Methods for Treating Inflammatory Diseases

Abstract

The present invention relates to the use of quinazolinone and related compounds that are PARP14 inhibitors for the treatment and prevention of inflammatory diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the use of quinazolinone and related compounds that are PARP14 inhibitors for the treatment and prevention of inflammatory diseases. [Background technology]

[0002] 2. Background of the Invention Inflammatory responses elicited by the detection of danger- and pathogen-associated molecular patterns are the primary mechanism of the innate immune system to deal with invasion. However, uncontrolled, chronic inflammation is a driver of numerous diseases, such as allergic asthma, atopic dermatitis, atherosclerosis, pulmonary fibrosis, irritable bowel syndrome, and multiple sclerosis. Despite advances in the treatment of many of these diseases, their incidence in the United States and worldwide is increasing, significantly impacting population health, quality of life, economic productivity, and healthcare costs. For example, asthma alone affects approximately 25 million patients in the United States, with approximately 20% of patients being children (https: / / www.cdc.gov / nchs / fastats / asthma.htm). In the majority of patients, the disease is adequately controlled with current medications, but 5-10% of patients have severe forms of asthma that are not controlled with inhaled corticosteroids or long-acting beta-agonists. In addition, atopic dermatitis and psoriasis are chronic inflammatory skin disorders that affect 7-10% and approximately 3% of adults in the United States, respectively (He et al., J. Allergy Clin. Immunol. 2021, 147(1), pp. 199-212). Summary of the Invention [Problem to be solved by the invention]

[0003] Existing treatments for inflammatory diseases are often limited. For example, several intravenously injected biological treatments have been approved for the treatment of severe asthma, but they only provide partial relief and do not control the disease in all patients. Furthermore, to date, oral small molecule therapies have not been shown to effectively treat any of the asthma endotypes. Furthermore, keloid disease exhibits high recurrence rates and the efficacy of current treatments is limited (Diaz, A. et al., “Keloid lesions show increased IL-4 / IL-13 signaling and respond to TH2-targeting dupilumab therapy,” JEADV 2019, 34, e159-e209). Thus, novel means of treating inflammatory diseases (e.g., asthma, atopic dermatitis, psoriasis, eosinophilic disorders, and keloids) continue to be explored. [Means for solving the problem]

[0004] Summary of the Invention The present invention provides a method of treating or preventing an inflammatory disease in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as a compound of formula I: [ka] (wherein the structural symbols are defined below.) or a pharma- ceutically acceptable salt thereof. Compounds of formula I are described in U.S. Patent Publication US2019 / 0194174, which is incorporated herein by reference in its entirety.

[0005] The present invention further provides a method of treating or preventing asthma in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as a compound of formula I: [ka] (wherein the structural symbols are defined below.) or a pharma- ceutically acceptable salt thereof.

[0006] The present invention further provides a method for suppressing immune cell infiltration and activation caused by an inflammatory disease in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, e.g., a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0007] The present invention further provides a method for suppressing immune cell infiltration and activation caused by asthma in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, e.g., a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0008] The present invention further provides a method for suppressing proinflammatory cytokines caused by an inflammatory disease in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, e.g., a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0009] The present invention further provides a method for suppressing inflammatory cytokines responsible for asthma in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, e.g., a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0010] The present invention further provides a PARP14 inhibitor, such as a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing an inflammatory disease in a patient.

[0011] The present invention further provides a PARP14 inhibitor, such as a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of asthma in a patient.

[0012] The invention further provides the use of a PARP14 inhibitor, such as a compound of formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and prevention of an inflammatory disease in a patient.

[0013] The invention further provides the use of a PARP14 inhibitor, such as a compound of formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment and prevention of asthma in a patient. [Brief description of the drawings]

[0014] [Figure 1] 1 shows the percentage of mucin in the airway mucosa of Alternaria-challenged mice treated with Compound 1.

[0015] [Diagram 2] 1 shows IgE levels (ng / mL) in serum of Alternaria-challenged mice administered various doses of Compound 1.

[0016] [Diagram 3] 1 shows the relative levels of eosinophils, neutrophils, lymphocytes and macrophages in bronchoalveolar lavage fluid of Alternaria -challenged mice treated with various doses of Compound 1.

[0017] [Figure 4] IL-4, IL-5, IL-13, IL-33 and TSLP levels in bronchoalveolar lavage fluid of Alternaria-challenged mice treated with various doses of Compound 1 are shown (pg / mL).

