoms or heteroatoms in the ring of a heterocycloalkyl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized linking groups), or nitrogen atoms can be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2~7Monocyclic heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahyropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0184] As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula heterocycloalkyl-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 methylene. 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 It is a monocyclic heterocycloalkyl group.

[0185] As used herein, the term "aryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, etc. In some embodiments, an aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, an aryl group is a monocyclic or bicyclic group. In some embodiments, an aryl group is phenyl or naphthyl.

[0186] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the aryl portion is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0187] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. Carbon atoms or heteroatoms in the ring of a heteroaryl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized linking group), or a nitrogen atom can be quaternized, provided that the aromatic nature of the ring is retained. In some embodiments, a 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, a heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 atoms forming the ring. In some embodiments, a heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0188] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the heteroaryl portion 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 portion has 5 to 10 carbon atoms.

[0189] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are contemplated unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or by stereoselective synthesis, are known in the art. Geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomers.

[0190] The compounds of the present invention also include tautomers. Tautomers result from the simultaneous migration of a proton along with the exchange of a single bond with an adjacent double bond. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.

[0191] The compounds of the present invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention contain at least one deuterium atom.

[0192] The term "compound," as used herein, unless otherwise specified, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0193] All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (eg, in the form of hydrates and solvates) or may be isolated.

[0194] In some embodiments, the compounds of the present invention or salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation can include, for example, a composition enriched in the compound of the present invention. Substantial isolation 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 compound of the present invention or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0195] The term "small molecule PARP14 targeting moiety" refers to a chemical group that binds to PARP14. A small molecule PARP14 targeting moiety can be a group derived from a compound that inhibits the activity of PARP14. In some embodiments, a small molecule PARP14 targeting moiety has a DC of less than 1 μM in an enzyme assay (see, e.g., Example A). 50 inhibits the activity of PARP14.

[0196] 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.

[0197] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0198] 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 has been modified by converting an acidic or basic moiety present therein 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 or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0199] synthesis The compounds of the present invention, including their salts, may be prepared using known organic synthesis techniques, and may be synthesized according to any of a number of possible synthetic routes.

[0200] The reaction for preparing the compound of the present invention can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, a suitable solvent for the specific reaction step can be selected by those skilled in the art.

[0201] The preparation of the compounds of the present invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0202] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), may be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry, or by chromatography such as high performance liquid chromatography.

[0203] The compounds of the present invention can be prepared according to a number of preparative routes known in the literature. Examples of synthetic methods for preparing compounds of the present invention are presented in the following schemes.

[0204] [ka]

[0205] Scheme 1 shows a general synthesis of the quinazolinone compounds of the present disclosure. Compounds of formula (1-A), many of which are commercially available or can be prepared by routes known to those skilled in the art, can be coupled with compounds of formula (1-B), in which "Hal" is a halogen (e.g., Br). Many compounds of formula (1-B) are known in the art and are described, for example, in U.S. Pat. No. 10,562,891. This coupling can be carried out under Pd coupling conditions (e.g., in the presence of a Pd reagent such as [Pd(allyl)Cl]) to provide compounds of formula (1-C).

[0206] [ka]

[0207] Scheme 2 shows the general synthesis of certain compounds of the present invention. Compounds of formula (2-A) can be prepared according to the route shown in Scheme 1 or, for example, according to the process described in U.S. Pat. No. 10,562,891. The N atom of the B ring of compounds of formula (2-A) can be coupled with compounds of formula (2-B) under peptide coupling conditions (e.g., EDCI, HOBt, and DIPEA; or HATU, DIPEA) to give compounds of formula (2-C), where "PG" refers to a protecting group (e.g., a BOC group). Group L 2 is a linker moiety L as defined herein 1 " refers to the internal moiety of the formula (2-C). The compound of formula (2-C) can be deprotected (e.g., by treatment with acid) to give the compound of formula (2-D). The compound of formula (2-D) can be coupled with the compound of formula (2-E) (where "Hal" is a halogen atom) to give the compound of formula (2-F). The compound of formula (2-E) is commercially available and is also known in the art. The coupling of the compound of formula (2-D) with the compound of formula (2-E), for example, when "Hal" is F, can be carried out in the presence of a base (e.g., triethylamine) under heating (e.g., 100°C) to give the compound of formula (2-F). The "-NH-L" of the compound of formula (2-F) can be 2 The "-C(O)-" group is defined herein as L 1 Equal to the base.

[0208] [ka]

[0209] Scheme 3 shows the general synthesis of the compounds of the present invention. A compound of formula (3-A), which can be prepared according to Scheme 1, can be treated with tert-butyl 2-bromoacetate to give a compound of formula (3-B). The compound of formula (3-B) can be deprotected (e.g., by treatment with acid) to give a compound of formula (3-C). The compound of formula (3-C) can be coupled with a compound of formula (3-D), which is known in the art. This coupling can be carried out under peptide coupling conditions (e.g., EDCI, HOBt, and DIPEA; or HATU, DIPEA) to give a compound of formula (3-E). The "-L" of the compound of formula (3-E) can be 2 The —N(H)—C(O)—CH— group is L as defined herein. 1 Equal to the base.

[0210] [ka]

[0211] Scheme 4 shows a general synthesis of the compounds of the present invention. The nucleophilic N atom of the B ring of a compound of formula (4-A), which can be prepared according to Scheme 1, can be reacted with an electrophilic compound of formula (4-B), many of which are commercially available and known in the art. This reaction affords a compound of formula (4-C), in which "PG" refers to a protecting group (e.g., an alcohol protecting group such as a silyl ether). The compound of formula (4-C) can be deprotected (e.g., with a fluoride ion source such as HF) to afford a compound of formula (4-D). The compound of formula (4-D) can be halogenated (e.g., by treatment with 3-nitrobenzenesulfonyl chloride) to form a compound of formula (4-E), in which "hal" is a halogen (e.g., Cl). Compounds of formula (4-E) can be reacted with nucleophilic compounds of formula (4-F) (many of which are commercially available or known in the art, where R is H, C 1~6 Alkyl, 4-6 membered heterocycloalkyl and C 1~6The compound of formula (4-G) can be obtained by reacting "-L" with "-Cycloalkyl" to obtain a compound of formula (4-G). 1 '-N(H)-(C 1~6 The "alkyl)-" group is defined herein as L 1 Equal to the base.

[0212] How to use The compounds of the present disclosure can bind to both PARP14 and ubiquitin E3 ligase, causing PARP14 degradation, which is useful for treating various diseases, including cancer. In some embodiments, the compounds provided herein can degrade PARP14 in cells, which includes contacting the cells with the compounds or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the present disclosure provides a method for degrading PARP14 in a patient, the method comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof. The term "degrading PARP14" refers to inactivating PARP14, for example, by modifying its structure or by degrading PARP14 into multiple peptide or amino acid fragments.

[0213] The compounds of the present invention are useful for treating various diseases associated with abnormalities in PARP14 expression or activity. For example, the compounds of the present invention are useful for treating cancer. In some embodiments, cancers treatable by the present invention include hematopoietic tissue malignancies such as leukemia and lymphoma. Examples of 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. Examples of leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0214] Other cancers that can 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.

[0215] 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.

[0216] The compounds of the present invention may also have therapeutic utility in PARP14-associated disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation and pain, particularly where the disease is characterized by overexpression or increased activity of PARP14.

[0217] In some embodiments, the compounds of the present invention are useful for treating inflammatory diseases. Genetic inactivation of poly(ADP-ribose) polymerase family member 14 (PARP14), also known as ADP-ribosyltransferase diphtheria toxin-like 8 (ARTD8) or B lymphoma protein 2 (BAL2), has been found to protect mice from allergen-induced airway disease (Mehrothra et al., J Allergy Clin Immunol, 2012;7;25;131(2):521-531; and Cho et al., Proc Natl Acad Sci USA, 2011;9;208(38):15972-15977), suppress the infiltration of immune cells such as eosinophils and neutrophils into the lungs, and reduce the release of inflammatory Th2 cytokines. Furthermore, treatment with a PARP14 inhibitor protected mice from severe asthma induced by inhalation of an Alternaria alternata extract followed by a recall challenge (Eddie et al., PMID 35817532). Animals treated with a PARP14 inhibitor showed reduced levels of airway mucus, serum IgE, immune cell (eosinophil, neutrophil, and lymphocyte) infiltration, Th2 cytokines (IL-4, IL-5, and IL-13), and alarmins (IL-33 and TSLP) (Eddie et al., PMID 35817532 and Ribon internal data).

[0218] Without being bound by theory, PARP14 has been shown to influence STAT6 and STAT3 signaling, signaling induced by Th2 and Th17 cytokines, M1 / M2 macrophage polarization, and signaling by lymphocytes. PARP14 has also been shown to be a regulator of Th2 / Th17 / THF T cell development, to be involved in B cell development, and to be involved in the recruitment / activation of eosinophils / neutrophils. These lymphocytes are thought to be likely ILCs (e.g., ILC2s and ILC3s) that are activated by alarmins (e.g., TSLP and IL-33) and are major producers of downstream cytokines (e.g., IL-4, IL-5, and IL-13). 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 it is also suggested that PARP14 inhibition suppresses the alarmins TSLP and IL-33, which are important upstream drivers of asthma that are released in response to allergens.

[0219] The present invention is directed, inter alia, to a method of treating or preventing an inflammatory disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Exemplary inflammatory diseases treatable by the disclosed methods include, for example, asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloids, eosinophilic disorders, pulmonary fibrosis, and other type 2 cytokine pathologies. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0220] Additional exemplary inflammatory diseases treatable by the disclosed methods include inflammatory bowel disease ("IBD"), including ulcerative colitis ("UC" or "colitis") and Crohn's disease. In some embodiments, the inflammatory disease is inflammatory bowel disease. In some embodiments, the inflammatory disease is ulcerative colitis. In some embodiments, the inflammatory disease is Crohn's disease.

[0221] In some embodiments, the inflammatory disease is irritable bowel syndrome.

[0222] Eosinophilic disorders treatable by the disclosed methods include, for example, eosinophilic esophagitis (esophagus - EoE), eosinophilic gastritis (stomach - EG), eosinophilic gastroenteritis (stomach and small intestine - EGE), eosinophilic enteritis (small intestine - EE), eosinophilic colitis (colon - EC), and eosinophilic chronic sinusitis.

[0223] The present invention is further directed, inter alia, 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.

[0224] In some embodiments, the asthma is steroid-insensitive asthma, steroid-refractory asthma, steroid-resistant asthma, atopic asthma, non-atopic asthma, persistent asthma, severe asthma, or steroid-refractory severe asthma. In some embodiments, the severe asthma is a T2-high endotype, a T2-low endotype, or a non-T2 endotype. In some embodiments, the severe asthma is a T2-high endotype. In some embodiments, the severe asthma is a T2-low endotype or a non-T2 endotype. In some embodiments, the severe asthma is a T2-low endotype. In some embodiments, the severe asthma is a non-T2 endotype.

[0225] The present invention is further directed to methods of treating or preventing fibrotic diseases, including, but not limited to, pulmonary fibrosis, renal fibrosis, liver fibrosis (e.g., NASH and NAFLD), systemic fibrosis, and idiopathic pulmonary fibrosis (IPF), among others. In some embodiments, the fibrotic disease is systemic fibrosis.

[0226] The present invention is further directed to methods of treating or preventing, inter alia, chronic obstructive pulmonary disease (COPD), emphysema, and chronic bronchitis.

[0227] The present invention is further directed to methods of treating or preventing inflammatory skin diseases, such as, inter alia, atopic dermatitis or rosacea.

[0228] The present invention relates to a method for treating a patient, (a) Reduces the level of airway mucus in lung tissue (b) Reduce serum IgE (c) Reduce immune cell infiltration and activation in bronchoalveolar lavage fluid (d) reducing the level of one or more inflammatory cytokines in bronchoalveolar lavage fluid or lung tissue; or (e) reducing the level of one or more alarmins in bronchoalveolar lavage fluid or lung tissue Further provided is a method, comprising the step of administering to a patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the present invention provides a method of reducing the level of airway mucus in lung tissue in a patient.

[0230] In some embodiments, the present invention provides a method of reducing immune cell infiltration and activation in bronchoalveolar lavage fluid in a patient, hi some embodiments, the immune cells are eosinophils, neutrophils, or lymphocytes.

[0231] In some embodiments, the present invention provides methods for reducing one or more inflammatory cytokines in bronchoalveolar lavage fluid or lung tissue in 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, IL13, or IL-17A. In some embodiments, the inflammatory cytokine is IL-4, IL-5, or IL13.

[0232] In some embodiments, the present invention provides methods of reducing alarmin in bronchoalveolar lavage fluid or lung tissue in a patient, hi some embodiments, the alarmin is IL-25, IL-33, or TSLP.

[0233] As used herein, the term "cell" is intended to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be 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 cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0234] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" PARP14 or "contacting" a cell with a compound of the present invention includes administering a compound of the present invention to an individual or patient, such as a human, that has PARP14, and introducing a compound of the present invention into a sample containing, for example, a cell preparation or purified preparation containing PARP14.

[0235] As used herein, the terms "individual" or "patient", used interchangeably, refer to mammals, particularly humans.

[0236] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that produces the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical physician, or other clinician.

[0237] As used herein, the term "treat" or "treatment" refers to 1) inhibiting a disease (i.e., halting further progression of the pathology and / or symptoms) in an individual experiencing or exhibiting pathology or symptoms of the disease, or 2) ameliorating a disease (i.e., reversing the pathology and / or symptoms) in an individual experiencing or exhibiting pathology or symptoms of the disease.

[0238] As used herein, the term "prevent" or "prevention" refers to preventing a disease in an individual who may be susceptible to the disease but who has not yet experienced or exhibited the pathology or symptoms of the disease.

[0239] As used herein, the term "reducing" refers to the level in a patient prior to administration. More particularly, when a biomarker or symptom is reduced in a patient, the reduction refers to the level or severity of the biomarker or symptom in the patient prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0240] Combination therapy For example, one or more additional pharmaceutical agents or treatments may be used in combination with the compounds of the present invention, such as chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapy, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic inhibitors, or signal transduction inhibitors. The agents may be combined with the compounds in a single dosage form, or the agents may be administered as separate dosage forms, either simultaneously or sequentially.

[0241] Suitable drugs for use in combination with the compounds of the present invention to treat cancer include chemotherapeutic agents, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds of the present invention may be effective in combination with antihormonal agents to treat breast cancer and other tumors.Suitable examples include, but are not limited to, tamoxifen and toremifene, aromatase inhibitors (including, but not limited to, letrozole, anastrozole, and exemestane), corticosteroids (e.g., prednisone), progestins (e.g., megasterol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal agents used to treat prostate cancer and other cancers may also be used in combination with the compounds of the present invention. These include, but are not limited to, antiandrogens, including flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0242] In some tumors, angiogenesis inhibitors may be effective in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR, or VEGFR kinase inhibitors. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0243] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents such as uracil mustard (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0244] Other anti-cancer agents include antibody therapeutics against costimulatory molecules such as CTLA-4, 4-1BB, PD-1 and PD-L1 or antibodies against cytokines (IL-10, TGF-β, etc.) Exemplary cancer immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab and rituximab.

[0245] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Moreover, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 ed., Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0246] Suitable agents for use in combination with the compounds of the invention to treat 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 drugs); 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)); antihypertensive agents (e.g., calcium chloride, These include: neuroblockers (e.g., amlodipine, 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, blisibimod); type-1 interferon receptor antagonists (e.g., anifrolumab); T-cell modulators (e.g., rigerimod); abatacept; anticoagulants (e.g., heparin, warfarin); and vitamin D supplements.

[0247] Additional agents suitable for use in combination with the present invention to treat inflammatory diseases include, but are not limited to, sulfonylureas, meglitinides, biguanides, alpha-glucosidase inhibitors, peroxisome proliferator-activated receptor gamma (i.e., PPAR-gamma) agonists, insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (e.g., fibrates, including fenofibrate, bezafibrate, gemfibrozil, clofibrate, and the like; bile acid sequestrants, including cholestyramine, colestipol, and the like; and niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists, including clopidogrel, ticlopidine, and the like), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and adiponectin.

