Quinazolinones as PARP14 inhibitors

Abstract

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

Description

Field of the Invention

[0001] The present invention relates to quinazolinones and related compounds that are inhibitors of PARP14 and are useful in the treatment of cancer. Background of the Invention

[0003] Poly (ADP-ribose) polymerase (PARP) is a member of a family of seventeen enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, and a variety of cellular stress responses (Vyas S et al., Nat Rev Cancer. 2014 Jun 5; 14 (7): 502–509). The ability of cancer cells to survive stress is a fundamental cancer mechanism and an emerging avenue for new therapies. PARP1, a member of the PARP family, has been shown to be an effective cancer target associated with cellular stress induced by DNA damage, either by genetic mutations or by cytotoxic chemotherapy, with three drugs approved clinically and several others in late-stage development (Ohmoto A et al., OncoTargets and Therapy. 2017; Vol. 10: 5195).

[0004] Based on homology within the catalytic domain, 17 members of the PARP family have been identified in the human genome (Vyas et al., Nat Commun. 2013 Aug 7;4:2240). However, their catalytic activities fall into three distinct categories. Most PARP family members catalyze the transfer of a single ADP-ribose unit to their substrate (monoPARP), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units to their substrate (polyPARP). Finally, PARP13 is the only PARP for which catalytic activity has not been demonstrated in vitro or in vivo.

[0005] PARP14 is both a cytoplasmic monoPARP and a nuclear monoPARP. It, along with two other monoPARPs (PARP9 or BAL1 and PARP15 or BAL3), was originally identified as BAL2 (B aggressive lymphoma 2), a gene associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL) (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 referred to as macroPARPs due to the presence of a macro-domain at their N-termini. The genes for these three macroPARPs are located at the same genomic locus, suggesting a common regulatory role. In fact, the gene expression of PARP14 and PARP9 is highly correlated between normal tissues and cancer types. Compared to normal tissues, PARP14 is overexpressed in tumors (including cancer cell lines established compared to normal counterparts). Literature examples of cancers with high PARP14 expression 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, RNA interference (RNAi)-mediated knockdown of PARP14 inhibits cell proliferation and survival. Other studies have shown that the enzymatic activity of PARP14 is required for the survival of prostate cancer cell lines in vitro (Bachmann SB et al., Mol Cancer. 2014 May 27;13:125).

[0006] PARP14 has been identified as a downstream regulator of IFN-γ and IL-4 signaling, affecting the downstream transcription of STAT1 (in the case of IFN-γ) (Iwata H et al., Nat Commun. 2016 Oct 31;7:12849) or STAT6 (in the case of IL-4) (Goenka S et al., Proc Natl Acad Sci USA. 2006 Mar 6;103(11):4210–4215; Goenka S et al., J Biol Chem. 2007 May 3;282(26):18732–18739; and Mehrotra P et al., J Biol Chem. 2010 Nov 16;286(3):1767–1776). Parp14- / - knockout (KO) mice have reduced marginal zone B cells, and in the Parp14 KO environment, the ability of IL-4 to confer B cell survival in vitro is also reduced (Cho SH et al., Blood. 2009 Jan 15; 113(11): 2416–2425). This reduced survival signaling is mechanistically related to the reduced ability of Parp14KO B cells to maintain metabolic fitness and increase Mcl-1 expression. Parp14 KO can prolong the survival of Eμ-Myc lymphoma models, indicating the role of PARP14 in Myc-driven lymphomagenesis (Cho SH et al., Proc Natl Acad Sci USA. 2011 Sep 12; 108(38): 15972–15977). Gene expression data also point to a role for PARP14 in human B cell lymphoma. BAL proteins, including PARP14, are highly expressed in host response (HR) DLBCL, a genomically defined subtype of B-cell lymphoma characterized by a rapid inflammatory infiltration of T cells and dendritic cells and the presence of an IFN-γ gene signature (Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Monti S et al., Blood. 2005; 105(5): 1851). In fact, PARP14 is considered an interferon-stimulated gene, and its mRNA is increased by stimulation of various cell systems with all types of interferons (I, II, and III; www.interferome.org).

[0007] Due to its role in the IL-4 and IFN-γ signaling pathways, PARP14 is associated with the differentiation of T helper cells and macrophages. Genetic inactivation of PARP14 in macrophages favors the pro-inflammatory M1 phenotype associated with anti-tumor immunity, while reducing the pro-tumor M2 phenotype. In human and mouse macrophage models, it was found that with PARP14 knockout or knockdown, the expression of M1 genes downstream of IFN-γ increased, while the expression of M2 genes downstream of IL-4 decreased. Similarly, genetic PARP14 knockout has been shown to reduce the Th2 T helper cell phenotype in the context of skin and airway inflammation, which is also related to the regulatory role of PARP14 in IL-4 signaling (Mehrotra P et al., J Allergy Clin Immunol. 2012 Jul 25; 131(2): 521 and Krishnamurthy P et al., Immunology. 2017 Jul 27; 152(3): 451–461).

[0008] PARP14 has been shown to regulate the transcription of STAT6 (activator of transcription 6) and promote T cell proliferation in T cells and B cells. H 2 reactions, known T H The 2 reaction can promote allergic airway disease (asthma condition). In a model of allergic airway disease, genetic depletion of PARP14 and its enzymatic activity led to reduced lung inflammation and IgE levels, which are key indicators of the asthma process in this model. In addition, the enzymatic activity of PARP14 promotes T in a STAT6-dependent manner. H 2 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 treatment for allergic airway diseases.

[0009] There is a pressing need for new drugs that can treat diseases such as certain cancers and inflammatory conditions that are characterized by aberrant expression or activity of PARP 14. The compounds, compositions, and methods described herein help to meet these and other needs. Summary of the Invention

[0010] The present invention relates to compounds of formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined as follows.

[0013] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0014] The present invention also relates to a method for inhibiting PARP14 activity, comprising contacting the compound of Formula I or a pharmaceutically acceptable salt thereof with PARP14.

[0015] The present invention also relates to a method for reducing IL-10 in a cell, comprising contacting the cell with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0016] The present invention also relates to a method for treating a disease or condition in a patient in need of treatment, wherein the disease or condition is characterized by overexpression or increased activity of PARP14, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0017] The present invention also relates to a method of treating cancer in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0018] The present invention also relates to a method of treating an inflammatory disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0019] The present invention also relates to a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for use in therapy.

[0020] The present invention also relates to the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in therapy, such as the treatment of cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shown are the mRNA expression levels of PARP14 in various cancer types compared with corresponding normal tissues.

[0023] Figure 2A and Figure 2B demonstrated that in vitro treatment with various PARP14 inhibitors reduced IL-10 production in IL-4-stimulated M2-like macrophages.

[0024] Figure 3A demonstrated that PARP14 inhibitors reduced tumor growth in the 4T1 mouse syngeneic model. Figure 3B Plasma concentrations of PARP14 inhibitors after the last dose at study endpoint are shown.

[0025] Figure 4A demonstrated that PARP14 inhibitors reduced tumor growth in the LL / 2 mouse syngeneic model. Figure 4B A survival benefit of PARP14 inhibitor administration was shown in the LL / 2 syngeneic model. Figure 4CPlasma concentrations of PARP14 inhibitors after the last dose at study endpoint are shown.

[0026] Details

[0027] The present invention relates to compounds of formula I:

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein:

[0030] W is CR W or N;

[0031] X is CR X or N;

[0032] Y is CR Y or N;

[0033] Z is CR Z or N;

[0034] Among them, at most two of W, X, Y and Z are N at the same time;

[0035] Ring A is monocyclic or polycyclic C 3-14 Cycloalkyl or Ring A is a monocyclic or polycyclic 4-18 membered heterocycloalkyl, wherein Ring A is optionally substituted by 1, 2, 3 or 4 R A and when ring A is polycyclic, ring A is connected to -(L) of formula I through a non-aromatic ring. m -part;

[0036] 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 R6 ) 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 -SO2-(CR 5 R 6 ) q -、-(CR 5 R 6 ) r -SONR 3 -(CR 5 R 6 ) s -, or -NR 3 CONR 4 -;

[0037] R 1 and R 2 are each independently selected from H and methyl;

[0038] R 3 and R 4 Each independently selected from H and C 1-4 alkyl;

[0039] R 5 and R 6 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, amino, C 1-4 Alkylamino and C 2-8 dialkylamino groups;

[0040] Each R A independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ; where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl groups are each optionally independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted with 1, 2, 3, 4 or 5 substituents;

[0041] R W 、R X、R Y and R Z are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; where R W 、RX 、R Y or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl groups are each optionally independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NRc2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 substituted with 1, 2, 3, 4 or 5 substituents;

[0042] When W is CR W , X is CR X , 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 not H;

[0043] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 Rd1 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 substituted with 1, 2, 3 or 4 substituents;

[0044] Each Cy 2 Independently selected from C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NRc2 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 substituted with 1, 2, 3 or 4 substituents;

[0045] Each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 or R d2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is optionally independently selected from Cy3 、Cy 3 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, 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 substituted with 1, 2, 3, 4 or 5 substituents;

[0046] Each Cy 3 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SRa3 、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 substituted with 1, 2, 3 or 4 substituents;

[0047] R a3 、R b3 、R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally independently selected from OH, CN, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 1, 2 or 3 substituents of the haloalkoxy group;

[0048] or R c1 and R d1 Together with the N atom to which they are attached, they form a radical optionally independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 Rd3 and S(O)2NR c3 R d3 4-7 membered heterocycloalkyl substituted with 1, 2 or 3 substituents;

[0049] or R c2 and R d2 Together with the N atom to which they are attached, they form a radical optionally independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 4-7 membered heterocycloalkyl substituted with 1, 2 or 3 substituents;

[0050] Each R e1 、R e2 and R e3 Independently selected from H, C 1-4 Alkyl and CN;

[0051] m is 0 or 1,

[0052] n is 0, 1, or 2;

[0053] p is 0, 1, or 2;

[0054] q is 0, 1 or 2, wherein p+q is 0, 1 or 2;

[0055] r is 0 or 1;

[0056] s is 0 or 1, wherein r+s is 0 or 1; and

[0057] t is 1, 2, or 3;

[0058] wherein any of the above heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S;

[0059] wherein one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups are optionally substituted with an oxo (=O) group;

[0060] wherein one or more ring-forming S atoms of any of the above heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups;

[0061] When W is CR W , X is CR X , Y is CR Y and Z is CR Z When m is 1 or 2, then R X and R Y Not all are methoxy;

[0062] Wherein the compound is not:

[0063]

[0064] In some embodiments, W is CR W ;X is CR X ;Y is CR Y ; and Z is CR Z .

[0065] In some embodiments, W is N; X is CR X ;Y is CR Y ; and Z is CR Z .

[0066] In some embodiments, W is CR W ; X is N; Y is CR Y ; and Z is CR Z .

[0067] In some embodiments, W is CR W ;X is CR X ; Y is N; and Z is CR Z .

[0068] In some embodiments, W is CR W ;X is CR X ;Y is CR Y ; and Z is N.

[0069] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted monocyclic or polycyclic C 3-14 Cycloalkyl, wherein when ring A is polycyclic, ring A is connected to -(L) of formula I through a non-aromatic ring m -part.

[0070] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted monocyclic C 3-7 Cycloalkyl.

[0071] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0072] In some embodiments, Ring A is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0073] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted cyclohexyl or cycloheptyl.

[0074] In some embodiments, Ring A is cyclohexyl or cycloheptyl.

[0075] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted cyclohexyl.

[0076] In some embodiments, Ring A is cyclohexyl.

[0077] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A substituted monocyclic or polycyclic 4-18 membered heterocycloalkyl, and wherein when ring A is polycyclic, ring A is connected to -(L) of formula I through a non-aromatic ring m -part.

[0078] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted monocyclic 4-7 membered heterocycloalkyl.

[0079] In some embodiments, Ring A is a monocyclic 4-7 membered heterocycloalkyl.

[0080] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R Asubstituted oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl.

[0081] In some embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.

[0082] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A substituted oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl or tetrahydrothiopyranyl.

[0083] In some embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or tetrahydrothiopyranyl.

[0084] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted piperidinyl.

[0085] In some embodiments, Ring A is piperidinyl.

[0086] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted piperidin-4-yl.

[0087] In some embodiments, Ring A is piperidin-4-yl.

[0088] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted tetrahydropyranyl.

[0089] In some embodiments, Ring A is tetrahydropyranyl.

[0090] In some embodiments, Ring A is optionally substituted with 1, 2, 3, or 4 R A Substituted tetrahydropyran-4-yl.

[0091] In some embodiments, Ring A is tetrahydropyran-4-yl.

[0092] In some embodiments, L is -(CR 5 R 6 ) t -.

[0093] In some embodiments, L is -(CR 5 R 6 ) t -and t is 1.

[0094] In some embodiments, L is -(CR 5 R 6 ) t -and t is 2.

[0095] In some embodiments, L is -(CR 5 R 6 ) t -and t is 3.

[0096] In some embodiments, L is -CH2-.

[0097] In some embodiments, m is 0.

[0098] In some embodiments, m is 1.

[0099] In some embodiments, n is 0.

[0100] In some embodiments, n is 1.

[0101] In some embodiments, n is 2.

[0102] In some embodiments, R 1 and R 2 All are H.

[0103] In some embodiments, R 1 and R 2 One of them is H and the other is methyl.

[0104] In some embodiments, each R A Independently selected from C 1-6 Alkyl, OR a1 、C(O)R b1 NR c1 R d1 and S(O)2R b1 wherein said C 1-6 Alkyl is optionally independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 Rd1 、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 substituted with 1, 2, 3, 4 or 5 substituents.

[0105] In some embodiments, each R A Independently selected from C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, OR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 NR c1 R d1 、S(O)2R b1 , 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl groups are each optionally independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted with 1, 2, 3, 4 or 5 substituents.

[0106] In some embodiments, each R A independently selected from halogen, C 1-6 Halogenated alkyl, OR a1 、C(O)NR c1 R d1 and C(O)OR a1 .

[0107] In some embodiments, R A is OR a1 .

[0108] In some embodiments, each R Aindependently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 、C(O)R b1 、C(O)OR a1 and S(O)2R b1 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally independently selected from halogen, CN, OR a1 NR c1 R d1 、C(O)R b1 and NR c1 C(O)R b1 substituted with 1, 2, 3, 4 or 5 substituents.

[0109] In some embodiments, each R W 、R X 、R Y and R Z independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, CN, OR a2 、C(O)NR c2 R d2 NR c2 R d2 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(=NRe2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 ; where R W 、R X 、R Y and R Z The C 1-6 Alkyl, C 1-6 Haloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl and C 6-10 Aryl-C 1-4 Alkyl groups are each optionally independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2Rb2 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 substituted with 1, 2, 3, 4 or 5 substituents.

[0110] In some embodiments, each R W 、R X 、R Y and R Z independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, CN, OR a2 、C(O)NR c2 R d2 NR c2 R d2 and NR c2 C(O)R b2 ; where R W 、R X 、R Y and R Z The C 1-6 Alkyl, C 1-6 Haloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl and C 6-10 Aryl-C 1-4 Alkyl groups are each optionally independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NRc2 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 substituted with 1, 2, 3, 4 or 5 substituents.

[0111] In some embodiments, W is CR W And R W Not H.

[0112] In some embodiments, W is CR W And R W It’s H.

[0113] In some embodiments, R W It's a halogen.

[0114] In some embodiments, R W It's F.

[0115] In some embodiments, R W Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, and OR a2 , wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally replaced by OR a2 replace.

[0116] In some embodiments, R W Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, CN, halogen, and OR a2 , wherein the C 1-6 Alkyl and C1-6 Each haloalkyl group is optionally replaced by OR a2 replace.

[0117] In some embodiments, R X and R Z Not all are halogen.

[0118] In some embodiments, R Z It’s H.

[0119] In some embodiments, when W is CR W , X is CR X , Y is CR Y and Z is CR Z When m is 1 or 2, then R X and R Y Not all C 1-6 Alkoxy.

[0120] In some embodiments, when W is CR W , X is CR X , Y is CR Y and Z is CR Z When m is 1 or 2, then R X and R Y Not the same.

[0121] In some embodiments, X is CR X And R X Not H.

[0122] In some embodiments, X is CR X And R X It’s H.

[0123] In some embodiments, R X Selected from C 1-6 Alkyl, halogen and OR a2 .

[0124] In some embodiments, Y is CR Y And R Y Not H.

[0125] In some embodiments, Y is CR Y And R Y It’s H.

[0126] In some embodiments, Y is CR Y and R Y Independently selected from NR c2 R d2 NR c2 C(O)R b2 NRc2 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 .

[0127] In some embodiments, Y is CR Y And R Y Independently selected from C 1-6 Alkyl, OR a2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 .

[0128] In some embodiments, Y is CR Y And R Y Independently selected from NR c2 R d2 and NR c2 C(O)R b2 .

[0129] In some embodiments, R Y Independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halogen, CN, OR a2 SR a2 、C(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 and NR c2 S(O)2NR c2 R d2 , where R Y The C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 NR c2 R d2 and S(O)2R b2 substituted with 1, 2, 3, 4 or 5 substituents.

[0130] In some embodiments, Y is CR Y And R Y Independently selected from C 1-6 Alkyl and OR a2 .

[0131] In some embodiments, Y is CR Y And RY is OR a2 .

[0132] In some embodiments, Z is CR Z And R Z Not H.

[0133] In some embodiments, Z is CR Z And R Z It’s H.

[0134] In some embodiments, Z is CR Z And R Z It is C 1-6 alkyl.

[0135] In some embodiments, Z is CR Z And R Z It is C 1-6 Alkyl, halogen or CN.

[0136] In some embodiments, each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, where C 1-6 Alkyl is optionally independently selected from Cy 3 、Cy 3 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 substituted with 1, 2, 3, 4 or 5 substituents.

[0137] In some embodiments, each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0138] In some embodiments, each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 The alkyl groups are each optionally independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, CN, OR a3 、C(O)R b3 、C(O)OR a3 and S(O)2R b3 substituted with 1, 2, 3, 4 or 5 substituents.

[0139] In some embodiments, R a2 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 The alkyl groups are each optionally independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, CN, OR a3 、C(O)R b3 、C(O)OR a3 and S(O)2R b3 substituted with 1, 2, 3, 4 or 5 substituents.

[0140] In some embodiments, R c2 and R d2 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 The alkyl groups are each optionally independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, CN, OR a3 、C(O)R b3 、C(O)OR a3 and S(O)2R b3 substituted with 1, 2, 3, 4 or 5 substituents.

[0141] In some embodiments, Cy 3 is optionally independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, CN, OR a3 、C(O)R b3 、C(O)OR a3 and S(O)2R b3 1, 2, 3, 4 or 5 substituents of 4-10 membered heterocycloalkyl.

[0142] In some embodiments, Cy 3 is optionally independently selected from C(O)R b3 1, 2, 3, 4 or 5 substituents of 4-10 membered heterocycloalkyl.

[0143] In some embodiments, Cy 3 is piperidinyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C(O)CH3.

[0144] In some embodiments, the compounds of the present invention have Formula II:

[0145]

[0146] In some embodiments, the compounds of the present invention have Formula IIIA, Formula IIIB, Formula IIIC, Formula IIID, or Formula IIIE:

[0147]

[0148]

[0149] In some embodiments, the compounds of the present invention have Formula IVA or Formula IVB:

[0150]

[0151] It should also be understood that, for clarity, certain features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment may also be provided individually or in any suitable subcombination.

[0152] At various places in this specification, substituents of compounds of the invention are disclosed in groups or ranges. It is specifically intended that the invention includes each individual subcombination of the members of these groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0153] Various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described in different places of this specification. Unless otherwise indicated, these rings can be connected to the rest of the molecule at any ring member where valence allows. For example, the term "pyridyl (pyridinyl)", "pyridyl (pyridyl)" or "pyridine ring" can refer to pyridin-2-yl, pyridin-3-yl or pyridin-4-yl rings.

[0154] The term "n-membered" (where "n" is an integer) generally describes the number of ring atoms in a moiety having "n" as the number of ring atoms. 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.

[0155] For compounds of the invention in which a variable occurs more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, when describing a structure having two R groups simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0156] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0157] 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.

[0158] As used herein, the term "C i-j” (where i and j are integers) specifies the range of the number of carbon atoms in a chemical group, where ij defines the range. For example, C 1-6 Alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0159] As used herein, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be straight or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, etc. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0160] As used herein, "alkenyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0161] As used herein, "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0162] As used herein, "halo" or "halogen," employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halogen is F or Cl.

[0163] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having up to a full valence of halogen atom substituents, which may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF , C F , CHF , CCl , CHCl , C Cl , etc.

[0164] As used herein, the term "alkoxy" used alone or in combination with other terms refers to a group of formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0165] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy group is -OCF3.

[0166] As used herein, "amino," employed alone or in combination with other terms, refers to NH2.

[0167] As used herein, the term "alkylamino" used alone or in combination with other terms refers to a group of formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0168] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of formula -N(alkyl). Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0169] As used herein, the term "cycloalkyl" used alone or in combination with other terms refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings, bridged rings, or spirocyclic) ring systems. The definition of cycloalkyl also includes a portion having one or more aromatic rings (e.g., aryl rings or heteroaryl rings) fused to (i.e., having a common bond with) a cycloalkyl ring, such as a benzo derivative of cyclopentane, cyclohexene, cyclohexane, or a pyrido derivative of cyclopentane or cyclohexane. The ring-forming carbon atoms of the cycloalkyl group can optionally be substituted with oxo. Cycloalkyl groups also include cycloalkylene groups. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., a non-aromatic cyclic hydrocarbon moiety containing at least one bridgehead carbon, such as adamantane-1-yl) and spirocycloalkyl groups (e.g., a non-aromatic hydrocarbon moiety containing at least two rings fused on a single carbon atom, such as spiro[2.5]octane, etc.). In some embodiments, the cycloalkyl group has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7 Monocyclic cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthyl, octahydronaphthyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0170] As used herein, the term "cycloalkylalkyl" used alone or in combination with other terms refers to a group of the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 Monocyclic cycloalkyl.

[0171] As used herein, the term "heterocycloalkyl" used alone or in combination with other terms refers to a non-aromatic ring or ring system that may optionally include one or more alkenylene or alkynylene groups as part of the ring structure, with at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus. Heterocycloalkyl may include a monocyclic or polycyclic ring system (e.g., with 2, 3 or 4 fused rings, bridged rings or spirocycles). In some embodiments, heterocycloalkyl is a monocyclic or bicyclic group with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Also included in the definition of heterocycloalkyl is a portion having one or more aromatic rings (e.g., aryl rings or heteroaryl rings) fused to (i.e., having a common bond with) a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydroquinoline, etc. Heterocycloalkyl groups may also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl groups containing at least one bridgehead atom, such as azaadamantan-1-yl, etc.) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl groups containing at least two rings fused on a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]dec-N-yl], etc.). In some embodiments, heterocycloalkyl groups have 3 to 10 ring atoms, 4 to 10 ring atoms, or about 3 to 8 ring atoms. In some embodiments, heterocycloalkyl groups have 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in one or more rings of heterocycloalkyl groups may be oxidized to form carbonyl groups, N-oxides, or sulfonyl groups (or other oxidized bonds), or the nitrogen atoms may be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7 Monocyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0172] 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 portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl portion is a methylene group. In some embodiments, the heterocycloalkyl portion has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is C 2-7 Monocyclic heterocycloalkyl.

[0173] As used herein, the term "aryl" used alone or in combination with other terms refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, etc. In some embodiments, the aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[0174] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the aryl moiety is a phenyl group. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is a benzyl group.

[0175] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, oxazolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. A carbon atom or heteroatom in one or more rings of a heteroaryl group may be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized linkage), or a nitrogen atom may be quaternized, provided that the aromatic nature of the ring is retained. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0176] As used herein, the term "heteroarylalkyl" used alone or in combination with other terms refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

[0177] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from non-optically active raw materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention can be separated as a mixture of isomers or as separated isomeric forms.

[0178] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium, or spatially locked into a form by appropriate substitution.

[0179] The compounds of the present invention also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom.

[0180] Unless otherwise indicated, the term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

[0181] All compounds and pharmaceutically acceptable salts thereof may exist together with other substances such as water and solvents (eg, in the form of hydrates and solvates), or may be isolated.

[0182] In some embodiments, the compound of the present invention or its salt is substantially separated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition rich in the compounds of the present invention. Substantially separated can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the present invention or its salt. Methods for separating compounds and their salts are conventional in the art.

[0183] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0184] 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 acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali or organic salts of acidic residues (such as carboxylic acids); and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two. Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is herein incorporated by reference in its entirety.

[0185] synthesis

[0186] The compounds of the present invention (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0187] The reaction of preparing the compounds of this invention can be carried out in a suitable solvent, and the synthetic solvent can be easily selected by the technician in the field of organic synthesis. Under the temperature of reacting, for example, the scope can be from the freezing temperature of the solvent to the temperature of the boiling temperature of the solvent, and suitable solvent and raw material (reactant), intermediate or product do not react substantially. Given reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on specific reactions steps, those skilled in the art can select the suitable solvent for the specific reactions step.

[0188] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of suitable protecting groups. The chemical properties of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0189] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0190] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are understood in the art and generally refer to a temperature, such as reaction temperature, that is approximately the temperature of the room in which the reaction is conducted, e.g., a temperature of about 20°C to about 30°C.

[0191] The compounds of the present invention can be prepared according to a number of preparative routes known in the literature. Exemplary synthetic methods for preparing compounds of the present invention are provided in the following schemes.

[0192] Solution 1

[0193]

[0194] Scheme 1 shows a general synthesis of the quinazolinone compounds of the present invention. Substituted aminobenzoic acids (1-A), many of which are commercially available or can be prepared by routes known to those skilled in the art, can be converted to chloromethylquinazolinones (1-B) by treatment with chloroacetonitrile in the presence of a pre-prepared solution of a metal (e.g., sodium) in a protic solvent (e.g., methanol) at room temperature (Step 1). The chloro group of 1-B can be converted to a thioacetate (1-C) by treatment with thioacetic acid in a polar solvent (e.g., DMF) at room temperature (Step 2). Introduction of the heterocycle (Ring A) can be accomplished by treatment with an appropriate electrophile (1-D) (wherein Lv is a suitable leaving group, such as Br, I, mesylate, or p-toluenesulfonate) in a polar solvent (e.g., DMF) in the presence of a base (e.g., aqueous sodium hydroxide) at elevated temperature (e.g., 90°C) (Step 3). Alternatively, the quinazolinones of the present invention can be prepared from chloromethylquinazolinone (1-B) by treating with a thioacetate-substituted heterocycle or trans-4-mercaptocyclohexanol in a polar solvent such as DMF in the presence of a base such as aqueous sodium hydroxide at room temperature (step 4).

[0195] Option 2

[0196]

[0197] Scheme 2 shows that substituted chloromethylquinazolinone intermediates (1-B) can also be prepared from substituted aminobenzoic acids (1-A) by treating them with R-Lv (wherein Lv is a leaving group such as iodide) in a polar solvent such as DMF in the presence of a base such as potassium carbonate at an appropriate temperature such as 0°C, first by converting them into esters (2-A) (such as where R is C 1-6 alkyl, such as methyl) (Step 1). Many esters (2-A) are also commercially available. Treatment of the ester with chloroacetonitrile in the presence of an acid (such as hydrochloric acid) in a solvent (such as dioxane) at an appropriate temperature (such as 50° C.) (Step 2) provides the chloromethylquinazolinone (1-B), which can then be further converted to the compounds of the present invention as described in Scheme 1.

[0198] Option 3

[0199]

[0200] Scheme 3 illustrates that functionalization of a starting bromoester (e.g., where one of W, X, Y, and Z is C-Br) can be achieved by palladium-mediated coupling, such as the Suzuki reaction, to prepare aromatic ring-substituted derivatives (Ar refers to an aromatic ring that is or can be further derivatized). Alternatively, the nitrile substituent can be introduced by treating the starting bromoester with CuCN at elevated temperatures (e.g., 180° C.) in a polar solvent (e.g., NMP). The functionalized ester can then be converted to a chloromethylquinazolinone as shown in Scheme 2.

[0201] Option 4

[0202]

[0203] Scheme 4 shows that the reaction can be carried out by reacting an excess of an amine (R'R"NH, where R' and R" can be, for example, R c2 and R d2 The amino group can be introduced by treating a fluorinated derivative (e.g., wherein one of W, X, Y, and Z is CF) with various groups defined herein.

[0204] Option 5

[0205]

[0206] Scheme 5 shows that amino substituents can also be introduced by treating 2-amino-4-fluorobenzoate (eg, where one of W, X, Y, and Z is CF) with an amine in a polar solvent (eg, DMSO) at elevated temperature (eg, 80°C).

[0207] Option 6

[0208]

[0209] Scheme 6 shows that an amino substituent can be introduced by treating the brominated starting material with a base such as LiHMDS and SEMCl in an ethereal solvent such as THF at an appropriate temperature such as 0°C (step 1). This reaction can be followed by coupling with an amine (R'R"NH), for example, in a non-polar solvent such as toluene at elevated temperature such as 110°C in the presence of a palladium catalyst such as Pd2(dba)3, a phosphine ligand such as BINAP, and a base such as t-BuONa (step 2). The SEM protecting group can then be removed by treatment with an acid such as HCl in a polar solvent such as dioxane at a slightly elevated temperature such as 40°C (step 3).

[0210] Option 7

[0211]

[0212] Scheme 7 shows that an alcohol functional group can be introduced into a SEM-protected brominated quinazolinone by first treating it with potassium hydroxide in the presence of a palladium catalyst (such as Pd2(dba)3) and a phosphine ligand (such as t-BuXPhos) at elevated temperature (such as 90°C), in a solvent (such as a mixture of dioxane and water), followed by addition of an electrophile (such as an alkyl bromide) and tetrabutylammonium bromide, and stirring at room temperature (Step 1, Lv is a leaving group, and R is an alkyl group or a group selected from R a2 Removal of the SEM group can be accomplished by treatment with an acid such as HCl (step 2).

