Targeted proteolysis of PARP14 for use in therapy

Abstract

The present invention relates to compounds of formula I that degrade PARP14 and are useful, for example, in the treatment of cancer and inflammatory diseases. TIFF2025525031000155.tif24161

Description

Technical Field

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

Background Art

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

[0003] The 17 members of the PARP family were identified in the human genome based on homology within their catalytic domains (Vyas S et al., Nat Commun. August 7, 2013;4:2240). However, their catalytic activities are classified into three different categories. Most of the PARP family members catalyze the transfer of mono-ADP-ribose units onto their substrates (monoART), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units onto their substrates (polyART). Finally, PARP13 is the only PARP that has not been demonstrated to have catalytic activity in vitro or in vivo to date.

[0004] PARP14 is a cytoplasmic and nuclear mono-ART. It was initially identified as BAL2 (B lymphoma 2), a gene associated with poor outcome in diffuse large B-cell lymphoma (DLBCL), together with two other mono-ARTs, PARP9 or BAL1 and PARP15 or BAL3 (Aguiar RC et al., Blood. December 9, 2000; 96(13):4328 - 4334 and Juszczynski P et al., Mol Cell Biol. July 1, 2006; 26(14):5348 - 5359). PARP14, PARP9, and PARP15 are also referred to as macroPARPs because they have a macrodomain at their N-terminus. The genes for the three macroPARPs are located at the same genomic locus, suggesting co-regulation. Indeed, the 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 are DLBCL (Aguiar RCT et al., J Biol Chem. August 1, 2005; 280(40):33756 - 33765), multiple myeloma (MM) (Barbarulo A et al., Oncogene. October 8, 2012; 32(36):4231 - 4242), and hepatocellular carcinoma (HCC) (Iansante V et al., Nat Commun. August 10, 2015; 6:7882). In MM and HCC cell lines, RNA interference (RNAi)-mediated PARP14 knockdown inhibits cell proliferation and survival. Other studies have shown that the enzymatic activity of PARP14 is required for the survival of prostate cancer cell lines in vitro (Bachmann SB et al., Mol Cancer. May 27, 2014; 13:125).

[0005] PARP14 is an interferon-stimulated gene that has mRNA that increases upon stimulation of various cell lines by all types of interferons (I, II, and III; www.interferome.org). PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling that affects transcription downstream of STAT1 (in the case of IFN-γ) (Iwata H et al., Nat Commun. October 31, 2016; 7:12849) or STAT6 (in the case of IL-4) (Goenka S et al., Proc Natl Acad Sci USA. March 6, 2006; 103(11):4210-4215; Goenka S et al., J Biol Chem. May 3, 2007; 282(26):18732-18739; and Mehrotra P et al., J Biol Chem. November 16, 2010; 286(3):1767-1776). Parp14- / - knockout (KO) mice have reduced marginal zone B cells, and the ability of IL-4 to keep B cells alive in vitro was also reduced in the Parp14 KO situation (Cho SH et al., Blood. January 15, 2009; 113(11):2416-2425). This decrease in survival signaling was mechanistically linked to a decrease in the ability of Parp14 KO B cells to maintain metabolic fitness and increase Mcl-1 expression. Parp14 KO was able to extend survival in the Eμ-Myc lymphoma model, suggesting a role for PARP14 in Myc-driven lymphoma development (Cho SH et al., Proc Natl Acad Sci USA. September 12, 2011; 108(38):15972-15977). Gene expression data also point to a role for PARP14 in human B cell lymphoma.BAL proteins containing PARP14 are highly expressed in host response (HR) DLBCL, a subtype of B-cell lymphoma defined by the genome characterized by active inflammatory infiltration of T cells and dendritic cells and the presence of the 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] Due to its role downstream of 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 anti-tumor immunity, while reducing the tumor-promoting M2 phenotype. In human and mouse macrophage models, it has been found that with PARP14 knockout or knockdown, M1 gene expression downstream of IFN-γ increases, while M2 gene expression downstream of IL-4 decreases. Similarly, genetic PARP14 knockout has been shown to reduce the Th2 T helper cell phenotype in the context of skin and airway inflammation, which is also related to the regulatory role of PARP14 in IL-4 signaling (Mehrotra P et al., J Allergy Clin Immunol. July 25, 2012;131(2):521 and Krishnamurthy P et al., Immunology. July 27, 2017;152(3):451-461).

[0007] PARP14 acts by serving as a co - activator of STAT6 - and STAT3 - driven transcription, promoting signaling by type 2 helper T cell (TH2) cytokines and type 17 helper T cell (TH17) cytokines (Goenka et al., 2006 PMID16537510, Mehrotra et al., 2015 PMID26222149). PARP14 is upregulated in tissues associated with inflammatory diseases such as skin lesions in patients with atopic dermatitis or psoriasis (He et al., 2021 PMID:32709423) or bronchial 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 PMID27796300, 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 are either approved or under investigation as treatments for multiple inflammatory diseases such as atopic dermatitis, asthma, chronic rhinosinusitis, 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, the central role of PARP14 in TH2 and TH17 - driven cytokine signaling, and the common underlying biology of many inflammatory diseases, small molecules targeting PARP14 could be promising therapeutic agents for a wide range of inflammatory diseases.

[0008] The most clinically used pharmaceutical agents are based on the inhibition of protein function by small molecules. However, alternative approaches that result in proteolysis rather than inhibition also have the potential to achieve clinical efficacy. Thus, targeted proteolysis by ubiquitination of protein targets has emerged as an effective strategy in drug discovery. Heterobifunctional small molecules that simultaneously bind to a target protein and recruit a ubiquitin ligase (e.g., ubiquitin E3 ligase) have been shown to result in ubiquitination and degradation of the target protein (Bondeson, D.P. et al., Nat Chem Biol. 2015 11(8):611-617). An example of such a small molecule that can bind to both PARP14 and ubiquitin E3 ligase is described in PCT Patent Publication WO2020 / 257416.

Prior Art Documents

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Summary of the Invention

Problems to be Solved by the Invention

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

Means for Solving the Problems

[0012] (Gist of the Invention) The present invention relates to a compound of formula (I):

[0013]

Chemical Formula

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

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

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

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

[0018] The present invention further relates to a method for treating an inflammatory disease in a patient in need of treatment, comprising administering to the 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 the compounds described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides the compounds described herein for use in therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

Figure 1

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Mode for Carrying Out the Invention

[0021] The present disclosure provides, inter alia, a compound of formula (I):

[0022]

Chemical Formula

[0023]

Chemical formula

[0024]

Chemical formula

[0025] In some embodiments, the compound is 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide; (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)heptanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide others other than these.

[0026] The present disclosure provides, inter alia, a compound of formula (I):

[0027] [Chemical formula] 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, None of W, X, and Z will be N at the same time. Y 1 is selected from NR 3 , CR 4 R 5 and O, Y 2 is selected from -S-, -S(O)-, -S(O)2-, -CH2-, -O-, -N(R 3 ), -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and (-NR 3 )CH2-, Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 3- to 18-membered heterocycloalkyl, and ring A is optionally substituted by one, two, three or four R A ; Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~14 cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring B is optionally substituted by one, two, three or four R B ; R 1 and R 2 are each independently selected from H and methyl, R 3 is selected from H and C 1~4 alkyl, R 4 and R 5 are each independently selected from H, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, amino, C 1~4 alkylamino and C 2~8 dialkylamino, R 6 and R 7 are each independently selected from H, halo, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, amino, C 1~4 alkylamino and C 2~8Independently selected from dialkylamino respectively, R A is respectively halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 aryl-C 1~4 alkyl, C 3~7 cycloalkyl-C 1~4 alkyl, 5- to 10-membered heteroaryl-C 1~4 alkyl, 4- to 10-membered heterocycloalkyl-C 1~4 alkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2Rb1 and S(O)2NR c1 R d1 is independently selected from, R A said C of 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, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 , C(O)R b1 , NR c1 , C(O)OR a1 , NR c1 , C(O)NR c1 R d1 , NR c1 , S(O)R b1 , NR c1 , S(O)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)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, 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 、 NR c2 S(O)R b2 、 NR c2 S(O)2R b2 、 NR c2 S(O)2NR c2 R d2 、 S(O)R b2 、 S(O)NR c2 R d2 、 S(O)2R b2 and S(O)2NR c2 R d2 is independently selected from, R B the C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 aryl-C 1~4 alkyl, C 3~7 cycloalkyl-C 1~4 alkyl, 5- to 10-membered heteroaryl-C 1~4 alkyl and 4- to 10-membered heterocycloalkyl-C 1~4 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 、 SR a2 、 C(O)R b2 、 C(O)NR c2 R d2 、 C(O)OR a2 、 OC(O)R b2 、 OC(O)NR c2 R d2 、 C(=NR e2 )NR c2 R d2 、 NR c2 C(=NR e2 )NR c2 R d2 、 NRc2 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, 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)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, 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 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 each independently optionally substituted with one, two, three, four or five substituents selected from Cy 1 each is independently selected from C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, and each of them is 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 1~4Alkyl, 4- to 10-membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 is optionally substituted by one, two, three or four substituents independently selected from Cy 2 each is independently selected from C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, and each of them is 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- to 10-membered heteroaryl-C 1~4 alkyl, 4- to 10-membered heterocycloalkyl-C 1~4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 , S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 is optionally substituted by one, two, three or four substituents independently selected from Cy 3 each is independently selected from C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, and each of them is 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- to 10-membered heteroaryl-C 1~4 Alkyl, 4- to 10-membered heterocycloalkyl-C 1~4 Alkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is optionally substituted with one, two, three or four 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 each, independently, 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, 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 or R d3 of said 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, SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 is optionally substituted by one, two, three, four or five substituents independently selected from Cy 4 each is C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is halo, C 1~4 alkyl, C 1~4 haloalkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4, OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 , C(O)R b4 , NR c4 , C(O)NR c4 R d4 , NR c4 , C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 , C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 , S(O)2R b4 , NR c4 , S(O)2NR c4 R d4 and S(O)2NR c4 R d4 is optionally substituted with one, two, three or four substituents independently selected from R a4 , R b4 , R c4 and R d4 are independently selected from H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 6~10 aryl, C 3~7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 aryl-C 1~4 alkyl, C 3~7 cycloalkyl-C 1~4 alkyl, 5- to 10-membered heteroaryl-C 1~4 alkyl and 4- to 10-membered heterocycloalkyl-C 1~4 alkyl, and said C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6Alkynyl, C 6~10 Aryl, C 3~7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~7 Cycloalkyl-C 1~4 Alkyl, 5- to 10-membered heteroaryl-C 1~4 Alkyl and 4- to 10-membered heterocycloalkyl-C 1~4 Alkyl is optionally substituted by one, two or three substituents independently selected from OH, CN, amino, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 Haloalkoxy, respectively, optionally substituted by one, two or three substituents independently selected therefrom, 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 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 , C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 , C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 , S(O)2Rb4 、 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 optionally substituted with one, two or three substituents independently selected from, forming a 4- to 7-membered heterocycloalkyl group or R c2 and R d2 together with the N atom to which they are attached, halo, C 1~4 alkyl, C 1~4 haloalkyl, CN, OR a4 、 SR a4 、 C(O)R b4 、 C(O)NR c4 R d4 、 C(O)OR a4 、 OC(O)R b4 、 OC(O)NR c4 R d4 、 NR c4 R d4 、 NR c4 C(O)R b4 、 NR c4 C(O)NR c4 R d4 、 NR c4 C(O)OR a4 、 C(=NR e4 )NR c4 R d4 、 NR c4 C(=NR e4 )NR c4 R d4 、 S(O)R b4 、 S(O)NR c4 R d4 、 S(O)2R b4 、 NR c4 S(O)2R b4 、 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 optionally substituted with one, two or three substituents independently selected from, forming a 4- to 7-membered heterocycloalkyl group or R c3 and R d3together with the N atom to which they are attached, halo, C 1~4 alkyl, C 1~4 haloalkyl, CN, OR a4 SR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 C(=NR e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 S(O)R b4 S(O)NR c4 R d4 S(O)2R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 optionally substituted by one, two or three substituents independently selected from 4- to 7-membered heterocycloalkyl groups which form, R e1 R e2 R e3 and R e4 are each independently selected from H, C 1~4 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 as follows: (i) A bond directly connecting ring A to moiety E (ii) -(C 1~4 alkyl)- (iii) -(C 2~4 alkenyl)- (iv) -(C 2~4 alkynyl) (v) The following structures:

[0028]

Chem.

[0029]

Chem.

[0030] In some embodiments, the compound is 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide; (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)heptanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and 3-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1r,4r)-4-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide is other than that.

[0031] In some embodiments, W is CR W is. In some embodiments, W is N.

[0032] In some embodiments, X is CR X is. In some embodiments, X is N.

[0033] In some embodiments, Z is CR Z is. In some embodiments, Z is N.

[0034] In some embodiments, Y 1 is -O-. In some embodiments, Y 1 is -CR 4 R 5 -. In some embodiments, Y 1 is -NR 3 -. In some embodiments, Y 1 is -O- or -NR 3 -.

[0035] In some embodiments, Y 1 is -(C 2~4 alkynyl)-. In some embodiments, Y 1 is -(C2 alkynyl)-. In some embodiments, Y 1 is -CR 4 R 5 - or -(C 2~4 alkynyl)-. In some embodiments, Y 1 is -CR 4 R 5 - or (C2 alkynyl)-.

[0036] 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 selected from -S-, -S(O)-, -S(O)2-, -CH2-, -O- and -N(R 3 ). In some embodiments, Y 2 is selected from -SCH2-, -S(O)CH2-, -S(O)2CH2-, -CH2CH2-, -OCH2- and -(NR 3 ). In some embodiments, Y 2 is -O-.

[0037] In some embodiments, ring A is a 4- to 18-membered heterocycloalkyl, and ring A is optionally substituted by one, two, three or four R A .

[0038] In some embodiments, ring A is a 4- to 7-membered heterocycloalkyl, and ring A is optionally substituted by one, two, three or four R A . In some embodiments, ring A is a 4- to 7-membered heterocycloalkyl, and ring A is optionally substituted by one or two R A . In some embodiments, ring A is a 4- to 7-membered heterocycloalkyl.

[0039] In some embodiments, ring A is a piperidinyl optionally substituted by one, two, three or four R A . In some embodiments, ring A is a piperidinyl optionally substituted by R A . In some embodiments, ring A is piperidinyl. In some embodiments, ring A is a piperazinyl optionally substituted by R A .

[0040] In some embodiments, ring A is 1-methylpiperidin-4-yl.

[0041] In some embodiments, ring A is piperazinyl.

[0042] In some embodiments, ring A is C 3~14 cycloalkyl, and ring A is optionally substituted by one, two, three, or four R A s. In some embodiments, ring A is C 3~7 cycloalkyl, and ring A is optionally substituted by one, two, three, or four R A s. In some embodiments, ring A is cyclohexyl.

[0043] In some embodiments, ring B is C 3~7 cycloalkyl or 4- to 7-membered heterocycloalkyl, and ring B is optionally substituted by one, two, three, or four R B s. In some embodiments, ring B is C 3~7 cycloalkyl, and ring B is optionally substituted by one, two, three, or four R B s. In some embodiments, ring B is 4- to 7-membered heterocycloalkyl, and ring B is optionally substituted by one, two, three, or four R B s.

[0044] In some embodiments, ring B is C 3~7 cycloalkyl or 4- to 7-membered heterocycloalkyl, and ring B is optionally substituted by one or two R B s. In some embodiments, ring B is C 3~7 cycloalkyl, and ring B is optionally substituted by one or two R B s. In some embodiments, ring B is 4- to 7-membered heterocycloalkyl, and ring B is optionally substituted by one or two R B s.

[0045] In some embodiments, ring B is C 3~7 cycloalkyl. In some embodiments, ring B is cyclopentyl or cyclopropyl. In some embodiments, ring B is cyclopentyl. In some embodiments, ring B is cyclopropyl.

[0046] In some embodiments, ring B is piperidinyl or tetrahydro-2H-pyranyl optionally substituted by one, two, three or four Rs B In some embodiments, ring B is piperidinyl or tetrahydro-2H-pyranyl optionally substituted by one or two Rs B In some embodiments, ring B is piperidinyl or tetrahydro-2H-pyranyl optionally substituted by Rs B respectively.

[0047] In some embodiments, ring B is piperidinyl optionally substituted by one, two, three or four Rs B In some embodiments, ring B is piperidinyl optionally substituted by one or two Rs B In some embodiments, ring B is piperidinyl substituted by Rs B

[0048] In some embodiments, ring B is tetrahydro-2H-pyranyl optionally substituted by one, two, three or four Rs B In some embodiments, ring B is tetrahydro-2H-pyranyl optionally substituted by one or two Rs B In some embodiments, ring B is tetrahydro-2H-pyranyl.

[0049] In some embodiments, ring B is tetrahydro-2H-pyran-4-yl or 1-acetylpiperidin-4-yl. In some embodiments, ring B is 1-acetylpiperidin-4-yl.

[0050] In some embodiments, ring B is piperidinyl, tetrahydro-2H-pyranyl, cyclopentyl or cyclobutyl, and ring B is optionally substituted by one, two, three or four R B s. In some embodiments, ring B is piperidinyl, tetrahydro-2H-pyranyl, cyclopentyl or cyclobutyl, and ring B is optionally substituted by one or two R B s. In some embodiments, ring B is piperidinyl, tetrahydro-2H-pyranyl, cyclopentyl or cyclobutyl, and ring B is optionally substituted by R B . In some embodiments, ring B is tetrahydro-2H-pyran-4-yl, 1-acetylpiperidin-4-yl, cyclobutyl or cyclopentyl.

[0051] 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.

[0052] In some embodiments, R 3 is H.

[0053] 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.

[0054] In some embodiments, R 6 and R 7 are each H. In some embodiments, R 6is H. In some embodiments, R 7 is H.

[0055] In some embodiments, R A is each independently halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 is independently selected from, and the C A alkyl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl and C 1~6 haloalkyl is Cy1 、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 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 、NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 is each optionally substituted with one, two, three, four or five substituents independently selected from

[0056] In some embodiments, R A is each, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, ORa1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 is independently selected from.

[0057] In some embodiments, R A is each, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1C(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 are independently selected from

[0058] 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 1~6 Alkyl or C 1~6 In some embodiments, R A is methyl.

[0059] 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. c2C(=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 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. c2S(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:

[0060] 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 Rd2 、 S(O)2R b2 and S(O)2NR c2 R d2 is independently selected from

[0061] In some embodiments, R B is each independently H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 is independently selected from

[0062] In some embodiments, R B is each independently halo, C 1~6 alkyl, C 1~6 haloalkyl, CN, NO2, C(O)R b2 or OR a2 is independently selected from. In some embodiments, R B is each independently halo, C 1~6 alkyl, C 1~6 haloalkyl and C(O)R b2 is independently selected from. In some embodiments, R B is each independently C(O)R b2 is independently selected from. In some embodiments, R B is each independently selected from C(O)CH3.

[0063] In some embodiments, R W , R X and R Zis H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is independently selected from each of W , R X or R Z wherein said 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, C2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 , NR b3 , NR c3 , C(O)OR a3 , NR c3 , C(O)NR c3 R d3 , NR c3 , S(O)R b3 , NR c3 , S(O)2R b3 , NR c3 , S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is optionally substituted by one, two, three, four or five substituents independently selected from

[0064] In some embodiments, R W is H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 Rd3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is selected from.

[0065] In some embodiments, R W is H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2 and OR a3 selected from. In some embodiments, R W is H, halo and C 1~6 haloalkyl selected from. In some embodiments, R W is H or F. In some embodiments, R W is F. In some embodiments, R W is H.

[0066] In some embodiments, R X is H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 C(=NR e3 )R b3 C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 and S(O)2NR c3 R d3 is selected from.

[0067] In some embodiments, R X is selected from C 6~10 aryl and 5- to 10-membered heteroaryl, and the C 6~10 aryl and 5- to 10-membered heteroaryl are halo, C 1~6 alkyl, C 2~6 alkenyl, C2~6 alkynyl, C 1~6 haloalkyl, CN, OR a3 and SR a3 each optionally substituted with one, two, three, four or five substituents independently selected from

[0068] In some embodiments, R X is H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, OR a3 and C 6~10 aryl. In some embodiments, R X is H.

[0069] In some embodiments, R Z is H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(=NR e3 )R b3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3, NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 is selected from

[0070] In some embodiments, R Z is selected from C 6~10 aryl and 5- to 10-membered heteroaryl, and the C 6~10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one, two, three, four or five substituents independently selected from halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, OR a3 and SR a3

[0071] In some embodiments, R Z is selected from H, halo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, CN, OR a3 and C 6~10 aryl. In some embodiments, R Z is H.

[0072] 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.

[0073] In some embodiments, L 1 is a bond that directly connects ring A to moiety E.

[0074] ​ In some embodiments, L 1 is -(C 1~4 alkyl)-.

