Targeted protein degradation of PARP14 for therapy

Abstract

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

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080044704.2, titled "Targeted Protein Degradation of PARP14 for Therapy", filed on June 18, 2020. Technical Field

[0002] The present invention relates to quinazolinones and related compounds that cause intracellular proteolysis of PARP14 and can be used for the treatment of cancer and inflammatory diseases. Background of the Invention

[0004] Poly(ADP-ribose) polymerases (PARPs) are members of a 17-enzyme family that regulate fundamental cellular processes, including gene expression, protein degradation, 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 an emerging approach for novel therapeutic agents. One member of the PARP family, PARP1, has been shown to be an effective cancer target associated with cell stress caused by DNA damage, whether induced by gene mutations or cytotoxic chemotherapy, with three approved drugs clinically and several others in late-stage development (Ohmoto A, et al. OncoTargets and Therapy. 2017; Vol. 10:5195).

[0005] 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 divided into 3 different categories. Most PARP family members catalyze the transfer of single-ADP-ribose units to their substrates (monoPARP), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units to substrates (polyPARP). Finally, PARP13 is the only PARP to date for which catalytic activity could not be demonstrated either in vitro or in vivo.

[0006] PARP14 is a cytosolic and nuclear mono-PARP. It was initially identified as BAL2 (B-invasive lymphoma 2), a gene associated with poor outcomes in diffuse large B-cell lymphoma (DLBCL), together with two other mono-PARPs (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 known as macro-PARPs due to the presence of a macrodomain at the N-terminus. The genes for the three macroPARPs are located in the same genomic locus, suggesting co-regulation. In fact, the gene expression of PARP14 and PARP9 is highly correlated in normal tissues and cancer types. PARP14 is overexpressed in tumors compared to normal tissues, including 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 knockdown of PARP14 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).

[0007] PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling, thereby affecting 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. Nov 16, 2010; 286(3):1767–1776). Marginal zone B cells are reduced in Parp14− / − knockout (KO) mice, and in the Parp14 KO setting, the ability of IL-4 to confer B cell survival in vitro is also reduced (Cho SH, et al. Blood. January 15, 2009; 113(11):2416–2425). This reduced survival signaling is mechanistically linked to a reduced ability of Parp14 KO B cells to maintain metabolic fitness and increase Mcl-1 expression. Parp14 KO prolongs survival in the Eμ-Myc lymphoma model, thus demonstrating the role of PARP14 in Myc-driven lymphomagenesis (Cho SH, et al. Proc Natl Acad Sci USA. September 12, 2011; 108(38):15972–15977). Gene expression data also suggest a role for PARP14 in human B cell lymphoma. BAL proteins, including PARP14, are highly expressed in host response (HR) DLBCL, a genomically defined subtype of B cell lymphoma characterized by a rapid inflammatory infiltration of T cells and dendritic cells and the presence of an IFN-γ gene signature (Molecular profiling of diffuse large B cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Monti S, et al. Blood. 2005; 105(5):1851). Indeed, PARP14 is considered an interferon-stimulated gene, in which its mRNA is increased by stimulating various cell systems with all types of interferon (I, II, and III; www.interferome.org).

[0008] Due to its role downstream of the IL-4 and IFN-γ signaling pathways, PARP14 has been implicated in T helper cell and macrophage differentiation. Inactivation of PARP14 in macrophages genetically biases towards the pro-inflammatory M1 phenotype associated with anti-tumor immunity while reducing the pro-tumor M2 phenotype. In human and murine macrophage models, with PARP14 knockout or knockdown, increased expression of M1 genes downstream of IFN-γ and decreased expression of M2 genes downstream of IL-4 were found. Similarly, genetic knockout of PARP14 has been shown to reduce the Th2 T helper cell phenotype in cutaneous and airway inflammatory settings, again related to the regulatory role of PARP14 in IL-4 signal transduction (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).

[0009] PARP14 has been shown to regulate the transcription of STAT6 (signal transducer and activator of transcription 6) and to promote T H 2 responses in T cells and B cells, which are known to promote allergic airway disease (asthma). Genetic depletion of PARP14 and its enzymatic activity in an allergic airway disease model resulted in reduced pulmonary inflammation and IgE levels, which are key readouts of the asthma process in this model. In addition, the enzymatic activity of PARP14 promotes T H 2 phenotype differentiation in a STAT6-dependent manner. (Mehrotra P, et al. J Allergy Clin Immunol. July 25, 2012;131(2):521) Thus, inhibiting the catalytic activity of PARP14 may be a potential new therapy for treating allergic airway diseases.

[0010] Most clinically used pharmaceutical agents are based on small molecule inhibition of protein function. However, alternative approaches that provide protein degradation rather than inhibition also have the potential to provide clinical efficacy. Thus, targeted protein degradation via ubiquitination of protein targets has emerged as an effective strategy in drug discovery. Heterobifunctional small molecules that bind simultaneously to the target protein and recruit ubiquitin ligases (e.g., ubiquitin E3 ligases) 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).

[0011] There is a need to develop new drugs, such as small molecules that can bind to both PARP14 and ubiquitin E3 ligases to cause PARP14 degradation, which can be used to treat various diseases, including cancer and inflammatory diseases. SUMMARY OF THE INVENTION

[0012] The present invention relates to a compound of formula (A1):

[0013] Q-L 1 -E(A1)

[0014] or a pharmaceutically acceptable salt thereof, wherein the components are defined below.

[0015] The present invention further relates to a pharmaceutical composition comprising a compound of formula (A1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0016] The present invention further relates to a method of degrading PARP14, the method comprising contacting a compound of formula (A1) or a pharmaceutically acceptable salt thereof with PARP14.

[0017] The present invention further relates to a method of reducing IL-10 in cells, the method comprising contacting a compound of formula (A1) or a pharmaceutically acceptable salt thereof with the cells.

[0018] The present invention further relates to a method of treating a disease or disorder in a patient in need of treatment, wherein the disease or disorder is characterized by overexpression or increased activity of PARP14, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (A1) or a pharmaceutically acceptable salt thereof.

[0019] The present invention further relates to a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (A1) or a pharmaceutically acceptable salt thereof.

[0020] The present invention further relates to a method of treating an immune disease in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (A1) or a pharmaceutically acceptable salt thereof.

[0021] The present disclosure also provides the use of the compounds described herein in the manufacture of a medicament for treatment. The present disclosure also provides the compounds described herein for treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Western blot showing the PARP14 degradation assay of the compound of Example 1.

[0023] Figure 2 Western blot showing the PARP14 degradation assay of the compound of Example 2.

[0024] Figure 3 Western blot showing the PARP14 degradation assay of the compound of Example 3.

[0025] Figure 4 Western blot showing the PARP14 degradation assay of the compound of Example 4.

[0026] Figure 5 Showing the mRNA expression levels of PARP14 in various cancer types compared to their matched normal tissues.

[0027] Figure 6A Showing the experimental layout of the procedure described in Example D, involving the reduction of IL-10 production in cells.

[0028] Figure 6B Showing the IL-10 levels in the tissue culture supernatants of cells treated as described in Example D, measured by ELISA. Detailed Description

[0029] The present disclosure particularly provides a compound of formula (A1):

[0030] Q-L 1 -E (A1)

[0031] or a pharmaceutically acceptable salt thereof, wherein:

[0032] Q is a small molecule PARP14 targeting moiety that binds to PARP14;

[0033] L 1 is a linker that covalently links to moiety Q and moiety E; and

[0034] E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase.

[0035] In some embodiments, the present disclosure provides a compound of formula (A1):

[0036] Q-L 1 -E(A1)

[0037] or a pharmaceutically acceptable salt thereof, wherein:

[0038] Q is a moiety represented by formula I:

[0039]

[0040] wherein:

[0041] W is CR W or N;

[0042] X is CR X or N;

[0043] Y is CRY or N;

[0044] Z is CR Z or N;

[0045] wherein no more than two of W, X, Y and Z are simultaneously N;

[0046] Ring A is a monocyclic or polycyclic C 3-14 cycloalkyl or Ring A is a monocyclic or polycyclic 4- to 18-membered heterocycloalkyl, wherein Ring A is optionally substituted by 1, 2, 3 or 4 R A and when Ring A is polycyclic, Ring A is connected to the -(L) m - moiety of Formula I through a non-aromatic ring;

[0047] L is -(CR 5 R 6 ) t -, -(CR 5 R 6 ) p -O-(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -S-(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -NR 3 -(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -CO-(CR 5 R 6 ) q -, -(CR 5 R 6 ) r -C(O)O-(CR 5 R 6 ) s -, -(CR 5 R 6 ) r -CONR 3 -(CR 5 R 6 ) s -, -(CR 5 R 6 ) p -SO-(CR 5 R6 ) q -, -(CR 5 R 6 ) p -SO2-(CR 5 R 6 ) q -, -(CR 5 R 6 ) r -SONR 3 -(CR 5 R 6 ) s - or -NR 3 CONR 4 -;

[0048] R 1 and R 2 each independently selected from H and methyl;

[0049] R 3 and R 4 each independently selected from H and C 1-4 alkyl;

[0050] R 5 and R 6 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;

[0051] each R A independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5 - 10 membered heteroaryl, 4 - 10 membered heterocycloalkyl, C 6-10 aryl - C 1-4 alkyl, C 3-7 cycloalkyl - C 1-4 alkyl, 5 - 10 membered heteroaryl - C 1-4 alkyl, 4 - 10 membered heterocycloalkyl - C 1-4 alkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)Rb1 、 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 ; wherein said C of RA 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 each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: Cy 1 、 Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 、 SRa1 , 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 , NR 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 ;

[0052] R W , R X , R Y and R Z are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SRa2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 , S(O)R b2 , NR c2 , S(O)2R b2 , NR c2 , S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein R W , R X , R Y or R Z of said 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 1-4Each alkyl group is optionally independently substituted by 1, 2, 3, 4 or 5 substituents selected from the following: 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 , 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 ;

[0053] wherein when W is CR W , X is CR X , Y is CR Y , and Z is CR Z , then at least one of R W , R X , R Y and R Z is not H;

[0054] Each Cy 1 is independently selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a1 , 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 ;

[0055] Each Cy2 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 optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ;

[0056] each R a1 , Rb1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 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, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 or R d2 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 optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from Cy 3 、Cy 3 -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 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)NR c3 R d3 , NR c3 , C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 , S(O)2R b3 , NR c3 , S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ;

[0057] Each Cy 3 is C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 substituents 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 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)NR c3 R d3 , NR c3C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ;

[0058] R a3 、R b3 、R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 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 Aryl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkyl and C 1-6 halogenated alkoxy group;

[0059] 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 1, 2 or 3 substituents independently selected from: halogen, C 1-4 alkyl, C 1-4 halogenated alkyl, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ;

[0060] 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 1, 2 or 3 substituents independently selected from: halogen, C 1-4 alkyl, C 1-4 halogenated alkyl, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NRc3 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)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ;

[0061] Each R e1 、R e2 and R e3 Independently selected from H, C 1-4 Alkyl and CN;

[0062] m is 0 or 1,

[0063] n is 0, 1, or 2;

[0064] p is 0, 1, or 2;

[0065] q is 0, 1 or 2, wherein p+q is 0, 1 or 2;

[0066] r is 0 or 1;

[0067] s is 0 or 1, wherein r+s is 0 or 1; and

[0068] t is 1, 2, or 3;

[0069] L 1 is a linker, which is covalently linked to portion Q and portion E;

[0070] E is an E3 ubiquitin ligase binding moiety, said binding moiety binding to an E3 ubiquitin ligase; and

[0071] wherein the wavy line represents the point of attachment to group L 1 ;

[0072] wherein any of the above-mentioned heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S;

[0073] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted with an oxo (=O) group; and

[0074] wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups.

[0075] In some embodiments, when W is CR W , X is CR X , Y is CR Y , and Z is CR Z and when m is 1, then R X and R Y are not both methoxy.

[0076] In some embodiments, Q is a moiety other than the following:

[0077]

[0078] wherein the wavy line represents the point of attachment to group L 1 .

[0079] In some embodiments, W is CR W ; X is CR X ; Y is CR Y ; and Z is CR Z .

[0080] In some embodiments, W is N; X is CR X ; Y is CR Y ; and Z is CR Z .

[0081] In some embodiments, W is CR W ; X is N; Y is CR Y ; and Z is CR Z .

[0082] In some embodiments, W is CR W ; X is CR X ; Y is N; and Z is CR Z .

[0083] In some embodiments, W is CR W ; X is CR X ; Y is CR Y ; and Z is N.

[0084] In some embodiments, ring A is a monocyclic or polycyclic C A cycloalkyl optionally substituted with 1, 2, 3, or 4 R 3-14 , wherein when ring A is polycyclic, ring A is attached to the -(L) m - moiety of formula I through a non-aromatic ring.

[0085] In some embodiments, ring A is a monocyclic C A cycloalkyl optionally substituted with 1, 2, 3, or 4 R 3-7 .

[0086] In some embodiments, ring A is a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl optionally substituted with 1, 2, 3, or 4 R A .