[0213] Option 8

[0214]

[0215] Scheme 8 summarizes the preparation of amide compounds (R is, for example, an optionally substituted alkyl group or an optionally substituted ring structure). Nitro derivatives can be reduced to amine derivatives by treatment with a reducing agent (such as iron) in the presence of ammonium chloride in a mixture of water and a protic solvent (such as ethanol) at elevated temperatures (e.g., 80°C). The resulting amine can then be converted to an amide by treatment with an acid chloride (having the appropriate R group) in the presence of an amine base (such as triethylamine) at room temperature in a nonpolar solvent (such as DCM).

[0216] Option 9

[0217]

[0218] Scheme 9 summarizes the preparation of carboxamides by treating carboxylic acid derivatives with amines in the presence of amide coupling agents such as EDCI and HOBt in polar solvents such as DMF at room temperature.

[0219] Plan 10

[0220]

[0221] Non-hydrogen R substituents can be introduced via the two-step procedure outlined in Scheme 10. Appropriately substituted 2-methylanilines (10-1) can be treated with chloral hydrate, sodium sulfate, and aqueous HCl, followed by the addition of hydroxylamine and heating at 70°C to afford the methylindoline-2,3-dione intermediate (10-2, step 1). Conversion to the aminobenzoic acid (10-3) can be accomplished by treatment with hydrogen peroxide and aqueous NaOH at 50°C (step 2). The resulting aminobenzoic acid can then be converted to the chloromethylquinazolinone using the methods described above.

[0222] Plan 11

[0223]

[0224] Scheme 11 shows that the thioacetate intermediate of step 4 of Scheme 1 can be prepared from a suitable electrophile (such as bromide, iodide, mesylate or p-toluenesulfonate) by treating the electrophile with potassium thioacetate in a polar solvent (such as DMF) at room temperature. In the case of Lv = mesylate or p-toluenesulfonate, the sulfonate group can be installed from the corresponding alcohol by treating the alcohol with the appropriate sulfonyl chloride and an amine base (such as triethylamine) in dichloromethane at 0°C and warming to ambient temperature.

[0225] Plan 12

[0226]

[0227] Scheme 12 shows that when Ring A contains a Boc-protected cyclic amine, it can first be deprotected by treatment with acid to expose the free amine, which can then be further functionalized. Representative examples of such modifications, including reductive amination, amide coupling, and sulfonylation reactions, are shown.

[0228] Plan 13

[0229]

[0230] Scheme 13 summarizes the method for preparing substituted cyclohexyl sulfides. The thioacetate 1-C from Scheme 1 can be coupled with 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate in the presence of a base such as sodium hydroxide (step 1). The acetal can be removed by treatment with an acid such as HCl in a polar solvent such as THF at room temperature (step 2). The resulting ketone can then be further functionalized by reduction with a hydride source such as sodium borohydride in a protic solvent such as methanol at room temperature (step 3). Alternatively, the ketone can be converted to an amine by reductive amination, for example, by treatment with an amine in the presence of a hydride source such as sodium cyanoborohydride in a polar solvent such as THF at room temperature (step 4).

[0231] Plan 14

[0232]

[0233] Scheme 14 summarizes the method for preparing substituted cyclohexyl sulfides. Chloromethylquinazolinone (Scheme 1) can be coupled with S-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thioacetate in the presence of sodium hydroxide to provide the desired thioether (step 1). Removal of the TBS group with a fluoride source (such as TBAF) in a polar solvent (such as THF) at elevated temperature (such as 50°C) provides the primary alcohol (step 2). The alcohol can be converted to a mesylate by treatment with methanesulfonyl chloride in the presence of an amine base (such as triethylamine) at room temperature in a non-polar solvent (such as DCM) (step 3). The mesylate can then be substituted with a secondary amine in the presence of a tertiary amine base (such as triethylamine) in a polar solvent (such as THF) at elevated temperature (such as 100°C) (step 4). Alternatively, the mesylate can be converted to the primary amine by first treating with sodium azide in a polar solvent such as DMF at 50°C, followed by treatment with triphenylphosphine in a THF / water mixture at room temperature (steps 5 and 6).

[0234] How to use

[0235] The compounds of the present invention can inhibit the activity of PARP 14. For example, the compounds of the present invention can be used to inhibit the activity of PARP 14 in cells, individuals or patients in need of enzyme inhibition by administering an inhibitory amount of the compounds of the present invention to the cells, individuals or patients.

[0236] The compounds of the present invention can also inhibit the production of IL-10 in cells. For example, the present invention relates to methods of inhibiting or reducing IL-10 production in cells by contacting the cells with a PARP14 inhibitor of the present invention.

[0237] As PARP14 inhibitors, the compounds of the present invention can be used to treat various diseases associated with abnormal expression or activity of PARP14. For example, the compounds of the present invention can be used to treat cancer. In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies, such as leukemias and lymphomas. Exemplary lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Exemplary leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0238] Other cancers that may be treated by administration of the compounds of the invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, stomach 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.

[0239] In some embodiments, the cancer treatable by administration of the compounds of the invention is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer, or melanoma.

[0240] The PARP14 inhibitors of the present invention may also have therapeutic utility in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, particularly in diseases characterized by overexpression or increased activity of PARP14, and in PARP14-related disorders.

[0241] In some embodiments, the compounds of the present invention can be used to treat inflammatory diseases. In some embodiments, inflammatory diseases treatable according to the present invention include inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), inflammatory arthritis, inflammatory demyelinating diseases, psoriasis, allergy and asthma sepsis, allergic airway disease (e.g., asthma) and lupus.

[0242] As used herein, the term "cell" means a cell in vitro, in vitro, or in vivo. In some embodiments, an in vitro cell can be a portion of a tissue sample removed from an organism (such as a mammal). In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism (such as a mammal).

[0243] As used herein, the term "contacting" refers to bringing together specified moieties in an in vitro system or an in vivo system. For example, "contacting" PARP14 with a compound of the present invention or "contacting" a cell with a compound of the present invention includes administering a compound of the present invention to an individual or patient (e.g., a human) having PARP14, and, for example, introducing a compound of the present invention into a sample containing a cell preparation or purified preparation containing PARP14.

[0244] As used herein, the terms "subject" or "patient" are used interchangeably to refer to a mammal, particularly a human.

[0245] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or agent that will elicit the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician.

[0246] As used herein, the terms "treating" or "treatment" refer to 1) inhibiting a disease in an individual who is experiencing or exhibiting signs or symptoms of the disease (i.e., preventing further development of the signs and / or symptoms), or 2) alleviating a disease in an individual who is experiencing or exhibiting signs or symptoms of the disease (i.e., reversing the signs and / or symptoms).

[0247] As used herein, the term "prevent" or "preventing" refers to preventing a disease in an individual who may be susceptible to the disease but who does not yet experience or display signs or symptoms of the disease.

[0248] Combination therapy

[0249] One or more additional agents or treatments, such as chemotherapy or other anticancer agents, immunopotentiators, immunosuppressants, immunotherapy, radiation, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.) and / or kinases (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be combined with the compounds of the present invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0250] Suitable agents for treating cancer in combination with the compounds of the present invention include chemotherapeutic agents, targeted cancer therapies, immunotherapy, or radiotherapy. The compounds of the present invention can be effectively used in combination with antihormonal agents for treating breast cancer and other tumors. Suitable examples are antiestrogens, including but not limited to tamoxifen and toremifene; aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane; adrenocortical steroids (e.g., prednisone); progestogens (e.g., megastrol acetate) and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormonal agents for treating prostate cancer and other cancers can also be combined with the compounds of the present invention. These include antiandrogens, including but not limited to flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs, including leuprorelin, goserelin, triptorelin, and histrelin; LHRH antagonists (e.g., degarelix); androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0251] Angiogenesis inhibitors combined with FGFR inhibitors may be effective in certain tumors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0252] Suitable chemotherapeutic or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uramustine, mechlorethamine, cyclophosphamide, and cytoxan. TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene melamine, triethylene thiophosphamide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0253] Other anticancer agents include antibody therapeutics against co-stimulatory molecules (such as CTLA-4, 4-1BB, PD-1 and PD-L1), or antibodies against cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab and rituximab.

[0254] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference in its entirety.

[0255] Drug preparations and dosage forms

[0256] When used as a medicine, the compounds of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is needed and the area to be treated. Administration can be oral, topical (including eyes and mucous membranes, including intranasal delivery, vaginal delivery and rectal delivery), pulmonary (e.g., by inhalation or blowing into powder or aerosol, including by a nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular or parenteral.

[0257] The present invention also includes pharmaceutical compositions comprising one or more of the above compounds of the present invention as active ingredients in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in such a carrier in the form of, for example, a capsule, bag, paper, or other container. When an excipient is used as a diluent, it can be a solid material, a semisolid material, or a liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, capsule, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders.

[0258] The compositions can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0259] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by a physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0260] In order to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulated composition comprising a homogeneous mixture of the compounds of the invention. When these preformulated compositions are referred to as homogeneous, the active ingredient is generally evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preformulation is then subdivided into unit dosage forms of the above type, comprising, for example, 0.1 mg to about 500 mg of the active ingredient of the invention.

[0261] Tablet or pill coating of the present invention or otherwise can be mixed to provide the dosage form with the advantage of prolonged effect.For example, tablet or pill can comprise inner dosage and outer dosage component, the latter is the coating form on the former.These two components can be separated by enteric layer, and enteric layer is used to resist the disintegration in the stomach and allows inner component to enter duodenum or delay release intactly.Various materials can be used for this type of enteric layer or coating, and this type of material comprises many polymeric acids and polymeric acids and the mixture of materials such as shellac, cetyl alcohol and cellulose acetate.

[0262] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral administration or by injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0263] 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 by oral or nasal respiratory route to produce a local or systemic effect. The composition can be atomized using an inert gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be connected to a face mask inhaler or intermittent positive pressure breathing machine. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0264] The amount of compound or composition administered to a patient will vary depending on the substance being administered, the purpose of administration (e.g., prophylaxis or treatment), the patient's condition, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0265] The compositions administered to the patient may be in the form of the above-described pharmaceutical compositions. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solutions may be packaged for use as is or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration.

[0266] The therapeutic dose of the compounds of the present invention can vary according to, for example, the specific use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in the pharmaceutical composition can vary according to many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided for parenteral administration in a physiological buffered aqueous solution containing about 0.1 to about 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1g / kg body weight per day. In some embodiments, the dosage range is about 0.01mg / kg body weight to about 100mg / kg body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0267] The compounds of the present invention may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as an antiviral agent, an anticancer agent, a vaccine, an antibody, an immunopotentiator, an immunosuppressant, an anti-inflammatory agent, and the like. Example

[0268] equipment: Recorded at 400 MHz using a Bruker AVANCE 400 MHz spectrometer 1 H NMR spectra. NMR interpretation was performed using MestReC or MestReNova software to assign chemical shifts and multiplicities. If two adjacent peaks were observed to be equal or unequal in height, the peaks could be labeled as a multiplet or doublet. In the case of a doublet, coupling constants could be assigned using the software. In any given instance, one or more protons may not be observed due to obscuration by water and / or solvent peaks. LCMS equipment and conditions were as follows:

[0269] LC: Agilent Technologies 1290 Series, binary pump, diode array detector. Agilent Poroshell 120EC-C18, 2.7 μm, 4.6 × 50 mm column. Mobile phase: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in ACN (v / v). Flow rate: 1 mL / min at 25°C. Detectors: 214 nm, 254 nm. Gradient stop time: 10 min. Schedule:

[0270] T(min) A(％) B(％) 0.0 90 10 0.5 90 10 8.0 10 90 10.0 0 100

[0271] MS: G6120A, quadrupole LC / MS, ion source: ES-API, TIC: 70-1000 m / z, fragmentor voltage: 60, drying gas flow rate: 10 L / min, nebulizer pressure: 35 psi, drying gas temperature: 350 °C, Vcap: 3000 V.

[0272] Sample preparation: Dissolve the sample in ACN or methanol at 1-10 mg / mL and filter through a 0.22 μm filter. Injection volume: 1-10 μL

[0273] definition: AcCl (acetyl chloride); ACN (acetonitrile); Ac2O (acetic anhydride); AcOH (acetic acid); AcSH (thioacetic acid); atm (atmospheric pressure); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); BnBr (benzyl bromide); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); CDCl3 (deuterated chloroform); CD3OD (deuterated methanol); conc. (concentrated); CO (carbon monoxide); dba (dibenzylideneacetone); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMAP ( 4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); eq (equivalent); ES-API (electrospray atmospheric pressure ionization); Et3N (triethylamine); Et2O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HOBt (hydroxybenzotriazole); 1H NMR (proton nuclear magnetic resonance); Hz (hertz); KSAc (potassium thioacetate); L (liter); LCMS (liquid chromatography-mass spectrometry); LiHMDS (lithium bis(trimethylsilyl)amide); M (mole); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter), mmol (millimole); MsCl (methanesulfonyl chloride); n-BuLi (n-butyllithium); NMP (N-methyl-2-pyrrolidone); PhOH (phenol); preparative HPLC (preparative high performance liquid chromatography); preparative TLC (preparative thin layer chromatography); p pm (parts per million); psi (pounds per square inch); p-TSA (p-toluenesulfonic acid); pyBOP ((benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate); RT (room temperature); SEM (2-(trimethylsilyl)ethoxymethyl); SEMCl (2-(trimethylsilyl)ethoxymethyl chloride); TBAF (tetra-n-butylammonium fluoride); t-BuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); v / v (volume / volume).

[0274] Synthesis of intermediates

[0275] Int-A1: 2-(Chloromethyl)-8-methylquinazolin-4(3H)-one

[0276]

[0277] Chloroacetonitrile (75 g, 0.99 mol, 3 eq) was added dropwise to a pre-prepared solution of sodium (1.52 g, 6.6 mmol, 0.2 eq) in methanol (200 mL) under a nitrogen atmosphere at room temperature over 10 minutes. After stirring for 1 hour, a solution of 2-amino-3-methylbenzoic acid (50 g, 0.33 mmol, 1.0 eq) in methanol (700 mL) was added and the mixture was stirred at room temperature for an additional 2 hours. The resulting precipitate was collected by filtration, washed with water and then with MeOH, and dried in vacuo to give the title compound (46.9 g, 68%) as a white solid. LCMS: [M+H] + 209.0.

[0278] The following intermediates in Table 1 were similarly prepared according to the method described for Int-A1 from the appropriate amino acid starting materials.

[0279] Table 1

[0280]

[0281]

[0282] Int-A16: Methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate

[0283]

[0284] Chloroacetonitrile (9 g, 120 mmol, 5 eq) and dimethyl 2-aminoterephthalate (5 g, 23.9 mmol, 1.0 eq) were dissolved in 4.5 M HCl / dioxane solution (80 mL) and the mixture was heated at 50° C. for 3 hours under a N atmosphere. The mixture was cooled to room temperature and the precipitate was collected by filtration, washed with dioxane (10 mL) and dried under vacuum to give the title compound as a white solid (6 g, 98%). LCMS: [M+H] + 253.0.

[0285] Int-A17: 2-(Chloromethyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile

[0286]

[0287] Step 1: Ethyl 2-amino-3-bromobenzoate

[0288] To a suspension of 2-amino-3-bromobenzoic acid (1.1 g, 5.1 mmol, 1.0 equiv) and Cs2CO3 (3.3 g, 10.2 mmol, 2 equiv) in DMF (10 mL) was added dropwise EtI (0.95 g, 6.1 mmol, 1.2 equiv) at 0°C. The mixture was then warmed to room temperature and stirred for 16 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL×3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 50:1, v / v) to give the title compound (820 mg, 68%) as a white solid. LCMS: [M+H] + 244.1.

[0289] Step 2: Ethyl 2-amino-3-cyanobenzoate

[0290] To a solution of ethyl 2-amino-3-bromobenzoate (340 mg, 1.4 mmol, 1.0 equiv) in NMP (4 mL) was added CuCN (251 mg, 2.8 mmol, 2.0 equiv), and the mixture was heated at 180 ° C for 4 hours. After cooling to room temperature, water (20 mL) was added, 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 (petroleum ether: EtOAc, 10: 1, v / v) to give the title compound (170 mg, 64%) as a white solid. LCMS: [M+H] + 191.3.

[0291] Step 3: 2-(Chloromethyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile

[0292] The title compound was prepared from ethyl 2-amino-3-cyanobenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 220.2.

[0293] Int-A18: 2-(Chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carbonitrile

[0294]

[0295] The title compound was prepared from 2-amino-4-bromobenzoic acid according to the method described for Int-A17. LCMS: [M+H] + 220.1.

[0296] Int-A19: 2-(Chloromethyl)-7-phenoxyquinazolin-4(3H)-one

[0297]

[0298] Step 1: Methyl 2-nitro-4-phenoxybenzoate

[0299] To a solution of methyl 4-fluoro-2-nitrobenzoate (1.0 g, 5 mmol, 1.0 equivalent) and PhOH (0.79 g, 7.5 mmol, 1.5 equivalents) in DMSO (10 mL) was added KCO (1.38 g, 10 mmol, 2 equivalents), and the mixture was heated at 90 ° C for 2 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (60 mL × 3). The combined organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 25: 1, v / v) to obtain the title compound (1.2 g, 88%) as a white solid, which was directly used in the next step.

[0300] Step 2: Methyl 2-amino-4-phenoxybenzoate

[0301] To a solution of methyl 2-nitro-4-phenoxybenzoate (1.2 g, 4.4 mmol) in EtOAc (20 mL) was added Pd(OH)2 / C (1.2 g, 5% wet) and the mixture was stirred at room temperature under a H2 atmosphere (1 atm). The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.15 g, 100%), which was used in the next step without further purification. LCMS: [M+H] + 244.1.

[0302] Step 3: 2-(Chloromethyl)-7-phenoxyquinazolin-4(3H)-one

[0303] The title compound was prepared from methyl 2-amino-4-phenoxybenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 287.1.

[0304] Int-A20: 2-(Chloromethyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

[0305]

[0306] Step 1: 7-Methyl-4-(trifluoromethyl)indoline-2,3-dione

[0307] To a solution of chloral hydrate (4.4 g, 26.4 mmol, 1.1 eq) and Na2SO4 (13.6 g) in water (20 mL) was added dropwise a solution of 2-methyl-5-(trifluoromethyl)aniline (4.2 g, 24 mmol, 1.0 eq) in concentrated HCl (2.5 mL), followed by a solution of hydroxylamine hydrochloride (5.46 g) in water (20 mL). The mixture was then heated at 70 ° C for 6 hours, then allowed to cool to room temperature and filtered. The filter cake was washed with water (20 mL × 3) and dried to give the title compound (2 g, 36%). LCMS: [M+H] + 247.3.

[0308] Step 2: 2-Amino-3-methyl-6-(trifluoromethyl)benzoic acid

[0309] To a solution of 7-methyl-4-(trifluoromethyl)indoline-2,3-dione (500 mg, 2.2 mmol, 1.0 equiv) in 2M NaOH (2.5 mL, 2.3 equiv) was added H2O2 (30%, 0.6 mL), and the mixture was heated at 50 ° C overnight. The mixture was cooled to room temperature, diluted with water (5 mL), and adjusted to pH 6-7 with 1M HCl. The resulting solid was collected by filtration, washed with water (10 mL×2), and dried to give the title compound (450 mg, 86%) as a brown solid. LCMS: [M+H] + 220.1.

[0310] Step 3: Methyl 2-amino-3-methyl-6-(trifluoromethyl)benzoate

[0311] To a suspension of 2-amino-3-methyl-6-(trifluoromethyl)benzoic acid (1.0 g, 4.4 mmol, 1.0 equiv) and K2CO3 (1.2 g, 8.8 mmol, 2 equiv) in DMF (20 mL) was added dropwise MeI (0.9 g, 6.1 mmol, 1.5 equiv) at 0°C, and the mixture was warmed to room temperature and stirred for 16 hours. The mixture was poured into 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, 50: 1, v / v) to give the title compound (740 mg, 69%) as a brown oil. LCMS: [M+H] + 234.2.

[0312] Step 4: 2-(Chloromethyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

[0313] The title compound was prepared from methyl 2-amino-3-methyl-6-(trifluoromethyl)benzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 277.1.

[0314] Int-A21: 2-(Chloromethyl)-5-fluoro-8-methylquinazolin-4(3H)-one

[0315]

[0316] The title compound was prepared from 4-fluoro-7-methylindoline-2,3-dione according to the method described for Int-A20 step 2, step 3, and step 4. LCMS: [M+H] + 227.1.

[0317] Int-A22: 5-Chloro-2-(chloromethyl)-8-methylquinazolin-4(3H)-one

[0318]

[0319] The title compound was prepared from 5-chloro-2-methylaniline according to the method described for Int-A20. LCMS: [M+H] + 243.0.

[0320] Int-A23: 2-(Chloromethyl)-7-fluoro-8-methylquinazolin-4(3H)-one

[0321]

[0322] Step 1: Methyl 2-amino-4-fluoro-3-methylbenzoate

[0323] The title compound was prepared from 2-amino-4-fluoro-3-methylbenzoic acid according to the procedure described for Int-A20 step 3. LCMS: [M+H] + 184.1.

[0324] Step 2: 2-(Chloromethyl)-7-fluoro-8-methylquinazolin-4(3H)-one

[0325] The title compound was prepared from methyl 2-amino-4-fluoro-3-methylbenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 227.1.

[0326] Int-A24: 7-Bromo-2-(chloromethyl)-8-methylquinazolin-4(3H)-one

[0327]

[0328] Step 1: Methyl 2-amino-4-bromo-3-methylbenzoate

[0329] The title compound was prepared from 2-amino-4-bromo-3-methylbenzoic acid according to the procedure described for Int-A20 step 3. LCMS: [M+H] + 229.9.

[0330] Step 2: 2-(Chloromethyl)-7-bromo-8-methylquinazolin-4(3H)-one

[0331] The title compound was prepared from methyl 2-amino-4-bromo-3-methylbenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 286.9.

[0332] Int-A25: 2-(Chloromethyl)-7,8-difluoroquinazolin-4(3H)-one

[0333]

[0334] Step 1: Methyl 2-amino-3,4-difluorobenzoate

[0335] The title compound was prepared from 2-amino-3,4-difluorobenzoic acid according to the procedure described for Int-A20 step 3. LCMS: [M+H] + 188.1.

[0336] Step 2: 2-(Chloromethyl)-7,8-difluoroquinazolin-4(3H)-one

[0337] The title compound was prepared from methyl 2-amino-3,4-difluorobenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 231.0.

[0338] Int-A26: 7,8-Dichloro-2-(chloromethyl)quinazolin-4(3H)-one

[0339]

[0340] Step 1: Methyl 2-amino-3,4-dichlorobenzoate

[0341] The title compound was prepared from 2-amino-3,4-dichlorobenzoic acid according to the procedure described for Int-A20 step 3. LCMS: [M+H] + 220.0.

[0342] Step 2: 7,8-Dichloro-2-(chloromethyl)quinazolin-4(3H)-one

[0343] The title compound was prepared from methyl 2-amino-3,4-dichlorobenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 263.0.

[0344] Int-A27: 2-(Chloromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one

[0345]

[0346] The title compound was prepared from methyl 3-aminopicolinate and chloroacetonitrile according to the method described for Int-A16, except at 120° C. in microwave for 1 hour. LCMS: [M+H] + 196.0.

[0347] Int-A28: 2-(Chloromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0348]

[0349] The title compound was prepared from methyl 3-aminoisonicotinate and chloroacetonitrile according to the method described for Int-A16, except at 120° C. in microwave for 1 hour. LCMS: [M+H] + 196.0.

[0350] Int-A29: 2-(Chloromethyl)-8-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0351]

[0352] Step 1: Methyl 3-amino-2-methylisonicotinate

[0353] To a solution of methyl 3-amino-2-chloroisonicotinate (2.0 g, 10.7 mmol, 1.0 equiv) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (4.0 g, 32.2 mmol, 3.0 equiv) in 1,4-dioxane (40 mL) was added Pd(dppf)Cl2 (1.6 g, 2.1 mmol, 0.2 equiv) and K2CO3 (3.0 g, 21.4 mmol, 2.0 equiv) under a N2 atmosphere, and the mixture was heated in a microwave at 100 ° C for 1 hour. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (40 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 5:1 to 3:1, v / v) to give the title compound (1.9 g, 100%) as a yellow solid. LCMS: [M+H] + 167.1.

[0354] Step 2: 2-(Chloromethyl)-8-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0355] The title compound was prepared from methyl 3-amino-2-methylisonicotinate and chloroacetonitrile according to the method described for Int-A16, except heating at 120° C. in a sealed tube for 3 days. LCMS: [M+H] + 210.1.

[0356] Int-A30: 2-(Chloromethyl)-8-methylpyrido[3,2-d]pyrimidin-4(3H)-one

[0357]

[0358] Step 1: Methyl 3-amino-4-methylpicolinate

[0359] To a solution of 2-bromo-4-methylpyridin-3-amine (1.0 g, 5.3 mmol) in methanol (20 mL) was added PdCl2(dppf) (390 mg, 5% wet) and the mixture was heated at 70 ° C overnight under a CO atmosphere (30 atmospheres). The mixture was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: EtOAc, 3: 1, v / v) to give the title compound (370 mg, 41%) as a light yellow solid. LCMS: [M+H] + 167.1.

[0360] Step 2: 2-(Chloromethyl)-8-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0361] The title compound was prepared from methyl 3-amino-4-methylpicolinate and chloroacetonitrile according to the method described for Int-A16, except heating at 100° C. in a sealed tube for 2 days. LCMS: [M+H] + 210.0.

[0362] Int-A31: 2-(Chloromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one

[0363]

[0364] To a mixture of 4-aminopyridine-3-carboxamide (50 mg, 0.36 mmol), DMAP (2 mg, 0.02 mmol) and DIPEA (141 mg, 1.1 mmol) was added 2-chloroacetyl chloride (82 mg, 0.7 mmol, 2 equiv), and the mixture was heated in a microwave at 100° C. for 10 minutes. The mixture was diluted with water (5 mL) and the solid was collected by filtration to give the title compound as a white solid (66 mg, 93%). LCMS: [M+H] + 196.0.

[0365] Int-A32: 2-(Chloromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one

[0366]

[0367] Step 1: 2-[(2-chloroacetyl)amino]pyridine-3-carboxamide

[0368] To a solution of 2-aminopyridine-3-carboxamide (400 mg, 2.9 mmol) and pyridine (0.7 mL, 8.8 mmol) in DCM (20 mL) was added 2-chloroacetyl chloride (362 mg, 3.2 mmol, 1.1 equivalents) dropwise at 0 ° C. The mixture was stirred at 0 ° C for 1 hour, then allowed to warm to room temperature and stirred overnight. The mixture was poured into water (20 mL) and extracted with DCM (20 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, 2: 1, v / v) to give the title compound (180 mg, 29%) as a black solid. LCMS: [M+H] + 214.1.

[0369] Step 2: 2-(Chloromethyl)-3H-pyrido[2,3-d]pyrimidin-4-one

[0370] To a solution of 2-[(2-chloroacetyl)amino]pyridine-3-carboxamide (100 mg, 0.5 mmol) in toluene (10 mL) was added p-TSA (161 mg, 0.9 mmol), and the mixture was heated at reflux for 4 hours. The mixture was then concentrated under reduced pressure and the residue was purified by reverse phase column (Biotage, C18 column, 30-80% ACN in water) to give the title compound (25 mg, 27%) as a gray solid. LCMS: [M+H] + 196.0.

[0371] Int-A33: 2-(1-chloroethyl)-8-methylquinazolin-4(3H)-one

[0372]

[0373] The title compound was prepared from 2-amino-3-methylbenzoic acid and 2-chloropropionitrile according to the method described for Int-A1. LCMS: [M+H] + 223.1.

[0374] Int-A34: 2-(2-Chloroethyl)-8-methylquinazolin-4(3H)-one

[0375]

[0376] The title compound was prepared from methyl 2-amino-3-methylbenzoate and 3-chloropropionitrile according to the method described for Int-A16. LCMS: [M+H] + 223.1.

[0377] Int-A35: 8-Benzyl-2-(chloromethyl)quinazolin-4(3H)-one

[0378]

[0379] Step 1: Ethyl 2-amino-3-benzylbenzoate

[0380] To a solution of ethyl 2-amino-3-bromobenzoate (488 mg, 2 mmol, 1.0 equiv) in THF / water (24 mL, 5:1) was added potassium benzyl trifluoroborate (400 mg, 2.0 mmol, 1.0 equiv), PdCl2(dppf) (80 mg, 0.1 mmol, 0.05 equiv) and Cs2CO3 (2.0 g, 6.1 mmol, 3.0 equiv) under N2 atmosphere, and the mixture was heated at 80°C for 3 days. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (40 mL×3). The combined organic layers were washed with water (40 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 10:1, v / v) to give the title compound (190 mg, 28%) as a brown oil. LCMS: [M+H] + 256.1.

[0381] Step 2: 8-Benzyl-2-(chloromethyl)quinazolin-4(3H)-one

[0382] The title compound was prepared from ethyl 2-amino-4-bromobenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 285.2.

[0383] Int-A36: 7-Benzyl-2-(chloromethyl)quinazolin-4(3H)-one

[0384]

[0385] The title compound was prepared from ethyl 2-amino-4-bromobenzoate according to the method described for Int-A35. LCMS: [M+H] + 285.1.

[0386] Int-A37: 2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

[0387]

[0388] Step 1: Methyl 2-amino-4,6-difluorobenzoate

[0389] The title compound was prepared from 4,6-difluoroindoline-2,3-dione according to the procedure described for Int-A20 steps 2 and 3. LCMS: [M+H] +188.0.

[0390] Step 2: Methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate

[0391] To a solution of methyl 2-amino-4,6-difluorobenzoate (3g, 16.0mmol, 1.0 equivalent) in DMSO (5mL) was added cyclopentylamine (2.73g, 32.0mmol, 2.0 equivalents), and the mixture was heated at 80 ° C overnight. The mixture was cooled to room temperature, diluted with water (5mL), and extracted with DCM (40mL×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 (863mg, 21%) as a red solid. LCMS: [M+H] + 253.1.

[0392] Step 3: 2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

[0393] The title compound was prepared from methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 296.1.

[0394] Int-A38: 2-(Chloromethyl)-7-(cyclobutylamino)-5-fluoroquinazolin-4(3H)-one

[0395]

[0396] Step 1: Methyl 2-amino-4-(cyclobutylamino)-6-fluorobenzoate

[0397] The title compound was prepared from methyl 2-amino-4,6-difluorobenzoate and cyclobutylamine according to the procedure described for Int-A37, step 2. LCMS: [M+H] + 239.1.