[0075] In some embodiments, L 1 is -(C 2~4 alkenyl)-.

[0076] In some embodiments, L 1 is -(C 2~4 alkynyl)-.

[0077] In some embodiments, L 1 is, -(C 2~4 alkynyl)-(G 3 )-.

[0078] In some embodiments, L 1 is the following structure:

[0079] [Chemical formula] and has. In some embodiments, L 1 is the following structure:

[0080] [Chemical formula] and has.

[0081] In some embodiments, L 1 is

[0082] [Chemical formula] and is.

[0083] In some embodiments, G 1 is -NR G C(O)- or -C(O)-. In some embodiments, G 1 is -NR G C(O)-. In some embodiments, G1 is -C(O)-. In some embodiments, G 1 is -NR G C(O)-, -C(O)- or -O-. In some embodiments, G1 is -O-.

[0084] In some embodiments, G 2 is a 4- to 10-membered heterocycloalkyl. In some embodiments, G 2 is piperidinyl, piperazinyl or azetidinyl. In some embodiments, G 2 is piperidinyl or piperazinyl. In some embodiments, G 2 is piperidinyl. In some embodiments, G 2 is piperazinyl. In some embodiments, G 2 is azetidinyl. In some embodiments, G 2 is pyrrolidinyl, piperidinyl, piperazinyl or azetidinyl. In some embodiments, G 2 is pyrrolidinyl.

[0085] In some embodiments, G 2 is C 3~7 cycloalkyl. In some embodiments, G 2 is cyclobutyl.

[0086] In some embodiments, G 3 is -NR G C(O)-, -NR G -, or -C(O)-. 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-.

[0087] In some embodiments, G 4 is piperidinyl or piperazinyl. In some embodiments, G4 is piperidinyl. In some embodiments, G 4 is piperazinyl.

[0088] In some embodiments, a is 0. In some embodiments, a is 1.

[0089] In some embodiments, b is 0. In some embodiments, b is 1.

[0090] In some embodiments, c is 0. In some embodiments, c is 1.

[0091] In some embodiments, d is 0. In some embodiments, d is 1.

[0092] In some embodiments, e is 0. In some embodiments, e is 1.

[0093] In some embodiments, f is 0. In some embodiments, f is 1.

[0094] In some embodiments, g is 0. In some embodiments, g is 1.

[0095] In some embodiments, R G is H.

[0096] The ubiquitin ligase binding moiety and the linker are known and are well described in the art, for example, in Bondeson, D.P. et al., Nat Chem Biol. 2015 11(8):611 - 617; An S et al., EBioMedicine 2018 36:553 - 562; Paiva S - L. 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.

[0097] 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 50 of less than about 10 μM as determined in a binding assay. For example, E is 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.

[0098] In some embodiments, E is an E3 ubiquitin ligase binding moiety that binds to cereblon.

[0099] In some embodiments, E comprises a chemical group derived from an imide, thioimide, amide, or thioamide.

[0100] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, analogs thereof, isostere thereof, or derivatives thereof.

[0101] In some embodiments, E is one of the following:

[0102]

Chemical formula

[0103] In some embodiments, E is

[0104]

Chemical formula

[0105] In some embodiments, E is

[0106] [Chemical formula] wherein the wavy line represents the bonding point to group L 1 to group L.

[0107] In some embodiments, E is the following:

[0108] [Chemical formula] selected from TIFF2025525031000016.tif239162, wherein the wavy line represents the bonding point to group L 1 to group L.

[0109] In some embodiments, the compound has the formula II:

[0110] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound has the formula IIIa:

[0112] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound has the formula IIIb:

[0114] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound has the formula IIIc:

[0116] [Chemistry] or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound is as follows: 4-(4-((1-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(6-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamido)hexyl)benzamide; 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamido)butyl)benzamide; N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; 3-((4-(1-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-(3-(4-(1-(2-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-2-oxoimidazolidin-1-yl)piperidine-2,6-dione; 4-(4-((1-(2-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 1-(4-(1-((1-(2-(4-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((2-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-((4-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-((4-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-((4-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 4-(4-((4-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-((1-(2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((1-(2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((1-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide; 2-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide; 5-(4-((4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-(4-(((7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-(5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(4-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and 5-(4-((4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; or is selected from any of the above pharmaceutically acceptable salts.

[0118] In some embodiments, the compound is 3-((4-(4-(2-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3 - ((4 - (4 - (2 - (4 - ((((7 - (Cyclopropylmethoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)ethyl)piperazin - 1 - yl)-3 - fluorophenyl)amino)piperidine - 2,6 - dione; 3 - ((4 - (4 - (3 - (4 - ((((7 - (Cyclopropylmethoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)azetidin - 1 - yl)piperidin - 1 - yl)-3 - fluorophenyl)amino)piperidine - 2,6 - dione; 3 - (6 - (4 - (2 - (4 - ((((7 - (Cyclopropylmethoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)ethyl)piperazin - 1 - yl)-2 - oxobenz[cd]indol - 1(2H)-yl)piperidine - 2,6 - dione; 3 - (5 - (4 - ((4 - ((((7 - (Cyclopropylmethoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)methyl)piperidin - 1 - yl)-1 - oxoisoindolin - 2 - yl)piperidine - 2,6 - dione; 3 - ((3 - fluoro - 4 - (4 - (3 - (4 - ((((5 - fluoro - 4 - oxo - 7 - ((tetrahydro - 2H - pyran - 4 - yl)methoxy)-3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)azetidin - 1 - yl)piperidin - 1 - yl)phenyl)amino)piperidine - 2,6 - dione; 3 - ((3 - fluoro - 4 - (4 - ((((5 - fluoro - 4 - oxo - 7 - ((tetrahydro - 2H - pyran - 4 - yl)methoxy)-3,4 - dihydroquinazolin - 2 - yl)methyl)thio)-[1,4’ - bipiperidin]-1’ - yl)phenyl)amino)piperidine - 2,6 - dione; 3-((4-(4-((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(((1r,4r)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-((4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione; 3-((4-(3-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)pyrrolidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 1-(4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-((4-(4-(4-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(1'-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[4,4'-bipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(3-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(((7-(Cyclopropyl ethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione or is selected from any of the above pharmaceutically acceptable salts.

[0119] For clarity, it is further understood that certain features of the invention described in the context of individual embodiments may also be provided in combination with a single embodiment. Conversely, for brevity, the various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable subcombination.

[0120] The substituents of the compounds of the invention are disclosed in groups or ranges at various places herein. The invention specifically contemplates including any and every individual subcombination of members of such groups and ranges. For example, the term "C 1~6 alkyl" specifically contemplates individually disclosing methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0121] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described at various places herein. Unless otherwise specified, these rings can be attached to any ring member and to the remainder of the molecule where valence permits. For example, the terms "pyridinyl", "pyridyl", or "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0122] The term "n-membered" (where "n" is an integer) typically describes the number of atoms forming a ring in a moiety, and the number of atoms forming the ring is "n". For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0123] At various places in this specification, variable groups defining a divalent linking group may be described. Each linking substituent is specifically intended to include both the forward form and the backward form of the linking substituent. For example, -C(O)NR G - is -C(O)NR G - and -NR G both of C(O)-, and each form is intended to be disclosed individually. When a structure requires a linking group, the Markush variable groups listed for that group are understood to be the linking group. For example, when a structure requires a linking group and a Markush group, the definition for that variable group lists "alkyl" or "aryl", and then "alkyl" or "aryl" is understood to represent a linking alkylene group or a linking arylene group, respectively.

[0124] For compounds of the invention in which a variable group appears more than once, each variable group can be a different moiety, independently selected from the group defining that variable group. For example, when a structure having two R groups simultaneously present in the same compound is described, these two R groups can represent different moieties independently selected from the group defined for R.

[0125] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0126] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution at a given atom is limited by the valence.

[0127] As used herein, the term "C i~j "(where i and j are integers) represents the range of the number of carbon atoms in a chemical group, and i to j define that range. For example, C 1~6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0128] As used herein, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chain or branched-chain. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl and the like. In some embodiments, the alkyl group is methyl, ethyl or propyl. The term "alkylene" refers to a linking alkyl group.

[0129] 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.

[0130] 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.

[0131] As used herein, the term "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.

[0132] As used herein, the term "haloalkyl", used alone or in combination with other terms, refers to an alkyl group having halogen atom substituents up to the maximum total valence, which may be the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0133] As used herein, the term "alkoxy", used alone or in combination with other terms, refers to a group of the 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.

[0134] As used herein, the term "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 -OCF3.

[0135] As used herein, "amino", when used alone or in combination with other terms, refers to NH2.

[0136] As used herein, the term "alkylamino", when used alone or in combination with other terms, refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0137] As used herein, the term "dialkylamino", when used alone or in combination with other terms, refers to a group of the formula -N(alkyl)2. Examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0138] As used herein, the term "cycloalkyl", used alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl groups and alkenyl groups. A cycloalkyl group can include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings, bridged rings, or spiro rings) ring system. Similarly, a cycloalkyl ring, for example, a benzene derivative such as cyclopentane, cyclohexene, cyclohexane, or a pyridine derivative of cyclopentane or cyclohexane, condensed with (i.e., having a common bond with the above derivatives) one or more aromatic rings (e.g., an aryl ring or a heteroaryl ring) is also included in the definition of cycloalkyl. The carbon atoms forming the ring of the cycloalkyl group can be optionally substituted by oxo. The cycloalkyl group also includes cycloalkylidene. The term "cycloalkyl" also includes a bridgehead cycloalkyl group (e.g., a non-aromatic cyclic hydrocarbon moiety containing at least one bridgehead carbon such as adamantan-1-yl) and a spirocycloalkyl group (e.g., a non-aromatic hydrocarbon moiety containing at least two rings fused at a single carbon atom such as spiro[2.5]octane). In some embodiments, the cycloalkyl group has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3~7 a monocyclic cycloalkyl group. 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.

[0139] As used herein, the term "cycloalkylalkyl", used alone or in combination with other terms, refers to a group of the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2 or 1 carbon atoms. In some embodiments, the alkyl moiety is methylene. In some embodiments, the cycloalkyl moiety has 3 to 10 or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3~7 a monocyclic cycloalkyl group.

[0140] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or non-aromatic ring system having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, optionally containing 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 rings, bridged rings, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, and oxygen. Similarly, a moiety having one or more aromatic rings (e.g., an aryl ring or heteroaryl ring) fused to (i.e., having a common bond with) a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydro-quinoline, is also included in the definition of heterocycloalkyl. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom such as azaadamantan-1-yl) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl]). In some embodiments, the heterocycloalkyl group has 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, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. A carbon atom or heteroatom in the ring of a heterocycloalkyl 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. In some embodiments, the heterocycloalkyl moiety is C 2~7It is a monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahyropyridine, an azetidine ring or a tetrahydrofuran ring.

[0141] As used herein, the term "heterocycloalkylalkyl", used alone or in combination with other terms, refers to a group of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2 or 1 carbon atom(s). 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.

[0142] 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, the aryl group has 6 to 10 or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic group or a bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[0143] As used herein, the term "arylalkyl," whether used alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is methylene. In some embodiments, the aryl moiety is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0144] As used herein, the term "heteroaryl," whether 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. A carbon atom or heteroatom 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, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 atoms forming the ring. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0145] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl 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.

[0146] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended, unless otherwise indicated. Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated as optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Geometric isomers, such as olefins, C=N double bonds, etc., can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the invention may be isolated as mixtures of isomers or as separated isomers.

[0147] The compounds of the present invention also include tautomers. Tautomers result from the simultaneous movement 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 having the same empirical formula and total charge. Examples of prototropic tautomers include the keto-enol pair, the amide-imino acid pair, the lactam-lactim pair, the enamine-imine pair, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic 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 an equilibrium state or can be stereochemically fixed in one form by appropriate substitution.

[0148] The compounds of the present invention also include all isotopes of atoms present in an intermediate or final compound. 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 include at least one deuterium atom.

[0149] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0150] All compounds and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.

[0151] In some embodiments, the compound of the present invention or a salt thereof is substantially isolated. "Substantially isolated" means that the compound is at least partially separated from or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched in the compound of the present invention. Substantial separation can include compositions 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 conventional in the art.

[0152] The term "small molecule PARP14 targeting moiety" refers to a chemical group that binds to PARP14. The small molecule PARP14 targeting moiety can be a group derived from a compound that inhibits the activity of PARP14. In some embodiments, the small molecule PARP14 targeting moiety inhibits the activity of PARP14 with a DC 50 below 1 μM in an enzyme assay (see, for example, Example A).

[0153] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting the substrate protein for degradation.

[0154] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0155] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting any acidic or basic moieties present into their salt forms. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compounds formed from, for example, non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent, or in a mixture of the two. A list 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.

[0156] Synthesis The compounds of the present invention containing such salts can be prepared using known organic synthetic techniques and can be synthesized according to any of a number of possible synthetic routes.

[0157] The reactions for preparing the compounds of the present invention can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, in the 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, the solvent suitable for the specific reaction step can be selected by those skilled in the art.

[0158] 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, as well as the selection of appropriate protecting groups, can be readily 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. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is hereby incorporated by reference in its entirety.

[0159] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry or by chromatography such as high performance liquid chromatography.

[0160] The compounds of the present invention can be prepared according to a number of preparation routes known in the literature. Examples of synthetic methods for preparing the compounds of the present invention are presented in the following schemes.

[0161]

Chemical formula

[0162] Scheme 1 shows the general synthesis of the quinazolinone compounds of the present disclosure. Compounds of formula (1-A), many of which are commercially available or can be made by routes known to those skilled in the art, many of which are known in the art and described, for example, in U.S. Patent No. 10,562,891, can be coupled with compounds of formula (1-B). This coupling can be carried out under Pd coupling conditions (e.g., in the presence of a Pd reagent such as [Pd(allyl)Cl]2), providing a compound of formula (1-C).

[0163]

Chemical formula

[0164] Scheme 2 shows the general synthesis of certain compounds of the present invention. The compound of formula (2-A) can be prepared according to the route presented in Scheme 1 or according to the process disclosed in U.S. Patent No. 10,562,891. The N atom of the A ring of the compound of formula (2-A) can be treated with tert-butyl 2-bromoacetate to obtain the compound of formula (2-B). The compound of formula (2-B) can be treated with an acid (e.g., trifluoroacetic acid) to obtain the compound of formula (2-C). The compound of formula (2-C) can be coupled with the compound of formula (2-D), where the group L 2 refers to the internal part of the linker moiety L 1 as defined herein. The compound of formula (2-D) is commercially available and is also known in the art. The coupling of the compounds of formula (2-C) and formula (2-D) is carried out under peptide coupling conditions (e.g., EDCI, HOBt and DIPEA; or HATU, DIPEA) to obtain the compound of formula (2-E). The "-CH2-C(O)-L 2 -" group of the compound of formula (2-E) is equal to the L 1 group as defined herein.

[0165]

Chemical formula

[0166] Scheme 3 shows the general synthesis of certain compounds of the present invention. The compound of formula (3-A) can be prepared according to the route presented in Scheme 1. The compound of formula (3-B), where the group L 2 refers to the internal part of the linker moiety L 1 as defined herein, can be oxidized (e.g., by Dess-Martin periodinane) to obtain an aldehyde intermediate in situ (not shown). The resulting reaction mixture can be treated with the compound of formula (3-A) followed by a hydride reducing agent (e.g., NaBH(OAc)3) to obtain the compound of formula (3-C). The "-CH2-L 2The "-" group is equal to the L defined in this specification. 1 is equal to the group.

[0167] Method of use The compounds of the present disclosure can bind to both PARP14 and ubiquitin E3 ligase, causing PARP14 degradation useful for the treatment of various diseases including cancer. In some embodiments, the compounds provided herein can degrade PARP14 in cells, which includes contacting the cells with the compound or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, provided herein is a method of 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. "Degrading PARP14" is intended to inactivate PARP14, for example, by modifying its structure or degrading PARP14 into multiple peptide or amino acid fragments.

[0168] The compounds of the present invention are useful for the treatment of various diseases associated with abnormal expression or activity of PARP14. For example, the compounds of the present invention are useful for the treatment of cancer. In some embodiments, cancers treatable by the present invention include hematopoietic tissue malignancies such as leukemia and lymphoma. Examples of lymphoma include Hodgkin lymphoma or non-Hodgkin 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 leukemia include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0169] Other cancers that can be treated by administration of the compounds of the present invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, stomach cancer, gastrointestinal tract 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.

[0170] In some embodiments, the cancers that can be treated by administration of the compounds of the present invention are multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer or melanoma.

[0171] The compounds of the present invention may also have therapeutic utility in PARP14-related disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation and pain, particularly when the disease is characterized by overexpression or increased activity of PARP14.

[0172] In some embodiments, the compounds of the invention are useful for the treatment of 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 (BAL2), protects mice from allergen-induced airway disease (Mehrothra et al., J Allergy Clin Immunol, July 25, 2012, 131(2):521-531; and Cho et al., Proc Natl Acad Sci USA, September 20, 2011, 108(38):15972-15977), suppresses the infiltration of immune cells such as eosinophils and neutrophils into the lung, and reduces the release of inflammatory Th2 cytokines. Furthermore, treatment with a PARP14 inhibitor protected mice in a severe asthma model induced by sensitization with an Alternaria alternata extract and recall challenge (Eddie et al PMID35817532). Animals treated with a PARP14 inhibitor showed reduced levels of airway mucus, serum IgE, infiltration of immune cells (eosinophils, neutrophils and lymphocytes), Th2 cytokines (IL-4, IL-5 and IL13) and alarmins (IL-33 and TSLP) (Eddie et al PMID35817532 and Ribon internal data).

[0173] Although not being bound by theory, PARP14 has been shown to affect STAT6 signaling and STAT3 signaling, signaling induced by Th2 cytokines 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 growth, to be involved in B cell growth, and to be involved in eosinophil / neutrophil recruitment / activation. These lymphocytes are likely to be 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), such as ILCs (e.g., ILC2 and ILC3). PARP14 inhibition not only affects the asthma phenotype at the level of secondary cytokine (e.g., IL-4, IL-5, and IL-13) and signaling to myeloid cells, but PARP14 inhibition is also suggested to suppress alarmins TSLP and IL-33, which are important upstream drivers of asthma released in response to allergens.

[0174] The present invention is directed, inter alia, to a method of treating or preventing an inflammatory disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Exemplary inflammatory diseases treatable by the disclosed method include, for example, asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloid, eosinophilic disorders, pulmonary fibrosis, and other type 2 cytokine pathologies. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0175] Additional exemplary inflammatory diseases treatable by the disclosed method include inflammatory bowel diseases ("IBD") including ulcerative colitis ("UC" or "colitis") and Crohn's disease. In some embodiments, the inflammatory disease is an inflammatory bowel disease. In some embodiments, the inflammatory disease is ulcerative colitis. In some embodiments, the inflammatory disease is Crohn's disease.

[0176] In some embodiments, the inflammatory disease is irritable bowel syndrome.

[0177] Examples of 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 (large intestine - EC), and eosinophilic chronic rhinosinusitis.

[0178] The present invention further targets, inter alia, a method of treating or preventing asthma in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0179] 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, severe asthma is a T2 - high endotype, T2 - low endotype, or non - T2 endotype. In some embodiments, severe asthma is a T2 - high endotype. In some embodiments, severe asthma is a T2 - low endotype or non - T2 endotype. In some embodiments, severe asthma is a T2 - low endotype. In some embodiments, severe asthma is a non - T2 endotype.

[0180] The present invention further targets, inter alia, methods of treating or preventing fibrotic diseases such as, but not limited to, pulmonary fibrosis, renal fibrosis, liver fibrosis (e.g., NASH and NAFLD), systemic fibrosis, and idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is systemic fibrosis.

[0181] The present invention further targets, inter alia, methods of treating or preventing chronic obstructive pulmonary disease (COPD), emphysema, and chronic bronchitis.

[0182] The present invention further targets, inter alia, methods for treating or preventing skin inflammatory diseases such as atopic dermatitis or urticaria.

[0183] The present invention relates to, in a patient, (a) reducing the level of airway mucus in lung tissue (b) reducing serum IgE (c) reducing 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 a method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the present invention provides a method for reducing the level of airway mucus in lung tissue in a patient.

[0185] In some embodiments, the present invention provides a method for reducing immune cell infiltration and activation in bronchoalveolar lavage fluid in a patient. In some embodiments, the immune cells are eosinophils, neutrophils or lymphocytes.

[0186] In some embodiments, the present invention provides a method 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.

[0187] In some embodiments, the present invention provides a method for reducing alarmins in bronchoalveolar lavage fluid or lung tissue in a patient. In some embodiments, the alarmin is IL-25, IL-33 or TSLP.

[0188] As used herein, the term "cell" is intended to refer to cells that are in vitro, ex vivo or in vivo. In some embodiments, ex vivo cells can be a portion of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells can be cells in a cell culture. In some embodiments, in vivo cells are cells that are living in an organism such as a mammal.

