Targeted protein degradation of PARP14 for use in therapy

Abstract

To provide compounds which cause intracellular proteolysis of PARP14 and are useful in the treatment of cancer and inflammatory diseases; and pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof.SOLUTION: The invention provides a compound represented by Formula (A1), Q-L1-E, or a pharmaceutically acceptable salt thereof, where: Q is selected from among quinazolinones and related compounds represented by Formula I in the figure; L1 is a linker, which is covalently linked to moiety Q and to moiety E; and E is an E3 ubiquitin ligase binding moiety, which binds to the E3 ubiquitin ligase.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

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

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

[0004] PARP14 is a monoPARP found in both the cytoplasm and the nucleus. PARP14 was initially identified as BAL2 (B Aggressive Lymphoma 2), a gene associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), along with two other monoPARPs, PARP9 or BAL1 and PARP15 or BAL3 (Aguiar RC, et al. Blood. 2000 Dec 9;96(13):4328-4334 and Juszczynski P, et al. Mol Cell Biol. 2006 Jul 1;26(14):5348-5359). PARP14, PARP9, and PARP15 are also called macroPARPs because they have a macrodomain at their N-terminus. The genes for these three macroPARPs are located within the same genomic locus, suggesting co-regulation. Indeed, 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, for example, in established cancer cell lines compared to normal subjects. Examples from the literature of cancers in which PARP14 is highly expressed are DLBCL (Aguiar RCT, et al. J Biol Chem. 2005 Aug 1;280(40):33756-33765), multiple myeloma (MM) (Barbarulo A, et al. Oncogene. 2012 Oct 8;32(36):4231-4242), and hepatocellular carcinoma (HCC) (Iansante V, et al. Nat Commun. 2015 Aug 10;6:7882). In MM and HCC cell lines, knockdown of PARP14 by RNA interference (RNAi) inhibits cell proliferation and survival. According to other studies, the enzymatic activity of PARP14 is required for the survival of prostate cancer cell lines in vitro (Bachmann SB, et al. Mol Cancer. 2014 May 27;13:125).

[0005] PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling, affecting transcription downstream of STAT1 (in the case of IFN-γ) (Iwata H, et al. Nat Commun. 2016 Oct 31;7:12849) or STAT6 (in the case of IL-4) (Goenka S, et al. Proc Natl Acad Sci USA. 2006 Mar 6;103(11):4210-4215, Goenka S, et al. J Biol Chem. 2007 May 3;282(26):18732-18739, and Mehrotra P, et al. J Biol Chem. 2010 Nov 16;286(3):1767-1776). Parp14- / - knockout (KO) mice had reduced marginal zone B cells, and in the setting of Parp14 KO, the ability of IL-4 to keep B cells alive in vitro was also reduced (Cho SH, et al. Blood. 2009 Jan 15;113(11):2416-2425). This decreased survival signaling was mechanistically associated with a reduced ability of Parp14 KO B cells to maintain metabolic fitness and increased expression of Mcl-1. Parp14 KO was able to extend survival in the Eμ-Myc lymphoma model, suggesting the involvement of PARP14 in Myc-driven lymphoma formation (Cho SH, et al. Proc Natl Acad Sci USA. 2011 Sep 12;108(38):15972-15977). Gene expression data also indicate the involvement of PARP14 in human B cell lymphoma. BAL proteins, including PARP14, are highly expressed in host response (HR) DLBCL, a genomically defined B cell lymphoma subtype characterized by active 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 whose mRNA increases upon stimulation of various cell lines by all types of interferons (I, II, and III; www.interferome.org).

[0006] PARP14 has been implicated in the differentiation of helper T cells and macrophages because it functions downstream of the IL-4 and IFN-γ signaling pathways. Inactivation of the PARP14 gene in macrophages reduces the tumor-promoting M2 phenotype and biases towards the inflammation-promoting M1 phenotype associated with anti-tumor immunity. When PARP14 was knocked out or knocked down in human and mouse macrophage models, it was found that the expression of M2 genes downstream of IL-4 decreased, while the expression of M1 genes downstream of IFN-γ increased. Similarly, knockout of the PARP14 gene has been shown to reduce the Th2 helper T cell phenotype in the context of skin and airway inflammation, which is also related to the regulatory role of PARP14 in IL-4 signaling (Mehrotra P, et al. J Allergy Clin Immunol. 2012 Jul 25;131(2):521 and Krishnamurthy P, et al. Immunology. 2017 Jul 27;152(3):451-461).

[0007] PARP14 has been shown to regulate the transcription of STAT6 (signal transducer and activator of transcription 6), and to promote the T H 2 response in T cells and B cells, which are known to promote allergic airway disease (asthmatic conditions). Genetic loss of PARP14 and its enzymatic activity in an allergic airway disease model resulted in a decrease in lung inflammation and IgE levels, which are important readouts in the asthma process of this model. Furthermore, the enzymatic activity of PARP14 is STAT6-dependent for T HIt promoted phenotypic differentiation (Mehrotra P, et al. J Allergy Clin Immunol. 2012 Jul 25;131(2):521). Therefore, inhibition of PARP14 catalytic activity may be a potential new therapy for allergic airway diseases.

[0008] Most pharmaceuticals used clinically are based on inhibition by small molecules of protein functions. However, alternative approaches that result in degradation rather than inhibition of proteins may also lead to clinical efficacy. Therefore, target protein degradation via ubiquitination of protein targets has emerged as an effective strategy for drug discovery. Heterobifunctional small molecules that bind to target proteins and recruit ubiquitin ligases (such as ubiquitin E3 ligases) at the same time have been shown to result in ubiquitination and degradation of target proteins (Bondeson, D.P., et al. Nat Chem Biol. 2015 11(8):611-617).

[0009] There is a need to develop new drugs such as small molecules that can bind to both PARP14 and ubiquitin E3 ligase to cause degradation of PARP14 and are useful in the treatment of various diseases including cancer and inflammatory diseases.

Summary of the Invention

[0010] The present invention relates to a compound of formula (A1): Q-L 1 -E (A1) and pharmaceutically acceptable salts thereof, wherein the constituents in the formula are defined below.

[0011] 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.

[0012] The present invention further relates to a method for degrading PARP14, which comprises contacting a compound of formula (A1) or a pharmaceutically acceptable salt thereof with PARP14.

[0013] The present invention further relates to a method for reducing IL-10 in a cell, which comprises contacting a cell with a compound of formula (A1) or a pharmaceutically acceptable salt thereof.

[0014] The present invention further relates to a method for treating a disease or disorder in a patient in need of treatment, which comprises administering to the patient a therapeutically effective amount of a compound of formula (A1) or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is characterized by overexpression or increased activity of PARP14.

[0015] The present invention further relates to a method for treating cancer in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of formula (A1) or a pharmaceutically acceptable salt thereof.

[0016] The present invention further relates to a method for treating an inflammatory disease in a patient in need of treatment, which comprises administering to the patient a therapeutically effective amount of a compound of formula (A1) or a pharmaceutically acceptable salt thereof.

[0017] The present invention also provides the use of the compounds described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides the compounds described herein for use in therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6A

Figure 6B

BRIEF DESCRIPTION OF THE INVENTION

[0019] The present disclosure provides, inter alia, a compound of formula (A1): Q-L 1 -E (A1) or a pharmaceutically acceptable salt thereof, wherein Q is a small molecule PARP14 targeting moiety that binds to PARP14, L 1 is a linker covalently attached to moiety Q and moiety E, E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase.

[0020] In some embodiments, provided herein is a compound of formula (A1): Q-L 1 -E (A1) or a pharmaceutically acceptable salt thereof, wherein Q is of formula I:

CHEMICAL FORMULA

[0021] In some embodiments, where W is CRW and X is CR X and Y is CR Y and Z is CR Z and when m is 1, R X and R Y are not both methoxy.

[0022] In some embodiments, Q is

Chemical formula

Chemical formula

[0023] In some embodiments, W is CR W and X is CR X and Y is CR Y and Z is CR Z and is.

[0024] In some embodiments, W is N and X is CR X and Y is CR Y and Z is CR Z and is.

[0025] In some embodiments, W is CR W and X is N and Y is CR Y and Z is CR Z and is.

[0026] In some embodiments, W is CR W and X is CR X and Y is N and Z is CR Z and is.

[0027] In some embodiments, W is CR W and X is CR X and Y is CR Y and Z is N.

[0028] In some embodiments, 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 attached to the -(L) m - moiety of formula I via a non-aromatic ring.

[0029] In some embodiments, ring A is a monocyclic C A cycloalkyl optionally substituted with 1, 2, 3, or 4 Rs 3-7 and when ring A is polycyclic, ring A is attached to the -(L)

[0030] In some embodiments, ring A is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl optionally substituted with 1, 2, 3, or 4 Rs A and when ring A is polycyclic, ring A is attached to the -(L)

[0031] In some embodiments, ring A is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl

[0032] In some embodiments, ring A is cyclohexyl or cycloheptyl optionally substituted with 1, 2, 3, or 4 Rs A and when ring A is polycyclic, ring A is attached to the -(L)

[0033] In some embodiments, ring A is cyclohexyl or cycloheptyl

[0034] In some embodiments, ring A is cyclohexyl optionally substituted with 1, 2, 3, or 4 Rs A and when ring A is polycyclic, ring A is attached to the -(L)

[0035] In some embodiments, ring A is cyclohexyl

[0036] In some embodiments, ring A is cyclohexyl optionally substituted with 1, 2, 3, or 4 Rs AA monocyclic or polycyclic 4- to 18-membered heterocycloalkyl optionally substituted by m - is attached to the -(L)

[0037] In some embodiments, ring A is a monocyclic 4- to 7-membered heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R A groups.

[0038] In some embodiments, ring A is a monocyclic 4- to 7-membered heterocycloalkyl.

[0039] In some embodiments, ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl optionally substituted by 1, 2, 3, or 4 R A groups.

[0040] In some embodiments, ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.

[0041] In some embodiments, ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or tetrahydrothiopyranyl optionally substituted by 1, 2, 3, or 4 R A groups.