[0248] Suitable agents for use in combination with the compounds of the invention to treat asthma include, but are not limited to, beclomethasone (Qvar™), budesonide (Pulmicort Flexhaler™), budesonide / formoterol (Symbicort™), ciclesonide (Alvesco™), flunisolide (Aerospan™), fluticasone (Flovent Diskus™, flovent HFA™, Arnuity Ellipta™), fluticasone / salmeterol (Advair™), mometasone (Asmanex™), mometasone / formoterol (Dulera™), albuterol sulfate (VoSpireER™), formoterol fumarate (Aerolizer™), salmeterol xinafoate (Serevent™), arformoterol tartrate (Brovana™), olodaterol (Striverdi™), fluticasone furoate / vilanterol (Breo Ellipta™), fluticasone furoate / umeclidinium / vilanterol (Trelegy Ellipta™), fluticasone propionate / salmeterol (AirDuo™), glycopyrrolate / formoterol fumarate (Bevespi Aerosphere™), indacaterol / glycopyrrolate (Utibron Neohaler™), tiotropium / olodaterol (Stiolto Respimat™), umeclidinium / vilanterol (Anoro Ellipta™), omalizumab (Xolair™), mepolizumab (NUCALA™), benralizumab (Fasenra™), reslizumab (Cinqair™), dupilumab, tralokinumab, lebrikizumab, etanercept, golimumab, brodalumab, and tezepelumab.

[0249] Pharmaceutical Preparations and Dosage Forms When used as a pharmaceutical, the compounds of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be oral, topical (including intraocular, and to mucous membranes, including intranasal, intravaginal, and intrarectal delivery), pulmonary (e.g., by inhalation or inhalation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), ocular, or parenteral.

[0250] The present invention also includes pharmaceutical compositions containing one or more of the compounds of the present invention as an active ingredient in combination with one or more pharmaceutically acceptable carriers.When preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container.When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance, which acts as a vehicle, carrier, or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders.

[0251] The compositions may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0252] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will normally be determined by a physician depending on the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0253] When preparing solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is usually dispersed uniformly throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

[0254] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form offering the advantage of extended action. For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0255] Liquid forms into which the compounds and compositions of the present invention may be incorporated to be administered orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0256] 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, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a tent-like face mask or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0257] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions may 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 condition being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the patient, and will be determined by the judgment of the attending clinician.

[0258] The composition administered to patients can be in the form of the above-mentioned pharmaceutical composition.These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.The aqueous solution can be packaged for immediate use or can be lyophilized and combined with a sterile aqueous carrier before administration to form a lyophilized preparation.

[0259] Therapeutic dosages of the compounds of the invention can vary depending, for example, on the particular use for which the treatment is made, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, a compound of the invention can be provided in an aqueous physiological buffer containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg to about 1 g per kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg to about 100 mg per kg of body weight per day. The dosage will likely depend on such variables as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological potency of the selected compound, the excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0260] 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 an antiviral agent, an anticancer agent, a vaccine, an antibody, an immunostimulant, an immunosuppressant, an anti-inflammatory agent, etc. [Example]

[0261] Device: 1 H NMR spectra were recorded at 300 MHz or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. NMR interpretation was performed using Bruker Topspin software, which assigned chemical shifts and multiplicities. When two adjacent peaks of equal or unequal height were observed, these two peaks may be labeled as either a multiplet or a doublet. In the case of a doublet, coupling constants may be assigned using this software. In any given example, one or more protons may not be observed because they are obscured by water and / or solvent peaks. The LCMS equipment and conditions are as follows:

[0262] 1. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-pack scepter C18 33*3.0mm, 3.0μm. Mobile phase: A: water / 6.5mM (NH4)HCO3; B: acetonitrile. Flow rate: 1.5mL / min, 40℃. Detector: 190-400nm.

[0263] Gradient stop time 2.0 min. Timetable:

[0264] [Table 1]

[0265] 2. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-pack scepter C18 33*3.0mm, 3.0μm. Mobile phase: A: water / 5mM (NH4)HCO3; B: acetonitrile. Flow rate: 1.5mL / min, 40℃. Detector: 190-400nm.

[0266] Gradient stop time 2.0 min. Timetable:

[0267] [Table 2]

[0268] 3. LC (acidic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Halo C18, 30*3.0mm, 2.0μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5mL / min, 40℃. Detector: 190-400nm. Gradient stop time: 2.0min. Timetable:

[0269] [Table 3]

[0270] 4. LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Halo C18, 30*3.0mm, 2.0μm. Mobile phase A: water / 0.1% FA; B: acetonitrile / 0.1% FA. Flow rate: 1.5mL / min, 40℃. Detector: 190-400nm. Gradient stop time: 3.0min. Timetable:

[0271] [Table 4]

[0272] 5. The MS detector was configured with electrospray ionization as the ionization source. Acquisition mode: scan; nebulization gas flow rate: 1.5 L / min; drying gas flow rate: 15 L / min; detector voltage: 0.95-1.25 kV; DL temperature: 250 °C; heating block temperature: 250 °C; scan range: 90.00-900.00 m / z.

[0273] 6. Sample preparation: Samples were dissolved in ACN or methanol at 1-10 mg / mL, and then filtered through a 0.22 μm filter membrane. Injection volume: 1-3 μL.

[0274] Definition: ACN (acetonitrile); Ac2O (acetic anhydride); BALF (bronchoalveolar lavage fluid); B2(OH)4 (tetrahydroxydiboron); BINAP ((±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene); Boc2O (di-tert-butyl dicarbonate); CaCl2 (calcium chloride); CH3CN (acetonitrile); Cs2CO3 (cesium carbonate); CsF (cesium fluoride); CuI (copper(I) iodide); Cu(OAc )2 (copper(II) acetate); DCE (1,2-dichloroethane); DCM or CH2Cl2 (dichloromethane); DEAD (diisopropyl azodicarboxylate); DIBAL-H (diisobutylaluminum hydride); DIEA (N,N-diisopropylethylamine); (DiMeIHeptCl)Pd(cinnamyl)Cl2 ([1,3-bis[2,6-bis[3-methyl-1-(2-methylpropyl)butyl]phenyl]-4,5-dichloro-1,3 -dihydro-2H-imidazol-2-ylidene]chloro[(1,2,3-η)-1-phenyl-2-propen-1-yl]-palladium;DMF (N,N-dimethylformamide);DMAP (4-dimethylaminopyridine);DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone);DMSO (dimethyl sulfoxide);DMSO-d6 (deuterated dimethyl sulfoxide);dtbpy (4,4'-di-tert- butyl-2,2'-dipyridyl; EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); equiv (equivalent); ESI (electrospray ionization); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); Fe (iron); g (gram); h (hour); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); 1H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); HOAc (acetic acid); HOBT (1-hydroxybenzotriazole hydrate); Hz (hertz); K2CO3 (potassium carbonate); KI (potassium iodide); K3PO4 (potassium phosphate tribasic); L (liter); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylamide); LiAlH4 (lithium aluminum hydride); LiCl (lithium chloride); LiHMDS (lithium bis(trimethylsilyl)amide); M (molar concentration); MeCN (acetonitrile); MeI (iodomethane); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter), mmol (millimol); NaBH4 (sodium borohydride); NaBH3CN (sodium cyanoborohydride); Na2CO3 (sodium carbonate); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); NaOCN (sodium cyanate um); NaOH (sodium hydroxide); Na2SO4 (sodium sulfate); Na2SO4.10H2O (sodium sulfate decahydrate); NH3 (ammonia); NH4Cl (ammonium chloride); (NH4)HCO3 (ammonium bicarbonate); nm (nanometers); (NiBr2. glyme (nickel(II) bromide ethylene glycol dimethyl ether complex); NMI (N-methylimidazole); NMP (N-methylpyrrolidone); PBS (phosphate buffered saline) [Pd(allyl)Cl]2 (bis(allyl)dichloropalladium); Pd / C (palladium on carbon); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)); Pd2(dba)3.CHCl3 (tris(dibenzylideneacetone)dipalladium-chloroform adduct); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Pd(OAc)2 (palladium(II) acetate); Pd PEPPSI IPentCl (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0));Pd(PPh3)2Cl2 (trans-dichlorobis(triphenylphosphine)palladium(II)); PE (petroleum ether); PPh3 (triphenylphosphine); Preparative HPLC (preparative high-performance liquid chromatography); ppm (parts per million); RockPhos (di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine); RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl); RuPhos-PdCl-2nd G (chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)); RuPhos Pd G3 ((2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate); SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride); STAB (sodium triacetoxyborohydride); TBAB (tetrabutylammonium bromide); TBAF (tetrabutylammonium fluoride); TBDPSCl (tert-butyldiphenylchlorosilane); t-BuBrettPhos (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'- Biphenyl; t-BuOK (potassium tert-butoxide); t-BuONa (sodium tert-butoxide); TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); TfOH (trifluoromethanesulfonic acid); THF (tetrahydrofuran); T3P (propylphosphonic anhydride); TsCl (p-toluenesulfonyl chloride); RT (retention time); UV (ultraviolet light); and XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

[0275] Intermediate A1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione

[0276] [ka]

[0277] Process A A solution of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (8.90 g, 31.4 mmol, 1.2 equiv.) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (7.23 g, 26.2 mmol, 1.0 equiv.) and TEA (7.95 g, 78.6 mmol, 3.0 equiv.) in NMP (70 mL) was stirred for 3 hours at 70° C. 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] + .

[0278] Process B A solution of 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, 7.8 mmol, 1.0 equiv) in trifluoroacetic acid (30 mL) and DCM (90 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and then diluted with DCM (60 mL) and water (50 ml). The mixture was neutralized to pH 7 with saturated 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)piperazin-1-yl)isoindoline-1,3-dione (3.9 g) as a crude yellow solid. The product was used without further purification. LCMS (ESI, m / z): 440.10 [M+H] + .

[0279] Intermediates A1-a to A1-p were synthesized following the procedure described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (Intermediate A1) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions as needed.

[0280] [Table 5] TIFF2025526433000055.tif216168TIFF2025526433000056.tif221168TIFF2025526433000057.tif210168

[0281] Intermediate A2: Synthesis of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0282] [ka]

[0283] To a solution of pomalidomide (1.0 g, 3.7 mmol, 1.0 equiv) in THF (20 mL) at 0° C. was added bromoacetyl chloride (1.44 g, 9.15 mmol, 2.5 equiv). The resulting mixture was stirred at 70° C. for 2 hours and then concentrated in vacuo. The crude product was dissolved in diethyl ether and stirred for 20 minutes. The precipitated solid was collected by filtration and washed with diethyl ether (3×20 mL) to give 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (1.2 g, 83% yield) as a yellow solid. LCMS (ESI, m / z): 393.95, 395.95 [M+H] + .

[0284] Intermediate A2-a was synthesized following the procedure described for the synthesis of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Intermediate A2) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0285] [Table 6]

[0286] Intermediate A3: Synthesis of 3-((4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0287] [ka]

[0288] Process A To a solution of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (600 mg, 2.09 mmol, 1.0 equiv) and tert-butyl 4-formylpiperidine-1-carboxylate (668 mg, 3.13 mmol, 1.5 equiv) in MeOH (20 mL) was added NaBHCN (262 mg, 4.18 mmol, 2.0 equiv) in small portions. The resulting solution was stirred for 4 h. The mixture was concentrated under reduced pressure and directly purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to afford tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (639 mg, 63% yield) as a yellow solid. LCMS (ESI, m / z): 485.30 [M+H] + .

[0289] Process B A solution of tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (639 mg, 1.32 mmol, 1.0 equiv) in HCl (20 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give 3-((4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (969 mg) as a crude white solid, which was used without further purification. LCMS (ESI, m / z): 385.30 [M+H] + . Intermediate A4: Synthesis of 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0290] [ka]

[0291] Process A A solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (500 mg, 1.8 mmol, 1.0 equiv) and acrylic acid (196 mg, 2.71 mmol, 1.5 equiv) in toluene (50 mL) was stirred at 120 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (8:1) to afford 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)propanoic acid (252 mg, 40% yield) as a yellow solid. LCMS (ESI, m / z): 347.25 [MH] - .

[0292] Process B A solution of 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)propanoic acid (240 mg, 0.69 mmol, 1 equiv.) and urea (83 mg, 1.4 mmol, 2 equiv.) in HOAc (25 mL) was stirred at 120 °C for 3 h. The mixture was neutralized to pH 7 with saturated aqueous NaHCO. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NHHCO) in water, 5% to 95% gradient in 20 min; detector, UV 254 nm, to give 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (95 mg, 50% yield) as a yellow oil. LCMS (ESI, m / z): 274.15 [M+H] + .

[0293] Process C A solution of 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (85 mg, 0.31 mmol, 1.0 equiv.), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (130 mg, 0.47 mmol, 1.5 equiv.), and DIEA (121 mg, 0.93 mmol, 3.0 equiv.) in NMP (5 mL) was stirred at 120° C. for 2 h. 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 NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 5% to 95% gradient in 35 min; detector, UV 254 nm, 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] + .

[0294] Process D 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 resulting mixture was concentrated in vacuo to give 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (28 mg) as a crude yellow solid, which was used without further purification. LCMS (ESI, m / z): 371.10 [M+H] + .

[0295] Intermediate A4-a was synthesized following the procedure described for the synthesis of 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate A4) hydrochloride, using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0296] [Table 7]

[0297] Intermediate A4-b was synthesized following the procedure described for the synthesis of 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (Intermediate A4) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0298] [Table 8]

[0299] Intermediate A5: Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0300] [ka]

[0301] Process A A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.55 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (288 mg, 1.55 mmol, 1.0 equiv.), Pd PEPPSI IPentCl (133 mg, 0.16 mmol, 0.1 equiv.), and CsCO (1008 mg, 3.09 mmol, 2.0 equiv.) in 1,4-dioxane (5 mL) was stirred under a nitrogen atmosphere at 100° C. for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (400 mg, 60%) as a white solid. LCMS (ESI, m / z): 429.15 [M+H] + .

[0302] Process B A solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (400 mg, 0.93 mmol, 1.0 equiv) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The resulting mixture was concentrated in vacuo to give 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (425 mg) as a crude yellow solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 329.10 [M+H] + .

[0303] Intermediates A5-a to A5-c were synthesized following the procedure described for the synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (Intermediate A5) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0304] [Table 9]

[0305] Intermediates A5-d and A5-e were synthesized following the procedure described for the synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (Intermediate A5), using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0306] [Table 10]

[0307] Intermediate A6: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)cyclobutoxy)-isoindoline-1,3-dione

[0308] [ka]

[0309] Process A To a stirred solution of 3-(hydroxymethyl)cyclobutan-1-ol (2.0 g, 19.6 mmol, 1.0 equiv.), TEA (5.94 g, 58.7 mmol, 3.0 equiv.), and DMAP (0.24 g, 1.96 mmol, 0.1 equiv.) in DCM (5 mL) at 0 °C, TBDPSCl (5.38 g, 19.6 mmol, 1.0 equiv.) was added dropwise. The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (13 / 7) to give 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-ol (3 g, 45% yield) as a colorless oil. LCMS (ESI, m / z): 341.20 [M+H] + .

[0310] Process B To a stirred solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-ol (300 mg, 0.88 mmol, 1.0 equiv.), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (362 mg, 1.32 mmol, 1.5 equiv.), and PPh3 (347 mg, 1.32 mmol, 1.5 equiv.) in THF (5 mL) was added DEAD (230 mg, 1.32 mmol, 1.5 equiv.) dropwise. The resulting mixture was stirred at 50 °C for 4 h. After concentration, the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 80% FA gradient in 20 min; detector, UV 254 nm. This gave 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (400 mg, 76% yield) as a white solid. LCMS (ESI, m / z): 597.23 [M+H]+.