[0189] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" PARP14 or contacting a cell with a compound of the present invention includes administering the compound of the present invention to an individual or patient such as a human having PARP14 and introducing the compound of the present invention into a sample containing a cell preparation or purified preparation containing PARP14, for example.

[0190] As used herein, the terms "individual" or "patient" used interchangeably refer to a mammal, particularly a human.

[0191] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual or human as determined by a researcher, veterinarian, medical doctor or other clinician.

[0192] As used herein, the term "treating" or "treatment" refers to 1) inhibiting a disease in an individual experiencing or displaying the pathology or symptoms of the disease (i.e., stopping further progression of the pathology and / or symptoms) or 2) ameliorating a disease in an individual experiencing or displaying the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms).

[0193] As used herein, the term "preventing" or "prevention" refers to preventing a disease in an individual who is at risk of developing the disease but who has not yet experienced or displayed the pathology or symptoms of the disease.

[0194] As used herein, the term "reducing" relates to the level in the patient prior to administration. More specifically, when a biomarker or symptom is reduced in a patient, the reduction relates 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.

[0195] Combination therapy For example, one or more additional pharmaceutical agents or treatment methods such as chemotherapeutic agents or other anti-cancer agents, immunostimulants, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (e.g., IL2, GM-CSF, etc.), and / or kinases (tyrosine or serine / threonine), epigenetic inhibitors or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be used in combination with the compound in a single dosage form or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0196] For treating cancer, agents suitable for use in combination with the compounds of the present invention include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiation therapies. The compounds of the present invention may be effective when used in combination with antihormonal agents for treating 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., megastrol acetate) and antiestrogen agents including estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormonal agents used for treating 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, antiandrogen drugs 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).

[0197] Angiogenesis inhibitors may be effective in some tumors when used in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Inhibitors of VEGFR kinase and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib and vandetanib.

[0198] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents such as uracil mustard (non-limiting, including nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes), chloromethine, cyclophosphamide (Cytoxan (trademark)), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine and temozolomide.

[0199] Other anti-cancer agents include antibody therapeutics against co-stimulatory molecules such as CTLA-4, 4-1BB, PD-1 and PD-L1 or antibodies against cytokines (such as IL-10, TGF-β). Exemplary cancer immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab and rituximab.

[0200] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Further, 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 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if fully set forth.

[0201] Suitable agents for use in combination with the compounds of the present invention for treating inflammatory diseases include, but are not limited to, corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone); disease-modifying antirheumatic drugs ("DMARDs", e.g., immunosuppressive agents or anti-inflammatory agents); antimalarial agents (e.g., hydroxychloroquine and chloroquine); immunosuppressive agents (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 channel blockers (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 stimulator agents ("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.

[0202] Additional agents suitable for use in combination with the present invention for treating inflammatory disorders 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 agents (e.g., fibrates including fenofibrate, bezafibrate, gemfibrozil, clofibrate, etc.; bile acid sequestrants including cholestyramine, colestipol, etc.; and niacin), antiplatelet agents (e.g., adenosine diphosphate receptor antagonists including aspirin and clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and adiponectin.

[0203] Suitable agents for use in combination with the compounds of the present invention for treating 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 (VoSpire ER™), 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.

[0204] Pharmaceutical formulations and dosage forms When the compounds of the present invention are used as pharmaceuticals, they can be administered in the form of pharmaceutical compositions. The pharmaceutical composition refers to a combination of the 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 ophthalmic, as well as those for mucous membranes including intranasal, intravaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols including those by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular or parenteral.

[0205] The present invention also includes pharmaceutical compositions containing, as an active ingredient, one or more of the above compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually admixed with excipients, diluted by the excipients or enclosed within such carriers in the form of, for example, capsules, sachets, paper or other containers. When the excipient serves as a diluent, the excipient can be a solid, semi-solid or liquid substance, which serves as a vehicle, carrier or medium for the active ingredient. Accordingly, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0206] The compositions can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0207] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, the amount of the compound actually administered will typically be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0208] When preparing solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present invention. When these pre-formulation compositions are referred to as homogeneous substances, the active ingredient is usually uniformly dispersed throughout the composition, and thus the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Next, this solid pre-formulation is subdivided into unit dosage forms of the above type, containing, for example, from 0.1 to about 500 mg of the active ingredient of the present invention.

[0209] The tablets or pills of the present invention can be coated or, if not, formulated to provide a dosage form that provides the advantage of extended action. For example, a tablet or pill can contain an inner administration component and an outer administration component, and the latter outer administration component is in a form that wraps around the former inner administration component. The two components are separated by an enteric layer that acts to be resistant to disintegration in the stomach, and it may be possible for the inner component to pass through the duodenum intact or for the release to be delayed. Various substances can be used for such enteric layers or coatings, and such substances include some polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol and cellulose acetate.

[0210] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous suspensions 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.

[0211] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid compositions may contain the above-mentioned suitable pharmaceutically acceptable excipients. In some embodiments, the compositions are administered by oral or intranasal respiratory routes for local or systemic action. The compositions can be sprayed by the use of an inert gas. The sprayed solution may be inhaled directly from the spraying device or the spraying device may be attached to a tent-shaped face mask or an intermittent positive pressure breathing apparatus. A solution, suspension or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0212] The amount of the compound or composition administered to a patient will vary depending on the nature of the agent administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic use, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose is determined by the judgment of the attending clinician according to the condition being treated, as well as factors such as the severity of the disease, the age, weight and general condition of the patient.

[0213] The composition administered to a patient may be in the form of the above-mentioned pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as such or lyophilized and combined with a sterile aqueous carrier prior to administration as a lyophilized preparation.

[0214] The therapeutic dosage of the compounds of the present invention can vary, for example, depending on the specific use for which the treatment is being carried out, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in the pharmaceutical composition can vary depending on several factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg to about 1 g per kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg to about 100 mg per kg of body weight per day. The dosage is likely to depend on variables such as the type and degree of progression of the disease or disorder, the overall health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and the route of its administration. The effective dosage can be extrapolated from a dose-response curve derived from in vitro or animal model test systems.

[0215] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients that can include any pharmaceutical agent, such as an antiviral agent, an anticancer agent, a vaccine, an antibody, an immunopotentiator, an immunosuppressant, an anti-inflammatory agent, and the like.

Examples

[0216] Apparatus: 1 1H NMR spectra were recorded at 300 MHz or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. The interpretation of NMR was performed using Bruker Topspin software that assigns 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, the coupling constant can be assigned using this software. In any given example, one or more protons may not be observed because they are obscured by the peaks of water and / or the solvent. The LCMS apparatus and conditions are as follows.

[0217] 1. LC (basic condition): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-pack scepter C18 33 * 3.0 mm, 3.0 μm. Mobile phase: A: water / 6.5 mM (NH4) HCO3; B: acetonitrile. Flow rate: 1.5 mL / min, 40 °C. Detector: 190 - 400 nm. Gradient stop time 2.0 min. Timetable:

[0218]

Table 1

[0219] 2. LC (basic condition): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-pack scepter C18 33 * 3.0 mm, 3.0 μm. Mobile phase: A: water / 5 mM (NH4) HCO3; B: acetonitrile. Flow rate: 1.5 mL / min, 40 °C. Detector: 190 - 400 nm. Gradient stop time 2.0 min. Timetable:

[0220]

Table 2

[0221] 3. LC (acidic condition): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Halo C18, 30 * 3.0 mm, 2.0 μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min, 40 °C. Detector: 190 - 400 nm. Gradient stop time, 2.0 min. Timetable:

[0222]

Table 3

[0223] 4. LC (under acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Halo C18, 30 * 3.0 mm, 2.0 μm. Mobile phase A: water / 0.1% FA; B: acetonitrile / 0.1% FA. Flow rate: 1.5 mL / min, 40 °C. Detector: 190 - 400 nm. Gradient stop time 3.0 min. Time table:

[0224]

Table 4

[0225] 5. The MS detector is configured with an electrospray ionization as the ionization source. Acquisition mode: scan; spray 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.

[0226] 6. Sample preparation: The sample was 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.

[0227] Definition: ACN (acetonitrile); AcOH (acetic acid); B2(OH)4 (tetrahydroxydiboron); Boc2O (di-tert-butyl decarbonate); t-BuOK (potassium tert-butoxide); t-BuONa (sodium tert-butoxide); Cs2CO3 (cesium carbonate); CH3CN (acetonitrile); CuI (copper(I) iodide); DCM (dichloromethane); DIEA (N,N-diisopropylethylamine); DMA (N,N-dimethylacetamide); DMF (N,N-dimethylformamide); DMAP (4-dimethylaminopyridine); DMP (dess-martin periodinane); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); equiv (equivalent); ESI (electrospray ionization); EtOAc (ethyl acetate); Et2O (diethyl ether); EtOH (ethanol); FA (formic acid); Fe (iron); FeCl3 (iron(III) chloride); FeCl3.6H2O (iron(III) chloride hexahydrate); g (gram); h (hour); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); 11H NMR (Proton Nuclear Magnetic Resonance); HCl (Hydrochloric Acid); HOBT (1-Hydroxybenzotriazole); Hz (Hertz); K2CO3 (Potassium Carbonate); KI (Potassium Iodide); KOH (Potassium Hydroxide); K3PO4 (Potassium Phosphate Tribasic); L (Liter); LCMS (Liquid Chromatography-Mass Spectrometry); M (Molarity); MeCN (Acetonitrile); MeOH (Methanol); mg (Milligram); MHz (Megahertz); min (Minute); mL (Milliliter); mmol (Millimole); NaBH3CN (Sodium Cyanoborohydride); NaBH(OAc)3 (Sodium Triacetoxyborohydride); Na2CO3 (Sodium Carbonate); NaH (Sodium Hydride); NH4Cl (Ammonium Chloride); NaHCO3 (Sodium Bicarbonate); NaOH (Sodium Hydroxide); Na2SO4 (Sodium Sulfate); (NH4)HCO3 (Ammonium Bicarbonate); nm (Nanometer); NMP (N-Methylpyrrolidone); PBS (Phosphate Buffered Saline); Pd / C (Palladium on Carbon); Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(0)); Pd-PEPPSI-IPentCl2-Methylpyridine(o-Picoline)((SP-4-1)-[1,3-Bis[2,6-Bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium(II)(2-methylpyridine)); Pd(PPh3)2Cl2 (trans-Dichlorobis(triphenylphosphine)palladium(II)); PE (Petroleum Ether); Preparative HPLC (Preparative High Performance Liquid Chromatography); ppm (Parts Per Million); STAB (Sodium Triacetoxyborohydride); TBAB (Tetrabutylammonium Bromide); TBAF (Tetrabutylammonium Fluoride); TBHP (tert-Butyl Hydroperoxide); TEA (Triethylamine); TFA (Trifluoroacetic Acid); TfOH (Trifluoromethanesulfonic Acid); THF (Tetrahydrofuran); RT (Retention Time); UV (Ultraviolet); Xphos (2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl).

[0228] Synthesis of Intermediate A1: 2-(2,6-Dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione

[0229]

Chem.

[0230] Step A A solution of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (8.90 g, 31.4 mmol, 1.2 eq), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (7.23 g, 26.2 mmol, 1.0 eq) and TEA (7.95 g, 78.6 mmol, 3.0 eq) in NMP (70 mL) was stirred at 70 °C for 3 h. 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] + 。

[0231] Step 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 eq) in TFA (30 mL) and DCM (90 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum and then diluted with DCM (60 mL) and water (50 mL). This mixture was neutralized to pH 7 with saturated aqueous Na2CO3. The resulting mixture was concentrated under vacuum 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 yellow crude solid. This product was used without further purification. LCMS (ESI, m / z): 440.10 [M+H] + 。

[0232] Intermediates A1-a to A1-e were synthesized in accordance with the procedures described for the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione using appropriate components and reaction conditions (reagents, reagent ratios, temperature, reaction time, etc.) and purification conditions as necessary and modified as appropriate.

[0233]

Table 5

[0234] Synthesis of Intermediate A2: N-(6-aminohexyl)-3-(2,4-dioxo-1,3-diazinan-1-yl)benzamide HCl salt

[0235]

Chemical formula

[0236] Step A A solution of 3-(2,4-dioxo-1,3-diazinan-1-yl)benzoic acid (170 mg, 0.72 mmol, 1.0 eq) and tert-butyl N-(6-aminohexyl)carbamate (157 mg, 0.72 mmol, 1.0 eq) in DMF (2 mL) was added with DIEA (281 mg, 2.18 mmol, 3.0 eq) and HATU (414 mg, 1.09 mmol, 1.5 eq). The resulting mixture was stirred for 1 h. 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, gradient 0% - 40% in 20 min; detector: UV254 nm to give tert-butyl N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]formamido}hexyl)carbamate (256 mg, 82% yield) as a white solid. LCMS (ESI, m / z): 433.24 [M+H] + 。

[0237] Step B A solution of tert-butyl N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]formamido}hexyl)carbamate (100 mg, 0.23 mmol, 1.0 eq) and HCl (1 mL, 4 M) in 1,4-dioxane (1 mL) in 1,4-dioxane was stirred for 2 h. The resulting mixture was concentrated under vacuum to give N-(6-aminohexyl)-3-(2,4-dioxo-1,3-diazinan-1-yl)benzamide (71 mg, 92% yield) as a white solid. LCMS (ESI, m / z): 333.18 [M+H] + 。

[0238] Intermediate A2-a was synthesized according to the procedure described for the synthesis of N-(6-aminohexyl)-3-(2,4-dioxo-1,3-diazinan-1-yl)benzamide using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions.

[0239]

Table 6

[0240] Synthesis of Intermediate A3: 3 - ((4 - (1 - (6 - aminohexyl) piperidin - 4 - yl) phenyl) amino) piperidine - 2,6 - dione hydrochloride

[0241]

Chem.

[0242] Step A A solution of tert - butyl 4 - (4 - aminophenyl) piperidine - 1 - carboxylate (1.0 g, 3.6 mmol, 1.0 eq), 3 - bromopiperidine - 2,6 - dione (1.4 g, 7.2 mmol, 2.0 eq) and DIEA (0.94 g, 7.2 mmol, 2.0 eq) in 1,4 - dioxane was stirred at 80 °C for 24 h. The resulting mixture was concentrated under reduced pressure and dissolved in DMSO (10 mL). The residue was purified by reverse - phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient from 0% to 60% in 20 min; UV 254 nm to give tert - butyl 4 - (4 - ((2,6 - dioxopiperidin - 3 - yl) amino) phenyl) piperidine - 1 - carboxylate (1.2 g, 86% yield) as a white solid. LCMS (ESI, m / z): 388.22 [M + H] + 。

[0243] Step B tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.2 g, 3.1 mmol, 1.0 eq) and a solution of HCl in 1,4-dioxane (10 mL, 4 M) were stirred for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by trituration with Et2O (50 mL) to give 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (998 mg) as a white crude solid, which was used without further purification. LCMS (ESI, m / z): 288.16 [M+H] + 。

[0244] Step C A solution of 3-{[4-(4-aminobutan-2-yl)phenyl]amino}piperidine-2,6-dione (350 mg, 1.27 mmol, 1.0 eq), tert-butyl N-(6-bromohexyl)carbamate (410 mg, 1.46 mmol, 1.2 eq) and K2CO3 (337 mg, 2.43 mmol, 2.0 eq) in DMF (5 mL) was stirred at 60 °C for 4 h. The mixture was acidified to pH 5 with citric acid. The mixture was purified directly by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient 0% - 50% in 20 min; detector: UV254 nm to give tert-butyl (6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)carbamate (254 mg, 43% yield) as a green solid. LCMS (ESI, m / z): 487.32 [M+H] + 。

[0245] Step D tert-Butyl N-[6-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)hexyl]carbamate (150 mg, 0.31 mmol, 1.0 eq) and a solution of HCl (1.5 mL, 4 M) in 1,4-dioxane were stirred for 6 h. The resulting mixture was concentrated under reduced pressure to give 3-((4-(1-(6-aminohexyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (256 mg) as a green crude solid, which was used in the next step without further purification. LCMS (ESI, m / z): 387.25 [M+H] + .

[0246] Intermediates A3-a to A3-d were synthesized according to the procedures described for the synthesis of 3-((4-(1-(6-aminohexyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride using appropriate components and, where necessary, modified reaction conditions (such as reagents, reagent ratios, temperature and reaction time) and purification conditions.

[0247]

Table 7

[0248] Intermediate A4: Synthesis of 3-((4-(1-(6-aminohexanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0249]

Chemical formula

[0250] Step A 3-{(4-(Piperidin-4-yl)phenyl)amino}piperidine-2,6-dione (300 mg, 1.04 mmol, 1.5 eq) and 6-[(tert-Butoxycarbonyl)amino]hexanoic acid (161 mg, 0.70 mmol, 1.0 eq) were added to a stirred solution in DMF (5 mL) of HATU (317 mg, 0.835 mmol, 1.2 eq) and DIEA (270 mg, 2.09 mmol, 3.0 eq). The resulting mixture was stirred for 4 h. The mixture was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient from 0% to 46% in 20 min; detector: UV 254 nm to give tert-butyl (6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)carbamate (219 mg, 63% yield) as a white solid. LCMS (ESI, m / z): 501.30 [M+H] + .

[0251] Step B A solution of tert-butyl (6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)carbamate (169 mg, 0.338 mmol, 1.0 eq) in HCl (2.5 mL, 4 M) in 1,4-dioxane was stirred for 6 h. The resulting mixture was concentrated under reduced pressure to give 3-((4-(1-(6-aminohexanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (238 mg) as a green crude solid. LCMS (ESI, m / z): 401.25 [M+H] + .

[0252] Intermediates A4-a to A4-e were synthesized according to the procedures described for the synthesis of 3-((4-(1-(6-aminohexanoyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride using appropriate components and reaction conditions (reagents, reagent ratios, temperature, reaction time, etc.) and purification conditions modified as necessary.

[0253]

Table 8

[0254] Synthesis of Intermediate A5: 3 - ((4 - (1 - (2 - aminoethyl)piperidin - 4 - yl)phenyl)amino)piperidine - 2,6 - dione hydrochloride

[0255]

Chemical formula

[0256] Step A A solution of 3 - ((4 - (piperidin - 4 - yl)phenyl)amino)piperidine - 2,6 - dione hydrochloride (250 mg, 0.77 mmol, 1.0 eq), tert - butyl (2 - oxoethyl)carbamate (184 mg, 1.16 mmol, 1.5 eq) and NaBH3CN (97 mg, 1.5 mmol, 2.0 eq) in MeOH (10 ml) was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give tert - butyl (2 - (4 - (4 - ((2,6 - dioxopiperidin - 3 - yl)amino)phenyl)piperidin - 1 - yl)ethyl)carbamate (200 mg, 48% yield) as a white solid. LCMS (ESI, m / z): 431.25 [M + H] + .

[0257] Step B A solution of tert - butyl (2 - (4 - (4 - ((2,6 - dioxopiperidin - 3 - yl)amino)phenyl)piperidin - 1 - yl)ethyl)carbamate (200 mg, 0.465 mmol, 1.0 eq) in HCl (11 mL, 4M) in 1,4 - dioxane was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give 3 - ((4 - (1 - (2 - aminoethyl)piperidin - 4 - yl)phenyl)amino)piperidine - 2,6 - dione hydrochloride (240 mg) as a crude white solid. The crude product was used without further purification. LCMS (ESI, m / z): 331.25 [M + H]+ .

[0258] Intermediate A5-a was synthesized in accordance with the procedure described for the synthesis of 3-((4-(1-(2-aminoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0259]

Table 9

[0260] Intermediate A6: Synthesis of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0261]

Chemical formula

[0262] To a solution of pomalidomide (1.0 g, 3.7 mmol, 1.0 equivalent) in THF (20 mL) was added bromoacetyl chloride (1.44 g, 9.15 mmol, 2.5 equivalents) at 0 °C. The resulting mixture was stirred at 70 °C for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was dissolved in diethyl ether and then 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%) as a yellow solid. LCMS (ESI, m / z): 412.95 [M+H] + .

[0263] Intermediate A6-a was synthesized in accordance with the procedure described for the synthesis of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0264]

Table 10

[0265] Intermediate A7: Synthesis of 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0266]

Chemical formula

[0267] Step A 1-[4-(Piperidin-4-yl)phenyl]-1,3-diazinan-2,4-dione (85 mg, 0.31 mmol, 1.0 eq), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (130 mg, 0.47 mmol, 1.5 eq) and DIEA (120 mg, 0.93 mmol, 3.0 eq) in NMP (5 mL) were 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 Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (10 mmol / L NH4HCO3), gradient of 5% - 95% over 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] + 。

[0268] Step B 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 eq) and TFA (1 mL) in DCM (1 mL) was stirred for 50 min. The mixture was concentrated under vacuum to give 1-(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (28 mg) as a yellow crude solid, which was used directly in the next step without further purification. LCMS (ESI, m / z): 371.10 [M+H] + 。

[0269] Synthesis of Intermediate A8: 3-(2-oxo-3-(4-(piperidin-4-yl)phenyl)imidazolidin-1-yl)piperidine-2,6-dione hydrochloride

[0270]

Chem.