[0398] Step 2: 2-(Chloromethyl)-7-(cyclobutylamino)-5-fluoroquinazolin-4(3H)-one

[0399] The title compound was prepared from methyl 2-amino-4-(cyclobutylamino)-6-fluorobenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 282.1.

[0400] Int-B1: S-(tetrahydro-2H-pyran-4-yl)thioacetate

[0401]

[0402] To a solution of 4-bromotetrahydro-2H-pyran (50.0 g, 303 mmol, 1.0 equiv) in DMF (300 mL) was added KSAc (41.5 g, 364 mmol, 1.2 equiv) under a N atmosphere, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (700 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (41.5 g, 68%) as a brown oil.

[0403] 1 H NMR (400MHz, CDCl3) δ3.91–3.87(m,2H),3.71-3.64(m,1H),3.57-3.51(m,2H),2.31(s,3H),1.92–1.88(m,2H),1.71–1.62(m,2H).

[0404] Int-B2: tert-Butyl 4-(acetylthio)piperidine-1-carboxylate

[0405]

[0406] The title compound was prepared according to the method described for Int-B1 from tert-butyl 4-bromopiperidine-1-carboxylate.

[0407] 1 H NMR (400MHz, CDCl3) δ3.87–3.84(m,2H),3.64–3.57(m,1H),3.08–3.02(m,2H),2.31(s,3H),1.92–1.87(m,2H),1.58–1.45(m,2H),1.45(s,9H).

[0408] Int-B3: S-(1-methylpiperidin-3-yl)thioacetate

[0409]

[0410] Step 1: 1-Methylpiperidin-3-yl methanesulfonate

[0411] To a solution of 1-methylpiperidin-3-ol (2.0 g, 17.4 mmol, 1.0 equiv) and triethylamine (3.5 g, 34.8 mmol, 2.0 equiv) in DCM (20 mL) was added methanesulfonyl chloride (2.4 g, 21 mmol, 1.2 equiv) dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with DCM (120 mL) and washed with 0.5 M HCl (40 mL) and water (40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (3.3 g, 99%) as a light yellow oil, which was used directly in the next step without further purification. LCMS: [M+H] + 194.1.

[0412] Step 2: S-(1-methylpiperidin-3-yl)thioacetate

[0413] To a solution of 1-methylpiperidin-3-yl methanesulfonate (1.6 g, 8.1 mmol, 1.0 equiv) in DMF (50 mL) was added KSAc (1.1 g, 9.7 mmol, 1.2 equiv) under N2 atmosphere, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (40 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, 10:1, v / v) to give the title compound (1 g, 71%) as a brown oil. LCMS: [M+H] + 174.1.

[0414] Int-B4: tert-Butyl 3-(acetylthio)piperidine-1-carboxylate

[0415]

[0416] The title compound was prepared from tert-butyl 3-hydroxypiperidine-1-carboxylate according to the method described for Int-B3. LCMS: [M+H-56] + 203.1.

[0417] Int-B5-trans: S-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)thioacetate

[0418]

[0419] and

[0420] Int-B5-cis: S-(cis-4-((tert-butoxycarbonyl)amino)cyclohexyl)thioacetate

[0421]

[0422] The title compound was prepared from cis / trans-tert-butyl(4-hydroxycyclohexyl)carbamate according to the method described for Int-B3. Purification by column chromatography (petroleum ether:EtOAc, 1:0 to 10:1, v / v) gave two separated isomers. Int-B5-trans: LCMS: [M+H-100] + 174.1; Int-B5-cis: LCMS: [M+H-100] + 174.1.

[0423] Int-B6: S-1,4-Dioxaspiro[4.5]dec-8-ylthioacetate

[0424]

[0425] The title compound was prepared from 1,4-dioxaspiro[4.5]decan-8-ol according to the method described for Int-B3.

[0426] 1 H NMR (400MHz, CDCl3) δ3.93(s,4H),3.56-3.51(m,1H),2.32(s,3H),2.00–1.96(m,2H),1.77–1.65(m,6H).

[0427] Int-B7: S-((trans)-3-(benzyloxy)cyclobutyl)thioacetate

[0428]

[0429] Step 1: cis-3-(Benzyloxy)cyclobutanol

[0430] The title compound (5.2 g, 100%) was prepared from 3-(benzyloxy)cyclobutanone (5.0 g, 28.4 mmol, 1.0 equiv) according to the procedure described in Bioorg. Med. Chem. 2013, 21, 643 as a colorless oil and was used in the next step without further purification.

[0431] 1 H NMR (400MHz, CDCl3) δ7.36–7.28(m,5H),4.42(s,2H),3.95-3.88(m,1H),3.66-3.60(m,1H),2.75–2.69(m,2H),1.98–1.90(m,2H).

[0432] Step 2: (cis)-3-(Benzyloxy)cyclobutyl methanesulfonate

[0433] The title compound was prepared according to the procedure described for Int-B3 Step 1 from cis-3-(benzyloxy)cyclobutanol.

[0434] 1 H NMR (400MHz, CDCl3) δ7.37–7.28(m,5H),4.69-4.61(m,1H),4.43(s,2H),3.77-3.70(m,1H),2.98(s,3H),2.86-2.81(m,2H),2.37–2.30(m,2H).

[0435] Step 3: S-(trans-3-(benzyloxy)cyclobutyl)thioacetate

[0436] The title compound was prepared according to the procedure described for Int-B3, Step 2 from (cis)-3-(benzyloxy)cyclobutyl methanesulfonate.

[0437] 1 H NMR (400MHz, CDCl3) δ7.37–7.27(m,5H),4.40(s,2H),4.29-4.23(m,1H),4.01-3.95(m,1H),2.64-2.57(m,2H),2.29(s,3H),2.28–2.23(m,2H).

[0438] Int-B8: S-Oxetan-3-ylthioacetate

[0439]

[0440] The title compound was prepared according to the procedure described for Int-B3, Step 2 from commercially available oxetan-3-yl 4-methylbenzenesulfonate.

[0441] 1 H NMR (400MHz, CDCl3) δ5.05 (t, J = 7.2 Hz, 2H), 4.69–4.62 (m, 1H), 4.58 (t, J = 6.8 Hz, 2H), 2.33 (s, 3H).

[0442] Int-B9: S-(trans-3-((tert-Butoxycarbonyl)amino)cyclobutyl)thioacetate

[0443]

[0444] Step 1: tert-Butyl (cis-3-hydroxycyclobutyl)carbamate

[0445] To a solution of cis-3-aminocyclobutanol hydrochloride (900 mg, 7.3 mmol, 1.0 equiv) in ethanol (5 mL) and Et3N (5 mL) was added Boc2O (800 mg, 3.7 mmol, 0.5 equiv) at 0°C, and the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (1.2 g, 88%) as a yellow solid, which was used in the next step without further purification. LCMS: [M+H] + 188.2.

[0446] Step 2: (cis)-3-((tert-Butoxycarbonyl)amino)cyclobutyl methanesulfonate

[0447] The title compound was prepared according to the procedure described for Int-B3 Step 1 from tert-butyl (cis-3-hydroxycyclobutyl)carbamate.

[0448] 1 H NMR (400MHz, DMSO-d6) δ7.21 (d, J=8.0Hz, 1H), 4.70-4.63 (m, 1H), 3.65–3. 58(m,1H),3.12(s,3H),2.69-2.63(m,2H),2.16-2.09(m,2H),1.37(s,9H).

[0449] Step 3: S-(trans-3-((tert-Butoxycarbonyl)amino)cyclobutyl)thioacetate

[0450] The title compound was prepared according to the procedure described for Int-B3, Step 2 from cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate.

[0451] 1 H NMR (400MHz, DMSO-d6) δ7.29 (d, J=7.6Hz, 1H), 4.11-4.04 (m, 1H), 3.84–3. 79(m,1H),2.46–2.39(m,2H),2.29(s,3H),2.18–2.12(m,2H),1.37(s,9H).

[0452] Int-B10: S-(4-((tert-Butoxycarbonyl)amino)cycloheptyl)thioacetate

[0453]

[0454] Step 1: tert-Butyl (4-oxocycloheptyl)carbamate

[0455] The title compound was prepared from tert-butyl (4-oxocyclohexyl)carbamate according to the procedure described in Liu, H. et al., Chem. Eur. J. 2012, 18, 11889: To a solution of n-BuLi (2M in hexanes, 9.76 mL, 24.4 mmol, 1.3 eq) in EtO (50 mL) was added dropwise TMSCHN (12 mL, 24.4 mmol, 1.3 eq) at -78°C under N2 atmosphere, and the mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl (4-oxocyclohexyl)carbamate (4.0 g, 18.8 mmol, 1.0 eq) in EtO (50 mL) was then added dropwise, and the solution was stirred at -78°C for another 30 minutes. The reaction is quenched with MeOH (1.6mL), and it is warmed to room temperature, diluted with water (50mL), and extracted with Et o (50mL).The organic layer merged is washed with salt water (50mL), through Na sO dried and concentrated under reduced pressure.The residue is passed through into column chromatography (petroleum ether: EtOAc, 8: 1 to 6: 1, v / v), and the title compound as a white solid is obtained, which is a 2: 1 mixture of isomers (1.8g, 42%).

[0456] 1 H NMR (400MHz, CDCl3) δ2.59-2.46(m,1H),2.33-2.12(m,4H),2.01-1.68(m,4H),1.43(s,9H),1.25-1.06(m,2H).

[0457] Step 2: S-(4-((tert-Butoxycarbonyl)amino)cycloheptyl)thioacetate

[0458] The title compound was prepared from tert-butyl (4-oxocycloheptyl)carbamate according to the method described for Int-B7 to give a 2:1 mixture of isomers.

[0459] 1 HNMR (400MHz, CDCl3) δ3.69-3.52(m,2H),2.32(s,1H),2.04(s,2H),2.12-1.85(m,4H),1.85-1.54(m,6H),1.43(s,9H).

[0460] Int-B11: trans-4-mercaptocyclohexanol

[0461]

[0462] To a solution of 7-oxabicyclo[2.2.1]heptane (1 g, 10.2 mmol, 1.0 equiv) in ethanol (10 mL) was added p-TSA (2.91 g, 15.3 mmol) and thiourea (1.2 g, 15.8 mmol, 1.5 equiv), and the mixture was heated at reflux for 21 hours. After cooling to room temperature, NaOH (1.3 g) and water (3 mL) were added, and the solution was heated at reflux for another 2 hours. The mixture was cooled to room temperature, NaOH (1.3 g) and water (3 mL) were added, and the solution was heated at reflux for another 2 hours, then allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water (15 mL), adjusted to pH 3-4 with 1 M HCl, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 10:1, v / v) to give the title compound (500 mg, 37%) as a yellow oil.

[0463] 1 HNMR(400MHz,DMSO-d6)δ6.18(br s,1H),4.51(br s,1H),3.41-3.36(m,1H),2.73-2.64(m,1H),1.96-1.86(m,2H),1.72-1.81(m,2H),1.36-1.26(m,2H),1.23-1.17(m,2H).

[0464] Int-B12: S-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thioacetate

[0465]

[0466] Step 1: 4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl methanesulfonate

[0467] The title compound was prepared from ethyl 4-hydroxycyclohexanecarboxylate (54.3 g, 300 mmol) according to the procedure described in US2005 / 0054658 to give a 1:1 mixture of cis / trans isomers as a white solid (91.0 g, 94%).

[0468] 1H NMR (400MHz, CDCl3) δ5.04–4.94(m,1H),4.64–4.52(m,1H),3.44(d,J=6.4 Hz,2H),3.40(d,J=6.4Hz,2H),3.01(s,3H),3.00(s,3H),2.21–2.15(m,2H) ,2.10–2.06(m,2H),1.90–1.83(m,2H),1.69–1.50(m,6H),1.40–1.33(m,4 H),1.12–1.01(m,2H),0.89(s,9H),0.88(s,9H),0.04(s,6H),0.03(s,6H).

[0469] Step 2: S-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thioacetate

[0470] The title compound was prepared according to the procedure described for Int-B3, Step 2, from 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl methanesulfonate.

[0471] Cis / trans isomer ratio = 1:2

[0472] 1 H NMR (400MHz, CDCl3) δ3.49–3.45(m,1H),3.42-3.38(m,2H),2.30(s,2H),2.29( s,1H),2.12–1.11(m,9H),0.89(s,6H),0.88(s,3H),0.04(s,4H),0.03(s,2H).

[0473] Int-B13: S-(3-(Hydroxymethyl)cyclohexyl)thioacetate

[0474]

[0475] Step 1: Ethyl 3-((methylsulfonyl)oxy)cyclohexanecarboxylate

[0476] The title compound was prepared according to the procedure described for Int-B3 Step 1 from ethyl 3-hydroxycyclohexanecarboxylate.

[0477] Cis / trans isomer ratio = 2:3

[0478] 1H NMR (400MHz, CDCl3) δ5.05 (m, 0.4H), 4.66–4.59 (m, 0.6H), 4.14 (q, J = 6.8Hz, 2H), 3.01 (s, 3H), 2. 39–2.37(m,1H),2.16–2.14(m,1H),1.94–1.87(m,2H),1.73–1.32(m,5H),1.25(t,J=6.4Hz,3H).

[0479] Step 2: 3-(Hydroxymethyl)cyclohexyl methanesulfonate

[0480] To a solution of ethyl 3-((methylsulfonyl)oxy)cyclohexanecarboxylate (7.2 g, 28.8 mmol, 1.0 equiv) in DME (20 mL) was added a solution of LiBH4 in THF (14.4 mL, 2 M, 28.8 mmol, 1.0 equiv) at 0°C, the mixture was allowed to warm to room temperature, and stirred overnight. The mixture was concentrated under reduced pressure, diluted with water (80 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (4.7 g, 78%) as a colorless oil, which was used in the next step without further purification.

[0481] Cis / trans isomer ratio = 3:7

[0482] 1 H NMR (400MHz, CDCl3) δ5.05(m,0.3H),4.64–4.59(m,0.7H),3.52–3.44(m,2H),2.99(s,3H),2.23–1.85(m,4H),1.78–1.21(m,5H).

[0483] Step 3: S-(3-(Hydroxymethyl)cyclohexyl)thioacetate

[0484] The title compound was prepared according to the procedure described for Int-B3, Step 2, from 3-(hydroxymethyl)cyclohexyl methanesulfonate.

[0485] 1 H NMR (400MHz, CDCl3) δ3.98–3.95(m,1H),3.53–3.45(m,2H),2.30(s,3H),1.86–1.46(m,9H).

[0486] Intermediate C1: ((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thioacetate

[0487]

[0488] To a solution of Int A1 (5.0 g, 24 mmol, 1 eq) in DMF (50 mL) was added AcSH (3.7 g, 48 mmol, 2 eq) at room temperature under N2 atmosphere, and the mixture was heated at 80 ° C. for 16 hours. After cooling to room temperature, the mixture was diluted with petroleum ether, and the resulting precipitate was collected by filtration and dried to give the title product as a yellow solid (6 g, 100%), which was used in the subsequent step without further purification. LCMS: [M+H] + 249.1.

[0489] The following intermediates in Table 2 were prepared similarly from the appropriate Intermediate A precursor and AcSH according to the method described for Intermediate C1.

[0490] Table 2

[0491]

[0492]

[0493] Int-C9: S-((8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thioacetate

[0494]

[0495] To a solution of Int-A7 (530 mg, 2.3 mmol, 1 eq) in THF (15 mL) and EtOH (5 mL) was added AcSH (266 mg, 3.5 mmol, 1.5 eq) at room temperature under N2 atmosphere and the mixture was heated at 70 ° C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 15: 1, v / v) to give the title compound (300 mg, 48%) as a white solid. LCMS: [M + H] + 269.0.

[0496] Int-C10: S-((8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thioacetate

[0497]

[0498] The title compound was prepared from Int-A4 according to the procedure described for Int-C9. LCMS: [M+H] + 265.1.

[0499] Int-C11: S-((7-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thioacetate

[0500]

[0501] To a suspension of Int A36 (27 mg, 0.1 mmol, 1 eq) and NaHCO (10 mg, 0.11 mmol, 1.1 eq) in DMF (3 mL) was added AcSH (8 mg, 0.12 mmol, 1.2 eq) at room temperature under N2 atmosphere, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (4 mL), and the resulting precipitate was collected by filtration and dried to give the title product as a white solid (20 mg, 70%). LCMS: [M+H] + 325.1.

[0502] Exemplary compounds

[0503] Example 1: 4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile

[0504]

[0505] Under N2 atmosphere, to a solution of Int-C7 (60 mg, 0.23 mmol, 1 equiv) and 4-bromotetrahydro-2H-pyran (38 mg, 0.23 mmol, 1.0e1) in DMF (2 mL) was added 1 M NaOH (0.5 mL) at room temperature, and the mixture was heated at 90 ° C for 16 hours. The mixture was poured into water (5 mL), extracted with EtOAc (10 mL×3), and the combined organic layers were washed with water (10 mL), 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 (15 mg, 22%) as a colorless oil. LCMS: [M+H] + 302.1.

[0506] 1 H NMR (400MHz, CD3OD) δ8.32(d,J=8.0Hz,1H),8.03(s,1H),7.78(dd,J=8.0,1.6Hz,1H),3.91(dt,J=11.6,3.6 Hz,2H),3.75(s,2H),3.43(td,J=11.6,2.3Hz,2H),3.09–3.01(m,1H),2.02–1.90(m,2H),1.63–1.53(m,2H).

[0507] The following examples in Table 3 were similarly prepared according to the procedure described for Example 1 from the appropriate intermediate C and 4-bromotetrahydro-2H-pyran.

[0508] Table 3

[0509]

[0510]

[0511] Example 12: 8-Methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one

[0512]

[0513] The title compound was prepared from Int-C1 and 4-(bromomethyl)tetrahydro-2H-pyran according to the method described for Example 1. LCMS: [M+H] + 305.1.

[0514] 1 H NMR (400MHz, CDCl3) δ10.2(s,1H),8.13(d,J=8.0Hz,1H),7.62(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),4.00–3.90(m,2H),3.74(d ,J=2.8Hz,2H),3.33(td,J=11.6,2.0Hz,2H),2.60(d,J=2.8Hz,3H),2.48(d,J=6.8Hz,2H),1.78-1.69(m,3H),1.35-1.24(m,2H).

[0515] Example 13: 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate

[0516]

[0517] Step 1: tert-Butyl 4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[0518] To a solution of Int-C1 (6.6 g, 26.6 mmol, 1.0 equiv) and tert-butyl 4-bromopiperidine-1-carboxylate (7.0 g, 26.6 mmol, 1.0 equiv) in DMF (130 mL) was added 1 M NaOH (50 mL) under N2 atmosphere at room temperature, and the mixture was heated at 80 ° C for 16 hours. The mixture was poured into water (50 mL), extracted with EtOAc (100 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 4:1, v / v) to give the title compound (7.2 g, 70%) as a light yellow solid. LCMS: [M+H] + 390.2.

[0519] Step 2: 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate

[0520] Tert-Butyl 4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (30 mg, 0.08 mmol, 1.0 equiv) was dissolved in TFA (5 mL), and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure to give the title product as a yellow solid (20 mg, 45%). LCMS: [M+H] + 290.2.

[0521] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=8.0Hz,1H),7.75–7.60(m,1H),7.39(t,J=7.6Hz,1H),3.80(s,2H),3.42 -3.36(m,2H),3.26–3.12(m,1H),3.09–2.97(m,2H),2.59(s,3H),2.32-2.28(m,2H),1.83–1.74(m,2H).

[0522] Example 14: 8-Methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[0523]

[0524] To a solution of Example 13 (160 mg, 0.37 mmol, 1.0 equiv) and formaldehyde (30% aqueous solution, 0.34 mL, 3.7 mmol, 10.0 equiv) in MeOH (10 mL) was added AcOH (67 mg, 1.1 mmol, 3.0 equiv) and NaCNBH3 (93 mg, 1.5 mmol, 4.0 equiv), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL), extracted with DCM (30 mL×3), and the combined organic layers were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 10:1, v / v) to give the title compound (50 mg, 30%) as a light yellow solid. LCMS: [M+H] + 304.2.

[0525] 1 H NMR (400MHz, CD3OD) δ7.94(d,J=8.0Hz,1H),7.58(d,J=7.2Hz,1H),7.30(t,J=7.6Hz,1H),3.74(s,2H),3.28-3.25(m,2H),3.02(br s,1H),2.79(t,J=11.8Hz,2H),2.60(s,3H),2.50(s,3H),2.25-2.21(m,2H),1.80–1.72(m,2H).

[0526] Example 15: 8-Methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate

[0527]

[0528] The title compound was prepared from Int-C1 and tert-butyl 3-bromopyrrolidine-1-carboxylate according to the method described for Example 13. LCMS: [M+H] + 276.1.

[0529] 1H NMR (400MHz, DMSO-d6) δ12.4(s,1H),9.00(s,2H),7.94(d,J=7.8Hz,1H),7.67(d,J=7.2Hz,1H),7.38(t,J=7.4Hz,1H),3.75(s,2H),3.6 5(dt,J=12.8,6.8Hz,1H),3.59–3.49(m,1H),3.31–3.15(m,2H),3.14–3.04(m,1H),2.52(s,3H),2.36–2.35(m,1H),1.90–1.78(m,1H).

[0530] Example 16: 8-Methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one

[0531]

[0532] The title compound was prepared from Example 15 according to the method described for Example 14. LCMS: [M+H] + 290.1.

[0533] 1 H NMR(400MHz,DMSO-d6)δ12.3(br s,1H),7.92(d,J=7.6Hz,1H),7.65(d,J=7.2Hz,1H),7.36(t,J=7.6Hz,1H),3.65(s,2H),3.48–3.38(m,1H),2.87–2.77(m,1 H), 2.50 (s, 3H), 2.43 (dd, J = 13.2, 6.4Hz, 2H), 2.28 (dd, J = 9.6, 5.6Hz, 1H), 2.22–2.11 (m, 4H), 1.56 (td, J = 13.2, 6.4Hz, 1H).

[0534] Example 17: 2-(((1-acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0535]

[0536] To a solution of Example 13 (20 mg, 0.07 mmol, 1.0 equiv) and Et3N (14 mg, 0.14 mmol, 2.0 equiv) in DCM (10 mL) was added dropwise Ac2O (8 mg, 0.11 mmol, 1.5 equiv) at 0°C, the mixture was allowed to warm to room temperature, and stirred overnight. The mixture was diluted with DCM (30 mL) and washed with water (30 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 20:1, v / v) to give the title compound (10 mg, 43%) as a light yellow solid. LCMS: [M+H] + 332.1.

[0537] 1 H NMR (400MHz, CD3OD) δ8.04(d,J=8.0Hz,1H),7.67(d,J=7.2Hz,1H),7.39(t,J=7.6Hz,1H),4.28(d,J=13.6Hz,1H),3.86(d, J=14.0Hz,1H),3.78(s,2H),3.23–3.06(m,2H),2.59(s,3H),2.87(t,J=12.4Hz,1H),2.12–2.04(m,5H),1.62–1.41(m,2H).

[0538] Example 18: 8-Methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[0539]

[0540] The title compound was prepared from the compound of Example 13 and pyridine carboxaldehyde according to the method described for Example 14. LCMS: [M+H] + 381.2.

[0541] 1 H NMR (400MHz, CD3OD) δ8.69(d,J=4.4Hz,1H),8.05(d,J=7.6Hz,1H),7.91(td,J=7.6,1.6Hz,1H),7.69(d,J=7.2Hz,1H),7.51–7.38 (m,3H),4.47(s,2H),3.83(s,2H),3.62–3.53(m,2H),3.21(t,J=11.6Hz,3H),2.60(s,3H),2.43–2.31(m,2H),2.08–1.91(m,2H).

[0542] Example 19: 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one

[0543]

[0544] To a solution of Example 2 (50 mg, 0.17 mmol, 1.0 equiv) in AcOH (2 mL) was added dropwise H2O2 (30% solution in water, 195 mg, 1.7 mmol, 10.0 equiv) at 0°C, and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with MeOH (2 mL) and purified by column chromatography (DCM:MeOH, 20:1, v / v) to give the title compound (6 mg, 11%) as a white solid. LCMS: [M+H] + 323.1.

[0545] 1 H NMR(400MHz,DMSO-d6)δ12.5(br s,1H),7.97(d,J=8.0Hz,1H),7.72(d,J=7.2Hz,1H),7.44(t,J=7.6Hz,1H),4.55(s,2H),4.02(dd,J=11.2, 4.0Hz,2H),3.95–3.86(m,1H),3.37(t,J=10.4Hz,2H),2.54(s,3H),2.13–2.05(m,2H),1.76–1.65(m,2H).

[0546] Example 20: 2-((Azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0547]

[0548] Step 1: tert-Butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate

[0549] The title compound was prepared from tert-butyl 4-hydroxyazepane-1-carboxylate according to the procedure described for Int-B3 step 1. LCMS: [M+H-56] + 238.1.

[0550] Step 2: tert-Butyl 4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azepane-1-carboxylate

[0551] To a solution of Int-C1 (615 mg, 2.5 mmol, 1 eq) and tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate (800 mg, 2.7 mmol, 1.1 eq) in DMF (20 mL) was added 1 M NaOH (5 mL) at room temperature under an N2 atmosphere, and the mixture was heated at 80 ° C for 6 hours. The mixture was poured into water (5 mL), extracted with EtOAc (10 mL×3), and the combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 5:1, v / v) to give the title compound (140 mg, 14%) as a white solid. LCMS: [M+H] + 404.2.

[0552] Step 3: 2-((Azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0553] Tert-butyl 4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azepane-1-carboxylate (140 mg, 0.34 mmol, 1.0 equiv) was dissolved in 3M HCl / dioxane solution (3 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with water (10 mL), and the pH was adjusted to 9-10 with saturated aqueous Na2CO3 solution, and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, 30%-70% can in water, 0.1% TFA) to give the title compound (50 mg, 35%) as a white solid. LCMS: [M+H] + 304.1.

[0554] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=8.0Hz,1H),7.67(d,J=7.2Hz,1H),7.39(t,J=7.6Hz,1H),3.79(s,2H),3.41–3.34( m,1H),3.24–3.11(m,4H),2.59(s,3H),2.41–2.30(m,1H),2.27–2.17(m,1H),2.06–1.94(m,2H),1.87–1.70(m,2H).

[0555] Example 21: 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0556]

[0557] Step 1: 1,4-Dioxaspiro[4.5]dec-8-yl methanesulfonate

[0558] The title compound was prepared according to the procedure described for Int-B3 Step 1 from 1,4-dioxaspiro[4.5]decan-8-ol. 1 H NMR (400MHz, CDCl3) δ4.85-4.80(m,1H),3.97-3.90(m,4H),3.00(s,3H),2.01-1.96(m,4H),1.87–1.78(m,2H),1.66-1.60(m,2H).

[0559] Step 2: 2-(((1,4-Dioxaspiro[4.5]dec-8-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0560] The title compound was prepared from 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate and Int-C1 according to the method described for Example 20, Step 2. LCMS: [M+H] + 347.1.

[0561] Step 3: 8-Methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0562] To a solution of 2-(((1,4-dioxaspiro[4.5]dec-8-yl)thio)methyl)-8-methylquinazolin-4(3H)-one (500 mg, 1.4 mmol, 1.0 equiv) in THF (20 mL) was added 1 M HCl (20 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (510 mg, 100%) as a yellow solid, which was used in the subsequent step without further purification. LCMS: [M+H] + 303.1.

[0563] Step 4: 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0564] To a solution of 8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one (68 mg, 0.22 mmol, 1.0 equiv) in THF (3 mL) was added Me2NH (2M solution in THF, 2.2 mL, 20.0 equiv) and NaBH(OAc)3 (950 mg, 4.5 mmol, 20.0 equiv), and the mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHCO3 (20 mL), extracted with EtOAc (30 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound (40 mg, 55%) as a light yellow solid. LCMS: [M+H] + 332.2.

[0565] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=8.0Hz,1H),7.66(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),3.75(d,J=14.0Hz,2H),3.36(s,1H),3.08-2. 98(m,1H),2.74(s,3H),2.70(s,3H),2.59(d,J=9.5Hz,3H),2.32-2.25(m,1H),2.11-2.05(m,2H),1.90-1.84(m,3H),1.53-1.37(m,2H).

[0566] Example 22: 2-(((4-Hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0567]

[0568] To a solution of 8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one (prepared in step 4 of Example 21) (100 mg, 0.33 mmol, 1.0 equiv) in MeOH (10 mL) was added NaBH4 (25 mg, 0.66 mmol, 2.0 equiv), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL), extracted with EtOAc (30 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound as a white solid as a 3:2 mixture of trans / cis isomers (50 mg, 50%). LCMS: [M+H] + 305.1.

[0569] Example 23: 2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one, and

[0570] Example 24: 2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0571]

[0572] The compound of Example 22 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title compound.

[0573] Example 23: LCMS: [M+H] + 305.1;

[0574] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=8.0Hz,1H),7.66(d,J=7.2Hz,1H),7.38(t,J=8.0Hz,1H),3.72(s,2H),3.52(t,J=1 1.2Hz, 1H), 2.75 (t, J = 11.6Hz, 1H), 2.59 (s, 3H), 2.11 (d, J = 12.8Hz, 2H), 1.95 (d, J = 12.4Hz, 2H), 1.44-1.15 (m, 4H).

[0575] Example 24: LCMS: [M+H] + 305.1;

[0576] 1 H NMR (400MHz, CD3OD) δ8.02(d,J=8.0Hz,1H),7.65(d,J=7.2Hz,1H),7.37(t,J=8.0Hz,1H) ,3.72(s,3H),2.99(t,J=6.0Hz,1H),2.58(s,3H),1.82-1.70(m,6H),1.64-1.49(m,2H).

[0577] Example 25: 2-((azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0578]

[0579] Step 1: tert-Butyl 3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azetidine-1-carboxylate

[0580] The title compound was prepared from Int-C1 and tert-butyl 3-iodoazetidine-1-carboxylate according to the procedure described for Example 13, step 1. LCMS: [M+H] + 362.2.