[0311] Process C To a stirred solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (365 mg, 0.61 mmol, 1.0 equiv.) in THF (5 mL) was added TBAF (320 mg, 1.22 mmol, 2.0 equiv.) in small portions. The resulting mixture was stirred for 1 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient from 0% to 20% in 20 min; detector, UV 254 nm. This gave 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)cyclobutoxy)isoindoline-1,3-dione (165 mg, 75% yield) as a white solid. LCMS (ESI, m / z): 359.12 [M+H] + .

[0312] Intermediate A6-a was synthesized following the procedure described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)cyclobutoxy)-isoindoline-1,3-dione (Intermediate A6) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0313] [Table 11]

[0314] Intermediate A7: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0315] [ka]

[0316] Process A A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (1.0 g, 3.62 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (0.74 g, 3.98 mmol, 1.1 equiv.), and DIEA (1.40 g, 10.9 mmol, 3.0 equiv.) in NMP (5 mL) was stirred at 120° C. for 2 hours. The mixture was cooled to room temperature and then diluted with water (25 mL). The precipitated solid was collected by filtration and washed with water (3×10 mL) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate (1.02 g, 64% yield) as a crude yellow solid. LCMS (ESI, m / z): 443.10 [M+H] + .

[0317] Process B A solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate (1.0 g, 2.26 mmol, 1.0 equiv) in HCl (50 mL, 4 M) in 1,4-dioxane was stirred for 50 minutes. The resulting mixture was concentrated in vacuo to give 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (1.1 g) as a crude yellow solid. The crude product was used directly in the next step without any further purification. LCMS (ESI, m / z): 343.15 [M+H] + .

[0318] Intermediates A7-a to A7-d were synthesized following the procedure described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (Intermediate A7), using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions as needed.

[0319] [Table 12]

[0320] Intermediate A8: Synthesis of 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione hydrochloride

[0321] [ka]

[0322] Process A To a solution of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (1.0 g, 3.59 mmol, 1.0 equiv.) in DMF (2 mL) was added NaH (0.17 g, 7.19 mmol, 2.0 equiv.) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes. Next, 3-bromopiperidine-2,6-dione (0.83 g, 4.31 mmol, 1.2 equiv.) was added, and the mixture was stirred for 12 hours. The reaction was quenched with water at 0° C. and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×7 mL), dried over anhydrous NaSO, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (300 mg, 21% yield) as a white solid. LCMS (ESI, m / z): 390.25 [M+H] + .

[0323] Process B A mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (300 mg, 0.77 mmol, 1.0 equiv) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give 3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione hydrochloride (250 mg, 99% yield) as a crude yellow solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 290.15 [M+H] + . Intermediate A9: Synthesis of 3-(methyl(4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0324] [ka]

[0325] Process A A solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (3.0 g, 10.8 mmol, 1.0 equiv.), TFAA (2.73 g, 13.0 mmol, 1.2 equiv.), and TEA (2.19 g, 21.6 mmol, 2.0 equiv.) in DCM (20 mL) was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give tert-butyl 4-(4-(2,2,2-trifluoroacetamido)phenyl)piperazine-1-carboxylate (8.3 g) as a crude brown solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 374.15 [M+H] + .

[0326] Process B A solution of tert-butyl 4-(4-(2,2,2-trifluoroacetamido)phenyl)piperazine-1-carboxylate (8.3 g, 22.2 mmol, 1.0 equiv.), MeI (3.16 g, 22.2 mmol, 1.0 equiv.), and KCO (6.14 g, 44.4 mmol, 2.0 equiv.) in DMF (10 mL) was stirred at 60 °C overnight. The product was precipitated by adding water. The solid was collected by filtration. This gave tert-butyl 4-(4-(2,2,2-trifluoro-N-methylacetamido)phenyl)piperazine-1-carboxylate (3.6 g, 42% yield) as a black solid. LCMS (ESI, m / z): 388.15 [M+H] + .

[0327] Process C A solution of tert-butyl 4-(4-(2,2,2-trifluoro-N-methylacetamido)phenyl)piperazine-1-carboxylate (3.6 g, 9.29 mmol, 1.0 equiv) and KCO (2.57 g, 18.6 mmol, 2.0 equiv) in water (5 mL) and MeOH (20 mL) was stirred for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (57:43) to afford tert-butyl 4-(4-(methylamino)phenyl)piperazine-1-carboxylate (2.5 g, 92% yield) as a white solid. LCMS (ESI, m / z): 292.15 [M+H] + .

[0328] Process D A solution of tert-butyl 4-(4-(methylamino)phenyl)piperazine-1-carboxylate (1.5 g, 5.15 mmol, 1.0 equiv.), 3-bromopiperidine-2,6-dione (1.19 g, 6.18 mmol, 1.2 equiv.), and NaHCO3 (0.86 g, 10.3 mmol, 2.0 equiv.) in ACN (50 mL) was stirred at 90 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (30:70) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazine-1-carboxylate (1.6 g, 77% yield) as a pale yellow powder. LCMS (ESI, m / z): 403.15 [M+H] + .

[0329] Process E A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazine-1-carboxylate (1.6 g, 3.98 mmol, 1.0 equiv) in HCl (30 mL, 4 M) in 1,4-dioxane was stirred for 50 min. The resulting mixture was concentrated under reduced pressure to give 3-(methyl(4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (2.1 g) as a light green solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 303.15 [M+H] + . Intermediate A10: Synthesis of 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione

[0330] [ka]

[0331] Process A A solution of tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (2.0 g, 7.23 mmol, 1.0 equiv.), 2,6-bis(benzyloxy)-3-bromopyridine (2.68 g, 7.24 mmol, 1.0 equiv.), t-BuONa (1.04 g, 10.9 mmol, 1.5 equiv.), Pd(dba).CHCl (0.75 g, 0.72 mmol, 0.1 equiv.), and Xantphos (0.42 g, 0.72 mmol, 0.1 equiv.) in toluene (30 mL) was stirred overnight at 100° C. The resulting mixture 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 (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 40 min; detector, UV 254 nm. This afforded tert-butyl 4-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidine-1-carboxylate (3.2 g, 78%) as a brown solid. LCMS (ESI, m / z): 566.25 [M+H] + .

[0332] Process B A solution of tert-butyl 4-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidine-1-carboxylate (3.2 g, 5.66 mmol, 1.0 equiv) and Pd / C (3.0 g) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 30 min. The resulting mixture was filtered, and the filter cake was washed with CHCl (3×20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (2.2 g, 96%) as a dark green solid. LCMS (ESI, m / z): 386.25 [MH] - .

[0333] Process C A solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (2.3 g, 5.94 mmol, 1.0 equiv) in HCl (20 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The resulting mixture was concentrated under reduced pressure to give 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (2.4 g) as a dark green crude powder. The product was used in the next step without further purification. LCMS (ESI, m / z): 288.15 [M+H] + .

[0334] Intermediate A11: Synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride

[0335] [ka]

[0336] Process A A solution of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (7.0 g, 37.9 mmol, 1.2 equiv.), and KCO (8.71 g, 63.1 mmol, 2.0 equiv.) in DMF (10 mL) was stirred at 80 °C for 5 h. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The solid was dried in an oven to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (9.6 g, 98%) as a yellow solid. LCMS (ESI, m / z): 309.15 [M+H] + .

[0337] Process B A solution of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (9.6 g, 31.1 mmol, 1.0 equiv.), Fe (10.4 g, 187 mmol, 6.0 equiv.), and NH4Cl (3.33 g, 62.3 mmol, 2.0 equiv.) in water (10 mL) and EtOH (10 mL) was stirred at 80 °C overnight. The resulting mixture was filtered, and the filter cake was washed with EtOH (10 × 10 mL). The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (8 g, 92%) as a red oil. LCMS (ESI, m / z): 279.20 [M+H] + .

[0338] Process C A solution of tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (2.0 g, 7.19 mmol, 1.0 equiv.), 3-bromopiperidine-2,6-dione (1.66 g, 8.62 mmol, 1.2 equiv.), and NaHCO3 (1.81 g, 21.6 mmol, 3.0 equiv.) in ACN (5 mL) was stirred at 90 °C overnight. The mixture was cooled to 0 °C. The precipitated solid was collected by filtration and washed with water (2 × 8 mL). The solid was dried in an oven to give tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (1.5 g, 54%) as a green solid. LCMS (ESI, m / z): 390.20 [M+H] + .

[0339] Process D A solution of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (1.5 g, 3.85 mmol, 1.0 equiv) in HCl (6 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The resulting mixture was concentrated in vacuo to give 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride (1.0 g, 90%) as a crude purple solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 290.15 [M+H] + .

[0340] Intermediates A11-a and A11-b were synthesized following the procedure described for the synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride (Intermediate A11) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0341] [Table 13]

[0342] Intermediate A12: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-ylethynyl)isoindoline-1,3-dione hydrochloride

[0343] [ka]

[0344] Process A A mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.58 g, 4.70 mmol, 1.0 equiv), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.00 g, 4.79 mmol, 1.0 equiv), Pd(PPh)Cl (329 mg, 0.47 mmol, 0.1 equiv), and TEA (1.42 g, 14.1 mmol, 3.0 equiv) in DMSO (7 mL) was stirred at 80° C. for 5 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DMSO (2 mL), and the filtrate was purified by C18 reverse-phase chromatography eluting with water (10 mmol / L NH4HCO3) / ACN (55:45) to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate (1.28 g, 59%) as a tan solid. LCMS (ESI, m / z): 410.15 [M+Ht-Bu] + .

[0345] Process B A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate (981 mg, 2.11 mmol) in HCl (30 mL, 4 M) in 1,4-dioxane was stirred for 1.5 hours. The resulting mixture was concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-ylethynyl)isoindoline-1,3-dione hydrochloride (815 mg, 96%) as a white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 366.15 [M+H] + . Intermediate A13: Synthesis of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinan-2,4-dione

[0346] [ka]

[0347] Process A A solution of 6-bromo-1-methylindazol-3-amine (10 g, 44.2 mmol, 1.0 equiv.), acrylic acid (3.2 g, 44.4 mmol, 1.0 equiv.), and HOAc (6.8 g, 113 mmol, 2.56 equiv.) in water (100 mL) was stirred at 100 °C overnight. NaOH (17.7 g, 443 mmol, 10 equiv.) was then added. The resulting mixture was extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with aqueous HCl. The precipitated solid was collected by filtration and washed with water to give 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoic acid (8 g, 61%) as an off-white solid. LCMS (ESI, m / z): 298.15 [M+H] + .

[0348] Process B A solution of 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoic acid (4.0 g, 13.4 mmol, 1.0 equiv.) and urea (3.0 g, 50.0 mmol, 3.72 equiv.) in HOAc (30 mL) was stirred at 120 °C overnight. After concentration, the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% HCl) in water, 0% to 40% gradient in 15 min; UV 254 nm detector. This afforded 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione (1.2 g, 14%) as a pink solid. LCMS (ESI, m / z): 323.15 [M+H] + .

[0349] Process C A solution of 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione (800 mg, 2.48 mmol, 1.0 equiv), tert-butyl 4-bromopiperidine-1-carboxylate (684 mg, 2.59 mmol, 1.05 equiv), NiBr glyme (153 mg, 0.50 mmol, 0.20 equiv), dtbpy (133 mg, 0.5 mmol, 0.20 equiv), Mn (545 mg, 9.92 mmol, 4.01 equiv), NaI (372 mg, 2.48 mmol, 1.00 equiv), and pyridine (196 mg, 2.48 mmol, 1.00 equiv) in DMPU (15 mL) was stirred overnight at 70 °C under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 52% gradient in 15 min; detector, UV 254 nm. This afforded tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidine-1-carboxylate (230 mg, 22%) as a pale yellow oil. LCMS (ESI, m / z): 428.50 [M+H] + .

[0350] Process D A solution of tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidine-1-carboxylate (230 mg, 0.54 mmol, 1.0 equiv.) in TFA (5 mL) and DCM (5 mL) was stirred for 1 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 42% B, 42% B in 9 min; Wavelength: 254 / 220 nm; RT1 (min): 8.9. This gave 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinan-2,4-dione (110 mg, 62%) as a white solid. LCMS (ESI, m / z): 328.39 [M+H] + .

[0351] Intermediate A13-a was synthesized following the procedure described for the synthesis of 1-[1-methyl-6-(piperidin-4-yl)indazol-3-yl]-1,3-diazinan-2,4-dione (Intermediate A13), using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions as needed.

[0352] [Table 14]

[0353] Intermediate A14: Synthesis of 3-((4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione hydrochloride

[0354] [ka]

[0355] Process A A solution of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1000 mg, 4.40 mmol, 1.0 equiv.), 1-fluoro-4-nitrobenzene (931 mg, 6.6 mmol, 1.5 equiv.), and t-BuOK (987 mg, 8.8 mmol, 2.0 equiv.) in DMSO (6 mL) was stirred for 1 h. The mixture was cooled to 0 °C. The product was precipitated by the addition of water. The precipitated solid was collected by filtration and washed with water (3 × 10 mL) to give tert-butyl (3aR,5r,6aS)-5-(4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.2 g, 78%) as a brown oil. LCMS (ESI, m / z): 349.15 [M+H] + .

[0356] Process B A solution of tert-butyl (3aR,5r,6aS)-5-(4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1100 mg, 3.16 mmol, 1.0 equiv.), Fe (882 mg, 15.8 mmol, 5.0 equiv.), and NHCl (338 mg, 6.31 mmol, 2.0 equiv.) in EtOH (4 mL) and water (4 mL) was stirred at 80 °C for 3 h. The resulting mixture was filtered, and the filter cake was washed with EtOH (10 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl (3aR,5r,6aS)-5-(4-aminophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (825 mg, 82%) as a blue solid. LCMS (ESI, m / z): 319.20 [M+H] + .

[0357] Process C A solution of tert-butyl (3aR,5r,6aS)-5-(4-aminophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (810 mg, 2.54 mmol, 1.0 equiv), 3-bromopiperidine-2,6-dione (733 mg, 3.82 mmol, 1.5 equiv), and NaHCO (641 mg, 7.63 mmol, 3.0 equiv) in ACN (5 mL) was stirred overnight at 90 °C. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl (3aR,5r,6aS)-5-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (804 mg, 74%) as a blue solid. LCMS (ESI, m / z): 429.23 [M+H] + .

[0358] Process D A solution of tert-butyl (3aR,5r,6aS)-5-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (816 mg, 3.85 mmol, 1.0 equiv) in HCl (6 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The resulting mixture was concentrated in vacuo to give 3-((4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione hydrochloride (804 mg, 90%) as a crude gray solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 330.17 [M+H] + . Intermediate A15: Synthesis of 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0359] [ka]

[0360] Process A A solution of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.86 mmol, 1.0 equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (689 mg, 2.23 mmol, 1.2 equiv), Pd(dppf)ClCHCl (151 mg, 0.19 mmol, 0.1 equiv), KPO (789 mg, 3.72 mmol, 2.0 equiv) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 80 °C for 1 h. After concentration, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 94%) as a white solid. LCMS (ESI, m / z): 370.10 [MH] - .

[0361] Process B A solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 1.75 mmol, 1.0 equiv) and Pd / C (186 mg) in EA (5 mL) was stirred under a hydrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 9 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-1-carboxylate (620 mg, 95%) as a white solid. LCMS (ESI, m / z): 372.15 [MH] - .

[0362] Process C A solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-1-carboxylate (600 mg, 1.61 mmol, 1.0 equiv) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The solution was concentrated to give 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg) as a crude white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 274.05 [M+H] + .

[0363] Intermediates A15-a to A15-d were synthesized following the procedure described for the synthesis of 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (Intermediate A15) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0364] [Table 15] TIFF2025526433000082.tif82168

[0365] Intermediate A16: Synthesis of 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride

[0366] [ka]

[0367] Process A A solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g, 2.9 mmol, 1.0 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.82 g, 5.91 mmol, 2.0 equiv.), KPO (1.88 g, 8.87 mmol, 3.0 equiv.), and Pd(dppf)ClCHCl (241 mg, 0.296 mmol, 0.1 equiv.) in dioxane (8 mL) was stirred at 80° C. for 2 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (567 mg, 43%) as a white solid. LCMS (ESI, m / z): 441.15 [M+H] + .