[0271] Project A To a solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.0 g, 7.2 mmol, 1.0 equiv) in DCM (10 mL) was added 1-chloro-2-isocyanatoethane (916 mg, 8.68 mmol, 1.2 equiv) portionwise at 0 °C. The solution was stirred at 0 °C for 1 h and then concentrated in vacuo to give tert-butyl 4-(4-(3-(2-chloroethyl)ureido)phenyl)piperidine-1-carboxylate (2.9 g, 99% yield) as a white solid. This product was used in the next step without further purification. LCMS (ESI, m / z): 326.25 [M+H-t-Bu] + 。

[0272] Project B To a solution of tert-butyl 4-(4-(3-(2-chloroethyl)ureido)phenyl)piperidine-1-carboxylate (2.9 g, 7.6 mmol, 1.0 equiv) in THF (10 mL) was added NaH (220 mg, 9.19 mmol, 1.2 equiv, 60% dispersion in oil) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. Then, after completion, water was added and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated in vacuo to give tert-butyl 4-(4-(2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (2.74 g, 93% yield) as a white solid. LCMS (ESI, m / z): 346.10 [M+H] + 。

[0273] Project C tert-Butyl 4-(4-(2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (500 mg, 1.5 mmol, 1.0 eq), 2,6-bis(benzyloxy)-3-bromopyridine (536 mg, 1.45 mmol, 1.0 eq), (1R,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (206 mg, 1.45 mmol, 1.0 eq), K3PO4 (922 mg, 4.34 mmol, 3.0 eq) and CuI (28 mg, 0.14 mmol, 0.10 eq) in toluene (10 mL) were stirred at 120 °C for 4 h. The solution was concentrated under vacuum and applied to a silica gel column eluting with ethyl acetate / petroleum ether (20:80) to give tert-butyl 4-(4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (720 mg, 63%) as a white solid. LCMS (ESI, m / z): 635.25 [M+H] + 。

[0274] Step D A solution of tert-butyl 4-(4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (600 mg, 0.95 mmol, 1.0 eq) and Pd / C (503 mg, 4.72 mmol, 5.0 eq) in ethyl acetate (10 mL) was stirred under a hydrogen atmosphere for 15 min. The resulting mixture was filtered and the filter cake was washed with DCM (3×200 mL). The filtrate was concentrated under vacuum to give tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (360 mg, 75%) as a brown solid. LCMS (ESI, m / z): 457.10 [M+H] + 。

[0275] Step E A solution of tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxoimidazolidin-1-yl)phenyl)piperidine-1-carboxylate (340 mg, 0.745 mmol, 1.0 eq) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 30 minutes. The resulting mixture was concentrated under vacuum to give 3-(2-oxo-3-(4-(piperidin-4-yl)phenyl)imidazolidin-1-yl)piperidine-2,6-dione hydrochloride (380 mg) as a brown crude solid, which was used without further purification. LCMS (ESI, m / z): 357.30 [M+H] + 。

[0276] Intermediate A9: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0277]

Chemical Structure

[0278] Step A To a stirred solution of 3-bromopiperidine-2,6-dione (5.0 g, 26.0 mmol, 1.0 eq), PPh3 (10.3 g, 39.1 mmol, 1.5 eq) and (4-methoxyphenyl)methanol (5.40 g, 39.1 mmol, 1.5 eq) in THF (50 mL) was added DEAD (6.80 g, 39.1 mmol, 1.5 eq) at 0 °C. The resulting solution was stirred at room temperature for 4 hours. After concentration, the residue was purified by silica gel column eluting with PE / EA (1:1) to give 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (7.3 g, 90% yield) as a yellow solid.

[0279] Step B A solution of 7-bromo-1-methyl-3H-1,3-benzodiazol-2-one (1.0 g, 4.4 mmol, 1 equiv) in ACN (8 mL) was treated with Cs2CO3 (4.30 g, 13.2 mmol, 3.0 equiv) at 0 °C for 5 min, and then 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (1.65 g, 5.29 mmol, 1.2 equiv) was added dropwise at 0 °C. The resulting solution was stirred at room temperature for 15 h. After concentration, the residue was purified by silica gel column eluting with PE / EA (1:1) to give 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (900 mg, 45% yield) as a white solid. LCMS (ESI, m / z): 458.15 [M+H] + 。

[0280] Step C A solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1.16 g, 2.53 mmol, 1.0 equiv) in methanesulfonic acid (4 mL) and toluene (8 mL) was stirred at 120 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding ice water (20 mL). The precipitated solid was collected by filtration and washed with water. The crude product was purified by silica gel chromatography eluting with PE / EA (1:3) to give 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (800 mg, 93% yield) as a gray solid. LCMS (ESI, m / z): 337.80 [M+H] + 。

[0281] Intermediate A9-a was synthesized in accordance with the procedure described for the synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0282]

Table 11

[0283] Intermediate A10: Synthesis of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0284]

Chemical formula

[0285] A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.55 mmol, 1 equiv), piperidin-4-ylmethanol (178 mg, 1.55 mmol, 1 equiv), Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (67 mg, 0.077 mmol, 0.05 equiv), and Cs2CO3 (1008 mg, 3.09 mmol, 2 equiv) in dioxane (5 mL) was stirred at 100 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (240 mg, 43%) as a yellow solid. LCMS (ESI, m / z): 358.25 [M+H] + 。

[0286] Intermediate A11: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one

[0287]

Chem.

[0288] A solution of piperidin-4-one hydrochloride (6.0 g, 44 mmol, 1 equiv), 1,2-difluoro-4-nitrobenzene (7.04 g, 44.3 mmol, 1 equiv) and TEA (13.4 g, 133 mmol, 3 equiv) in DMF (40 mL) was stirred at 80 °C overnight. The product was precipitated by adding water. The precipitated solid was collected by filtration and washed with water (3 × 80 mL), and 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (9 g, 85%) was obtained as a yellow solid. LCMS (ESI, m / z): 239.10 [M+H] + 。

[0289] Intermediate A12: Synthesis of 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride

[0290]

Chem.

[0291] Step A To a stirred solution of 6-bromobenzo[cd]indol-2(1H)-one (2.0 g, 8.1 mmol, 1 equiv) and THF (150 mL) at 0 °C was added portionwise NaH (1.61 g, 40.3 mmol, 5 equiv, 60% dispersion in oil). The mixture was stirred at room temperature for 1 h. A solution of 3-bromopiperidine-2,6-dione (3.87 g, 20.2 mmol, 2.5 equiv) in THF (10 mL) was added dropwise at 0 °C. The mixture was stirred at 60 °C overnight. The reaction was quenched by slowly adding saturated aqueous NH4Cl (80 mL) at 0 °C. The mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Trituration of the residue with DCM (10 mL) afforded 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (940 mg, 33%) as a yellow to green solid. LCMS (ESI, m / z): 359.18 [M+H] + .

[0292] Step B 3-(6-Bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (400 mg, 1.11 mmol, 1 equiv), tert-butyl piperazine-1-carboxylate (311 mg, 1.67 mmol, 1.5 equiv), Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (94 mg, 0.111 mmol, 0.1 equiv) and Cs2CO3 (544 mg, 1.67 mmol, 1.5 equiv) in dioxane (10 mL) were stirred at 100 °C overnight under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (361 mg, 70%) as a yellow solid. LCMS (ESI, m / z): 465.52 [M+H] + 。

[0293] Step C tert-Butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperazine-1-carboxylate (341 mg, 0.73 mmol, 1 equiv) and HCl in 1,4-dioxane (10 mL, 4 M) were stirred for 30 minutes. The mixture was concentrated to give 3-(2-oxo-6-(piperazin-1-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride (335 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 365.41 [M+H] + 。

[0294] Intermediate A13: Synthesis of 1-(3-Fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0295]

Chemical Structure

[0296] Project A A solution of 1-(4-bromo-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.74 mmol, 1 equiv), 1,4-dioxo-8-azaspiro[4.5]decane (374 mg, 2.61 mmol, 1.5 equiv), Cs2CO3 (1135 mg, 3.48 mmol, 2 equiv) and Pd-PEPPSI-IPentCl2-methylpyridine o-picoline (147 mg, 0.174 mmol, 0.1 equiv) in dioxane (8 mL) was stirred at 85 °C for 1 h under a nitrogen atmosphere. 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-dioxo-8-azaspiro[4.5]decane-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (520 mg, 85%) as a white solid. LCMS (ESI, m / z): 350.35 [M+H] + 。

[0297] Project B A solution of 1-(3-fluoro-4-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (510 mg, 1.46 mmol, 1 equiv) and HCl (10 mL, 6M) in THF (10 mL) was stirred overnight. The mixture was neutralized to pH 7 with saturated aqueous NaHCO3. The mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (460 mg) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 306.15 [M+H] + 。

[0298] Synthesis of Intermediate A14: 3-((3-Fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione.

[0299] [Chemical Formula]

[0300] Step A A solution of tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (2.0 g, 7.4 mmol, 1 equiv), 1,2-difluoro-4-nitrobenzene (1.18 g, 7.42 mmol, 1 equiv), and TEA (2.25 g, 22.3 mmol, 3 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 PE / EtOAc (5:1) to give tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.2 g, 72%) as a brown solid. LCMS (ESI, m / z): 409.30 [M+H] + .

[0301] Step B A solution of tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.2 g, 5.39 mmol, 1 equiv), NH4Cl (0.86 g, 16 mmol, 3 equiv), and Fe (1.50 g, 26.9 mmol, 5 equiv) in EtOH (50 mL) and water (10 mL) was stirred at 80 °C for 1 h. The mixture was concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (1:4) to give tert-butyl 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.9 g, 99%) as a brown solid. LCMS (ESI, m / z): 379.30 [M+H] + .

[0302] Step C tert-Butyl 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.9 g, 5.02 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (4.82 g, 25.1 mmol, 5 equiv) and NaHCO3 (2.11 g, 25.1 mmol, 5 equiv) in ACN (50 mL) were stirred at 90 °C overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (2:3) to give tert-butyl 4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.7 g, 69%) as a brown solid. LCMS (ESI, m / z): 490.25 [M+H] + 。

[0303] Step D A solution of tert-butyl 4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.7 g, 3.5 mmol, 1 equiv) in HCl (30 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to give 3-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (2.2 g) as a brown solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 390.20 [M+H] + 。

[0304] Intermediate A15: Synthesis of 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0305]

Chemical formula

[0306] Step A A solution of 6-bromo-1-methyl-1H-indazol-3-amine (30 g, 132 mmol, 1 equiv), acrylic acid (14.3 g, 199 mmol, 1.5 equiv) and TBAB (4.28 g, 13.3 mmol, 0.1 equiv) in 2M HCl (1.2 L) was stirred at 100 °C overnight. The mixture was neutralized to pH 7 with aqueous NaOH (4M). The precipitated solid was collected by filtration and washed with water (3 × 100 mL). Drying the obtained solid under infrared light gave 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (35.9 g, 77%) as a grey solid. LCMS (ESI, m / z): 300.10 [M+H] + 。

[0307] Step B A solution of 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid (10 g, 34 mmol, 1 equiv) in AcOH (150 mL) was treated with sodium cyanate (6.54 g, 101 mmol, 3 equiv) at 80 °C for 12 h, then HCl (150 mL, 4M) was added dropwise at room temperature. The solution was then stirred at 80 °C overnight. The precipitated solid was collected by filtration and washed with water (3 × 30 mL). Drying the obtained solid under infrared light gave 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (4.28 g, 40%) as a white solid. LCMS (ESI, m / z): 325.00 [M+H] + 。

[0308] Step C 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 3.7 mmol, 1 equiv), piperidin-4-one (0.55 g, 5.6 mmol, 1.5 equiv), Cs2CO3 (3.63 g, 11.1 mmol, 3 equiv) and Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (0.31 g, 0.37 mmol, 0.1 equiv) in dioxane (8 mL) were stirred at 85 °C overnight. After concentration, the residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give 1-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (480 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 342.10 [M+H] + 。

[0309] Intermediate A16: Synthesis of 3-((4-([4,4'-bipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione hydrochloride

[0310]

Chemical formula

[0311] Step A A mixture of tert-butyl [4,4'-bipiperidin]-1-carboxylate (2.0 g, 7.5 mmol, 1 equiv), 1,2-difluoro-4-nitrobenzene (1.78 g, 11.2 mmol, 1.5 equiv) and NaHCO3 (2.50 g, 29.8 mmol, 4 equiv) in ACN (5 mL) was stirred at 90 °C for 4 h. After concentration, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give tert-butyl 1'-(2-fluoro-4-nitrophenyl)-[4,4'-bipiperidin]-1-carboxylate (2.7 g, 89%) as a yellow solid. LCMS (ESI, m / z): 408.35 [M+H] + 。

[0312] Project B A mixture of tert-butyl 1'-(2-fluoro-4-nitrophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.7 g, 6.6 mmol, 1 equiv), Fe (1.85 g, 33.1 mmol, 5 equiv), and NH4Cl (0.71 g, 13 mmol, 2 equiv) in EtOH (4 mL) and water (1 mL) was stirred at 80 °C for 4 h. After concentration, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:7) to give tert-butyl 1'-(4-amino-2-fluorophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.34 g, 94%) as a yellow solid. LCMS (ESI, m / z): 378.15 [M+H] + 。

[0313] Project C A mixture of tert-butyl 1'-(4-amino-2-fluorophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.3 g, 6.09 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (3.51 g, 18.3 mmol, 3 equiv), and NaHCO3 (2.56 g, 30.5 mmol, 5 equiv) in ACN (6 mL) was stirred at 90 °C overnight. After concentration, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl 1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.6 g, 87%) as a green solid. LCMS (ESI, m / z): 487.25 [M-H] - 。

[0314] Project D A mixture of tert-butyl 1'-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-[4,4'-bipiperidine]-1-carboxylate (2.6 g, 5.3 mmol, 1 equiv) in HCl (8 mL, 4 M) in 1,4-dioxane was stirred for 3 h. Concentration of this mixture gave 3-((4-([4,4'-bipiperidine]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione hydrochloride (2.8 g) as a white solid. This product was used in the next step without further purification. LCMS (ESI, m / z): 389.20 [M+H] + 。

[0315] Intermediate A17: Synthesis of 1-(8-(piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0316]

Chemical Structure

[0317] Step A A solution of 8-bromoisoquinoline (5 g, 24.0 mmol, 1 equiv), I2 (12.2 g, 48.1 mmol, 2 equiv) and TBHP (6.50 g, 72.1 mmol, 3 equiv, 70% aqueous) in DCE (50 mL) was stirred at 120 °C overnight. At room temperature, the reaction was quenched with aqueous sodium sulfite. The aqueous layer was extracted with DCM (3 × 20 mL). Concentration of the resulting mixture under reduced pressure gave 8-bromo-4-iodoisoquinoline (5.3 g, 66%) as a red solid. LCMS (ESI, m / z): 333.80 [M+H] + 。

[0318] Step B 8-Bromo-4-iodoisoquinoline (1 g, 3.0 mmol, 1 equiv), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.91 g, 3.89 mmol, 1.3 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.21 g, 1.50 mmol, 0.5 equiv), Cs2CO3 (1.95 g, 6.0 mmol, 2 equiv) and CuI (0.23 g, 1.20 mmol, 0.4 equiv) in dioxane (6 mL) were stirred at 65 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (45:55) to afford 1-(8-bromoisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (730 mg, 55%) as a yellow solid. LCMS (ESI, m / z): 440.05 [M+H] + 。

[0319] Step C A solution of 1-(8-bromoisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.6 g, 3.63 mmol, 1 equiv) in TFA (5 mL) and TfOH (1 mL) was stirred for 4 h. The residue was diluted with EtOAc (4 mL) and then basified to pH 8 using TEA. The precipitated solid was collected by filtration and washed with water (3 × 5 mL). This afforded 1-(8-bromoisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.5 g) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 320.00 [M+H] + 。

[0320] Step D 1-(8-Bromoisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.56 mmol, 1 equiv), tert-butyl piperazine-1-carboxylate (436 mg, 2.34 mmol, 1.5 equiv), Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (131 mg, 0.16 mmol, 0.1 equiv) and Cs2CO3 (1018 mg, 3.12 mmol, 2 equiv) in dioxane (4 mL) were stirred at 85 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / EtOH (92:8) to afford tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-8-yl)piperazine-1-carboxylate (377 mg, 57%) as a yellow solid. LCMS (ESI, m / z): 426.21 [M+H] + 。

[0321] Step E A solution of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-8-yl)piperazine-1-carboxylate (367 mg, 0.86 mmol, 1 equiv) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to dryness to afford 1-(8-(piperazin-1-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 326.15 [M+H] + 。

[0322] Intermediate B1: Synthesis of 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid

[0323]

Chemical Structure

[0324] Project A A solution of tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (5.0 g, 10.5 mmol, 1.0 equiv) in HCl (60 mL, 4 M) in 1,4-dioxane was stirred at 40 °C for 2 h. The resulting mixture was concentrated under vacuum. The mixture was diluted with ethyl acetate (60 mL), and the precipitated solid was collected by filtration to give the HCl salt of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (5.0 g) as a gray solid. The crude product mixture was used directly without further purification. LCMS (ESI, m / z): 377.15 [M+H] + 。

[0325] Project B A solution of the hydrochloride salt of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (4.28 g, 11.4 mmol, 1.0 equiv), tert-butyl 2-bromoacetate (1.69 g, 8.65 mmol, 0.76 equiv), and K2CO3 (6.28 g, 45.5 mmol, 4.0 equiv) in DMF (45 mL) was stirred at 70 °C for 3 h. The resulting mixture was diluted with brine (30 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Trituration with EtOAc (20 mL) was used to purify the crude product to give tert-butyl 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (2.6 g, 47%) as an off-white solid. LCMS (ESI, m / z): 491.15 [M+H] + 。

[0326] Project C A solution of tert-butyl 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (2.6 g, 5.3 mmol, 1.0 eq) in trifluoroacetic acid (20 mL) and DCM (40 mL) was stirred for 16 h. The resulting mixture was concentrated under vacuum and then diluted with DCM (20 mL) and water (20 mL). This mixture was neutralized to pH 6.0 with saturated aqueous Na2CO3. The resulting mixture was concentrated under vacuum to remove DCM. The precipitated solid was collected by filtration to give 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid (1.4 g, 61%) as a white solid. LCMS (ESI, m / z): 435.10 [M+H] + 。

[0327] Intermediate B2: Synthesis of 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid

[0328]

Chemical Structure

[0329] Step A A solution of NaOH (0.37 g, 9.2 mmol, 3.0 equiv) in water (10 mL) was added to 2-(chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (1.0 g, 3.0 mmol, 1.0 equiv) and tert-butyl 4-mercaptopiperidine-1-carboxylate (0.80 g, 3.7 mmol, 1.2 equiv) at room temperature. The solution was stirred for 4 h and then acidified to pH 6 with aqueous HCl. The precipitated solid was collected by filtration and washed with water (3 × 10 mL) to give tert-butyl 4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1.47 g, 95% yield) as a white solid. LCMS (ESI, m / z): 508.30 [M+H] + .

[0330] Step B A solution of tert-butyl 4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1.46 g, 2.88 mmol, 1.0 equiv) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to give the HCl salt of 5-fluoro-2-((piperidin-4-ylthio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (1.52 g) as a white crude solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 408.19 [M+H] + .

[0331] Step C 5-Fluoro-2-((piperidin-4-ylthio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.51 g, 3.40 mmol, 1.0 eq), K2CO3 (0.94 g, 6.8 mmol, 2.0 eq) and tert-butyl 2-bromoacetate (0.66 g, 3.4 mmol, 1.0 eq) in ACN (20 mL) were stirred at 70 °C for 16 h. The organics were removed under vacuum. The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The obtained solid was dried in an oven to give tert-butyl 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (1.1 g, 62% yield) as a white solid. LCMS (ESI, m / z): 522.25 [M+H] + .

[0332] Step D tert-Butyl 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetate (1.15 g, 2.20 mmol, 1.0 eq) and TFA (1 mL) in DCM (5 mL) were stirred at room temperature for 16 h. The obtained mixture was concentrated under vacuum to give 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid (15.8 g) as a brown crude oil. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 466.20 [M+H] + .

[0333] Intermediate B3 was synthesized in accordance with the procedure described for the synthesis of 2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0334]

Table 12

[0335] Synthesis of Intermediate B4: 2-(4-(2-(7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetic acid

[0336]

Chem.