[0581] Step 2: 2-((azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one hydrochloride

[0582] Tert-butyl 3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azetidine-1-carboxylate (40 mg, 0.11 mmol, 1.0 equiv) was dissolved in 1.5 M HCl / EtOAc solution (3 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL), the pH was adjusted to 9-10 with saturated Na2CO3 aqueous solution, and extracted with EtOAc (10 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250x21.2 mm column, gradient eluted with 0.1% TFA in MeOH aqueous solution at a flow rate of 20 mL / min) to give the title compound (1.8 mg, 6%) as a white solid. LCMS: [M+H] + 262.1.

[0583] 1 H NMR (400MHz, CD3OD) δ8.04(d,J=8.0Hz,1H),7.68(d,J=7.2Hz,1H),7.41(t,J=7.6Hz,1H), 4.35(t,J=9.6Hz,2H),4.27-4.21(m,1H),3.89(t,J=9.2Hz,2H),3.81(s,2H),2.62(s,3H); 19 F NMR (400 MHz, CD3OD) δ-78.2.

[0584] Example 26: 2-((((trans)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0585] and

[0586] Example 27: 2-((((cis)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0587]

[0588] Step 1: 4-Methoxycyclohexyl methanesulfonate

[0589] The title compound was prepared from 4-methoxycyclohexanol according to the procedure described for Int-B3 Step 1.

[0590] 1 H NMR (400MHz, CDCl3) δ4.80-4.70(m,1H),3.32(s,3H),3.30-3.25(m,1H),3.01(s, 3H),2.12-2.05(m,1H),2.04-1.93(m,2H),1.86-1.65(m,4H),1.55-1.45(m,1H).

[0591] Step 2: 2-(((4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0592] The title compound was prepared from 4-methoxycyclohexyl methanesulfonate and Int-C1 according to the procedure described for Example 20, Step 2. LCMS: [M+H] + 319.1.

[0593] Step 3: 2-(((trans-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one and 2-(((cis-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0594] 2-(((4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one was purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title compound.

[0595] Example 26: LCMS: [M+H] + 319.1;

[0596] 1H NMR (400MHz, CDCl3) δ8.13(d,J=8.0Hz,1H),7.61(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),3.79(s,2H),3.31(s,3 H),3.17-3.10(m,1H),2.64-2.71(m,1H),2.59(s,3H),2.14-1.99(m,4H),1.44-1.30(m,2H),1.27-1.17(m,2H).

[0597] Example 27: LCMS: [M+H] + 319.1;

[0598] 1 H NMR (400MHz, CDCl3) δ8.06(d,J=7.8Hz,1H),7.55(d,J=7.2Hz,1H),7.31(t,J=7.6Hz,1H),3.78(s,2H),3.29-3.2 3(m,1H),3.22(s,3H),2.72-2.66(m,1H),2.55(s,3H),1.88-1.76(m,2H),1.72-1.64(m,4H),1.46-1.36(m,2H).

[0599] Example 28: 4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile

[0600]

[0601] To a solution of Int-A17 (36 mg, 0.16 mmol, 1.0 equiv) and Int-B1 (26 mg, 0.16 mmol, 1.0 equiv) in DMF (2 mL) was added 1 M NaOH (2 mL), and the mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1, v / v) to give the title compound (12 mg, 24%) as a white solid. LCMS: [M+H] + 302.1;

[0602] 1H NMR (400MHz, CDCl3) δ10.4(s,1H),8.48(d,J=8.0Hz,1H),8.10(d,J=7.6Hz,1H),7.56(t,J=7.6Hz,1H),3.97(dd,J=12.0, 3.6Hz, 2H), 3.87 (s, 2H), 3.42 (t, J = 11.2Hz, 2H), 2.99 (td, J = 10.8, 5.2Hz, 1H), 1.96 (d, J = 12.8Hz, 2H), 1.72-1.62 (m, 2H).

[0603] The following examples in Table 4 were similarly prepared from the appropriate Intermediate A and Intermediate B according to the method described for Example 28.

[0604] Table 4

[0605]

[0606]

[0607]

[0608] Example 46: 7-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0609]

[0610] To a solution of Int-A9 (200 mg, 0.94 mmol, 1.0 equiv) and Int-B11 (249 mg, 1.13 mmol) in DMF (5 mL) was added 1 M NaOH (3 mL), and the mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (100% EtOAc) to give the title compound (260 mg, 90%) as a white solid. LCMS: [M+H] + 309.1.

[0611] 1H NMR(400MHz, DMSO-d6)δ12.4(s,1H),8.15(dd,J=6.4,8.8Hz,1H),7.42-7.34(m,2H),4.52(d,J=4.4Hz,1H), 3.63(s,2H),3.41-3.32(m,1H),2.78-2.68(m,1H),2.01-1.92(m,2H),1.85-1.76(m,2H),1.29-1.10(m,4H).

[0612] Example 47: 2-(((trans-3-hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0613]

[0614] To a solution of Example 38 (100 mg, 0.27 mmol, 1.0 equiv) in DCM (5 mL) were added N,N-dimethylaniline (2 mg, catalytic) and AlCl3 (364 mg, 2.7 mmol, 10.0 equiv), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL), the pH was adjusted to 3-4 with 1M HCl, and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with hexane (5 mL) to give the title compound (40 mg, 53%) as a yellow solid. LCMS: [M+H] + 277.1.

[0615] 1 H NMR (400 MHz, DMSO-d6) δ 12.3 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.29 (p, J = 6.6 Hz, 1H), 3.60 (s, 2H), 3.54-3.47 (m, 1H), 3.30 (1H (OH) may be obscured by water peak), 2.52 (s, 3H), 2.25-2.15 (m, 2H), 2.13-2.07 (m, 2H).

[0616] Example 48: 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[0617]

[0618] Step 1: tert-Butyl 3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[0619] The title compound was prepared from Int-A1 and Int-B4 according to the method described for Example 28. LCMS: [M+H] + 362.2.

[0620] Step 2: 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[0621] Tert-butyl 3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (120 mg, 0.31 mmol, 1.0 equiv) was dissolved in 1.5 M HCl / EtOAc solution (10 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound as a white solid (70 mg, 79%). LCMS: [M+H] + 290.1.

[0622] 1 H NMR(400MHz,DMSO-d6)δ12.4(br s,1H),9.27–9.14(m,2H),7.93(d,J=7.6Hz,1H),7.67(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),3.87–3.72(m,2H),3.52–3.45(m,1H),3. 29–3.18(m,1H),3.18–3.09(m,1H),2.89–2.78(m,2H),2.55(s,3H),2.04(dd,J=18.4,7.6Hz,1H),1.85–1.63(m,2H),1.56–1.41(m,1H).

[0623] Example 49: 2-(((trans-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one hydrochloride

[0624]

[0625] The title compound was prepared from Int-A1 and Int-B5-trans according to the method described for Example 48. LCMS: [M+H] + 304.1.

[0626] 1H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.76 (br s,3H),7.66(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),3.65(s,2H),3.29-3.25(m,1H),3.05(br s,1H),2.5(s,3H),1.90–1.57(m,8H).

[0627] Example 50: 2-(((cis-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetic acid

[0628]

[0629] The title compound was prepared from Int-A1 and Int-B5-cis according to the method described for Example 48. LCMS: [M+H] + 304.1.

[0630] 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.75 (s, 3H), 7.66 ( d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),3.65(s,2H),3.29-3.25(m,1H),3.05(br s,1H),2.50(s,3H),1.90–1.57(m,8H).

[0631] Example 51: 5-Fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[0632]

[0633] The title compound was prepared from Int-A21 and Int-B2 according to the method described for Example 48. LCMS: [M+H] + 308.1.

[0634] 1H NMR (400MHz, DMSO-d6) δ12.4(s,1H),9.11–8.83(m,2H),7.64(t,J=7.2Hz,1H),7.13(t,J=9.6Hz,1H),3.70 (s,2H),3.25-3.11(m,3H),2.88(q,J=11.2Hz,2H),2.43(s,3H),2.15(d,J=14.0Hz,2H),1.73-1.64(m,2H).

[0635] Example 52: 2-(((trans-3-aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one hydrochloride

[0636]

[0637] The title compound was prepared from Int-A1 and Int-B9 according to the method described for Example 48. LCMS: [M+H] + 276.1.

[0638] 1 H NMR(400MHz,DMSO-d6)δ12.3(br s,1H),8.38(br s,3H),7.93(d,J=7.2Hz,1H),7.66(d,J=7.1Hz,1H),7.37(t,J=7.6Hz,1H),3.82–3.71(m,2H),3.69(s,2H),2.53(s,5H),2.21–2.11(m,2H).

[0639] Example 53: 2-(((4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0640]

[0641] The title compound was prepared from Int-A1 and Int-B10 according to the method described for Example 48. LCMS: [M+H] + 318.2.

[0642] Example 54: 2-(((trans-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate and Example 55: 2-(((cis-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0643]

[0644] The compound of Example 53 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound.

[0645] Example 54: LCMS: [M+H] + 318.2.

[0646] 1 H NMR (400 MHz, CD3OD) δ8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), ~3.30 (2H, obscured by solvent peak), 3.29-3.22 (m, 1H), 3.09-3.01 (m, 1H), 2.59 (s, 3H), 2.26-2.16 (m, 1H), 2.11-2.00 (m, 3H), 1.76-1.49 (m, 6H).

[0647] Example 55: LCMS: [M+H] + 318.2.

[0648] 1 H NMR (400 MHz, CD3OD) δ8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), ~3.30 (2H, obscured by solvent peak), 3.28-3.20 (m, 1H), 3.17-3.09 (m, 1H), 2.58 (s, 3H), 2.25-2.15 (m, 1H), 2.12-2.06 (m, 1H), 2.0-1.93 (m, 2H), 1.92-1.80 (m, 3H), 1.57–1.42 (m, 3H).

[0649] Example 56: 5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0650]

[0651] Step 1: 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-5-fluoro-8-methylquinazolin-4(3H)-one

[0652] The title compound was prepared from Int-A21 and Int-B6 according to the method described for Example 28. LCMS: [M+H] + 365.1.

[0653] Step 2: 5-Fluoro-8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0654] The title compound was prepared from 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-5-fluoro-8-methylquinazolin-4(3H)-one according to the method described for step 3 of example 21. LCMS: [M+H] + 321.1.

[0655] Step 3: 5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one The title compound was prepared from 5-fluoro-8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one according to the procedure described for Example 22. LCMS: [M+H] + 323.1.

[0656] Example 57: 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one and Example 58: 5-Fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0657]

[0658] The compound of Example 56 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title compound.

[0659] Example 57: LCMS: [M+H] + 323.1.

[0660] 1 H NMR (400MHz, CD3OD) δ7.62(dd,J=8.4,5.6Hz,1H),7.06(dd,J=11.2,8.4Hz,1H),3.69(s,2H),3.56-3.49(m,1H ),2.80-2.73(m,1H),2.52(s,3H),2.16-2.08(m,2H),2.00-1.91(m,2H),1.42-1.33(m,2H),1.30-1.20(m,2H).

[0661] Example 58: LCMS: [M+H] + 323.1.

[0662] 1 H NMR (400MHz, CD3OD) δ7.61 (dd, J=8.4, 5.6Hz, 1H), 7.06 (dd, J=11.2, 8.4Hz, 1H), 3.77-3.72 (m ,1H),3.69(s,2H),3.00(m,J=6.0Hz,1H),2.51(s,3H),1.83-1.69(m,6H),1.63-1.56(m,2H).

[0663] Example 59: 2-(((4-Hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

[0664]

[0665] The title compound was prepared from Int-A20 and Int-B6 according to the method described for Example 56. LCMS: [M+H] + 373.1.

[0666] Example 60: 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one and Example 61: 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

[0667]

[0668] The compound of Example 59 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title compound.

[0669] Example 60: LCMS: [M+H] + 373.1.

[0670] 1 H NMR (400MHz, CD3OD) δ7.78-7.73(m,2H),3.71(s,2H),3.58-3.46(m,1H),2.81-2.73(m ,1H),2.64(s,3H),2.12(d,J=12.8Hz,2H),1.96(d,J=12.8Hz,2H),1.43-1.18(m,4H).

[0671] Example 61: LCMS: [M+H] + 373.1.

[0672] 1 H NMR (400MHz, CD3OD) δ7.89-7.58(m,2H),3.77-3.73(m,1H),3.71(s,2H),3.04-2. 96(m,1H),2.62(s,3H),1.84-1.79(m,4H),1.77-1.69(m,2H),1.65-1.53(m,2H).

[0673] Example 62: 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one and Example 63: 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0674]

[0675] Step 1: 2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0676] The title compound was prepared from Int-A1 and Int-B12 according to the method described for Example 28. LCMS: [M+H] + 433.2.

[0677] Step 2: 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one and 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0678] To a solution of 2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one (1.2 g, 2.7 mmol, 1.0 eq) in THF (10 mL) was added TBAF (913 mg, 3.5 mmol, 1.3 eq), and the mixture was heated at 50 ° C for 6 hours. The mixture was cooled to room temperature, 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 to 15: 1, v / v) to give Example 62 (100 mg, 12%) and Example 63 (150 mg, 17%) as white solids. A mixed fraction of Example 62 / Example 63 in a ratio of 1: 3 (400 mg, 47%) was also obtained.

[0679] Example 62: LCMS: [M+H] + 319.1.

[0680] 1 H NMR (400MHz, CDCl3) δ8.15(d,J=7.6Hz,1H),7.66(d,J=7.2Hz,1H),7.44(t,J=7.6Hz,1H),4.14(s,2H),3.42(d,J=6.0Hz,2H),2.71( s,3H),2.70-2.59(m,1H),2.11(d,J=12.8Hz,2H),1.85(d,J=13.2Hz,2H),1.56-1.43(m,1H),1.41-1.25(m,2H),1.06-0.92(m,2H).

[0681] Example 63: LCMS: [M+H] + 319.1.

[0682] 1 H NMR (400MHz, CDCl3) δ8.13(d,J=7.2Hz,1H),7.65(d,J=7.2Hz,1H),7.42(t,J=7.6Hz,1H),4.06(s,2H),3.51(d,J=5.6Hz ,2H),3.22-3.11(m,1H),2.70(s,3H),1.91-1.80(m,2H),1.79-1.69(m,2H),1.61-1.54(m,3H),1.47(t,J=11.6Hz,2H).

[0683] Example 64: 2-(((4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate and Example 65: 2-(((cis-4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0684]

[0685] Step 1: (4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate

[0686] To a solution of Example 62 / Example 63 (1:3 mixture, 400 mg, 1.3 mmol, 1.0 equiv) and Et3N (381 mg, 3.8 mmol, 3.0 equiv) in DCM (12 mL) was added dropwise MsCl (288 mg, 2.6 mmol, 2.0 equiv) at 0°C under N2 atmosphere, and the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (498 mg, 100%) as a yellow solid. LCMS: [M+H] + 397.1.

[0687] Step 2: 2-(((4-(Azidomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0688] To a solution of (4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate (350 mg, 0.88 mmol, 1.0 equiv) in DMF (8 mL) was added NaN3 (172 mg, 2.6 mmol, 3.0 equiv) under N2 atmosphere, and the mixture was heated at 50 ° C for 5 hours. The mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 10: 1 to 5: 1, v / v) to give the title compound (200 mg, 75%) as a yellow solid. LCMS: [M+H] + 344.2.

[0689] Step 3: 2-(((4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate and 2-(((cis-4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0690] To a solution of 2-(((4-(azidomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one (190 mg, 0.54 mmol, 1.0 equiv) in THF (8 mL) and water (0.1 mL) was added PPh (217 mg, 0.84 mmol, 1.5 equiv) under N2 atmosphere, and the mixture was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to afford Example 64 (45.8 mg, 26%) and Example 65 (45.1 mg, 26%) as white solids.

[0691] Example 64: LCMS: [M+H] + 318.2;

[0692] Example 65: LCMS: [M+H] + 318.2; 1 H NMR (400MHz, DMSO-d6) δ12.3(s,1H),7.94(d,J=7.6Hz,1H),7.67(d,J=7.6Hz,4H),7.38(t,J=7.6Hz,1H),3.64(s,2H),3.28- 3.24(m,1H),2.71(t,J=5.2Hz,2H),2.50(s,3H),1.82-1.67(m,4H),1.65-1.60(m,1H),1.55-1.50(m,2H),1.39-1.30(m,2H).

[0693] Example 66: 2-(((trans-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0694]

[0695] The compound of Example 64 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 15 mL / min) to give the title compound. LCMS: [M+H] + 318.2.

[0696] 1H NMR (400MHz, CD3OD) δ8.03(d,J=7.2Hz,1H),7.65(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),3.75(s,2H),2.78-2.70(m,3H),2.5 8(s,3H),2.25-2.08(m,2H),1.92-1.78(m,2H),1.66-1.55(m,1H),1.34(qd,J=12.8,3.2Hz,2H),1.05(qd,J=12.8,3.2Hz,2H).

[0697] Example 67: 2-(((4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate and Example 68: 2-(((cis-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0698]

[0699] A mixture of (4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate (200 mg, 0.5 mmol, 1.0 equiv), Et3N (101 mg, 1 mmol, 2.0 equiv) and dimethylamine (2M solution in THF, 5 mL, 10 mmol, 20.0 equiv) was heated at 100 °C for 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to afford Example 67 (65 mg, 37%) and Example 68 (49.3 mg, 28%) as white solids.

[0700] Example 67: LCMS: [M+H] + 346.2;

[0701] Example 68: LCMS: [M+H] + 346.2; 1H NMR (400MHz, DMSO-d6) δ12.3(s,1H),9.05(s,1H),7.93(d,J=8.0Hz,1H),7.66(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),3.63(s,2H),3.29-3.22 (m,1H),2.97(d,J=6.4Hz,2H),2.74(d,J=4.8Hz,6H),2.50(s,3H),1.86 -1.78(m,1H),1.78-1.70(m,4H),1.57-1.44(m,2H),1.38-1.29(m,2H).

[0702] Example 69: 2-(((trans-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0703]

[0704] The compound of Example 67 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 15 mL / min) to give the title compound. LCMS: [M+H] + 346.2.

[0705] 1 H NMR (400MHz, DMSO-d6) δ12.3(s,1H),9.12(s,1H),7.93(d,J=8.0Hz,1H),7.65(d,J=7.2Hz,1H),7.36(t,J=7.6Hz,1H),3.66(s,2H),2. 90(s,2H),2.80-2.77(m,1H),2.74(d,J=4.8Hz,6H),2.51(s,3H),2.08(d,J=11.6Hz,2H),1.82-1.64(m,3H),1.26(m,2H),0.96(m,2H).

[0706] Example 70: 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one and Example 71: 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0707]

[0708] Step 1: 2-(((3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0709] To a solution of Int-B13 (316 mg, 1.7 mmol, 1.0 equivalent) in THF (10 mL) was added 1 M NaOH (4 mL), and the mixture was stirred at room temperature under N2 atmosphere for 10 minutes. Int-A1 (350 mg, 1.7 mmol, 1.0 equivalent) was then added, and the mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with water (5 mL) and 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, 10:1, v / v) to give the title compound as a white solid, which was a 5:1 mixture of cis / trans isomers (200 mg, 38%). LCMS: [M+H] + 319.1.

[0710] Step 2: 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one and

[0711] 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0712] 2-(((3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one (100 mg) was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the compound of Example 70 (2.5 mg) and the compound of Example 71 (20 mg).

[0713] Example 70: LCMS: [M+H] + 319.1.

[0714] 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.0Hz,1H),7.63(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),3.83(s,2H),3.45(t,J=5.2Hz,2H ),2.74–2.64(m,1H),2.60(s,3H),2.10(m,2H),1.88–1.69(m,2H),1.51–1.45(m,1H),1.35–1.20(m,3H),0.98–0.84(m,1H).

[0715] Example 71: LCMS: [M+H] + 319.1.

[0716] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.0Hz,1H),7.60(d,J=7.2Hz,1H),7.36(t,J=7.6Hz,1H),3.86–3.70(m,2H),3.55–3.3 2(m,2H),3.24–3.11(m,1H),2.59(s,3H),2.02–1.91(m,1H),1.89–1.81(m,1H),1.80–1.60(m,5H),1.60–1.48(m,2H).

[0717] Example 72: 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0718]

[0719] Step 1: (3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate

[0720] The title compound was prepared from 2-(((3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one according to the procedure described for Example 64, Step 1. LCMS: [M+H] + 397.1.

[0721] Step 2: 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0722] The title compound was prepared from (3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate according to the methods described for Examples 67 and 68. The minor trans isomer was not isolated. LCMS: [M+H] + 346.2.

[0723] 1H NMR (400MHz, CD3OD) δ8.03(dd,J=8.0,1.6Hz,1H),7.67(d,J=7.2Hz,1H),7.39(t,J=7.6Hz,1H),3.75–3.71(m,2H),3.46–3.40(m,1H),3.05–2. 88(m,2H),2.84(d,J=5.2Hz,6H),2.58(s,3H),2.25–2.16(m,1H),1.93 –1.82(m,2H),1.80–1.69(m,3H),1.65–1.50(m,2H),1.18–1.06(m,1H).

[0724] Example 73: 8-Methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0725]

[0726] Step 1: (trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate

[0727] The title compound was prepared from Example 62 according to the procedure described for Step 1 of Example 64. LCMS: [M+H] + 397.1.

[0728] Step 2: 8-Methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0729] A mixture of (trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate (80 mg, 0.2 mmol, 1.0 equiv), Et3N (40 mg, 0.2 mmol, 2.0 equiv) and methylamine (2M solution in THF, 5 mL, 10 mmol, 50.0 equiv) was heated at 90 ° C for 2 days. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10: 1, v / v) to give the title compound (10 mg, 15%) as a white solid. LCMS: [M + H] + 332.2.

[0730] 1H NMR (400MHz, CD3OD) δ8.03(d,J=8.0Hz,1H),7.66(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),3.75(s,2H),2.83(d,J=7.2Hz,2H),2.77–2 .70(m,1H),2.67(s,3H),2.58(s,3H),2.23–2.15(m,2H),1.88–1.81(m,2H),1.73–1.62(m,1H),1.40–1.29(m,2H),1.13–1.01(m,2H).

[0731] Example 74: 7-amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0732]

[0733] Step 1: 7-Nitro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0734] The title compound was prepared from Int-A11 and Int-B1 according to the method described for Example 28. LCMS: [M+H] + 322.0.

[0735] Step 2: 7-amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0736] To a solution of 7-nitro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one (100 mg, 0.31 mmol, 1.0 equiv) and NHCl (100 mg, 1.88 mmol, 6.0 equiv) in EtOH (3 mL) and water (2 mL) was added Fe (104 mg, 1.88 mmol, 6.0 equiv), and the mixture was heated at 80 ° C for 2 hours. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 60: 1, v / v) to give the title compound (40 mg, 44%) as a white solid. LCMS: [M + H] + 292.1.

[0737] 1H NMR (400MHz, DMSO-d6) δ11.7(s,1H),7.72(d,J=8.8Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),6.56(d,J=2.0Hz,1H),6.05(s,2H), 3.81(dt,J=11.6,3.6Hz,2H),3.57(s,2H),3.33–3.27(m,2H),3.04(t,J=10.8Hz,1H),1.93–1.85(m,2H),1.49–1.39(m,2H).

[0738] Example 75: N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide

[0739]

[0740] To a solution of Example 74 (60 mg, 0.21 mmol, 1.0 equiv) and Et3N (42 mg, 0.41 mmol, 2.0 equiv) in DCM (10 mL) was added dropwise AcCl (32 mg, 0.41 mmol, 2.0 equiv) at 0°C, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with water (10 mL), extracted with DCM (20 mL×3), and the combined organic layers were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 60:1, v / v) to give the title compound (13 mg, 19%) as an off-white solid. LCMS: [M+H] + 334.1.

[0741] 1 H NMR (400MHz, CD3OD) δ8.13–8.09(m,2H),7.59(dd,J=8.8,1.6Hz,1H),3.97–3.82(m,2H),3.72(s ,2H),3.51–3.37(m,2H),3.09–2.96(m,1H),2.19(s,3H),2.00–1.89(m,2H),1.66–1.50(m,2H).

[0742] Example 76: N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide

[0743]

[0744] The title compound was prepared from the compound of Example 74 and benzoyl chloride according to the method described for Example 75. LCMS: [M+H] + 396.1.

[0745] 1 H NMR (400MHz, DMSO-d6) δ10.7(s,1H),8.25(d,J=1.6Hz,1H),8.08(d,J=8.8Hz,1H),8.04–7.96(m,2H),7.90(dd,J=8.8,2.0Hz,1H),7.67–7. 60(m,1H),7.60–7.52(m,2H),3.85–3.79(m,2H),3.75(s,2H),3.36–3 .29(m,2H),3.15–3.07(m,1H),1.99–1.86(m,2H),1.53–1.38(m,2H).

[0746] Example 77: N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide

[0747]

[0748] Step 1: 4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxylic acid

[0749] The title compound was prepared from Int-A16 and Int-B1 according to the method described for Example 28. The coupling reaction was accompanied by hydrolysis of the methyl ester to directly afford the title compound. LCMS: [M+H] + 321.1.

[0750] Step 2: N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide

[0751] To a solution of 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxylic acid (150 mg, 0.47 mmol, 1.0 equiv) in DMF (5 mL) was added MeNH (2M solution in THF, 0.94 mL, 1.88 mmol, 4.0 equiv), EDCI (180 mg, 0.94 mmol, 2.0 equiv) and HOBt (127 mg, 0.94 mmol, 2.0 equiv) at room temperature under N atmosphere, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), and the combined organic layers were washed with water (20 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound (100 mg, 64%) as a white solid. LCMS: [M+H] + 334.1.

[0752] 1 H NMR (400MHz, DMSO-d6) δ12.4(s,1H),8.72(d,J=4.4Hz,1H),8.15(d,J=8.0Hz,1H),8.05(s,1H),7.93–7.82(m,1H),3.83–3.80 (m,2H),3.69(s,2H),3.32–3.30(m,2H),3.10–3.04(m,1H),2.82(d,J=4.8Hz,3H),1.90(d,J=12.2Hz,2H),1.50-1.41(m,2H).

[0753] Example 78: 4-Oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide

[0754]

[0755] The title compound was prepared from 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxylic acid and PhNH 2 according to the procedure described for Example 77, Step 2. LCMS: [M+H] + 396.1.

[0756] 1H NMR(400MHz,DMSO-d6)δ12.5(br s,1H),10.5(s,1H),8.22–8.20(m,2H),7.98(d,J=8.4Hz,1H),7.81(d,J=8.0Hz,2H),7.38(t,J=8.0Hz,2H),7.13(t,J=7.2 Hz,1H),3.83–3.80(m,2H),3.69(s,2H),3.32-3.30(m,2H),3.10-3.04(m,1H),1.90(d,J=12.2Hz,2H),1.50-1.41(m,2H).

[0757] Example 79: 7-(Phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0758]

[0759] Step 1: 7-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0760] The title compound was prepared from Int-A8 and Int-B1 according to the method described for Example 28. LCMS: [M+H] + 355.0.

[0761] Step 2: 7-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0762] To a solution of 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one (7.5 g, 21.1 mmol, 1.0 equiv) in anhydrous THF (100 mL) was added LiHMDS (1 M in THF, 42.2 mL, 42.2 mmol, 2.0 equiv) dropwise at 0°C under N2 atmosphere, and the mixture was stirred at 0°C for 1 hour. SEMCl (5.3 g, 31.7 mmol, 1.5 equiv) was added, and the mixture was stirred for another 1.5 hours. The reaction was quenched with water (30 mL), and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 10:1, v / v) to give the title compound (7.8 g, 76%) as a colorless oil. LCMS: [M+H] + 485.1.

[0763] 1H NMR (400MHz, CD3OD) δ8.12(d,J=8.4Hz,1H),7.80(d,J=1.2Hz,1H),7.58(dd,J=8.4,1.2Hz,1H),5.73(s,2H),3.98–3.94(m,4H),3.66( t,J=8.0Hz,2H),3.45–3.39(m,2H),3.09-3.02(m,1H),1.93(d,J=13.2Hz,2H),1.70-1.62(m,2H),0.93(t,J=8.0Hz,2H),0.02(s,9H).

[0764] Step 3: 7-(Phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0765] To a solution of 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (60 mg, 0.12 mmol, 1.0 eq) and PhNH (14 mg, 0.15 mmol, 1.2 eq) in toluene (5 mL) was added t-BuONa (35 mg, 0.37 mmol, 3.0 eq), BINAP (15 mg, 0.024 mmol, 0.2 eq) and Pd(dba) (11 mg, 0.012 mmol, 0.1 eq) under N atmosphere, and the mixture was heated at reflux for 3 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1, v / v) to give the title compound (40 mg, 60%) as a yellow solid. LCMS: [M+H] + 498.3.

[0766] Step 4: 7-(Phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0767] To a solution of 7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (60 mg, 0.12 mmol, 1.0 equiv) in dioxane (3 mL) was added 3M HCl / dioxane solution (1 mL), and the mixture was heated at 40° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound (13 mg, 29%) as a light yellow solid. LCMS: [M+H] + 368.1.

[0768] 1 H NMR (400MHz, CD3OD) δ7.98(d,J=8.8Hz,1H),7.39–7.33(m,2H),7.26(d,J=8.0Hz,2H),7.17–7.05(m,3H),3.89(dt,J=11 .6,4.0Hz,2H),3.69(s,2H),3.42(td,J=11.2,2.4Hz,2H),3.05-2.98(m,1H),1.93(d,J=13.2Hz,2H),1.62-1.52(m,2H).

[0769] Example 80: 7-(Pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0770]

[0771] Step 1: 7-(Pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0772] The title compound was prepared from 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one and pyridin-3-amine according to the procedure described for Example 79, Step 3. LCMS: [M+H] + 499.2.

[0773] Step 2: 7-(Pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0774] To a solution of 7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (30 mg, 0.06 mmol, 1.0 equiv) in THF (1 mL) was added 2M HCl (1 mL), and the mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 8-9 with saturated NaHCO3 aqueous solution and extracted with EtOAc (15 mL×3). The combined organic layers were concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH, 20:1, v / v) to give the title compound (10 mg, 45%) as a white solid. LCMS: [M+H] + 369.1.

[0775] 1 HNMR(400HMz,DMSO-d6)δ12.0(s,1H),9.01(s,1H),8.46(d,J=4.0Hz,1H),8.22( dd,J=8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.66(d,J=12.0Hz,1H),7.38-7.35(m,1 H),7.13(dd,J=12.0Hz,1H),7.04(d,J=4.0Hz,1H),3.85-3.76(m,2H),3.61(s,2 H),3.31-3.26(m,2H),3.10-3.00(m,1H),1.92-1.84(m,2H),1.49-1.37(m,2H).