[0018] [Diagram 5] IL-4, IL-5, IL-13, IL-33 and TSLP levels (pg / mg) in lung tissue of Alternaria-challenged mice treated with various doses of Compound 1.

[0019] [Figure 6] 1 shows the percentage of mucin in the airway mucosa of Alternaria -challenged mice treated with Compound 1 and Compound 2.

[0020] [Figure 7] 1 shows IgE levels (ng / mL) in serum of Alternaria -challenged mice treated with Compound 1 and Compound 2.

[0021] [Figure 8] Figure 1 shows the number of eosinophils, neutrophils, lymphocytes and macrophages per mL of bronchoalveolar lavage fluid from Alternaria -challenged mice treated with Compound 1 and Compound 2.

[0022] [Figure 9] IL-4, IL-5, IL-13 and IL-33 levels in bronchoalveolar lavage fluid of Alternaria-challenged mice treated with compound 1 and compound 2 (pg / mL) [Figure 10] IL-4, IL-5, IL-13 and IL-33 levels in lung tissue of Alternaria-challenged mice treated with various doses of Compound 1 and Compound 2 are shown (pg / mL).

[0023] [Figure 11A] Immunohistochemistry images of normal human skin at 20x magnification.

[0024] [Figure 11B] Immunohistochemistry image at 20x magnification of skin from a patient with systemic sclerosis.

[0025] [Figure 12] 1 shows plots of body temperature for Groups 1 and 4 up to 60 hours post-administration in a DNCB-induced atopic dermatitis model.

[0026] [Figure 13A] 1 shows plots of the clinical scores for each group from 9 to 24 days after the initial DNCB exposure in the DNCB-induced atopic dermatitis model.

[0027] [Figure 13B] 1 shows the area under the curve of the clinical score for each group after the first DNCB exposure in the DNCB-induced atopic dermatitis model.

[0028] [Figure 14]1 shows a plot of transepidermal water loss over time in a DNCB-induced atopic dermatitis model.

[0029] [Figure 15] 1 shows a plot of body weight over time in a DNCB-induced atopic dermatitis model.

[0030] [Figure 16] 1 shows plots of body temperature for vehicle and Compound 1 treatment groups in an IMQ-induced psoriasis model.

[0031] [Figure 17] 1 shows plots of ear thickness before and after days of Compound 1, DEX and vehicle administration in an IMQ-induced psoriasis model.

[0032] [Figure 18A] A plot of the total clinical score on days after the first IMQ exposure is shown.

[0033] [Figure 18B] The area under the curve for the total clinical score of each group in the IMQ-induced psoriasis model is shown.

[0034] [Figure 19] 1 shows plots of body weight over time for vehicle, DEX, Compound 1 and naive groups in the IMQ-induced psoriasis model.

[0035] [Figure 20] 1 shows a plot of body temperature of vehicle and Compound 1 treated animals in a hIL-23 induced psoriasis model.

[0036] [Figure 21A] 1 shows a plot of ear thickness for naive, vehicle and Compound 1 groups in a hIL-23 induced psoriasis model.

[0037] [Figure 21B] 1 shows a graph of normalized ear thickness AUC for naive, vehicle and Compound 1 groups in a hIL-23 induced psoriasis model.

[0038] [Figure 22A] 1 shows a graph of ear thickness for naive, vehicle and compound 1 groups in a hIL-23 induced psoriasis model.

[0039] [Figure 22B] 1 shows a graph of ear weight increase in naive, vehicle and compound 1 groups in a hIL-23 induced psoriasis model.

[0040] [Figure 23] 1 shows plots of body weight for naive, vehicle and Compound 1 groups in a hIL-23 induced psoriasis model.

[0041] [Figure 24A] 1 shows the body weight and lung weight of mice in each treatment group in a bleomycin (BLM)-induced pulmonary fibrosis model test.

[0042] [Figure 24B] 1 shows the left lung weight of mice in each treatment group in the BLM-induced pulmonary fibrosis model test.

[0043] [Figure 24C] 1 shows the weight of the ascending vena cava lobe in mice of each treatment group in the BLM-induced pulmonary fibrosis model test.

[0044] [Figure 24D] 1 shows the right lower lobe weight of mice in each treatment group in the BLM-induced pulmonary fibrosis model test.

[0045] [Figure 25A] 1 shows the total number of immune cells in bronchoalveolar lavage fluid of mice in each treatment group in the BLM-induced pulmonary fibrosis model test.