[0087] In some embodiments, ring A is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0088] In some embodiments, ring A is a cyclohexyl or cycloheptyl optionally substituted with 1, 2, 3, or 4 R A .

[0089] In some embodiments, ring A is cyclohexyl or cycloheptyl.

[0090] In some embodiments, ring A is a cyclohexyl optionally substituted with 1, 2, 3, or 4 R A .

[0091] In some embodiments, ring A is cyclohexyl.

[0092] In some embodiments, ring A is a monocyclic or polycyclic 4- to 18-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 R A , and wherein when ring A is polycyclic, ring A is attached to the -(L) m - moiety of formula I through a non-aromatic ring.

[0093] In some embodiments, ring A is a monocyclic 4- to 7-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 R A .

[0094] In some embodiments, ring A is a monocyclic 4- to 7-membered heterocycloalkyl.

[0095] In some embodiments, ring A is a cyclohexyl optionally substituted with 1, 2, 3, or 4 R AA substituted oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl.

[0096] In some embodiments, ring A is an oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl.

[0097] In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A substituted oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl or thiane.

[0098] In some embodiments, ring A is an oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl or thiane.

[0099] In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A substituted piperidinyl.

[0100] In some embodiments, ring A is piperidinyl.

[0101] In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A substituted piperidin-4-yl.

[0102] In some embodiments, ring A is piperidin-4-yl.

[0103] In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A substituted tetrahydropyranyl.

[0104] In some embodiments, ring A is tetrahydropyranyl.

[0105] In some embodiments, ring A is optionally substituted with 1, 2, 3 or 4 R A substituted tetrahydropyran-4-yl.

[0106] In some embodiments, ring A is tetrahydropyran-4-yl.

[0107] In some embodiments, L is -(CR 5 R 6 ) t -.

[0108] In some embodiments, L is -(CR 5 R 6 ) t -, and t is 1.

[0109] In some embodiments, L is -(CR 5 R 6 ) t -, and t is 2.

[0110] In some embodiments, L is -(CR 5 R 6 ) t -, and t is 3.

[0111] In some embodiments, L is -CH2-.

[0112] In some embodiments, m is 0.

[0113] In some embodiments, m is 1.

[0114] In some embodiments, n is 0.

[0115] In some embodiments, n is 1.

[0116] In some embodiments, n is 2.

[0117] In some embodiments, R 1 and R 2 are both H.

[0118] In some embodiments, one of R 1 and R 2 is H and the other is methyl.

[0119] In some embodiments, each R A is independently selected from C 1-6 alkyl, OR a1 , C(O)R b1 , NR c1 R d1 and S(O)2R b1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 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 。

[0120] In some embodiments, each R A is independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , S(O)2R b1 , 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C 1-4 alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C 1-4 alkyl and 5-10 membered heteroaryl-C 1-4 alkyl is each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from Cy 1 , Cy 1-C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 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 .

[0121] In some embodiments, each R A is independently selected from halo, C 1-6 haloalkyl, OR a1 , C(O)NR c1 R d1 and C(O)OR a1 .

[0122] In some embodiments, R A is OR a1 .

[0123] In some embodiments, each RA independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, OR a1 , NR c1 R d1 , C(O)NR c1 R d1 , NR c1 C(O)R b1 , C(O)R b1 , C(O)OR a1 and S(O)2R b1 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: halo, CN, OR a1 , NR c1 R d1 , C(O)R b1 and NR c1 C(O)R b1 .

[0124] In some embodiments, each R W , R X , R Y and R Z is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, CN, OR a2 , C(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 , NR c2 R d2 , C(=NR e2 )Rb2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 ; wherein R W , R X , R Y and R Z of said C 1-6 alkyl, C 1-6 haloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl and C 6-10 aryl-C 1-4 alkyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from: 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 , 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)Rb2 , 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 .

[0125] In some embodiments, each R W , R X , R Y and R Z is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, CN, OR a2 , C(O)NR c2 R d2 , NR c2 R d2 and NR c2 C(O)R b2 ; wherein the C W , R X , R Y and R Z of 1-6 alkyl, C 1-6 haloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl and C 6-10 aryl-C 1-4 alkyl is each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from 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(=NRe2 )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 .

[0126] In some embodiments, W is CR W And R W Not H.

[0127] In some embodiments, W is CR W And R W It’s H.

[0128] In some embodiments, R W It is a halogen group.

[0129] In some embodiments, R W It's F.

[0130] In some embodiments, R W Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, Halogen, and OR a2 , wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally replaced by OR a2 replace.

[0131] In some embodiments, R W is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, CN, halo, and ORa2 , wherein said C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with OR a2 .

[0132] In some embodiments, R X and R Z are not both halogen.

[0133] In some embodiments, R Z is H.

[0134] In some embodiments, when W is CR W , X is CR X , Y is CR Y , and Z is CR Z and when m is 1 or 2, then R X and R Y are not both C 1-6 alkoxy.

[0135] In some embodiments, when W is CR W , X is CR X , Y is CR Y , and Z is CR Z and when m is 1 or 2, then R X and R Y are not the same.

[0136] In some embodiments, X is CR X and R X is not H.

[0137] In some embodiments, X is CR X and R X is H.

[0138] In some embodiments, R X is selected from C 1-6 alkyl, halo, and OR a2 .

[0139] In some embodiments, Y is CR Y and R Y is not H.

[0140] In some embodiments, Y is CR Y and R Y is H.

[0141] In some embodiments, Y is CR Y and R Y is independently selected from NR c2 R d2, NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 .

[0142] In some embodiments, Y is CR Y and R Y is independently selected from C 1-6 alkyl, OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR, e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 .

[0143] In some embodiments, Y is CR Y and R Y is independently selected from NR c2 Rd2 and NR c2 C(O)R b2 .

[0144] In some embodiments, R Y Independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halogen, CN, OR a2 SR a2 、C(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 , where R Y The C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 NR c2 R d2 and S(O)2R b2 .

[0145] In some embodiments, Y is CR Y And R Y Independently selected from C 1-6 Alkyl and OR a2 .

[0146] In some embodiments, Y is CR Y and R Y is OR a2 .

[0147] In some embodiments, Z is CR Z and R Z is not H.

[0148] In some embodiments, Z is CR Z and R Z is H.

[0149] In some embodiments, Z is CR Z and R Z is C 1-6 alkyl.

[0150] In some embodiments, Z is CR Z and R Z is C 1-6 alkyl, halo, or CN.

[0151] In some embodiments, each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Cy 3 , Cy 3 -C 1-4 alkyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, 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 c3C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 .

[0152] In some embodiments, each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0153] In some embodiments, each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl are each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: C 1-4 Alkyl, C 1-4 Haloalkyl, halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 .

[0154] In some embodiments, R a2 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl are each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: C 1-4 Alkyl, C 1-4 Haloalkyl, halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 .

[0155] In some embodiments, R c2 and R d2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10Aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl is each optionally independently substituted with 1, 2, 3, 4, or 5 substituents selected from: C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 .

[0156] In some embodiments, Cy 3 is a 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 .

[0157] In some embodiments, Cy 3 is a 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C(O)R b3 .

[0158] In some embodiments, Cy 3 is a piperidinyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo and C(O)CH3

[0159] In some embodiments, Q is a moiety represented by formula II:

[0160]

[0161] wherein the wavy line represents the point of attachment to the group L 1 .

[0162] In some embodiments, Q is a moiety represented by formula IIIA, IIIB, IIIC, IIID or IIIE:

[0163]

[0164] where the wavy line represents the point of attachment to the group L 1 of.

[0165] In some embodiments, Q is a moiety represented by formula IVA or IVB:

[0166]

[0167] where the wavy line represents the point of attachment to the group L 1 of.

[0168] In some embodiments, Q is a group of a compound selected from the following:

[0169] 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile;

[0170] 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0171] 6-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0172] 6-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0173] 8-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0174] 8-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0175] 8-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)thio)ethyl)quinazolin-4(3H)-one;

[0176] 5-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0177] 5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0178] 8-Benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0179] 7-Benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0180] 8-Methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one;

[0181] 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate;

[0182] 8-Methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0183] 8-Methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-one;

[0184] 8-Methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one;

[0185] 2-(((1-acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0186] 8-Methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0187] 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one;

[0188] 2-((azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one;

[0189] 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0190] 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0191] 2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0192] 2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0193] 2-((azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one;

[0194] 2-((((trans)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0195] 2-((((cis)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0196] 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile;

[0197] 7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0198] 7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0199] 7-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0200] 8-methyl-2-(((1-methylpiperidin-3-yl)thio)methyl)quinazolin-4(3H)-one;

[0201] 7-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0202] 5-chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0203] 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one;

[0204] 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;

[0205] 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0206] 2-((((trans)-3-(benzyloxy)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0207] 8-Methyl-2-((oxetan-3-ylthio)methyl)quinazolin-4(3H)-one;

[0208] 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0209] 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;

[0210] 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0211] 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one;

[0212] 6-Chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0213] 7,8-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0214] 7-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0215] 2-(((trans-3-hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0216] 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one;

[0217] 2-(((trans-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0218] 2-(((cis-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0219] 5-Fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0220] 2-(((trans-3-aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0221] 2-(((4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0222] 2-(((trans-4-Aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0223] 2-(((cis-4-Aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0224] 5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0225] 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0226] 5-Fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0227] 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one;

[0228] 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one;

[0229] 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one;

[0230] 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0231] 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0232] 2-(((4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0233] 2-(((cis-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0234] 2-(((trans-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0235] 2-(((4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0236] 2-(((cis-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0237] 2-(((trans-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0238] 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0239] 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0240] 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0241] 8-methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0242] 7-amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0243] N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide;

[0244] N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide;

[0245] N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-carboxamide;

[0246] 4-oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-carboxamide;

[0247] 7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0248] 7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0249] 7-(Pyridin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0250] 7-((4-Methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0251] 7-((3-Methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0252] 7-((2-Methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0253] 7-(Pyrazin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0254] 7-(Pyridin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0255] 7-(Pyrimidin-5-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0256] 7-((1-Methyl-1H-imidazol-2-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0257] 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(thiazol-2-ylamino)quinazolin-4(3H)-one;

[0258] 7-((2-Methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0259] 7-((4-Methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0260] 7-((5-Methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0261] 7-(4-Amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0262] 7-(Isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0263] 8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0264] 7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0265] 2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one;

[0266] 2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one;

[0267] 2-(((cis-4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one;

[0268] 2-(((cis-4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one;

[0269] 2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one;

[0270] 7-(Cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0271] 7-(Cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0272] 2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one;

[0273] 2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one;

[0274] 2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one;

[0275] 2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one;

[0276] 7-(Cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0277] 7-(Dimethylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0278] 7-(Methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0279] 7-Morpholino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0280] 7-(4-Methylpiperazin-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0281] 7-((1-Methylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0282] 7-((Tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0283] 7-(Cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0284] 7-(Isopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0285] 7-((Pyridin-4-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0286] 7-((Pyridin-2-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0287] 7-(Benzylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0288] 7-((1-Phenylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0289] 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)amino)quinazolin-4(3H)-one;

[0290] 7-(Cyclobutylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0291] 7-((Pyridin-3-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0292] 7-(Cyclopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0293] 7-(Cyclohexyl(methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0294] 7-[(1-Benzyl-3-piperidinyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one;

[0295] 7-(3-Piperidinylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one;

[0296] 7-((1-Benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0297] 7-(Piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0298] 7-(Pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0299] 7-((1-Acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0300] 7-((1-Acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0301] 7-((1-Methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0302] 7-((1-Acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0303] 8-Methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0304] 7-(Cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0305] 7-(Cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0306] 8-Methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0307] N-(4-((4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide;

[0308] 2-(((1-(4-(Dimethylamino)benzyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0309] 4-((4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)benzonitrile;

[0310] 2-(((1-((1H-Pyrazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0311] 8-Methyl-2-(((1-((1-methyl-1H-indazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-quinazolin-4(3H)-one;

[0312] 2-(((1-((1,3-Dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0313] 8-Methyl-2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0314] 8-Methyl-2-(((1-((3-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0315] 8-Methyl-2-(((1-(phenethylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0316] 8-Methyl-2-(((1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0317] 8-Methyl-2-(((1-((3-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0318] N-(3-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide;

[0319] 2-(((1-((1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0320] 2-(((1-(imidazo[1,2-a]pyridin-3-ylmethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0321] 2-(((1-((1-benzyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0322] 2-(((1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0323] 2-(2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenoxy)acetonitrile;

[0324] 8-Methyl-2-(((1-((2-oxoindolin-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0325] 2-(((1-((5-Methoxypyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0326] 8-Methyl-2-(((1-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0327] (S)-2-(((1-(2,3-Dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0328] (R)-2-(((1-(2,3-Dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0329] (S)-8-Methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0330] 2-(((1-(2-Hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0331] 2-(((1-(2-Aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0332] N-(2-(4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)nicotinamide;