[0042] In some embodiments, ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or tetrahydrothiopyranyl.

[0043] In some embodiments, ring A is piperidinyl optionally substituted by 1, 2, 3, or 4 R A groups.

[0044] In some embodiments, ring A is piperidinyl.

[0045] In some embodiments, ring A is piperidin-4-yl optionally substituted with 1, 2, 3, or 4 R A groups.

[0046] In some embodiments, ring A is piperidin-4-yl.

[0047] In some embodiments, ring A is tetrahydropyranyl optionally substituted with 1, 2, 3, or 4 R A groups.

[0048] In some embodiments, ring A is tetrahydropyranyl.

[0049] In some embodiments, ring A is tetrahydropyran-4-yl optionally substituted with 1, 2, 3, or 4 R A groups.

[0050] In some embodiments, ring A is tetrahydropyran-4-yl.

[0051] In some embodiments, L is -(CR 5 R 6 ) t -.

[0052] In some embodiments, L is -(CR 5 R 6 ) t - and t is 1.

[0053] In some embodiments, L is -(CR 5 R 6 ) t - and t is 2.

[0054] In some embodiments, L is -(CR 5 R6 ) t - and t is 3.

[0055] In some embodiments, L is -CH2-.

[0056] In some embodiments, m is 0.

[0057] In some embodiments, m is 1.

[0058] In some embodiments, n is 0.

[0059] In some embodiments, n is 1.

[0060] In some embodiments, n is 2.

[0061] In some embodiments, R 1 and R 2 are both H.

[0062] In some embodiments, one of R 1 and R 2 is H and the other is methyl.

[0063] 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 and the C 1-6 alkyl is Cy 1 Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NRc1 R d1 、 C(O)OR a1 、 OC(O)R b1 、 OC(O)NR c1 R d1 、 C(=NR e1 )NR c1 R d1 、 NR c1 C(=NR e1 )NR c1 R d1 、 NR c1 R d1 、 NR c1 C(O)R b1 、 NR c1 C(O)OR a1 、 NR c1 C(O)NR c1 R d1 、 NR c1 S(O)R b1 、 NR c1 S(O)2R b1 、 NR c1 S(O)2NR c1 R d1 、 S(O)R b1 、 S(O)NR c1 R d1 、 S(O)2R b1 、 and S(O)2NR c1 R d1 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0064] 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- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl and 5- to 10-membered heteroaryl-C 1-4 alkyl, and the C1-6 Alkyl, C 1-6 Haloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl and 5- to 10-membered heteroaryl-C 1-4 Each alkyl is Cy 1 、Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 、NR c1 C(=NR e1 )NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)OR a1 、NR c1 C(O)NR c1 R d1 、NR c1 S(O)R b1 、NR c1 S(O)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 Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0065] 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 .

[0066] In some embodiments, R A is OR a1 .

[0067] In some embodiments, each R A is 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 , where the 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 are 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 .

[0068] In some embodiments, each RW , 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 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 is independently selected from R W , R X , R Y , and R Z of said C 1-6 alkyl, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl-C 1-4 alkyl are each 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 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0069] In some embodiments, each R W , R X , R Y , and R Z is 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 , and NR c2 C(O)Rb2 independently selected from, R W , R X , R Y , and R Z of said C 1-6 alkyl, C 1-6 haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl-C 1-4 alkyl are each, 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 d2Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0070] In some embodiments, W is CR W and R W is other than H.

[0071] In some embodiments, W is CR W and R W is H.

[0072] In some embodiments, R W is halo.

[0073] In some embodiments, R W is F.

[0074] In some embodiments, R W is selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, and OR a2 wherein the C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with OR a2

[0075] In some embodiments, R W is selected from C 1-6 alkyl, C 1-6 haloalkyl, CN, halo, and OR a2 wherein the C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with OR a2

[0076] In some embodiments, neither R X nor R Z is halogen.

[0077] In some embodiments, R Z is H. ​​

[0078] In some embodiments, W is CR W and X is CR X and Y is CR Y and Z is CR Z and when m is 1 or 2, neither R X nor R Y is C 1-6 alkoxy.

[0079] In some embodiments, W is CR W and X is CR X and Y is CR Y and Z is CR Z and when m is 1 or 2, R X and R Y are not both the same.

[0080] In some embodiments, X is CR X and R X is other than H.

[0081] In some embodiments, X is CR X and R X is H.

[0082] In some embodiments, R X is selected from C 1-6 alkyl, halo, and OR a2 .

[0083] In some embodiments, Y is CR Y and R Y is other than H.

[0084] In some embodiments, Y is CR Y and R Y is H.

[0085] In some embodiments, Y is CR Y and R Y is NR c2 Rd2 , 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 is independently selected from

[0086] In some embodiments, Y is CR Y , and R Y is 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 is independently selected from

[0087] In some embodiments, Y is CR Y and R Y is independently selected from NR c2 R d2 and NR c2 C(O)R b2 .

[0088] In some embodiments, R Y is C 1-6 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, halo, 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 and is independently selected from R Y wherein said C 1-6 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO2, OR a2 , NR c2 R d2 , and S(O)2Rb2 Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0089] In some embodiments, Y is CR Y and R Y is independently selected from C 1-6 alkyl and OR a2

[0090] In some embodiments, Y is CR Y and R Y is OR a2

[0091] In some embodiments, Z is CR Z and R Z is other than H.

[0092] In some embodiments, Z is CR Z and R Z is H.

[0093] In some embodiments, Z is CR Z and R Z is C 1-6 alkyl.

[0094] In some embodiments, Z is CR Z and R Z is C 1-6 alkyl, halo, or CN.

[0095] 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, and C 1-6 alkyl is 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 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0096] In some embodiments, each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 alkyl, and C 1-6It is independently selected from haloalkyl.

[0097] 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, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, and 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, and 4- to 10-membered heterocycloalkyl-C 1-4 alkyl are each 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 .

[0098] In some embodiments, R a2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, and 4- to 10-membered heterocycloalkyl-C 1-4 Selected from alkyl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, and 4- to 10-membered heterocycloalkyl-C 1-4 Each alkyl is 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 Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0099] In some embodiments, R c2 And R d2 Are each, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, and 4- to 10-membered heterocycloalkyl-C 1-4 Selected independently from alkyl, wherein said C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, and 4- to 10-membered heterocycloalkyl-C1-4 Each alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-4 alkyl, C 1-4 haloalkyl, halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 and is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0100] In some embodiments, Cy 3 is a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-4 alkyl, C 1-4 haloalkyl, halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)2R b3 and is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0101] In some embodiments, Cy 3 is a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from b3 C(O)R

[0102] In some embodiments, Cy 3 is piperidinyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo and C(O)CH3.

[0103] In some embodiments, Q is a moiety represented by Formula II:

Chemical formula

[0104] In some embodiments, Q is Formula IIIA, IIIB, IIIC, IIID, or IIIE:

Chemical formula

[0105] In some embodiments, Q is of formula IVA or IVB:

Chemical formula

[0106] In some embodiments, Q is a radical of a compound selected from: 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile, 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 6-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 6-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)thio)ethyl)quinazolin-4(3H)-one, 5-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-Benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate, 8-Methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((1-acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-Methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one, 2-((azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-((Azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one, 2-((((Trans)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-((((Cis)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile, 7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(((1-methylpiperidin-3-yl)thio)methyl)quinazolin-4(3H)-one, 7-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one, 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one, 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 2-((((Trans)-3-(benzyloxy)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-methyl-2-((oxetan-3-ylthio)methyl)quinazolin-4(3H)-one, 2-(((Tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one, 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 6-Chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7,8-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 2-(((trans-3-hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one, 2-(((trans-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((cis-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 5-Fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 2-(((trans-3-aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((trans-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((cis-4-Aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 5-Fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one, 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one, 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one, 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((cis-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((trans-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((cis-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((trans-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide, N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide, N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-carboxamide, 4-oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-carboxamide, 7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(pyridin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((4-Methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((3-Methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((2-Methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Pyrazin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Pyridin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Pyrimidin-5-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Methyl-1H-imidazol-2-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(thiazol-2-ylamino)quinazolin-4(3H)-one, 7-((2-Methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((4-Methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((5-Methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(4-Amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one, 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one, 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one, 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one, 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one, 7-(cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-(cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one, 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one, 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one, 2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Dimethylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-Morpholino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(4-Methylpiperazin-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Methylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Isopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Pyridin-4-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Pyridin-2-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Benzylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Phenylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)amino)quinazolin-4(3H)-one, 7-(Cyclobutylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Pyridin-3-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexyl(methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-[(1-Benzyl-3-piperidyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one, 7-(3-Piperidylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one, 7-((1-Benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 7-((1-Acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, N-(4-((4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide, 2-(((1-(4-(Dimethylamino)benzyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 4-((4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)benzonitrile, 2-(((1-((1H-Pyrazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-Methyl-2-(((1-((1-methyl-1H-indazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-quinazolin-4(3H)-one, 2-(((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-methyl-2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(((1-((3-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(((1-phenethylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(((1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-methyl-2-(((1-((3-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, N-(3-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide, 2-(((1-((1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-(imidazo[1,2-a]pyridin-3-ylmethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-((1-benzyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenoxy)acetonitrile, 8-Methyl-2-(((1-((2-oxoindolin-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((1-((5-methoxypyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 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, (S)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, (R)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, (S)-8-Methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-(2-aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, N-(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)picolylamide, 2-(((1-(3-aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-(3-aminopropanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-(3-(Dimethylamino)propanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, (R)-1-(4-Amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine, (S)-1-(4-Amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine, 2-(((1-(L-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 2-(((1-(D-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 8-Methyl-2-(((1-(3-(pyridin-2-yl)propanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, and 7-(Cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, N-(((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl)acetamide, 7-(Cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-((((1R,4R)-4-(hydroxymethyl)cyclohexyl)thio)-methyl)quinazolin-4(3H)-one, 2 - ((((trans)-4-(2 - aminoethyl)cyclohexyl)thio)methyl)-8 - methylquinazolin-4(3H)-one, 2 - ((((3-(aminomethyl)cyclobutyl)thio)methyl)-8 - methylquinazolin-4(3H)-one, 2 - ((((trans)-3-(2 - aminoethyl)cyclopentyl)thio)methyl)-8 - methylquinazolin-4(3H)-one 7 - (cyclopentylamino)-5 - fluoro - 2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin-4(3H)-one, 7 - (cyclopentylamino)-5 - fluoro - 2 - ((((1R,4R)-4 - hydroxycyclohexyl)thio)methyl)-quinazolin-4(3H)-one, 7 - (cyclopentylamino)-2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)pyrido[2,3 - d]pyrimidin-4(3H)-one, (S)-7 - ((tetrahydro - 2H - pyran - 3 - yl)amino)-2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin-4(3H)-one, 7 - (cyclopentylamino)-2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)pyrido[3,2 - d]pyrimidin-4(3H)-one, 7 - (cyclopentylamino)-2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)pyrido[4,3 - d]pyrimidin-4(3H)-one, 2 - ((azepan - 4 - ylthio)methyl)-7 - (cyclopentylamino)quinazolin-4(3H)-one, 2 - ((((3-(aminomethyl)cyclopentyl)thio)methyl)-8 - methylquinazolin-4(3H)-one, 7 - ((3 - methylisoxazol - 5 - yl)amino)-2 - ((((tetrahydro - 2H - pyran - 4 - yl)thio)methyl)quinazolin-4(3H)-one, (R)-7-((1-(Methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-((1-(Methylsulfonyl)azetidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, (R)-7-((1-(Methylsulfonyl)piperidin-3-yl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 8-Methyl-2-((oxepan-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one, 7-(Cyclobutylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, (R)-7-((1-(Methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 7-Isobutyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, Cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide, trans-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide, 5-Chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, Methyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate, 2-((trans)-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-((Cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one cis-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide 7-(Cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide 2-(((cis-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one 7-(Cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one 7-(Cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 7-(Cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 7-(Cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 7-((Cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-((2,2-Difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, (R)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, (S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-((((cis)-6-(Aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one, 2-(((trans-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one, 2-(((cis-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one, 6-Fluoro-7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, (R)-5-Fluoro-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((2-Cyclopentylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Chloro-7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((2-(Tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1-(2,2-difluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1-(3,3,3-trifluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-(((cis-6-(Hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)methyl)-8-methylquinazolin-4(3H)-one, 7-((Cyclobutylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(((2,2-Difluorocyclopropyl)methyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1-(2,2-difluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Cyclopropylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-((3,3-Difluorocyclopentyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one, (R)-2-(((1-Acetylpiperidin-4-yl)thio)methyl)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one, 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one, 7-((Cyclopropylmethyl)amino)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-((piperidin-4-ylthio)methyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1-(1,1-dioxidothietan-3-yl)piperidin-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one, 7-((Cyclopropylmethyl)amino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((2-morpholinoethyl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-methylacetamide, 7-(((2,2-Difluorocyclopropyl)methyl)amino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 2-(4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetonitrile, 2-(trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, 5-Fluoro-7-((2-morpholinoethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-4(3H)-one, 7-((Cyclobutylmethyl)amino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one, 7-(Cyclohexylamino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Cyclopropylmethyl)amino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-6-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Cyclobutylmethyl)amino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-6-fluoroquinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)methoxy)quinazolin-4(3H)-one, 7-((1-(2,2-Difluoropropyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-(2,2-Difluoroethyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Cyclobutylmethyl)amino)-6-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylmethoxy)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one, 5-Fluoro-7-((trans-2-fluorocyclopentyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-isobutoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylmethoxy)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclobutylmethoxy)-2-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one, 7-(Cyclobutylmethoxy)-2-((cyclohexylthio)methyl)-5-fluoroquinazolin-4(3H)-one, 2-((Cyclohexylthio)methyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one, trans-4-(((7-(Cyclobutylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide, 7-((1-(2,2-Difluoroethyl)piperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5,6-difluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-((2,2-Difluorocyclopropyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one, 7-((3,3-Difluorocyclobutyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-7-((tetrahydro-2H-pyran-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one (R)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one, (S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one, 5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one, (S)-5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one, (R)-5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one, 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((S)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-7-((((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-((((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, N-((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, 7-(((cis)-3-Ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 2-((((trans)-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclobutylmethoxy)-5-fluoroquinazolin-4(3H)-one, 5-Fluoro-7-(((3S,4S)-3-fluoropiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((3R,4R)-3-fluoropiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one 7-((Cyclopropylmethyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((Cyclobutylmethyl)amino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one, 5-Fluoro-7-(((trans)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((cis)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-7-(oxetan-3-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1,4-dioxan-2-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((2,2-difluorocyclohexyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-(((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-(((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, (R)-5,6-Difluoro-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(((R)-1-acetylpyrrolidin-3-yl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-4(3H)-one, 7-((5,5-Dimethyltetrahydrofuran-3-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-((((trans)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-2-((((cis)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-2-(((4-methyltetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 5-Fluoro-7-(((cis)-2-hydroxycyclopentyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, (trans)-4-((5,6-Difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile, (cis)-4-((5,6-Difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile, 5,6-Difluoro-7-(((trans)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one, 5-Methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 2-(((4,4-Difluorocyclohexyl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 7-((1-Acetylpyrrolidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(2-Cyclohexylethyl)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(((1-Acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)thio)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((cis)-4-fluoropyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((cis)-4-fluoro-1-methylpyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, 5,6-Difluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one, 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((trans)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one, 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((trans)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one, N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propionamide, 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one, N-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-methylcyclohexyl)acetamide, 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydro-2H-pyran-3-yl)amino)quinazolin-4(3H)-one, 5-Fluoro-2-((((trans)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazoline-5-carbonitrile, 5,6-Difluoro-7-(neopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((cis)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(((trans)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, N-((cis)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide, 5-Fluoro-7-(((cis)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, N-((trans)-4-(((5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, 7-((1-(Cyclopropanecarbonyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, N-((trans)-4-(((5-Fluoro-4-oxo-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, N-((trans)-4-(((7-(Cyclobutylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, N-((trans)-3-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide, 7-(1-Cyclopentylethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, N-((trans)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)cyclopropanecarboxamide, 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((1-isobutyrylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((1-propionylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(piperidin-4-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Acetylpiperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((cis)-3-(trifluoromethoxy)cyclobutyl)amino)quinazolin-4(3H)-one, 7-Amino-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopropylmethoxy)-2-((((trans)-4-(dimethylamino)cyclohexyl)thio)methyl)-5-fluoro-7,8-dihydroquinazolin-4(3H)-one, 5-Fluoro-2-((((cis)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 5,6-Difluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-((2-methoxy-2-methylpropyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 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, 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one, Methyl 4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate, 5-Fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((trans)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-(Cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((4-methylmorpholin-2-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-(neopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((cis)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 5,6-Difluoro-7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(3,3,3-trifluoro-2,2-dimethylpropoxy)quinazolin-4(3H)-one, 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one, 7-((1-Acetylpiperidin-4-yl)methoxy)-5-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 5-Fluoro-7-((1-(2-methoxyacetyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one, 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, N-((trans)-4-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide, and 7-((3,3-Difluoro-1-methylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one.

[0107] The compounds were found to have PARP14 inhibitory activity by the assay described in Example A.

[0108] In some embodiments, L 1 is linked to moiety Q by a covalent bond to ring A.

[0109] The ubiquitin ligase binding moiety and the linker are known in the art and are described in, 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, which are hereby incorporated by reference in their entirety.

[0110] 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 apoptosis inhibitor protein (IAP) E3 ubiquitin ligase binding moiety, each of which has an IC 50 of less than about 10 μM as determined by a binding assay. For example, E is a cereblon E3 ubiquitin ligase binding moiety. E may be a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety. E may be an MDM2 E3 ubiquitin ligase binding moiety. E may be an IAP E3 ubiquitin ligase binding moiety.

[0111] In some embodiments, E comprises a chemical group derived from an imide, thioimide, amide, or thioamide.

[0112] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, analogs thereof, ligands thereof, or derivatives thereof.

[0113] In some embodiments, E is

Chemical formula

Chemical formula

[0114] In some embodiments, E has the following structure:

Chemical formula

[0115] In some embodiments, E has the following structure:

Chemical formula

[0116] In some embodiments, E has the following structure:

Chemical formula

[0117] In some embodiments, 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 optionally substituted with 1 to 3 R q substituents, and one or more chain carbon atoms of L 1 may be oxidized to form a carbonyl (C=O), and one or more N and S chain atoms may optionally be oxidized to form an amine oxide, a sulfoxide, or a sulfonyl group, respectively. Each R q is OH, CN, -COOH, NH2, halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, C3-6 Cycloalkyl, NH(C 1-6 alkyl), and N(C 1-6 alkyl)2 are independently selected, and R q 's C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with halo, OH, CN, -COOH, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl. In some embodiments, Rq is independently selected from OH, CN, -COOH, NH2, halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NH(C 1-6 alkyl), and N(C 1-6 alkyl)2.

[0118] In some embodiments, L 1 has the following structure: [Chemical formula] In the formula, 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. c is 0 or 1. The wavy line represents the bonding point to moieties Q and E.

[0119] In some embodiments, a is 0.

[0120] In some embodiments, a is 1.

[0121] In some embodiments, b is 0.

[0122] In some embodiments, b is 1.

[0123] In some embodiments, c is 0.

[0124] In some embodiments, c is 1.

[0125] In some embodiments, a is 1, b is 1, and c is 1.

[0126] In some embodiments, a is 0, b is 1, and c is 0.

[0127] In some embodiments, a is 1, b is 1, and c is 0.

[0128] 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)-.

[0129] In some embodiments, R G is H.