[0046] [Figure 25B] BALF monocyte ratios of mice in each treatment group in the BLM-induced pulmonary fibrosis model test are shown.

[0047] [Figure 25C] BALF lymphocyte ratios of mice in each treatment group in the BLM-induced pulmonary fibrosis model test are shown.

[0048] [Figure 25D] BALF neutrophil ratios of mice in each treatment group in the BLM-induced pulmonary fibrosis model test are shown.

[0049] [Figure 26A] BALF IL-6 concentrations in mice of each treatment group in a BLM-induced pulmonary fibrosis model test are shown.

[0050] [Figure 26B] BALF IL-10 concentrations in mice of each treatment group in the BLM-induced pulmonary fibrosis model test are shown.

[0051] [Figure 27] FIG. 1 shows lung hydroxyproline content in each treatment group in the BLM-induced pulmonary fibrosis model study.

[0052] [Figure 28A] FIG. 1 shows photomicrographs of Masson's trichrome-stained lung sections from a sham-treated group in a BLM-induced pulmonary fibrosis model study.

[0053] [Figure 28B] 1 shows photomicrographs of Masson's trichrome stained lung sections from the vehicle-treated group in a BLM-induced pulmonary fibrosis model study.

[0054] [Figure 28C] 1 shows micrographs of Masson's trichrome stained lung sections from the compound 1 treatment group in a BLM-induced pulmonary fibrosis model test.

[0055] [Figure 28D] 1 shows photomicrographs of Masson's trichrome-stained lung sections from the tofacitinib free base treatment group in a BLM-induced pulmonary fibrosis model study.

[0056] [Figure 29]1 shows the Ashcroft scores of mice in each treatment group in the BLM-induced pulmonary fibrosis model study.

[0057] [Figure 30A] This is an immunohistochemical image (20x) of normal human skin.

[0058] [Figure 30B] Immunohistochemistry image (20x) of skin from a patient with atopic dermatitis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain.

[0059] [Figure 30C] Immunohistochemistry image (20x) of skin from a patient with psoriasis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain.

[0060] [Figure 31A] Immunohistochemistry image of normal human lung tissue (20x magnification).

[0061] [Figure 31B] Immunohistochemistry image (20x) of bronchial epithelial cells from lung tissue of a patient with idiopathic pulmonary fibrosis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain.

[0062] [Figure 31C] Immunohistochemistry image (20x magnification) of inflammatory cells in lung tissue from a patient with idiopathic pulmonary fibrosis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain.

[0063] [Figure 32A] Figure 1 shows in-life weight loss scoring of disease severity in an OXZ-induced colitis mouse model.

[0064] [Figure 32B]Figure 1 shows in-life DAI scoring of disease severity in an OXZ-induced colitis mouse model.

[0065] [Figure 32C] 1 shows the AUC of in-life weight change scoring of disease severity in an OXZ-induced colitis mouse model.

[0066] [Fig. 32D] Figure 1 shows the AUC of in-life DAI scoring of disease severity in an OXZ-induced colitis mouse model.

[0067] [Figure 33A] 1 shows a graph of colon density in an OXZ-induced colitis mouse model.

[0068] [Figure 33B] 1 shows a graph of colon length in an OXZ-induced colitis mouse model.

[0069] [Figure 33C] 1 shows a graph of colon weight in an OXZ-induced colitis mouse model.

[0070] [Figure 34A] Shown are H&E (hematoxylin and eosin) stained photographs at 200x magnification of samples from the sham group in the OXZ-induced colitis mouse model.

[0071] [Figure 34B] 1 shows H&E stained photographs at 200x magnification of samples from the vehicle group in an OXZ-induced colitis mouse model.

[0072] [Figure 34C] Shown are H&E stained photographs at 200x magnification of samples from the tofacitinib group in an OXZ-induced colitis mouse model.

[0073] [Fig. 34D]1 shows H&E stained photographs at 200x magnification of samples from the Compound 1 group in an OXZ-induced colitis mouse model.