[0333] 2-(((1-(3-Aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0334] 2-(((1-Glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0335] 2-(((1-(3-Aminopropionyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0336] 2-(((1-(3-(Dimethylamino)propionyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0337] (R)-1-(4-Amino-5-(4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine;

[0338] (S)-1-(4-Amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine;

[0339] 2-(((1-(L-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0340] 2-(((1-(D-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0341] 8-Methyl-2-(((1-(3-(pyridin-2-yl)propanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0342] 8-Methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0343] 8-Methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0344] 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; and

[0345] 7-(Cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0346] N-(((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl)acetamide;

[0347] 7-(Cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0348] 7-(Cyclopentylamino)-2-((((1R,4R)-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0349] 2-((((trans)-4-(2-aminoethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0350] 2-(((3-(aminomethyl)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0351] 2-((((trans)-3-(2-Aminoethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0352] 7-(Cyclopentylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0353] 7-(Cyclopentylamino)-5-fluoro-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-quinazolin-4(3H)-one;

[0354] 7-(Cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one;

[0355] (S)-7-((Tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0356] 7-(Cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;

[0357] 7-(Cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0358] 2-((Azepan-4-ylthio)methyl)-7-(cyclopentylamino)quinazolin-4(3H)-one;

[0359] 2-(((3-(Aminomethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0360] 7-((3-Methylisoxazol-5-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0361] (R)-7-((1-(Methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0362] 7-(Cyclobutylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0363] 7-((1-(Methylsulfonyl)azetidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0364] (R)-7-((1-(Methylsulfonyl)piperidin-3-yl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0365] 7-(Cyclopentyloxy)-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0366] 8-Methyl-2-((oxepan-4-ylthio)methyl)quinazolin-4(3H)-one;

[0367] 7-(Cyclopentylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one;

[0368] 7-(Cyclobutylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0369] (R)-7-((1-(Methylsulfonyl)piperidin-3-yl)amino)-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one;

[0370] 7-Isobutyl-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0371] 7-(Cyclopentylamino)-5-methyl-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0372] cis-4-((((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide;

[0373] trans-4-((((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide;

[0374] 5-Chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0375] 7-(Cyclopentylamino)-5-methoxy-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0376] Methyl 4-((((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate;

[0377] 2-((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0378] 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0379] 7-(cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0380] 7-(cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0381] 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0382] 7-(cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0383] 7-(cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0384] 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0385] 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one;

[0386] cis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid;

[0387] trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid;

[0388] trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide;

[0389] 7-(Cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0390] 4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide;

[0391] 2-(((Cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0392] 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0393] 7-(Cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one;

[0394] 7-(Cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0395] 7-(Cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0396] 7-(Cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0397] 7-(Cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0398] 7-(Cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0399] 7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one;

[0400] 7-((Cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0401] 7-((2,2-Difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0402] 7-(Cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0403] 5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0404] 5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0405] 7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0406] 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0407] 7-(Cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0408] 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one;

[0409] (R)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one;

[0410] (S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one;

[0411] 7-(Cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0412] 7-(Cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0413] 2-((((cis)-6-(Aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one;

[0414] 2-(((trans-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one;

[0415] 2-(((cis-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one;

[0416] 6-fluoro-7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0417] 7-(cyclopentylamino)-5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0418] 7-(cyclohexylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0419] 7-(cyclohexylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0420] 7-(cyclohexylamino)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0421] (R)-5-fluoro-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0422] 7-(cyclobutylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0423] 7-((2-cyclopentylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0424] 5-chloro-7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0425] 7-(cyclopentylamino)-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0426] 7-(Cyclopentylamino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0427] 7-((2-(Tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0428] 7-(Cyclopentylamino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0429] 7-(Cyclopentylamino)-2-(((1-(2,2-difluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0430] 7-(Cyclopentylamino)-2-(((1-(3,3,3-trifluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0431] 2-(((cis-6-(Hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)methyl)-8-methylquinazolin-4(3H)-one;

[0432] 7-((Cyclobutylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0433] 7-(((2,2-Difluorocyclopropyl)methyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0434] 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0435] 7-(Cyclopentylamino)-2-(((1-(2,2-difluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0436] 7-((Cyclopropylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0437] 7-((3,3-Difluorocyclopentyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0438] 2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one;

[0439] (R)-2-(((1-Acetylpiperidin-4-yl)thio)methyl)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one;

[0440] 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one;

[0441] 7-(Cyclopentylamino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one;

[0442] 7-((Cyclopropylmethyl)amino)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0443] 5-Fluoro-2-((piperidin-4-ylthio)methyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one;

[0444] 7-(Cyclopentylamino)-2-(((1-(1,1-dioxidosulfolan-3-yl)piperidin-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one;

[0445] 7-((Cyclopropylmethyl)amino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0446] 7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0447] 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0448] 5-Fluoro-7-((2-morpholinoethyl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0449] 7-(Cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0450] 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0451] 7-(Cyclobutylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0452] 7-(Cyclopentylamino)-5-fluoro-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0453] 7-(Cyclopentylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0454] 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-methylethanamide;

[0455] 7-(((2,2-Difluorocyclopropyl)methyl)amino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0456] 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetonitrile;

[0457] 2-(trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0458] 5-Fluoro-7-((2-morpholinoethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0459] 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-4(3H)-one;

[0460] 7-((Cyclobutylmethyl)amino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one;

[0461] 7-(Cyclohexylamino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0462] 7-(Cyclopropylmethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0463] 7-((Cyclopropylmethyl)amino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0464] 7-(Cyclopentylamino)-6-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0465] 7-(Cyclopentylamino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0466] 7-(Cyclopropylmethoxy)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0467] 7-((Cyclobutylmethyl)amino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-6-fluoroquinazolin-4(3H)-one;

[0468] 7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0469] 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)methoxy)quinazolin-4(3H)-one;

[0470] 7-((1-(2,2-Difluoropropyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0471] 7-((1-(2,2-Difluoroethyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0472] 5-Fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0473] 5-Fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0474] 7-((Cyclobutylmethyl)amino)-6-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0475] 7-(Cyclobutylmethoxy)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one;

[0476] 5-Fluoro-7-((trans-2-fluorocyclopentyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0477] 5-Fluoro-7-isobutoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0478] 7-(Cyclobutylmethoxy)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0479] 7-(Cyclobutylmethoxy)-2-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one;

[0480] 7-(Cyclobutylmethoxy)-2-((cyclohexylthio)methyl)-5-fluoroquinazolin-4(3H)-one;

[0481] 2-((Cyclohexylthio)methyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one;

[0482] trans-4-(((7-(Cyclobutylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide;

[0483] 7-((1-(2,2-Difluoroethyl)piperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0484] 7-(Cyclopentylamino)-5,6-difluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0485] 7-(Cyclopentylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0486] 7-((2,2-Difluorocyclopropyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0487] 7-(Cyclopentylamino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one;

[0488] 7-((3,3-Difluorocyclobutyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0489] 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-4(3H)-one;

[0490] 5-Fluoro-7-((tetrahydro-2H-pyran-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0491] 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one

[0492] (R)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one;

[0493] (S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one;

[0494] 5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one;

[0495] (S)-5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one;

[0496] (R)-5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one;

[0497] 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one;

[0498] 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one;

[0499] 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((S)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one;

[0500] 5-Fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0501] 5-Fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0502] 5-Fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0503] 5,6-Difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0504] N-((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0505] N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0506] 7-(((cis)-3-ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0507] 5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0508] 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0509] 2 - ((((trans)-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclobutylmethoxy)-5-fluoroquinazolin-4(3H)-one;

[0510] 5-fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2 - ((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0511] 5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2 - ((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0512] 7-((cyclopropylmethyl)amino)-5,6-difluoro-2 - ((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0513] 5,6-difluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2 - ((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0514] 7-((cyclobutylmethyl)amino)-2 - ((((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one;

[0515] 5-fluoro-7-(((trans)-2-fluorocyclopentyl)amino)-2 - ((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0516] 5-fluoro-7-(((cis)-2-fluorocyclopentyl)amino)-2 - ((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0517] 5-fluoro-2 - ((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0518] 5-fluoro-7-(oxetan-3-ylmethoxy)-2 - ((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0519] 7-((1,4-dioxan-2-yl)methoxy)-5-fluoro-2 - ((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0520] 7-((2,2-Difluorocyclohexyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0521] 5,6-Difluoro-7-(((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0522] 5,6-Difluoro-7-(((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0523] (R)-5,6-Difluoro-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0524] 7-(((R)-1-Acetylpyrrolidin-3-yl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0525] 7-((2,2-Difluorocyclopentyl)amino)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0526] 7-((1,1-Dioxotetrahydro-2H-thiopyran-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0527] 5-Fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0528] 5-Chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0529] 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-4(3H)-one;

[0530] 7-((5,5-Dimethyltetrahydrofuran-3-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0531] 5-Fluoro-2-((((trans)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0532] 5-Fluoro-2-((((cis)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0533] 5-Fluoro-2-((((4-methyltetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0534] 5-Fluoro-7-((((cis)-2-hydroxycyclopentyl)methoxy)-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0535] (trans)-4-((5,6-Difluoro-4-oxo-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile;

[0536] (cis)-4-((5,6-Difluoro-4-oxo-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile;

[0537] 5,6-Difluoro-7-((((trans)-3-methoxycyclobutyl)amino)-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0538] 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one;

[0539] 5-Methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0540] 5-Fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0541] 2-((((4,4-Difluorocyclohexyl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0542] 7 - ((1 - Acetylpyrrolidin - 3 - yl)methoxy)-5 - fluoro - 2 - (((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H)-one;

[0543] 7 - (2 - Cyclohexylethyl)-5 - fluoro - 2 - (((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H)-one;

[0544] 7 - ((((1 - Acetylpiperidin - 4 - yl)methyl)amino)-5,6 - difluoro - 2 - (((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H)-one;

[0545] 5 - Fluoro - 7 - ((((tetrahydro - 2H - pyran - 4 - yl)methyl)thio)-2 - (((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H)-one;

[0546] 5 - Fluoro - 7 - ((((cis)-4 - fluoropyrrolidin - 3 - yl)methoxy)-2 - (((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H)-one;

[0547] 5 - Fluoro - 7 - ((((cis)-4 - fluoro - 1 - methylpyrrolidin - 3 - yl)methoxy)-2 - (((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H)-one;

[0548] 5 - Fluoro - 2 - ((((cis)-4 - hydroxy - 4 - methylcyclohexyl)thio)methyl)-7 - ((tetrahydrofuran - 3 - yl)methoxy)quinazolin - 4(3H)-one;

[0549] 5,6 - Difluoro - 2 - ((((cis)-4 - hydroxy - 4 - methylcyclohexyl)thio)methyl)-7 - ((((cis)-3 - methoxycyclobutyl)amino)quinazolin - 4(3H)-one;

[0550] 5 - Fluoro - 7 - ((tetrahydro - 2H - pyran - 4 - yl)methoxy)-2 - ((((trans)-4 - (trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin - 4(3H)-one;

[0551] 5 - Bromomethyl - 2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)-7 - ((tetrahydrofuran - 3 - yl)methoxy)quinazolin - 4(3H)-one;

[0552] 5,6 - Difluoro - 2 - ((((trans)-4 - hydroxycyclohexyl)thio)methyl)-7 - ((((trans)-4 - methoxycyclohexyl)amino)quinazolin - 4(3H)-one;

[0553] N-((trans)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propanamide;

[0554] 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one;

[0555] N-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-methylcyclohexyl)acetamide;

[0556] 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydro-2H-pyran-3-yl)amino)quinazolin-4(3H)-one;

[0557] 5-Fluoro-2-((((trans)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0558] 4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazoline-5-carbonitrile;

[0559] 5,6-Difluoro-7-(neopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0560] 5-Fluoro-7-(((cis)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0561] 5-Fluoro-7-(((trans)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0562] N-((cis)-3-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide;

[0563] 5-Fluoro-7-(((cis)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0564] N-((trans)-4-((((5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0565] 7-((1-(cyclopropanecarbonyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0566] N-((trans)-4-((((5-fluoro-4-oxo-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0567] N-((trans)-4-((((7-(cyclobutylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide;

[0568] N-((trans)-3-((((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide;

[0569] 7-(1-cyclopentylethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one;

[0570] N-((trans)-4-((((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)cyclopropanecarboxamide;

[0571] 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0572] 5-fluoro-7-((1-isobutyrylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0573] 5-fluoro-7-((1-propionylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0574] 5-fluoro-7-(piperidin-4-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0575] 5,6-Difluoro-7-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0576] 7-((1-Acetylpiperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0577] 5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((cis)-3-(trifluoromethoxy)cyclobutyl)amino)quinazolin-4(3H)-one;

[0578] 7-Amino-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0579] 7-(Cyclopropylmethoxy)-2-((((trans)-4-(dimethylamino)cyclohexyl)thio)methyl)-5-fluoro-7,8-dihydroquinazolin-4(3H)-one;

[0580] 5-Fluoro-2-((((cis)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0581] 5,6-Difluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0582] 5,6-Difluoro-7-((2-methoxy-2-methylpropyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0583] 5,6-Difluoro-7-((((cis)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0584] 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0585] Methyl 4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate;

[0586] 5-Fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one;

[0587] 7-(Cyclopentylamino)-5-fluoro-2-((((trans)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0588] 7-(Cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0589] 5-Fluoro-7-((4-methylmorpholin-2-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0590] 5-Fluoro-7-((1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0591] 5-Fluoro-7-(neopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0592] 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0593] 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((cis)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0594] 7-(((1-Acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one;

[0595] 5,6-Difluoro-7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one;

[0596] 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(3,3,3-trifluoro-2,2-dimethylpropoxy)quinazolin-4(3H)-one;

[0597] 7 - ((1 - acetylpiperidin - 4 - yl)methoxy) - 5 - fluoro - 2 - ((((cis) - 4 - hydroxycyclohexyl)thio)methyl)quinazolin - 4(3H) - one;

[0598] 7 - ((1 - acetylpiperidin - 4 - yl)methoxy) - 5 - chloro - 2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H) - one;

[0599] 5 - fluoro - 7 - ((1 - (2 - methoxyacetyl)piperidin - 4 - yl)methoxy) - 2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H) - one;

[0600] 5,6 - difluoro - 7 - ((((trans) - 3 - fluoro - 1 - methylpiperidin - 4 - yl)methyl)amino) - 2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H) - one;

[0601] N - ((trans) - 4 - ((((5 - fluoro - 4 - oxo - 7 - ((tetrahydro - 2H - pyran - 4 - yl)methoxy) - 3,4 - dihydroquinazolin - 2 - yl)methyl)thio)cyclohexyl)acetamide; and

[0602] 7 - ((3,3 - difluoro - 1 - methylpiperidin - 4 - yl)methoxy) - 5 - fluoro - 2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin - 4(3H) - one.