[0130] In some embodiments, linker L 1 is

Chemical formula

[0131] In some embodiments, the compounds of the present disclosure are of formula (A2):

Chemical formula

[0132] In some embodiments, the compounds of the present disclosure are of formula (A3):

Chemical formula

[0133] In some embodiments, the compounds of the present disclosure are of formula (A4):

Chemical formula

[0134] In some embodiments, the compounds of the present disclosure are of formula (A5):

Chemical formula

[0135] In some embodiments, the compounds of the present disclosure are of formula (A6):

Chemical formula

[0136] In some embodiments, the compounds of formula (A1) are as follows:

Chemical formula

Chemical formula

[0137] Furthermore, as will be appreciated, the specific features of the invention that are described in separate embodiments for clarity can also be provided in combination in a single embodiment. Conversely, the various features of the invention that are described in a single embodiment for brevity can also be provided separately or in any suitable partial combination.

[0138] Throughout this specification, substituents of the compounds of the invention are disclosed in groups or ranges. It is specifically intended that each and every individual partial combination of members of such groups and ranges is included in the invention. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0139] 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 by any ring member as valence permits. For example, the terms "pyridinyl", "pyridyl", or "pyridine ring" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0140] The term "n-membered" (where "n" is an integer) typically represents the number of ring-forming atoms in a moiety, and 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, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0141] Throughout this specification, there may be descriptions of variable elements that define a divalent linking group. It is specifically intended that each linking substituent includes both the forward and reverse forms of that linking substituent. For example, -C(O)NR G - is -C(O)NR G-and -NR G Both contain C(O)-, and each form is intended to be disclosed individually. When the structure requires a linking group, the Markush variable elements listed for that group are understood to be the linking group. For example, when the structure requires a linking group and the definition of the Markush group for its variable element lists "alkyl" or "aryl", this "alkyl" or "aryl" is understood to represent an alkylene group or an arylene group that links, respectively.

[0142] When a variable element appears two or more times in a compound of the present invention, each variable element can be a different moiety independently selected from the group defining that variable element. For example, when a certain structure is described as having two R groups that are present simultaneously in the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0143] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0144] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

[0145] As used herein, the "C" used in combination with a chemical group i-j "(where i and j are integers)" is a term that specifies the range of the number of carbon atoms in the chemical group, and i - j defines the range. For example, C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0146] As used herein, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chain or branched-chain. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl. The term "alkylene" refers to a linking alkyl group.

[0147] As used herein, the term "alkenyl", used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0148] As used herein, the term "alkynyl", used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0149] As used herein, the term "halo" or "halogen", used alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0150] 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 its maximum valence, which may be the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0151] As used herein, the term "alkoxy," used alone or in combination with other terms, refers to a group of the formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0152] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example of a haloalkoxy group is -OCF3.

[0153] As used herein, the term "amino," used alone or in combination with other terms, refers to NH2.

[0154] As used herein, the term "alkylamino," used alone or in combination with other terms, refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0155] As used herein, the term "dialkylamino", used alone or in combination with other terms, refers to a group of the formula -N(alkyl)2. Examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0156] As used herein, the term "cycloalkyl", used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon containing a cyclic alkyl and alkenyl group. A cycloalkyl group can include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings, bridged rings, or spiro rings) ring system. The definition of cycloalkyl includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to the cycloalkyl ring (i.e., having a common bond), 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. The cycloalkyl group also includes cycloalkylidene. The term "cycloalkyl" includes bridged cycloalkyl groups (e.g., a non-aromatic cyclic 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 by a single carbon atom such as spiro[2.5]octane). In some embodiments, the cycloalkyl group has 3 to 10 or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7It is a monocyclic cycloalkyl group. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0157] As used herein, the term "cycloalkylalkyl," used alone or in combination with other terms, refers to a group of the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 It is a monocyclic cycloalkyl group.

[0158] As used herein, the term "heterocycloalkyl," whether used alone or in combination with other terms, refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and optionally containing one or more alkenylene or alkynylene groups as part of the ring structure. The heterocycloalkyl group can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings, bridged rings, 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. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydro-quinoline. The heterocycloalkyl group can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azadamantan-1-yl) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused by a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl]). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group may be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom may be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7It is a monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine, an azetidine ring, or a tetrahydrofuran ring.

[0159] As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to a group of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the heterocycloalkyl moiety has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl moiety is monocyclic. In some embodiments, the heterocycloalkyl moiety is C 2-7 It is a monocyclic heterocycloalkyl group.

[0160] As used herein, the term "aryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a 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.

[0161] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). 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.

[0162] As used herein, the term "heteroaryl," whether used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group may be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or the nitrogen atom may be quaternized, provided that the aromatic nature of the ring is preserved. 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.

[0163] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). 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.

[0164] The compounds described herein can be asymmetric (e.g., have one or more stereocenters). Unless otherwise stated, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the invention containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. Geometric isomers such as olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the invention can be isolated as a mixture of isomers or as separated isomeric forms.

[0165] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond involving conjugated proton transfer. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imino acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in an equilibrium state or may be sterically locked into one form by appropriate substitution.

[0166] The compounds of the present invention also include any isotopes of atoms that occur in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom.

[0167] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures shown, unless otherwise specified.

[0168] All compounds and their pharmaceutically acceptable salts may be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or may be isolated.

[0169] In some embodiments, the compound of the invention or a salt thereof is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition in which the compound of the invention is concentrated. Substantial separation can include a composition containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compound or a salt thereof. Methods for isolating compounds and their salts are conventional in the art.

[0170] The term "small molecule PARP14 targeting moiety" refers to a chemical group that binds to PARP14. The small molecule PARP14 targeting moiety can be a group derived from a compound that inhibits the activity of PARP14. In some embodiments, the small molecule PARP14 targeting moiety inhibits the activity of PARP14 with an IC 50 less than 1 μM in an enzyme assay (see, e.g., Example A).

[0171] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein and target the substrate protein for degradation.

[0172] The term "pharmaceutically acceptable" as used herein refers to 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, and having a reasonable benefit / risk ratio.

[0173] 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 to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from 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 an organic solvent, or in a mixture of the two. Lists of suitable salts are described 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 hereby incorporated by reference in their entirety.

[0174] Synthesis 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 a number of possible synthetic routes.

[0175] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, in the range from the freezing temperature to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected by one skilled in the art.

[0176] 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, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is hereby incorporated by reference in its entirety.

[0177] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0178] As used herein, the expressions "ambient temperature", "room temperature", and "r.t." are understood in the art and generally refer to a temperature near the temperature in the room where the reaction is carried out, e.g., the reaction temperature, e.g., a temperature of about 20 °C to about 30 °C.

[0179] The compounds of the present invention can be prepared according to a number of preparation routes known in the literature. Examples of synthetic methods for preparing the compounds of the present invention are presented in the following schemes.

[0180] Scheme 1

Chemical formula

[0181] Scheme 2

Chemical formula

[0182] Scheme 3

Chemical formula

[0183] Method of use The compounds of the present disclosure can bind to both PARP14 and ubiquitin E3 ligase to degrade PARP14, which is useful in the treatment of various diseases including cancer. In some embodiments, the compounds provided herein can degrade intracellular PARP14, which includes contacting the cells with the compound or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, provided herein is a method of degrading PARP14 in a patient, which includes administering to the patient an effective amount of the compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof. "Degrading PARP14" means, for example, inactivating PARP14 by changing its structure or breaking down PARP14 into multiple peptide or amino acid fragments.

[0184] 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 of inhibiting or reducing the production of IL-10 in cells by contacting the cells with the compounds of the present invention.

[0185] The compounds of the present invention are useful in the treatment of various diseases associated with abnormal expression or activity of PARP14. For example, the compounds of the present invention are useful in the treatment of cancer. In some embodiments, the cancers treatable by the present invention include hematological malignancies such as leukemia and lymphoma. Examples of lymphoma include Hodgkin lymphoma or non-Hodgkin lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic leukemia (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt lymphoma. Examples of leukemia include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0186] Other cancers that can be treated by administration of the compounds of the present invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0187] In some embodiments, the cancers that can be treated by administration of the compounds of the present invention are multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colorectal cancer, or melanoma.

[0188] The compounds of the present invention may also have therapeutic utility in PARP14-related disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, particularly when the disease is characterized by overexpression or increased activity of PARP14.

[0189] In some embodiments, the compounds of the present invention are useful in the treatment of inflammatory diseases. In some embodiments, the inflammatory diseases treatable by the present invention include inflammatory bowel diseases (e.g., Crohn's disease or ulcerative colitis), inflammatory arthritis, inflammatory demyelinating diseases, psoriasis, allergy and septic shock, allergic airway diseases (e.g., asthma), and lupus.

[0190] As used herein, the term "cell" is intended to refer to cells that are in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells can be cells in a cell culture. In some embodiments, in vivo cells are cells that are living in an organism such as a mammal.

[0191] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" PARP14 or contacting a cell with a compound of the invention includes not only administering the compound of the invention to an individual or patient, such as a human, having PARP14, but also introducing the compound of the invention into a sample containing a cell preparation or purified preparation containing PARP14, for example.

[0192] As used herein, the terms "individual" or "patient" are used interchangeably and refer to a mammal, particularly a human.

[0193] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical that induces a biological or pharmaceutical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

[0194] As used herein, the terms "treating" or "treatment" refer to: 1) inhibiting a disease in an individual experiencing or presenting the morbidity or general symptoms of the disease (i.e., arresting further development of the morbidity and / or general symptoms), or 2) ameliorating a disease in an individual experiencing or presenting the morbidity or general symptoms of the disease (i.e., reversing the morbidity and / or general symptoms).

[0195] As used herein, the terms "preventing" or "prevention" refer to preventing a disease in an individual who may have a predisposition to the disease but has not yet experienced or presented the morbidity or general symptoms of the disease.

[0196] Combination therapy One or more additional pharmaceuticals or treatment methods, such as chemotherapeutic agents or other anti-cancer agents, immunopotentiators, immunosuppressants, immunotherapies, radiation, anti-tumor vaccines and anti-viral vaccines, cytokine therapies (e.g., IL2, GM-CSF, etc.), and / or kinases (tyrosine or serine / threonine), epigenetic inhibitors or signal transduction inhibitors, etc. may be used in combination with the compounds of the present invention. The agent may be combined with the compound of the present invention in a single dosage form, or the agent may be administered simultaneously or sequentially as separate dosage forms.