[0337] Step A To a solution of methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (2.0 g, 6.2 mmol, 1.0 eq) in MeOH (18 mL) was added a solution of KOH (3.46 g, 61.7 mmol, 10.0 eq) in water (6 mL). The resulting mixture was stirred at 40 °C overnight and then concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluting with MeOH / DCM (1:9) gave 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid (1.12 g, 59% yield) as a yellow solid. LCMS (ESI, m / z): 311.15 [M+H] + 。

[0338] Step B A solution of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid (580 mg, 1.87 mmol, 1.0 equiv) and NH4Cl (200 mg, 3.74 mmol, 2.0 equiv) in DMF (4 mL) was added DIEA (725 mg, 5.61 mmol, 3.0 equiv) and HATU (1066 mg, 2.804 mmol, 1.5 equiv) portionwise at room temperature. The resulting mixture was stirred for 1 h and then purified directly by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (10 mmol / L NH4HCO3), 10% - 50% gradient over 10 min; detector: UV254 nm), to give 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzamide (428 mg, 72% yield) as a yellow solid. LCMS (ESI, m / z): 310.15 [M+H] + .

[0339] Step C A stirred solution of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzamide (569 mg, 1.84 mmol, 1.0 equiv) and tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (882 mg, 3.66 mmol, 2.0 equiv) in water (10 mL) was added FeCl3 (594 mg, 3.65 mmol, 2.0 equiv) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 1 h and then the solution was cooled to room temperature and the pH was adjusted to pH 7 with saturated aqueous NaHCO3. The resulting mixture was filtered and the filter cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (4:1) to give crude 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (529 mg) as a yellowish brown oil. LCMS (ESI, m / z): 431.25 [M+H] + .

[0340] Project D A solution of 7 - ((1 - acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2-(2-(piperidin - 4 - yl)ethyl)quinazolin - 4(3H)-one (339 mg, 0.787 mmol, 1.0 eq), DIEA (305 mg, 2.36 mmol, 3.0 eq) and tert - butyl 2 - bromoacetate (461 mg, 2.36 mmol, 3.0 eq) in NMP (3 mL) was stirred at room temperature for 2 h. This solution was purified directly by reverse - phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% - 50% gradient in 10 min; detector: UV254 nm), to give tert - butyl 2-(4-(2-(7 - ((1 - acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)ethyl)piperidin - 1 - yl)acetate (240 mg, 51% yield) as a colorless oil. LCMS (ESI, m / z): 545.30[M + H] + 。

[0341] Project E A solution of tert - butyl 2-(4-(2-(7 - ((1 - acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)ethyl)piperidin - 1 - yl)acetate (224 mg, 0.411 mmol, 1.0 eq) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give 2-(4-(2-(7 - ((1 - acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)ethyl)piperidin - 1 - yl)acetic acid as a colorless oil. The crude product was used without further purification. LCMS (ESI, m / z): 489.30[M + H] + 。

[0342] Synthesis of Intermediate B5: 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((1-(prop-2-yn-1-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[0343]

Chem.

[0344] A solution of 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (500 mg, 1.03 mmol, 1.0 eq), DIEA (400 mg, 3.09 mmol, 3.0 eq) and 3-bromoprop-1-yne (172 mg, 1.44 mmol, 1.4 eq) in DMSO (2 mL) was stirred at room temperature for 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 0% - 35% gradient in 20 minutes; detector, UV 254 nm), and 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((1-(prop-2-yn-1-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (200 mg, 40% yield) was obtained as a white solid. LCMS (ESI, m / z): 487.20 [M+H] + 。

[0345] Synthesis of Intermediate B6: 7-(Cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[0346]

Chem.

[0347] Step A 2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (3 g, 10.6 mmol, 1.0 eq), tert-butyl 4-(acetylthio)piperidine-1-carboxylate (2.78 g, 10.7 mmol, 1.01 eq) and NaOH (1.27 g, 31.8 mmol, 3.0 eq) in H2O (30 mL) were stirred at room temperature for 1.5 h. The mixture was acidified to pH 3 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3 × 5 mL). Drying the solid under infrared light gave the title compound (4.8 g, 97% yield) as a white solid. LCMS (ESI, m / z): 464.19 [M+H] + 。

[0348] Step B tert-Butyl 4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (2.5 g, 5.4 mmol, 1.0 eq) and HCl (10 mL, 4 M) in 1,4-dioxane were stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the title compound (2.09 g, 97% yield) as a white solid. LCMS (ESI, m / z): 364.14 [M+H] + 。

[0349] Synthesis of Intermediate B7: 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

[0350]

Chem.

[0351] Step A A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (230 mg, 0.63 mmol, 1 equiv) in NMP (5 mL) was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (167 mg, 0.70 mmol, 1.1 equiv) and DIEA (245 mg, 1.90 mmol, 3 equiv), and then stirred at 80 °C overnight. Water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 72% over 20 min; detector, UV 254 nm to give 2-(((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (97 mg, 29%) as a brown solid. LCMS (ESI, m / z): 522.25 [M+H] + 。

[0352] Step B A solution of 2-(((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (97 mg, 0.19 mmol, 1 equiv) was treated with HCl (15 mL, 4 M) in 1,4-dioxane for 3 h. The resulting mixture was concentrated to dryness to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (118 mg) as a brown solid, which was used directly in the next step without further purification. LCMS (ESI, m / z): 408.15 [M+H] + 。

[0353] Step C A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (100 mg, 0.25 mmol, 1 equiv) in DCM (2 mL) was treated with 3-nitrobenzenesulfonyl chloride (54 mg, 0.25 mmol, 1 equiv) and TEA (75 mg, 0.74 mmol, 3 equiv) and stirred for 2 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (1 / 9) to give 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (30 mg, 29%) as a yellow solid. LCMS (ESI, m / z): 426.15 [M+H] + 。

[0354] Intermediate B8: Synthesis of 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[0355]

Chemical Structure

[0356] 5-Fluoro-7-(oxan-4-ylmethoxy)-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (500 mg, 1.23 mmol, 1 equiv), chloroacetaldehyde (239 mg, 1.23 mmol, 1 equiv, 40 wt%) in water and STAB (520 mg, 2.45 mmol, 2 equiv) in DCM (5 mL) were stirred for 1 h. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (200 mg, 35%) as a white solid. LCMS (ESI, m / z): 470.20 [M+H] + 。

[0357] Intermediate B9: Synthesis of 2-(((1-(azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride

[0358]

Chem.

[0359] Step A 5-Fluoro-2-((piperidin-4-ylthio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (2.0 g, 4.9 mmol, 1 equiv), tert-butyl 3-oxoazetidine-1-carboxylate (1.54 g, 9.01 mmol, 2 equiv) and STAB (1.91 g, 9.01 mmol, 2 equiv) in DCM (7 mL) were stirred for 3 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (97:3) to afford tert-butyl 3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidine-1-carboxylate (1.17 g, 46%) as a yellow solid. LCMS (ESI, m / z): 563.26 [M+H] + .

[0360] Step B A solution of tert-butyl 3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidine-1-carboxylate (1.17 g, 2.08 mmol, 1 equiv) in HCl (7 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The mixture was concentrated to dryness to afford 2-(((1-(azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.06 g) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 463.21 [M+H] + .

[0361] Intermediates B9-a to B9-c were synthesized in accordance with the procedures described for the synthesis of 2-(((1-(azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride using appropriate components and reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions modified as necessary.

[0362]

Table 13

[0363] Intermediate B10: Synthesis of 2-(((1-(2-chloroethyl)piperidin-4-yl)oxy)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[0364]

Chemical formula

[0365] Step A 2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (2.0 g, 6.1 mmol, 1 eq), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.97 g, 9.79 mmol, 1.6 eq) and t-BuOK (2.06 g, 18.4 mmol, 3 eq) in DMA (10 mL) were stirred at 40 °C for 5 h. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 50% in 25 min; detector, UV 254 nm to give tert-butyl 4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidine-1-carboxylate (2 g, 59%) as a pale pink solid. LCMS (ESI, m / z): 492.10 [M+H] + 。

[0366] Step B A solution of tert-butyl 4-((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidine-1-carboxylate (1.99 g, 4.05 mmol, 1 eq) in HCl (20 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated under vacuum to give 5-fluoro-2-((piperidin-4-yloxy)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (2 g) as a light brown solid, which was used directly in the next step without further purification. LCMS (ESI, m / z): 392.15 [M+H] + 。

[0367] Step C 5-Fluoro-2-((piperidin-4-yloxy)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (500 mg, 1.28 mmol, 1 equiv), 2-chloroacetaldehyde (501 mg, 2.55 mmol, 2.0 equiv, 40 wt%) and STAB (541 mg, 2.55 mmol, 2 equiv) in DCE (2 mL) were stirred for 1 h. The mixture was purified by silica gel column chromatography eluting with DCM / MeOH (12:1) to give 2-(((1-(2-chloroethyl)piperidin-4-yl)oxy)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (180 mg, 31%) as a white solid. LCMS (ESI, m / z): 454.25 [M+H] + 。

[0368] Intermediate B11: Synthesis of 2-(2-chloroethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

[0369]

Chem.

[0370] A solution of methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate (300 mg, 1.2 mmol, 1 equiv) and acrylonitrile (332 mg, 6.27 mmol, 5 equiv) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 2-(2-chloroethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (250 mg, 67%) as a brown oil. LCMS (ESI, m / z): 297.10 [M+H] + 。

[0371] Synthesis of Intermediate B12: 2-(2-([1,4'-Bipiperidin]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride

[0372]

Chem.

[0373] Step A A solution of methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate (2 g, 8.36 mmol, 1 equiv) and KOH (3.75 g, 66.9 mmol, 8 equiv) in MeOH (40 mL) and water (10 mL) was stirred at 60 °C overnight. The mixture was concentrated and then acidified to pH 4 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (3 × 100 mL) to give 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoic acid (1.8 g, 96%) as a pale yellow solid. LCMS (ESI, m / z): 226.0 [M+H] + 。

[0374] Step B A solution of 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoic acid (1.8 g, 7.99 mmol, 1 equiv), NH4Cl (0.43 g, 7.99 mmol, 1 equiv), DIEA (4.13 g, 32.0 mmol, 4 equiv) and HATU (4.56 g, 12.0 mmol, 1.5 equiv) in DMF (10 mL) was stirred for 1 h. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min; detector, UV254 nm. This gave 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzamide (1.5 g, 84%) as a white solid. LCMS (ESI, m / z): 225.01 [M+H] + 。

[0375] Step C A solution of 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzamide (0.50 g, 2.23 mmol, 1 equiv), tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (1.08 g, 4.46 mmol, 2 equiv), and FeCl3·6H2O (1.21 g, 4.46 mmol, 2 equiv) in water (7 mL) was stirred at 100 °C for 1 h. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to afford the crude compound (300 mg) as a yellow solid. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 50% over 10 min; detector, UV 254 nm. This gave 7-(cyclopropylmethoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (155 mg, 20%) as a white solid. LCMS (ESI, m / z): 346.01 [M+H] + 。

[0376] Step D A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(2-(piperidin-4-yl)ethyl)quinazolin-4(3H)-one (135 mg, 0.391 mmol, 1 equiv), tert-butyl 4-oxopiperidine-1-carboxylate (156 mg, 0.782 mmol, 2 equiv), and STAB (166 mg, 0.782 mmol, 2 equiv) in DCE (13.5 mL) was stirred overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to afford tert-butyl 4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidine]-1'-carboxylate (80 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 529.3 [M+H] + 。

[0377] Step E tert-Butyl 4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidine]-1'-carboxylate (80 mg, 0.151 mmol, 1 equiv) and a solution of HCl (10 mL, 4 M) in 1,4-dioxane were stirred for 1 h. The mixture was concentrated to dryness to afford 2-(2-([1,4'-bipiperidine]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride (100 mg) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 429.16 [M+H] + .

[0378] [Example 1] Synthesis of 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0379] [[ID=,10]] [Chemical formula]

[0380] 2-(2,6-Dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (1.31 g, 3.00 mmol, 1.0 eq), 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetic acid (1.37 g, 3.15 mmol, 1.05 eq), HOBT (608 mg, 4.50 mmol, 1.5 eq), EDCI (863 mg, 4.50 mmol, 1.5 eq) and DIEA (1.55 g, 12.0 mmol, 4.0 eq) in DMF (12 mL) and DCM (9 mL) were stirred at 45 °C for 5 h. The resulting mixture was diluted with brine (100 mL) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by trituration with ethyl acetate (20 mL x 3), ethanol (20 mL x 3) and MeCN (20 mL x 3) to give 4-(4-((1-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.28 g, 50% yield) as a yellow solid. LCMS (ESI, m / z): 856.45 [M+H] +. 1H NMR (300 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.10 (s, 1H), 7.71 (t, J = 9.0 1H), 7.35 (t, J = 9.0 Hz, 2H), 6.84 (d, J = 6.5 Hz, 1H), 6.42 (dd, J = 13.9, 2.1 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 5.10 (dd, J = 12.7, 5.4 Hz, 1H), 4.31 (d, J = 12.8 Hz, 1H), 4.03 (d, J = 12.9 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.53 (s, 2H), 3.38 - 3.30 (m, 4H), 3.24 - 3.15 (m, 1H), 3.03 - 2.69 (m, 6H), 2.67 - 2.53 (m, 5H), 2.25 - 2.16 (m, 2H), 2.14 - 2.00 (m, 3H), 1.99 - 1.85 (m, 4H), 1.84 - 1.30 (m, 12H), 1.19 - 0.81 (m, 3H).

[0381] Examples 2 - 29 were synthesized in accordance with the procedures described for the synthesis of 4-(4-((1-(2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione using appropriate components and, where necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0382] [Table 14] TIFF2025525031000067.tif142168TIFF2025525031000068.tif118168TIFF2025525031000069.tif137168TIFF2025525031000070.tif170168TIFF2025525031000071.tif158168TIFF2025525031000072.tif103168TIFF2025525031000073.tif133168TIFF2025525031000074.tif229168TIFF2025525031000075.tif127168TIFF2025525031000076.tif166168TIFF2025525031000077.tif137168TIFF2025525031000078.tif137168TIFF2025525031000079.tif119168TIFF2025525031000080.tif137168TIFF2025525031000081.tif161168TIFF2025525031000082.tif214168TIFF2025525031000083.tif126168TIFF2025525031000084.tif113168TIFF2025525031000085.tif123168TIFF2025525031000086.tif221168TIFF2025525031000087.tif114168TIFF2025525031000088.tif129168TIFF2025525031000089.tif146168TIFF2025525031000090.tif142168

[0383] [Example 30] Synthesis of 5-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0384] [Chemical formula]

[0385] 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (200 mg, 0.45 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (123 mg, 0.45 mmol, 1.0 equiv) and DIEA (230 mg, 1.78 mmol, 4.0 equiv) in NMP (5 mL) were stirred at 120 °C for 12 h. The residue was purified directly by reverse-phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% - 70% gradient in 15 min; detector, UV 254 nm) to give 5-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (47 mg, 15%) as a green solid. LCMS (ES, m / z): 705.35 [M+H] + . 1 H NMR (300 MHz, methanol-d4) δ 7.66 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 6.96 - 6.90 (m, 1H), 6.84 (dd, J = 12.5, 2.4 Hz, 1H), 5.08 (dd, J = 12.3, 5.4 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 4.04 - 3.88 (m, 5H), 3.72 (d, J = 4.8 Hz, 1H), 3.26 - 3.04 (m, 4H), 2.97 - 2.63 (m, 4H), 2.21 - 2.01 (m, 7H), 2.00 - 1.81 (m, 2H), 1.77 - 1.56 (m, 2H), 1.47 - 1.20 (m, 3H).

[0386] [Example 31] Synthesis of 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0387] [Chemical Structure]

[0388] A solution of 7-[(1-acetylpiperidin-4-yl)methoxy]-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (100 mg, 0.223 mmol, 1.0 equiv), 2-bromo-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]acetamide (83 mg, 0.21 mmol, 0.95 equiv), and K2CO3 (62 mg, 0.45 mmol, 2.0 equiv) in DMF (2 mL) was stirred at 70 °C for 2 h. The residue was purified directly by reverse-phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 5% - 95% gradient over 25 min; detector, UV 254 nm), and further purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 17% - B 42% over 9 min, B 42%; wavelength: 254 / 220 nm; RT (min): 8.9), to give 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (12 mg, 7%) as a white solid. LCMS (ESI, m / z): 762.25 [M+H] +; 1 1H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 11.01 (s, 1H), 8.79 (d, J = 9.0 Hz, 1H), 8.22 (s, 1H), 7.85 (t, J = 9.0 Hz, 1H), 7.59 (d, J = 6.0 Hz, 1H), 6.95 - 6.82 (m, 2H), 5.22 - 5.10 (m, 1H), 4.39 (d, J = 12.0 Hz, 1H), 4.00 (d, J = 6.0 Hz, 2H), 3.91 - 3.71 (m, 2H), 3.62 (s, 2H), 3.21 (d, J = 9.0 Hz, 2H), 3.11 - 2.99 (m, 1H), 2.98 - 2.81 (m, 4H), 2.68 - 2.52 (m, 2H), 2.39 - 2.28 (m, 2H), 2.12 - 1.85 (m, 7H), 1.82 - 1.61 (m, 4H), 1.32 - 1.05 (m, 2H).

[0389] Example 32 was synthesized in accordance with the procedure described for the synthesis of 2-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide using appropriate components and, as necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0390] [Table 15]

[0391] [Example 33] Synthesis of 5-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0392]

Chem.

[0393] A solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-(hydroxymethyl)piperidin-1-yl]isoindole-1,3-dione (200 mg, 0.54 mmol, 1.0 eq) and Dess-Martin periodinane (251 mg, 0.59 mmol, 1.1 eq) in DCM (3 mL) was stirred for 2 h. To this mixture, 7-[(1-acetylpiperidin-4-yl)methoxy]-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (241 mg, 0.539 mmol, 1 eq) was added dropwise. The resulting mixture was stirred for 2 h, then NaBH(OAc)3 (5716 mg, 2.69 mmol, 5.0 eq) was added and then stirred for 16 h. The mixture was concentrated under vacuum and the residue was purified by reverse-phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% - 43% gradient in 25 min; detector, UV 254 nm). The crude product was further purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 15% - B 45% in 7 min, B 45%; wavelength: 254 / 220 nm; RT (min): 5.5), to give 5-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4.2 mg, 1%) as a yellow solid. LCMS (ES, m / z): 802.33 [M+H] + ; 11H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.06 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.93 - 6.82 (m, 2H), 5.11 - 5.05 (m, 1H), 4.38 (d, J = 12.7 Hz, 1H), 4.08 - 3.95 (m, 4H), 3.83 (d, J = 13.8 Hz, 1H), 3.58 (s, 2H), 3.05 - 2.74 (m, 6H), 2.59 - 2.51 (m, 1H), 2.09 - 1.69 (m, 17H), 1.51 - 1.48 (m, 2H), 1.29 - 1.05 (m, 5H).

[0394] [Example 34] Synthesis of 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0395] [Chemical Structure]

[0396] 7 - ((1 - acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - (((1 - (prop - 2 - yn - 1 - yl)piperidin - 4 - yl)thio)methyl)quinazolin - 4(3H)-one (200 mg, 0.41 mmol, 1.0 equiv), 5 - bromo - 2 - (2,6 - dioxopiperidin - 3 - yl)isoindoline - 1,3 - dione (139 mg, 0.41 mmol, 1.0 equiv), TEA (83 mg, 0.82 mmol, 2.0 equiv) and Pd(PPh3)2Cl2 (29 mg, 0.041 mmol, 0.10 equiv) in DMSO (2 mL) were stirred at 80 °C for 2 h. After concentration, the residue was purified by C18 reverse - phase chromatography eluting with water / CH3CN (56:44) and further purified by preparative HPLC under the following conditions: (column: XSelect CSH Fluoro Phenyl, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 28% - B 49% in 9.5 min; detector: 254 / 220 nm; RT (min): 8.55) to give 5 - (3 - (4 - (((7 - ((1 - acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)prop - 1 - yn - 1 - yl)-2 - (2,6 - dioxopiperidin - 3 - yl)isoindoline - 1,3 - dione (24 mg, 8% yield) as a white solid. LCMS (ESI, m / z): 743.30 [M + H] +; 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.15 (s, 1H), 7.89 - 7.75 (m, 2H), 7.88 (s, 1H), 6.89 (s, 1H), 6.87 (s, 1H), 5.17 (dd, J = 12.9, 5.6 Hz, 1H), 4.38 (d, J = 13.0 Hz, 1H), 3.97 (d, J = 6.5 Hz, 2H), 3.80 - 3.70 (m, 1H), 3.60 (d, J = 16.0 Hz, 4H), 3.01 - 2.89 (m, 1H), 2.84 - 2.68 (m, 4H), 2.61 - 2.54 (m, 2H), 2.28 - 2.19 (m, 2H), 2.01 - 1.75 (m, 8H), 1.76 - 1.59 (m, 2H), 1.54 - 1.30 (m, 2H), 1.22 - 1.10 (m, 2H).