[0603] In the assays described in Example A, the above - mentioned compounds were found to have PARP14 inhibitory activity.

[0604] In some embodiments, L 1 is linked to moiety Q by a covalent bond to ring A.

[0605] Ubiquitin ligase - binding moieties and linkers are known and well - described in the art, for example: 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. WO2017 / 197056, each of which is incorporated by reference in its entirety.

[0606] 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 having an IC determined in a binding assay of less than about 10 μM 50 . 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.

[0607] In some embodiments, E comprises a chemical group derived from an imide, thioimide, amide, or thioamide.

[0608] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, an analogue thereof, an isostere thereof, or a derivative thereof.

[0609] In some embodiments, E is a moiety having a structure selected from:

[0610]

[0611]

[0612] where the wavy line represents the point of attachment to the group L 1 . In some embodiments, E has the following structure:

[0613]

[0614] where the wavy line represents the point of attachment to L 1 .

[0615] In some embodiments, E has the following structure:

[0616]

[0617] where the wavy line represents the point of attachment to L 1 .

[0618] In some embodiments, E has the following structure:

[0619]

[0620] where the wavy line represents the point of attachment to L 1 .

[0621] In some embodiments, the linker L 1is a chain of 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10 or 1 to 5 chain atoms, optionally substituted by 1 - 3 R q substituents, and wherein one or more of the chain carbon atoms of L 1 may be oxidized to form a carbonyl (C=O), and wherein one or more of the N and S chain atoms may each optionally be oxidized to form an N-oxide, sulfoxide or sulfonyl group; and

[0622] each R q is independently selected from OH, CN, -COOH, NH2, halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5 - 6 membered heteroaryl, 4 - 6 membered heterocycloalkyl, C 3-6 cycloalkyl, NH(C 1-6 alkyl) and N(C 1-6 alkyl)2, wherein the C q of R 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4 - 6 membered heterocycloalkyl and 5 - 6 membered heteroaryl are each optionally substituted by halogen, OH, CN, -COOH, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5 - or 6 - membered heteroaryl or 4 - 6 membered heterocycloalkyl. In some embodiments, Rq is independently selected from OH, CN, -COOH, NH2, halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NH(C 1-6 alkyl) and N(C 1-6 alkyl)2.

[0623] In some embodiments, L 1 has the following structure:

[0624]

[0625] wherein each G is independently selected from -C(O)-, -NR G C(O)-, -NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -, -NR G C(O)NRG -、 -S(O2)- or -S(O)NR G -;

[0626] Each R G is independently selected from H, methyl, and ethyl;

[0627] a is 0 or 1;

[0628] b is 0 or 1; and

[0629] c is 0 or 1, where the wavy line represents the point of attachment to moieties Q and E.

[0630] In some embodiments, a is 0.

[0631] In some embodiments, a is 1.

[0632] In some embodiments, b is 0.

[0633] In some embodiments, b is 1.

[0634] In some embodiments, c is 0.

[0635] In some embodiments, c is 1.

[0636] In some embodiments, a is 1, b is 1, and c is 1.

[0637] In some embodiments, a is 0, b is 1, and c is 0.

[0638] In some embodiments, a is 1, b is 1, and c is 0.

[0639] In some embodiments, each G is independently selected from -C(O)- and -NR G C(O)-. In some embodiments, G is -NR G C(O)-.

[0640] In some embodiments, R G is H.

[0641] In some embodiments, linker L 1 is selected from:

[0642]

[0643] where the wavy line represents the point of attachment to moieties Q and E.

[0644] In some embodiments, the compounds of the present disclosure are compounds of formula (A2):

[0645]

[0646] or a pharmaceutically acceptable salt thereof.

[0647] In some embodiments, a compound of the present disclosure is a compound of formula (A3):

[0648]

[0649] or a pharmaceutically acceptable salt thereof.

[0650] In some embodiments, a compound of the present disclosure is a compound of formula (A4):

[0651]

[0652] or a pharmaceutically acceptable salt thereof.

[0653] In some embodiments, a compound of the present disclosure is a compound of formula (A5):

[0654]

[0655] or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments, a compound of the present disclosure is a compound of formula (A6):

[0657]

[0658] or a pharmaceutically acceptable salt thereof.

[0659] In some embodiments, the compound of formula (A1) is selected from the following:

[0660]

[0661]

[0662] or a pharmaceutically acceptable salt of any of the foregoing.

[0663] It should be further understood that, for clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0664] Throughout this specification, substituents of the compounds of the invention are disclosed in groups or in ranges. The invention is expressly intended to include each and every individual sub-combination of such group members and range members. For example, the term "C 1-6 alkyl" is expressly intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0665] Throughout this specification, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings may be attached to the remainder of the molecule at any ring member where valency permits. For example, the term "pyridinyl", "pyridyl", or "pyridine ring" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0666] The term "n-membered", where "n" is an integer, generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is "n". For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0667] Throughout this specification, variables defining divalent linking groups may be described. Each linking substituent is specifically intended to include the forward and backward forms of the linking substituent. For example, -C(O)NR G - includes -C(O)NR G - and -NR G C(O)- both, and each form is intended to be disclosed separately. When a linking group is required for a structure, the Markush variables listed for said group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", then "alkyl" or "aryl" should be understood to represent a linking alkylene group or arylene group, respectively.

[0668] For the compounds of the present invention where a variable appears more than once, each variable may independently be selected from a different part of the group defining said variable. For example, when describing a structure having two R groups that are present on the same compound simultaneously, the two R groups may represent independently selected different parts of the group defining R.

[0669] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0670] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution of a given atom is limited by valency.

[0671] As used herein, the term "C i-j " (where i and j are integers) indicates a range of a certain number of carbon atoms in said chemical group, where the range is defined by i - j. For example, C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0672] As used herein, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that can 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.

[0673] 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. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0674] 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. Exemplary alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0675] As used herein, the term "halo" or "halogen", used alone or in combination with other terms, includes fluorine, chlorine, bromine, and iodine. In some embodiments, the halo group is F or Cl.

[0676] 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 full valence, where the substituents can be the same or different. In some embodiments, the halogen atoms are fluorine atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0677] As used herein, the term "alkoxy", used alone or in combination with other terms, refers to a group having the formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0678] As used herein, the term "haloalkoxy", used alone or in combination with other terms, refers to a group having the formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy group is -OCF3.

[0679] As used herein, the term "amino", alone or in combination with other terms, refers to NH2.

[0680] As used herein, the term "alkylamino", alone or in combination with other terms, refers to a group having the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0681] As used herein, the term "dialkylamino", alone or in combination with other terms, refers to a group having the formula -N(alkyl)2. Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0682] As used herein, the term "cycloalkyl", alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon, including cycloalkylated alkyl and alkenyl groups. The cycloalkyl group may include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring system. Also included in the definition of cycloalkyl is a portion where one or more aromatic rings (e.g., aryl or heteroaryl rings) are fused to the cycloalkyl ring (i.e., share a bond with the cycloalkyl ring), such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, etc., or pyrido derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of the cycloalkyl group may optionally be substituted with oxo groups. The cycloalkyl group also includes cycloalkylidene. The term "cycloalkyl" also includes bridged cycloalkyl groups (e.g., a non-aromatic ring hydrocarbon moiety containing at least one bridgehead carbon, such as adamantan-1-yl) and spirocycloalkyl groups (e.g., a non-aromatic hydrocarbon moiety containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane, etc.). In some embodiments, the cycloalkyl group has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7 monocyclic cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthyl, octahydronaphthyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0683] As used herein, the term "cycloalkylalkyl", alone or in combination with other terms, refers to a group having the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 a monocyclic cycloalkyl group.

[0684] As used herein, the term "heterocycloalkyl", alone or in combination with other terms, refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure and that has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. The heterocycloalkyl group may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Also included in the definition of heterocycloalkyl is a portion in which one or more aromatic rings (e.g., aryl or heteroaryl rings) are fused (i.e., share bonds) with a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydro-quinoline, etc. The heterocycloalkyl group may also include bridged heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as 1-azatricyclo[3.3.1.13,7]dec-1-yl, etc.) and spiro heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxo-8-aza-spiro[4.5]dec-N-yl], etc.). In some embodiments, the heterocycloalkyl group has 3 to 10 ring atoms, 4 to 10 ring atoms, or about 3 to 8 ring atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring of the heterocycloalkyl group may be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized linkages), or the nitrogen atom may be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7 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 tetrahydropyridine, an azetidine ring, or a tetrahydrofuran ring.

[0685] As used herein, the term "heterocycloalkylalkyl", used alone or in combination with other terms, refers to a group having the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is 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 a monocyclic heterocycloalkyl group.

[0686] 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 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[0687] As used herein, the term "arylalkyl", used alone or in combination with other terms, refers to a group having the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is 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.

[0688] As used herein, the term "heteroaryl", 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 ring members that are independently selected from the group consisting of nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, oxazolyl, quinolinyl, isoquinolinyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. The carbon atoms or heteroatoms in the ring of the heteroaryl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized linkages), or the 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 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0689] As used herein, the term "heteroarylalkyl", alone or in combination with other terms, refers to a group having the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

[0690] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are meant. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the present invention can be separated as mixtures of isomers or as separated isomeric forms.

[0691] The compounds of the invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be locked in space in one form by appropriate substitution.

[0692] The compounds of the invention also include all isotopes of atoms present in intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds include at least one deuterium atom.

[0693] As used herein, unless otherwise specified, the term "compound" means to include all stereoisomers, geometric isomers, tautomeric forms, and isotopes of the depicted structure.

[0694] All compounds and their pharmaceutically acceptable salts can be obtained together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.

[0695] In some embodiments, the compounds or salts of the invention are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound or salt of the invention. Methods for separating compounds and their salts are conventional in the art.

[0696] 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 has an IC in an enzymatic assay of less than 1 μM 50 Inhibit the activity of PARP14 (see, for example, Example A).

[0697] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, thereby targeting the substrate protein for degradation.

[0698] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0699] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into the salt form of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); base or organic salts of acidic residues (such as carboxylic acids), and the like. Pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. 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 base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both solvents. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), which are incorporated herein by reference in their entirety.

[0700] Synthesis

[0701] The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0702] The reactions used to prepare the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by a person skilled in the art of organic synthesis. Suitable solvents can substantially not react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature within the range from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a person skilled in the art can select a suitable solvent for a specific reaction step.

[0703] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be 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 incorporated herein by reference in its entirety.

[0704] The reaction can be monitored according to any suitable method known in the art. For example, it 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 (HPLC) or thin layer chromatography to monitor the formation of the product.

[0705] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature (e.g., the reaction temperature) of about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20 °C to about 30 °C.

[0706] The compounds of the present invention can be prepared according to numerous preparative routes known in the literature. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0707] Scheme 1

[0708]

[0709] Scheme 1 shows the general synthesis of the quinazolinone compounds of the present disclosure, corresponding to group Q as defined above. Substituted aminobenzoic acids (1-A) (many of which are commercially available or can be prepared by methods known to those skilled in the art) can be converted to chloromethyl quinazolinones (1-B) by treatment with chloroacetonitrile in the presence of a pre-prepared solution of a metal (such as sodium) in a protic solvent (such as methanol) at room temperature. Treatment with thioacetic acid in a polar solvent such as DMF at room temperature can convert the chlorine group of 1-B to a thioacetate (1-C). The introduction of the heterocycle (ring A) can be accomplished by treatment with an appropriate electrophile (1-D) in the presence of a base such as an aqueous sodium hydroxide solution in a polar solvent (such as DMF) at an elevated temperature such as 90 °C, where Lv is an appropriate leaving group such as Br, I, mesylate or tosylate. Alternatively, the quinazolinones of the present invention can be prepared from chloromethyl quinazolinone (1-B) by treatment with a thioacetate-substituted heterocycle or trans-4-mercaptocyclohexanol in the presence of a base such as an aqueous sodium hydroxide solution in a polar solvent such as DMF at room temperature.