[0776] The following examples in Table 5 were similarly prepared using the two-step procedure in Example 80 starting from 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one and the appropriate amine.

[0777] Table 5

[0778]

[0779]

[0780]

[0781] Example 93: 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate

[0782]

[0783] Step 1: 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0784] To a solution of 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (50 mg, 0.10 mmol, 1.0 equiv) and 1H-pyrazol-4-amine (10 mg, 0.12 mmol, 1.2 equiv) in toluene (5 mL) was added t-BuONa (20 mg, 0.20 mmol, 2.0 equiv), t-BuXphos (18 mg, 0.04 mmol, 0.4 equiv) and Pd2(dba)3 (9 mg, 0.01 mmol, 0.1 equiv) under N2 atmosphere, and the mixture was heated at reflux for 24 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1, v / v) to give the title compound (19 mg, 40%) as a yellow oil. LCMS: [M+H] + 488.2.

[0785] Step 2: 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0786] The title compound was prepared from 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one according to the procedure described for Example 80, Step 2. LCMS: [M+H] + 358.1.

[0787] 1 H NMR(400MHz,DMSO-d6)δ12.4(br s,1H),8.57(s,1H),8.18(d,J=9.2Hz,1H),7.99-7.97(m,2H),7.78(s,1H),3.86-3.78(m,2H), 3.70(s,2H),3.36-3.30(m,2H),3.12-3.01(m,1H),1.89(d,J=11.8Hz,2H),1.51-1.42(m,2H).

[0788] Example 94: 7-(Isoxazolyl-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0789]

[0790] Step 1: 7-(Isoxazolyl-3-ylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one

[0791] The title compound was prepared from 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one and isoxazol-3-amine according to the procedure described for Example 79, Step 3. LCMS: [M+H] + 489.2.

[0792] Step 2: 7-(Isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0793] A mixture of 7-(isoxazol-3-ylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (25 mg, 0.05 mmol, 1.0 equiv) and formic acid (1.0 mL) was stirred at room temperature overnight. The mixture was diluted with MeOH (1 mL) and purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound (4 mg, 22%) as a white solid. LCMS: [M+H] + 359.1.

[0794] 1H NMR (400 MHz, DMSO-d6) δ 12.0 (s, 1H), 9.80 (s, 1H), 8.70 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 8.8, 2.4 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H), 3.81 (d, J = 11.6 Hz, 2H), 3.65 (s, 2H), 3.40-3.28 (2H obscured by water peak), 3.06 (td, J = 10.8, 5.2 Hz, 1H), 1.90 (d, J = 13.2 Hz, 2H), 1.61–1.38 (m, 2H).

[0795] Example 95: 8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0796]

[0797] Step 1: 7-Bromo-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0798] The title compound was prepared from Int-A24 and Int-B1 according to the method described for Example 28. LCMS: [M+H] + 369.0.

[0799] Step 2: 8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0800] The title compound was prepared from 7-bromo-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one according to the procedure described for Example 79, Steps 2 and 3. LCMS: [M+H] + 512.1.

[0801] Step 3: 8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0802] The title compound was prepared from 8-methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one according to the procedure described for Example 80, Step 2. LCMS: [M+H] + 382.2.

[0803] 1 H NMR (400MHz, CDCl3) δ9.77(s,1H),8.02(d,J=8.8Hz,1H),7.40–7.35(m,2H),7.32(d,J=8.8Hz,1H),7.18(d,J=7.6Hz,2H),7.14–7.09(m,1H) ,5.90(s,1H),4.00–3.92(m,2H),3.79(s,2H),3.41–3.33(m,2H),2.99 –2.85(m,1H),2.51(s,3H),1.94(d,J=14.6Hz,2H),1.76–1.61(m,2H).

[0804] Example 96: 7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0805]

[0806] Step 1: 7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0807] To a solution of 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (80 mg, 0.16 mmol, 1.0 eq) and KOH (28 mg, 0.49 mmol, 3.0 eq) in dioxane (1 mL) and water (1 mL) under N2 atmosphere were added Pd2(dba)3 (15 mg, 0.016 mmol, 0.1 eq) and t-BuXPhos (25 mg, 0.06 mmol, 0.4 eq), and the mixture was heated at 90°C overnight. After cooling to room temperature, BnBr (136 mg, 0.8 mmol, 5.0 eq) and n-Bu4NBr (257 mg, 0.8 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 6 hours. The mixture 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 preparative TLC (petroleum ether:EtOAc, 3:1 to 1:1, v / v) to give the title compound (28 mg, 34%) as a gray solid. LCMS: [M+H] + 513.2.

[0808] Step 2: 7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0809] To a solution of 7-(benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (45 mg, 0.09 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by C18 reverse phase column (Biotage, 45%-55% can in water) to give the title compound (6 mg, 18%) as a white solid. LCMS: [M+H] + 383.1.

[0810] 1 H NMR (400MHz, CDCl3) δ8.20 (d, J = 8.8Hz, 1H), 7.46–7.36 (m, 5H), 7.19-7.15 (m, 2H), 5.19 (s, 2H), 3.96–3. 92(m,2H),3.82(s,2H),3.37(t,J=11.2Hz,2H),2.91–2.84(m,1H),1.92–1.88(m,2H),1.71–1.62(m,2H).

[0811] Example 97: 2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0812]

[0813] Step 1: 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-one

[0814] The title compound was prepared from Int-A8 and Int-B6 according to the method described for Example 28. LCMS: [M+H] + 411.0.

[0815] Step 2: 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0816] The title compound was prepared from 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-one according to the procedure described for steps 2 and 3 of Example 79. LCMS: [M+H]+ 541.1.

[0817] Step 3: 2-(((4-oxocyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0818] To a solution of 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (100 mg, 0.18 mmol, 1.0 equiv) in THF (5 mL) was added 1 M HCl (5 mL), and the mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 8-9 with saturated aqueous NaHCO₃ solution 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, 10:1, v / v) to give the title compound (28 mg, 41%) as a white solid. LCMS: [M+H] + 450.2.

[0819] Step 4: 2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0820] The title compound was prepared from 2-(((4-oxocyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one according to the method described for Example 22. LCMS: [M+H] + 382.2.

[0821] Example 98: 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one and Example 99: 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0822]

[0823] The compound of Example 97 was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title compound.

[0824] Example 98: LCMS: [M+H] + 382.2.

[0825] 1H NMR (400MHz, CD3OD) δ7.98(d,J=8.8Hz,1H),7.36(t,J=7.6Hz,2H),7.26(d,J=7.6Hz,2H),7.16(d,J=2.0Hz,1H),7.14-7.04(m,2H),3. 65(s,2H),3.52-2.46(m,1H),2.73-2.65(m,1H),2.05(d,J=16.0Hz,2H),1.94(d,J=10.4Hz,2H),1.38-1.32(m,2H),1.26-1.22(m,2H).

[0826] Example 99: LCMS: [M+H] + 382.2.

[0827] 1 H NMR (400MHz, CD3OD) δ7.97(d,J=8.4Hz,1H),7.36(t,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),7.16(d,J=2.0Hz, 1H),7.14-7.04(m,2H),3.72(s,1H),3.64(s,2H),2.97-2.89(m,1H),1.81-1.72(m,4H),1.72-1.55(m,4H).

[0828] Example 100: 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one and Example 101: 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0829]

[0830] Step 1: 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0831] The title compound was prepared from 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-one using pyridin-3-amine according to the procedure described for steps 2 and 3 of Example 79. LCMS: [M+H] + 425.2.

[0832] Step 2: 2-(((4-Oxocyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0833] The title compound was prepared from 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one according to the procedure described for Example 97, Step 3. LCMS: [M+H] + 381.2.

[0834] Step 3: 2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0835] The title compound was prepared from 2-(((4-oxocyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one according to the method described for Example 22. LCMS: [M+H] + 383.2.

[0836] Step 4: 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0837] and 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0838] 2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound.

[0839] Example 100: LCMS: [M+H] + 383.2.

[0840] 1 H NMR (400MHz, CD3OD) δ8.45(d,J=2.8Hz,1H),8.18(dd,J=4.8,1.2Hz,1H),8.04(d,J=8.8Hz,1H),7.82–7.75(m,1H),7.41(dd,J=8.4,4.8H z,1H),7.21(d,J=2.4Hz,1H),7.16(dd,J=8.8,2.4Hz,1H),3.72(d,J=3.2Hz,1H),3.35(s,2H),2.95(d,J=4.4Hz,1H),1.97–1.45(m,8H).

[0841] Example 101: LCMS: [M+H] + 383.2.

[0842] 1 H NMR(400MHz,CD3OD)δ8.45(d,J=2.4Hz,1H),8.22–8.17(m,1H),8.05(d,J=8.8Hz, 1H),7.81–7.75(m,1H),7.42(dd,J=8.4,4.8Hz,1H),7.22(d,J=2.0Hz,1H),7.17( dd,J=8.8,2.2Hz,1H),3.52(td,J=10.4,5.2Hz,1H),3.35(s,2H),2.70(td,J=11. 2,3.6Hz,1H),2.06(d,J=12.4Hz,2H),1.93(d,J=11.6Hz,2H),1.40–1.22(m,4H).

[0843] Example 102: 7-(Cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one and Example 103: 7-(Cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0844]

[0845] Step 1: 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-(cyclopentylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0846] The title compound was prepared from 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-one and cyclopentylamine according to the method described for Step 2 and Step 3 of Example 79. LCMS: [M+H] + 446.3.

[0847] Step 2: 7-(Cyclopentylamino)-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0848] The title compound was prepared from 2-((1,4-dioxaspiro[4.5]dec-8-ylthio)methyl)-7-(cyclopentylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one according to the procedure described for Example 97, Step 3. LCMS: [M+H] + 372.2.

[0849] Step 3: 7-(Cyclopentylamino)-2-(((4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0850] The title compound was prepared from 7-(cyclopentylamino)-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one according to the method described for Example 22. LCMS: [M+H] + 374.2.

[0851] Step 4: 7-(Cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one and 7-(Cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0852] 7-(Cyclopentylamino)-2-(((4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with aqueous ACN at a flow rate of 20 mL / min) to give the title compound.

[0853] Example 102: LCMS: [M+H] + 374.2.

[0854] 1 HNMR (400MHz, DMSO-d6) δppm: 11.6 (br s, 1H), 7.70 (d, J = 8.0Hz, 1H), 6.69 (dd, J = 8.0, 2.0Hz, 1H), 6.50 (m, 1H), 6.45 (d, J = 2.0Hz, 1H), 4.52 (br s,1H),3.74-3.82(m,1H),3.52(s,2H),3.39-3.35(m,1H),2.76-2.64(m,1H),2.03–1.90(m,4H) ,1.82-1.76(m,2H),1.73-1.63(m,2H),1.62-1.53(m,2H),1.52–1.42(m,2H),1.24-1.13(m,4H).

[0855] Example 103: LCMS: [M+H] + 374.2.

[0856] 1HNMR (400MHz, DMSO-d6) δppm: 11.6 (br s, 1H), 7.70 (d, J = 8.0Hz, 1H), 6.69 (d, J = 8.0, 2.0Hz, 1H), 6.50 (m, 1H), 6.45 (s, 1H), 4.41 (br s,1H),3.80-3.75(m,1H),3.59-3.56(m,1H),3.51(s,2H),2.97-2.90(m,1H),1.97-1.90(m,2H),1.72-1.61(m,6H),1.62-1.42(m,8H).

[0857] Example 104: 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one and Example 105: 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0858]

[0859] Step 1: 7-Bromo-2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0860] The title compound was prepared from Int-A8 and Int-B12 according to the procedures described in Example 70 and Step 1 of Example 71 as a 1:1 mixture of cis / trans isomers, which was used directly in the next step.

[0861] Step 2: 2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0862] The title compound was prepared from 7-bromo-2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one according to the procedure described for Example 79, steps 2 and 3. LCMS: [M+H] + 640.3.

[0863] Step 3: 2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0864] To a solution of 2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (600 mg, 0.94 mmol, 1.0 equiv) in THF (4 mL) was added 2M HCl (4 mL), and the mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 8-9 with saturated NaHCO3 aqueous solution 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, 50:1, v / v) to give the title compound (90 mg, trans / cis=3:1, 24%) as a white solid. LCMS: [M+H] + 396.2.

[0865] Step 4: 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one and 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

[0866] 2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound.

[0867] Example 104: LCMS: [M+H] + 396.2.

[0868] 1 H NMR (400 MHz, DMSO-d6) δ 11.9 (br s, 1H), 8.87 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 7.10–6.99 (m, 3H), 3.51 (s, 2H), 3.30 (1H (OH) may be obscured by water peak), 3.17 (d, J = 5.2 Hz, 2H), 2.67 (t, J = 6.8 Hz, 1H), 2.00 (d, J = 10.8 Hz, 2H), 1.73 (d, J = 11.2 Hz, 2H), 1.35–1.31 (m, 1H), 1.21–1.11 (m, 2H), 0.94–0.85 (m, 2H).

[0869] Example 105: LCMS: [M+H] + 396.2.

[0870] 1 H NMR (400 MHz, DMSO-d6) δ 12.1 (br s, 1H), 8.89 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.10–7.00 (m, 3H), 3.55 (t, J = 6.0 Hz, 2H), 3.30 (1H (OH) may be obscured by water peak), 3.22–3.17 (m, 3H), 1.75-1.65 (m, 4H), 1.48–1.37 (m, 3H), 1.32–1.23 (m, 2H).

[0871] Example 106: 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one and Example 107: 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0872]

[0873] Step 1: 2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0874] The title compound was prepared from 7-bromo-2-(((4-((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one and pyridin-3-amine according to the procedure described for Example 79, steps 2 and 3. LCMS: [M+H] + 641.3.

[0875] Step 2: 2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0876] The title compound was prepared from 2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one according to the method described for Example 104 and Example 105 Step 3. LCMS: [M+H] + 397.2.

[0877] Step 3: 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one and 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

[0878] 2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound.

[0879] Example 106: LCMS: [M+H] + 397.2.

[0880] 1 HNMR (400MHz, CD3OD) δ8.45(d,J=4.0Hz,1H),8.20(d,J=4.0Hz,1H),8.04(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,1H),7.44-7.40(m,1H),7.21(s ,1H),7.17(d,J=8.0Hz,1H),3.63(s,2H),3.37(d,J=4.0Hz,2H),3.20- 3.16(m,1H),2.05-2.00(m,1H),1.84-1.70(m,4H),1.45-1.29(m,4H).

[0881] Example 107: LCMS: [M+H] + 397.2.

[0882] 1 HNMR(400MHz,CD3OD)δ8.46(d,J=2.4Hz,1H),8.21(dd,J=4.8,1.2Hz,1H),8.0 5(d,J=8.8Hz,1H),7.79(d,J=10.0Hz,1H),7.42(m,1H),7.22(s,1H),7.18(dd, J=8.8,2.4Hz,1H),3.70(s,2H),3.32(m,2H),2.66(m,1H),2.07(d,J=12.4Hz,2 H), 1.82 (d, J = 13.2Hz, 2H), 1.59 (m, 1H), 1.33–1.24 (m, 2H), 1.06–0.94 (m, 2H).

[0883] Example 108: 7-(Cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0884]

[0885] A mixture of the compound of Example 30 (100 mg, 0.34 mmol, 1.0 equivalent) and cyclohexylamine (2 mL) was heated at 120 ° C in a sealed tube for 2 days. The mixture was cooled to room temperature and concentrated under reduced pressure. 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 preparative TLC (petroleum ether: EtOAc, 3: 1 to 1: 1, v / v) to give the title compound (35 mg, 28%) as a gray solid. LCMS: [M+H] + 374.2.

[0886] 1 HNMR (400MHz, DMSO-d6) δ11.7(s,1H),7.72(d,J=8.8Hz,1H),6.72(d,J=8.8Hz,1H),6.49(s,1H),6.46(d,J=7.6Hz,1H),3.83-3.79(m,2H),3.5 8(s,2H),3.34-3.29(m,3H),3.08-3.00(m,1H),1.95-1.86(m,4H),1.76 -1.71(m,2H),1.63-1.59(m,1H),1.49-1.33(m,4H),1.23-1.14(m,3H).

[0887] The following examples in Table 6 were prepared similarly according to the procedure described for Example 108 from Example 30 and the appropriate amine.

[0888] Table 6

[0889]

[0890]

[0891]

[0892]

[0893] Example 126: 7-[(1-Benzyl-3-piperidinyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one

[0894]

[0895] A mixture of the compound of Example 30 (150 mg, 0.5 mmol, 1.0 equivalent) and 1-benzylpiperidin-3-amine (1 mL) was heated at 120 ° C in a sealed tube for 2 days. The mixture was cooled to room temperature, 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 preparative TLC (DCM: MeOH, 10 / 1, v / v) to give the title compound (70 mg, 30%) as a yellow solid. LCMS: [M+H] + 465.2.

[0896] 1 H-NMR: (400MHz, CD3OD) δ7.85 (d, J=4.8Hz, 1H), 7.40-7.23 (m, 5H), 6.86 (dd, J=2.4Hz, 9.2Hz, 1H),6.32(s,1H),3.94-3.85(m,2H),3.67(s,2H),3.66-3.54(m,3H),3.46-3.37(m,2H),3.09 -2.96(m,2H),2.84-2.74(m,1H),2.27-2.17(m,1H),2.16-2.06(m,1H),2.05-1.97(m,1H),1. 97-1.90(m,2H),1.85-1.76(m,1H),1.75-1.65(m,1H),1.63-1.51(m,2H),1.45-1.33(m,1H).

[0897] Example 127: 7-(3-piperidinylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one

[0898]

[0899] To a solution of the compound of Example 126 (65 mg, 0.14 mmol, 1.0 equiv) in DCE (3 mL) was added 1-chloroethyl chloroformate (80 mg, 0.56 mmol, 4.0 equiv) and DIPEA (0.1 mL, 0.56 mmol), 4.0 equiv). The mixture was stirred at 25 ° C for 48 hours and then concentrated under reduced pressure. Methanol (5 mL) was added and the mixture was heated at reflux for 2 hours, then allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1, v / v) to give the title compound (10 mg, 19%) as a yellow solid. LCMS: [M + H] + 375.2.

[0900] 1 H-NMR:(400MHz,DMSO-d6)δ11.7(br s,1H),7.78(d,J=8.8Hz,1H),6.78(dd,J=2.0Hz,8.8Hz,1H),6.73(d,J=8.0Hz, 1H),6.62(d,J=1.6Hz,1H),3.86-3.76(m,2H),3.75-3.67(m,1H),3.60(s,2H), 3.19-3.11(m,2H),3.07-2.98(m,2H),2.85-2.76(m,2H),2.68-2.57(m,2H),2. 01-1.92(m,1H),1.87(d,J=12.0Hz,3H),1.77-1.64(m,1H),1.57-1.38(m,3H).

[0901] Example 128: 7-((1-benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0902]

[0903] The title compound was prepared from the compound of Example 30 and 1-benzylpiperidin-4-amine according to the method described for Example 126. LCMS: [M+H] + 465.2.

[0904] 1 H NMR(400MHz,CD3OD)δ7.88(d,J=8.8Hz,1H),7.49–7.35(m,5H),6.82(dd,J=8.9 ,2.0Hz,1H),6.65(d,J=1.6Hz,1H),3.99–3.86(m,4H),3.68(s,2H),3.65–3.54( m,1H),3.47–3.37(m,2H),3.27–3.16(m,2H),3.07–2.97(m,1H),2.81–2.64(m,2 H),2.23–2.10(m,2H),1.99–1.89(m,2H),1.79–1.64(m,2H),1.66–1.50(m,2H).

[0905] Example 129: 7-(Piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0906]

[0907] The title compound was prepared from Example 128 according to the method described for Example 127. LCMS: [M+H] + 375.1.

[0908] 1 H NMR (400MHz, CD3OD) δ7.91 (d, J=4.8Hz 1H),6.87-6.85(m,1H),6.71-6.68(m,1H),3.93-3.86(m,2H),3.83-3.74(m,1H),3.70(s,2H),3.56–3.39(m,4H),3. 24-3.17(m,2H),3.08-2.95(m,1H),2.30-2.26(m,2H),1.93(d,J=6.8Hz,2H),1.79-1.69(m,2H),1.63-1.55(m,2H).

[0909] Example 130: 7-(Pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0910]

[0911] Step 1: 7-((1-benzylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0912] The title compound was prepared from Example 30 and 1-benzylpyrrolidin-3-amine according to the method described for Example 126. LCMS: [M+H] + 451.2.

[0913] Step 2: 7-(Pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0914] The title compound was prepared from 7-((1-benzylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one according to the method described for Example 127. LCMS: [M+H] + 361.2.

[0915] 1H NMR (400MHz, CDCl3) δ7.98-7.91(m,1H),6.91-6.85(m,1H),6.69(d,J=10.4Hz,1H),4.39-4.32(m,1H),3.93-3.86(m,2H),3.72(s,2H),3.60-3.5 4(m,1H),3.45-3.31(m,4H),3.31-3.22(m,1H),3.07-2.97(m,1H),2.39 -2.25(m,1H),2.21-2.09(m,1H),1.90(d,J=6.4,2H),1.64-1.52(m,2H).

[0916] Example 131: 7-((1-acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0917]

[0918] A solution of Example 30 (110 mg, 0.37 mmol, 1.0 equiv) and 1-(4-aminopiperidin-1-yl)ethanone (53 mg, 0.37 mmol, 1.0 equiv) in THF (10 mL) was heated at 120 ° C in a sealed tube for 2 days. The mixture was cooled to room temperature, 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 preparative TLC (DCM:MeOH, 10 / 1, v / v) to give the title compound (20 mg, 12%) as a white solid. LCMS: [M+H] + 417.2.

[0919] 1 H NMR(400MHz, DMSO-d6)δ11.9(s,1H),7.93-7.72(m,2H),7.13(dd,J=9.2,2.4Hz,1H),6.90-6.85(m,1H),3.95-3.85(m,2H),3.85-3.75(m,3H) ,3.61(s,2H),3.36-3.34(m,1H),3.31-3.27(m,1H),3.10-2.95(m,3H) ,1.94-1.84(m,2H),1.84-1.81(m,2H),1.79(s,3H),1.35-1.51(m,4H).

[0920] Example 132: 7-((1-acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0921]

[0922] The title compound was prepared from the compound of Example 30 and 1-(3-aminopiperidin-1-yl)ethanone according to the method described for Example 131. LCMS: [M+H] + 417.2.

[0923] 1 H NMR (400MHz, DMSO-d6) δ11.8 (s, 1H), 7.90 (d, J = 7.2Hz, 1H), 7.84 (d, J = 9.2Hz, 1H),7.09(dd,J=9.2,2.4Hz,1H),6.86(d,J=2.4Hz,1H),3.86-3.72(m,4H),3.7 2-3.65(m,1H),3.60(s,2H),3.34-3.27(m,2H),3.09-2.96(m,2H),2.86-2.76 (m,1H),1.93-1.81(m,3H),1.87(s,3H),1.79-1.72(m,1H),1.56-1.38(m,4H).

[0924] Example 133: 7-((1-methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0925]

[0926] The title compound was prepared from the compound of Example 127 and formaldehyde according to the method described for Example 14. LCMS: [M+H] + 389.2.

[0927] 1 H NMR (400MHz, CDCl3) δ9.85(s,1H),7.59(d,J=8.8Hz,1H),6.68(d,J=7.6Hz,1H),6.64(s,1H),3.92(d,J=10.4Hz,2H),3.85-3.78(m,1H ),3.75(s,2H),3.36(t,J=10.8Hz,2H),2.93-2.83(m,2H),2.80-2.63(m,2H),2.44-2.25(m,4H),1.97-1.85(m,4H),1.66-1.54(m,4H).

[0928] Example 134: 7-((1-acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0929]

[0930] The title compound was prepared from the compound of Example 130 according to the method described for Example 17. LCMS: [M+H] + 403.2.

[0931] 1 H NMR (400MHz, CD3OD) δ7.97–7.87(m,1H),6.90–6.81(m,1H),6.68(s,1H),4.58(s,2H),4.23(m,1H),3.91(m,2H),3.69(s ,3H),3.58(t,J=7.2Hz,1H),3.44(m,3H),3.07–2.97(m,1H),2.31(m,1H),2.15–1.98(m,3H),1.94(m,2H),1.58(m,2H).

[0932] Example 135: 8-Methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[0933]

[0934] To a solution of the compound of Example 33 (108 mg, 0.35 mmol, 1.0 equivalent) and PhOH (70 mg, 0.74 mmol, 2.1 eq) in DMSO (1 mL) was added KCO (99 mg, 0.72 mmol, 2.0 equivalents) under N2 atmosphere, and the mixture was heated at 120 ° C overnight. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 5: 1, v / v) and subsequently purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250x21.2 mm column, gradient elution with ACN aqueous solution, flow rate of 20 mL / min) to give the title compound (1 mg, 1%) as a white solid. LCMS: [M+H] + 383.2.

[0935] 1H NMR(400MHz, CD3OD)δ8.01(d,J=8.8Hz,1H),7.43–7.36(m,2H),7.17(t,J=7.2Hz,1H),7.03–6.96(m,3H),3.97–3.89 (m,2H),3.77(s,2H),3.51–3.38(m,2H),3.15-3.13(m,1H),2.51(s,3H),2.01(d,J=11.6Hz,2H),1.68–1.55(m,2H).

[0936] Example 136: 7-(Cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one and Example 137: 7-(Cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0937]

[0938] Step 1: 2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-fluoroquinazolin-4(3H)-one

[0939] The title compound was prepared from Int-A9 and Int-B12 according to the method described for Example 28. LCMS: [M+H] + 437.2.

[0940] Step 2: 7-(Cyclohexylamino)-2-(((4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0941] The title compound was prepared from 2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-fluoroquinazolin-4(3H)-one and cyclohexylamine according to the method described for Example 108. Loss of the TBS protecting group occurred during this reaction. LCMS: [M+H] + 437.2.

[0942] Step 3: 7-(Cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one and 7-(Cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

[0943] 7-(Cyclohexylamino)-2-(((4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one was purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title compound.

[0944] Example 136: LCMS: [M+H] + 402.2.

[0945] 1 H NMR (400MHz, CD3OD) δ7.84(d,J=8.8Hz,1H),6.78(dd,J=8.8,2.0Hz,1H),6.60(s,1H),3.66(s,2H),3.39–3.32(m,3H),2.71–2 .61(m,1H),2.12–2.01(m,4H),1.87–1.77(m,4H),1.74–1.66(m,1H),1.49–1.37(m,3H),1.31–1.21(m,5H),1.05–0.96(m,2H).

[0946] Example 137: LCMS: [M+H] + 402.2.

[0947] 1 H NMR (400MHz, CD3OD) δ7.84(d,J=8.8Hz,1H),6.78(dd,J=8.8,2.4Hz,1H),6.60(s,1H),3.61(s,2H),3.38 (m,3H),3.21–3.15(m,1H),2.10–2.04(m,2H),1.88–1.63(m,7H),1.61–1.38(m,7H),1.26–1.21(m,3H).

[0948] Example 138: 8-Methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one bis(trifluoroacetate)

[0949]

[0950] To a solution of Example 13 (53 mg, 0.17 mmol, 1.0 eq) and 1-methyl-1H-imidazole-2-carbaldehyde (28 mg, 0.25 mmol, 1.5 eq) in THF (2 mL) was added NaBH(OAc) (72 mg, 0.34 mmol, 2.0 eq) under N2 atmosphere, and the mixture was stirred at room temperature overnight. The mixture was purified by C18 reverse phase column (Biotage, 30% to 70% ACN in water, 0.1% TFA) to give the title compound (22 mg, 34%) as a white solid. LCMS: [M+H] + 384.2.

[0951] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.4Hz,1H),7.65(d,J=7.2Hz,1H),7.41(s,2H),7.20(s,1H),4.78(s, 2H),3.98(s,3H),3.80(s,2H),3.40(m,2H),3.17–3.00(m,3H),2.59(s,3H),2.24(m,2H),1.95(m,2H).

[0952] The following examples in Table 7 were similarly prepared from Example 13 and the appropriate aldehyde according to the procedure described for Example 138.

[0953] Table 7

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960] Example 159: (S)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0961]

[0962] The title compound was prepared from the compound of Example 13 and (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to the method described for Example 138. Purification by C18 reverse phase column (Biotage, 40% to 60% ACN in water, 0.1% TFA) resulted in loss of the protecting group and directly afforded the title compound. LCMS: [M+H] + 364.2.

[0963] 1 H NMR (400MHz, CD3OD) δ8.04(d,J=8.0Hz,1H),7.67(d,J=7.2Hz,1H),7.40(t,J=7.6Hz,1H),4.06–3.97(m,1H),3.85–3.7 7(m,2H),3.74–3.61(m,2H),3.59–3.38(m,3H),3.22–2.94(m,4H),2.60(s,3H),2.45–1.99(m,2H),1.92–1.75(m,2H).

[0964] Example 160: (R)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one trifluoroacetate

[0965]

[0966] The title compound was prepared from Example 13 and (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to the method described for Example 138. Purification by C18 reverse phase column (Biotage, 40% to 60% ACN in water, 0.1% TFA) resulted in loss of the protecting group and directly afforded the title compound. LCMS: [M+H] + 364.2.

[0967] 1 H NMR (400MHz, CD3OD) δ8.04(d,J=8.0Hz,1H),7.67(d,J=7.2Hz,1H),7.40(t,J=7.6Hz,1H),4.06–3.97(m,1H),3.85–3.7 7(m,2H),3.74–3.61(m,2H),3.59–3.38(m,3H),3.22–2.94(m,4H),2.60(s,3H),2.45–1.99(m,2H),1.92–1.75(m,2H).

[0968] Example 161: (S)-8-Methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[0969]

[0970] Step 1: (S)-tert-Butyl 2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate

[0971] The title compound was prepared from the compound of Example 13 and (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate according to the method described for Example 138. LCMS: [M+H-56] + 417.3.

[0972] Step 2: (S)-8-Methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[0973] The title compound was prepared from (S)-tert-butyl 2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 373.2.