[0197] Suitable agents for use in combination with the compounds of the present invention for treating cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiation therapies. The compounds of the present invention may be effective in the treatment of breast cancer and other tumors in combination with anti-hormonal agents. Suitable examples include anti-estrogen agents including, but not limited to, tamoxifen and toremifene, aromatase inhibitors including, but not limited to, letrozole, anastrozole, and exemestane, adrenal corticosteroids (e.g., prednisone), progestins (e.g., megestrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable anti-hormonal agents used in the treatment of prostate cancer and other cancers may be combined with the compounds of the present invention. These include anti-androgen agents including, but not limited to, flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including, but not limited to, leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0198] An angiogenesis inhibitor may be effective against some tumors when combined with an FGFR inhibitor. These include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Inhibitors of VEGFR kinase and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0199] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (such as, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chloromethine, cyclophosphamide (Cytoxan (trademark)), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0200] Other anti-cancer agents (s) include antibody therapeutics against co-stimulatory molecules such as CTLA-4, 4-1BB, PD-1, and PD-L1, or antibodies against cytokines (such as IL-10, TGF-β). Exemplary cancer immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab, and rituximab.

[0201] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature. For example, "Physicians’ Desk Reference" (PDR, such as the 1996 edition, Medical Economics Company, Montvale, NJ) describes the administration of many chemotherapeutic agents, the disclosure of which is hereby incorporated by reference in its entirety as if fully set forth herein.

[0202] Pharmaceutical Preparations and Dosage Forms When used as a medicine, the compound of the present invention can be administered in the form of a pharmaceutical composition. The pharmaceutical composition refers to a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and depending on the area to be treated. Administration can be oral, topical (including mucosal administration such as ocular, as well as intranasal, vaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of powder or aerosol (including by nebulizer); intratracheal, intranasal, epithelial, and transdermal), ocular, or parenteral.

[0203] The present invention also includes pharmaceutical compositions containing, as an active ingredient, one or more of the above-mentioned compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is typically mixed with excipients and diluted by the excipients or enclosed in such carriers in the form of, for example, capsules, sachets, paper, or other containers. The excipient can be a solid, semi-solid, or liquid material that functions as a vehicle, carrier, or medium for the active ingredient when functioning as a diluent. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0204] The composition may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0205] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, as will be understood, the amount of the compound actually administered will usually be determined by the physician according to the relevant circumstances including the condition to be treated, the selected route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0206] When preparing solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are said to be homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preliminary formulation is then subdivided into unit dosage forms of the above type containing, for example, from 0.1 to about 500 mg of the active ingredient of the present invention.

[0207] The tablets or pills of the present invention can be coated or otherwise formulated to provide dosage forms with the advantage of long-term action. For example, the tablets or pills may contain an inner administration component and an outer administration component, the latter being in the form of a coating covering the former. The two components may be separated by an enteric layer that helps withstand degradation in the stomach and allows the inner component to enter the duodenum intact or be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, and such materials include several polymeric acids as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0208] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0209] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via the oral or nasal respiratory route for local or systemic effects. The composition may be nebulized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizer device or the nebulizer device may be attached to a face mask tent or intermittent positive pressure ventilator. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0210] The amount of the compound or composition administered to a patient varies depending on the nature of the material being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. For therapeutic use, 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 of the disease and its complications. The effective dosage depends on the condition being treated and on the judgment of the attending physician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0211] The composition administered to a patient can be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or may be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier prior to administration.

[0212] The therapeutic dosage of the compounds of the present invention can vary according to the specific use for which treatment is being administered, 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 compound of the present invention in the pharmaceutical composition can vary depending on several factors including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be prepared 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 body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage is likely to depend on variable factors such as the type and degree of progression of the disease or disorder, the overall health status of the particular patient, the relative bioavailability of the selected compound, the formulation of the excipients, and the route of its administration. The effective dosage can be extrapolated from a dosage-response curve derived from in vitro or animal model test systems.

[0213] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical such as antiviral agents, anticancer agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, and the like.

Example

[0214] Equipment: 1 The 1H NMR spectra were recorded at 400 MHz using a Bruker AVANCE 400 MHz spectrometer. NMR analysis was performed by assigning chemical shifts and multiplicities using MestReC or MestReNova software. When two adjacent peaks of equal or unequal height were observed, they could be displayed as either a multiplet or a doublet. In the case of a doublet, the coupling constant could be assigned using this software. In any of the examples, one or more protons may not have been observed because they were obscured by water and / or solvent peaks. The LCMS equipment and conditions are as follows.

[0215] 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 aqueous solution (v / v), B: 0.05% formic acid ACN solution (v / v). Flow rate: 1 mL / min at 25 °C. Detector: 214 nm, 254 nm. Gradient stop time, 10 min. Time table:

Table 1

[0216] MS: G6120A, quadrupole LC / MS, ion source: ES-API, TIC: 70~1000 m / z, fragmentor: 60, dry gas flow: 10 L / min, nebulizer pressure: 35 psi, dry gas temperature: 350 °C, Vcap: 3000 V.

[0217] Sample preparation: The sample was dissolved in ACN or methanol at 1~10 mg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1~10 μL.

[0218] Definitions: ACN (acetonitrile); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); CDCl3 (deuterated chloroform); CD3OD (deuterated 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); 11H 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).

[0219] Synthesis of Intermediate Intermediate 1: tert - Butyl 4 - (acetylthio)piperidine - 1 - carboxylate

Chemical Structure

[0220] Intermediate 2: 4 - (6 - aminohexylamino)-2 - (2,6 - dioxo - 3 - piperidyl)isoindoline - 1,3 - dione hydrochloride

Chemical Structure

[0221] Step 2: 4-(6-Aminohexylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hydrochloride To a solution of tert-butyl N-[6-[[2-(2,6-dioxo-3-piperidyl)-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 at room temperature overnight. The mixture was concentrated under reduced pressure and washed with EtOAc to give the title compound (140 mg, 81%) as a green solid. LCMS: [M+H] + 373.2.

[0222] Intermediate 3: S-((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)ethanethioate

Chemical Structure

[0223] Step 2: S-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethanethioate (1s,4s)-4-((tert-Butoxycarbonyl)amino)cyclohexylmethanesulfonate (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 for 2 h under N2 atmosphere. The residue was diluted with water (20 mL) and extracted with EtOAc (30 mL×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 (0.9 g, 29% yield) as a brown solid. LCMS: [M+H] + 274.3.

[0224] Intermediate 4: 8-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]octanoic acid

Chemical formula

[0225] Intermediate 5: 3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]propanoic acid

Chemical Structure

[0226] 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)acetamidotrifluoroacetate

Chemical formula

[0227] Step 2: Methyl 2-amino-4,6-difluorobenzoate 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), iodomethane (92.5 g, 651.6 mmol) was added dropwise under a N2 atmosphere. The mixture was stirred at 20 °C for 2 hours. The mixture was quenched with water (3.5 L) and stirred at 20 °C for 30 minutes. The suspension was filtered. The cake was washed with 1 L of a 20:1 petroleum ether:EtOAc solution and dried under vacuum to obtain the title compound (89 g, 88%) as a brown solid. LCMS: [M+H] + 188.1.

[0228] Step 3: Methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate To a solution of methyl 2-amino-4,6-difluorobenzoate (3 g, 16.0 mmol, 1.0 eq) in DMSO (5 mL) was added cyclopentanamine (2.73 g, 32.0 mmol, 2.0 eq), 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 × 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 (863 mg, 21%) as a red solid. LCMS: [M+H] + 253.1.

[0229] Step 4: 2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one 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 / dioxane (240.0 mL, 960 mmol) was heated at 100 °C overnight in a sealed tube. The mixture was diluted with 770 mL of a 10:1 solution of petroleum ether:EtOAc and stirred at room temperature for 1 h. The suspension was filtered, and the cake was dried under vacuum to give the title compound (56.0 g, 99.5% yield) as a brown solid. LCMS: [M+H] + 296.1.

[0230] Step 5: tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate 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 with 2M NaOH (6.8 mL, 13.5 mmol), and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 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 obtain the title compound (500 mg, 31%) as a yellow solid. LCMS: [M+H] + 477.2.

[0231] Step 6: 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride 40 mL of a 1.5M HCl / EtOAc solution containing tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (450 mg, 0.94 mmol) was stirred at 25 °C overnight. The mixture was concentrated under reduced pressure to obtain 7-(cyclopentylamino)-5-fluoro-2-(4-piperidylsulfanylmethyl)-3H-quinazolin-4-one (350 mg, 98.5% yield) as a yellow solid. LCMS: [M+H] + 377.2. 11H 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).

[0232] Step 7: tert-Butyl 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetate 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) were added tert-butyl 2-bromoacetate (567 mg, 2.91 mmol) and K2CO3 (1.0 g, 7.26 mmol). The mixture was stirred at 40 °C overnight. The mixture was allowed to cool to room temperature naturally and filtered. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL × 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 (430 mg, 36%) as a yellow solid. LCMS: [M+H] + 491.1.

[0233] Step 8: 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetic acid hydrochloride tert-Butyl 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetate (430 mg, 0.88 mmol) in 2 M HCl / EtOAc solution (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 (390 mg, 94.5% yield) as a yellow solid. LCMS: [M+Na]+ 435.2.

[0234] Step 9: 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]-N-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]hexyl]acetamide trifluoroacetate To a DMF solution (20 mL) of hydrochloride of 2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetic acid (127 mg, 0.27 mmol) and hydrochloride of 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (110 mg, 0.27 mmol), under N2 atmosphere, EDCI (258 mg, 1.35 mmol), HOBt (91 mg, 0.67 mmol) and DIPEA (139 mg, 1.08 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×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 / water, 0.1% TFA), and preparative HPLC (Shimadzu, Sepax BR prep-C18, 10 μm, 250×21.2 mm column, eluted with a gradient of ACN / 0.1% aqueous TFA solution at a flow rate of 20 mL / min) to give the title compound (85 mg, 35% yield) as a green solid. LCMS: [M+H]+ 789.2. 1HNMR (400 MHz, 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).