[0074] [Diagram 35] 1 shows the pathological scores of colitis severity in an OXZ-induced colitis mouse model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] Detailed Description The present invention provides a method of treating or preventing an inflammatory disease in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as a compound of formula I: [ka] [During the ceremony, W is CR W or N; X is CR X or N; Y is CR Y or N; Z is CR Z or N; where no more than two of W, X, Y, and Z are simultaneously N; Ring A is a monocyclic or polycyclic C 3-14 cycloalkyl or ring A is a monocyclic or polycyclic 4-18 membered heterocycloalkyl, where ring A is optionally substituted with 1, 2, 3 or 4 R A When ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. m -Binding to parts; 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 R6 ) q -, -(CR 5 R 6 ) p -NR 3 -(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -CO-(CR 5 R 6 ) q -, -(CR 5 R 6 ) r -C(O)O-(CR 5 R 6 ) s -, -(CR 5 R 6 ) r -CONR 3 -(CR 5 R 6 ) s -, -(CR 5 R 6 ) p -SO-(CR 5 R 6 ) q -, -(CR 5 R 6 ) p -SO2-(CR 5 R 6 ) q -, -(CR 5 R 6 ) r -SONR 3 -(CR 5 R 6 ) s -OR-NR 3 CONR 4 - and; R 1 and R 2 are each independently selected from H and methyl; R 3 and R 4 are each independently H and C 1-4 alkyl; R 5 and R 6 are each independently H, halo, or C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, Amino, C 1-4 Alkylamino and C 2-8 dialkylamino; Each R A is independent of Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 Rd1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 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 The alkyl is optionally selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from: R W , R X , R Y and R Z are each independently H, halo, or C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )Rb2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 where R W , R X , R Y or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 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 The alkyl is optionally selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2, O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from: W is CR W and X is CR X and Y is CR Y and Z is CR Z If so, then R W , R X , R Y and R Z at least one of is other than H; Each Cy 1 is independently C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each optionally selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and is substituted with 1, 2, 3 or 4 substituents independently selected from: Each Cy 2 is independently C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each optionally selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 and is substituted with 1, 2, 3 or 4 substituents independently selected from: Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is H, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, 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 The alkyl group may optionally be Cy. 3 , Cy 3 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 Rd3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Each Cy 3 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each optionally containing halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R.c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 and is substituted with 1, 2, 3 or 4 substituents independently selected from: R a3 , R b3 , R c3 and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is optionally OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 substituted with 1, 2 or 3 substituents independently selected from haloalkoxy; or R c1 and R d1 together with the N atom to which they are attached, optionally halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2 or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, optionally halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2 or 3 substituents independently selected from: Each R e1 , R e2 and R e3 is H, C 1-4 independently selected from alkyl and CN; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, where p+q is 0, 1 or 2; r is 0 or 1; s is 0 or 1, where r+s is 0 or 1; and t is 1, 2 or 3; wherein any of said heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups is optionally substituted with an oxo (=O) group; and One or more ring-forming S atoms of any of the above heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups. or a pharma- ceutically acceptable salt thereof.