[0710] Scheme 2

[0711]

[0712] Scheme 2 shows the general synthesis of the compounds of the present invention. Substituted indoline-2,3-diones (1-1) (many of which are commercially available or can be prepared by methods known to those skilled in the art) can be converted to carboxylic acids (1-2) by treatment with hydrogen peroxide and a base (e.g., NaOH). Treatment with methyl iodide in the presence of a base (e.g., K2CO3) provides the methyl ester (1-3). Treatment with 2-chloroacetonitrile in the presence of an acid (e.g., HCl) provides the corresponding quinazolinone (1-4). Treatment with a thioacetate-substituted heterocycle in the presence of a base (e.g., NaOH) followed by treatment with an acid provides the thioether (1-5). Alkylation with a bromomethyl ester in the presence of a base (e.g., K2CO3) provides compound (1-6), which can be converted to acid 1-7 by treatment with an acid (e.g., HCl). Acid 1-7 can be linked to moiety E under peptide coupling conditions (e.g., EDCI, HOBt and DIPEA; or HATU, DIPEA) to provide compound 1-8.

[0713] Scheme 3

[0714]

[0715] Scheme 3 shows the synthesis of compound 2-2. Treatment of compound 1-4 with a cycloalkyl group substituted with thioacetate in the presence of a base (e.g., NaOH) provides compound 2-1. Compound 2-1 can be linked to moiety E under peptide coupling conditions (e.g., EDCI, HOBt, and DIPEA; or HATU, DIPEA) to provide compound 2-2.

[0716] Method of Use

[0717] The compounds of the present disclosure can bind to both PARP14 and ubiquitin E3 ligase to cause PARP14 degradation, which can be used to treat various diseases including cancer. In some embodiments, the compounds provided herein can degrade PARP14 in cells, which includes contacting the cells with the compound or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, methods for degrading PARP14 in a patient are provided herein, wherein the method includes administering to the patient an effective amount of the compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof. "Degrading PARP14" refers to inactivating PARP14 by, for example, altering its structure or breaking PARP14 into multiple peptide or amino acid fragments.

[0718] The compounds of the present invention can further inhibit the production of IL-10 in cells. For example, the present invention relates to a method for inhibiting or reducing the production of IL-10 in the cells by contacting the cells with the compounds of the present invention.

[0719] The compounds of the present invention can be used to treat various diseases associated with abnormal expression or activity of PARP14. For example, the compounds of the present invention can be used to treat cancer. In some embodiments, cancers treatable according to the present invention include hematological malignancies such as leukemia and lymphoma. Exemplary lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic leukemia (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Exemplary leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0720] Other cancers treatable by administering 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, gastric cancer, gastrointestinal tumors, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0721] In some embodiments, the cancers treatable by administration of the compounds of the invention are 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.

[0722] The compounds of the 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.

[0723] In some embodiments, the compounds of the invention can be used to treat inflammatory diseases. In some embodiments, the inflammatory diseases treatable according to the invention include inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), inflammatory arthritis, inflammatory demyelinating diseases, psoriasis, allergy, and asthma sepsis, allergic airway diseases (e.g., asthma), and lupus.

[0724] As used herein, the term "cell" means an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell can be a part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0725] As used herein, the term "contact" means bringing together the designated moieties in an in vitro system or an in vivo system. By way of example, "contacting" PARP14 or bringing a cell into "contact" with a compound of the invention includes administering the compound of the invention to an individual or patient (such as a human) having PARP14, and also includes, for example, introducing the compound of the invention into a sample containing a cell or a purified preparation having PARP14.

[0726] As used herein, the terms "individual" or "patient", which are used interchangeably, mean a mammal, and particularly a human.

[0727] As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or pharmaceutical agent that elicits the biological or medical response sought by a researcher, veterinarian, medical doctor, or other clinician in a tissue, system, animal, individual, or human.

[0728] As used herein, the terms "treating" or "treatment" refer to: 1) inhibiting a disease in an individual suffering from or displaying the pathology or symptoms of the disease (i.e., preventing further development of the pathology or symptoms), or 2) ameliorating a disease in an individual suffering from or displaying the pathology or symptoms of the disease (i.e., reversing the pathology or symptoms).

[0729] As used herein, the terms "preventing" or "prevention" refer to preventing a disease in an individual who may be susceptible to the disease but has not yet suffered from or displayed the pathology or symptoms of the disease.

[0730] Combination Therapy

[0731] One or more additional pharmaceutical agents or therapeutic methods (such as chemotherapeutic agents or other anti-cancer agents, immunopotentiators, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (such as IL2, GM-CSF, etc.) and / or kinases (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors) can be used in combination with the compounds of the present invention. The agents can be combined with the compounds of the present invention into a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.

[0732] Agents suitable for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiation therapies. The compounds of the present invention can be effectively combined with antihormonal agents for the treatment of breast cancer and other tumors. Suitable examples are antiestrogen agents, including but not limited to tamoxifen and toremifene; aromatase inhibitors, including but not limited to letrozole, anastrozole and exemestane; adrenocortical steroids (such as prednisone); progestins (such as megesterol acetate) and estrogen receptor antagonists (such as fulvestrant). Suitable antihormonal agents for the treatment of prostate cancer and other cancers can also be combined with the compounds of the present invention. These include antiandrogens, including but not limited to flutamide, bicalutamide and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin and histrelin; LHRH antagonists (such as degarelix) and androgen receptor blockers (such as enzalutamide) and agents that inhibit androgen production (such as abiraterone).

[0733] In some tumors, the combination of an angiogenesis inhibitor and an FGFR inhibitor can be effective. These angiogenesis inhibitors include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Inhibitors of the VEGFR kinase and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0734] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, thiotepa, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0735] Other anti-cancer agents include antibody therapeutic agents against co-stimulatory molecules such as CTLA-4, 4-1BB, PD-1, and PD-L1 or antibodies against cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab, and rituximab.

[0736] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those of skill in the art. Additionally, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, N.J.), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0737] Pharmaceutical Preparations and Dosage Forms

[0738] When used as a medicine, the compounds of the present invention can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well-known in the pharmaceutical art and can be administered by various routes depending on whether local treatment or systemic treatment is required and the area to be treated. Administration can be oral, topical (including ophthalmic and to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ophthalmic, or parenteral.

[0739] The present invention also encompasses pharmaceutical compositions containing a combination of one or more of the above compounds of the present invention as active ingredients and one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually admixed with an excipient, diluted by the excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form 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.

[0740] The compositions can be formulated into unit dosage forms. 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 material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0741] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of the compound actually administered will generally be determined by the physician in accordance with the relevant circumstances, which include the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0742] For preparing solid compositions such as tablets, the principal active ingredient is admixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be readily redivided into equivalent unit dosage forms such as tablets, pills and capsules. This solid preformulation is then redivided 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.

[0743] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that offers the advantage of extended action. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component, the latter in the form of a coating located over the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and permits the inner component to pass intact into the duodenum or be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0744] Liquid forms in which the compounds and compositions of the present invention can be included for oral or parenteral administration include aqueous solutions, syrups suitable for flavoring, aqueous or oily suspensions, and flavored emulsions having an edible oil (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0745] Compositions for inhalation or insufflation include solutions and suspensions, and powders, in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to achieve local or systemic effects. The compositions can be nebulized using an inert gas. The nebulized solution can be breathed directly from the nebulizing device or the nebulizing device can be connected to a face mask tent or intermittent positive pressure ventilator. The solution, suspension, or powder compositions can be administered orally or nasally from a device that appropriately delivers the formulation.

[0746] The amount of the compound or composition administered to a patient will vary depending on the administered substance, the purpose of administration (such as prophylaxis or treatment), the patient's condition, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms and complications of the disease. The effective dose will depend on the disease condition to be treated and the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0747] The compositions administered to a patient can be in the form of the above-described pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged for use as such or lyophilized, where the lyophilized preparation is combined with a sterile aqueous carrier before administration.

[0748] The therapeutic dosage of the compounds of the present invention can vary depending on, for example, the particular use for which treatment is desired, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in a pharmaceutical composition can vary depending on many factors, including the dosage, chemical characteristics (such as hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing from about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on such variables as the type and progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients, and its route of administration. The effective dosage can be extrapolated from the dose-response curve obtained from in vitro or animal model test systems.

[0749] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical agent, such as antiviral agents, anticancer agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, etc.

[0750] Examples

[0751] Equipment: Recorded at 400 MHz using a Bruker AVANCE 400 MHz spectrometer 1 H NMR spectra. NMR interpretation was performed using MestReC or MestReNova software to assign chemical shifts and multiplicities. In cases where the heights of two adjacent peaks were equal or unequal, the two peaks were labeled as a multiplet or doublet. In the case of a doublet, the coupling constant was assigned using this software. In any given example, one or more protons may not be observed due to the ambiguity of the water and / or solvent peaks. LCMS equipment and conditions were as follows:

[0752] LC: Agilent Technologies 1290 series, binary pump, diode array detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6 × 50 mm column. Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v). Flow rate: 1 mL / min, at 25 °C. Detectors: 214 nm, 254 nm. Gradient stop time, 10 minutes. Schedule:

[0753] T (min) A(％) B(％) 0.0 90 10 0.5 90 10 8.0 10 90 10.0 0 100

[0754] MS: G6120A, quadrupole LC / MS, ion source: ES-API, TIC: 70 to 1000 m / z, fragmenter: 60, drying gas flow rate: 10 L / min, nebulizer pressure: 35 psi, drying gas temperature: 350 °C, Vcap: 3000 V.

[0755] Sample preparation: Dissolve the sample in ACN or MeOH at approximately 1 to 10 mg / mL, then filter through a 0.22 μm filter membrane. Injection volume: 1 to 10 μL.

[0756] Definition: ACN (acetonitrile); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); CDCl3 (deuterochloroform); CD3OD (deutero-methanol); conc. (concentrated); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); ES-API (electrospray atmospheric pressure ionization); EtOAc (ethyl acetate); g (gram); h (hour); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HOBt (hydroxybenzotriazole); 1 1H NMR (proton nuclear magnetic resonance); HPLC (high performance liquid chromatography); Hz (hertz); KSAc (potassium thioacetate); L (liter); LCMS (liquid chromatography - mass spectrometry); M (mole); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter), mmol (millimole); MsCl (methanesulfonyl chloride); NMP (N-methyl-2-pyrrolidone); ppm (parts per million); RT (room temperature); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TIC (total ion chromatogram); TLC (thin layer chromatography); v / v (volume / volume).

[0757] Synthesis of Intermediates

[0758] Intermediate-1: tert-Butyl 4-(acetylthio)piperidine-1-carboxylate

[0759]

[0760] To a solution of tert-butyl 4-bromopiperidine-1-carboxylate (50 g, 189.3 mmol) in DMF (200 mL) was added KSAc (25.9 g, 227.1 mmol). The mixture was stirred at 25 °C under N2 atmosphere for 24 h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (500 mL x 3), dried over Na2SO4 and concentrated to give the title compound as a brown oil (47.2 g, 96.1%). 1 H NMR (400 MHz, CDCl3) δ 3.87–3.84 (m, 2H), 3.64–3.57 (m, 1H), 3.08–3.02 (m, 2H), 2.31 (s, 3H), 1.92–1.87 (m, 2H), 1.58–1.45 (m, 2H), 1.45 (s, 9H).

[0761] Intermediate 2: 4-(6-Aminohexylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione hydrochloride

[0762]

[0763] Step 1: tert-Butyl N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]hexyl]carbamate

[0764] To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (300 mg, 1.1 mmol; purchased from Sigma Aldrich) and tert-butyl N-(6-aminohexyl)carbamate (258 mg, 1.2 mmol) in NMP (12 mL) was added DIPEA (280 mg, 2.2 mmol) and the mixture was stirred at 90 °C overnight. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 30:1, v / v) to give the title compound as a green solid (200 mg, 39%). LCMS: [M+Na] + 495.2.