[0235] 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

Chem.

[0236] Step 2: 7-[[2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetyl]amino]heptanoic acid To a MeOH solution (5 mL) of ethyl 7-[[2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetyl]amino]heptanoate (168 mg, 0.28 mmol), 2N NaOH (0.57 mL, 1.14 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated to give the title compound (128 mg, 0.23 mmol, 80% yield) as a yellow solid. LCMS: [M+H] + 562.1.

[0237] 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 To a solution of 7-[[2-[4-[[7-(cyclopentylamino)-5-fluoro-4-oxo-3H-quinazolin-2-yl]methylsulfanyl]-1-piperidyl]acetyl]amino]heptanoic acid (50 mg, 0.09 mmol) in NMP (5 mL) were 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), and DIPEA (46 mg, 0.36 mmol). The mixture was stirred at room temperature overnight, then water was added and the resulting suspension was filtered. The filtrate was purified by preparative HPLC (Shimadzu, Sepax BR prep-C18, 10 μm, 250 × 21.2 mm column, gradient of ACN / 0.1% aqueous TFA, eluting at a flow rate of 20 mL / min) to give the title compound (5 mg, 6% yield) as a yellow solid. LCMS: [M+H] + 975.2. 1HNMR (400 MHz, CD3OD) δ 8.98(s, 1H), 7.48-7.41(m, 5H), 6.47(t,J = 12.0Hz, 2H), 4.65-4.62(m, 1H), 4.58-4.51(m, 3H), 4.38-4.34 (t,J = 15.6Hz, 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).

[0238] 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

Chemical formula

[0239] Step 2: Methyl 2,6 - difluoro - 4 - hydroxy - benzoate To a solution of 2,6-difluoro-4-hydroxy-benzoic acid (811 g, 4658 mmol) in methanol (3500 mL) at 0 °C, thionyl chloride (1386 g, 11646 mmol) was added slowly, and the mixture was refluxed overnight. The mixture was concentrated, the residue was diluted with water (2500 mL), and stirred at room temperature for 30 minutes. The suspension was filtered. The cake was washed with water and dried under vacuum to give the title compound (739 g, 84% yield) as an off-white solid. LCMS: [M+H] + 189.1.

[0240] Step 3: Methyl 2,6-difluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate A mixture of methyl 2,6-difluoro-4-hydroxy-benzoate (20 g, 106 mmol), 4-(bromomethyl)tetrahydropyran (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 under vacuum to give the title compound (30 g, 99% yield) as a yellow solid. LCMS: [M+H] + 287.2.

[0241] Step 4: Methyl 2-[(2,4-dimethoxyphenyl)methylamino]-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate A mixture of methyl 2,6-difluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate (30 g, 105 mmol), (2,4-dimethoxyphenyl)methanamine (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×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (40 g, 88% yield) as a yellow solid. 11H 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, 2 H), 4.26 (d, 2 H, J = 5.6 Hz), 3.90-3.83 (m, 4 H), 3.81 (s, 3 H), 3.75 (s, 6 H), 3.35-3.29 (m, 2 H), 1.96-1.91 (m, 1 H), 1.68-1.62 (m, 2 H), 1.31-1.26 (m, 2 H).

[0242] Step 5: Methyl 2-amino-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate To a DCM solution (200 mL) 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) 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 × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (20 g, 77% yield) as a yellow solid. LCMS: [M+H] + 284.2.

[0243] Step 6: 2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one A mixture of methyl 2-amino-6-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzoate (20 g, 71 mmol) and 2-chloroacetonitrile (13.4 mL, 211.8 mmol) in 2N HCl / dioxane (120 mL, 240 mmol) was 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 under vacuum to give the title compound (14 g, 61%) as a yellow solid. LCMS: [M+H] + 327.1.

[0244] Step 7: ((1r,4r)-4-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamic acid tert-butyl To a THF solution (2 mL) of 2-(chloromethyl)-5-fluoro-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-4-one (200 mg, 0.61 mmol) and S-[4-(tert-butoxycarbonylamino)cyclohexyl]ethanethioate (201 mg, 0.73 mmol) was added 2N NaOH (2 mL, 4 mmol), and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (20 mL × 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 (250 mg, 78%) as a brown solid. LCMS: [M+H] + 522.3.

[0245] Step 8: 2-[(4-Aminocyclohexyl)sulfanylmethyl]-5-fluoro-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-4-one hydrochloride 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 afford the title compound (120 mg, 55%) as a brown solid. LCMS: [M+H] + 422.3.

[0246] Step 9: 8-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]-N-[4-[[5-fluoro-4-oxo-7-(tetrahydropyran-4-ylmethoxy)-3H-quinazolin-2-yl]methylsulfanyl]cyclohexyl]octanamide To a solution of 8-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-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 this reaction mixture were added DIPEA (31 mg, 0.24 mmol) and 2-[(4-aminocyclohexyl)sulfanylmethyl]-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×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 afford the title compound (45 mg, 46%) as a yellow solid. LCMS: [M+H] + 819.0. 11H NMR (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).

[0247] 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

Chemical formula

[0248] Example A. Enzyme assay for inhibition of PARP14 The catalytic domain of human PARP14 (residues 1611 - 1801, GenBank accession number NM_017554) was overexpressed in Escherichia coli cells. The protein was purified from cell lysates using an N-terminal His-TEV fusion tag. The His-TEV tag was left on the protein and used for enzyme assays.

[0249] Dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) was used to monitor the auto-modification of PARP14 by biotinylated nicotinamide adenine dinucleotide (biotin-NAD) to measure the enzymatic inhibition of PARP14. A dose-response curve of 1 μL of each test compound was spotted onto 384-well nickel-coated white microplates (Thermo) using a Mosquito (TTP Labtech). 40 μL of assay buffer containing PARP14 (20 mM HEPES pH = 8, 100 mM NaCl, 0.1% bovine serum albumin, 2 mM DTT, and 0.002% Tween 20) was added and incubated with the test compound at 25 °C for 30 min, and then the reaction was carried out in a 50 μL volume by adding 10 μL of biotin-NAD (Biolog). The final concentrations of PARP14 and biotin-NAD were 50 nM and 3 μM, respectively. After continuing the reaction at 25 °C for 3 h, the reaction was quenched with 5 μL of 10 mM native nicotinamide adenine dinucleotide (Sigma-Aldrich). The quenched reaction was washed three 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 with DELFIA assay buffer (Perkin Elmer) was added to the washed and dried plates. After incubation at 25 °C for 30 min, the plates were washed five times with TBST wash buffer. Finally, 25 μL of DELFIA enhancement solution was added. After a 5-min incubation, the plates were read using an Envision plate reader (Perkin Elmer) equipped with a LANCE / DELFIA top mirror at an excitation of 340 nm and an emission of 615 nm to measure the amount of europium present in each well and report the amount of biotin-NAD transferred in the auto-modification reaction. % Inhibition was calculated as follows using control wells containing 2% DMSO vehicle for the negative control or 100 μM rucaparib for the positive control.

Number

[0250] The % inhibition values were plotted as a function of compound concentration and the following four-parameter fit was applied to determine the IC 50 value:

Equation

[0251] The IC of the specific compound corresponding to the Q group defined herein 50 data is presented in Table A-1 below (「+」 means < 1 μM, 「++」 means ≥ 1 μM and < 10 μM, 「+++」 means ≥ 10 μM).

Table 2

[0252] Example B: PARP14 Degradation Assay KYSE270 cells were seeded at 0.5e 6Cells / well density was seeded in 6-well plates and incubated overnight. Once attached, the cells were treated with increasing concentrations of the compounds of Examples 1-4 (0.001 μM, 0.01 μM, 0.1 μM, 1 μM, and 10 μM; for the compound of Example 1, 0.003 μM, 0.03 μM, 0.3 μM, and 3 μM were also evaluated), or DMSO for 24 hours. The medium was gently aspirated, and the cells were washed 3 times on ice with 2 mL of ice-cold PBS. The PBS was completely aspirated, and 75 μl of freshly prepared lysis buffer (Thermo Fisher 78501) was added to the cells and then scraped into the buffer. The lysate was collected in a microcentrifuge tube and incubated on ice for 15 minutes. The lysate was centrifuged at 10,000 rpm for 15 minutes at 4 °C, and the supernatant was collected in a new microcentrifuge tube. Protein concentration was 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 analyzed on 4-12% Tris-acetate gels in MOPS running buffer using 60 μg of protein per well. Western blot transfer was performed using a PVDF membrane (LI-COR Immobilon) at 20 volts for 14 minutes. Odyssey blocking buffer (LI-COR 927-50000) was used, and primary antibodies (PARP14: mouse antibody (15A6 Lot1C) generated in-house, β-actin: D6A8 (8457)) were incubated at a 1:1,000 dilution for 2 hours at room temperature and detected using secondary antibodies (LI-COR 926-68072, 926-32211). The mouse antibody 15A6 Lot1C was generated by immunizing 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.The supernatant of the monoclonal clone was tested by Western blotting against THP-1 and THP-1 PARP14 KO cells to confirm reactivity. The PARP14 antibody was generated by culturing the 15A6-1 hybridoma monoclonal clone in 1 L of serum-free medium + 2% low IgG FBS. This antibody was purified from the culture medium by protein G affinity chromatography.

[0253] Treatment of KYSE270 cells with the compounds of Examples 1-4 for 24 hours results in a dose-dependent loss of PARP14. At higher concentrations, Examples 1, 3, and 4 show an improvement in efficacy consistent with a ternary complex-mediated mechanism, known as the "hook effect" and described in Crews et al, Nature Chem. Biol. 2015, 11, 611. Figure 1 shows a Western blot of the PARP14 degradation assay for the compound of Example 1. Figure 2 shows a Western blot of the PARP14 degradation assay for the compound of Example 2. Figure 3 shows a Western blot of the PARP14 degradation assay for the compound of Example 3. Figure 4 shows a Western blot of the PARP14 degradation assay for the compound of Example 4.