[0076] The present invention provides a method of treating or preventing asthma in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as a compound of formula I: [ka] [During the ceremony, W is CR W or N; X is CR X or N; Y is CR Y or N; Z is CR Z or N; where no more than two of W, X, Y, and Z are simultaneously N; Ring A is a monocyclic or polycyclic C 3-14 cycloalkyl or ring A is a monocyclic or polycyclic 4-18 membered heterocycloalkyl, where ring A is optionally substituted with 1, 2, 3 or 4 R A When ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. m -Binding to parts; L is -(CR 5 R 6) t -、-(CR 5 R 6 ) p -O-(CR 5 R 6 ) q -、-(CR 5 R 6 ) p -S-(CR 5 R 6 ) q -、-(CR 5 R 6 ) p -NR 3 -(CR 5 R 6 ) q -、-(CR 5 R 6 ) p -CO-(CR 5 R 6 ) q -、-(CR 5 R 6 ) r -C(O)O-(CR 5 R 6 ) s -、-(CR 5 R 6 ) r -CONR 3 -(CR 5 R 6 ) s -、-(CR 5 R 6 ) p -SO-(CR 5 R 6 ) q -、-(CR 5 R 6 ) p -SO2-(CR 5 R 6 ) q -、-(CR 5 R 6 ) r -SONR 3 -(CR 5 R 6 ) s -または-NR 3 CONR 4 -であり; R 1 およびR 2are each independently selected from H and methyl; R 3 and R 4 are each independently H and C 1-4 alkyl; R 5 and R 6 are each independently H, halo, or C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Amino, C 1-4 Alkylamino and C 2-8 dialkylamino; Each R A is independent of Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1, N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 where R A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 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 The alkyl is optionally selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NRe1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from: R W , R X , R Y and R Z are each independently H, halo, or C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 Rd2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 where R W , R X , R Y or R Z The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 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 The alkyl is optionally selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from: W is CR W and X is CR X and Y is CR Y and Z is CR Z If so, then R W , R X , R Y and R Z at least one of is other than H; Each Cy 1 is independently C 6-10 Aryl, C 3-7cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each optionally selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and is substituted with 1, 2, 3 or 4 substituents independently selected from: Each Cy2 is independently C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each optionally selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2and is substituted with 1, 2, 3 or 4 substituents independently selected from: Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, 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 The alkyl group may optionally be Cy. 3 , Cy 3 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from: Each Cy 3 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each optionally containing halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 Rd3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 and is substituted with 1, 2, 3 or 4 substituents independently selected from: R a3 , R b3 , R c3 and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 Alkyl, C 1-6Haloalkyl, 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 OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 substituted with 1, 2 or 3 substituents independently selected from haloalkoxy; or R c1 and R d1 together with the N atom to which they are attached, optionally halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3, S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2 or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, optionally halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2 or 3 substituents independently selected from: Each Re1 , R e2 and R e3 are independently H, C 1-4 alkyl and CN; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, where p+q is 0, 1 or 2; r is 0 or 1; s is 0 or 1, where r+s is 0 or 1; and t is 1, 2 or 3; wherein any of said heteroaryl or heterocycloalkyl groups contains 1, 2, 3 or 4 ring-forming heteroatoms independently selected from O, N and S; one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups is optionally substituted with an oxo (=O) group; and One or more ring-forming S atoms of any of the above heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups. or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, W is CR W and X is CR X and Y is CR Y and Z is CR Z and m is 1 or 2, then R X and R Y Neither of them is methoxy.

[0078] In one embodiment, the compound is [ka] It is unexpected.

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

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

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

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

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

[0084] In some embodiments, ring A is optionally substituted with 1, 2, 3, or 4 R A Monocyclic or polycyclic C 3-14 cycloalkyl, where when ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. m - Bind to part.

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

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

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

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

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

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

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

[0092] In some embodiments, ring A is optionally substituted with 1, 2, 3, or 4 R A wherein when ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. m - Bind to part.

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

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

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

[0096] In certain embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.

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

[0098] In certain embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or tetrahydrothiopyranyl.

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

[0100] In certain embodiments, Ring A is piperidinyl.

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

[0102] In certain embodiments, Ring A is piperidin-4-yl.

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

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

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

[0106] In certain embodiments, Ring A is tetrahydropyran-4-yl.

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

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

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

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

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

[0112] In certain embodiments, m is 0.

[0113] In certain embodiments, m is 1.

[0114] In certain embodiments, n is 0.

[0115] In certain embodiments, n is 1.

[0116] In some embodiments, n is 2.

[0117] In one embodiment, R 1 and R 2 are both H.

[0118] In one embodiment, R 1 and R 2One of them is H and the other is methyl.

[0119] In certain embodiments, each R A is independently C 1-6 Alkyl, OR a1 , C(O)R b1 , N.R. c1 R d1 and S(O)R b1 wherein said C 1-6 The alkyl group may optionally be Cy. 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NRc1 R d1 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

[0120] In certain embodiments, each R A is independently C 1-6 Alkyl, halo, C 1-6 Haloalkyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. 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; 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 Each alkyl is optionally Cy 1 , Cy 1 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 Rd1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)NR c1 R d1 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

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

[0122] In one embodiment, R A OR a1 It is.

[0123] In certain embodiments, each R A is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1 , C(O)Rb1 , C(O)OR a1 and S(O)R b1 wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is optionally halo, CN, OR a1 , N.R. c1 R d1 , C(O)R b1 and N.R. c1 C(O)R b1 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

[0124] In certain embodiments, each R W , R X , R Y and R Z are independently H, halo, and C 1-6 Alkyl, C 1-6 Haloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, CN, OR a2 , C(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2Rb2 and N.R. 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 The alkyl is optionally selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2Rb2 and S(O)NR c2 R d2 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

[0125] In certain embodiments, each R W , R X , R Y and R Z are independently H, halo, and C 1-6 Alkyl, C 1-6 Haloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, CN, OR a2 , C(O)NR c2 R d2 , N.R. c2 R d2 and N.R. 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 The alkyl is optionally selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NRe2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)NR c2 R d2 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

[0126] In some embodiments, W is CR W and R W is other than H.