[0368] Process B A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (413 mg, 0.938 mmol, 1.0 equiv) and 10% Pd / C (2 g) in EtOAc (7 mL) was stirred under a hydrogen atmosphere for 1 h. The solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (243 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 443.15 [M+H] + .

[0369] Process C A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (210 mg, 0.475 mmol, 1.0 equiv.) in hydrochloric acid (10 mL, 4 M) in 1,4-dioxane was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (224 mg) as a crude brown oil. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 343.15 [M+H] + .

[0370] Intermediate A17: Synthesis of 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride

[0371] [ka]

[0372] Process A A solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (413 mg, 2.2 mmol, 1.5 equiv.), RuPhos-PdCl-2nd G (115 mg, 0.15 mmol, 0.1 equiv.), RuPhos (69.1 mg, 0.15 mmol, 0.1 equiv.), and LiHMDS (2.9 mL, 2.9 mmol, 2 equiv., 1 M in THF) in toluene (5 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 25% gradient over 20 min; detector, UV 254 nm. This afforded tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (220 mg, 33% yield) as a gray solid. LCMS (ESI, m / z): 444.20 [M+H] + .

[0373] Process B A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (220 mg, 0.50 mmol, 1 equiv.) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The resulting mixture was concentrated in vacuo to give crude 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (240 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 344.15 [M+H] + .

[0374] Intermediate A18: Synthesis of 3-(isoindolin-5-ylamino)piperidine-2,6-dione

[0375] [ka]

[0376] Process A A solution of tert-butyl 5-aminoisoindoline-2-carboxylate (3.0 g, 12.8 mmol, 1 equiv.), 3-bromopiperidine-2,6-dione (4.92 g, 25.6 mmol, 2 equiv.), and NaHCO (5.38 g, 64.0 mmol, 5 equiv.) in ACN (20 mL) was stirred at 90 °C for 2 days. The solution was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / PE (50:50) to give tert-butyl 5-((2,6-dioxopiperidin-3-yl)amino)isoindoline-2-carboxylate (5 g, 90%) as a dark blue solid. LCMS (ESI, m / z): 346.25 [M+H] + .

[0377] Process B A solution of tert-butyl 5-((2,6-dioxopiperidin-3-yl)amino)isoindoline-2-carboxylate (5.0 g, 14.5 mmol, 1 equiv.) in HCl (40 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The resulting mixture was concentrated in vacuo to give 3-(isoindolin-5-ylamino)piperidine-2,6-dione (3.4 g, 96%) as a brown solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 246.20 [M+H] + .

[0378] Intermediate A18-b was synthesized following the procedure described for the synthesis of 3-(isoindolin-5-ylamino)piperidine-2,6-dione hydrochloride (Intermediate A18) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0379] [Table 16]

[0380] Intermediate A19: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide

[0381] [ka]

[0382] Process A A solution of methyl 4-bromo-2-fluorobenzoate (5.0 g, 21.5 mmol, 1 equiv.) in dioxane (20 mL) was treated with tert-butyl piperazine-1-carboxylate (4.80 g, 25.7 mmol, 1.2 equiv.), Pd(OAc) (0.48 g, 2.15 mmol, 0.1 equiv.), and BINAP (1.34 g, 2.15 mmol, 0.1 equiv.) under a nitrogen atmosphere at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (72:28) to give tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (6 g, 83%) as a yellow solid. LCMS (ESI, m / z): 339.16 [M+H] + .

[0383] Process B A solution of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.0 g, 5.91 mmol, 1 equiv.) in MeOH (5 mL) was treated with a solution of NaOH (4.73 g, 118 mmol, 20 equiv.) in water (15 mL) for 3 h. The mixture was acidified to pH 7 with concentrated HCl, and the precipitated solid was collected by filtration. This gave 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (1.9 g, 99%) as a white solid. LCMS (ESI, m / z): 325.15 [M+H] + .

[0384] Process C A solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (1.9 g, 5.86 mmol, 1.0 equiv) in DMF (15 mL) was treated with 3-aminopiperidine-2,6-dione (0.90 g, 7.03 mmol, 1.2 equiv), DIEA (2.27 g, 17.6 mmol, 3.0 equiv), HOBT (1.19 g, 8.79 mmol, 1.5 equiv), and EDCI (1.68 g, 8.79 mmol, 1.5 equiv) overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 40% gradient in 15 min; detector, UV 254 nm, to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (1.29 g, 50%) as a gray solid. LCMS (ESI, m / z): 435.20 [M+H] + .

[0385] Process D A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (1.28 g, 2.94 mmol, 1 equiv.) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The resulting mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (1.35 g) as an off-white solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 335.14 [M+H] + .

[0386] Intermediate A20: Synthesis of N-methyl-N-(4-nitrophenyl)piperidin-4-amine

[0387] [ka]

[0388] Process A A solution of tert-butyl 4-((4-nitrophenyl)amino)piperidine-1-carboxylate (4.0 g, 12.4 mmol, 1 equiv.) in THF (25 mL) was treated with NaH (0.90 g, 37.3 mmol, 3 equiv.) at 0° C. for 30 minutes, followed by the dropwise addition of methyl iodide (3.53 g, 24.9 mmol, 2 equiv.) at room temperature. The solution was stirred at room temperature for 4 hours. The reaction was quenched with water at 0° C. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure. This afforded tert-butyl 4-(methyl(4-nitrophenyl)amino)piperidine-1-carboxylate (4 g, 96%) as a yellow solid. LCMS (ESI, m / z): 336.15 [M+H] + .

[0389] Process B A solution of tert-butyl 4-(methyl(4-nitrophenyl)amino)piperidine-1-carboxylate (4.8 g, 14.3 mmol, 1 equiv.) in HCl (20 mL, 4 M) in 1,4-dioxane was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure. This gave N-methyl-N-(4-nitrophenyl)piperidin-4-amine (4 g) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 236.20 [M+H] + .

[0390] Intermediate A21: Synthesis of 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0391] [ka]

[0392] Process A A solution of 2,4-difluoro-1-nitrobenzene (5.0 g, 31.4 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (5.85 g, 31.4 mmol, 1 equiv.), and TEA (9.54 g, 94.3 mmol, 3 equiv.) in DMF (20 mL) was stirred at 80 °C for 5 h. The reaction was quenched with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a mixture of regioisomers. The residue was purified by C18 reverse-phase chromatography eluting with water / MeCN (40:60) to give the desired isomer, tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (5 g, 48%), as a pale yellow solid. LCMS (ESI, m / z): 326.15 [M+H] + .

[0393] Process B A solution of tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (5 g, 15.1 mmol, 1 equiv.), Fe (4.21 g, 75.3 mmol, 5 equiv.), and NHCl (1.61 g, 30.1 mmol, 2 equiv.) in EtOH (10 mL) and water (10 mL) was stirred at 80° C. for 3 h. The resulting mixture was concentrated in vacuo and applied to a silica gel column with MeOH / DCM (10:90) to give tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (3.3 g, 88%) as a black oil. LCMS (ESI, m / z): 296.15 [M+H] + .

[0394] Process C A solution of tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (800 mg, 2.71 mmol, 1 equiv.), 3-bromopiperidine-2,6-dione (1.56 g, 10.2 mmol, 2 equiv.), and NaHCO3 (1.13 g, 25.4 mmol, 5 equiv.) in ACN (5 mL) was stirred at 90 °C for 2 days. The resulting mixture was concentrated in vacuo, and the residue was purified by C18 reverse-phase chromatography eluting with water / ACN (33:67) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (800 mg, 73%). LCMS (ESI, m / z): 407.20 [M+H] + .

[0395] Process D A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (800 mg, 1.23 mmol, 1 equiv.) in 1,4-dioxane (5 mL, 4 M) was stirred for 30 minutes. The resulting mixture was concentrated in vacuo to give 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (800 mg) as a black solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 307.10 [M+H] + .

[0396] Intermediate A22: Synthesis of 2-(4-(1-(4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol

[0397] [ka]

[0398] A solution of 1-(4-nitrophenyl)piperidin-4-one (1.0 g, 4.54 mmol, 1 equiv.), 2-(piperazin-1-yl)ethan-1-ol (0.59 g, 4.54 mmol, 1 equiv.), and STAB (1.92 g, 9.08 mmol, 2 equiv.) in DCE (30 mL) was stirred for 2 h. After concentration, the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient from 0% to 50% over 40 min; detector, UV 254 nm. This afforded 2-(4-(1-(4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol (455 mg, 30%) as a yellow oil. LCMS (ESI, m / z): 335.20 [M+H] + .

[0399] Synthesis of Intermediate A23: 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione.

[0400] [ka]

[0401] Process A A mixture of 1,2,3-trifluoro-5-nitrobenzene (5.0 g, 28.2 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (5.25 g, 28.2 mmol, 1.0 equiv.), and TEA (8.56 g, 84.6 mmol, 3.0 equiv.) in DMF (8 mL) was stirred at 80° C. for 1 h. After addition of water, the precipitated solid was collected by filtration and washed with water to give tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (9.4 g, 97%) as a yellow solid. LCMS (ESI, m / z): 344.20 [M+H] + .

[0402] Process B A mixture of tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (4.5 g, 13.1 mmol, 1 equiv.), Fe (3.6 g, 64.5 mmol, 4.9 equiv.), and NH₄Cl (2.1 g, 39.3 mmol, 3.0 equiv.) in EtOH (20 mL) and water (5 mL) was stirred at 80°C overnight. The resulting mixture was filtered, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography eluting with water (10 mmol / L NH₄HCO₃) / ACN (30:70). The resulting mixture in tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (3 g, 73%) was obtained as a purple solid. LCMS (ESI, m / z): 314.15 [M+H] + .

[0403] Process C A mixture of tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (1.5 g, 4.79 mmol, 1 equiv.), 3-bromopiperidine-2,6-dione (7.3 g, 38.0 mmol, 7.94 equiv.), and NaHCO3 (3.6 g, 42.9 mmol, 8.95 equiv.) in ACN (40 mL) was stirred at 90 °C for 2 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (4:1) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (3.45 g) as a white solid. LCMS (ESI, m / z): 425.10 [M+H] + .

[0404] Process D A mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (1.0 g, 2.36 mmol, 1 equiv.) in HCl (30 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (990 mg, crude) as a white solid. LCMS (ESI, m / z): 325.20 [M+H] + . Intermediate A24: Synthesis of 2-(4-(1-(4-nitrophenyl)azetidin-3-yl)piperazin-1-yl)ethan-1-ol

[0405] [ka]

[0406] Process A A mixture of 2-(piperazin-1-yl)ethan-1-ol (5 g, 38.4 mmol, 1 equiv.), tert-butyl 3-oxoazetidine-1-carboxylate (16.4 g, 96.0 mmol, 2.5 equiv.), and STAB (16.3 g, 76.8 mmol, 2 equiv.) in DCE (20 mL) was stirred for 2 h. The residue was concentrated and purified by silica gel column chromatography eluting with DCM / MeOH (92:8) to give tert-butyl 3-(4-(2-hydroxyethyl)piperazin-1-yl)azetidine-1-carboxylate (10.3 g, 94%) as a yellow oil. LCMS (ESI, m / z): 286.15 [M+H] + .

[0407] Process B A solution of tert-butyl 3-(4-(2-hydroxyethyl)piperazin-1-yl)azetidine-1-carboxylate (5 g, 17.5 mmol, 1 equiv.) in HCl (15 mL, 4 M) in 1,4-dioxane was stirred for 2 h. The resulting mixture was concentrated under reduced pressure to give 2-(4-(azetidin-3-yl)piperazin-1-yl)ethan-1-ol (4.8 g) as a yellow oil. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 186.15 [M+H] + .

[0408] Process C A solution of 2-(4-(azetidin-3-yl)piperazin-1-yl)ethan-1-ol (3.8 g, 20.5 mmol, 1 equiv.), KCO (8.50 g, 61.5 mmol, 3 equiv.), and 1-fluoro-4-nitrobenzene (5.79 g, 41.0 mmol, 2 equiv.) in DMF (20 mL) was stirred at 80 °C overnight. After cooling to room temperature, the mixture was quenched with water (40 mL). The precipitated solid was collected by filtration and washed with water. The solid was triturated with diethyl ether (30 mL). After filtration, 2-(4-(1-(4-nitrophenyl)azetidin-3-yl)piperazin-1-yl)ethan-1-ol (2.4 g, 39%) was isolated as a yellow solid. LCMS (ESI, m / z): 307.10 [M+H] + .

[0409] Intermediate A25: Synthesis of 3-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]piperidine-2,6-dione

[0410] [ka]

[0411] Process A To a mixture of 6-bromo-3-iodo-1H-indazole (500 mg, 1.54 mmol, 1.0 equiv) and NaH (111 mg, 4.64 mmol, 3.0 equiv) in DMF (2 mL) was added MeI (330 mg, 2.32 mmol, 1.5 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h, then quenched with water at 0 °C and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 6-bromo-3-iodo-1-methylindazole (275 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 336.8 [M+H] + .

[0412] Process B A solution of 6-bromo-3-iodo-1-methylindazole (500 mg, 1.48 mmol, 1.0 equiv.) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (929 mg, 2.23 mmol, 1.5 equiv.) and KCO (615 mg, 4.45 mmol, 3.0 equiv.) in dioxane (2 mL) and water (1 mL) was stirred under a nitrogen atmosphere at 80° C. for 1 hour. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methylindazole (490 mg, 66%) as a yellow oil. LCMS (ESI, m / z): 500.1 [M+H] + .

[0413] Process C A solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methylindazole (1.7 g, 3.48 mmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (1.0 g, 5.21 mmol, 1.5 equiv.), CsCO (3.4 g, 10.4 mmol, 3.0 equiv.), Ruphos (160 mg, 0.34 mmol, 0.1 equiv.), and RuPhos Pd G (291 mg, 0.34 mmol, 0.1 equiv.) in 1,4-dioxane (10 mL) was stirred at 90 °C under a nitrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}piperazine-1-carboxylate (1.1 g, 52%) as a yellow oil. LCMS (ESI, m / z): 606.3 [M+H] + .

[0414] Process D To a mixture of tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methylindazol-6-yl}piperazine-1-carboxylate (3.5 g, 5.78 mmol, 1.0 equiv.) in MeOH (250 mL) was added Pd / C (500 mg, 4.70 mmol, 0.8 equiv.). The resulting mixture was stirred under a hydrogen atmosphere for 3 days. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 100 mL). 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 (0.1% FA) in water, 10% to 90% gradient in 30 min; detector, UV 254 nm. This gave tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperazine-1-carboxylate (624 mg, 25%) as a purple solid. LCMS (ESI, m / z): 428.2 [M+H] + .

[0415] Process E A solution of tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperazine-1-carboxylate (400 mg, 0.94 mmol, 1.0 equiv) in dioxane (2 mL) was treated with HCl in 1,4-dioxane (2 mL, 4 M) and then stirred under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by trituration with diethyl ether (50 mL) to give 3-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]piperidine-2,6-dione (180 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 328.15 [M+H] + .

[0416] Intermediate A25-b was synthesized following the procedures described for steps A to D of the synthesis of 3-[1-methyl-6-(piperazin-1-yl)indazol-3-yl]piperidine-2,6-dione (Intermediate A25), using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0417] [Table 17]

[0418] Intermediate A26: Synthesis of (4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate

[0419] [ka]

[0420] Process A To a solution of tert-butyl (4-hydroxyphenyl)carbamate (5.6 g, 26.8 mmol, 1.0 equiv.), methyl 4-hydroxycyclohexane-1-carboxylate (6.35 g, 40.1 mmol, 1.5 equiv.), and PPh3 (10.5 g, 40.1 mmol, 1.5 equiv.) in THF (50 mL) at 0 °C, DEAD (6.99 g, 40.1 mmol, 1.5 equiv.) was added portionwise over 10 min. The resulting mixture was stirred at 50 °C for 4 h. The solution was concentrated in vacuo and applied to a silica gel column eluted with EtOAc / PE (30:70) to give methyl 4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexane-1-carboxylate (4.4 g, 47%) as a brown oil. LCMS (ESI, m / z): 350.20 [M+H] + .