[0254] Example C: mRNA expression levels of PARP14 in various cancer types Figure 5 illustrates the mRNA expression levels of PARP14 in various cancer types compared to the corresponding normal tissues. RNA sequencing data were downloaded and analyzed from The Cancer Genome Consortium (TCGA). Each point represents the value of each sample, the box represents the interquartile range or the central 50% of the data, the horizontal line is the group median, and the vertical lines represent the upper and lower quartiles of the data. In several cancers, it is clear that PARP14 mRNA is higher 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 carcinoma, READ = rectal cancer, STAD = gastric cancer, THCA = thyroid cancer, UCEC = uterine cancer. *p < 0.05, **p < 0.01, ***p < 0.001, Wilcoxon test.

[0255] Example D: Reduction of IL-10 production in cells Figures 6A and 6B show that in vitro treatment with the compound of Example 1 decreased the production of IL-10 in IL-4-stimulated M2-like macrophages. Figure 6A shows the experimental layout.

[0256] Monocytes were isolated from human peripheral 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 M0 macrophages. Then, 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.

[0257] Figure 6B shows the IL-10 levels measured by ELISA in the tissue culture supernatant of the cells treated as described above.

[0258] Isolation of primary human monocytes from whole blood: Primary monocytes were isolated from whole blood (iSPECIMEN; 500 mL) collected from healthy donors. The blood was diluted with EasySep buffer (STEMCELL Technologies 20144) at a ratio of 1:1 and layered onto Lymphoprep (STEMCELL Technologies 07811) in a SepMate tube (STEMCELL Technologies 85450) for PBMC isolation according to the manufacturer's instructions. 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. Monocytes were isolated from the PBMC cell population using the EasySep Human Monocyte Isolation Kit (STEMCELL Technologies 19359) according to the manufacturer's instructions. The concentrated monocyte cell population was resuspended in fresh EasySep buffer, counted, and seeded for subsequent assays.

[0259] Differentiation of monocytes into macrophages, M2 polarization, and PARP14 inhibition: Monocytes were seeded on day 0 in ImmunoCult SF Macrophage Medium (STEMCELL Technologies 10961) containing 50 ng / mL of M-CSF (STEMCELL Technologies 78057) in 12-well plates at a density of 1 million cells per mL of medium and grown for 6 days to differentiate into macrophages. 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 of human recombinant IL-4 (STEMCELL Technologies 78045), and samples (medium and cells) were collected at the 72-hour time point. 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 on day 6 after seeding.

[0260] Quantification of IL-10: The IL-10 ELISA kit (STEMCELL Technologies 02013) was used according to the manufacturer's instructions to determine the level of IL-10 in the supernatant of human primary M2 macrophages. Briefly, the supernatant was collected at the indicated time points, any floating cells were removed, and then stored at -80°C until ready for use. The IL-10 concentration was determined from the IL-10 standard curve of the kit and normalized to total cell protein.

[0261] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All patents, patent applications, and publications cited in this application, each reference is hereby incorporated by reference in its entirety into this specification.

Claims

1. A compound of formula (A1): Q - L １ - E (A1) or a pharmaceutically acceptable salt thereof, wherein Q is a moiety represented by formula I: 【Chemical 1】 [wherein W is CR Ｗ or N, and X is CR Ｘ or N, and Y is CR Ｙ or N, and Z is CR Ｚ or N, and wherein not more than three of W, X, Y, and Z are simultaneously N, Ring A is a monocyclic or polycyclic C ３－１４ cycloalkyl, or Ring A is a monocyclic or polycyclic 4- to 18-membered heterocycloalkyl, and Ring A is optionally substituted with 1, 2, 3, or 4 R Ａ and when Ring A is polycyclic, Ring A is attached to the -(L) ｍ - moiety of Formula I via a non-aromatic ring, 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 -, -(CR ５ R ６ ). ｐ -SO ２ -(CR ５ R ６ ). ｑ -, -(CR ５ R ６ ). ｒ -SONR ３ -(CR ５ R ６ ). ｓ -, or -NR ３ CONR ４ - and 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 are each independently selected from H, halo, C １－４ alkyl, C １－４ alkoxy, C １－４ haloalkyl, amino, C １－４ alkylamino, and C ２－８ dialkylamino Each R Ａ is halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, 4- to 10-membered heterocycloalkyl-C １－４ alkyl, CN, NO ２ , OR ａ１ , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , NR ｃ１ C(O)OR ａ１ , NR ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), R ｂ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ , S(O)R ｂ１ , NR ｃ１ , S(O) ２ R ｂ１ , NR ｃ１ , S(O) ２ , NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ 、and S(O) ２ NR ｃ１ R ｄ１ independently selected from (wherein, R Ａ 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- 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 are each Cy １ 、Cy １ -C １－４ alkyl, halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, CN, NO ２ 、OR ａ１ 、SR ａ１ 、C(O)R ｂ１ 、C(O)NR ｃ１ R ｄ１ 、C(O)OR ａ１ 、OC(O)R ｂ１ 、OC(O)NR ｃ１ R ｄ１ 、C(=NR ｅ１ )NR ｃ１ R ｄ１ 、NR ｃ１ C(=NR ｅ１ )NR ｃ１ R ｄ１ 、NR ｃ１ R ｄ１ 、NR ｃ１ C(O)R ｂ１ 、NR ｃ１ C(O)OR ａ１ 、NR ｃ１ C(O)NR ｃ１ R ｄ１ 、NR ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Ｗ 、R Ｘ 、R Ｙ 、and R Ｚ are each, H, halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, 4- to 10-membered heterocycloalkyl-C １－４ alkyl, CN, NO ２ 、OR ａ２ 、SR ａ２ 、C(O)R ｂ２ 、C(O)NR ｃ２ R ｄ２ 、C(O)OR ａ２ 、OC(O)R ｂ２ 、OC(O)NR ｃ２ R ｄ２ 、NR ｃ２ R ｄ２ 、NR ｃ２ C(O)R ｂ２ 、NR ｃ２ C(O)OR ａ２ 、NR ｃ２ C(O)NR ｃ２ R ｄ２ 、C(=NR ｅ２ )R ｂ２ 、C(=NR ｅ２ )NR ｃ２ R ｄ２ 、NR ｃ２ C(=NR ｅ２ )NR ｃ２ R ｄ２ 、NR ｃ２ S(O)R ｂ２ 、NR ｃ２ S(O) ２ R ｂ２ 、NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ 、S(O)R ｂ２ 、 S(O)NR ｃ２ R ｄ２ 、 S(O) ２ R ｂ２ 、 and S(O) ２ NR ｃ２ R ｄ２ selected independently from (where R Ｗ R Ｘ R Ｙ or R Ｚ of the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl are each Cy ２ Cy ２ -C １－４ alkyl, halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, CN, NO ２ , OR ａ２ , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ C(O)R ｂ２ , NR ｃ２ C(O)OR ａ２ , NR ｃ２ C(O)NR ｃ２ R ｄ２ , NR ｃ２ S(O)R ｂ２ , NR ｃ２ S(O) ２ R ｂ２ , NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ optionally selected with 1, 2, 3, 4, or 5 substituents independently selected from Here, W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ When, R Ｗ , R Ｘ , R Ｙ , and R Ｚ At least one of them is other than H, Each Cy １ is halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, 4- to 10-membered heterocycloalkyl-C １－４ alkyl, CN, NO ２ , OR ａ１ , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , NR ｃ１ C(O)OR ａ１ , NR ｃ１ C(O)NR ｃ１ R ｄ１ , NR ｃ１ , S(O)R ｂ１ , NR ｃ１ , S(O) ２ R ｂ１ , NR ｃ１ , S(O) ２ , NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ , NR ｃ１ R ｄ１ C optionally substituted in each case with 1, 2, 3 or 4 substituents independently selected from ６－１０ aryl, C ３－７ independently selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, Each Cy ２ is halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, 4- to 10-membered heterocycloalkyl-C １－４ alkyl, CN, NO ２ , OR ａ２ , SR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ C(O)R ｂ２ , NR ｃ２ C(O)OR ａ２ , NR ｃ２ , C(O)NR ｃ２ R ｄ２ , NR ｃ２ , S(O)R ｂ２ , NR ｃ２ , S(O) ２ R ｂ２ , NR ｃ２ , S(O) ２ , NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ , NR ｃ２ R ｄ２ 1, 2, 3, or 4 substituents independently selected from ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, respectively, optionally substituted in each case 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl (wherein R ａ１ 、R ｂ１ 、R ｃ１ 、R ｄ１ 、R ａ２ 、R ｂ２ 、R ｃ２ 、or R ｄ２ 's said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl is Cy 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 , 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) ２ R ｂ３ , NR ｃ３ S(O) ２ R ｂ３ , NR ｃ３ S(O) ２ , NR ｃ３ R ｄ３ , and S(O) ２ , NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each Cy ３ is 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) ２ R ｂ３ , NR ｃ３ S(O) ２ R ｂ３ , NR ｃ３ S(O) ２ , NR ｃ３ R ｄ３ , and S(O) ２ , NR ｃ３ R ｄ３ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from C ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, R ａ３ 、R ｂ３ 、R ｃ３ 、and R ｄ３ are each independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, where said 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 may each independently be optionally 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). Alternatively, R ｃ１ and R ｄ１ together with the N atom to which they are attached, are optionally substituted with one, two, or three substituents independently selected from 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) ２ R ｂ３ , NR ｃ３ , S(O) ２ R ｂ３ , NR ｃ３ , S(O) ２ , NR ｃ３ R ｄ３ , and S(O) ２ , NR ｃ３ R ｄ３ to form an optionally substituted 4- to 7-membered heterocycloalkyl group, Alternatively, R ｃ２ and R ｄ２ together with the N atom to which they are attached, are optionally substituted with one, two, or three substituents independently selected from 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) ２ R ｂ３ , NR ｃ３ S(O) ２ R ｂ３ , NR ｃ３ S(O) ２ , NR ｃ３ R ｄ３ , and S(O) ２ , NR ｃ３ R ｄ３ to form a 4- to 7-membered heterocycloalkyl group optionally substituted with one, two, or three substituents independently selected from Each R ｅ１ , R ｅ２ , and R ｅ３ are 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, and p + q is 0, 1, or 2, r is 0 or 1, s is 0 or 1, and r + s is 0 or 1, t is 1, 2, or 3] and E is an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase, L １ is a linker covalently bonded to the partial Q and the partial E, any of said heteroaryl or heterocycloalkyl groups contains 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S, The wavy line is L １ represents the bonding point to the base, one or more ring-forming C or N atoms of any of said heterocycloalkyl groups are optionally substituted with an oxo (=O) group, one or more ring-forming S atoms of any of said heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups, said compound or a pharmaceutically acceptable salt thereof.