[0397] Examples 35 to 38 were synthesized in accordance with the procedures described for the synthesis of 5-(3-(4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione using appropriate components and, as necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0398]

Table 16

[0399] [Example 39] Synthesis of 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0400] [Chemical formula]

[0401] Step A A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (5.0 g, 18 mmol, 1.0 equiv), piperidin-4-ylmethanol (2.50 g, 21.7 mmol, 1.2 equiv), and DIEA (7.02 g, 54.3 mmol, 3.0 equiv) in NMP (100 mL) was stirred at 120 °C for 4 hours. The resulting mixture was diluted with water and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluting with PE / EtOAc (2:3) gave 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (6.7 g, 99%) as a yellow oil. LCMS (ESI, m / z): 372.15 [M+H] + .

[0402] Step B A solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindole-1,3-dione (500 mg, 1.35 mmol, 1.0 equiv), p-toluenesulfonyl chloride (308 mg, 1.25 mmol, 1.2 equiv), TEA (409 mg, 4.04 mmol, 3.0 equiv) and DMAP (82 mg, 0.67 mmol, 0.5 equiv) in DCM (40 mL) was stirred for 16 h. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to afford (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (620 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 526.15 [M+H] + .

[0403] Step C (1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (100 mg, 0.19 mmol, 1.0 eq), 7-[(1-acetylpiperidin-4-yl)methoxy]-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (85 mg, 0.19 mmol, 1.0 eq), KI (16 mg, 0.095 mmol, 0.5 eq) and a solution of DIEA (74 mg, 0.57 mmol, 3.0 eq) in ACN (5 mL) were stirred at 60 °C for 1 h. The resulting mixture was concentrated under vacuum and the residue was purified by reverse-phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 5% - 95% gradient over 20 min; detector, UV 254 nm) and further purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 20% - B 45% over 9.5 min; detector: 254 / 220 nm; RT (min): 9.78), to give 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (17 mg, 11%) as a yellow solid. LCMS (ESI, m / z): 802.35 [M+H] + ; 11H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 11.05 (s, 1H), 7.56 (dd, J = 8.6, 6.9 Hz, 1H), 7.16 - 7.04 (m, 2H), 6.95 - 6.84 (m, 2H), 5.06 (dd, J = 12.6, 5.6 Hz, 1H), 4.40 (d, J = 13.0 Hz, 1H), 4.00 (d, J = 6.3 Hz, 2H), 3.84 (d, J = 13.4 Hz, 1H), 3.74 - 3.54 (m, 4H), 3.53 - 3.42 (m, 1H), 3.11 - 3.00 (m, 1H), 2.94 - 2.52 (m, 8H), 2.39 - 2.34 (m, 2H), 2.34 - 2.12 (m, 1H), 2.12 - 1.68 (m, 11H), 1.63 - 1.20 (m, 7H), 1.01 - 0.89 (m, 1H).

[0404] Example 40 was synthesized in accordance with the procedure described for the synthesis of 4-(4-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0405]

Table 17

[0406] [Example 41] Synthesis of 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0407] [Chemistry]

[0408] Project A A solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (160 mg, 0.49 mmol, 1.0 equiv), azetidin-3-ylmethanol hydrochloride (73 mg, 0.59 mmol, 1.2 equiv), Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (42 mg, 0.050 mmol, 0.1 equiv), and Cs2CO3 (323 mg, 0.99 mmol, 2.0 equiv) in dioxane (10 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase: MeCN in water, 5% - 20% gradient over 10 minutes; detector, UV 254 nm), to give 3-(4-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95 mg, 58%) as a white solid. LCMS (ESI, m / z): 330.15 [M+H] + .

[0409] Project B A stirred solution of 3-(4-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.27 mmol, 1.0 equiv), TEA (138 mg, 1.37 mmol, 5.0 equiv) and DMAP (17 mg, 0.14 mmol, 0.5 equiv) in DCM (25 mL) was treated portionwise with methanesulfonic anhydride (143 mg, 0.82 mmol, 3.0 equiv) at 0 °C and then stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN in water, 5% - 30% gradient over 10 min; detector, UV 254 nm) to afford (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)azetidin-3-yl)methyl methanesulfonate (78.2 mg, 70%) as a white solid. LCMS (ESI, m / z): 408.15 [M+H] + 。

[0410] Step C (1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)azetidin-3-yl)methyl methanesulfonate (61 mg, 0.15 mmol, 1.0 equiv), 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (67 mg, 0.15 mmol, 1.0 equiv), DIEA (96 mg, 0.75 mmol, 5.0 equiv) and KI (50 mg, 0.29 mmol, 2.0 equiv) in ACN (30 mL) were stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography eluting with water / CH3CN (67:33) and further purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35% - 40% B in 8 min, 40% B; wavelength: 254 nm; RT (min): 8) to give 3-(4-(3-((4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7 mg, 6%) as a white solid. LCMS (ESI, m / z): 760.30 [M+H] + . 11H NMR (300 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.95 (s, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.97 - 6.80 (m, 2H), 6.54 (d, J = 7.9 Hz, 1H), 5.08 (dd, J = 13.1, 5.2 Hz, 1H), 4.48 - 4.23 (m, 3H), 4.21 - 3.94 (m, 4H), 3.91 -3.80 (m, 1H), 3.79 - 3.46 (m, 5H), 2.92 - 2.72 (m, 4H), 2.67 - 2.59 (m, 1H), 2.58 - 2.54 (m, 2H), 2.10 - 1.82 (m, 8H), 1.82 - 1.71 (m, 2H), 1.47 - 1.36(m, 2H), 1.32 - 1.09 (m, 5H), 0.90 - 0.80 (m, 1H).

[0411] [Example 42] Synthesis of 3-((4-(4-(2-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0412] [Chemical formula]

[0413] A solution of 2-(((1-(2-chloroethyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (173 mg, 0.406 mmol, 1 equiv) in DMSO (5 mL) was treated with 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (117 mg, 0.406 mmol, 1 equiv) and DIEA (210 mg, 1.62 mmol, 4 equiv) at 80 °C for 3 h. The mixture was concentrated and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 41% over 20 min; detector, UV 254 nm. This gave the product (85 mg) as a brown solid. The product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 24% - B 34% over 10 min, then B 34%; wavelength: 220 / 254 nm; RT (min): 11.80) to give 3-((4-(4-(2-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (49.2 mg, 18%) as a brown solid. LCMS (ESI, m / z): 678.20 [M+H] +. 1H NMR (300 MHz, DMSO-d6) δ 12.02 (br, 1H), 10.77 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.74 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 8.5 Hz, 2H), 5.38 (d, J = 7.2 Hz, 1H), 4.25 - 4.15 (m, 1H), 3.96 (d, J = 7.1 Hz, 2H), 3.70 - 3.59 (m, 5H), 2.91 (s, 3H), 2.85 - 2.65 (m, 3H), 2.62 - 2.55 (m, 2H), 2.41 (s, ZH), 2.05 - 1.84 (m, 5H), 1.51 - 1.35 (m, 2H), 1.30 - 1.15 (m, 2H), 0.63 - 0.52 (m, 2H), 0.41 - 0.31 (m, 2H).

[0414] Examples 43 to 49 were synthesized according to the procedure described for the synthesis of 3 - ((4 - (4 - (2 - (4 - (((7 - (cyclopropylmethoxy) - 5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)ethyl)piperazin - 1 - yl)phenyl)amino)piperidine - 2,6 - dione (Example 42) using appropriate components and, where necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0415] [Table 18] TIFF2025525031000105.tif161162TIFF2025525031000106.tif122162TIFF2025525031000107.tif137162TIFF2025525031000108.tif141162TIFF2025525031000109.tif150162TIFF2025525031000110.tif152162

[0416] [Example 50] Synthesis of 3-(5-(4-((4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0417]

Chemical formula

[0418] A solution of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, 0.336 mmol, 1 equiv) and DMP (285 mg, 0.672 mmol, 2 equiv) in DCM (2 mL) was stirred at room temperature for 1 h. To the above mixture, at 0 °C, 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (123 mg, 0.338 mmol, 1 equiv) and NaBH3CN (42.4 mg, 0.68 mmol, 2 equiv) were added. The resulting mixture was stirred at room temperature for 1 h. This residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% - 45% gradient in 10 min; detector, UV 254 nm. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: B 55% - B 60% in 8 min, B 60%; wavelength: 254 nm; RT (min): 8), and 3-(5-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28.6 mg, 12%) was obtained as a white solid. LCMS (ESI, m / z): 703.30 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.93 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 15.7 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 - 4.19 (m, 2H), 3.96 (d, J = , 2H), 3.85 (d, J = 12.5 Hz, 2H), 3.60 (s, 2H), 2.93 - 2.68 (m, 6H), 2.64 - 2.54 (m, 2H), 2.40 - 2.32 (m, 1H), 2.11 (d, J = 6.6 Hz, 2H), 2.01 - 1.85 (m, 4H), 1.79 - 1.65 (m, 3H), 1.52 - 1.39 (m, 2H), 1.29 - 1.06 (m, 3H), 0.70 - 0.60 (d, J = 7.8 Hz, 2H), 0.38 - 0.27 (m, 2H).

[0419] [Example 51] Synthesis of 3-((3-Fluoro-4-(4-(3-(4-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione formate

[0420]

Chemical formula

[0421] Step A 2-(((1-(Azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride (1.04 g, 2.26 mmol, 1 eq), 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (0.75 g, 3.14 mmol, 1.5 eq), and STAB (0.89 g, 4.18 mmol, 2 eq) in DCM (8 mL) were stirred for 2 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (91:9) to give 5-fluoro-2-(((1-(1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (733 mg, 51%) as a yellow solid. LCMS (ESI, m / z): 685.29 [M+H] + .

[0422] Step B A solution of Fe (295 mg, 5.28 mmol, 5 eq) and NH4Cl (113 mg, 2.11 mmol, 2 eq) in EtOH (6 mL) and water (3 mL) was stirred at 80 °C for 10 min, then 5-fluoro-2-(((1-(1-(1-(2-fluorophenyl)-4-nitrophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (723 mg, 1.06 mmol, 1 eq) was added portionwise at 80 °C. The final reaction mixture was irradiated with microwave radiation at 80 °C for 30 min. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (91:9) to give 2-(((1-(1-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (669 mg, 97%) as a yellow solid. LCMS (ESI, m / z): 655.32 [M+H] + .

[0423] Step C 2-(((1-(1-(1-(4-Amino-2-fluorophenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one (200 mg, 0.305 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (176 mg, 0.915 mmol, 3 equiv) and NaHCO3 (180 mg, 2.14 mmol, 7 equiv) in ACN (4 mL) were stirred at 90 °C overnight. The mixture was concentrated and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% - 50% gradient over 20 min; detector, UV 254 nm to give the crude material as a white solid. The crude product was further purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B5% - B5% for 2 min, B9% - B19% for 10 min; wavelength: 254 nm / 220 nm) to give 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione formate (27.8 mg, 12%) as a white solid. LCMS (ESI, m / z): 766.25 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.22 (s, 2H), 6.93 - 6.79 (m, 3H), 6.50 (dd, J = 15.0, 2.6 Hz, 1H), 6.41 (dd, J = 8.7, 2.6 Hz, 1H), 5.79 (d, J = 7.6 Hz, 1H), 4.30 - 4.20 (m, 1H), 3.993 (d, J=6.4Hz, 2H), 3.92 - 3.83 (m, 2H), 3.66 - 3.50 (m, 4H), 3.40 - 3.28 (m, 2H), 3.11 - 3.01 (m, 3H), 2.95 - 2.80 (m, 2H), 2.79 - 2.70 (m, 1H), 2.68 - 2.58 (m, 3H), 2.57 - 2.54 (m, 1H), 2.51 - 2.50 (m, 3H), 2.40 - 2.30 (m, 1H), 2.11 - 1.63 (m, 10H), 1.50 - 1.30 (m, 6H).

[0424] Examples 52-53 were synthesized in accordance with the procedure described for the synthesis of 3-((3-fluoro-4-(4-(3-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione formate (Example 51) using appropriate components and, as necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0425]

Table 19

[0426] [Example 54] Synthesis of 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate

[0427]

Chem.

[0428] Step A A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (2 g, 5.50 mmol, 1 equiv) in DCE (100 mL) was treated with 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (1.97 g, 8.26 mmol, 1.5 equiv) for 3 h, then STAB (2.33 g, 11.0 mmol, 2 equiv) was added portionwise. The resulting mixture was stirred for 1 day. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (7:1) to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(2-fluoro-4-nitrophenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (1.4 g, 43%) as a yellow oil. LCMS (ESI, m / z): 586.35 [M+H] + 。

[0429] Step B A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1’-(2-fluoronitro-phenyl)-[1,4’-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (500 mg, 0.854 mmol, 1 equiv), 4,4’-bipyridine (13.3 mg, 0.085 mmol, 0.1 equiv) and B2(OH)4 (230 mg, 2.56 mmol, 3 equiv) in DMF (10 mL) was stirred for 30 min. Purification of the residue by silica gel column chromatography eluting with DCM / MeOH (5:1) gave 2-(((1’-(4-amino-2-fluorophenyl)-[1,4’-bipiperidin]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (300 mg, 63%) as a yellow solid. LCMS (ESI, m / z): 556.45 [M+H] + .

[0430] Step C 2-(((1’-(4-Amino-2-fluorophenyl)-[1,4’-bipiperidin]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (300 mg, 0.54 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (1037 mg, 5.4 mmol, 10 equiv) and NaHCO3 (453.5 mg, 5.4 mmol, 10 equiv) in ACN (30 mL) were stirred at 90 °C for 3 days. The resulting mixture was concentrated and the residue was purified by C18 reverse phase chromatography eluting with water / ACN (45:55) and further purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B5% to B5% in 2 min, B12% to B22% in 10 min; wavelength: 254 nm / 220 nm; RT (min): 9.6) to give 3-((4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4’-bipiperidin]-1’-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (63.4 mg, 17%) as a grey solid. LCMS (ESI, m / z): 667.25 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 10.76 (s, H), 8.18 (s, 1H), 6.93 - 6.76 (m, 3H), 6.50 (dd, J = 15.0, 2.6 Hz, 1H), 6.40 (dd, J = 8.8, 2.5 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 4.30 - 4.19 (m, 1H), 3.99 (d, J=6.8Hz, 2H), 3.65 (s, 2H), 3.15 (d, J = 10.9 Hz, 2H), 2.89 - 2.76 (m, 4H), 2.76 - 2.67 (m, 2H), 2.35 - 2.27 (m, 1H), 2.27 - 2.23 (m, 2H), 2.13 - 2.04 (m, 1H), 2.03 - 1.74 (m, 5H), 1.57 - 1.39 (m, 4H), 1.31 - 1.13 (m, 2H), 0.64 - 0.54 (m, 2H), 0.40 - 0.32 (m, 2H).

[0431] [Example 55] Synthesis of 3-((4-(4-(2-(((1r,4r)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0432] [Chemical Structure]

[0433] Step A 7-(Cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one (1000 mg, 2.64 mmol, 1 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (759 mg, 3.17 mmol, 1.2 equiv) and K2CO3 (1096 mg, 7.93 mmol, 3 equiv) in DMF (5 mL) were stirred at 80 °C for 3 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 90% in 30 min; detector, UV 254 nm. This gave 2-((((1r,4r)-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (870 mg, 61%) as a white solid. LCMS (ESI, m / z): 537.20 [M+H] + .

[0434] Step B A solution of 2-((((1r,4r)-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (820 mg, 1.53 mmol, 1 equiv) in HCl (10 mL, 4 M) in 1,4-dioxane was stirred for 30 min. The resulting mixture was concentrated under vacuum to give crude 7-(cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one (990 mg) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI, m / z): 423.50 [M+H] + .

[0435] Step C A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one (990 mg, 2.34 mmol, 1 equiv) and TEA (711 mg, 7.03 mmol, 3 equiv) in DCM (5 mL) was stirred at room temperature for 1 h. To the above mixture, 3-nitrobenzenesulfonyl chloride (779 mg, 3.51 mmol, 1.5 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 40 °C for 3 h. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (8:1) to afford 2-((((1r,4r)-4-(2-chloroethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (500 mg, 48%) as a white solid. LCMS (ESI, m / z): 441.90 [M+H] + .

[0436] Step D 2-((((1r,4r)-4-(2-chloroethoxy)cyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (500 mg, 1.13 mmol, 1 equiv), 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (521 mg, 1.70 mmol, 1.5 equiv), KI (37.7 mg, 0.227 mmol, 0.2 equiv) and K2CO3 (313 mg, 2.27 mmol, 2 equiv) in ACN (5 mL) were stirred at 80 °C for 3 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% - 90% gradient in 30 min; detector, UV 254 nm. The crude product (200 mg) was purified by preparative HPLC under the following conditions (column: Xselect CSH OBD column 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B5% - B5% in 2 min, B16% - B26% in 10 min; wavelength: 254 nm / 220 nm, RT (min): 8.9) to give 3-((4-(4-(2-(((1r,4r)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (76 mg, 9%) as a white solid. LCMS (ESI, m / z): 711.50 [M+H] + . 11H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.02 - 6.78 (m, 3H), 6.58 - 6.39 (m, 2H), 6.05 - 5.79 (m, 1H), 4.58 - 4.40 (m, 2H), 4.30 - 4.10 (m, 2H), 4.04 - 3.94 (m, 4H), 3.83 - 3.20 (m, 3H), 3.11 - 2.79 (m, 4H), 2.79 - 2.53 (m, 6H), 2.15 - 1.93 (m, 3H), 1.93 - 1.74 (m, 3H), 1.39 - 1.01 (m, 5H), 0.66 - 0.54 (m, 2H), 0.42 - 0.31 (m, 2H).

[0437] [Example 56] Synthesis of 3 - ((4 - (4 - ((4 - ((((7 - (Cyclopropylmethoxy) - 5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)piperidin - 1 - yl)methyl)piperidin - 1 - yl) - 3 - fluorophenyl)amino)piperidine - 2,6 - dione formate

[0438] [Chemical formula]

[0439] Step A A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-[(piperidin-4-ylsulfanyl)methyl]-3H-quinazolin-4-one (1 g, 2.75 mmol, 1 equiv), tert-butyl 4-formylpiperidine-1-carboxylate (0.88 g, 4.13 mmol, 1.5 equiv), and STAB (1.75 g, 8.25 mmol, 3 equiv) in DCE (8 mL) was stirred for 1 h. After concentration, the residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give tert-butyl 4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.6 g, 99%) as an orange oil. LCMS (ESI, m / z): 561.30 [M+H] + .

[0440] Step B A solution of tert-butyl 4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.6 g, 2.85 mmol, 1 equiv) in HCl (8 mL, 4 M) in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to dryness to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride (1 g, 65%) as a yellow solid. LCMS (ESI, m / z): 461.20 [M+H] + .

[0441] Step C 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride (1.00 g, 0.022 mmol, 1 equiv), 1,2-difluoro-4-nitrobenzene (415 mg, 0.026 mmol, 1.2 equiv) and a solution of NaHCO3 (547 mg, 0.066 mmol, 3 equiv) in ACN (5 mL) were stirred at 90 °C for 5 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:97) to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (580 mg, 39%) as a yellow solid. LCMS (ESI, m / z): 600.30 [M+H] + 。

[0442] Step D A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one (550 mg, 0.917 mmol, 1 equiv), Fe (256 mg, 0.085 mmol, 5 equiv) and NH4Cl (98.1 mg, 1.83 mmol, 2 equiv) in EtOH (5 mL) and water (1 mL) was stirred at 80 °C for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH (5 × 10 mL). The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to give 2-(((1-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (487 mg, 93%) as a yellow solid. LCMS (ESI, m / z): 570.15 [M+H] + 。

[0443] Step E A solution of 2-(((1-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (477 mg, 0.84 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (482 mg, 2.51 mmol, 3 equiv), and NaHCO3 (352 mg, 4.19 mmol, 5 equiv) in ACN (3 mL) was stirred at 90 °C overnight. The mixture was concentrated and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient of 10% - 50% over 10 min; detector, UV 254 nm. This gave 3-((4-(4-((4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (184 mg, 29%) as a dark blue solid. LCMS (ESI, m / z): 681.25 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.77 (s, 1H), 8.15 (s, 1H), 6.93 - 6.77 (m, 3H), 6.49 (dd, J = 14.9, 2.6 Hz, 1H), 6.41 (dd, J = 8.8, 2.6 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 4.30 - 4.19 (m, 1H), 3.97 (d, J = 7.1 Hz, 2H), 3.60 (s, 2H), 3.10 (d, J = 11.1 Hz, 2H), 2.83 - 2.65 (m, 4H), 2.62 - 2.53 (m, 3H), 2.15 (d, J = 7.1 Hz, 2H), 2.12 - 2.04 (m, 3H), 2.00 - 1.78 (m, 5H), 1.73 (d, J = 12.1 Hz, 2H), 1.64 - 1.36 (m, 3H), 1.30 - 1.15 (m, 3H), 0.64 - 0.55 (m, 2H), 0.40 - 0.32 (m, 2H).