[0421] Process B A solution of methyl 4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexane-1-carboxylate (4.4 g, 12.6 mmol, 1 equiv.) in THF (20 mL) was treated with LiAlH (0.96 g, 25.2 mmol, 2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched with water at 0 °C and extracted with EtOAc (3 × 100 mL). The combined organic extracts were concentrated in vacuo to give tert-butyl (4-((4-(hydroxymethyl)cyclohexyl)oxy)phenyl)carbamate (3.7 g, 91%) as a crude brown oil. LCMS (ESI, m / z): 322.20 [M+H] + .

[0422] Process C A solution of tert-butyl (4-((4-(hydroxymethyl)cyclohexyl)oxy)phenyl)carbamate (500 mg, 1.56 mmol, 1 equiv.) in DCM (10 mL) was treated with TEA (472 mg, 4.67 mmol, 3 equiv.) at room temperature for 5 min, followed by the addition of 4-methylbenzenesulfonyl chloride (356 mg, 1.87 mmol, 1.2 equiv.) in small portions at 0° C. The resulting mixture was stirred at room temperature for 1 h. The solution was concentrated in vacuo and purified on a silica gel column eluted with ethyl acetate / petroleum ether (20:80) to give (4-(4-((tert-butoxycarbonyl)amino)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate (550 mg, 74%) as a brown oil. LCMS (ESI, m / z): 476.20 [M+H] + .

[0423] Intermediate A27: Synthesis of 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride

[0424] [ka]

[0425] Process A To a solution of 6-bromobenzo[cd]indol-2(1H)-one (1 g, 4.03 mmol, 1 equiv.) in THF (30 mL) was added NaH (0.48 g, 20.2 mmol, 5 equiv.) in small portions at 0° C. The resulting mixture was stirred at room temperature for 1 hour. To the above mixture was added 3-bromopiperidine-2,6-dione (1.93 g, 10.1 mmol, 2.5 equiv.) at 0° C. The resulting mixture was stirred at 60° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (169 mg, 12%) as a yellow solid. LCMS (ESI, m / z): 359.00, 361.00 [M+H] + .

[0426] Process B A solution of 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (149 mg, 0.42 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (115.9 mg, 0.622 mmol, 1.5 equiv.), Pd PEPPSI IPentCl (36 mg, 0.042 mmol, 0.1 equiv.) and CsCO (203 mg, 0.622 mmol, 1.50 equiv.) in dioxane (5 mL) was stirred at 90° C. for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (162 mg, 84%) as a yellow solid. LCMS (ESI, m / z): 465.25 [M+H] + .

[0427] Process C A solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (152 mg, 0.327 mmol, 1 equiv.) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give crude 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (153 mg) as a yellow solid. The crude material was used in the next step without further purification. LCMS (ESI, m / z): 365.30 [M+H] + .

[0428] Intermediate A28: Synthesis of 2-(6-(4-nitrophenyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate

[0429] [ka]

[0430] Process A A solution of methyl 2-(6-chloropyridin-3-yl)acetate (3.0 g, 16.2 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (4.02 g, 16.2 mmol, 1 equiv.), CsF (4.91 g, 32.3 mmol, 2 equiv.), and Pd(PPh)Cl (1.13 g, 1.62 mmol, 0.1 equiv.) in water (6 mL) and EtOH (18 mL) was stirred at 100 °C under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give methyl 2-(6-(4-nitrophenyl)pyridin-3-yl)acetate (3.1 g, 70%) as a yellow oil. LCMS (ESI, m / z): 273.25 [M+H] + .

[0431] Process B A solution of methyl 2-(6-(4-nitrophenyl)pyridin-3-yl)acetate (1.5 g, 5.51 mmol, 1 equiv.), CaCl (1.22 g, 11.0 mmol, 2 equiv.), and NaBH (0.417 g, 11.0 mmol, 2 equiv.) in EtOH (10 mL) was stirred at 0 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give 2-(6-(4-nitrophenyl)pyridin-3-yl)ethan-1-ol (900 mg, 67%) as a white solid. LCMS (ESI, m / z): 245.10 [M+H] + .

[0432] Process C A solution of 2-(6-(4-nitrophenyl)pyridin-3-yl)ethan-1-ol (500 mg, 2.05 mmol, 1 equiv.), TEA (621 mg, 6.14 mmol, 3 equiv.), TsCl (390 mg, 2.04 mmol, 1 equiv.), and DMAP (25.0 mg, 0.205 mmol, 0.1 equiv.) in DCM (5 mL) was stirred for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give 2-(6-(4-nitrophenyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (450 mg, 55%) as a yellow solid. LCMS (ESI, m / z): 399.20 [M+H] + .

[0433] Intermediate A28-a was synthesized following the procedure described for the synthesis of 2-(6-(4-nitrophenyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (Intermediate A28) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0434] [Table 18]

[0435] Intermediate A29: Synthesis of 2-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)ethan-1-ol

[0436] [ka]

[0437] Process A A solution of tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (5 g, 18.6 mmol, 1 equiv.), 2-bromoethan-1-ol (4.64 g, 37.1 mmol, 2 equiv.), and KCO (7.70 g, 55.7 mmol, 3 equiv.) in DMF (25 mL) was stirred at 80 °C for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (4 × 50 mL). The combined organic layers were concentrated under reduced pressure to give tert-butyl 4-(1-(2-hydroxyethyl)piperidin-4-yl)piperazine-1-carboxylate (8 g) as a crude yellow solid. LCMS (ESI, m / z): 314.25 [M+H] + .

[0438] Process B A solution of tert-butyl 4-(1-(2-hydroxyethyl)piperidin-4-yl)piperazine-1-carboxylate (8 g, 25.5 mmol, 1 equiv.) in HCl (50 ml, 4 M) in 1,4-dioxane was stirred for 1 h. The precipitated solid was collected by filtration and washed with PE (2 × 10 mL). The resulting solid was dried in an oven to give 2-(4-(piperazin-1-yl)piperidin-1-yl)ethan-1-ol hydrochloride (7 g) as a crude white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 214.20 [M+H] + .

[0439] Process C A solution of 2-(4-(piperazin-1-yl)piperidin-1-yl)ethan-1-ol hydrochloride (6 g, 28 mmol, 1 equiv.) and 1,2-difluoro-4-nitrobenzene (4.47 g, 28.2 mmol, 1 equiv.), NaHCO (11.8 g, 140.6 mmol, 5 equiv.) in ACN (50 mL) was stirred at 80 °C for 1 h. The solution was concentrated, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give 2-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidin-1-yl)ethan-1-ol (3.64 g, 37%) as a yellow solid. LCMS (ESI, m / z): 353.20 [M+H] + .

[0440] Intermediate A30: Synthesis of 3-((4-fluoro-3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0441] [ka]

[0442] Process A A solution of 2-bromo-1-fluoro-4-nitrobenzene (5 g, 22.7 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (4.23 g, 22.7 mmol, 1 equiv.), Pd(OAc) (510 mg, 2.27 mmol, 0.1 equiv.), Xantphos (1.32 g, 2.27 mmol, 0.1 equiv.), and CsCO (14.8 g, 45.5 mmol, 2 equiv.) in 1,4-dioxane (50 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 4-(2-fluoro-5-nitrophenyl)piperazine-1-carboxylate (3.7 g, 50%) as a yellow solid. LCMS (ESI, m / z): 326.14 [M+H] + .

[0443] Process B A solution of tert-butyl 4-(2-fluoro-5-nitrophenyl)piperazine-1-carboxylate (2 g, 6.15 mmol, 1 equiv.), Fe (1.72 g, 30.7 mmol, 5 equiv.), and NH4Cl (0.66 g, 12.3 mmol, 2 equiv.) in EtOH (30 mL) and water (10 mL) was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (8:1) to give tert-butyl 4-(5-amino-2-fluorophenyl)piperazine-1-carboxylate (1.62 g, 89%) as a brown solid. LCMS (ESI, m / z): 296.17 [M+H] + .

[0444] Process C A solution of tert-butyl 4-(5-amino-2-fluorophenyl)piperazine-1-carboxylate (790 mg, 2.68 mmol, 1 equiv.), 3-bromopiperidine-2,6-dione (1541 mg, 8.03 mmol, 3 equiv.), and NaHCO3 (449.4 mg, 5.35 mmol, 2 equiv.) in ACN (15 mL) was stirred at 90 °C for 2 days. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1.35 g, quantitative) as a light blue solid. LCMS (ESI, m / z): 407.20 [M+H] + .

[0445] Process D A solution of tert-butyl 4-{5-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1-carboxylate (1.3 g, 3.2 mmol, 1 equiv.) and HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 14 h. The precipitated solid was collected by filtration and washed with PE (3 × 5 mL) to give 3-((4-fluoro-3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (822 mg, 75%) as a light green solid. LCMS (ESI, m / z): 307.15 [M+H] + .

[0446] Intermediate A31: Synthesis of (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methyl 4-methylbenzenesulfonate

[0447] [ka]

[0448] Process A A solution of methyl 3-aminocyclobutane-1-carboxylate (4.9 g, 37.9 mmol, 1 equiv.), 1,2-difluoro-4-nitrobenzene (5.43 g, 34.1 mmol, 0.9 equiv.), and DIEA (14.7 g, 114 mmol, 3 equiv.) in NMP (30 mL) was stirred at 80° C. for 2 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 25 min; detector, UV 254 nm, to give methyl 3-((2-fluoro-4-nitrophenyl)amino)cyclobutane-1-carboxylate (7.5 g, 74%) as a yellow solid. LCMS (ESI, m / z): 269.10 [M+H] + .

[0449] Process B To a stirred solution of methyl 3-((2-fluoro-4-nitrophenyl)amino)cyclobutane-1-carboxylate (4.5 g, 16.8 mmol, 1 equiv.) and CsCO (10.9 g, 33.6 mmol, 2 equiv.) in DMF (30 mL) at room temperature was added methyl iodide (4.76 g, 33.6 mmol, 2 equiv.) dropwise. The resulting mixture was stirred for 2 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with PE / EA (41:9) to give methyl 3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutane-1-carboxylate (4.1 g, 87%) as an orange oil. LCMS (ESI, m / z): 283.30 [M+H]+.

[0450] Process C To a solution of methyl 3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutane-1-carboxylate (1.0 g, 3.54 mmol, 1 equiv.) in DCM (20 mL) was added DIBAL-H (7.9 mL, 38.9 mmol, 11 equiv.) dropwise at −65° C. under a nitrogen atmosphere. The resulting mixture was stirred at −65° C. for 15 minutes and then diluted with cold ethyl ether (20 mL). The mixture was warmed to 0° C. The reaction was quenched at 0° C. with water (1 mL) and 15% NaOH (1 mL). The resulting mixture was stirred at room temperature for 15 minutes. Anhydrous MgSO4 was added to the mixture in small portions at room temperature. The resulting mixture was stirred for 15 minutes and then filtered, and the filter cake was washed with water (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (71:29) to give (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methanol (513 mg, 57%) as an orange oil. LCMS (ESI, m / z): 255.25 [M+H] + .

[0451] Process D A solution of (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methanol (593 mg, 2.33 mmol, 1 equiv) in DCM (12 mL) was treated with TEA (472 mg, 4.66 mmol, 2 equiv) at room temperature, followed by the addition of p-toluenesulfonyl chloride (667 mg, 3.5 mmol, 1.5 equiv) in small portions at 0° C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (19:6) to give (3-((2-fluoro-4-nitrophenyl)(methyl)amino)cyclobutyl)methyl 4-methylbenzenesulfonate (792 mg, 83%) as a yellow solid. LCMS (ESI, m / z): 409.75 [M+H] + .

[0452] Synthesis of Intermediate A32: 3-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dionedione hydrochloride.

[0453] [ka]

[0454] Process A A solution of tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol, 1 equiv.), 2,3-difluoro-5-nitropyridine (430 mg, 2.68 mmol, 1 equiv.), and TEA (815 mg, 8.05 mmol, 3 equiv.) in DMF (3 mL) was stirred at 80° C. for 2 hours. The product was precipitated by adding water. The precipitated solid was collected by filtration and washed with water (2×10 mL). The resulting solid was dried in an oven to give tert-butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (300 mg, 34%) as a yellow solid. LCMS (ESI, m / z): 327.15 [M+H] + .

[0455] Process B A solution of tert-butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (780 mg, 2.39 mmol, 1 equiv.) and Pd / C (254 mg, 2.39 mmol, 1 equiv.) in EtOAc (6 mL) was stirred under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 6 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(5-amino-3-fluoropyridin-2-yl)piperazine-1-carboxylate (625 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 297.15 [M+H] + .

[0456] Process C A solution of tert-butyl 4-(5-amino-3-fluoropyridin-2-yl)piperazine-1-carboxylate (600 mg, 2.03 mmol, 1 equiv.), 2,6-bis(benzyloxy)-3-bromopyridine (750 mg, 2.03 mmol, 1 equiv.), t-BuONa (584 mg, 6.08 mmol, 3 equiv.), Pd(dba)CHCl (210 mg, 0.20 mmol, 0.1 equiv.), and Xantphos (117 mg, 0.20 mmol, 0.1 equiv.) in toluene (10 mL) was stirred overnight at 100° C. under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl 4-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (1 g, 84%) as a yellow solid. LCMS (ESI, m / z): 586.30 [M+H] + .

[0457] Process D A solution of tert-butyl 4-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (500 mg, 0.854 mmol, 1 equiv.) in EtOAc (15 mL) was treated with Pd / C (91 mg, 0.85 mmol, 1 equiv.) under a hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2×10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (330 mg, 95%) as a yellow solid. LCMS (ESI, m / z): 408.20 [M+H] + .

[0458] Process E A solution of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)-3-fluoropyridin-2-yl)piperazine-1-carboxylate (350 mg, 0.86 mmol, 1 equiv.) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 3 hours. The resulting mixture was concentrated under reduced pressure to give 3-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione hydrochloride (650 mg) as a crude dark green solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 308.15 [M+H] + .

[0459] Synthesis of Intermediate A33: 2-(4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-ol

[0460] [ka]

[0461] Process A A solution of 1,2-difluoro-4-nitrobenzene (5.0 g, 31.4 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (5.85 g, 31.4 mmol, 1 equiv.), and NaHCO (7.92 g, 94.3 mmol, 3 equiv.) in ACN (120 mL) was stirred overnight at 90 °C. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (8.7 g, 85%) as a yellow solid. LCMS (ESI, m / z): 326.20 [M+H] + .

[0462] Process B A solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (8.7 g, 27 mmol, 1 equiv.) in HCl (120 mL, 4 M) in 1,4-dioxane was stirred for 2 hours. The mixture was concentrated in vacuo to give 1-(2-fluoro-4-nitrophenyl)piperazine (7.0 g) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 226.20 [M+H] + .

[0463] Process C A solution of 1-(2-fluoro-4-nitrophenyl)piperazine (4.0 g, 18 mmol, 1 equiv.), tert-butyl 4-formylpiperidine-1-carboxylate (4.55 g, 21.3 mmol, 1.2 equiv.), and STAB (7.53 g, 35.5 mmol, 2 equiv.) in DCE (120 mL) was stirred for 2 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (7.9 g) as a crude yellow solid, which was used without further purification. LCMS (ESI, m / z): 423.15 [M+H] + .

[0464] Process D A solution of tert-butyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (7.9 g, 19 mmol, 1 equiv.) in HCl (150 mL, 4 M) in 1,4-dioxane was stirred for 2 hours. The mixture was concentrated in vacuo to give 1-(2-fluoro-4-nitrophenyl)-4-(piperidin-4-ylmethyl)piperazine (7.0 g) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 323.30 [M+H] + .

[0465] Process E A solution of 1-(2-fluoro-4-nitrophenyl)-4-(piperidin-4-ylmethyl)piperazine (2.5 g, 7.8 mmol, 1 equiv.), 2-bromoethan-1-ol (0.97 g, 7.8 mmol, 1 equiv.), and KCO (4.29 g, 31.0 mmol, 4 equiv.) in ACN (120 mL) was stirred at 80 °C for 6 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (5:1) to give 2-(4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-ol (1.3 g, 46%) as a yellow oil. LCMS (ESI, m / z): 367.20 [M+H] + .