[0765] Step 2: 4-(6-Aminohexylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione hydrochloride

[0766] To a solution of tert-butyl N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]hexyl]carbamate (200 mg, 0.42 mmol) was added HCl / EtOAc (10 mL, 18 mmol), and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and washed with EtOAc to afford the title compound as a green solid (140 mg, 81%). LCMS: [M+H] + 373.2。

[0767] Intermediate 3: S-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl) thioacetate

[0768]

[0769] Step 1: (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate

[0770] To a solution of tert-butyl ((1S,4S)-4-hydroxycyclohexyl)carbamate (5 g, 23.2 mmol) and triethylamine (4.7 g, 46.5 mmol) in DCM (25 mL) was added MsCl (4.0 g, 34.8 mmol) at room temperature under a N2 atmosphere and the mixture was stirred for 2 h. The mixture was diluted with water (20 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 15:1, v / v) to afford 6.4 g of the title compound. 1 1H NMR (400 MHz, DMSO-d6) δ 6.90 - 6.82 (m, 1H), 4.8 (br s, 1H), 3.35 - 3.32 (m, 1H), 3.15 (s, 3H), 1.94 - 1.88 (m, 2H), 1.71–1.59 (m, 4H), 1.51–1.46 (m, 2H), 1.39 (s, 9H).

[0771] Step 2: S-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl) thioacetate

[0772] To a solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (3.3 g, 11.3 mmol) in DMF (15 mL) was added KSAc (1.9 g, 16.9 mmol), and the mixture was stirred at 70 °C under N2 atmosphere for 2 h. The residue was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 15:1, v / v) to give the title compound as a brown solid (0.9 g, 29% yield). LCMS: [M+H] + 274.3。

[0773] Intermediate 4: 8-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]octanoic acid

[0774]

[0775] To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoroisoindoline-1,3-dione (100 mg, 0.36 mmol; purchased from Sigma Aldrich) in NMP (2 mL) was added 8-aminooctanoic acid (69 mg, 0.43 mmol) and DIPEA (234 mg, 1.8 mmol). The mixture was stirred at 90 °C overnight. The mixture was diluted with 10 mL of 1N HCl and extracted with EtOAc (20 mL x3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 40:1 to 20:1, v / v) to give the title compound as a yellow solid (50 mg, 33%). LCMS: [M+H] + 416.2。

[0776] Intermediate 5: 3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]propanoic acid

[0777]

[0778] To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (200 mg, 0.72 mmol; purchased from Sigma Aldrich) in NMP (4 mL) was added 3-aminopropionic acid (97 mg, 1.1 mmol) and DIPEA (467 mg, 3.6 mmol). The mixture was stirred overnight at 90 °C. The mixture was diluted with 1N HCl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 20:1, v / v) to give the title compound as a yellow solid (60 mg, 24%). LCMS: [M+H] + 346.1。

[0779] Example 1: 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 trifluoroacetate

[0780]

[0781] Step 1: 2-Amino-4,6-difluorobenzoic acid

[0782] To a suspension of 4,6-difluoroindoline-2,3-dione (25.0 g, 136.5 mmol) in 1N NaOH (137 mL, 137 mmol) at 0 °C was added dropwise H2O2 (30%, 45.0 mL), and the mixture was warmed to room temperature and stirred for 5 h. The mixture was poured into water (200 mL) and adjusted to pH 6 - 7 with 1N HCl. The precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound as a yellow solid (21.7 g, 92%). LCMS: [M+H] + 174.1。

[0783] Step 2: Methyl 2-amino-4,6-difluorobenzoate

[0784] To a suspension of 2-amino-4,6-difluorobenzoic acid (94.0 g, 543.0 mmol) and K2CO3 (112.6 g, 814.5 mmol) in DMF (1 L) was added dropwise methyl iodide (92.5 g, 651.6 mmol) under a N2 atmosphere, and the mixture was stirred at 20 °C for 2 h. The mixture was quenched with water (3.5 L) and stirred at 20 °C for 30 min. The suspension was filtered. The cake was washed with a 1 L solution of 20:1 petroleum ether:EtOAc and dried in vacuo to give the title compound as a brown solid (89 g, 88%). LCMS: [M+H] + 188.1

[0785] Step 3: Methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate

[0786] To a solution of methyl 2-amino-4,6-difluorobenzoate (3 g, 16.0 mmol, 1.0 equiv) in DMSO (5 mL) was added cyclopentylamine (2.73 g, 32.0 mmol, 2.0 equiv) and the mixture was heated at 80 °C overnight. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with DCM (40 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:DCM, 40:1, v / v to petroleum ether:EtOAc, 30:1 to 20:1, v / v) to give the title compound as a red solid (863 mg, 21%). LCMS: [M+H] + 253.1

[0787] Step 4: 2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

[0788] A mixture of methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate (48.0 g, 190.3 mmol) and 2-chloroacetonitrile (60.2 mL, 951.3 mmol) in 4N HCl in dioxane (240.0 mL, 960 mmol) was heated at 100 °C in a sealed tube overnight. The mixture was diluted with 770 mL of a 10:1 petroleum ether:EtOAc solution and stirred at room temperature for 1 h. The suspension was filtered, and the cake was dried in vacuo to give the title compound as a brown solid (56.0 g, 99.5% yield). LCMS: [M+H] + 296.1

[0789] Step 5: tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[0790] To a solution of 2-(chloromethyl)-7-(cyclopentylamino)-5-fluoro-3H-quinazolin-4-one (1 g, 3.4 mmol) and tert-butyl 4-acetylsulfanylpiperidine-1-carboxylate (1.1 g, 4.1 mmol) in THF (20 mL) was added 2 M NaOH (6.8 mL, 13.5 mmol), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 30:1, v / v) to give the title compound as a yellow solid (500 mg, 31%). LCMS: [M+H] + 477.2。

[0791] Step 6: 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[0792] A solution of tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (450 mg, 0.94 mmol) in 40 mL of 1.5 M HCl in EtOAc was stirred overnight at 25 °C. The mixture was concentrated under reduced pressure to give 7-(cyclopentylamino)-5-fluoro-2-(4-piperidylsulfanylmethyl)-3H-quinazolin-4-one as a yellow solid (350 mg, 98.5% yield). LCMS: [M+H] + 377.2。

[0793] 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (br s, 1H), 8.77 (br s, 1H), 6.53 (s, 1H), 6.51 (d, J = 14.0 Hz, 1H), 3.80–3.77 (m, 1H), 3.73 (s, 2H), 3.25–3.22 (m, 2H), 3.17–3.11 (m, 1H), 2.94 - 2.86 (m, 2H), 2.16–2.13 (m, 2H), 2.02–1.93 (m, 2H), 1.78–1.66 (m, 4H), 1.63–1.52 (m, 2H), 1.50–1.42 (m, 2H).

[0794] Step 7: tert-Butyl 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidyl]acetate

[0795] To a solution of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (1.0 g, 2.4 mmol) in NMP (10 mL) was added tert-butyl 2-bromoacetate (567 mg, 2.91 mmol) and K2CO3 (1.0 g, 7.26 mmol). The mixture was heated at 40 °C overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 100:1 to 50:1, v / v) to give the title compound as a yellow solid (430 mg, 36%). LCMS: [M+H] + 491.1。

[0796] Step 8: 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetic acid hydrochloride

[0797] A solution of tert-butyl 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetate (430 mg, 0.88 mmol) in 2M HCl / EtOAc (12 mL, 24 mmol) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (390 mg, 94.5% yield). LCMS: [M+Na]+ 435.2.

[0798] Step 9: 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]-N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]hexyl]acetamide trifluoroacetate

[0799] To a solution of 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetic acid hydrochloride (127 mg, 0.27 mmol) and 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione hydrochloride (110 mg, 0.27 mmol) in DMF (20 mL) was added EDCI (258 mg, 1.35 mmol), HOBt (91 mg, 0.67 mmol) and DIPEA (139 mg, 1.08 mmol) under N2 atmosphere, and the mixture was stirred overnight at room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 1:1, v / v), reverse-phase column (Biotage, 45%-55% ACN aqueous solution, 0.1% TFA) and preparative HPLC (Shimadzu, Sepax BR preparative-C18, 10 μm, 250 x 21.2 mm column, gradient elution with ACN aqueous solution containing 0.1% TFA, flow rate 20 mL / min) to give the title compound as a green solid (85 mg, 35% yield). LCMS: [M+H]+ 789.2. 1 HNMR(400MHz,DMSO-d6)δ11.11(s,1H),9.73(s,1H),8.55-8.44(m,1H),7.60-7.57(m,1H),7.10-7.08(m,1H),7.04-7.02(m,1H),6.88(s,1H),6.56-6.36(m,3H),5.07-5.03(m,1H),3.96-3.74(m,3H),3.59(s,1H),3.50-3.41(m,2H),3.34-3.25(m,2H),3.20-2.99(m,4H),2.97-2.84(m,2H),2.63-2.54(m,2H),2.22-2.21(m,2H),2.09-1.84(m,4H),1.80-1.63(m,4H),1.61-1.52(m,4H),1.49-1.39(m,4H),1.37-1.27(m,4H).

[0800] Example 2: (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamido)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0801]

[0802] Step 1: Ethyl 7-[[2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetyl]amino]heptanoate

[0803] To a solution of 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetic acid hydrochloride (200 mg, 0.42 mmol, from Example 1, Step 8) in DMF (10 mL) was added ethyl 7-aminoheptanoate (160 mg, 0.92 mmol), EDCI (265 mg, 1.38 mmol), triethylamine (233 mg, 2.3 mmol) and HOBt (187 mg, 1.38 mmol) at room temperature under a N2 atmosphere. The mixture was stirred overnight at room temperature. The mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound as a yellow solid (170 mg, 61% yield). LCMS: [M+H] + 590.2.

[0804] Step 2: 7-[[2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetyl]amino]heptanoic acid

[0805] To a solution of ethyl 7-[[2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetyl]amino]heptanoate (168 mg, 0.28 mmol) in MeOH (5 mL / ) was added 2N NaOH (0.57 mL, 1.14 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated to give the title compound as a yellow solid (128 mg, 0.23 mmol, 80% yield). LCMS: [M+H] + 562.1.

[0806] Step 3: (2S,4R)-1-((S)-2-(7-(2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetamido)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0807] To a solution of 7-[[2-[4-[[7-(Cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylthio]-1-piperidinyl]acetyl]amino]heptanoic acid (50 mg, 0.09 mmol) in NMP (5 mL) was added (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (115 mg, 0.27 mmol), EDCI (42 mg, 0.27 mmol), HOBt (36 mg, 0.27 mmol), DIPEA (46 mg, 0.36 mmol). The mixture was stirred overnight at room temperature, then water was added and the resulting suspension was filtered. The filtrate was purified by preparative HPLC (Shimadzu, Sepax BR preparative-C18, 10 μm, 250 x 21.2 mm column, gradient elution with ACN in water containing 0.1% TFA, flow rate 20 mL / min) to give the title compound as a yellow solid (5 mg, 6% yield). LCMS: [M+H] + 975.2。 1 1H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 7.48 - 7.41 (m, 5H), 6.47 (t, J = 12.0 Hz, 2H), 4.65 - 4.62 (m, 1H), 4.58 - 4.51 (m, 3H), 4.38 - 4.34 (t, J = 15.6 Hz, 1H), 3.91 - 3.78 (m, 5H), 3.70 - 3.60 (m, 2H), 3.25 - 3.21 (m, 2H), 3.13 - 3.07 (m, 2H), 2.48 (s, 3H), 2.30 - 2.19 (m, 5H), 2.11 - 2.00 (m, 4H), 1.87 - 1.83 (m, 2H), 1.79 - 1.75 (m, 2H), 1.69 - 1.64 (m, 2H), 1.62 - 1.50 (m, 6H), 1.34 - 1.29 (m, 6H), 1.03 (s, 9H).

[0808] Example 3: 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

[0809]

[0810] Step 1: 2,6-difluoro-4-hydroxy-benzoic acid

[0811] To a solution of 2,6-difluoro-4-hydroxy-benzonitrile (200 g, 1290 mmol) in water (933 mL) was added a solution of NaOH (181 g, 4513 mmol) in water (533 mL), and the mixture was stirred at 100 °C for 4 h. The mixture was cooled to room temperature and adjusted to pH 2 with 6N HCl. The suspension was filtered. The filter cake was washed with water (500 mL) and dried in vacuo to give the title compound as a white solid (222.2 g, 99% yield). LCMS: [M-H] 173.0.

[0812] Step 2: Methyl 2,6-difluoro-4-hydroxy-benzoate

[0813] To a solution of 2,6-difluoro-4-hydroxy-benzoic acid (811 g, 4658 mmol) in methanol (3500 mL) was slowly added thionyl chloride (1386 g, 11646 mmol) at 0 °C, and the mixture was refluxed overnight. The mixture was concentrated, and the residue was diluted with water (2500 mL) and stirred at room temperature for 30 min. The suspension was filtered. The filter cake was washed with water and dried in vacuo to give the title compound as an off-white solid (739 g, 84% yield). LCMS: [M+H] + 189.1.

[0814] Step 3: Methyl 2,6-difluoro-4-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

[0815] A mixture of methyl 2,6-difluoro-4-hydroxy-benzoate (20 g, 106 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (22.8 g, 127.6 mmol) and K2CO3 (22 g, 160 mmol) in DMSO (150 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (1000 mL). The precipitate was collected by filtration and dried in vacuo to give the title compound as a yellow solid (30 g, 99% yield). LCMS: [M+H] + 287.2.