2.

3. 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 optionally substituted with 1 to 3 R ｑ substituents, and one or more chain carbon atoms of L １ may be oxidized to form a carbonyl (C=O), and one or more N and S chain atoms may optionally be oxidized to form an amine oxide, a sulfoxide, or a sulfonyl group, respectively Each R ｑ is independently selected from OH, CN, -COOH, NH ２ , halo, C １－６ haloalkyl, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkoxy, C １－６ alkylthio, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl, NH(C １－６ alkyl) and N(C １－６ alkyl), and the C ２ alkyl, phenyl, C ｑ cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl of R １－６ are each optionally substituted with halo, OH, CN, -COOH, NH ３－６ , C ２ , 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- to 6-membered heterocycloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. a is 0 or 1, Linker L １ has the following structure, 【Chemical Formula 2】 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)NR Ｇ -, -S(O ２ )-, or -S(O)NR Ｇ -, and is independently selected from Each R Ｇ is independently selected from H, methyl, and ethyl, b is 0 or 1, c is 0 or 1, and the wavy line represents the point of attachment to moieties Q and E, the compound or a pharmaceutically acceptable salt thereof according to Claim 1.

4. a is 1, b is 1, and c is 1, the compound or a pharmaceutically acceptable salt thereof according to Claim 3.

5. a is 0, b is 1, and c is 0, the compound or a pharmaceutically acceptable salt thereof according to Claim 3.

6. a is 1, b is 1, and c is 0, the compound or a pharmaceutically acceptable salt thereof according to Claim 3.

7.

8. Each G is independently selected from -C(O)- and -NR Ｇ The compound according to any one of claims 3 to 6 or a pharmaceutically acceptable salt thereof, which is independently selected from C(O)-. selected from, and the wavy line represents the point of attachment to moieties Q and E, the compound or a pharmaceutically acceptable salt thereof according to Claim 1. Linker L １ is 【Chemical Formula 3】

9. E is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 8.

10. E is

11. 【Chemical Formula 4】 【Chemical Formula 5】 a moiety having a structure selected from, and the wavy line is L １ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which represents a bonding point to a group. E is E has the following structure: 【Chemical Formula 6】 having, and the wavy line represents the junction point to L １ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which represents the junction point to L

12. E has the following structure: 【Chemical Formula 7】 having, and the wavy line represents the junction point to L １ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which represents a junction point to L.

13. E has the following structure: [Chemical Formula 8] having, the wavy line represents the junction point to L １ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which represents a junction point to L.

14. W is CR Ｗ wherein X is CR Ｘ wherein Y is CR Ｙ wherein Z is CR Ｚ The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. W is N, and X is CR Ｘ wherein Y is CR Ｙ wherein Z is CR Ｚ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

16. W is CR Ｗ wherein X is N, Y is CR Ｙ wherein Z is CR Ｚ The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

17. W is CR Ｗ wherein X is CR Ｘ wherein Y is N and Z is CR Ｚ The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

18. W is CR Ｗ wherein X is CR Ｘ wherein Y is CR Ｙ wherein Z is N, the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

19. Ring A is a monocyclic or polycyclic C that is optionally substituted with 1, 2, 3, or 4 Rs Ａ cycloalkyl, and when Ring A is polycyclic, Ring A is attached to the -(L)- ３－１４ moiety of Formula I via a non-aromatic ring, a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof. ｍ ​

20. Ring A is cyclohexyl optionally substituted with 1, 2, 3, or 4 Rs Ａ The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, which is cyclohexyl optionally substituted with Ａ .

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

22. Ring A is piperidinyl optionally substituted with 1, 2, 3, or 4 Rs Ａ The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, which is piperidinyl optionally substituted with Ａ .

23. Ring A is piperidin-4-yl optionally substituted with 1, 2, 3, or 4 Rs Ａ The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, which is piperidin-4-yl optionally substituted with Ａ .

24. L is -CH ２ - and is a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 0.

26. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 1.

27. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein n is 0.

28. R １ and R ２ both are H, the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. Each R Ａ is independently selected from C １－６ alkyl, OR ａ１ C(O)R ｂ１ NR ｃ１ R ｄ１ and S(O) ２ R ｂ１ wherein said C １－６ alkyl is Cy １ Cy １ -C １－４ alkyl, halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, CN, NO ２ OR ａ１ SR ａ１ C(O)R ｂ１ C(O)NR ｃ１ R ｄ１ C(O)OR ａ１ OC(O)R ｂ１ OC(O)NR ｃ１ R ｄ１ C(=NR ｅ１ )NR ｃ１ R ｄ１ NR ｃ１ C(=NR ｅ１ )NR ｃ１ R ｄ１ NR ｃ１ R ｄ１ NR ｃ１ C(O)R ｂ１ NR ｃ１ C(O)OR ａ１ NR ｃ１ C(O)NR ｃ１ R ｄ１ NR ｃ１ S(O)R ｂ１ NR ｃ１ S(O) ２ R ｂ１ NR ｃ１ S(O) ２ NR ｃ１ R ｄ１ S(O)R ｂ１ S(O)NR ｃ１ R ｄ１ S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

30. 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 and is a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

31. Each R Ｗ 、R Ｘ 、R Ｙ 、and R Ｚ are 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 、and NR ｃ２ C(O)R ｂ２ and the C Ｗ 、R Ｘ 、R Ｙ 、and R Ｚ alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C １－６ aryl-C ６－１０ alkyl are each Cy １－４ 、Cy ２ 、Cy ２ -C １－４ alkyl, halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, CN, NO ２ 、OR ａ２ 、SR ａ２ 、C(O)R ｂ２ 、C(O)NR ｃ２ R ｄ２ 、C(O)OR ａ２ 、OC(O)R ｂ２ 、OC(O)NR ｃ２ R ｄ２ 、C(=NR ｅ２ )NR ｃ２ R ｄ２ 、NR ｃ２ C(=NR ｅ２ )NR ｃ２ R ｄ２ 、NR ｃ２ R ｄ２ 、NR ｃ２ C(O)R ｂ２ 、NR ｃ２ C(O)OR ａ２ , NR ｃ２ C(O)NR ｃ２ R ｄ２ , NR ｃ２ S(O)R ｂ２ , NR ｃ２ S(O) ２ R ｂ２ , NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ The compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

32. W is CR Ｗ wherein R Ｗ is other than H, a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

33. R Ｗ is a halo, a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

34. R Ｗ is F, a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

35. X is CR Ｘ wherein R Ｘ is H, the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof.

36. Y is CR Ｙ wherein R Ｙ is other than H, a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

37. Y is CR Ｙ wherein 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) ２ R ｂ２ , and NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ and is a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

38. Y is CR Ｙ wherein R Ｙ is independently selected from C １－６ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, halo, 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) ２ R ｂ２ , and NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ and the C Ｙ alkyl, C １－６ cycloalkyl-C ３－７ alkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl of R １－４ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C １－６ alkyl, C １－６ haloalkyl, CN, NO ２ , OR ａ２ , NR ｃ２ R ｄ２ , and S(O) ２ R ｂ２ The compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

39. Y is CR Ｙ wherein 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) ２ R ｂ２ , and NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ and is a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

40. Y is CR Ｙ wherein R Ｙ is independently selected from C １－６ alkyl and OR ａ２ The compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

41. R ａ２ is H, C １－６ alkyl, C １－６ haloalkyl, C ６－１０ aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl selected from, said C １－６ alkyl, C １－６ haloalkyl, C ６－１０ aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl are each, C １－４ alkyl, C １－４ haloalkyl, halo, CN, OR ａ３ , C(O)R ｂ３ , C(O)OR ａ３ and S(O) ２ R ｂ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from, a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

42. Y is CR Ｙ wherein R Ｙ is independently selected from NR ｃ２ R ｄ２ and NR ｃ２ C(O)R ｂ２ and is a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

43. 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- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the C １－６ alkyl, C １－６ haloalkyl, C ６－１０ aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－４ alkyl, C ３－７ cycloalkyl-C １－４ alkyl, and 4- to 10-membered heterocycloalkyl-C １－４ alkyl are each 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) ２ R ｂ３ and is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from, a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

44. Z is CR Ｚ wherein R Ｚ is H, a compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof.

45. Q is of formula II: 【Chemical Formula 9】 is a part having, and the wavy line is L １ The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which represents a bonding point to a group.

46. Q is of formula IIIA, IIIB, IIIC, IIID, or IIIE: 【Chemical 10】 is a part having, and the wavy line is L １ The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, which represents a bonding point to a group.

47. Q is of formula IVA or IVB: 【Chemical Formula 11】 is a part having, and the wavy line is L １ The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which represents a bonding point to a group.

48. Formula (A2): 【Chemical 12】 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, having the formula.

49. Formula (A3): 【Chemical Formula 13】 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, having the formula.

50. Formula (A4): 【Chemical Formula 14】 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, having the formula.

51. Formula (A5): 【Chemical Formula 15】 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, having the formula.

52. Formula (A6): 【Chemical 16】 The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, having the formula.

53. The following: 【Chemical 17】 The compound according to claim 1, selected from, or a pharmaceutically acceptable salt of any of the foregoing compounds.

54. A pharmaceutical composition comprising the compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

55. An agent for degrading PARP14, comprising the compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

56. A medicament comprising the compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

57. The medicament according to claim 56, wherein the cancer is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, renal cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colorectal cancer, or melanoma.

58. A medicament comprising the compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof.

59. An agent for reducing IL-10 in cells, comprising the compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof.

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