[0444] [Example 57] Synthesis of 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione

[0445] [Chemical formula]

[0446] Step A 2-(([1,4'-Bipiperidin]-4-ylthio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride (600 mg, 1.24 mmol, 1 equiv), 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (260 mg, 1.24 mmol, 1 equiv) and a solution of NaHCO3 (313 mg, 3.73 mmol, 3 equiv) in ACN (10 mL) were stirred at 80 °C overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(4-nitro-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (420 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 636.10 [M+H] + 。

[0447] Step B A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(((1'-(4-nitro-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)quinazolin-4(3H)-one (420 mg, 0.661 mmol, 1 equiv), Fe (185 mg, 3.31 mmol, 5 equiv) and NH4Cl (70.7 mg, 1.32 mmol, 2 equiv) in EtOH (5 mL) and water (1 mL) was stirred at 80 °C for 3 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (7:1) to give 2-(((1'-(4-amino-2-(trifluoromethyl)phenyl)-[1,4'-bipiperidin]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (350 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 606.10 [M+H] + 。

[0448] Step C 2-(((1’-(4-Amino-2-(trifluoromethyl)phenyl)-[1,4’-bipiperidin]-4-yl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (320 mg, 0.528 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (304 mg, 1.58 mmol, 3 equiv) and NaHCO3 (222 mg, 2.64 mmol, 5 equiv) in ACN (5 mL) were stirred at 90 °C overnight. The resulting mixture was concentrated and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% - 50% gradient in 10 min; detector, UV 254 nm. Thereby, 3-((4-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4’-bipiperidin]-1’-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (135 mg, 36%) was obtained as a white solid. LCMS (ESI, m / z): 717.25 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.79 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.94 - 6.83 (m, 4H), 6.17 (d, J = 7.8 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.97 (d, J = 7.1 Hz, 2H), 3.60 (s, 2H), 2.86 - 2.79 (m, 4H), 2.77 - 2.63 (m, 3H), 2.62 - 2.55(m, 2H), 2.32 - 2.25 (m, 1H), 2.22 - 2.11 (m, 2H), 2.09 - 2.03 (m, 2H), 1.96 - 1.86 (m, 3H), 1.72 (d, J = 8.0 Hz, 2H), 1.54 -1.42 (m, 3H), 1.29 - 1.22(m, 1H), 0.64 - 0.55 (m, 2H), 0.40 - 0.33 (m, 2H).

[0449] Examples 58 - 59 were synthesized in accordance with the procedures described for the synthesis of 3 - ((4 - (4 - ((((7 - (cyclopropylmethoxy) - 5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio) - [1,4’ - bipiperidine] - 1’ - yl) - 3 - (trifluoromethyl)phenyl)amino)piperidine - 2,6 - dione (Example 57), using appropriate components and, as necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0450] [Table 20] TIFF2025525031000120.tif142162

[0451] [Example 60] Synthesis of 1 - (4 - (4 - ((((7 - (cyclopropylmethoxy) - 5 - fluoro - 4 - oxo - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio) - [1,4’ - bipiperidine] - 1’ - yl) - 3 - fluorophenyl)dihydropyrimidine - 2,4(1H,3H) - dione

[0452] [Chemical Formula]

[0453] A solution of 1-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (140 mg, 0.46 mmol, 1 equiv), 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one (167 mg, 0.46 mmol, 1 equiv) and STAB (194 mg, 0.92 mmol, 2 equiv) in DMF (8 mL) was stirred at 60 °C for 1 h. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% - 50% gradient in 10 min; detector, UV 254 nm. Thereby, 100 mg of the crude product was obtained as a white solid. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B5% - B5% in 2 min, B10% - B20% in 10 min; wavelength: 254 / 220 nm; RT (min): 9.2), and 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (49.4 mg, 16%) was obtained as a white solid. LCMS (ESI, m / z): 653.30 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.25 (br, 1H), 10.45 - 10.24 (m, 1H), 8.29 (d, J = 16.3 Hz, 1H), 7.40 - 6.80 (m, 4H), 4.06 - 3.92 (m, 2H), 3.75 (dd, J = 14.4, 7.6 Hz, 2H), 3.62 (d, J = 11.5 Hz, 2H), 3.42 - 3.30 (m, 2H), 2.89 - 2.79 (m 3H), 2.78 - 2.54 (m, 4H), 2.40 - 2.32 (m, 1H), 2.23 - 2.17 (m, 2H), 2.00 - 1.90 (d, J = 15.3 Hz, 2H), 1.89 - 1.70 (m, 2H), 1.68 - 1.34 (m,4H), 1.32 - 1.14 (m,1H), 0.70 - 0.50 (m, 2H), 0.46 - 0.26 (m, 2H).

[0454] Examples 61 - 62 were synthesized according to the procedure described for the synthesis of 1-(4-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (Example 60) using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0455] [Table 21] TIFF2025525031000123.tif148162

[0456] [Example 63] Synthesis of 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate

[0457]

Chem.

[0458] A solution of 2-(2-chloroethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (180 mg, 0.607 mmol, 1 equiv), 3-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (236 mg, 0.607 mmol, 1 equiv), K2CO3 (168 mg, 1.21 mmol, 2 equiv) and KI (10.1 mg, 0.061 mmol, 0.1 equiv) in ACN (20 mL) was stirred at 60 °C for 1 h. The resulting mixture was concentrated and purified by silica gel column chromatography eluting with DCM / MeOH (8:1), and then by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column 19*250 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 16% B to 26% B in 10 min; wavelength: 254 / 220 nm; RT (min): 12.8), to give 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (17.6 mg, 4%) as a dark grey solid. LCMS (ESI, m / z): 650.25 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.15 (br, 1H), 10.76 (s, 1H), 8.27 (s, 1H), 6.93 - 6.77 (m, 3H), 6.49 (dd, J = 15.0, 2.6 Hz, 1H), 6.40 (dd, J = 8.7, 2.5 Hz, 1H), 5.78 (d, J = 7.6 Hz, 1H), 4.30 - 4.19 (m, 1H), 3.95 (d, J = 7.0 Hz, 2H), 3.65 - 3.55(m, 3H), 3.15 (d, J = 11.0 Hz, 2H), 2.85 - 2.76 (m, 1H), 2.81 - 2.66 (m, 6H), 2.62 - 2.50 (m, 4H), 2.44 - 2.30 (m, 4H), 2.27 - 2.19 (m, 1H), 2.13 - 2.04 (m, 1H), 1.95 - 1.72 (m, 4H), 1.58 - 1.46 (m, 2H), 0.64 - 0.55 (m, 2H), 0.39 - 0.29 (m, 2H).

[0459] Example 64 was synthesized in accordance with the procedure described for the synthesis of 3-((4-(4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (Example 63) using appropriate components and, if necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0460]

Table 22

[0461] [Example 65] Synthesis of 3-((4-(4-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[0462] [Chemical formula]

[0463] Step A A solution of 2-(2-([1,4'-bipiperidin]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one hydrochloride (90 mg, 0.194 mmol, 1 equiv), 1,2-difluoro-4-nitrobenzene (30.8 mg, 0.194 mmol, 1 equiv), and DIEA (100 mg, 0.776 mmol, 4 equiv) in NMP (4 mL) was stirred at 80 °C for 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 minutes; detector, UV 254 nm. This gave 7-(cyclopropylmethoxy)-5-fluoro-2-(2-(1'-(2-fluoro-4-nitrophenyl)-[1,4'-bipiperidin]-4-yl)ethyl)quinazolin-4(3H)-one (100 mg, 91%) as a yellow solid. LCMS (ESI, m / z): 568.16 [M+H] + .

[0464] Step B A solution of 7-(cyclopropylmethoxy)-5-fluoro-2-(2-(1'-(2-fluoronitro-phenyl)-[1,4'-bipiperidin]-4-yl)ethyl)quinazolin-4(3H)-one (100 mg, 0.176 mmol, 1 equiv), Fe (49.2 mg, 0.880 mmol, 5 equiv) and NH4Cl (18.9 mg, 0.352 mmol, 2 equiv) in EtOH (5 mL) and water (1 mL) was stirred at 80 °C for 1 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give 2-(2-(1'-(4-amino-2-fluorophenyl)-[1,4'-bipiperidin]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (80 mg, 85%) as a white solid. LCMS (ESI, m / z): 538.16 [M+H] + .

[0465] Step C A solution of 2-(2-(1'-(4-amino-2-fluorophenyl)-[1,4'-bipiperidin]-4-yl)ethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (70 mg, 0.13 mmol, 1 equiv), 3-bromopiperidine-2,6-dione (50.0 mg, 0.26 mmol, 2 equiv) and NaHCO3 (43.8 mg, 0.52 mmol, 4 equiv) in ACN (10 mL) was stirred at 90 °C overnight. The resulting mixture was concentrated and the residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 50% over 10 min; detector, UV254 nm. This gave 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (22.2 mg, 24%) as a purple solid. LCMS (ESI, m / z): 649.30 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ12.07 (br, 1H), 10.77 (s, 1H), 8.23 (s, 2H), 6.91 - 6.76 (m, 3H), 6.50 (dd, J = 15.0, 2.6 Hz, 1H), 6.41 (dd, J = 8.7, 2.6 Hz, 1H), 5.79 (d, J = 7.6 Hz, 1H), 4.28 - 4.22 (m, 1H), 3.96 (d, J = 7.1 Hz, 2H), 3.17 (d, J = 11.0 Hz, 2H), 2.99 - 2.90 (m, 2H), 2.76 - 2.65 (m, 2H), 2.61 - 2.57(m,2H),2.56 - 2.51(m, 3H), 2.28 - 2.15 (m, 2H), 2.10 - 2.01 (m, 1H), 1.95 - 1.80 (m, 3H), 1.72 - 1.59 (m, 6H), 1.34 - 1.14 (m, 4H), 0.62 - 0.56 (m, 2H), 0.36 (t, J = 5.1 Hz, 2H).

[0466] Example 66 was synthesized according to the procedure described for 3-((4-(4-(2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Example 65) using appropriate components and, where necessary, modified reaction conditions (such as reagents, reagent ratios, temperature, and reaction time) and purification conditions.

[0467] [Table 23]

[0468] [Example 67] Synthesis of 3-((4-(4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate

[0469]

Chem.

[0470] Project A A solution of tert-butyl 4-(((7-bromo-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1000 mg, 2.12 mmol, 1 equiv), ethynylcyclopropane (420 mg, 6.35 mmol, 3 equiv), Pd(PPh3)2Cl2 (149 mg, 0.21 mmol, 0.1 equiv), CuI (40.3 mg, 0.21 mmol, 0.1 equiv) and TEA (429 mg, 4.23 mmol, 2 equiv) in DMSO (10 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:9) to afford tert-butyl 4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (1.3 g) as a brown oil. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 458.10 [M+H] + 。

[0471] Project B A solution of tert-butyl 4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (260 mg, ০.৫৭ mmol, 1 equiv) in HCl (5 mL, 4 M) in 1,4-dioxane was stirred for 1 hour. The mixture was concentrated to dryness to afford 7-(cyclopropylethynyl)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (130 mg, 64%) as a white solid. LCMS (ESI, m / z): 358.10 [M+H] + 。

[0472] Project C A solution of 7-(cyclopropylethynyl)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (100 mg, 0.28 mmol, 1 equiv), 3-((3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)amino)piperidine-2,6-dione (179 mg, 0.56 mmol, 2 equiv), STAB (119 mg, 0.56 mmol, 2 equiv) and TEA (2.83 mg, 0.028 mmol, 0.1 equiv) in DCE (1 mL) 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 in water (10 mmol / L NH4HCO3), gradient 10% - 50% in 10 min; detector, UV 254 nm. The crude product (100 mg) was further purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: B 23% - B 33% in 10 min; wavelength: 254 / 220 nm; RT (min): 9) to give 3-((4-(4-(((7-(cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4’-bipiperidin]-1’-yl)-3-fluorophenyl)amino)piperidine-2,6-dione formate (14.3 mg, 8%) as a white solid. LCMS (ESI, m / z): 661.25 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.21(s, 1H), 7.34 (s, 1H), 7.20 (d, J = 11.2 Hz, 1H), 6.82 (t, J = 9.3 Hz, 1H), 6.59 - 6.36 (m, 2H), 5.78 (d, J = 7.6 Hz, 1H), 4.32 - 4.18 (m, 1H), 3.61 - 3.54 (m, 5H), 3.15 (d, J = 10.7 Hz, 3H), 2.84 - 2.65 (m, 5H), 2.62 - 2.56 (m, 2H), 2.28 - 2.22 (m, 3H), 2.14 - 2.02 (m, 1H), 1.94 - 1.89(m, 2H), 1.88 - 1.81 (m, 1H), 1.77 - 1.60 (m, 2H), 1.66 - 1.54 (m, 3H), 1.49 - 1.39 (m, 2H), 0.97 - 1.91 (m, 2H), 0.83 - 0.76 (m, 2H).

[0473] Example A: NanoLuc assay for PARP14 degradation NanoLuc plasmid The catalytic domain of human PARP14 (residues 1611 - 1801, GenBank accession number NM_017554) was inserted into the pcDNA3.1(-) vector. This insert also contained a NanoLuc tag on the N-terminus of the PARP14 protein.

[0474] Assay for PARP14 degradation The degradation of PARP14 protein was evaluated using the measured value of the NanoLuc tag as a proxy for the PARP14 protein. Using the plasmids described in Table 1, PARP14 with the NanoLuc tag was overexpressed in HEK-293T cells (ATCC). Plasmid DNA was diluted with empty vector DNA and then added to 1.163 mL of phenol red-free OptiMEM (Thermo Fisher). The plasmid DNA concentrations used in each assay described in Table 1. The plasmid DNA was mixed with 78.5 μL of Fugene HD (Promega) and incubated for 5 minutes.

[0475]

Table 24

[0476] Next, 1.125 mL was added to 10 million 293T cells in DMEM (Thermo Fisher) supplemented with 10% FBS (VWR) and 1X Glutamax (Gibco). Transfection was incubated at 37 degrees for 24 hours in an incubator supplemented with 5% CO2. Next, the cells were trypsinized and grown in phenol red-free OptiMEM medium. The transfected HEK-293T cells were diluted to 125,000 cells per mL and then added to the assay plate (Corning 3574) using a Multidrop (Thermo Fisher) to add 40 μL per well of the 384-well plate, resulting in 5,000 cells per well. Using a Mosquito (TTP Labtech), 40 nL of the dose-response curve of each test compound diluted in DMSO was added to the cell plate, and this plate was incubated at 37 degrees for 2 hours. The assay plate was brought to room temperature, and then 20 μL of NanoGlo (Promega) per well was added to this plate. Luminescence was measured in an Envision (Perkin Elmer).

[0477] The DMSO average value was calculated from 32 wells containing only 0.1% DMSO in columns 12 and 24 of the assay plate. The % of DMSO values was calculated as described below.

[0478] [Number]

[0479] The % of DMSO values was plotted as a function of the compound concentration, and the 4-parameter fit below was applied to derive the DC 50 value.

[0480] [Number] (The maximum value, minimum value, and Hill coefficient are not fixed.) Y is the % of DMSO, and X is the compound concentration.

[0481] DC for the example compound 50 data are presented in Table 2 below ("+" is less than 0.1 μM. "++" is 0.1 μM or more and less than 1 μM. "+++" is 1 μM or more.).

[0482] Example B: HiBiT Assay for PARP14 Degradation HiBiT-tagged PARP14 in Jurkat cells expressing LgBiT Jurkat cells stably transfected with LgBiT (Promega) were engineered to contain the HiBiT tag on both alleles of the PARP14 gene (GenBank accession number: NM_017554) via CRISPR / Cas9 editing. This HiBiT tag is an 11-amino acid tag created by Promega that binds to the LgBiT protein to form a NanoLuc® tag on the C-terminus of PARP14. Clones were isolated and the HiBiT tag was confirmed by Sanger sequencing.

[0483] Assay for PARP14 Degradation The degradation of PARP14 protein was evaluated by measuring the luminescence of the HiBiT tag bound to the LgBiT protein as a proxy for the PARP14 protein.

[0484] Jurkat cells were diluted to 250,000 cells per mL and then added to an assay plate (Corning 3574) using a Multidrop (Thermo Fisher) to add 20 μL per well of the 384-well plate, resulting in 5,000 cells per well. Using a Mosquito (TTP Labtech), 20 nL of the dose-response curve of each test compound diluted in DMSO was added to the cell plate, and the plate was incubated at 37 °C for 2 hours or 24 hours. The assay plate was brought to room temperature, and then 5 μL per well of Live Cell Substrate (Promega) was added to this plate. Luminescence was measured using an Envision (Perkin Elmer).

[0485] The DMSO average value was calculated from 32 wells containing only 0.1% DMSO in columns 12 and 24 of the assay plate. The % of the DMSO value was calculated as described below.

[0486]

Number

[0487] The % of the DMSO value was plotted as a function of the compound concentration, and the DC 50 value was derived by applying the following four-parameter fit.

[0488]

Number

[0489] The DC for the example compound 50The data is presented in Table 2 below (where "+" means less than 0.03 μM and "++" means 0.03 μM or more).

[0490]

Table 25

[0491] Example C: Decrease in cell number and cytokines in BALF and lung homogenate after sensitization with Alternaria and treatment with PARP14 degrader.

[0492] In an Alternaria asthma mouse model, the effect of Compound 17 was investigated. On days 1 to 5, male Balb / c mice under isoflurane anesthesia were challenged by instilling 40 μL of a solution of 5 μg (protein weight) of Alternaria in PBS into each nostril. Compound 17 was administered 2 days before Alternaria challenge (the day of challenge was defined as day -1). The animals were treated subcutaneously once a day for 7 days (defined as days -1 to 5) with vehicle (10% DMSO / 45% PEG - 400 / 45% water with "20% HP-β-CD") or Compound 17 (30 and 100 mg / kg). The total cell number and differences in BALF fluid samples were measured using an XT - 2000iV analyzer (Sysmex). Cytokine concentrations in BALF supernatants were measured in samples from all groups using an ELISA kit (Biotechne, UK). Statistical significance was calculated using one - way ANOVA followed by Dunnett's post - hoc test, comparing the treatment groups to the vehicle control (P < 0.05). Figure 1 shows that Compound 17 significantly decreases the total cell number in a dose - dependent manner starting from a dose of 30 mg / kg. Figure 2 also shows that Compound 17 significantly decreases eosinophils and cytokines IL - 33, IL - 4, and IL - 5 in BALF in a dose - dependent manner starting from 30 mg / kg.

[0493] Various modifications of the present invention will be apparent to those skilled in the art from the foregoing description in addition to those described herein. Such modifications are also intended to fall within the scope of the appended claims. Each reference document is hereby incorporated by reference in its entirety, including all patents, patent applications and publications cited in this application.