[0127] In some embodiments, W is CR W and R W is H.

[0128] In one embodiment, R W is a halo.

[0129] In one embodiment, R W is F.

[0130] In one embodiment, R W is C 1-6 Alkyl, C 1-6 Haloalkyl, Halo and OR a2 wherein C is selected from 1-6 Alkyl and C 1-6 Haloalkyl is optionally OR a2 has been replaced with.

[0131] In one embodiment, R W is C 1-6 Alkyl, C 1-6 Haloalkyl, CN, Halo and OR a2 wherein C is selected from 1-6 Alkyl and C 1-6 Haloalkyl is optionally OR a2 has been replaced with.

[0132] In one embodiment, R X and R Z Neither of these are halogens.

[0133] In one embodiment, R Z is H.

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

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

[0136] In some embodiments, X is CR X and R X is other than H.

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

[0138] In one embodiment, R X is C 1-6 Alkyl, Halo and OR a2 is selected from.

[0139] In some embodiments, Y is CR Y and R Y is other than H.

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

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

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

[0143] In some embodiments, Y is CR Y and R Y is NR c2 R d2 and N.R. c2 C(O)R b2 are independently selected from

[0144] In one embodiment, R Y is C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, OR a2 , S.R. a2 , C(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 Rd2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 and N.R. 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 selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , N.R. c2 R d2 and S(O)R b2 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

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

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

[0147] In some embodiments, Z is CR Z and R Z is other than H.

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

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

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

[0151] In certain embodiments, each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is H, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6 The alkyl group may optionally be Cy. 3 , Cy 3 -C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3S(O)2R b3 , N.R. c3 S(O)2NR c3 R d3 and S(O)NR c3 R d3 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

[0152] In certain embodiments, each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0153] In certain embodiments, each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each alkyl is optionally C1-4 Alkyl, C 1-4 Haloalkyl, Halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)R b3 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

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

[0155] In one embodiment, R c2 and R d2 are H and C respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Each alkyl is optionally C 1-4 Alkyl, C 1-4 Haloalkyl, Halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)R b3 and is substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

[0156] In one embodiment, Cy 3 In some cases, C 1-4 Alkyl, C 1-4 Haloalkyl, Halo, CN, OR a3 , C(O)R b3 , C(O)OR a3 and S(O)R b3 is a 4- to 10-membered heterocycloalkyl substituted by 1, 2, 3, 4, or 5 substituents independently selected from:

[0157] In one embodiment, Cy 3 In some cases, C(O)R b3 is a 4- to 10-membered heterocycloalkyl substituted by 1, 2, 3, 4, or 5 substituents independently selected from:

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

[0159] In some embodiments, the compounds described herein have formula II: [ka] has.

[0160] In certain embodiments, the compounds described herein have formula IIIA, IIIB, IIIC, IIID or IIIE: [ka] has.

[0161] In some embodiments, the compounds described herein have formula IVA or IVB: [ka] has.