[0466] Intermediate A34: Synthesis of methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate

[0467] [ka]

[0468] Process A A solution of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.6 mmol, 1 equiv.), 1,4-dioxa-8-azaspiro[4.5]decane (1.11 g, 7.72 mmol, 0.9 equiv.), Pd(dba) CHCl (0.89 g, 0.86 mmol, 0.1 equiv.), Xantphos (0.50 g, 0.86 mmol, 0.1 equiv.), and CsCO (5.59 g, 17.2 mmol, 2 equiv.) in toluene (10 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (88:12) to give methyl 2-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate (988 mg, 39%) as a yellow solid. LCMS (ESI, m / z): 296.12 [M+H] + .

[0469] Process B A solution of methyl 2-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate (978 mg, 3.31 mmol, 1 equiv.) and HCl (5 mL, 2 M) in THF (5 mL) was stirred at 70° C. for 1 h. The mixture was neutralized to pH 7 with saturated NaHCO (aq.). The aqueous layer was extracted with EtOAc (2×20 mL). The mixture was concentrated to dryness to afford methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate (822 mg, 99%) as a yellow oil. The crude product was used without further purification. LCMS (ESI, m / z): 252.10 [M+H] + .

[0470] Intermediate A34-a was synthesized following the procedure described for the synthesis of methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate (Intermediate A34) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0471] [Table 19]

[0472] Intermediate A35: Synthesis of 1-(3-fluoro-4-nitrophenyl)piperidin-4-one

[0473] [ka]

[0474] A solution of 4-piperidinone (5.0 g, 50.4 mmol, 1 equiv.), TEA (15.3 g, 151 mmol, 3 equiv.), and 2,4-difluoro-1-nitrobenzene (12.0 g, 75.7 mmol, 1.5 equiv.) in DMF (20 mL) was stirred at 80° C. for 4 h. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (85:15) to give 1-(3-fluoro-4-nitrophenyl)piperidin-4-one (3.38 g, 28%) as a yellow solid. LCMS (ESI, m / z): 239.25 [M+H] + .

[0475] Intermediate A36: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride

[0476] [ka]

[0477] Process A A solution of 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.5 g, 4.23 mmol, 1 equiv.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.76 g, 4.23 mmol, 1 equiv.), Pd(dppf)Cl (0.31 g, 0.42 mmol, 0.1 equiv.) and KCO (1.17 g, 8.45 mmol, 2 equiv.) in dioxane (8 mL) and water (4 mL) was stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1.0 g, 46%) as a yellow solid. LCMS (ESI, m / z): 518.35 [M+H] + .

[0478] Process B A solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1.0 g, 1.93 mmol, 1 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (597 mg, 1.93 mmol, 1 equiv.), Pd(dppf)Cl (141 mg, 0.193 mmol, 0.1 equiv.) and KCO (533 mg, 3.86 mmol, 2 equiv.) in dioxane (0.8 mL) and water (0.4 mL) was stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (7:1) to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 84%) as a yellow solid. LCMS (ESI, m / z): 621.15 [M+H] + .

[0479] Process C A solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 1.6 mmol, 1 equiv.) and 10% Pd / C (200 mg) in MeOH (60 mL) was stirred under a hydrogen atmosphere for 1 h. The mixture was filtered, and the filter cake was washed with MeOH (4×25 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (653 mg, 91%) as a gray solid. LCMS (ESI, m / z): 445.25 [M+H] + .

[0480] Process D A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (640 mg, 1.44 mmol, 1 equiv.) and HCl (20 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to dryness to give 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (600 mg) as a gray solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 345.25 [M+H] + .

[0481] Intermediate A37: Synthesis of 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0482] [ka]

[0483] Process A A solution of 1-(4-bromo-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.74 mmol, 1 equiv.), 1,4-dioxa-8-azaspiro[4.5]decane (374 mg, 2.61 mmol, 1.5 equiv.), CsCO (1.14 g, 3.48 mmol, 2 equiv.), and Pd-PEPPSI-IPentCl (147 mg, 0.174 mmol, 0.1 equiv.) in dioxane (8 mL) was stirred at 85 °C under a nitrogen atmosphere for 1 h. 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]decan-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (520 mg, 85%) as a white solid. LCMS (ESI, m / z): 350.35 [M+H] + .

[0484] Process B A solution of 1-(3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-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 NaHCO. The mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous NaSO. 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] + .

[0485] Intermediates A37-a to A37-c were synthesized following the procedure described for the synthesis of 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate A37) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0486] [Table 20]

[0487] Intermediate A38: Synthesis of 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0488] [ka]

[0489] Process A A solution of tert-butyl acetate (0.63 g, 5.42 mmol, 1 equiv.) in THF (10 mL) was treated with LDA (2 M in THF) (1.16 g, 10.8 mmol, 2 equiv.) under a nitrogen atmosphere at −78° C. for 15 minutes, followed by the addition of 1-(3-fluoro-4-nitrophenyl)piperidin-4-one (1.49 g, 6.2 mmol, 1.15 equiv.) in small portions at −78° C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (10 mL) at room temperature. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (958 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 355.15 [M+H] + .

[0490] Process B A mixture of tert-butyl 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (940 mg, 2.65 mmol, 1 equiv.) in HCl (3 mL, 4 M) in 1,4-dioxane was stirred for 2 hours. The mixture was concentrated to dryness to give 2-(1-(3-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetic acid (716 mg, 91%) as a yellow solid, which was used without further purification. LCMS (ESI, m / z): 299.15 [M+H] + .

[0491] Intermediate A39: Synthesis of (3S)-N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pyrrolidine-3-carboxamide

[0492] [ka]

[0493] Process A A solution of 2-fluoro-4-nitroaniline (2.0 g, 13 mmol, 1 equiv.) in DMF (10 mL) was treated with (3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.76 g, 12.8 mmol, 1 equiv.) and DIEA (4.97 g, 38.4 mmol, 3 equiv.), followed by the dropwise addition of T3P (16.3 g, 51.2 mmol, 4 equiv.), and the mixture was stirred at 80° C. overnight. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 65% gradient in 35 min; detector, UV 254 nm, to give tert-butyl (S)-3-((2-fluoro-4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate (3.04 g, 67%) as an orange solid. LCMS (ESI, m / z): 352.10 [MH] - .

[0494] Process B A solution of tert-butyl (3S)-3-[(2-fluoro-4-nitrophenyl)carbamoyl]pyrrolidine-1-carboxylate (3.02 g, 8.55 mmol, 1 equiv.) in EtOH (28 mL) was treated with NH4Cl (0.91 g, 17 mmol, 2 equiv.) in water (7 mL), followed by the addition of Fe (2.39 g, 42.7 mmol, 5 equiv.) in small portions at 80 °C. The mixture was stirred at 80 °C for 2 h and then concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (93:7) to give tert-butyl (S)-3-((4-amino-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate (2.6 g, 94%) as an orange solid. LCMS (ESI, m / z): 322.25 [MH] - .

[0495] Process C A solution of tert-butyl (3S)-3-[(4-amino-2-fluorophenyl)carbamoyl]pyrrolidine-1-carboxylate (800 mg, 2.47 mmol, 1 equiv.), 3-bromopiperidine-2,6-dione (475 mg, 2.47 mmol, 1 equiv.), and NaHCO3 (624 mg, 7.42 mmol, 3 equiv.) in ACN (10 mL) was stirred at 90 °C overnight and then concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (19:1) to give tert-butyl (3S)-3-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate (730 mg, 68%) as a green solid. LCMS (ESI, m / z): 433.30 [MH] - .

[0496] Process D A solution of tert-butyl (3S)-3-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate (710 mg, 1.63 mmol, 1 equiv.) in TFA (3 mL) and DCM (12 mL) was stirred for 30 min. The mixture was concentrated to dryness to give (3S)—N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pyrrolidine-3-carboxamide trifluoroacetate (1.3 g) as a dark blue solid. This product was used directly in the next step without further purification. LCMS (ESI, m / z): 335.15 [M+H] + .

[0497] Intermediates A39-a and A39-b were synthesized following the procedure described for the synthesis of (3S)—N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pyrrolidine-3-carboxamide trifluoroacetate (Intermediate A39) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0498] [Table 21]

[0499] Intermediate A40: Synthesis of N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-N-methylpiperidine-4-carboxamide

[0500] [ka]

[0501] Process A A solution of tert-butyl 4-[(2-fluoro-4-nitrophenyl)carbamoyl]piperidine-1-carboxylate (4 g, 10.9 mmol, 1 equiv.) in DMF (10 mL) was treated with NaH (0.87 g, 21.8 mmol, 2 equiv., 60% dispersion in oil) and stirred under a nitrogen atmosphere at 0° C. for 15 min. Methyl iodide (1.55 g, 10.9 mmol, 1 equiv.) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 h. The reaction was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-((2-fluoro-4-nitrophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.79 g, 67%) as a white solid. LCMS (ESI, m / z): 382.2 [M+H] + .

[0502] Process B A solution of tert-butyl 4-[(2-fluoro-4-nitrophenyl)(methyl)carbamoyl]piperidine-1-carboxylate (2.79 g, 7.31 mmol, 1 equiv.) and 10% Pd / C (0.78 g) in MeOH (10 mL) was stirred under 1 atmosphere of hydrogen for 1 hour. The mixture was filtered and washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-((4-amino-2-fluorophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.65 g) as a white solid, which was used without further purification. LCMS (ESI, m / z): 352.2 [M+H] + .

[0503] Process C A solution of tert-butyl 4-[(4-amino-2-fluorophenyl)(methyl)carbamoyl]piperidine-1-carboxylate (2.0 g, 5.69 mmol, 1 equiv.), 3-bromopiperidine-2,6-dione (1.31 g, 6.83 mmol, 1.2 equiv.), and NaHCO (1.43 g, 17.1 mmol, 3 equiv.) in ACN (40 mL) was stirred at 90° C. for 3 days. The solution was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.5 g, 95%) as a white solid. LCMS (ESI, m / z): 463.3 [M+H] + .

[0504] Process D A solution of tert-butyl 4-((4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)(methyl)carbamoyl)piperidine-1-carboxylate (500 mg, 1.08 mmol, 1 equiv) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to dryness to give N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-N-methylpiperidine-4-carboxamide (440 mg) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 363.3 [M+H] + .

[0505] Intermediate A41: Synthesis of 1"-(2-fluoro-4-nitrophenyl)-4-(hydroxymethyl)-[1,4':1',4"-terpiperidin]-2-one

[0506] [ka]

[0507] Process A A solution of methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (1.35 g, 8.82 mmol, 1 equiv.), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (3.00 g, 13.2 mmol, 1.5 equiv.), Cu(OAc) (0.48 g, 2.7 mmol, 0.3 equiv.) and pyridine (4.18 g, 52.9 mmol, 6 equiv.) in THF (10 mL) was stirred under air at 50° C. for 15 h. After concentration, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to give 1'-(tert-butyl) 4-methyl 2-oxo-3',6'-dihydro-2H-[1,4'-bipyridine]-1',4(2'H)-dicarboxylate (1.4 g, 47%) as a white solid. LCMS (ESI, m / z): 335.10 [M+H] + .

[0508] Process B A mixture of 1'-(tert-butyl) 4-methyl 2-oxo-3',6'-dihydro-2H-[1,4'-bipyridine]-1',4(2'H)-dicarboxylate (1.4 g, 4.2 mmol, 1 equiv.) and 10% Pd / C (0.14 g) in 5 mL of EtOAc was stirred under 1 atmosphere of hydrogen overnight. The mixture was filtered and washed with 3 x 5 mL of EtOAc. The filtrate was concentrated under reduced pressure to give 1'-(tert-butyl) 4-methyl 2-oxo-[1,4'-bipiperidine]-1',4-dicarboxylate (1.2 g, 84%) as a white solid. LCMS (ESI, m / z): 339.20 [MH] - .

[0509] Process C A mixture of 1'-(tert-butyl) 4-methyl 2-oxo-[1,4'-bipiperidine]-1',4-dicarboxylate (1.2 g, 3.5 mmol, 1 equiv.) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 4 hours. The mixture was concentrated to dryness to give methyl 2-oxo-[1,4'-bipiperidine]-4-carboxylate hydrochloride (1.4 g) as a white solid. The product was used in the next step without further purification. LCMS (ESI, m / z): 241.10 [M+H] + .

[0510] Process D A mixture of methyl 2-oxo-[1,4'-bipiperidine]-4-carboxylate hydrochloride (1.4 g, 5.8 mmol, 1 equiv.), 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (2.36 g, 9.90 mmol, 1.7 equiv.), and STAB (2.47 g, 11.7 mmol, 2 equiv.) in DCE (5 mL) was stirred for 2 days. The solution was concentrated, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 15 min; detector, UV at 254 nm, to give methyl 1"-(2-fluoro-4-nitrophenyl)-2-oxo-[1,4':1',4"-terpiperidine]-4-carboxylate (900 mg, 33%) as a yellow solid. LCMS (ESI, m / z): 463.20 [M+H] + .

[0511] Process E A mixture of methyl 1"-(2-fluoro-4-nitrophenyl)-2-oxo-[1,4':1',4"-terpiperidine]-4-carboxylate (900 mg, 1.95 mmol, 1 equiv.), NaBH4 (110 mg, 2.92 mmol, 1.5 equiv.), and CaCl2 (432 mg, 3.89 mmol, 2 equiv.) in EtOH (3 mL) was stirred overnight. The reaction was quenched with water at 0 °C. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (8:1) to give 1"-(2-fluoro-4-nitrophenyl)-4-(hydroxymethyl)-[1,4':1',4"-terpiperidine]-2-one (400 mg, 47%) as a yellow solid. LCMS (ESI, m / z): 435.20 [M+H] + .

[0512] Intermediate A42: Synthesis of 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetic acid

[0513] [ka]

[0514] Process A A mixture of tert-butyl 2-(azetidin-3-yl)acetate hydrochloride (2.05 g, 9.86 mmol, 1 equiv.) and 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (3.52 g, 14.8 mmol, 1.5 equiv.) in DCE (20 mL) was stirred for 1 h. To the above mixture, STAB (6.27 g, 29.6 mmol, 3 equiv.) was added, and the mixture was stirred for 1 h. After concentration, the residue was purified by silica gel column chromatography eluted with CHCl / MeOH (4:1) to give tert-butyl 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetate (2.4 g, 54%) as an orange oil. LCMS (ESI, m / z): 394.3 [M+H] + .

[0515] Process B A mixture of tert-butyl 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetate (2.38 g, 6.05 mmol, 1 equiv.) and TFA (5 mL) in DCM (25 mL) was stirred for 2 hours. The mixture was concentrated to give 2-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)acetic acid (3.5 g) as an orange oil. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 338.1 [M+H] + . Intermediate A43: Synthesis of 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetaldehyde

[0516] [ka]

[0517] Process A A solution of piperazin-2-one (5.0 g, 50 mmol, 1 equiv.), 1,2-difluoro-4-nitrobenzene (11.9 g, 74.9 mmol, 1.5 equiv.), and NaHCO (12.6 g, 150 mmol, 3 equiv.) in ACN (60 mL) was stirred at 80 °C overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give 4-(2-fluoro-4-nitrophenyl)piperazin-2-one (6.44 g, 54%) as a yellow solid. LCMS (ESI, m / z): 239.10 [M+H] + .

[0518] Process B To a solution of 4-(2-fluoro-4-nitrophenyl)piperazin-2-one (5.25 g, 21.9 mmol, 1 equiv.) in THF (20 mL) was added NaH (1.05 g, 26.3 mmol, 1.2 equiv., 60% dispersion in oil) in small portions at 0° C. The mixture was stirred at 0° C. for 20 minutes. Ethyl bromoacetate (9.16 g, 54.9 mmol, 2.5 equiv.) was added dropwise, and the mixture was stirred at 0° C. for 1 hour. Water (10 mL) was added at 0° C., and then the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were concentrated to dryness to give ethyl 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetate (8.37 g) as a yellow solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 325.10 [M+H] + .