[0816] Step 4: Methyl 2-[(2,4-dimethoxyphenyl)methylamino]-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate

[0817] A mixture of methyl 2,6-difluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate (30 g, 105 mmol), (2,4-dimethoxyphenyl)methylamine (23.6 mL, 157.2 mmol) and K2CO3 (36.2 g, 262 mmol) in NMP (200 mL) was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (1500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow solid (40 g, 88% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 8.05 - 8.03 (m, 1H), 7.18–7.16 (m, 1H), 6.59 (s, 1H), 6.49–6.45 (m, 1H), 6.05–6.01 (m, 2H), 4.26 (d, 2H, J = 5.6 Hz), 3.90–3.83 (m, 4H), 3.81 (s, 3H), 3.75 (s, 6H), 3.35–3.29 (m, 2H), 1.96–1.91 (m, 1H), 1.68–1.62 (m, 2H), 1.31–1.26 (m, 2H).

[0818] Step 5: Methyl 2-amino-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate

[0819] A solution of methyl 2-[(2,4-dimethoxyphenyl)methylamino]-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate (40 g, 92 mmol) and triethylsilane (29.5 mL, 184.6 mmol) in DCM (200 mL) was added TFA (100 mL, 1346 mmol). The reaction mixture was stirred at 25 °C for 2 h. The mixture was adjusted to pH 8 - 9 with saturated aqueous NaHCO3 and extracted with EtOAc (400 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow solid (20 g, 77% yield). LCMS: [M+H] + 284.2

[0820] Step 6: 2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[0821] Methyl 2-amino-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate (20 g, 71 mmol) and chloroacetonitrile (13.4 mL, 211.8 mmol) in 2N HCl / dioxane (120 mL, 240 mmol) were stirred at 80 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the precipitate was collected by filtration and washed with EtOAc (100 mL) and water (100 mL). The residue was dried in vacuo to give the title compound as a yellow solid (14 g, 61%). LCMS: [M+H] + 327.1。

[0822] Step 7: tert-Butyl ((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamate

[0823] To a solution of 2-(chloromethyl)-5-fluoro-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-4-one (200 mg, 0.61 mmol) and S-[4-(tert-butoxycarbonylamino)cyclohexyl] thioacetate (201 mg, 0.73 mmol) in THF (2 mL) was added 2N NaOH (2 mL, 4 mmol), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 30:1, v / v) to give the title compound as a brown solid (250 mg, 78%). LCMS: [M+H] + 522.3。

[0824] Step 8: 2-[(4-Aminocyclohexyl)thio]methyl-5-fluoro-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-4-one hydrochloride

[0825] A solution of tert-Butyl ((1r,4r)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamate (250 mg, 0.48 mmol) in 1N HCl / EtOAc (5 mL, 5 mmol) was stirred at 25 °C for 2 h. The residue was concentrated under reduced pressure to give the title compound as a brown solid (120 mg, 55%). LCMS: [M+H] + 422.3。

[0826] Step 9: 8-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]-N-[4-[[5-fluoro-4-oxo-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-2-yl]methylthio]cyclohexyl]octanamide

[0827] To a solution of 8-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]octanoic acid (50 mg, 0.12 mmol) in DMF (1 mL) was added HATU (69 mg, 0.18 mmol), and the mixture was stirred at room temperature for 0.5 h. To the reaction mixture were added DIPEA (31 mg, 0.24 mmol) and 2-[(4-aminocyclohexyl)thiomethyl]-5-fluoro-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-4-one hydrochloride (66 mg, 0.14 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1, v / v) to give the title compound as a yellow solid (45 mg, 46%). LCMS: [M+H] + 819.0。 1 HNMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.10 (s, 1H), 7.64 - 7.53 (m, 2H), 7.10 - 7.06 (m, 1H), 7.03 - 6.99 (m, 1H), 6.91 - 6.85 (m, 2H), 6.59 - 6.49 (m, 1H), 5.10 - 4.99 (m, 1H), 4.01 - 3.93 (m, 2H), 3.92–3.84 (m, 2H), 3.59 (s, 2H), 3.53 - 3.44 (m, 1H), 3.31 - 3.27 (m, 2H), 2.94 - 2.81 (m, 1H), 2.73 - 2.64 (m, 1H), 2.62 - 2.54 (m, 1H), 2.05 - 1.95 (m, 6H), 1.90 - 1.72 (m, 2H), 1.70 - 1.61 (m, 2H), 1.59 - 1.50 (m, 2H), 1.49 - 1.41 (m, 2H), 1.37 - 1.09 (m, 15H).

[0828] Example 4: 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

[0829]

[0830] To a solution of 2-[(4-aminocyclohexyl)thiolan-1-ylmethyl]-5-fluoro-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-4-one hydrochloride (30 mg, 0.07 mmol; from Example 3, Step 8) and EDCI (25 mg, 0.13 mmol) in DMF (1 mL) was added HOBt (18 mg, 0.13 mmol), triethylamine (27 mg, 0.26 mmol) and 3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]propanoic acid (27 mg, 0.08 mmol). The mixture was stirred at room temperature for 3 h. Water (2 mL) was added to the mixture. The resulting precipitate was collected by filtration, washed with water and dried in vacuo. The crude material was purified by a reverse-phase column (H2O / ACN = 60 / 40 v / v) to give the title compound as a yellow solid (15 mg, 31%). LCMS: [M+H] + 748.9; 1 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 11.10 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.91 - 6.87 (m, 2H), 6.71 (s, 1H), 5.07 - 5.01 (m, 1H), 3.98 (d, J = 6.4 Hz, 2H), 3.88 - 3.86 (m, 2H), 3.59 (s, 2H), 3.55 - 3.45 (m, 3H), 3.36 - 3.27 (m, 2H), 2.90 - 2.84 (m, 1H), 2.74 - 2.64 (m, 1H), 2.60 - 2.56 (m, 1H), 2.45 - 2.42 (m, 1H), 2.39 - 2.31 (m, 2H), 2.05 - 1.94 (m, 4H), 1.80 - 1.76 (m, 2H), 1.68 - 1.65 (m, 2H), 1.38 - 1.23 (m, 4H), 1.20 - 1.08 (m, 2H).

[0831] Example A. Enzymatic assay for inhibiting PARP14

[0832] The catalytic domain of human PARP14 (residues 1611 to 1801, GenBank accession number NM_017554) was overexpressed in Escherichia coli cells. An N-terminal His-TEV fusion tag was used to purify the protein from cell lysates, and the His-TEV tag remained on the protein for use in enzymatic assays.

[0833] Enzymatic inhibition of PARP14 was measured using dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) that monitors the automodification of PARP14 by biotinylated nicotinamide adenine dinucleotide (biotin-NAD). Each test compound for the dose-response curve was spotted at 1 μL using a Mosquito (TTPLabtech) in 384-well nickel-coated white microplates (Thermo). The reaction was carried out in a 50 μL volume by adding 40 μL of PARP14 in assay buffer (20 mM HEPES pH = 8, 100 mM NaCl, 0.1% bovine serum albumin, 2 mM DTT, and 0.002% Tween 20), incubating with the test compound at 25 °C for 30 minutes, and then adding 10 μL of biotin-NAD (Biolog). The final concentrations of PARP14 and biotin-NAD were 50 nM and 3 μM, respectively. The reaction was carried out at 25 °C for 3 hours and then quenched with 5 μL of 10 mM unmodified nicotinamide adenine dinucleotide (Sigma-Aldrich). The quenched reactants were washed 3 times with 100 μL of TBST wash buffer (50 mM Tris-HCl, 150 mM NaCl, and 0.1% Tween 20). Next, 25 μL of DELFIA Europium-N1 streptavidin (Perkin Elmer) diluted in DELFIA assay buffer (Perkin Elmer) was added to the washed and dried plate. After incubation at 25 °C for 30 minutes, the plate was washed 5 times with TBST wash buffer. Finally, 25 μL of DELFIA enhancement solution was added. After incubation for 5 minutes, the plate was read on an Envision plate reader equipped with a LANCE / DELFIA top mirror (Perkin Elmer), and the amount of europium present in each well was measured using 340 nm excitation and 615 nm emission, which informed the amount of biotin-NAD transferred in the automodification reaction. Control wells with a negative control containing 2% DMSO vehicle or a positive control of 100 μM rucaparib were used to calculate the inhibition %, as described below:

[0834]

[0835] where ex615 cmpdIs the emission from the compound treatment wells, ex615 min Is the emission from the positive control wells treated with rucaparib, and ex615 max Is the emission from the negative control wells treated with DMSO.

[0836] The percent inhibition values were plotted as a function of compound concentration and the following 4-parameter fit was applied to derive the IC 50 value:

[0837]

[0838] wherein the top and bottom are typically allowed to float, but can be fixed at 100 or 0, respectively, in a 3-parameter fit. The Hill Coefficient is typically allowed to float, but can also be fixed at 1 in a 3-parameter fit. Y is percent inhibition and X is compound concentration.

[0839] IC for certain compounds corresponding to Q groups as defined herein is provided in Table A-1 below 50 data (“+” is <1 μM; “++” is ≥1 μM and <10 μM; and “+++” is ≥10 μM).

[0840] Table A-1

[0841]

[0842]

[0843] Example B: PARP14 Degradation Assay

[0844] The KYSE270 cells were seeded at 0.5e 6Cells were seeded at a density of cells / well in a 6-well plate and incubated overnight. Once attached, the cells were treated with increasing concentrations (0.001 μM, 0.01 μM, 0.1 μM, 1 μM, and 10 μM; 0.003 μM, 0.03 μM, 0.3 μM, and 3 μM were also evaluated for the compounds of Example 1) of the compounds of Examples 1-4 or DMSO for 24 hours. The medium was gently aspirated and the cells were washed 3 times with 2 mL of ice-cold PBS on ice. The PBS was completely aspirated and 75 μl of freshly prepared lysis buffer (Thermo Fisher 78501) was added to the cells before scraping into the buffer. The lysates were collected in microcentrifuge tubes and incubated on ice for 15 minutes. The lysates were centrifuged at 10,000 rpm for 15 minutes at 4 °C and the supernatants were collected into fresh microcentrifuge tubes. Protein concentrations were measured using a reducing agent compatible with the Pierce BCA Protein Assay Kit (Thermo Fisher 23250). Samples were prepared in loading buffer (LI-COR 928-40004) containing 5% β-mercaptoethanol and incubated at 95 °C for 5 minutes. Protein lysates were resolved on a 4%-12% Tris-acetate gel in MOPS running buffer, with 60 μg of protein per well. Protein blotting transfer was performed at 20 volts for 14 minutes using a PVDF membrane (LI-COR Immobilon). Primary antibodies (PARP14: internally generated mouse antibody (15A6 Lot1C), β-actin: D6A8 (8457)) were incubated at a 1:1,000 dilution in Odyssey blocking buffer (LI-COR 927-50000) for 2 hours at room temperature and detected with secondary antibodies (LI-COR 926-68072, 926-32211). The mouse antibody 15A6 Lot1C was generated by immunization with recombinant human PARP14 catalytic domain protein. After hybridoma fusion, parental clones were screened for reactivity against the PARP14 catalytic domain and then subcloned to generate monoclonal clones including 15A6-1. Monoclonal supernatants were tested by Western blotting against THP-1 and THP-1 PARP14 KO cells to confirm reactivity. The PARP14 antibody was generated by culturing 15A6-1 hybridoma monoclonal cells in 1 L of serum-free medium + 2% low IgG FBS. The antibody was purified from the medium by protein G affinity chromatography.

[0845] Treatment of KYSE270 cells with the compounds of Examples 1-4 for 24 hours resulted in dose-dependent depletion of PARP14. At higher concentrations, Examples 1, 3 and 4 demonstrated improved efficacy consistent with a ternary complex-mediated mechanism, which is referred to as the "hook effect" and was described in Crews et al., Nature Chem. Biol. 2015, 11, 611. Figure 1 Western blot showing PARP14 degradation assay of the compound of Example 1. Figure 2 Western blot showing PARP14 degradation assay of the compound of Example 2. Figure 3 Western blot showing PARP14 degradation assay of the compound of Example 3. Figure 4 Western blot showing PARP14 degradation assay of the compound of Example 4.

[0846] Example C: mRNA expression levels of PARP14 in various cancer types

[0847] Figure 5 Shows the mRNA expression levels of PARP14 in various cancer types compared to their matched normal tissues. RNA sequencing data were downloaded from The Cancer Genome Consortium (TCGA) and analyzed. Individual points represent values from individual samples, boxes represent the quartiles or middle 50% of the data, horizontal lines represent the group medians, and vertical lines represent the upper and lower quartiles of the data. It is evident that PARP14 mRNA is higher in several cancer types compared to normal tissues. BLCA = bladder cancer, BRCA = breast cancer, ESCA = esophageal cancer, HNSC = head and neck cancer, KIRP = papillary renal cell carcinoma, KIRC = clear cell renal cell carcinoma, READ = rectal cancer, STAD = gastric cancer, THCA = thyroid cancer, UCEC = uterine cancer. *p < 0.05, **p < 0.01, ***p < 0.001, Wilcoxon test.