[0162] In one embodiment, the PARP14 inhibitor 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile; 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 6-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 6-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(1-((tetrahydro-2H-pyran-4-yl)thio)ethyl)quinazolin-4(3H)-one; 5-Fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate; 8-Methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one; 2-((azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile; 7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-methylpiperidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 7-Fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2-((((trans)-3-(benzyloxy)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-((oxetan-3-ylthio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 6-Chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7,8-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 2-(((trans-3-hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-Fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-3-aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-Fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-Amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide; N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide; N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide; 4-Oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide; 7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((4-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((3-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrazin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrimidin-5-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methyl-1H-imidazol-2-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(thiazol-2-ylamino)quinazolin-4(3H)-one; 7-((2-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((4-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((5-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 7-(Cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(Cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(Dimethylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-Morpholino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(4-methylpiperazin-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(isopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-4-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-2-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(benzylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-phenylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)amino)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-3-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexyl(methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-[(1-benzyl-3-piperidyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one; 7-(3-piperidylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one; 7-((1-benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-Methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 7-((1-acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(4-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide; 2-(((1-(4-(dimethylamino)benzyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 4-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)benzonitrile; 2-(((1-((1H-pyrazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-(((1-((1-methyl-1H-indazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-quinazolin-4(3H)-one; 2-(((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-((3-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-phenethylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-((3-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(3-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide; 2-(((1-((1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(imidazo[1,2-a]pyridin-3-ylmethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-((1-benzyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenoxy)acetonitrile; 8-Methyl-2-(((1-((2-oxoindolin-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-((5-methoxypyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-(((1-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; (S)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (R)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (S)-8-methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(2-aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; N-(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)picolinamide; 2-(((1-(3-aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(3-aminopropanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(3-(dimethylamino)propanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (R)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine; (S)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine; 2-(((1-(L-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(D-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-Methyl-2-(((1-(3-(pyridin-2-yl)propanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; N-(((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl)acetamide; 7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-((((1R,4R)-4-(hydroxymethyl)cyclohexyl)thio)-methyl)quinazolin-4(3H)-one; 2-((((trans)-4-(2-aminoethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((3-(aminomethyl)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-3-(2-aminoethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one 7-(cyclopentylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; (S)-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 2-((azepan-4-ylthio)methyl)-7-(cyclopentylamino)quinazolin-4(3H)-one; 2-(((3-(aminomethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-((3-methylisoxazol-5-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1-(methylsulfonyl)azetidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methyl-2-((oxepan-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 7-Isobutyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 5-chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; Methyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate; 2-((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; cis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid; trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid; trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 7-(cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide; 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; (R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; (S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((((cis)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 2-(((trans-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 2-(((cis-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 6-Fluoro-7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; (R)-5-fluoro-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-cyclopentylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Chloro-7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2-difluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(3,3,3-trifluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(((2,2-difluorocyclopropyl)methyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2-difluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-((3,3-difluorocyclopentyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; (R)-2-(((1-acetylpiperidin-4-yl)thio)methyl)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-((piperidin-4-ylthio)methyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(1,1-dioxidothietan-3-yl)piperidin-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((2-morpholinoethyl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-methylacetamide; 7-(((2,2-difluorocyclopropyl)methyl)amino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetonitrile; 2-(trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 5-Fluoro-7-((2-morpholinoethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-6-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-6-fluoroquinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-(2,2-difluoropropyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-(2,2-difluoroethyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 5-Fluoro-7-((trans-2-fluorocyclopentyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-isobutoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-((cyclohexylthio)methyl)-5-fluoroquinazolin-4(3H)-one; 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one; trans-4-(((7-(cyclobutylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 7-((1-(2,2-difluoroethyl)piperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one; 7-((3,3-difluorocyclobutyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-7-((tetrahydro-2H-pyran-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; (R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; (S)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; (S)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; (R)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((S)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-(((cis)-3-ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((((trans)-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclobutylmethoxy)-5-fluoroquinazolin-4(3H)-one; 5-Fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one; 5-Fluoro-7-(((trans)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((cis)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-7-(oxetan-3-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1,4-dioxan-2-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclohexyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-5,6-difluoro-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((R)-1-acetylpyrrolidin-3-yl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-4(3H)-one; 7-((5,5-dimethyltetrahydrofuran-3-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-((((trans)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-2-((((cis)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-2-(((4-methyltetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-Fluoro-7-(((cis)-2-hydroxycyclopentyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (trans)-4-((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile; (cis)-4-((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile; 5,6-difluoro-7-(((trans)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one; 5-Methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 2-(((4,4-difluorocyclohexyl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpyrrolidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(2-cyclohexylethyl)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)thio)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((cis)-4-fluoropyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((cis)-4-fluoro-1-methylpyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5,6-Difluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one; 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((trans)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((trans)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propionamide; 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one; N-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-methylcyclohexyl)acetamide; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydro-2H-pyran-3-yl)amino)quinazolin-4(3H)-one; 5-Fluoro-2-((((trans)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazoline-5-carbonitrile; 5,6-Difluoro-7-(neopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((cis)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(((trans)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((cis)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide; 5-Fluoro-7-(((cis)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-((1-(cyclopropanecarbonyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5-fluoro-4-oxo-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-4-(((7-(cyclobutylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide; 7-(1-cyclopentylethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)cyclopropanecarboxamide; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((1-isobutyrylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((1-propionylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(piperidin-4-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((cis)-3-(trifluoromethoxy)cyclobutyl)amino)quinazolin-4(3H)-one; 7-Amino-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((((trans)-4-(dimethylamino)cyclohexyl)thio)methyl)-5-fluoro-7,8-dihydroquinazolin-4(3H)-one; 5-Fluoro-2-((((cis)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((2-methoxy-2-methylpropyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((((cis)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one; Methyl 4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate; 5-Fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((trans)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((4-methylmorpholin-2-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-(neopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((cis)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5,6-Difluoro-7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(3,3,3-trifluoro-2,2-dimethylpropoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(2-methoxyacetyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((((trans)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; and 7-((3,3-difluoro-1-methylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one or a pharma- ceutically acceptable salt thereof.