[0974] 1 H NMR (400MHz, CD3OD) δ8.09(d,J=7.6Hz,1H),7.75(d,J=7.2Hz,1H),7.50(t,J=7.2Hz,1H),4.16(m,1H),3.83(m,1H),3.68(t,J=4. 8Hz,2H),3.63(m,2H),3.56(t,J=4.8Hz,2H),3.42(m,2H),3.20(m,2H),2.65(s,3H),2.40(m,3H),2.14–1.90(m,4H),1.82(m,1H).

[0975] Example 162: 2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[0976]

[0977] The title compound was prepared from the compound of Example 13 and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde according to the method described for Example 138. Purification by preparative TLC (DCM:MeOH, 10:1, v / v) resulted in loss of the protecting group and directly afforded the title compound. LCMS: [M+H] + 334.2.

[0978] 1 H NMR (400MHz, CD3OD) δ8.02(d,J=8.0Hz,1H),7.65(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),3.75(s,2H),3.71(t,J=5.6Hz,2H),3.10 (d,J=12.0Hz,2H),3.00–2.89(m,1H),2.70(t,J=5.6Hz,2H),2.58(s,3H),2.49–2.36(m,2H),2.18–2.08(m,2H),1.78–1.63(m,2H).

[0979] Example 163: 2-(((1-(2-aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one dihydrochloride

[0980]

[0981] Step 1: tert-Butyl (2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)carbamate

[0982] The title compound was prepared from the compound of Example 13 and tert-butyl (2-oxoethyl)carbamate according to the method described for Example 138. LCMS: [M+H] + 433.2.

[0983] Step 2: 2-(((1-(2-aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one dihydrochloride

[0984] The title compound was prepared from tert-butyl (2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)carbamate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 333.2.

[0985] 1H NMR (400MHz, CD3OD) δ8.11(d,J=7.6Hz,1H),7.77(d,J=6.8Hz,1H),7.53(t,J=7.6Hz,1H),3.71(d,J=1 1.2Hz,2H),3.58–3.42(m,6H),3.27–3.08(m,3H),2.65(s,3H),2.47–2.34(m,2H),2.12–1.92(m,2H).

[0986] Example 164: N-(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)picolinamide

[0987]

[0988] To a solution of the compound of Example 163 (40 mg, 0.12 mmol, 1.0 equiv), picolinic acid (16 mg, 0.13 mmol, 1.1 equiv) and DIPEA (47 mg, 0.36 mmol, 3.0 equiv) in DCM (3 mL) was added EDCI (25 mg, 0.13 mmol, 1.1 equiv) and HOBt (18 mg, 0.13 mmol, 1.1 equiv) at room temperature under N2 atmosphere, and the mixture was stirred overnight. The mixture was diluted with water (40 mL), extracted with EtOAc (20 mL×3), and the combined organic layers were washed with water (15 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound (10 mg, 17%) as a white solid. LCMS: [M+H] + 438.2.

[0989] 1 H NMR (400MHz, CD3OD) δ8.62(d,J=4.0Hz,1H),8.08(d,J=7.6Hz,1H),8.03(d,J=7.6 Hz,1H),7.98–7.92(m,1H),7.65(d,J=7.2Hz,1H),7.57–7.51(m,1H),7.38(t,J=7. 6Hz,1H),3.75(s,2H),3.58(t,J=6.4Hz,2H),3.10–3.00(m,2H),2.96–2.85(m,1H) ,2.69(t,J=6.4Hz,2H),2.57(s,3H),2.29(m,2H),2.11(m,2H),1.72–1.60(m,2H).

[0990] Example 165: 2-(((1-(3-aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one dihydrochloride

[0991]

[0992] Step 1: tert-Butyl (3-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)propyl)carbamate

[0993] The title compound was prepared from the compound of Example 13 and tert-butyl (3-oxopropyl)carbamate according to the method described for Example 138. LCMS: [M+H] + 447.2.

[0994] Step 2: 2-(((1-(3-aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one dihydrochloride

[0995] The title compound was prepared from tert-butyl (3-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)propyl)carbamate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 347.2.

[0996] 1 H NMR (400MHz, CD3OD) δ8.01(d,J=7.6Hz,1H),7.63(d,J=7.2Hz,1H),7.36(t,J=8.0Hz,1H),3.73(s, 2H),2.97–2.69(m,5H),2.56(s,3H),2.39(t,J=8.0Hz,2H),2.12–1.99(m,4H),1.76–1.52(m,4H).

[0997] Example 166: 2-(((1-glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one hydrochloride

[0998]

[0999] Step 1: tert-Butyl (2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)carbamate

[1000] To a solution of 2-((tert-butoxycarbonyl)amino)acetic acid (36 mg, 0.20 mmol, 1.1 equiv) and DIPEA (72 mg, 0.55 mmol, 3.0 equiv) in NMP (5 mL) was added HATU (105 mg, 0.28 mmol, 1.5 equiv) at room temperature under N2 atmosphere, and the mixture was stirred for 1 hour, followed by the addition of Example 13 (60 mg, 0.19 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight, then diluted with water (10 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, 3:1, v / v) to give the title compound (50 mg, 61%) as a yellow solid. LCMS: [M+H] + 447.2.

[1001] Step 2: 2-(((1-glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one hydrochloride

[1002] The title compound was prepared from tert-butyl (2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)carbamate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 347.2.

[1003] 1 H NMR (400MHz, CD3OD) δ8.11(d,J=8.0Hz,1H),7.77(s,1H),7.56–7.48(m,1H),4.29(m,1H),4.04–3.85(m,3H),3.71(m, 1H),3.36–3.34(m,1H),3.26–3.16(m,2H),3.02(t,J=12.1Hz,1H),2.65(s,3H),2.18–2.16(m,2H),1.69–1.46(m,2H).

[1004] Example 167: 2-(((1-(3-aminopropionyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one hydrochloride

[1005]

[1006] The title compound was prepared from the compound of Example 13 and 3-((tert-butoxycarbonyl)amino)propanoic acid according to the method described for Example 166. LCMS: [M+H] + 361.2.

[1007] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=7.6Hz,1H),7.66(d,J=7.2Hz,1H),7.39(t,J=7.6Hz,1H),4.34–4.26(m,1H),3.87–3.75( m,3H),3.22–3.10(m,4H),2.97–2.88(m,1H),2.74(t,J=12.4Hz,2H),2.59(s,3H),2.16–2.05(m,2H),1.61–1.44(m,2H).

[1008] Example 168: 2-(((1-(3-(Dimethylamino)propionyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[1009]

[1010] The title compound was prepared from the compound of Example 167 and formaldehyde according to the method described for Example 14. LCMS: [M+H] + 389.2.

[1011] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=7.6Hz,1H),7.64(d,J=7.2Hz,1H),7.40(t,J=7.6Hz,1H),4.26(m,1H),3.82(s,2H), 3.77(m,1H),3.22–3.05(m,2H),3.04–2.90(m,5H),2.88(s,6H),2.59(s,3H),2.14–1.95(m,2H),1.69–1.47(m,2H).

[1012] Example 169: (R)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine trihydrochloride

[1013]

[1014] Step 1: (R)-tert-Butyl(5-guanidino-1-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-1-oxopentan-2-yl)carbamate

[1015] To a solution of the compound of Example 13 (100 mg, 0.33 mmol, 1.0 equiv), (R)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanoic acid (93 mg, 0.33 mmol, 1.0 equiv) and DIPEA (213 mg, 1.65 mmol, 5.0 equiv) in DMF (4 mL) was added BOP (146 mg, 0.36 mmol, 1.1 equiv) at room temperature under N2 atmosphere, and the mixture was stirred for 5 hours. The mixture was diluted with water (40 mL), extracted with EtOAc (30 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound (85 mg, 52%) as a white solid. LCMS: [M+H] + 546.3.

[1016] Step 2: (R)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentan-2-yl)guanidine trihydrochloride The title compound was prepared from (R)-tert-butyl(5-guanidino-1-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-1-oxopentan-2-yl)carbamate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 446.3.

[1017] 1 H NMR (400MHz, CD3OD) δ8.12(d,J=8.0Hz,1H),7.81–7.76(m,1H),7.58–7.50(m,1H),4.55–4.45(m,1H),4.42–4.17(m,1H),3. 92(m,1H),3.34–3.18(m,6H),3.23–2.96(m,1H),2.66(d,J=4.0Hz,3H),2.25–2.11(m,2H),1.89(m,2H),1.77–1.46(m,4H).

[1018] Example 170: (S)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine trihydrochloride

[1019]

[1020] The title compound was prepared from the compound of Example 13 and (S)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanoic acid according to the method described for Example 169. LCMS: [M+H] + 446.3.

[1021] 1 H NMR (400MHz, CD3OD) δ8.12–8.04(m,1H),7.78–7.70(m,1H),7.54–7.43(m,1H),4.55–4.4 5(m,1H),4.42–4.17(m,1H),3.92(m,1H),3.34–3.18(m,6H),3.23–2.96(m,1H),2.66(br s,3H),2.26–2.07(m,2H),1.85(m,2H),1.75–1.45(m,4H).

[1022] Example 171: 2-(((1-(L-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one dihydrochloride

[1023]

[1024] The title compound was prepared from the compound of Example 13 and (S)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid according to the method described for Example 166. LCMS: [M+H] + 418.2.

[1025] 1 H NMR(400MHz,DMSO-d6)δ12.5(br s,1H),8.30(s,3H),8.17(s,3H),7.93(d,J=7.6Hz,1H),7.66(d,J=7.2Hz,1 H),7.38(t,J=7.6Hz,1H),4.41–4.27(m,1H)),4.27–4.05(m,1H),3.91–3.7 8(m,1H),3.76(s,2H),3.25–3.11(m,2H),3.03–2.77(m,1H),2.80–2.66(m, 2H),2.51(s,3H),2.13–1.99(m,2H),1.73–1.61(m,2H),1.57–1.27(m,6H).

[1026] Example 172: 2-(((1-(D-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one dihydrochloride

[1027]

[1028] The title compound was prepared from the compound of Example 13 and (R)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid according to the method described for Example 166. LCMS: [M+H] + 418.2.

[1029] 1 H NMR (400MHz, CD3OD) δ8.14(d,J=7.6Hz,1H),7.83(dd,J=3.2,1.2Hz,1H),7.66–7.53(m,1H),4.57–4.11(m, 3H),4.03–3.82(m,1H),3.35(s,2H),3.22–2.90(m,3H),2.70(s,3H),2.32–2.09(m,2H),1.96–1.42(m,9H);

[1030] 1 H NMR(400MHz,DMSO-d6)δ12.5(br s,1H),8.30(s,3H),8.17(s,3H),7.93(d,J=7.6Hz,1H),7.66(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),4.41–4.27(m,1H)),4.27–4.05(m,1H),3.91–3.78(1H, covered by water peak),3.76(2H, covered by water peak),3.25–3.11(m,2H),3.03–2.77(m,1H),2.80–2.66(m,2H),2.51(s,3H),2.13–1.99(m,2H),1.73–1.61(m,2H),1.57–1.27(m,6H).

[1031] Example 173: 8-Methyl-2-(((1-(3-(pyridin-2-yl)propionyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1032]

[1033] To a solution of the compound of Example 13 (50 mg, 0.15 mmol, 1.0 equiv), 3-(pyridin-2-yl)propanoic acid (23 mg, 0.15 mmol, 1.0 equiv) and EtN (46 mg, 0.46 mmol, 3.0 equiv) in DMF (3 mL) was added PyBOP (96 mg, 0.18 mmol, 1.2 equiv) at room temperature under N2 atmosphere, and the mixture was stirred for 4 hours. The mixture was diluted with water (40 mL), extracted with EtOAc (30 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound (16 mg, 25%) as a white solid. LCMS: [M+H] + 423.2.

[1034] 1 H NMR (400 MHz, CDCl3) δ 10.2 (br s,1H),8.52(d,J=4.8Hz,1H),8.12(d,J=8.0Hz,1H),7.71–7.63(m,1H),7.61( d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),7.30(d,J=8.0Hz,1H),7.18(dd,J=7.6 ,5.2Hz,1H),4.33(m,1H),3.85(m,1H),3.79(s,2H),3.20–3.13(m,2H),3.07( m,1H),2.96–2.77(m,4H),2.58(s,3H),2.03–1.95(m,2H),1.56–1.43(m,2H).

[1035] Example 174: 8-Methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1036]

[1037] To a solution of Example 13 (100 mg, 0.31 mmol, 1.0 equiv) and Et3N (94 mg, 0.93 mmol, 3.0 equiv) in DCM (5 mL) was added MsCl (42 mg, 0.37 mmol, 1.2 equiv) at room temperature under N2 atmosphere, and the mixture was stirred for 2 hours. The mixture was diluted with water (20 mL), extracted with EtOAc (30 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 15:1, v / v) to give the title compound (12 mg, 11%) as a white solid. LCMS: [M+H]+ 368.2.

[1038] 1 H NMR (400MHz, CDCl3) δ8.14(d,J=7.6Hz,1H),7.65(d,J=7.6Hz,1H),7.42(t,J=8.0Hz,1H),3.98(s,2H),3. 65(d,J=11.8Hz,2H),2.99–2.79(m,3H),2.76(s,3H),2.65(s,3H),2.18–2.06(m,2H),1.80–1.70(m,2H).

[1039] Example 175: 8-Methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1040]

[1041] To a solution of Example 13 (50 mg, 0.15 mmol, 1.0 equiv) and EtN (47 mg, 0.47 mmol, 3.0 equiv) in DMF (3 mL) was added pyridine-2-sulfonyl chloride hydrochloride (41 mg, 0.23 mmol, 1.5 equiv) at room temperature under N2 atmosphere, and the mixture was stirred for 3 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 15:1, v / v) to give the title compound (12 mg, 18%) as a white solid. LCMS: [M+H] + 431.1.

[1042] 1 H NMR (400MHz, CD3OD) δ8.69(d,J=4.8Hz,1H),8.08–7.99(m,2H),7.94(d,J=7.9Hz,1H),7.67–7.59(m,2H),7.3 8(t,J=7.6Hz,1H),3.79–3.69(m,4H),2.98–2.83(m,3H),2.53(s,3H),2.12–2.03(m,2H),1.68–1.55(m,2H).

[1043] Example 176: 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1044]

[1045] Step 1: tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1046] To a solution of Int-B2 (44 mg, 0.17 mmol, 1.0 equiv) and Int-A37 (50 mg, 0.17 mmol, 1.0 equiv) in THF (4 mL) was added 1 M NaOH (2 mL), and the mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with water (5 mL) and 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, 10:1, v / v) to give the title compound (25 mg, 31%) as a white solid. LCMS: [M+H] + 477.2.

[1047] Step 2: 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1048] The title compound was prepared from tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 377.2.

[1049] 1 H NMR(400MHz,DMSO-d6)δ8.90(br s,1H),8.77(br s,1H),6.53(s,1H),6.51(d,J=14.0Hz,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).

[1050] Example 177: 7-(Cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1051]

[1052] Step 1: tert-Butyl 4-(((7-(cyclobutylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1053] The title compound was prepared from Int-A38 and Int-B2 according to the procedure described for Example 176, Step 1. LCMS: [M+H] + 463.2.

[1054] Step 2: 7-(Cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1055] The title compound was prepared from tert-butyl 4-(((7-(cyclobutylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 363.2.

[1056] 1 H NMR(400MHz,DMSO-d6)δ9.01(br s,1H),8.88(br s,1H),6.52(s,1H),6.47(d,J=13.6Hz,1H),3.96–3.88(m,1H),3.77(s,2H),3.24–3.15(m,3H), 2.93-2.85(m,2H),2.38-2.33(m,2H),2.19-2.14(m,2H),1.92-1.85(m,2H),1.78-1.61(m,4H).

[1057] Table 8 lists the analytical data of the Examples.

[1058] Table 8

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070] Table 9 provides additional exemplary compounds of the invention prepared by the methods described herein.

[1071] Table 9

[1072]

[1073]

[1074]

[1075]

[1076]

[1077] Int-A39: 2-(Chloromethyl)-7-isobutylquinazolin-4(3H)-one

[1078]

[1079] Step 1: 2-Amino-4-(2-methylprop-1-en-1-yl)benzoic acid

[1080] Under N2 atmosphere, to a solution of 2-amino-4-bromo-benzoic acid (500 mg, 2.31 mmol, 1.0 eq) in 1,4-dioxane / water (4:1, 20 mL) were added 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (548 mg, 3.01 mmol, 1.3 eq), Pd(dppf)Cl2 (169 mg, 0.23 mmol, 0.1 eq) and potassium carbonate (640 mg, 4.63 mmol, 2.0 eq), and the mixture was heated at 100 ° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with water (40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (400 mg, 90%) as a brown oil. LCMS: [M+H] + 192.2.

[1081] Step 2: Methyl 2-amino-4-(2-methylprop-1-en-1-yl)benzoate

[1082] Prepared from 2-amino-4-(2-methylprop-1-en-1-yl)benzoic acid according to the method described for Int-A20 step 3. LCMS: [M+H] + 206.2.

[1083] Step 3: Methyl 2-amino-4-isobutylbenzoate

[1084] A solution of methyl 2-amino-4-(2-methylprop-1-enyl)benzoate (200 mg, 0.97 mmol) and Pt / C (10% wet, 20 mg) in EtOAc (20 mL) was stirred overnight at room temperature under a H atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (200 mg, 99%) as a colorless oil. LCMS: [M+H] + 208.2.

[1085] Step 4: 2-(Chloromethyl)-7-isobutylquinazolin-4(3H)-one

[1086] Prepared according to the method described for Int-A16 from methyl 2-amino-4-isobutylbenzoate and chloroacetonitrile. LCMS: [M+H] + 251.1.

[1087] Int-A40: 5-Bromo-2-(chloromethyl)-7-fluoroquinazolin-4(3H)-one

[1088]

[1089] Prepared from 3-bromo-5-fluoroaniline according to the method described for Int-A20. LCMS: [M+H] + 290.9.

[1090] 1 HNMR (400MHz, DMSO-d6) δ7.76 (dd, J = 8.8, 2.8 Hz, 1H), 7.51 (dd, J = 9.2, 2.4 Hz, 1H), 4.52 (s, 2H).

[1091] Int-A41: 5-Chloro-2-(chloromethyl)-7-(cyclopentylamino)quinazolin-4(3H)-one

[1092]

[1093] Step 1: Methyl 4-bromo-2-chloro-6-fluorobenzoate

[1094] Prepared according to the procedure described for Int-A20, Step 3 from 4-bromo-2-chloro-6-fluorobenzoic acid.

[1095] 1 HNMR (400MHz, CDCl3) δ7.41 (s, 1H), 7.26-7.24 (m, 1H), 3.96 (s, 3H).

[1096] Step 2: Methyl 2-chloro-4-(cyclopentylamino)-6-fluorobenzoate

[1097] Under N2 atmosphere, to a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (2.0 g, 7.48 mmol, 1.0 equivalent) and cyclopentaneamine (0.76 g, 8.97 mmol, 1.2 equivalent) in toluene (5 mL) was added Cs2CO3 (4.87 g, 15.0 mmol, 2.0 equivalent), BINAP (931 mg, 1.5 mmol, 0.2 equivalent) and Pd(OAc)2 (168 mg, 0.75 mmol, 0.1 equivalent), and the mixture was heated at reflux for 30 minutes. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 10: 1, v / v) to give the title compound (2.0 g, 98%) as a colorless oil. LCMS: [M+H] + 272.1.

[1098] Step 3: Methyl 2-chloro-4-(cyclopentylamino)-6-((2,4-dimethoxybenzyl)amino)benzoate

[1099] To a solution of methyl 2-chloro-4-(cyclopentylamino)-6-fluorobenzoate (2.0 g, 7.36 mmol, 1.0 equivalent) and (2,4-dimethoxyphenyl)methylamine (3.69 g, 22.1 mmol, 3.0 equivalents) in NMP (30 mL) was added KCO (2.03 g, 14.7 mmol, 2.0 equivalents) under an N atmosphere, and the mixture was heated at 100 ° C overnight. After cooling to room temperature, the mixture was diluted with water (90 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 8: 1 to 5: 1, v / v) to give the title compound (1.6 g, 56%) as a white solid. LCMS: [M + H] + 419.1.

[1100] Step 4: Methyl 2-amino-6-chloro-4-(cyclopentylamino)benzoate

[1101] To a solution of methyl 2-chloro-4-(cyclopentylamino)-6-((2,4-dimethoxybenzyl)amino)benzoate (1.6 g, 3.82 mmol, 1.0 equivalent) in DCM (10 mL) was added TFA (5 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous Na2CO3 solution (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, 5:1, v / v) to give the title compound (610 mg, 59%) as a yellow solid. LCMS: [M+H] + 269.1.

[1102] Step 5: 5-chloro-2-(chloromethyl)-7-(cyclopentylamino)quinazolin-4(3H)-one

[1103] Prepared according to the method described for Int-A16 from methyl 2-amino-6-chloro-4-(cyclopentylamino)benzoate and chloroacetonitrile. LCMS: [M+H] + 312.1.

[1104] Int-A42: 2-(Chloromethyl)-7-(cyclopentylamino)-5-methoxyquinazolin-4(3H)-one

[1105]

[1106] Step 1: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

[1107] Prepared from methyl 4-bromo-2,6-difluorobenzoate according to the procedure described for Int-A41, step 3. LCMS: [M+H] + 398.0.

[1108] Step 2: 4-Bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoic acid

[1109] To a solution of methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (3.98 g, 9.99 mmol, 1.0 equiv) in methanol (20 mL) and NMP (20 mL) was added NaH (60% w / w suspension in oil, 2.0 g, 50.0 mmol, 5.0 equiv) and the mixture was heated at 120 °C overnight. After cooling to room temperature, the pH of the mixture was adjusted to 4 with 6 M HCl and the resulting precipitate was collected by filtration to give the title compound as a white solid (1.4 g, 35%). LCMS: [M+H] + 396.0.

[1110] Step 3: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate

[1111] Prepared from 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoic acid according to the method described for Int-A20, step 3. LCMS: [M+H] + 410.1.

[1112] Step 4: Methyl 4-(cyclopentylamino)-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate

[1113] Under N2 atmosphere, to a solution of methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate (820 mg, 2.0 mmol, 1.0 equiv) and cyclopentylamine (255 mg, 3.0 mmol, 1.5 equiv) in toluene (15 mL) were added Cs2CO3 (1.95 g, 6.0 mmol, 3.0 equiv), Xantphos (231 mg, 0.4 mmol, 0.2 equiv) and Pd(OAc)2 (45 mg, 0.20 mmol, 0.1 equiv), and the mixture was heated at reflux for 8 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 7:1, v / v) to give the title compound (680 mg, 82%) as a white solid. LCMS: [M+H] + 415.2.

[1114] Step 5: 2-Amino-4-(cyclopentylamino)-6-methoxy-benzoic acid methyl ester

[1115] Prepared from methyl 4-(cyclopentylamino)-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate according to the method described for Int-A41, step 4. LCMS: [M+H] + 265.2.

[1116] Step 6: 2-(Chloromethyl)-7-(cyclopentylamino)-5-methoxyquinazolin-4(3H)-one

[1117] Prepared according to the method described for Int-A16 from 2-amino-4-(cyclopentylamino)-6-methoxy-benzoic acid methyl ester and chloroacetonitrile. LCMS: [M+H] + 308.1.

[1118] Int-A43: 2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

[1119]

[1120] Step 1: Methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate

[1121] Prepared from methyl 4-bromo-2,6-difluorobenzoate according to the method described for Int39 step 2, step 3 and step 4. LCMS: [M+H] + 253.1.

[1122] Step 2: 2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

[1123] Prepared according to the method described for Int-A16 from methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate and chloroacetonitrile. LCMS: [M+H] + 296.1.

[1124] Int-A44: 7-Chloro-2-(chloromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one

[1125]

[1126] A solution of 2-amino-6-chloropyridine-3-carboxamide (500 mg, 2.91 mmol, 1.0 equiv) in 2-chloro-1,1,1-trimethoxy-ethane (5 mL) was heated at 120 ° C. for 3 hours under N2 atmosphere. The mixture was then filtered and the filter cake was washed with EtOAc / petroleum ether (1:3, 20 mL) and then dried under reduced pressure to give the title compound as a brown solid (450 mg, ~50% purity, 33%), which was used without further purification. LCMS: [M+H] + 230.0.

[1127] Int-A45: 7-Bromo-2-(chloromethyl)-6-methoxyquinazolin-4(3H)-one

[1128]

[1129] Step 1: Ethyl 2-amino-4-bromo-5-methoxybenzoate

[1130] Prepared from 4-bromo-5-fluoro-2-nitrobenzoic acid according to the procedure described in WO2014128655.

[1131] Step 2: 7-Bromo-2-(chloromethyl)-6-methoxyquinazolin-4(3H)-one

[1132] Prepared from ethyl 2-amino-4-bromo-5-methoxybenzoate and chloroacetonitrile according to the method described for Int-A16. LCMS: [M+H] + 303.0.

[1133] Int-A46: 7-Bromo-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one

[1134]

[1135] Step 1: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

[1136] Prepared from methyl 4-bromo-2,6-difluorobenzoate and (2,4-dimethoxyphenyl)methanamine according to the method described for Int-A41, step 3. LCMS: [M+H] + 398.0.

[1137] Step 2: 7-Bromo-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one

[1138] A mixture of 4-bromo-2-[(2,4-dimethoxyphenyl)methylamino]-6-fluoro-benzoic acid methyl ester (100 g, 251 mmol, 1.0 equiv), 2-chloroacetonitrile (47.7 mL, 753 mmol, 3.0 equiv) and 4M HCl in dioxane (300 mL) was heated at 100 ° C overnight. After cooling to room temperature, the mixture was filtered and the collected solid was purified by column chromatography (DCM:MeOH, 50:1 to 10:1, v / v) to give the title compound (84 g, >100%) as a light yellow solid, which was used in the subsequent step without further purification. LCMS: [M+H] + 290.9.

[1139] Int-A47: 2-(Chloromethyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one

[1140]

[1141] Step 1: Methyl 6-amino-2,3,4-trifluorobenzoate

[1142] Prepared from 3,4,5-trifluoroaniline according to the method described for Int-A20 step 1, step 2 and step 3. LCMS: [M+H] + 206.0.

[1143] Step 2: Methyl 6-amino-4-(cyclopentylamino)-2,3-difluorobenzoate

[1144] A mixture of 6-amino-2,3,4-trifluoro-benzoic acid methyl ester (2.05 g, 9.99 mmol, 1.0 equiv), cyclopentylamine (1.18 mL, 12.0 mmol) and K2CO3 (1.38 g, 9.99 mmol, 1.0 equiv) in DMSO (20 mL) was heated at 55 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with brine (20 mL × 3), and the organic layer was concentrated under reduced pressure. The residue was purified by C18 reverse phase column (Biotage, 40% to 80% ACN in water) to give the title compound (1.1 g, 41%) as a light green solid. LCMS: [M+H] + 271.1.

[1145] Step 3: 2-(Chloromethyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one

[1146] Prepared according to the method described for Int-A16 from methyl 6-amino-4-(cyclopentylamino)-2,3-difluorobenzoate and chloroacetonitrile. LCMS: [M+H] + 314.1.

[1147] Int-A48: 7-Bromo-2-(chloromethyl)-6-fluoroquinazolin-4(3H)-one

[1148]

[1149] Step 1: Methyl 4-bromo-5-fluoro-2-nitrobenzoate

[1150] Prepared according to the procedure described for Int-A20, step 3 from 4-bromo-5-fluoro-2-nitrobenzoic acid.

[1151] 1 HNMR (400MHz, CDCl3) δ8.20 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 3.94 (s, 3H).

[1152] Step 2: Methyl 2-amino-4-bromo-5-fluorobenzoate

[1153] To a solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (2.0 g, 7.19 mmol, 1.0 equivalent) in ethanol (20 mL) and water (10 mL) was added NH4Cl (1.15 g, 21.6 mmol, 3.0 equivalents) and zinc (1.41 g, 21.6 mmol, 3.0 equivalents), and the mixture was heated at 40 ° C for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue 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 (petroleum ether: EtOAc, 20: 1, v / v) to give the title compound (390 mg, 22%) as a white solid. LCMS: [M+H] + 248.0.

[1154] Step 3: 7-Bromo-2-(chloromethyl)-6-fluoroquinazolin-4(3H)-one

[1155] Prepared according to the method described for Int-A16 from methyl 2-amino-4-bromo-5-fluorobenzoate and chloroacetonitrile. LCMS: [M+H] + 291.0.

[1156] Int-A49: 2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

[1157]

[1158] Step 1: Methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate

[1159] To a solution of methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (50 g, 126 mmol, 1.0 equiv; see Int-A42 step 1) in 1,4-dioxane (150 mL) and water (150 mL) was added NaOH (12.6 g, 314 mmol, 3.0 equiv), Pd2(dba)3 (2.3 g, 2.51 mmol, 0.01 equiv) and t-BuXphos (1.06 g, 2.51 mmol, 0.01 equiv), and the mixture was heated at 90 ° C under N2 atmosphere for 3 hours. After cooling to room temperature, the mixture was filtered, the pH of the filtrate was adjusted to 5 with 0.5 M HCl, and extracted with EtOAc (300 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, 5:1, v / v) to give the title compound (25 g, 48%) as a yellow solid. LCMS: [M+H] +336.1.

[1160] Step 2: Methyl 4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

[1161] To a solution of methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate (3.2 g, 8.11 mmol, 1.0 equiv) in DMF (20 mL) was added bromomethylcyclopropane (1.31 g, 9.73 mmol, 1.2 equiv) and K2CO3 (2.24 g, 16.2 mmol, 2.0 equiv), and the mixture was heated at 80 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 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, 10 / 1, v / v) to give the title compound (2.4 g, 76%) as a white solid. LCMS: [M+H] + 390.2.

[1162] Step 3: Methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate

[1163] To a solution of methyl 4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (1.6 g, 4.11 mmol, 1.0 equiv) in DCM (8.0 mL) was added TFA (4.0 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH, 20 / 1, v / v) to give the title compound (0.9 g, 91%) as a brown solid. LCMS: [M+H] + 240.1.

[1164] Step 4: 2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

[1165] Prepared according to the method described for Int-A16 from methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate and chloroacetonitrile. LCMS: [M+H] + 283.1.