[0848] Example D: Reduction of IL-10 production in cells

[0849] Figure 6A and 6B Shows that in vitro treatment with the compound of Example 1 reduces the production of IL-10 in IL-4-stimulated M2-like macrophages. Figure 6A Shows the experimental layout.

[0850] Monocytes were isolated from peripheral human blood and cultured for 72 hours in the presence of M-CSF and the compound of Example 1 (1, 0.1 or 0.01 μM). M-CSF differentiates monocytes into M-0 macrophages. Subsequently, the medium was replaced with fresh medium containing IL-4 and the compound of Example 1 (1, 0.1 or 0.01 μM), and the cells were incubated for an additional 48 hours.

[0851] Figure 6B The levels of IL-10 in the tissue culture supernatants of the cells treated as described above were measured by ELISA.

[0852] Isolation of primary human monocytes from whole blood: Primary monocytes were isolated from whole blood (iSPECIMEN; 500 mL) collected from healthy donors. According to the manufacturer's instructions, the blood was diluted 1:1 with EasySep buffer (STEMCELL Technologies 20144) and layered on lymphoprep (STEMCELL Technologies 07811) in a SepMate tube (STEMCELL Technologies 85450) for PBMC isolation. The isolated PBMCs were pooled, washed with EasySep buffer, resuspended in an appropriate volume of ammonium chloride solution (STEMCELL Technologies 07850; 10 - 15 mL) for RBC lysis, and gently shaken for 10 minutes. The total volume was increased to 40 mL with EasySep buffer to dilute the RBC lysate, and then the cells were centrifuged at 1500 rpm for 5 minutes. Fresh EasySep buffer was used to resuspend the PBMCs for counting. According to the manufacturer's instructions, monocytes were isolated from the PBMC cell population using the EasySep Human Monocyte Isolation Kit (STEMCELL Technologies 19359). The enriched monocyte population was resuspended in fresh EasySep buffer for counting and seeding for subsequent assays.

[0853] Monocyte differentiation into macrophages, M2 polarization, and PARP14 inhibition: On day 0, monocytes were seeded in ImmunoCult SF Macrophage Medium (STEMCELL Technologies 10961) containing 50 ng / mL M-CSF (STEMCELL Technologies 78057) in 12-well plates at a density of 1 million cells per 1 mL of medium and allowed to grow and differentiate into macrophages for 6 days. On day 4, half of the initial volume of medium was added to each well. Six days after monocyte seeding, the cells were treated with 25 ng / mL human recombinant IL-4 (STEMCELL Technologies 78045), and samples (medium and cells) were collected after 72 hours. On day 6 after seeding, the cells were treated with the compound of Example 1 or DMSO at 1 μmol / L, 0.1 μmol / L, and 0.01 μmol / L.

[0854] IL-10 assay: The IL-10 levels in the supernatants of human primary M2 macrophages were determined using an IL-10 ELISA kit (STEMCELL Technologies 02013) according to the manufacturer's instructions. Briefly, supernatants were collected at the designated time points and any floating cells were depleted before storing at -80 °C until ready for use. The IL-10 concentration was determined from the IL-10 standard curve of the kit and normalized against the total cellular protein.

[0855] Various modifications of the invention other than those described herein will be apparent to those skilled in the art in light of the foregoing description. Such modifications are also intended to be within the scope of the appended claims. All references cited in this application, including all patents, patent applications, and publications, are hereby incorporated by reference in their entirety.

Claims

1. A compound of formula (A1) or a pharmaceutically acceptable salt thereof: Q-L 1 -E(A1), Wherein: Q is a moiety represented by formula I: Wherein: W is CR W or N; X is CR X or N; Y is CR Y or N; Z is CR Z or N; Wherein no more than two of W, X, Y and Z are simultaneously N; Ring A is a single or polycyclic C 3-14 alkyl or Ring A is a single or polycyclic 4- to 18-membered heterocycloalkyl, where Ring A is optionally substituted with 1, 2, 3, or 4 R A substituents, and when Ring A is polycyclic, Ring A is attached to the -(L) of formula I via a non-aromatic ring m - moiety; L is -(CR 5 R 6 ) t -, -(CR 5 R 6 ) p -O-(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -S-(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -NR 3 -(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -CO-(CR 5 R 6 ) q -, -(CR 5 R 6 ) r -C(O)O-(CR 5 R 6 ) s -, -(CR 5 R 6 ) r -CONR 3 -(CR 5 R 6 ) s -, -(CR 5 R 6 ) p -SO-(CR 5 R 6 ) q -, -(C R 5 R 6 ) p -SO2-(CR 5 R 6 ) q -, -(CR 5 R 6 ) r -SONR 3 -(CR 5 R 6 ) s - or -NR 3 CONR 4 -; R 1 and R 2 are each independently selected from H and methyl; R 3 and R 4 are each independently selected from H and C 1-4 alkyl; R 5 and R 6 each independently selected from H, a halogen group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, amino, C 1-4 alkylamino and C 2-8 dialkylamino; Each R A is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a1 , 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 ; wherein said 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 each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: Cy 1 、Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 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 ； R W 、R X 、R Y and R Z Each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 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 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; wherein R W , R X , R Y or R Z of said 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 are each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: Cy 2 , Cy 2 -C 1-4 alkyl, halogen, 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 , 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 和S(O)2NR c2 R d2 ; Wherein when W is CR W , X is CR X , Y is CR Y , and Z is CR Z , then at least one of R W , R X , R Y and R Z is not H; Each Cy 1 is 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 optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)2NR c1 R d1 ; Each Cy 2 is independently selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; Each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 or R d2 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 3 、Cy 3 -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 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)NR c3 R d3 , NR c3 , C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 , NR b3 , S(O)2R c3 , NR c3 R d3 and S(O)2NR c3 R d3 ; Each Cy 3 is C 6-10 aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following: halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ; R a3 、R b3 、R c3 and R d3 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, 5-10 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 aryl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally independently substituted with 1, 2 or 3 substituents 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 with 1, 2 or 3 substituents independently selected from the following: halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ; 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 1, 2 or 3 substituents independently selected from the following: halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ; Each R e1 、R e2 and R e3 is independently selected from H, C 1-4 alkyl, and CN; m is 0 or 1, n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, where p + q is 0, 1 or 2; r is 0 or 1; s is 0 or 1, where r + s is 0 or 1; and t is 1, 2 or 3; L 1 is a linker, and the linker is covalently linked to part Q and part E; E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; and wherein the wavy line represents the connection point with the group L 1 ; Wherein any of the above heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; Wherein one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups are optionally substituted with an oxo group (=O); and Wherein one or more ring-forming S atoms of any of the above heterocycloalkyl groups are optionally substituted with one or two oxo groups (=O).

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the linker L 1 is a chain of 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10 or 1 to 5 chain atoms, which is optionally substituted by 1 - 3 R q substituents, and wherein one or more chain carbon atoms of L 1 may be oxidized to form a carbonyl (C=O), and wherein one or more N and S chain atoms may each optionally be oxidized to form an N-oxide, sulfoxide or sulfonyl group; and Each R q Independently selected from OH, CN, -COOH, NH2, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, NH(C 1-6 alkyl) and N(C 1-6 alkyl)2, wherein R q The C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with halo, OH, CN, -COOH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, phenyl, C 3-10 The group is substituted with cycloalkyl, 5- or 6-membered heteroaryl or 4- to 6-membered heterocycloalkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the linker L 1 has the following structure: where each G is independently selected from –C(O)-, -NR G C(O)-, -NR G -, -O-, -S-, -C(O)O-, -OC(O)NR G -, -NR G C(O)NR G -, -S(O2)- or -S(O)NR G -; Each R G is independently selected from H, methyl, and ethyl; a is 0 or 1; b is 0 or 1; and c is 0 or 1, where the wavy line represents the point of attachment to moieties Q and E.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein a is 1, b is 1, and c is 1.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein a is 0, b is 1, and c is 0.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein a is 1, b is 1, and c is 0.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein each G is independently selected from -C(O)- and -NR G C(O)-.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the linker L 1 is selected from: And Where the wavy line represents the point of attachment to moieties Q and E.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein E is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein E is a moiety having a structure selected from: where the wavy line represents the point of attachment to the group L 1 ​ 11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein E has the following structure: where the wavy line indicates the connection point with L 1 ​ 12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein E has the following structure: where the wavy line indicates the connection point with L 1 ​ 13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein E has the following structure: where the wavy line indicates the connection point with L 1 ​ 14. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein W is CR W ; X is CR X ; Y is CR Y ; and Z is CR Z .

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein W is N; X is CR X ; Y is CR Y ; and Z is CR Z .

16. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein W is CR W ; X is N; Y is CR Y ; and Z is CR Z .

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein W is CR W ; X is CR X ; Y is N; and Z is CR Z .

18. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein W is CR W ; X is CR X ; Y is CR Y ; and Z is N.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein ring A is a monocyclic or polycyclic C A cycloalkyl optionally substituted with 1, 2, 3 or 4 Rs 3-14 , and when ring A is polycyclic, ring A is connected to the -(L) m - moiety of formula I through a non-aromatic ring.

20. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein ring A is a cyclohexyl optionally substituted by 1, 2, 3 or 4 R A substituted cyclohexyl.

21. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein ring A is a monocyclic or polycyclic 4- to 18-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 Rs A and wherein when ring A is polycyclic, ring A is attached to the -(L) m - moiety of formula I via a non-aromatic ring.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein ring A is a piperidinyl optionally substituted with 1, 2, 3 or 4 R A substituents.

23. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein ring A is a piperidin-4-yl optionally substituted with 1, 2, 3 or 4 R A substituents.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein L is -CH2-.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein m is 0.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein m is 1.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein n is 0.

28. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H.

29. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from C 1-6 alkyl, OR a1 、C(O)R b1 、NR c1 R d1 and S(O)2R b1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Cy 1 、Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 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 .

30. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from halo, C 1-6 haloalkyl, OR a1 , C(O)NR c1 R d1 and C(O)OR a1 .

31. A compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein each R W , R X , R Y and R Z is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, CN, OR a2 , C(O)NR c2 R d2 , NR c2 R d2 and NR c2 C(O)R b2 ; wherein the C W , R X , R Y and R Z of C 1-6 alkyl, C 1-6 haloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl and C 6-10 aryl-C 1-4 alkyl are each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from 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 , 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 。 32. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein W is CR W and R W is not H.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R W is a halogen group.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R W is F.

35. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein X is CR X and R X is H.

36. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Y is CR Y and R Y is not H.

37. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Y is CR Y , and R Y is independently selected from C 1-6 alkyl, OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 .

38. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein Y is CR Y , and R Y is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, halogen, CN, OR a2 , SR a2 , C(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 , wherein the C Y alkyl, C 1-6 cycloalkyl-C 3-7 alkyl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: halogen, C 1-4 alkyl, C 1-6 haloalkyl, CN, NO2, OR 1-6 , NR a2 R c2 R d2 and S(O)2R b2 .

39. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein Y is CR Y , and R Y is independently selected from NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 .

40. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein Y is CR Y , and R Y is independently selected from C 1-6 alkyl and OR a2 .

41. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R a2 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: C 1-4 alkyl, C 1-4 haloalkyl, halogen, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 .

42. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein Y is CR Y , and R Y is independently selected from NR c2 R d2 and NR c2 C(O)R b2 .

43. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R c2 and R d2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally independently substituted with 1, 2, 3, 4 or 5 substituents selected from: C 1-4 alkyl, C 1-4 haloalkyl, halogen, CN, OR a3 、C(O)R b3 、C(O)OR a3 and S(O)2R b3 .

44. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein Z is CR Z and R Z is H.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein Q is a moiety having formula II: where the wavy line represents the attachment point to the group L 1 ​ 46. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein Q is a moiety having formula IIIA, IIIB, IIIC, IIID or IIIE: where the wavy line represents the point of attachment to the group L 1 ​ 47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein Q is a moiety having formula IVA or IVB: where the wavy line represents the point of attachment to the group L 1 .

48. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, which has formula (A2): or a pharmaceutically acceptable salt thereof.

49. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, which has formula (A3): or a pharmaceutically acceptable salt thereof.

50. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, which has formula (A4): or a pharmaceutically acceptable salt thereof.

51. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, which has formula (A5): or a pharmaceutically acceptable salt thereof.

52. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, which has formula (A6): or a pharmaceutically acceptable salt thereof.

53. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the following: or a pharmaceutically acceptable salt of any of the foregoing.

54. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-53 and at least one pharmaceutically acceptable carrier.

55. A method for degrading PARP14 in vitro, the method comprising contacting the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-53 with the PARP14 in an in vitro system.

56. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-53 in the manufacture of a medicament for treating cancer in a patient in need of treatment.

57. The use according to claim 56, 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.

58. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-53 in the manufacture of a medicament for treating an inflammatory disease in a patient in need of treatment.

59. A method for reducing IL-10 in cells in vitro or ex vivo, the method comprising contacting the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-53 with the cells in an in vitro system.

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