[0519] Process C A solution of ethyl 2-[4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl]acetate (8.37 g, 25.7 mmol, 1 equiv.) and NaOH (3.09 g, 77.2 mmol, 3 equiv.) in MeOH (10 mL) and water (40 mL) was stirred for 2 h. The product was precipitated by adjusting the pH to 6 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3 × 5 mL). The solid was dried under infrared light to give 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetic acid (6 g, 78%) as a yellow solid. LCMS (ESI, m / z): 297.10 [M+H] + .

[0520] Process D A solution of 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetic acid (2.29 g, 7.70 mmol, 1 equiv.), benzyl bromide (1.58 g, 9.25 mmol, 1.2 equiv.), and K2CO3 (2.13 g, 15.4 mmol, 2 equiv.) in DMF (10 mL) was stirred overnight. The product was precipitated by adding water. The precipitated solid was collected by filtration and washed with water (3 × 5 mL) to give benzyl 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetate (1.98 g, 66%) as a yellow solid. LCMS (ESI, m / z): 387.10 [M+H] + .

[0521] Process E To a stirred solution of benzyl 2-[4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl]acetate (516 mg, 1.33 mmol, 1 equiv.) and LiCl (113 mg, 2.66 mmol, 2 equiv.) in EtOH (6 mL) and THF (6 mL) at 0 °C, NaBH (101 mg, 2.66 mmol, 2 equiv.) was added portionwise. The mixture was stirred at room temperature for 1 h. The solution was cooled to 0 °C, and water was added. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give 4-(2-fluoro-4-nitrophenyl)-1-(2-hydroxyethyl)piperazin-2-one (278 mg, 74%) as a yellow solid. LCMS (ESI, m / z): 283.10 [M+H] + .

[0522] Process F A solution of 4-(2-fluoro-4-nitrophenyl)-1-(2-hydroxyethyl)piperazin-2-one (278 mg, 0.981 mmol, 1 equiv.) and Dess-Martin periodinane (624 mg, 1.47 mmol, 1.5 equiv.) in DCM (5 mL) was stirred for 3 h. The solution was cooled to 0 °C, and saturated aqueous NaHCO (10 mL) was added. The mixture was extracted with CHCl (3 × 15 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-(4-(2-fluoro-4-nitrophenyl)-2-oxopiperazin-1-yl)acetaldehyde (153 mg, 55%) as a yellow oil. LCMS (ESI, m / z): 281.10 [M+H] + .

[0523] Intermediate A44: Synthesis of 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylic acid

[0524] [ka]

[0525] Process A A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.5 g, 7.5 mmol, 1 equiv.) in DCE (15 mL) was treated with methyl azetidine-3-carboxylate hydrochloride (1.30 g, 11.3 mmol, 1.5 equiv.) and STAB (3.19 g, 15.1 mmol, 2 equiv.) at 40° C. for 3 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (55:45) to give tert-butyl 4-(3-(methoxycarbonyl)azetidin-1-yl)piperidine-1-carboxylate (2.21 g, 98%) as a white solid. LCMS (ESI, m / z): 299.10 [M+H] + .

[0526] Process B A solution of tert-butyl 4-(3-(methoxycarbonyl)azetidin-1-yl)piperidine-1-carboxylate (2.4 g, 8.0 mmol, 1 equiv.) in HCl (25 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to dryness to give methyl 1-(piperidin-4-yl)azetidine-3-carboxylate (2.05 g) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 199.15 [M+H] + .

[0527] Process C A solution of methyl 1-(piperidin-4-yl)azetidine-3-carboxylate (2.05 g, 10.1 mmol, 1 equiv.) in ACN (15 mL) was treated with 1,2-difluoro-4-nitrobenzene (3.21 g, 20.2 mmol, 2 equiv.) and NaHCO (2.54 g, 30.3 mmol, 3 equiv.) at 80 °C for 2 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (95:5) to give methyl 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylate (2.27 g, 67%) as a yellow solid. LCMS (ESI, m / z): 338.15 [M+H] + .

[0528] Process D A solution of methyl 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylate (2.25 g, 6.66 mmol, 1 equiv.) in MeOH (3 mL) was treated with NaOH (1.07 g, 26.6 mmol, 4 equiv.) and water (15 mL) for 1 h. The mixture was adjusted to pH 6 with aqueous HCl. The precipitated solid was collected by filtration to give 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidine-3-carboxylic acid (2.13 g, 99%) as a yellow solid. LCMS (ESI, m / z): 324.15 [M+H] + .

[0529] Intermediate A45: Synthesis of 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0530] [ka]

[0531] Process A A mixture of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (1.6 g, 5.4 mmol, 1 equiv.) and NaOCN (697 mg, 10.7 mmol, 2 equiv.) in HOAc (19 mL) was stirred under nitrogen at 60° C. overnight. To this mixture was added HCl (19 mL, 2 M) dropwise. The mixture was stirred at 60° C. for 3 h. The mixture was cooled to room temperature and concentrated. The residue was purified by trituration with water (130 mL) to give, after filtration, 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.19 g, 66%) as an off-white solid. LCMS (ESI, m / z): 324.95 [M+H] + .

[0532] Process B A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (360 mg, 1.11 mmol, 1 equiv.), piperidin-4-one hydrochloride (151 mg, 1.11 mmol, 1 equiv.), Pd PEPPSI IPentCl (94 mg, 0.11 mmol, 0.1 equiv.), and CsCO (726 mg, 2.23 mmol, 2 equiv.) in 1,4-dioxane (4 mL) was stirred overnight at 85° C. under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 20 min; detector, UV 254 nm, to give 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 47%) as an orange solid. LCMS (ESI, m / z): 342.10 [M+H] + .

[0533] Intermediate A45-a was synthesized following the procedure described for the synthesis of 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate A45) using the appropriate building blocks and modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions as needed.

[0534] [Table 22]

[0535] Intermediate A46: Synthesis of 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0536] [ka]

[0537] Process A A solution of 4-bromo-2,5-difluorobenzonitrile (3.0 g, 14 mmol, 1 equiv.), methylhydrazine sulfate (9.92 g, 68.8 mmol, 5 equiv.), and KCO (9.51 g, 68.8 mmol, 5 equiv.) in n-BuOH (100 mL) was stirred at 100° C. for 5 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 6-bromo-5-fluoro-1-methyl-1H-indazol-3-amine (1.7 g, 51%) as a yellow solid. LCMS (ESI, m / z): 243.98 [M+H] + .

[0538] Process B A solution of 6-bromo-5-fluoro-1-methyl-1H-indazol-3-amine (1.7 g, 6.97 mmol, 1 equiv.) and acrylic acid (3.01 g, 41.8 mmol, 6 equiv.) in toluene (50 mL) was stirred overnight. The mixture was concentrated, and the residue was diluted with water (5 mL). The mixture was neutralized to pH 7 with saturated aqueous NaHCO. The mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 20% gradient over 10 min; detector, UV 254 nm, to give 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propanoic acid (998 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 316.00 [M+H] + .

[0539] Process C A solution of 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propanoic acid (988 mg, 3.13 mmol, 1 equiv.) and NaOCN (406 mg, 6.25 mmol, 2 equiv.) in HOAc (6 mL) was stirred at 60° C. overnight. HCl (6 mL, 2 M) was then added dropwise over 1 min at room temperature. The mixture was stirred at 60° C. for 3 h. The solution was diluted with water (15 mL) and concentrated to remove volatiles. The precipitated solid was collected by filtration and washed with water (30 mL) to give 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (688 mg, 65%) as an off-white solid. LCMS (ESI, m / z): 341.00 [M+H] + .

[0540] Process D A solution of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (688 mg, 2.02 mmol, 1 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (748 mg, 2.42 mmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (164 mg, 0.202 mmol, 0.1 equiv.), KCO (558 mg, 4.03 mmol, 2 equiv.) in water (2 mL) and dioxane (20 mL) was stirred at 80 °C for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:99) to give tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (715 mg, 80%) as an off-white solid. LCMS (ESI, m / z): 444.20 [M+H] + .

[0541] Process E A solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (705 mg, 1.59 mmol, 1 equiv.) and 10% Pd / C (508 mg) in EtOAc (20 mL) was stirred under a hydrogen atmosphere for 30 minutes. After filtration, the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated to give tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (320 mg, 45%) as an off-white solid. LCMS (ESI, m / z): 446.21 [M+H] + .

[0542] Process F A solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (310 mg, 0.70 mmol, 1 equiv.) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 1 hour. The mixture was concentrated to dryness to give 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (255 mg, 96%) as an off-white solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 346.10 [M+H] + .

[0543] Intermediate A47: Synthesis of 1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0544] [ka]

[0545] Process A A solution of 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.17 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (325 mg, 1.75 mmol, 1.5 equiv.), and CsCO (38.0 mg, 0.117 mmol, 0.1 equiv.) in dioxane (5 mL) was treated with Pd PEPPSI IPentCl (98.0 mg, 0.117 mmol, 0.1 equiv.) under a nitrogen atmosphere at 90° C. for 4 h. After concentration, the crude product was purified by silica gel chromatography eluting with DCM / MeOH (95:5) to give tert-butyl 4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)piperazine-1-carboxylate (576 mg, 93%) as a yellow-green solid. LCMS (ESI, m / z): 535.25 [M+H] + .

[0546] Process B A solution of tert-butyl 4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-7-yl)piperazine-1-carboxylate (250 mg, 0.468 mmol, 1 equiv.) and TFA (10 mL) in DCM (30 mL) was stirred for 1 h. The mixture was concentrated to dryness to give 3-(4-methoxybenzyl)-1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (230 mg) as a dark green solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 435.30 [M+H] + .

[0547] Process C A solution of 3-(4-methoxybenzyl)-1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (230 mg, 0.529 mmol, 1 equiv.) and TfOH (5 mL) in TFA (25 mL) was stirred for 3 h. The solution was adjusted to pH 7 with saturated aqueous NaHCO. The mixture was concentrated to dryness, and the residue was purified on a silica gel column eluted with DCM / MeOH (90:10) to give 1-(7-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (170 mg, crude) as a dark green solid. LCMS (ESI, m / z): 315.05 [M+H] + .

[0548] Intermediate A48: Synthesis of 1-(8-(piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0549] [ka]

[0550] Process A: A solution of 8-bromo-4-iodoisoquinoline (1.00 g, 2.99 mmol, 1 equiv.), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.91 g, 3.89 mmol, 1.3 equiv.), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0....

Claims

1. Compounds of formula (I): 【Chemical 1】 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, No three of W, X and Z are simultaneously N, Y １ is -NR ３ -, -CR ４ R ５ -, -O- and -(C ２～４ alkynyl)-, Y ２ is a bond, -S-, -S(O)-, -S(O) ２ -, -CH ２ -, -O-, -N(R ３ ) -, -SCH ２ -, -S(O)CH ２ -, -S(O) ２ CH ２ -, -CH ２ CH ２ -, -OCH ２ - and - (NR ３ ) CH ２ - is selected from, Ring A is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring A is selected from 1, 2, 3, or 4 R Ａ and optionally substituted by Ring B is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and Ring B is selected from 1, 2, 3, or 4 R Ｂ and optionally substituted by R １ and R ２ are each independently selected from H and methyl; R ３ is H and C １～４ alkyl, R ４ and R ５ is H, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, amino, C １～４ Alkylamino and C ２～８ are each independently selected from dialkylamino; R ６ and R ７ is H, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, amino, C １～４ Alkylamino and C ２～８ are each independently selected from dialkylamino; R Ａ are halo and C, respectively. 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and R Ａ 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 Alkyl is Cy １ , Cy １ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｂ are H, halo, and C, respectively. 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and R Ｂ 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 Alkyl is Cy ２ , Cy ２ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｗ , R Ｘ and R Ｚ is 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, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ are each independently selected from R Ｗ , R Ｘ or R Ｚ 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 Alkyl is Cy ３ , Cy ３ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy １ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy ２ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy ３ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 are H and C, respectively. 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; 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 C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～７ Cycloalkyl-C １～４ Alkyl, 5- to 10-membered heteroaryl-C １～４ Alkyl and 4- to 10-membered heterocycloalkyl-C １～４ Alkyl is 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 , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy ４ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is selected from halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ａ４ , R ｂ４ , R ｃ４ and R ｄ４ is 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; 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 is OH, CN, amino, halo, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl and C １～６ each optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from or R ｃ３ and R ｄ３ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ｅ１ , R ｅ２ , R ｅ３ and R ｅ４ are H and C, respectively. １～４ independently selected from 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 is a linker covalently connecting moieties Q and E, Any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 heteroatoms forming the ring, independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups is optionally substituted by an oxo (=O) group; One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

2. Compounds of formula (I): 【Chemistry 2】 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, No three of W, X and Z are simultaneously N, Y １ is -NR ３ -, -CR ４ R ５ - and -O-; Y ２ is a bond, -S-, -S(O)-, -S(O) ２ -, -CH ２ -, -O-, -N(R ３ ) -, -SCH ２ -, -S(O)CH ２ -, -S(O) ２ CH ２ -, -CH ２ CH ２ -, -OCH ２ - and - (NR ３ ) CH ２ - is selected from, Ring A is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring A is selected from 1, 2, 3, or 4 R Ａ and optionally substituted by Ring B is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and Ring B is selected from 1, 2, 3, or 4 R Ｂ and optionally substituted by R １ and R ２ are each independently selected from H and methyl; R ３ is H and C １～４ alkyl, R ４ and R ５ is H, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, amino, C １～４ Alkylamino and C ２～８ are each independently selected from dialkylamino; R ６ and R ７ is H, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, amino, C １～４ Alkylamino and C ２～８ are each independently selected from dialkylamino; R Ａ are halo and C, respectively. 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and R Ａ 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 Alkyl is Cy １ , Cy １ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｂ are H, halo, and C, respectively. 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and R Ｂ 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 Alkyl is Cy ２ , Cy ２ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｗ , R Ｘ and R Ｚ is 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, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ are each independently selected from R Ｗ , R Ｘ or R Ｚ 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 Alkyl is Cy ３ , Cy ３ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy １ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy ２ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy ３ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 are H and C, respectively. 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; 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 C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～７ Cycloalkyl-C １～４ Alkyl, 5- to 10-membered heteroaryl-C １～４ Alkyl and 4- to 10-membered heterocycloalkyl-C １～４ Alkyl is 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 , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy ４ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is selected from halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ａ４ , R ｂ４ , R ｃ４ and R ｄ４ is 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; 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 is OH, CN, amino, halo, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl and C １～６ each optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from or R ｃ３ and R ｄ３ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ｅ１ , R ｅ２ , R ｅ３ and R ｅ４ are H and C, respectively. １～４ independently selected from 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 is a linker covalently connecting moieties Q and E, Any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 heteroatoms forming the ring, independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups is optionally substituted by an oxo (=O) group; One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

3. Compounds of formula (I): 【Chemistry 3】 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, No three of W, X and Z are simultaneously N, Y １ is -NR ３ -, -CR ４ R ５ - and -O-; Y ２ is -S-, -S(O)-, -S(O) ２ -, -CH ２ -, -O-, -N(R ３ ) -, -SCH ２ -, -S(O)CH ２ -, -S(O) ２ CH ２ -, -CH ２ CH ２ -, -OCH ２ - and - (NR ３ ) CH ２ - is selected from, Ring A is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring A is selected from 1, 2, 3, or 4 R Ａ and optionally substituted by Ring B is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and Ring B is selected from 1, 2, 3, or 4 R Ｂ and optionally substituted by R １ and R ２ are each independently selected from H and methyl; R ３ is H and C １～４ alkyl, R ４ and R ５ is H, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, amino, C １～４ Alkylamino and C ２～８ are each independently selected from dialkylamino; R ６ and R ７ is H, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, amino, C １～４ Alkylamino and C ２～８ are each independently selected from dialkylamino; R Ａ are halo and C, respectively. 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and R Ａ 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 Alkyl is Cy １ , Cy １ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｂ are H, halo, and C, respectively. 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and R Ｂ 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 Alkyl is Cy ２ , Cy ２ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｗ , R Ｘ and R Ｚ is 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, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ are each independently selected from R Ｗ , R Ｘ or R Ｚ 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 Alkyl is Cy ３ , Cy ３ -C １～４ Alkyl, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy １ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy ２ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy ３ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is 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 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, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 are H and C, respectively. 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; 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 C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～７ Cycloalkyl-C １～４ Alkyl, 5- to 10-membered heteroaryl-C １～４ Alkyl and 4- to 10-membered heterocycloalkyl-C １～４ Alkyl is 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 , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy ４ are respectively, C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which is selected from halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ａ４ , R ｂ４ , R ｃ４ and R ｄ４ is 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; 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 is OH, CN, amino, halo, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl and C １～６ each optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from or R ｃ３ and R ｄ３ together with the N atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O.)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ｅ１ , R ｅ２ , R ｅ３ and R ｅ４ are H and C, respectively. １～４ independently selected from 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 is a linker covalently connecting moieties Q and E, Any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 heteroatoms forming the ring, independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups is optionally substituted by an oxo (=O) group; One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

4. W is CR Ｗ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. X is CR Ｘ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

6. Z is CR Ｚ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

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

8. Y １ Ga-CR ４ R ５ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein

9. Y １ Ga-NR ３ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein

10. Y １ But-(C ２～４ 7. The compound of any one of claims 1 and 4 to 6, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 2

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

12. Y ２ Ga-CH ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein

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

14. Y ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is a bond.

15. Ring A is a 4- to 18-membered heterocycloalkyl, and Ring A is a heterocycloalkyl group having 1, 2, 3, or 4 R Ａ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted by:

16. Ring A is a 4- to 7-membered heterocycloalkyl, and ... Ａ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted by:

17. Ring A is tetrahydro-2H-pyranyl or piperidinyl, which are each substituted with one, two, three or four R Ａ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted by:

18. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring A is tetrahydro-2H-pyran-4-yl or 1-methylpiperidin-4-yl.

19. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, or 1-(2,2,2-trifluoroethyl)piperidin-4-yl.

20. Ring A is C ３～１４ cycloalkyl, and ring A is one, two, three or four R Ａ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted by:

21. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is tetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 4-hydroxycyclohexyl.

22. Ring B is C ３～７ cycloalkyl or 4- to 7-membered heterocycloalkyl, and ring B is one, two, three, or four R Ｂ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, optionally substituted by:

23. Ring B is a 4- to 7-membered heterocycloalkyl, and Ring B has 1, 2, 3, or 4 R Ｂ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, optionally substituted by:

24. Ring B is one, two, three or four R Ｂ 22. The compound of any one of claims 1 to 21, which is piperidinyl optionally substituted by: or a pharmaceutically acceptable salt thereof.

25. 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is piperidinyl.

26. Ring B is piperidinyl, piperazinyl, or azetidinyl, each of which is substituted with one, two, three, or four R Ｂ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, optionally substituted by:

27. Ring B is C ３～７ cycloalkyl, and ring B is one, two, three or four R Ｂ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, optionally substituted by:

28. 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclopropyl, cyclobutyl, or cyclohexyl.

29. R １ and R ２ and R are each H; or a pharmaceutically acceptable salt thereof.

30. R ４ and R ５ and R are each H; or a pharmaceutically acceptable salt thereof.

31. R ６ and R ７ and each are H; or a pharmaceutically acceptable salt thereof.

32. R Ａ are respectively Halo and C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, independently selected from:

33. R Ａ are respectively Halo and C １～６ Alkyl, C １～６ Haloalkyl, CN, NO ２ OR ａ１ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, independently selected from:

34. R Ａ are respectively, C １～６ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, which is alkyl.

35. R Ａ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein is methyl.

36. R Ａ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein is methyl, OH, or 2,2,2-trifluoroethyl.

37. R Ｂ are H, halo, and C, respectively. １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, independently selected from:

38. R Ｂ are respectively Halo and C １～６ Alkyl, C １～６ Haloalkyl, CN, NO ２ OR ａ２ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, independently selected from:

39. R Ｂ or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1 to 36, wherein each is independently selected from halo.

40. R Ｂ The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each of

41. R Ｗ But, H, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) R ｂ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, selected from:

42. R Ｗ But, H, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ and OR ａ３ 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, selected from:

43. R Ｗ H, halo and C １～６ 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, selected from haloalkyl.

44. R Ｗ The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein

45. R Ｘ But C ６～１０ aryl and 5- to 10-membered heteroaryl; ６～１０ Aryl and 5-10 membered heteroaryl are selected from halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, OR ａ３ and S.R. ａ３ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

46. R Ｘ But, 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 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, selected from: aryl.

47. R Ｘ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein

48. R Ｘ The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein is H or F.

49. R Ｚ But, H, halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, CN, NO ２ and OR ａ３ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, selected from:

50. R Ｚ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein:

51. 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein m is 2.

52. 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein m is 1.

53. 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein m is 0.

54. L １ but the following: (i) a bond directly connecting ring B to moiety E (ii) -(C １～４ alkyl)- (iii) -(C ２～４ alkenyl)- (iv) -(C ２～４ alkynyl)- (v) -(C ２～４ alkynyl)-(G ３ )- (vi) a compound having the following structure: 【Chemistry 4】 (vii) a molecule having the following structure: 【Chemistry 5】 and (viii) a molecule having the following structure: 【Chemistry 6】 [In the formula, G １ is -C(O)-, -NR Ｇ C(O)-, -NR Ｇ -, -O-, -S-, -C(O)O-, -OC(O)NR Ｇ -, -NR Ｇ C(O)NR Ｇ -, -S(O ２ )- and -S(O)NR Ｇ - is selected from, G ２ is C ６～１０ Aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl; G ３ is -C(O)-, -NR Ｇ C(O)-, -NR Ｇ -, -O-, -S-, -C(O)O-, -OC(O)NR Ｇ -, -NR Ｇ C(O)NR Ｇ -, -S(O ２ )- and -S(O)NR Ｇ - is selected from, G ４ is C １～６ Alkyl, hydroxyl, C １～６ 4-10 membered heterocycloalkyl optionally substituted with alkoxy or halo; R Ｇ are each independently selected from H, methyl and ethyl; a is 0 or 1; b is 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1; g is 0, 1 or 2; At least one of b, c, e, and f is 1.] 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, selected from:

55. L １ is the bond directly connecting ring B to moiety E; or a pharmaceutically acceptable salt thereof.

56. L １ But-(C １～４ 55. The compound of claim 54, wherein:

57. L １ But-(C ２～４ 55. The compound of claim 54, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

58. L １ But-(C ２～４ 55. The compound of claim 54, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

59. L １ But-(C ２～４ alkynyl)-(G ３ 55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein:

60. L １ but has the following structure: 【Chemistry 7】 55. The compound of claim 54, having the formula: or a pharmaceutically acceptable salt thereof.

61. L １ but 【Chemistry 8】 55. The compound of claim 54, wherein:

62. G １ But, -NR Ｇ 62. The compound according to any one of claims 54 to 61, or a pharmaceutically acceptable salt thereof, which is -C(O)- or -C(O)-.

63. G １ But, -NR Ｇ The compound according to any one of claims 54 to 61, or a pharmaceutically acceptable salt thereof, which is -C(O)-, -C(O)-, or -O-.

64. G ２ 64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein is 4 to 10 membered heterocycloalkyl.

65. G ２ 64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein is piperidinyl, piperazinyl, or azetidinyl.

66. G ２ 64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein is azetidinyl.

67. G ２ 64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein is piperidinyl, piperazinyl, azetidinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,4-dihydroquinazolin-7-yl, or cyclobutyl.

68. G ２ or a pharmaceutically acceptable salt thereof.

69. G ２ is C ３～７ 64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

70. G ２ 64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein is cyclobutyl.

71. G ３ But, -NR Ｇ 71. The compound according to any one of claims 54 to 70, or a pharmaceutically acceptable salt thereof, wherein R is - or -O-.

72. G ４ 72. The compound of any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein is piperidinyl or piperazinyl.

73. G ４ 72. The compound of any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein is azetidinyl, piperidinyl, or piperazinyl.

74. G ４ 72. The compound of any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein is piperazinyl.

75. 75. The compound of any one of claims 54 to 74, wherein a is 0, or a pharmaceutically acceptable salt thereof.

76. 75. The compound of any one of claims 54 to 74, or a pharmaceutically acceptable salt thereof, wherein a is 1.

77. 77. The compound of any one of claims 54 to 76, or a pharmaceutically acceptable salt thereof, wherein b is 0.

78. 77. The compound of any one of claims 54 to 76, or a pharmaceutically acceptable salt thereof, wherein b is 1.

79. 79. The compound of any one of claims 54 to 78, or a pharmaceutically acceptable salt thereof, wherein c is 0.

80. 79. The compound of any one of claims 54 to 78, or a pharmaceutically acceptable salt thereof, wherein c is 1.

81. 81. The compound of any one of claims 54 to 80, or a pharmaceutically acceptable salt thereof, wherein d is 0.

82. 81. The compound of any one of claims 54 to 80, or a pharmaceutically acceptable salt thereof, wherein d is 1.

83. 83. The compound of any one of claims 54 to 82, or a pharmaceutically acceptable salt thereof, wherein e is 0.

84. 83. The compound of any one of claims 54 to 82, or a pharmaceutically acceptable salt thereof, wherein e is 1.

85. 85. The compound of any one of claims 54 to 84, or a pharmaceutically acceptable salt thereof, wherein f is 0.

86. 85. The compound of any one of claims 54 to 84, or a pharmaceutically acceptable salt thereof, wherein f is 1.

87. 87. The compound of any one of claims 54 to 86, or a pharmaceutically acceptable salt thereof, wherein g is 0.

88. 87. The compound of any one of claims 54 to 86, or a pharmaceutically acceptable salt thereof, wherein g is 1.

89. R Ｇ or a pharmaceutically acceptable salt thereof.

90. 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein E is an E3 ubiquitin ligase binding moiety that binds to cereblon.

91. E is the following: 【Chemistry 9】 【change】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, selected from:

92. E is the following: 【Chemistry 10】 【change】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, selected from:

93. E is the following: 【Chemistry 11】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, selected from:

94. E, 【Chemistry 12】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, wherein:

95. E is the following: 【Chemistry 13】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, selected from:

96. E is the following: 【Chemistry 14】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, selected from:

97. E is the following: 【Chemistry 15】 90. The compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, selected from:

98. Formula II: 【Chemistry 16】 98. The compound of any one of claims 1 to 97, or a pharmaceutically acceptable salt thereof, having the formula:

99. Formula III: 【Chemistry 17】 98. The compound of any one of claims 1 to 97, or a pharmaceutically acceptable salt thereof, having the formula:

100. below: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-4-((9-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-9-oxononyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-3-oxopropoxy)propyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione; N-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)ethyl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 3-(4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 1-(4-(1-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethoxy)ethyl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetamide; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione; 3-(5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione; 3-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione; 5-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)prop-1-en-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)isoindoline-1,3-dione; 3-(4-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-yl)amino)phenyl)piperidine-2,6-dione; 3-((4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutyl)methoxy)phenyl)amino)piperidine-2,6-dione; 3-({4-[3-({4-[({5-fluoro-2-[(oxan-4-ylsulfanyl)methyl]-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}methyl)cyclobutoxy]phenyl}amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione and 1-(3-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione The compound according to any one of claims 1 to 3, selected from: or a pharmaceutically acceptable salt of any of the foregoing.

101. below: 3-((4-(4-(2-(3,3-difluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclobutyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 7-(((1s,3s)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((1r,3r)-3-(4-(4-aminophenyl)piperazin-1-yl)cyclobutyl)methoxy)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-3-(4-methoxybenzyl)-7-((1-(2-(4-nitrophenoxy)ethyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (S)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; (R)-3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione; 3-((3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione; 3-((3-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione; 1-(4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)ethynyl)isoindoline-1,3-dione; 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(((3aR,5r,6aS)-2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)piperidine-2,6-dione; 1-(4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1r,3r)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1s,3s)-3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)isoindoline-1,3-dione; 3-((4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)methyl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)methyl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione; 3-((4-(4-(4-(2-(5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((1-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione and 3-((4-(3-((4-(((5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione The compound according to any one of claims 1 to 3, selected from: or a pharmaceutically acceptable salt of any of the foregoing.

102. below: 3-(5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-((2-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)isoindolin-5-yl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)benzamide; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)amino)phenyl)amino)piperidine-2,6-dione; 3-((4-(8-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-((4-fluoro-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((2-(cyclobutylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(2-(4-(((2-(cyclopentylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-((4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutoxy)phenyl)amino)piperidine-2,6-dione; 3-((4-((4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclohexyl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)piperidine-2,6-dione; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-((1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)(methyl)amino)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)cyclohexyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)phenyl)amino)piperidine-2,6-dione; 3-((4-(5-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(6-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyridin-3-yl)phenyl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-3-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxamide; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-chloro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(7-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((2,5-difluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-chloro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)(methyl)amino)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)phenyl)amino)piperidine-2,6-dione and N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)benzamide 3. The compound of claim 1 or 2, selected from: or a pharmaceutically acceptable salt of any of the foregoing.

103. below: 3-((3-fluoro-4-((3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)cyclobutyl)amino)phenyl)amino)piperidine-2,6-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)benzamide; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 1-(3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrrolidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-2-oxoethyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1'-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidin]-1'-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)isoindoline-1,3-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(3-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-({4-[4-(2-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl)piperazin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione; 3-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (3S)—N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide; (3R)—N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)pyrrolidine-3-carboxamide; N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidine-4-carboxamide; N-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-N-methylpiperidine-4-carboxamide; 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((3-fluoro-4-(4-(2-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(5-fluoro-6-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-fluoro-4-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(1-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-6-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((3-fluoro-4-(4-((1-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-2-oxo-[1,4':1',4''-terpiperidine]-1''-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(9-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2,5-difluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((2-(cyclopropylmethyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((2-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carbonyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)ethynyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(6-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4':1',4''-terpiperidine]-1''-yl)phenyl)amino)piperidine-2,6-dione; 3-((5-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)-[1,4'-bipiperidine]-1'-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-((4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(((4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)-3-oxopiperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(3-(4-(2-((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)ethyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-fluoro-3-(4-(3-(4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-({4-[4-(3-{4-[({2-[(cyclohexylsulfanyl)methyl]-5-fluoro-4-oxo-3H-quinazolin-7-yl}oxy)methyl]piperidin-1-yl}azetidin-1-yl)piperidin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt of any of the foregoing.

104. 104. A pharmaceutical composition comprising a compound according to any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

105. A method for degrading PARP14, comprising the step of contacting PARP14 with a compound according to any one of claims 1 to 103 or a pharmaceutically acceptable salt thereof.

106. 104. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 103 or a pharmaceutically acceptable salt thereof.

107. 104. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 103, or a pharmaceutically acceptable salt thereof, in combination with an additional therapy or agent.

108. The method of claim 106 or 107, wherein the cancer is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer or melanoma.

109. 104. A method of treating an inflammatory disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 103 or a pharmaceutically acceptable salt thereof.

110. 110. The method of claim 109, wherein the inflammatory disease is selected from asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloids, eosinophilic disorders, pulmonary fibrosis, and type 2 cytokine pathology.

111. 110. The method of claim 109, wherein the inflammatory disease is atopic dermatitis.

112. 110. The method of claim 109, wherein the inflammatory disease is systemic sclerosis.

113. 111. The method of claim 110, wherein the asthma is steroid-insensitive asthma, steroid-refractory asthma, steroid-resistant asthma, atopic asthma, non-atopic asthma, persistent asthma, severe asthma, or steroid-refractory severe asthma.

114. 114. The method of claim 113, wherein the severe asthma is T2 high endotype, T2 low endotype or non-T2 endotype.

115. 114. The method of claim 113, wherein the severe asthma is T2 low endotype or non-T2 endotype.

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