[1166] Alternative Synthesis of Int-A49: 2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

[1167]

[1168] Step 1: Methyl 4-(cyclopropylmethoxy)-2,6-difluorobenzoate

[1169] A mixture of methyl 2,6-difluoro-4-hydroxybenzoate (180 g, 957 mmol), (bromomethyl)cyclopropane (102 mL, 1.05 mol), and K2CO3 (330 g, 2.39 mol) in DMSO (1 L), whose preparation is described in Example 333, Step 4, was heated at 80°C overnight. The mixture was diluted with water (5 L) and extracted with EtOAc (1 L x 3). The combined organic extracts were washed with water (800 mL), brine (800 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (214 g, 92%) as a brown oil. LCMS: [M+H] + 243.1.

[1170] Step 2: Methyl 4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

[1171] A mixture of methyl 4-(cyclopropylmethoxy)-2,6-difluorobenzoate (214 g, 881 mmol), (2,4-dimethoxyphenyl)methylamine (139 mL, 926 mmol) and K2CO3 (243 g, 1.76 mol) in NMP (1 L) was heated at 80 ° C overnight. The mixture was poured into water (5 L), the resulting precipitate was collected by filtration and washed with water (800 mL). The filter cake was dissolved in DCM (2.5 L) and washed with brine (800 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (343 g, 99%) as an off-white solid. LCMS: [M+Na] + 412.1.

[1172] Step 3: Methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate

[1173] To a solution of methyl 4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (1.6 g, 4.11 mmol, 1.0 equiv) in DCM (8.0 mL) was added TFA (4.0 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH, 20 / 1, v / v) to give the title compound (0.9 g, 91%) as a brown solid. LCMS: [M+H] + 240.1.

[1174] Step 4: 2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

[1175] Prepared according to the method described for Int-A16 from methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate and chloroacetonitrile. LCMS: [M+H] + 283.1.

[1176] Int-A50: 2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[1177]

[1178] Step 1: Methyl 2-amino-6-fluoro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate

[1179] Prepared from methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate and 4-(bromomethyl)tetrahydro-2H-pyran according to the procedure described for Int-A49 steps 2 and 3. LCMS: [M+H] + 284.1.

[1180] Step 2: 2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

[1181] Prepared according to the method described for Int-A16 from methyl 2-amino-6-fluoro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate and chloroacetonitrile. LCMS: [M+H] + 327.1.

[1182] Int-A51: 2-(Chloromethyl)-7-(cyclobutylmethoxy)-5-methylquinazolin-4(3H)-one

[1183]

[1184] Step 1: Methyl 4-bromo-2-fluoro-6-methylbenzoate

[1185] Prepared according to the procedure described for Int-A20, step 3 from 4-bromo-2-fluoro-6-methylbenzoic acid.

[1186] Step 2: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methylbenzoate

[1187] Prepared from methyl 4-bromo-2-fluoro-6-methylbenzoate and (2,4-dimethoxyphenyl)methanamine according to the method described for Int-A41, step 3. LCMS: [M+H] + 394.1.

[1188] Step 3: Methyl 2-amino-4-(cyclobutylmethoxy)-6-methylbenzoate

[1189] Prepared from methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methylbenzoate and (bromomethyl)cyclobutane according to the method described for Int-A49 step 1, step 2 and step 3. LCMS: [M+H] + 250.1.

[1190] Step 4: 2-(Chloromethyl)-7-(cyclobutylmethoxy)-5-methylquinazolin-4(3H)-one

[1191] Prepared according to the method described for Int-A16 from methyl 2-amino-4-(cyclobutylmethoxy)-6-methylbenzoate and chloroacetonitrile. LCMS: [M+H] + 293.1.

[1192] Int-A52: 2-(Chloromethyl)-5-fluoro-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

[1193]

[1194] Step 1: (Tetrahydrofuran-3-yl)methyl methanesulfonate

[1195] Prepared from (tetrahydrofuran-3-yl)methanol according to the method described for Int-B3, Step 1 and used directly in the next step.

[1196] Step 2: Methyl 2-amino-6-fluoro-4-((tetrahydrofuran-3-yl)methoxy)benzoate

[1197] Prepared from methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate and (tetrahydrofuran-3-yl)methyl methanesulfonate according to the method described for Int-A47 steps 2 and 3. LCMS: [M+H] + 270.1.

[1198] Step 3: 2-(Chloromethyl)-5-fluoro-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

[1199] Prepared according to the method described for Int-A16 from methyl 2-amino-6-fluoro-4-((tetrahydrofuran-3-yl)methoxy)benzoate and chloroacetonitrile. LCMS: [M+H] + 313.0.

[1200] Int-A53: 2-(Chloromethyl)-5-fluoro-7-hydroxyquinazolin-4(3H)-one

[1201]

[1202] Step 1: Methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate

[1203] To a solution of methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (50.0 g, 125 mmol) in 1,4-dioxane (150 mL) and water (150 mL) were added KOH (14.1 g, 251.1 mmol), Pd2(dba)3 (1.15 g, 1.26 mmol) and t-BuXphos (1.06 g, 2.51 mmol), and the mixture was heated at 90 ° C for 3 hours under N2 atmosphere. After cooling to room temperature, the mixture was extracted with EtOAc (300 mL). The organic layer was washed with brine (100 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 5:1, v / v) to give the title compound (29.0 g, 55%) as a yellow solid. LCMS: [M+H] + 336.0.

[1204] Step 2: 2-(Chloromethyl)-5-fluoro-7-hydroxyquinazolin-4(3H)-one

[1205] Prepared according to the method described for Int-A16 from methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate and chloroacetonitrile. LCMS: [M+H] + 229.0.

[1206] Int-B14: 4-(Acetylthio)cyclohexane-1-carboxylic acid ethyl ester

[1207]

[1208] Prepared from ethyl 4-hydroxycyclohexane-1-carboxylate according to the method described for Int-B3 steps 1 and 2, and obtained as a 2:1 mixture of cis and trans isomers.

[1209] 1 H NMR(400MHz, CDCl3)4.10-4.02(m,2H),3.70(m,0.67H),3.31(m,0.33H),2.51-2.44(m,1H),2.24 (s,2H),2.23(s,1H),2.19-2.17(m,2H),2.04–1.91(m,4H),1.66–1.46(m,2H),1.20–1.17(m,3H).

[1210] Int-B15: ethyl 2-(trans-4-(acetylthio)cyclohexyl)acetate

[1211]

[1212] Step 1: Ethyl 2-(cis-4-hydroxycyclohexyl)acetate

[1213] Prepared from ethyl 2-(4-hydroxyphenyl)acetate according to the procedure described in WO2006 / 044524.

[1214] Step 2: Ethyl 2-(trans-4-(acetylthio)cyclohexyl)acetate

[1215] Prepared from ethyl 2-(cis-4-hydroxycyclohexyl)acetate according to the procedure described for Int-B3 steps 1 and 2.

[1216] 1 H NMR (400MHz, CDCl3) δ4.06 (q, J = 7.2Hz, 2H), 3.26 (m, 1H), 2.29 (s, 3H), 2.18 (d, J = 6.8Hz, 2H), 1. 99-1.96(m,2H),1.83-1.79(m,3H),1.43-1.33(m,2H),1.18(t,J=7.2Hz,3H),1.13-1.03(m,2H).

[1217] Int-B16: S-((cis)-4-hydroxy-4-methylcyclohexyl)thioacetate

[1218]

[1219] Step 1: (trans)-4-hydroxy-4-methylcyclohexyl methanesulfonate

[1220] Prepared according to the method described for Int-B3, Step 1 from (cis)-1-methylcyclohexane-1,4-diol. 1 H NMR (400 MHz, DMSO-d6) δ 4.60–4.49 (m, 1H), 3.15 (s, 3H), 1.86–1.70 (m, 4H), 1.63–1.51 (m, 2H), 1.45–1.32 (m, 2H), 1.09 (s, 3H). No signal (OH) was observed.

[1221] Step 2: S-((cis)-4-hydroxy-4-methylcyclohexyl)thioacetate

[1222] Prepared according to the method described for Int-B3, Step 2 from (trans)-4-hydroxy-4-methylcyclohexyl methanesulfonate.1 H NMR (400 MHz, DMSO-d6) δ 3.60–3.50 (m, 1H), 2.29 (s, 3H), 2.02–1.89 (m, 2H), 1.49–1.37 (m, 6H), 1.08 (s, 3H). No (OH) signal was observed.

[1223] Int-C12: S-((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thioacetate

[1224]

[1225] Prepared from Int-A41 and KSAc according to the method described for Int-C1. LCMS: [M+H] + 336.1.

[1226] Example 202: 7-Isobutyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1227]

[1228] To a solution of Int-A39 (100 mg, 0.40 mmol, 1.0 equiv) and Int-B1 (64 mg, 0.40 mmol, 1.0 equiv) in THF (2 mL) was added 2M NaOH (0.8 mL), and the mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 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 give the title compound (45 mg, 34%) as a yellow solid. LCMS: [M+H] + 333.2.

[1229] 1 H NMR (400MHz, DMSO-d6) δ12.2(s,1H),7.99(d,J=8.0Hz,1H),7.39(s,1H),7.31(d,J=8.0Hz,1H),3.81(m,2H),3.6 6(s,2H),3.34-3.28(m,2H),3.06(m,1H),2.60(d,J=7.2Hz,2H),1.91(m,3H),1.45(m,2H),0.88(d,J=6.4Hz,6H).

[1230] Example 203: 7-(Cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1231]

[1232] Step 1: 5-Bromo-7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1233] Prepared from Int-A40 and Int-B1 according to the method described for Example 202. LCMS: [M+H] + 373.0.

[1234] Step 2: 7-Fluoro-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1235] To a solution of 5-bromo-7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one (373 mg, 1.0 mmol, 1.0 equiv) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (376 mg, 3.0 mmol, 3.0 equiv) in dioxane / water (10:1, 22 mL) was added KCO (276 mg, 2.0 mmol, 2.0 equiv) and PdCl(dppf) (82 mg, 0.1 mmol, 0.1 equiv) under N2 atmosphere, and the mixture was heated at 100°C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH, 100:1, v / v) to give the title compound (230 mg, 75%) as a pink solid. LCMS: [M+H] + 309.1.

[1236] Step 3: 7-(Cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1237] Prepared from 7-fluoro-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one and cyclopentylamine according to the method described for Example 126. LCMS: [M+H] + 374.2.

[1238] 1H NMR (400MHz, CD3OD) δ6.54(s,1H),6.49(s,1H),3.95-3.80(m,3H),3.63(s,2H),3.42(t,J=10.4Hz,2H),3.06-2.95( m,1H),2.69(s,3H),2.09-1.98(m,2H),1.95-1.89(m,2H),1.81-1.75(m,2H),1.72-1.63(m,2H),1.63-1.50(m,4H).

[1239] Example 204: cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

[1240]

[1241] Step 1: 4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid

[1242] Prepared from Int-A1 and Int-B14 according to the method described for Example 202. The coupling reaction proceeds with hydrolysis of the ester to directly afford the title compound. LCMS: [M+H] + 333.1.

[1243] Step 2: cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid and trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid

[1244] 4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the trans isomer as the first eluting isomer, LCMS: [M+H] + 333.1, and the cis isomer as the second eluting isomer, LCMS: [M+H] + 333.1.

[1245] Step 3: cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

[1246] Prepared from cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid and NH4Cl according to the procedure described for Example 77, Step 2. LCMS: [M+H] + 332.2.

[1247] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=8.0Hz,1H),7.66(d,J=7.2Hz,1H),7.39(t,J=8.0Hz,1H),3.72( s,2H),3.26-3.22(m,1H),2.58(s,3H),2.31-2.23(m,1H),1.95-1.76(m,6H),1.66-1.56(m,2H).

[1248] Example 205: trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

[1249]

[1250] Prepared from trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid and NH4Cl according to the procedure described for Example 77, Step 2. LCMS: [M+H] + 332.2.

[1251] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=7.6Hz,1H),7.66(d,J=6.8Hz,1H),7.38(t,J=7.6Hz,1H),3.75(s,2H),2. 74-2.81(m,1H),2.60(s,3H),2.25-2.14(m,3H),1.90-1.87(m,2H),1.53-1.43(m,2H),1.38-1.29(m,2H).

[1252] Example 206: 5-Chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1253]

[1254] Step 1: tert-Butyl 4-(((5-chloro-7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1255] Prepared from Int-A41 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 493.2.

[1256] Step 2: 5-Chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1257] Prepared from tert-butyl 4-(((5-chloro-7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 393.2.

[1258] 1 H NMR (400MHz, CD3OD) δ6.91(d,J=2.0Hz,1H),6.73(d,J=2.0Hz,1H),4.00-3.96(m,2H),3.90-3.84(m,1H),3.46-3.37(m, 2H),3.35-3.26(m,1H),3.16-3.10(m,2H),2.37-2.28(m,2H),2.12-2.04(m,2H),1.84-1.64(m,6H),1.62-1.53(m,2H).

[1259] Example 207: 7-(Cyclopentylamino)-5-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1260]

[1261] Prepared from Int-A42 and Int-B1 according to the method described for Example 202. LCMS: [M+H] + 390.1.

[1262] 1 H NMR (400MHz, DMSO-d6) δ11.3(s,1H),6.52(d,J=6.0Hz,1H),6.19(s,1H),6.12(s,1H),3.87-3.76(m,3H),3.73(s,3H),3.51 (s,2H),3.33-3.27(m,2H),3.10-2.97(m,1H),2.01-1.82(m,4H),1.76-1.63(m,2H),1.60-1.52(m,2H),1.52-1.36(m,4H).

[1263] Example 208: Methyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1264]

[1265] Step 1: tert-Butyl 4-(((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1266] Prepared from Int-A9 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 394.1.

[1267] Step 2: tert-Butyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1268] Prepared from tert-butyl 4-(((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate and cyclopentylamine according to the method described for Example 126. LCMS: [M+H] + 459.2.

[1269] Step 3: 7-(Cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1270] Prepared from tert-butyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 359.2.

[1271] Step 4: Methyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1272] To a solution of 7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (110 mg, 0.28 mmol, 1.0 equiv) in NMP (4 mL) was added KCO (85 mg, 0.61 mmol, 2.2 equiv) dropwise followed by methyl chloroformate (32 mg, 0.33 mmol, 1.2 equiv) and the mixture was heated at 40 ° C overnight. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (20 mL), dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1, v / v) to give the title compound (5 mg, 4%) as a yellow solid. LCMS: [M+H] + 417.2.

[1273] 1 H NMR (400MHz, CD3OD) δ7.85(d,J=8.8Hz,1H),6.80(dd,J=8.8,2.4Hz,1H),6.62(s,1H),4.00-3.90(m,2H),3.91-3.82(m,1H),3.68(s, 2H),3.66(s,3H),3.05-2.94(m,3H),2.11-1.93(m,4H),1.84-1.73(m,2H),1.73-1.64(m,2H),1.64-1.54(m,2H),1.52-1.39(m,2H).

[1274] Example 209: 2-((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

[1275]

[1276] Step 1: 2-(trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetic acid

[1277] Prepared from Int-A1 and Int-B15 according to the method described for Example 202. The coupling reaction proceeds with ester hydrolysis to directly afford the title compound. LCMS: [M+H] + 347.1.

[1278] Step 2: 2-((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

[1279] Prepared from 2-(trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetic acid and NH4Cl according to the method described for Example 77, Step 2. LCMS: [M+H] + 346.2.

[1280] 1 H NMR (400 MHz, DMSO-d6) δ 12.3 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.20 (br s, 1H), 6.89 (br s, 1H), 3.65 (s, 2H), 2.72-2.80 (m, 1H), 2.50 (3H, obscured by solvent peak), 2.00-2.09 (m, 2H), 1.89 (d, J = 7.6 Hz, 2H), 1.70-1.73 (m, 2H), 1.65-1.59 (m, 1H), 1.26-1.18 (m, 2H), 0.98-0.88 (m, 2H).

[1281] Example 210: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1282]

[1283] Step 1: cis-tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

[1284] Prepared from tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate according to document WO2011036576.

[1285] Step 2: cis-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[1286] Prepared from cis-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate according to the method described for Int B3, Step 1. LCMS: [M+H] + 298.1.

[1287] Step 3: trans-tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylate

[1288] To a solution of Int-C12 (100 mg, 0.30 mmol, 1.0 equiv) and cis-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (177 mg, 0.90 mmol, 3.0 equiv) in DMF (2 mL) was added 2M NaOH (0.6 mL) at room temperature under N2 atmosphere, and the mixture was heated at 100 ° C for 3 hours. The mixture was poured into water (5 mL), extracted with EtOAc (10 mL×3), and the combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:2, v / v) to give the title compound (30 mg, 20%) as a yellow solid. LCMS: [M+H] + 495.2.

[1289] Step 4: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1290] Prepared from tert-butyl trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 395.1.

[1291] 1 HNMR(400MHz,DMSO-d6)δ12.0(br s,1H),9.37(br s,1H),9.09(br s,1H),6.50-6.46(m,2H),4.96-4.84(m,1H),3.83-3.74(m,3H),3.53-3.34(m,2H),3.28-3.18(m,1 H),3.12-2.97(m,2H),2.34-2.22(m,1H),1.99-1.93(m,2H),1.85-1.77(m,1H),1.42-1.73(m,6H).

[1292] Example 211: 7-(Cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one and 7-(Cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1293]

[1294] Example 210 was further purified by chiral preparative HPLC (Chiralpak IE-3, 3 μm, 0.46 x 5 cm column, eluting with a 50:50 MTBE (0.1% DEA):IPA gradient at a flow rate of 1.0 mL / min) to afford the title compounds with retention times of 1.99 minutes (211a) and 2.72 minutes (211b).

[1295] Example 211a: LCMS: [M+H] + 395.2.

[1296] 1 H NMR (400MHz, CD3OD) δ6.48-6.43(m,2H),4.84-4.80(m,1H),3.86-3.70(m,3H),3.45-3. 30(m,2H),3.15-2.96(m,3H),2.40-2.28(m,1H),2.07-2.02(m,2H),1.80-1.52(m,7H).

[1297] Example 211b: LCMS: [M+H] + 395.2.

[1298] 1 H NMR (400MHz, CD3OD) δ6.48-6.42(m,2H),4.84-4.80(m,1H),3.86-3.72(m,3H),3.31-3. 20(m,2H),2.96-2.74(m,3H),2.20-2.17(m,1H),2.07-2.00(m,2H),1.80-1.52(m,7H).

[1299] Example 212: 7-(Cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1300]

[1301] Step 1: trans-tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

[1302] Prepared from tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate according to document WO2011036576.

[1303] Step 2: trans-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[1304] Prepared from tert-butyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate according to the method described for Int B3, Step 1. LCMS: [M+H] + 298.1.

[1305] Step 3: cis-tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylate

[1306] Prepared from Int-C12 and trans-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate according to the procedure described for Example 210, Step 3. LCMS: [M+H] + 495.2.

[1307] Step 4: 7-(Cyclopentylamino)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1308] Prepared from cis-tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 395.2.

[1309] 1 H NMR(400MHz,DMSO-d6)δ11.9(br s,1H),9.28(br s,1H),8.67(br s,1H),7.00(br s,1H),6.48-6.42(m,2H),5.09(d,J=44.8Hz,1H),3.84-3.65(m,3H),3.57(m,1H),3.43-3.16(m ,3H),2.96(m,1H),2.09-1.82(m,4H),1.72-1.64(m,2H),1.63-1.52(m,2H),1.52-1.41(m,2H).

[1310] Example 213: 7-(Cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one and

[1311] 7-(Cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1312]

[1313] Example 212 was further purified by chiral preparative HPLC (Chiralpak IG-3, 3 μm, 0.46×10 cm column, eluting with a 70:30 MTBE (0.1% DEA):EtOH gradient at a flow rate of 1.0 mL / min) to afford the title compound with retention times of 3.79 minutes ( 213a ) and 4.87 minutes ( 213b ).

[1314] Example 213a: LCMS: [M+H] + 395.2.

[1315] 1 H NMR(400MHz,DMSO-d6)δ11.66(br s,1H),6.84-6.83(m,1H),6.43-6.36(m,2H),4.69-4.57(m,1H),3.81-3.77(m,1H),3.60-3.51(m,2H),3.37- 3.02(m,2H),2.87-2.83(m,1H),2.70-2.51(m,2H),2.50-2.43(m,1H),1.97-1.94(m,2H),1.65-1.48(m,8H).

[1316] Example 213b: LCMS: [M+H] + 395.2.

[1317] 1 H NMR(400MHz,DMSO-d6)δ11.66(br s,1H),6.84-6.83(m,1H),6.43-6.36(m,2H),4.69-4.57(m,1H),3.81-3.77(m,1H),3.60-3.51(m,2H),3.37- 3.02(m,2H),2.87-2.83(m,1H),2.70-2.51(m,2H),2.50-2.43(m,1H),1.97-1.94(m,2H),1.65-1.48(m,8H).

[1318] Example 214: 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1319]

[1320] Step 1: tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1321] Prepared from Int-A43 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 477.1.

[1322] Step 2: 7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1323] Prepared from tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 377.1.

[1324] Step 3: 7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

[1325] To a solution of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (100 mg, 0.24 mmol, 1.0 equiv) and EtN (75 mg, 0.72 mmol, 3.0 equiv) in DMF (3 mL) was added 2-hydroxyacetic acid (37 mg, 0.48 mmol, 2.0 equiv), EDCI (98 mg, 0.51 mmol, 2.1 equiv) and HOBt (68 mg, 0.51 mmol, 2.1 equiv), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 10:1, v / v) to give the title compound (35 mg, 33%) as a white solid. LCMS: [M+H] + 435.2.

[1326] 1H NMR (400MHz, DMSO-d6) δ11.7(s,1H),6.82(d,J=6.4Hz,1H),6.41(d,J=14.0Hz,1H),6.36(s,1H),4.47(t,J=5.6Hz,1H),4.11-4.03(m,3H),3.78(m,1 H),3.62-3.58(m,1H),3.56(s,2H),3.05-3.03(m,2H),2.90-2.80(m,1H), 2.02-1.86(m,4H),1.67-1.65(m,2H),1.57-1.56(m,2H)1.50-1.29(m,4H).

[1327] Example 215: 2-((Cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

[1328]

[1329] Prepared from Int-A43 and cyclohexanethiol according to the method described for Example 202. LCMS: [M+H] + 376.1.

[1330] 1 H NMR (400MHz, DMSO-d6) δ11.6(s,1H),6.81(d,J=6.8Hz,1H),6.41(dd,J=13.6,2.4Hz,1H),6.35(d,J=2.4Hz,1H),3.83-3 .75(m,1H),3.51(s,2H),2.87-2.74(m,1H),2.02-1.87(m,4H),1.75-1.60(m,4H),1.60-1.39(m,5H),1.30-1.15(m,5H).

[1331] Example 216: cis-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid and

[1332] Example 217: trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid

[1333]

[1334] Step 1: 4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid

[1335] Prepared from Int-A43 and Int-B14 according to the method described for Example 202. The coupling reaction proceeds with ester hydrolysis to directly afford the title compound. LCMS: [M+H] + 420.1.

[1336] Step 2: cis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid and trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid

[1337] 4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at 20 mL / min) to give the title compound.

[1338] Example 216: LCMS: [M+H] + 420.1.

[1339] 1 H NMR(400MHz,DMSO-d6)δ12.0(br s,1H),6.90(br s,1H),6.43(d,J=13.6Hz,1H),6.37(s,1H),3.82-3.76(m,1H),3.52(s,2H),3.09(m,1H),2.36-2.33( m,1H),1.99-1.91(m,2H),1.79-1.76(m,4H),1.67-1.66(m,2H),1.59-1.49(m,6H),1.48-1.43(m,2H).

[1340] Example 217: LCMS: [M+H] + 420.1.

[1341] 1H NMR(400MHz,DMSO-d6)δ12.0(br s,1H),7.07(br s,1H),6.45(dd,J=13.6,2.0Hz,1H),6.39(d,J=1.6Hz,1H),3.96(s,1H),3.82-3.76(m,1H),3.59(s,2H),2.79-2.73(m, 1H),2.23-2.22(m,1H),2.03-1.89(m,6H),1.70-1.66(m,2H),1.59-1.50(m,2H),1.48-1.42(m,2H),1.38-1.20(m,4H).

[1342] Example 218: trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

[1343]

[1344] Prepared from trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid and NH4Cl according to the procedure described for Example 77, Step 2. LCMS: [M+H] + 419.1.

[1345] 1 H NMR(400MHz,DMSO-d6)δ11.6(br s,1H),7.17(s,1H),6.83(d,J=6.4Hz,1H),6.66(s,1H),6.41(d,J=14.0Hz,1H), 6.36(s,1H),3.81-3.76(m,1H),3.53(s,2H),3.17(d,J=5.2Hz,1H),2.75-2.68( m,1H),2.08-2.02(m,2H),1.97-1.91(m,2H),1.78-1.75(m,2H),1.70-1.63(m,2 H),1.61-1.64(m,2H),1.49-1.43(m,2H),1.39-1.29(m,2H),1.23-1.14(m,2H).

[1346] Example 219: 7-(Cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1347]

[1348] To a solution of 7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (200 mg, 0.41 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) and water (2 mL) under N2 atmosphere were added t-BuXPhos (70 mg, 0.16 mmol, 0.4 equiv), Pd2(dba)3 (38 mg, 0.04 mmol, 0.1 equiv) and sodium hydroxide (49 mg, 1.24 mmol, 3.0 equiv) and the mixture was heated at 90 °C overnight. After cooling to room temperature, t-Bu4NBr (322 mg, 1 mmol, 2.5 equivalents) and bromomethylcyclopropane (696 mg, 5.16 mmol, 12.0 equivalents) were added, and the mixture was heated at 40 ° C overnight. Loss of the SEM protecting group also occurred in the reaction to directly obtain the title compound. After cooling to room temperature, the mixture was diluted with water (30 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 preparative TLC (petroleum ether: EtOAc, 1: 1, v / v) to give the title compound (10 mg, 10%) as a white solid. LCMS: [M+H] + 347.1.

[1349] 1 H NMR(400MHz,DMSO-d6)δ12.1(br s,1H),7.97(d,J=8.8Hz,1H),7.06(dd,J=8.8,2.4Hz,1H),7.00(d,J=2.4Hz,1H),3.95(d,J=7.2Hz,2H),3.85-3.78(m,2H),3.64(s,2H) ,3.31-3.27(m,2H),3.10-3.02(m,1H),1.92-1.85(m,2H),1.50-1.40(m,2H),1.33-1.21(m,1H),0.65-0.55(m,2H),0.40-0.31(m,2H).

[1350] Example 220: 4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide

[1351]

[1352] To a solution of 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride (100 mg, 0.24 mmol, 1.0 equiv) and Et3N (74 mg, 0.72 mmol, 3.0 equiv) in DCM (4.0 mL) was added N,N-dimethylcarbamoyl chloride (31 mg, 0.29 mmol, 1.2 equiv) under an N2 atmosphere, and the mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL×2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 15:1, v / v) to give the title compound (50 mg, 46%) as a white solid. LCMS: [M+H] + 448.2.

[1353] 1 H NMR (400MHz, DMSO-d6) δ11.7(s,1H),6.82(d,J=6.4Hz,1H),6.41(d,J=14.0Hz,1H),6.36(s,1H),3.82-3.75(m,1H),3.55(s,2H),3.46-3. 42(m,2H),3.01-2.94(m,1H),2.78-2.75(m,2H),2.70(s,6H),1.98-1 .90(m,4H),1.72-1.63(m,2H),1.61-1.52(m,2H),1.50-1.35(m,4H).

[1354] Example 221: 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[1355]

[1356] Step 1: 6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol

[1357] It was prepared from 3,4-dihydro-2H-pyran-2-carbaldehyde according to the literature Bioorg. Med. Chem. 2006, 14, 3953. The obtained product was a 7:3 mixture of trans / cis isomers.

[1358] Step 2: trans-6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl methanesulfonate and cis-6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl methanesulfonate

[1359] Under N2 atmosphere, to a solution of 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (1.1 g, 2.97 mmol, 1.0 equiv) and Et3N (450 mg, 4.45 mmol, 1.5 equiv) in DCM (25 mL) was added methanesulfonyl chloride (408 mg, 3.56 mmol, 1.2 equiv), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (50 mL), extracted with DCM (20 mL × 3), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 1:0 to 10:1, v / v) to give the trans isomer (730 mg, 55%) and cis isomer (330 mg, 25%) as a white solid.

[1360] Trans isomer: 1 H NMR (400MHz, CDCl3) δ7.66-7.36(m,10H),4.64-4.58(m,1H),4.14-4.11(m,1H),3.72-3.71(m,1H),3.69-3.31 (m,3H),3.05(s,3H),2.33-2.30(m,1H),1.90-1.87(m,1H),1.73-1.70(m,1H),1.48-1.45(m,1H),1.09(s,9H).

[1361] Cis isomer: 1 H NMR (400MHz, CDCl3) δ7.61-7.31(m,10H),4.10-4.07(m,1H),3.70-3.67(m,1H),3 .66-3.40(m,4H),3.02(s,3H),2.18-2.14(m,1H),1.80-1.56(m,3H),0.99(s,9H).

[1362] Step 3: 2-(((cis-6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[1363] Prepared from Int-C1 and trans-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl methanesulfonate according to the procedure described for Example 210, Step 3. LCMS: [M+H] + 559.2.

[1364] Step 4: 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

[1365] To a solution of 2-(((cis-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one (120 mg, 0.21 mmol, 1.0 equiv) in DCM (2 mL) was added TBAF (0.64 mL, 0.64 mmol, 3.0 equiv), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (10 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1, v / v) followed by purification on a C18 reverse phase column (Biotage, 0% to 40% MeCN in water) to give the title compound (12 mg, 17%) as a white solid. LCMS: [M+H] + 321.1.

[1366] 1 H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 3.83 (d, J = 12.0 Hz, 1H), 3.68 (dd, J = 12.0, 2.4 Hz, 1H), 3.63 (d, J = 2.0 Hz, 2H), 3.29-3.22 (m, 3H), 3.19 (m, 1H), 2.49 (3H, obscured by solvent peak), 1.93-1.85 (m, 2H), 1.52-1.38 (m, 2H).