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof [wherein, W is CR Ｗ or N, and X is CR Ｘ or N, Z is CR Ｚ or N, and Three of W, X and Z do not simultaneously become N, Y １ is selected from -NR ３ -, -CR ４ R ５ -, -O- and -(C ２～４ alkynyl)-, Y ２ is selected from -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 - and is selected from Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 3- to 18-membered heterocycloalkyl, and ring A is optionally substituted by one, two, three or four R Ａ s. Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring B is optionally substituted by one, two, three or four R Ｂ s, R １ and R ２ are each independently selected from H and methyl, R ３ is selected from H and C １～４ alkyl, and R ４ and R ５ are each independently selected from H, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, amino, C １～４ alkylamino and C ２～８ dialkylamino, respectively R ６ and R ７ are each independently selected from H, halo, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, amino, C １～４ alkylamino and C ２～８ dialkylamino, respectively R Ａ each represents 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 ａ１ , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , NR ｃ１ C(O)OR ａ１ , NR ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), R ｂ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , NR ｂ１ , NR ｃ１ , S(O)R ２ R ｂ１ , NR 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 is independently selected from, R Ａ of 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 , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ , C(O)R ｂ１ , NR ｃ１ , C(O)OR ａ１ , NR ｃ１ , C(O)NR ｃ１ R ｄ１ , NR ｃ１ , S(O)R ｂ１ , NR ｃ１ S(O) ２ R ｂ１ , NR 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 one, two, three, four or five substituents independently selected from R Ｂ is each, 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 ａ２ , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ C(O)R ｂ２ , NR ｃ２ C(O)OR ａ２ , NR ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), R ｂ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , NR ｂ２ , NR ｃ２ , S(O)R ２ R ｂ２ , NR 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 is independently selected from, R Ｂ of 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 、SR ａ２ 、C(O)R ｂ２ 、C(O)NR ｃ２ R ｄ２ 、C(O)OR ａ２ 、OC(O)R ｂ２ 、OC(O)NR ｃ２ R ｄ２ 、C(=NR ｅ２ )NR ｃ２ R ｄ２ 、NR ｃ２ C(=NR ｅ２ )NR ｃ２ R ｄ２ 、NR ｃ２ R ｄ２ 、NR ｃ２ C(O)R ｂ２ 、NR ｃ２ C(O)OR ａ２ 、NR ｃ２ C(O)NR ｃ２ R ｄ２ 、NR ｃ２ S(O)R ｂ２ , NR ｃ２ S(O) ２ R ｂ２ , NR 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 optionally substituted by one, two, three, four or five 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 、NR ｃ３ S(O)R ｂ３ 、NR ｃ３ S(O) ２ R ｂ３ 、NR 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 one, two, three, four or five substituents independently selected from Cy １ is each independently selected from C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and each of them is 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 , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , NR ｃ１ C(O)OR ａ１ , NR ｃ１ C(O)NR ｃ１ R ｄ１ , NR ｃ１ , S(O)R ｂ１ , NR ｃ１ , S(O) ２ R ｂ１ , NR 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 optionally substituted with one, two, three or four substituents independently selected from Cy ２ is each independently selected from C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is independently 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 , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ , C(O)R ｂ２ , NR ｃ２ , C(O)OR ａ２ , NR ｃ２ , C(O)NR ｃ２ R ｄ２ , NR ｃ２ , S(O)R ｂ２ , NR ｃ２ , S(O) ２ R ｂ２ , NR 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 optionally substituted with one, two, three or four substituents independently selected from Cy ３ is each independently selected from C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and each of them is 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 , SR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , OC(O)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ), NR ｃ３ R ｄ３ , NR ｃ３ C(=NR ｅ３ ), NR ｃ３ R ｄ３ , NR ｃ３ R ｄ３ , NR ｃ３ C(O)R ｂ３ , NR ｃ３ , C(O)OR ａ３ , NR ｃ３ , C(O)NR ｃ３ R ｄ３ , NR ｃ３ , S(O)R ｂ３ , NR ｃ３ , S(O) ２ R ｂ３ , NR 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 optionally substituted with one, two, three or four 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 each independently selected from H, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ aryl-C １～４ alkyl, C ３～７ cycloalkyl-C １～４ alkyl, 5- to 10-membered heteroaryl-C １～４ alkyl and 4- to 10-membered heterocycloalkyl-C １～４ alkyl, and 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 of 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 is each, C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is independently 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 , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ and is optionally substituted with one, two, three or four substituents independently selected from R ａ４ 、R ｂ４ 、R ｃ４ and R ｄ４ are each independently selected from H, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ aryl-C １～４ alkyl, C ３～７ cycloalkyl-C １～４ alkyl, 5- to 10-membered heteroaryl-C １～４ alkyl and 4- to 10-membered heterocycloalkyl-C １～４ alkyl, and are each optionally substituted by one, two or three substituents independently selected from OH, CN, amino, halo, C １～６ alkyl, C １～６ alkoxy, C ２～６ haloalkyl and C ２～６ haloalkoxy, ６～１０ C ３～７ alkyl, C ６～１０ aryl, C １～４ alkyl, C ３～７ cycloalkyl-C １～４ alkyl, 5- to 10-membered heteroaryl-C １～４ alkyl and 4- to 10-membered heterocycloalkyl-C １～４ alkyl is optionally substituted by one, two or three substituents independently selected from OH, CN, amino, halo, C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl and C １～６ haloalkoxy, or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl group optionally substituted by one, two or three substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl, CN, OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ , C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ optionally substituted by one, two or three substituents independently selected from the group consisting of S(O)NR or R ｃ２ and R ｄ２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl, CN, OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ , S(O) ２ R ｂ４ , NR ｃ４ , S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ optionally substituted with one, two or three substituents independently selected from the group consisting of S(O) or R ｃ３ and R ｄ３ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl, CN, OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ and is optionally substituted with one, two or three substituents independently selected from S(O)NR R ｅ１ 、R ｅ２ 、R ｅ３ and R ｅ４ are each independently selected from H, C １～４ 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 as follows: (vii) A bond directly connecting ring A to moiety E (viii) -(C １～４ alkyl)- (ix) -(C ２～４ alkenyl)- (x) - (C ２～４ alkynyl) (xi) The following structure: 【Chemical 2】 and (xii) The following structure: 【Chemical 3】 (wherein, G １ is selected from -C(O)-, -NR Ｇ C(O)-, -NR Ｇ -, -O-, -S-, -C(O)O-, -OC(O)NR Ｇ -, -NR Ｇ C(O)NR Ｇ -, -S(O ２ )- and -S(O)NR Ｇ - and 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 selected from -C(O)-, -NR Ｇ C(O)-, -NR Ｇ -, -O-, -S-, -C(O)O-, -OC(O)NR Ｇ -, -NR Ｇ C(O)NR Ｇ -, -S(O ２ ), - and -S(O)NR Ｇ -, and is selected from G ４ is a 4- to 10-membered heterocycloalkyl, R Ｇ is 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, At least one of b, c, e and f is 1.) Selected from, Any of the above-mentioned heteroaryl groups or heterocycloalkyl groups contains one, two, three or four heteroatoms forming a ring, independently selected from O, N and S, One or more C atoms or N atoms forming the ring of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group, One or more S atoms forming the ring of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.] provided that the compound is the following: 2-(4-((((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide; (2S,4R)-1-(((S)-2-(7-(2-(4-((((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)heptanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(((1r,4r)-4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and 3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(((1r,4r)-4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide A compound or a pharmaceutically acceptable salt thereof, provided that it is other than **Claim 2** A compound of formula (I): 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof [wherein W is CR Ｗ or N, and X is CR Ｘ or N, and Z is CR Ｚ or N, and Three of W, X and Z do not simultaneously become N, Y １ is selected from -NR ３ -, -CR ４ R ５ -, and -O-, and Y ２ is selected from -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 - and is selected from Ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 3- to 18-membered heterocycloalkyl, and ring A is optionally substituted by one, two, three or four R Ａ s. Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１４ cycloalkyl and 4- to 18-membered heterocycloalkyl, and ring B is optionally substituted by one, two, three or four R Ｂ groups, R １ and R ２ are each independently selected from H and methyl, R ３ is selected from H and C １～４ alkyl, and R ４ and R ５ are each independently selected from H, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, amino, C １～４ alkylamino and C ２～８ dialkylamino, respectively R ６ and R ７ are each independently selected from H, halo, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, amino, C １～４ alkylamino and C ２～８ dialkylamino, respectively R Ａ is each, 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 ａ１ , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , NR ｃ１ C(O)OR ａ１ , NR ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), R ｂ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , NR ｂ１ , NR ｃ１ , S(O)R ２ R ｂ１ , NR 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 is independently selected from, R Ａ of 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 , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ , C(O)R ｂ１ , NR ｃ１ , C(O)OR ａ１ , NR ｃ１ , C(O)NR ｃ１ R ｄ１ , NR ｃ１ , S(O)R ｂ１ , NR ｃ１ S(O) ２ R ｂ１ , NR 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 one, two, three, four or five substituents independently selected from R Ｂ is each, 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 ａ２ , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ C(O)R ｂ２ , NR ｃ２ C(O)OR ａ２ , NR ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), R ｂ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ S(O)R ｂ２ , NR ｃ２ S(O) ２ R ｂ２ , NR 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 are independently selected from, R Ｂ C of 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 , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ , C(O)R ｂ２ , NR ｃ２ , C(O)OR ａ２ , NR ｃ２ , C(O)NR ｃ２ R ｄ２ , NR ｃ２ , S(O)R ｂ２ , NR ｃ２ S(O) ２ R ｂ２ , NR 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 optionally substituted by one, two, three, four or five substituents independently selected from R Ｗ 、R Ｘ and R Ｚ are 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 、SR ａ３ 、C(O)R ｂ３ 、C(O)NR ｃ３ R ｄ３ 、C(O)OR ａ３ 、OC(O)R ｂ３ 、OC(O)NR ｃ３ R ｄ３ 、NR ｃ３ R ｄ３ 、NR ｃ３ C(O)R ｂ３ 、NR ｃ３ C(O)OR ａ３ 、NR ｃ３ C(O)NR ｃ３ R ｄ３ 、C(=NR ｅ３ )R ｂ３ 、C(=NR ｅ３ )NR ｃ３ R ｄ３ 、NR ｃ３ C(=NR ｅ３ )NR ｃ３ R ｄ３ 、NR ｃ３ S(O)R ｂ３ 、NR ｃ３ S(O) ２ R ｂ３ 、NR 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 、NR ｃ３ S(O)R ｂ３ 、NR ｃ３ S(O) ２ R ｂ３ 、NR 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 one, two, three, four or five substituents independently selected from Cy １ is each independently selected from C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and each of them is 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 , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ , C(O)R ｂ１ , NR ｃ１ , C(O)OR ａ１ , NR ｃ１ , C(O)NR ｃ１ R ｄ１ , NR ｃ１ , S(O)R ｂ１ , NR ｃ１ , S(O) ２ R ｂ１ , NR 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 optionally substituted with one, two, three or four substituents independently selected from Cy ２ is each independently selected from C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, and each of them is 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 , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ , C(O)R ｂ２ , NR ｃ２ , C(O)OR ａ２ , NR ｃ２ , C(O)NR ｃ２ R ｄ２ , NR ｃ２ , S(O)R ｂ２ , NR ｃ２ , S(O) ２ R ｂ２ , NR 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 optionally substituted with one, two, three or four substituents independently selected from Cy ３ is each independently selected from C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is independently 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 , SR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , OC(O)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ), NR ｃ３ R ｄ３ , NR ｃ３ , C(=NR ｅ３ ), NR ｃ３ R ｄ３ , NR ｃ３ R ｄ３ , NR ｃ３ , C(O)R ｂ３ , NR ｃ３ , C(O)OR ａ３ , NR ｃ３ , C(O)NR ｃ３ R ｄ３ , NR ｃ３ , S(O)R ｂ３ , NR ｃ３ , S(O) ２ R ｂ３ , NR 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 optionally substituted with one, two, three or four 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 , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ NR ｃ４ R ｄ４ and S(O) ２ NR ｃ４ R ｄ４ optionally substituted with one, two, three, four or five substituents independently selected from Cy ４ is each, C ６～１０ aryl, C ３～７ cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is independently 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 , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ )NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ )NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ optionally substituted by one, two, three or four 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 a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl, CN, OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ optionally substituted with one, two or three substituents independently selected from and S(O) or R ｃ２ and R ｄ２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl, CN, OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ , C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ , S(O) ２ R ｂ４ , NR ｃ４ , S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ 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 a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halo, C １～４ alkyl, C １～４ haloalkyl, CN, OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , NR ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , NR ｃ４ , S(O) ２ R ｂ４ , NR ｃ４ , S(O) ２ , NR ｃ４ R ｄ４ and S(O) ２ , NR ｃ４ R ｄ４ and is optionally substituted with one, two or three substituents independently selected from S(O) R ｅ１ 、 R ｅ２ 、 R ｅ３ and R ｅ４ are each independently selected from H, C １～４ 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 as follows: (xiii) A bond directly connecting ring A to moiety E (xiv)-(C １～４ alkyl)- (xv) -(C ２～４ alkenyl)- (xvi) -(C ２～４ alkynyl)- (xvii) The following structure: 【Chemical Formula 5】 and (xviii) The following structure: 【Chemical Formula 6】 (wherein G １ is selected from -C(O)-, -NR Ｇ C(O)-, -NR Ｇ -, -O-, -S-, -C(O)O-, -OC(O)NR Ｇ -, -NR Ｇ C(O)NR Ｇ -, -S(O ２ )- and -S(O)NR Ｇ - and 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 selected from -C(O)-, -NR Ｇ C(O)-, -NR Ｇ -, -O-, -S-, -C(O)O-, -OC(O)NR Ｇ -, -NR Ｇ C(O)NR Ｇ -, -S(O ２ ), - and -S(O)NR Ｇ -, and is selected from G ４ is a 4- to 10-membered heterocycloalkyl, R Ｇ is 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, At least one of b, c, e and f is 1.) Selected from Any of the above-mentioned heteroaryl groups or heterocycloalkyl groups contains one, two, three or four heteroatoms forming a ring, independently selected from O, N and S, One or more C atoms or N atoms forming the ring of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group, One or more S atoms forming the ring of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.], provided that the compound is the following: 2-(4-((((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(6-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide; (2S,4R)-1-(((S)-2-(7-(2-(4-((((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide)heptanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 8-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(((1r,4r)-4-((((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)octanamide; and 3-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(((1r,4r)-4-((((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide A compound or a pharmaceutically acceptable salt thereof, provided that it is other than the above.

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

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

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

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

7. Y １ is - NR ３ - and is a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. Y １ is -(C ２～４ alkynyl)-, a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

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

10. Y ２ is -CH ２ -, the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

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

12. Ring A is a monocyclic or polycyclic heterocycloalkyl having 4 to 18 members, and Ring A is optionally substituted by one, two, three or four Rs Ａ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is optionally substituted by Ａ .

13. Ring A is a 4- to 7-membered monocyclic heteroalkyl, and Ring A is optionally substituted by one, two, three, or four Rs Ａ The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, which is optionally substituted by Ａ .

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

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

16. Ring A is C ３～１４ is cycloalkyl, and ring A is optionally substituted by one, two, three or four Rs Ａ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is optionally substituted by

17. Ring A is C ３～７ cycloalkyl, and ring A is optionally substituted by one, two, three or four Rs Ａ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the compound or salt is optionally substituted by one, two, three or four Rs

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

19. Ring B is a 4- to 18-membered heterocycloalkyl, and Ring B is optionally substituted by one, two, three, or four Rs Ｂ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, which is optionally substituted by Ｂ .

20. Ring B is piperidinyl or tetrahydro-2H-pyranyl optionally substituted by one, two, three or four Rs Ｂ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein Ring B is piperidinyl or tetrahydro-2H-pyranyl optionally substituted by one, two, three or four Rs.

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

22. Ring B is C ３～１４ is cycloalkyl, and ring B is optionally substituted by one, two, three or four Rs Ｂ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein Ring B is cyclopentyl or cyclopropyl.

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

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

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

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

28. R Ａ is each, halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, NO ２ , OR ａ１ , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ , NR ｂ１ , NR ｃ１ , NR ａ１ , NR ｃ１ , NR ｃ１ R ｄ１ , C(=NR ｅ１ ), R ｂ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , NR ｂ１ , NR ｃ１ , NR ２ , SR ｂ１ , NR ｃ１ , NR ２ , NR ｃ１ , SR ｄ１ , SR ｂ１ , SR ｃ１ , SR ｄ１ , SR ２ , SR ｂ１ and SR ２ , SR ｃ１ , SR ｄ１ independently selected from, the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. R Ａ is each halo, C １～６ alkyl, C １～６ haloalkyl, CN, NO ２ or OR ａ１ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, which is independently selected from.

30. R Ｂ is each independently H, halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, NO ２ , OR ａ２ , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ , NR ｂ２ , NR ｃ２ , NR ａ２ , NR ｃ２ , NR ｃ２ R ｄ２ , C(=NR ｅ２ ), R ｂ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , NR ｂ２ , NR ｃ２ , NR ２ , SR ｂ２ , NR ｃ２ , NR ２ , NR ｃ２ , SR ｄ２ , SR ｂ２ , SR ｃ２ , SR ｄ２ , SR ２ , SR ｂ２ and SR ２ , SR ｃ２ , SR ｄ２ selected independently from, a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

31. R Ｂ is each, halo, C １～６ alkyl, C １～６ haloalkyl, CN, NO ２ , C(O)R ｂ２ or OR ａ２ is independently selected from, the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

32. R Ｂ each is C(O)CH ３ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein

33. R Ｗ is H, halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, NO ２ , OR ａ３ , SR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , OC(O)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , NR ｃ３ R ｄ３ , NR ｃ３ , NR ｂ３ , NR ｃ３ , NR ａ３ , NR ｃ３ , NR ｃ３ R ｄ３ , C(=NR ｅ３ ), R ｂ３ , C(=NR ｅ３ ), NR ｃ３ R ｄ３ , NR ｃ３ , C(=NR ｅ３ ), NR ｃ３ R ｄ３ , NR ｃ３ , NR ｂ３ , NR ｃ３ , S(O)R ２ R ｂ３ , NR 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 The compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, selected from

34. R Ｗ is selected from H, halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, NO ２ and OR ａ３ and is the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32

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

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

37. R Ｘ is selected from C ６～１０ aryl and 5- to 10-membered heteroaryl, and C ６～１０ aryl and 5- to 10-membered heteroaryl are each optionally substituted with one, two, three, four or five substituents independently selected from halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, OR ａ３ and SR ａ３ and the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 is each optionally substituted with

38. R Ｘ is selected from H, halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, OR ａ３ and C ６～１０ aryl, and is the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36.

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

40. R Ｚ is selected from H, halo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, CN, NO ２ and OR ａ３ and the compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

47. L １ has the following structure: 【Chemical Formula 7】 The compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof.

48. L １ has the following structure: 【Chemical Formula 8】 The compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

70. E is as follows: 【Chemical Formula 9】 The compound according to any one of claims 1 to 68 or a pharmaceutically acceptable salt thereof, which is selected from.

71. E is as follows: 【Chemical 10】 【Chem.】 【Chem.】 The compound according to any one of claims 1 to 68 or a pharmaceutically acceptable salt thereof, which is selected from.

72. E is 【Chemical Formula 11】 A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, selected from

73. where E is 【Chemical 12】 A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof.

74. Formula II: 【Chemical 13】 A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, having

75. Formula IIIa: 【Chemical 14】 A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, having

76. Formula IIIb: 【Chemical Formula 15】 A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, having

77. Formula IIIc: 【Chemical 16】 A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, having

78. 4-(4-((1-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, 2-(2,6-dioxopiperidin-3-yl)-4-(4-((1-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(6-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamido)hexyl)benzamide; 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamido)butyl)benzamide; N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-6-oxohexyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)butyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-4-oxobutyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)ethyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; N-(6-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)hexyl)-2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamide; 3-(((4-(1-(((1-(2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione; 3-(3-(4-(1-(2-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)phenyl)-2-oxoimidazolidin-1-yl)piperidine-2,6-dione; 4-(4-((1-(2-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 1-(4-(1-(((1-(2-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((2-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-(((4-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-(((4-(4-((((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(((2-(4-((((7-(((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(((4-(4-((((7-(((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carbonyl)phenyl)amino)piperidine-2,6-dione; 4-(4-(((4-(4-(2-(7-(((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-(4-(((1-(2-(4-(2-(7-(((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(((1-(2-(4-((((7-(((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((1-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-((((7-(((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(4-((((7-(((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide; 2-(4-((((7-(((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide; 5-(4-(((4-((((7-(((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3-(4-((((7-(((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-(5-(3-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(4-(3-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-(3-(4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 4-(4-((4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(4-(3-(((4-((((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and 5-(4-((4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione The compound according to claim 1 or 2, selected from the above, or a pharmaceutically acceptable salt of any of the foregoing.

79. 3-((4-(4-(2-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((3-fluoro-4-(4-(2-(4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-(2-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-(3-(4-((((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-(6-(4-(2-(4-((((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)piperazin-1-yl)-2-oxobenz[cd]indol-1(2H)-yl)piperidine-2,6-dione; 3-(5-(4-((((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-((3-Fluoro-4-(4-(3-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; 3-((3-Fluoro-4-(4-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)phenyl)amino)piperidine-2,6-dione; 3-((4-(4-((((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-((4-(4-((((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-(((4-(4-(2-((((1r,4r)-4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-(((4-(4-((4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 3-(((4-(4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione; 3-(((4-(4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione; 3-(((4-(3-(4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)pyrrolidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; 1-(4-(4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1h,3h)-dione; 1-(6-(4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-1-methyl-1h-indazol-3-yl)dihydropyrimidine-2,4(1h,3h)-dione; 1-(8-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-((4-(4-(4-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(1'-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[4,4'-bipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-(2-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(3-(4-((((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione 3-((4-(4-((((7-(Cyclopropylethynyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-[1,4'-bipiperidin]-1'-yl)-3-fluorophenyl)amino)piperidine-2,6-dione The compound according to claim 1 or a pharmaceutically acceptable salt of any of the above, selected from the group consisting of:

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

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

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

83. A method of treating cancer in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 79 or a pharmaceutically acceptable salt thereof in combination with an additional therapy or therapeutic agent.

84. The method according to claim 82 or 83, wherein the cancer is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer or melanoma.

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

86. The method according to claim 85, wherein the inflammatory disease is selected from asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloid, eosinophilic disorder, pulmonary fibrosis and type 2 cytokine pathology.

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

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

89. The method according to claim 86, 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.

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

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

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