[1367] Example 222: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1368]

[1369] Step 1: tert-Butyl trans-4-(acetylthio)-3-(trifluoromethyl)piperidine-1-carboxylate

[1370] Prepared according to the method described for Int-B3 from cis-tert-butyl 4-hydroxy-3-(trifluoromethyl)piperidine-1-carboxylate.

[1371] 1H NMR (400MHz, CDCl3) δ5.23(br s,1H),4.41(br s,1H),3.94-3.89(m,2H),2.34(s,3H),1.62-1.58(m,2H),1.42(s,9H).

[1372] Step 2: trans-tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-(trifluoromethyl)piperidine-1-carboxylate

[1373] Prepared from tert-butyl trans-4-(acetylthio)-3-(trifluoromethyl)piperidine-1-carboxylate and Int-A43 according to the method described for Example 202. LCMS: [M+H] + 545.2.

[1374] Step 3: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1375] Prepared from tert-butyl trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-(trifluoromethyl)piperidine-1-carboxylate according to the method described for Example 48, Step 2. LCMS: [M+H] + 445.1.

[1376] 1 H NMR(400MHz,DMSO-d6)δ9.52-9.18(m,2H),7.08(br s,1H),6.49-6.48(m,2H),3.79-3.76(m,1H),3.75-3.69(m,2H),3.51-3.42(m,1H),3.39- 3.23(m,2H),3.14-2.91(m,3H),2.37-2.28(m,1H),2.02-1.92(m,3H),1.74-1.43(m,6H).

[1377] Example 223: 7-(Cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate

[1378]

[1379] Step 1: cis-tert-Butyl 3-(benzoylthio)-4-fluoropyrrolidine-1-carboxylate

[1380] To a solution of trans-3-fluoro-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.44 mmol, 1.0 equiv), thiobenzoic acid (673 mg, 4.87 mmol, 2.0 equiv) and PPh3 (1.28 g, 4.87 mmol, 2.0 equiv) in THF (15 mL) was added DEAD (849 mg, 4.87 mmol, 2.0 equiv) and the mixture was stirred at room temperature under N2 atmosphere overnight. The mixture was diluted with water (80 mL) and extracted with DCM (80 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, 8:1, v / v) to give the title compound (550 mg, 24%) as a yellow solid.

[1381] 1 H NMR (400MHz, DMSO-d6) δ 8.16-7.91 (m, 5H), 5.33 (d, J = 52.8Hz, 1H), 4.40-4.23 (m, 1H), 3.92-3.54 (m, 3H), 3.26-3.18 (m, 1H), 1.42 (s, 9H).

[1382] Step 2: cis-tert-Butyl 3-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-4-fluoropyrrolidine-1-carboxylate

[1383] Prepared from Int-A43 and cis-tert-butyl 3-(benzoylthio)-4-fluoropyrrolidine-1-carboxylate according to the method described for Example 202. LCMS: [M+H] + 481.2.

[1384] Step 3: 7-(Cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate

[1385] Prepared from tert-butyl cis-3-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-4-fluoropyrrolidine-1-carboxylate according to the procedure described for Example 48, Step 2. Purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to provide the title compound. LCMS: [M+H] + 381.1.

[1386] 1H NMR(400MHz,DMSO-d6)δ11.8(br s,1H),9.47(br s,1H),9.27(br s,1H),6.97(br s,1H),6.43(dd,J=14.0,1.6Hz,1H),6.38(d,J=1.2Hz,1H),5.34(d,J=54.8Hz,1H),3.79-3.67(m,5H),3.64- 3.36(m,2H),3.09-2.96(m,1H),2.00-1.88(m,2H),1.74-1.63(m,2H),1.63-1.51(m,2H),1.51-1.40(m,2H).

[1387] Example 224: 7-(Cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1388]

[1389] Step 1: Methyl 7-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-5-carboxylate

[1390] To a suspension of 5-bromo-7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one (300 mg, 0.80 mmol, 1.0 equiv) in methanol (5 mL) was added EtN (163 mg, 1.61 mmol, 2.0 equiv) and PdCl(dppf) (59 mg, 0.08 mmol, 0.1 equiv), and the mixture was heated at 100° C. under a carbon monoxide atmosphere (50 psi) for 15 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was dried over NaSO and concentrated under reduced pressure to give the title compound (230 mg, 81%) as a brown solid. LCMS: [M+H] + 353.1.

[1391] Step 2: 7-Fluoro-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1392] To a solution of methyl 7-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-5-carboxylate (30 mg, 0.09 mmol, 1.0 equiv) in THF (3 mL) was added sodium borohydride (10 mg, 0.26 mmol, 3.0 equiv), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 1:1, v / v) to give the title compound (10 mg, 36%) as a white solid. LCMS: [M+H] + 325.1.

[1393] Step 3: 7-(Cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1394] Prepared from 7-fluoro-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one and cyclopentylamine according to the method described for Example 126. LCMS: [M+H] + 390.2.

[1395] 1 HNMR (400MHz, CD3OD) δ6.78(d,J=2.4Hz,1H),6.45(s,1H),4.81(s,2H),3.82-3.76(m,3H),3.56-3.54(m,2H),3.36-3.29( m,2H),2.95-2.87(m,1H),1.98-1.91(m,2H),1.86-1.80(m,2H),1.70-1.65(m,2H),1.61-1.55(m,2H),1.52-1.45(m,4H).

[1396] Example 225: 7-(Cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1397]

[1398] To a solution of -(cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one (100 mg, 0.26 mmol, 1.0 eq) in DCM (5 mL) was added EtN (52 mg, 0.51 mmol, 2.0 eq) and DAST (207 mg, 1.28 mmol, 5.0 eq) at -78 ° C under N2 atmosphere, and the mixture was stirred at -78 ° C for 2 hours. After warming to room temperature, the reaction was quenched with water (5 mL) and the mixture was extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound as a white solid (3.5 mg, 3%). LCMS: [M+H] + 392.1.

[1399] 1 HNMR (400 MHz, CD3OD) δ7.03 (s, 1H), 6.58 (d, J = 2.0 Hz, 1H), 5.92 (d, J = 48.4 Hz, 2H), 3.96-3.90 (m, 3H), 3.49-3.43 (m, 2H), 3.33 (2H, obscured by solvent peak), 3.12-3.06 (m, 1H), 2.10-2.04 (m, 2H), 1.98-1.95 (m, 2H), 1.80-1.58 (m, 8H).

[1400] Example 226: 7-(Cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1401]

[1402] Step 1: tert-Butyl 4-(((7-bromo-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1403] Prepared from Int-A48 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 472.1.

[1404] Step 2: tert-Butyl 4-(((7-bromo-3-(2-(tert-butoxy)-2-oxoethyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1405] To a solution of tert-butyl 4-(((7-bromo-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (790 mg, 1.67 mmol, 1.0 equiv) in DMF (12 mL) was added chloromethyl 2,2-dimethylpropanoate (302 mg, 2.01 mmol, 1.2 equiv) and KCO (347 mg, 2.51 mmol, 1.5 equiv), and the mixture was heated at 80 ° C under N atmosphere for 2 hours. The mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (20 mL×3), dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc, 15:1, v / v) to give the title compound (550 mg, 56%) as a brown oil. LCMS: [M+H] + 586.1.

[1406] Step 3: tert-Butyl 4-(((3-(2-(tert-Butoxy)-2-oxoethyl)-7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1407] To a solution of tert-butyl 4-(((7-bromo-3-(2-(tert-butoxy)-2-oxoethyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (200 mg, 0.34 mmol, 1.0 eq) and cyclopentylamine (35 mg, 0.41 mmol, 1.2 eq) in toluene (5 mL) was added CsCO (167 mg, 0.51 mmol, 1.5 eq), BINAP (42 mg, 0.07 mmol, 0.2 eq) and Pd(dba) (31 mg, 0.03 mmol, 0.1 eq) under N2 atmosphere, and the mixture was heated at 100 ° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc, 3:1, v / v) to give the title compound (90 mg, 45%) as a yellow solid. LCMS: [M+H] + 591.3.

[1408] Step 4: tert-Butyl 4-(((7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1409] To a solution of tert-butyl 4-(((3-(2-(tert-butoxy)-2-oxoethyl)-7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate (90 mg, 0.15 mmol, 1.0 equiv) in methanol (2 mL) was added 1 M NaOH (0.5 mL), and the mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water (30 mL), extracted with EtOAc (20 mL×2), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 20:1, v / v) to give the title compound (66 mg, 91%) as a white solid. LCMS: [M+H] + 477.2.

[1410] Step 5: 7-(Cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1411] Prepared from tert-butyl 4-(((7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 377.1.

[1412] 1 H NMR (400MHz, DMSO-d6) δ9.04-8.90(m,2H),7.58(d,J=11.6Hz,1H),6.92(d,J=7.2Hz,1H),6.68(br s,1H),3.85-3.78(m,3H),3.24-3.14(m,3H),2.94-2.86(m,2H),2.17-2.13(m,2H),2.03-1.95(m,2H),1.71-1.53(m,8H).

[1413] Example 227: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one bis(trifluoroacetate)

[1414]

[1415] Step 1: cis-tert-Butyl 4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate

[1416] Prepared according to the procedure described in WO201391773 from tert-butyl 4-oxo-2-(trifluoromethyl)piperidine-1-carboxylate.

[1417] Step 2: cis-tert-Butyl 4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate

[1418] Prepared from cis-tert-butyl 4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate according to the procedure described for Int-B3, Step 1. LCMS: [M+H] + 348.1.

[1419] Step 3: trans-tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylate

[1420] Prepared from Int-C12 and cis-tert-butyl 4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate according to the procedure described for Example 210, Step 3. LCMS: [M+H] + 545.2.

[1421] Step 4: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one bis(trifluoroacetate)

[1422] Prepared from tert-butyl trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. Purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to provide the title compound. LCMS: [M+H] + 445.1.

[1423] 1 H NMR(400MHz,CD3OD)δ6.49-6.43(m,2H),4.52-4.43(m,1H),3.87-3.81(m,1H),3.69-3.65(m,1H),3.49 -3.40(m,2H),2.71(s,2H),2.41-2.33(m,1H),2.27-2.16(m,2H),2.15-2.00(m,3H),1.82-1.53(m,6H).

[1424] 19 F NMR (400MHz, CD3OD) δ-75.9,-76.3,-77.3,-113.1.

[1425] Example 228: 7-(Cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1426]

[1427] Step 1: trans-tert-Butyl 4-((4-nitrobenzoyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate

[1428] To a solution of cis-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.86 mmol, 1.0 equiv), 4-nitrobenzoic acid (621 mg, 3.71 mmol, 2.0 equiv) and triphenylphosphine (974 mg, 3.71 mmol, 2.0 equiv) in THF (15 mL) was added DEAD (647 mg, 3.71 mmol, 2.0 equiv) at 0 ° C under N2 atmosphere, and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL × 3), and the combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 20: 1, v / v) to give the title compound (430 mg, 55%) as a white solid. LCMS: [M+H] + 419.1.

[1429] Step 2: trans-tert-butyl 4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate

[1430] A mixture of tert-butyl trans-4-(4-nitrobenzoyl)oxy-2-(trifluoromethyl)piperidine-1-carboxylate (400 mg, 0.96 mmol, 1.0 equiv) and 2M NaOH (8.0 mL) in methanol (16 mL) was stirred at 20° C. for 2 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to give the title compound (200 mg, 78%) as an off-white solid.

[1431] 1HNMR(400MHz,DMSO-d6)δ4.96(br s,1H),4.93-4.73(m,1H),4.10-3.96(m,1H),3.77-3.65(m,1H),2.94-2.69(m,1H),2. 06-1.98(m,1H),1.88-1.78(m,1H),1.58-1.44(m,1H),1.40(s,9H),1.24-1.65(m,1H).

[1432] Step 3: trans-tert-Butyl 4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate

[1433] Prepared from tert-butyl trans-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate according to the procedure described for Int-B3, Step 1. LCMS: [M+H] + 348.1.

[1434] Step 4: cis-tert-Butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylate

[1435] Prepared from Int-C12 and trans-tert-butyl 4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate according to the procedure described for Example 210, Step 3. LCMS: [M+H] + 545.2.

[1436] Step 5: 7-(Cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one hydrochloride

[1437] Prepared from cis-tert-butyl 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 445.1.

[1438] 1H NMR(400MHz,DMSO-d6)δ12.1(br s,1H),10.0(br s,2H),7.07(br s,1H),6.53-6.40(m,2H),4.40-4.31(m,1H),3.78-3.69(m,3H),3.43-3.36(m,1H),3.18-3.04(m,2 H),2.54-2.52(m,1H),2.21-2.13(m,1H),1.99-1.91(m,2H),1.72-1.54(m,6H),1.51-1.42(m,2H).

[1439] Example 229: 7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one hydrochloride

[1440]

[1441] Step 1: tert-Butyl 4-(((7-chloro-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate

[1442] Prepared from Int-A44 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 411.1.

[1443] Step 2: tert-Butyl 4-(((7-(cyclopropylmethoxy)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate

[1444] To a solution of cyclopropylmethanol (53 mg, 0.73 mmol, 5.5 equiv) in THF (3 mL) at 0°C was added portionwise NaH (60% w / w dispersion in oil, 58 mg, 1.46 mmol, 10 equiv), and the mixture was stirred for 30 minutes. A solution of tert-butyl 4-(((7-chloro-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate (60 mg, 0.15 mmol, 1.0 equiv) in THF (0.5 mL) was then added, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0°C, diluted with water (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 60:1, v / v) to give the title compound (30 mg, 46%) as a pale yellow solid. LCMS: [M+H] + 447.1.

[1445] Step 3: 7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one hydrochloride

[1446] Prepared from tert-butyl 4-(((7-(cyclopropylmethoxy)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 347.1.

[1447] 1 H NMR(400MHz,DMSO-d6)δ12.5(br s,1H),8.60(br s,2H),8.29(d,J=8.8Hz,1H),6.93(d,J=8.4Hz,1H),4.21(d,J=7.2Hz,2H),3.72(s,2H),3.27-3.20(m,2H),3.13-3.05(m ,1H),2.96-2.87(m,2H),2.17-2.07(m,2H),1.69-1.59(m,2H),1.32-1.23(m,1H),0.60-0.55(m,2H),0.40-0.32(m,2H).

[1448] Example 230: 7-((Cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1449]

[1450] Step 1: tert-Butyl 4-(((7-bromo-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1451] Prepared from Int-A45 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 484.1.

[1452] Step 2: tert-Butyl 4-(((7-((cyclobutylmethyl)amino)-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1453] Prepared from tert-butyl 4-(((7-bromo-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate and cyclobutylmethylamine according to the procedures described for Example 226, Step 2, Step 3, and Step 4. LCMS: [M+H]+ 489.2.

[1454] Step 3: 7-((Cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1455] Prepared from tert-butyl 4-(((7-((cyclobutylmethyl)amino)-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 389.1.

[1456] 1 H NMR(400MHz,DMSO-d6)δ13.5(br s,1H),9.11-8.88(m,2H),7.25(s,1H),6.88(s,1H),6.64(br s,1H),3.96(s,2H),3.93(s,3H),3.28-3.18(m,5H),2.94-2.85(m,2H),2.69-2.60( m,1H),2.22-2.12(m,2H),2.07-1.95(m,2H),1.90-1.80(m,2H),1.77-1.60(m,4H).

[1457] Example 231: 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1458]

[1459] Step 1: 7-Bromo-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1460] Prepared from Int-A46 and Int B1 according to the method described for Example 202. LCMS: [M+H] + 373.0.

[1461] Step 2: 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1462] Prepared from 7-bromo-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one and 2,2-difluorocyclopentan-1-amine according to the procedures described for Example 226, Step 2, Step 3, and Step 4. LCMS: [M+H] +414.1.

[1463] 1 H NMR (400MHz, DMSO-d6) δ11.7(s,1H),6.93(d,J=8.0Hz,1H),6.57-6.54(m,2H),4.22-4.15(m,1H),3.82-3.79(m,2H),3.55(s,2H),3 .36-3.27(m,2H),3.06-3.00(m,1H),2.25-2.03(m,3H),1.89-1.86(m,2H),1.78-1.72(m,2H),1.65-1.60(m,1H),1.48-1.38(m,2H).

[1464] Example 232: 7-(Cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1465]

[1466] Step 1: tert-Butyl 4-(((7-(cyclopentylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

[1467] Prepared from Int-A47 and Int-B2 according to the method described for Example 202. LCMS: [M+H] + 495.2.

[1468] Step 2: 7-(Cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one hydrochloride

[1469] Prepared from tert-butyl 4-(((7-(cyclopentylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the procedure described for Example 48, Step 2. LCMS: [M+H] + 395.1.

[1470] 1H NMR(400MHz,DMSO-d6)δ12.2(br s,1H),8.95(br s,1H),8.83(br s,1H),6.81(br s,1H),6.63(d,J=7.2Hz,1H),3.91-3.82(m,1H),3.67(s,2H),3.21-3.17(m,2H),3.16-3 .04(m,1H),2.95-2.85(m,2H),2.19-2.06(m,2H),2.04-1.91(m,2H),1.78-1.53(m,8H).

[1471] Example 233: 5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate and

[1472] Example 234: 5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate

[1473]

[1474] Step 1: 7-((1,4-Dioxaspiro[4.5]dec-8-yl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1475] Prepared from 7-bromo-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one and 1,4-dioxaspiro[4.5]decan-8-amine according to the procedures described for Example 226, Step 2, Step 3, and Step 4. LCMS: [M+H] + 450.2.

[1476] Step 2: 5-Fluoro-7-((4-oxocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1477] Prepared from 7-((1,4-dioxaspiro[4.5]dec-8-yl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one according to the method described for Example 21, Step 3. LCMS: [M+H] + 406.1.

[1478] Step 3: 5-Fluoro-7-((4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1479] To a solution of 5-fluoro-7-((4-oxocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one (30 mg, 0.07 mmol, 1.0 equiv) in methanol (2 mL) was added morpholine (32 mg, 0.37 mmol, 5.0 equiv), and the mixture was stirred at room temperature for 30 minutes. NaCNBH3 (24 mg, 0.38 mmol, 5.0 equiv) was then added, and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 (20 mL), and the mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (10 mg, 28%) as a white solid. LCMS: [M+H] + 477.2.

[1480] Step 4: 5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate and 5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one trifluoroacetate

[1481] 5-Fluoro-7-((4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in ACN at a flow rate of 20 mL / min) to give the title compound.

[1482] Example 233: LCMS: [M+H] + 477.2.

[1483] 1H NMR (400MHz, CD3OD) δ6.63-6.58(m,2H),4.10(d,J=12.0Hz,2H),3.93-3.89(m,2H),3.82-3.73(m,2H),3.51-3.41(m,5H),3.35-3.31(m,2 H),3.26-3.20(m,3H),3.09-3.04(m,1H),2.28-2.25(m,4H),1.98-1.93(m,2H),1.78-1.69(m,2H),1.63-1.54(m,2H),1.49-1.37(m,2H).

[1484] Example 234: LCMS: [M+H] + 477.2.

[1485] 1 H NMR (400MHz, CD3OD) δ6.63-6.58(m,2H),4.10(d,J=13.2Hz,2H),3.93-3.90(m,2H),3.83-3.77(m,3H),3.51-3.41(m,4H),3.35-3.31(m,2 H),3.27-3.22(m,3H),3.10-3.03(m,1H),2.15-2.12(m,2H),2.05-2.02(m,2H),1.97-1.94(m,2H),1.88-1.77(m,4H),1.63-1.53(m,2H).

[1486] Example 235: 7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

[1487]

[1488] To a solution of Int-A49 (300 mg, 1.06 mmol, 1.0 equiv) in THF (5 mL) was added Int-B11 (168 mg, 1.27 mmol, 1.2 equiv) and 2M NaOH (2 mL) under N2 atmosphere, and the mixture was stirred at room temperature overnight. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 reverse phase column (Biotage, 40% ACN in water) to give the title compound (130 mg, 32%) as a white solid. LCMS: [M+H] + 379.1;

[1489] 1 H NMR (400MHz, DMSO-d6) δ12.1(s,1H),6.89-6.86(m,2H),4.52(d,J=4.4Hz,1H),3.96(d,J=7.2Hz,2H),3.57(s,2H),3.40-3.3 8(m,1H),2.74-2.67(m,1H),1.97-1.94(m,2H),1.82-1.80(m,2H),1.28-1.11(m,5H),0.60-0.58(m,2H),0.37-0.33(m,2H).

[1490] Example 236: 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1491]

[1492] Prepared from Int-A50 and Int-B1 according to the method described for Example 202. LCMS: [M+H] + 409.1.

[1493] 1 H NMR (400MHz, DMSO-d6) δ12.2 (s, 1H), 6.95-6.84 (m, 2H), 3.99 (d, J = 6.4Hz, 2H), 3.92-3.77 (m, 4H), 3.61 (s, 2H), 3.38-3.32 (m,2H),3.31-3.27(m,2H),3.10-3.00(m,1H),2.08-1.97(m,1H),1.93-1.84(m,2H),1.72-1.63(m,2H),1.51-1.27(m,4H).

[1494] Example 237: 7-(Cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

[1495]

[1496] Prepared from Int-A51 and Int-B1 according to the method described for Example 202. LCMS: [M+H] + 375.1.

[1497] 1H NMR (400MHz, DMSO-d6) δ11.9(s,1H),6.85(s,1H),6.82(s,1H),4.05(d,J=6.4Hz,2H),3.83-3.80(m,2H),3.60(s,2H),3.35 -3.32(m,2H),3.08-3.01(m,1H),2.77-2.70(m,1H),2.70(s,3H),2.11-2.04(m,2H),1.95-1.79(m,6H),1.49-1.40(m,2H).

[1498] Example 238: 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

[1499]

[1500] Prepared from Int-A52 and Int-B1 according to the method described for Example 202. LCMS: [M+H] + 395.0.

[1501] 1 H NMR(400MHz,DMSO-d6)δ12.2(s,1H),6.94-6.84(m,2H),4.10-4.00(m,2H) ,3.84-3.72(m,4H),3.69-3.62(m,1H),3.60(s,2H),3.55-3.48(m,1H),3.3 7-3.34(m,1H),3.30-3.27(m,1H),3.08-2.99(m,1H),2.70-2.63(m,1H),2 .07-1.96(m,1H),1.92-1.83(m,2H),1.70-1.62(m,1H),1.48-1.37(m,2H).

[1502] Example 239: (R)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one and

[1503] (S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

[1504]

[1505] Example 238 was further purified by chiral preparative HPLC (Chiralpak IE-3, 3 μm, 0.46×5 cm column, eluting with a gradient of hexanes:DCM (0.1% DEA):MeOH 50:50 at a flow rate of 1.0 mL / min) to afford the title compound with retention times of 2.09 minutes ( 239a ) and 3.35 minutes ( 239b ).

[1506] Example 239a: LCMS: [M+H] + 395.2.

[1507] 1 H NMR(400MHz,DMSO-d6)δ12.2(s,1H),6.91-6.87(m,2H),4.11-4.01(m,2H) ,3.84-3.75(m,4H),3.69-3.63(m,1H),3.62(s,2H),3.56-3.52(m,1H),3.3 4-3.33(m,1H),3.30-3.27(m,1H),3.06-2.99(m,1H),2.68-2.63(m,1H),2 .04-1.96(m,1H),1.91-1.88(m,2H),1.70-1.65(m,1H),1.49-1.40(m,2H).

[1508] Example 239b: LCMS: [M+H] + 395.2.

[1509] 1 H NMR(400MHz,DMSO-d6)δ12.2(s,1H),6.88-6.82(m,2H),4.10-4.02(m,2H) ,3.84-3.75(m,4H),3.69-3.63(m,1H),3.62(s,2H),3.56-3.52(m,1H),3.3 4-3.33(m,1H),3.30-3.27(m,1H),3.09-3.03(m,1H),2.68-2.63(m,1H),2 .04-1.96(m,1H),1.91-1.88(m,2H),1.70-1.65(m,1H),1.49-1.42(m,2H).

[1510] Example 240: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one

[1511]

[1512] Step 1: tert-Butyl 3-fluoro-5-hydroxyazepane-1-carboxylate

[1513] Prepared from 1,3-dichloropropane-2-one according to the procedure described in US2015197493.

[1514] Step 2: tert-Butyl 3-fluoro-5-((methylsulfonyl)oxy)azepane-1-carboxylate

[1515] Prepared from tert-butyl 3-fluoro-5-hydroxyazepane-1-carboxylate according to the method described for Int-B3 step 1. LCMS: [M+H] + 312.1.

[1516] Step 3: tert-Butyl 5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate

[1517] Prepared from Int-C12 and tert-butyl 3-fluoro-5-((methylsulfonyl)oxy)azepane-1-carboxylate according to the procedure described for Example 210, Step 3. LCMS: [M+H] + 509.2.

[1518] Step 4: trans-tert-butyl 5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate and cis-tert-butyl 5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate

[1519] Tert-butyl 5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate was further purified by preparative HPLC (Agilent 10prep-C18, 10 μm, 250 x 21.2 mm column, gradient elution with 0.1% TFA in MeOH at a flow rate of 20 mL / min) to give the title trans isomer, LCMS: [M+H] + 509.2 and cis isomer, LCMS: [M+H] + 509.2. (Assignment of cis and trans is arbitrary).

[1520] Step 5: 7-(Cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one

[1521] Prepared from tert-butyl trans-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate according to the method described for Example 48, Step 2. The crude product was partitioned between saturated aqueous Na2CO3 solution (10 mL) and EtOAc (30 mL). The layers were separated, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH, 10:1, v / v) to give the title compound. LCMS: [M+H] + 409.1.

[1522] 1 H NMR (400MHz, DMSO-d6) δ11.7(s,1H),6.85(d,J=6.0Hz,1H),6.42(d,J=13.6Hz,1H),6.36(s,1H),4.96(d,J=43.6Hz,1H),3.78-3.75(m,1H),3.5 7(s,2H),3.17-2.85(m,4H),2.40-2.30(m,1H),2.17-2.08(m,2H),2.00 -1.87(m,3H),1.76-1.68(m,3H),1.58-1.54(m,2H),1.47-1.42(m,2H).

[1523] Example 241: 7-(Cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one

[1524]

[1525] Prepared from tert-butyl cis-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate according to the method described for Example 48, Step 2. The crude product was partitioned between saturated aqueous Na2CO3 solution (10 mL) and EtOAc (30 mL). The layers were separated, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH, 10:1, v / v) to give the title compound. LCMS: [M+H] + 409.1.

[1526] 1H NMR (400MHz, DMSO-d6) δ11.7(s,1H),6.86(d,J=6.0Hz,1H),6.42(d,J=14.0Hz,1H),6.36(s,1H),4.96(d,J=48.0Hz,1H),3.78-3.75(m,1H),3.5 6(s,2H),3.11-3.01(m,4H),2.76-2.70(m,1H),2.43-2.34(m,1H),2.05 -1.93(m,4H),1.73-1.62(m,3H),1.58-1.54(m,2H),1.47-1.42(m,2H).

[1527] Example 242: 2-((((cis)-6-(Aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one dihydrochloride

[1528]

[1529] Step 1: (3,4-Dihydro-2H-pyran-2-yl)methanol

[1530] It was prepared from 3,4-dihydro-2H-pyran-2-carbaldehyde according to the literature Bioorg. Med. Chem. 2006, 14, 3953.

[1531] Step 2: (3,4-Dihydro-2H-pyran-2-yl)methyl methanesulfonate

[1532] Prepared according to the method described for Int B3, Step 1 from (3,4-dihydro-2H-pyran-2-yl)methanol.

[1533] 1 H NMR (400MHz, CDCl3) δ6.36 (d, J = 6.0Hz, 1H), 4.80-4.72 (m, 1H), 4.32-4.29 (m, 2H), 4.14-4.06 (m ,1H),3.07(s,3H),2.18-2.08(m,1H),2.08-2.03(m,1H),1.91-1.84(m,1H),1.78-1.67(m,1H).

[1534] Step 3: 2-((3,4-dihydro-2H-pyran-2-yl)methyl)isoindoline-1,3-dione

[1535] To a mixture of 3,4-dihydro-2H-pyran-2-ylmethyl methanesulfonate (500 mg, 2.6 mmol, 1.0 equiv) in DMSO (3 mL) was added potassium phthalimide (578 mg, 3.12 mmol, 1.2 equiv) and the mixture was heated at 90 ° C for 16 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc, 1: 0 to 10: 1, v / v) to give the title compound (350 mg, 55%) as a white solid. LCMS: [M+H] + 244.0.

[1536] Step 4: (3,4-Dihydro-2H-pyran-2-yl)methanamine

[1537] To a mixture of 2-(3,4-dihydro-2H-pyran-2-ylmethyl)isoindoline-1,3-dione (500 mg, 2.06 mmol) in methanol (5 mL) was added hydrazine hydrate (0.25 mL, 4.11 mmol, 2.0 equiv) at 0 ° C., and the mixture was heated at 50 ° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was triturated with DCM (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (230 mg, 99%) as a light yellow solid, which was used directly in the next step.

[1538] Step 5: tert-Butyl ((3,4-dihydro-2H-pyran-2-yl)methyl)carbamate

[1539] To a solution of (3,4-dihydro-2H-pyrans-2-yl)methylamine (230mg, 2.03mmol, 1.0 equivalent) in DCM (4mL) was added EtN (0.34mL, 2.44mmol, 2.2 equivalents), followed by addition of tert-butyl dicarbonate (532mg, 2.44mmol, 2.2 equivalents), and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with DCM (10mL) and washed with water (5mL). The organic layer was dried over NaSO and concentrated under reduced pr...

Claims

1. A compound which is 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof.

2. A compound which is 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one.

3. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising the compound of claim 2 and at least one pharmaceutically acceptable carrier.

5. Use of the compound of claim 1 or 2 or the pharmaceutical composition of claim 3 or 4 in the preparation of a medicament for treating cancer in a patient in need of treatment.

6. The method of claim 5, wherein the cancer is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer or melanoma.

7. Use of a compound according to claim 1 or 2 or a pharmaceutical composition according to claim 3 or 4 in the preparation of a medicament for treating an inflammatory disease in a patient in need of treatment.

8. The use according to claim 7, wherein the inflammatory disease is inflammatory bowel disease, inflammatory arthritis, inflammatory demyelinating disease, psoriasis, allergy, asthma, sepsis, allergic airway disease and lupus.

9. The use according to claim 7, wherein the inflammatory disease is asthma.

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