[0163] The PARP14 inhibitors described herein are described in U.S. Patent Publication US2019 / 0194174, which is incorporated by reference in its entirety.

[0164] It will be further recognized that certain features of the invention that are, for clarity, described in the context of a separate embodiment, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0165] At various places in the present specification, substituents of compounds of the invention are described in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0166] Various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described in various places in this specification.Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member that is available due to valence.For example, the term "pyridinyl", "pyridyl" or "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl ring.

[0167] The term "n-membered" (where "n" is an integer) typically refers to the number of ring-forming atoms in a moiety where the number of ring-forming atoms is "n." For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0168] For compounds of the invention in which a variable occurs more than once, each variable may be a different moiety independently selected from the group defining that variable. For example, when a structure is depicted in which two R groups are simultaneously present in the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0169] As used herein, the term "optionally substituted" means unsubstituted or substituted.

[0170] As used herein, the term "substituted" means that a hydrogen atom is replaced with a non-hydrogen group. It is to be understood that substitution of a given atom is limited by valence.

[0171] As used herein, the term "C" used in combination with chemical groups i-j " (where i and j are integers) specifies a range of the number of carbon atoms in a chemical group, with ij defining the range. For example, C 1-6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0172] The term "alkyl" as used herein, alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. In certain embodiments, the alkyl group contains 1-7, 1-6, 1-4, or 1-3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In certain embodiments, the alkyl group is methyl, ethyl, or propyl.

[0173] 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 certain embodiments, the alkenyl moiety contains 2-6 or 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0174] 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. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0175] As used herein, "halo" or "halogen," employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In certain embodiments, halo is F or Cl.

[0176] The term "haloalkyl," as used herein, alone or in combination with other terms, refers to an alkyl group having halogen atom substituents, which may be the same or different, up to full valence. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1-6 or 1-4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0177] The term "alkoxy," as used herein, employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In certain embodiments, alkyl groups have 1 to 6 or 1 to 4 carbon atoms.

[0178] As used herein, "haloalkoxy," employed alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In certain embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example of a haloalkoxy group is -OCF3.

[0179] As used herein, "amino," employed alone or in combination with other terms, refers to NH2.

[0180] The term "alkylamino" as used herein, used alone or in combination with other terms, refers to a group of formula -NH(alkyl). In certain embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0181] The term "dialkylamino," as used herein, employed alone or in combination with other terms, refers to a group of formula -N(alkyl). Examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In certain embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0182] The term "cycloalkyl" as used herein, alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to the cycloalkyl ring moiety, such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, or pyrido derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of a cycloalkyl group may be optionally substituted with oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at one carbon atom, such as spiro[2.5]octane). In some embodiments, the cycloalkyl group has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0183] The term "cycloalkylalkyl" as used herein, employed alone or in combination with other terms, refers to a group of formula cycloalkyl-alkyl-. In certain embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In certain embodiments, the alkyl moiety is methylene. In certain embodiments, the cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In certain embodiments, the cycloalkyl group is monocyclic or bicyclic. In certain embodiments, the cycloalkyl moiety is monocyclic. In certain embodiments, the cycloalkyl moiety is C 3-7 It is a monocyclic cycloalkyl group.

[0184] The term "heterocycloalkyl" as used herein, alone or in combination with other terms, refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Included in or within the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to a non-aromatic heterocycloalkyl ring moiety, such as 1,2,3,4-tetrahydro-quinoline. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadamantan-1-yl) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused to one atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl]). In some embodiments, heterocycloalkyl groups have 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming 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. Carbon atoms or heteroatoms of the ring of a heterocycloalkyl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized. In certain embodiments, the heterocycloalkyl moiety is C 2-7Monocyclic heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0185] The term "heterocycloalkylalkyl" as used herein, employed alone or in combination with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In certain embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In certain embodiments, the alkyl moiety is methylene. In certain embodiments, the heterocycloalkyl moiety has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In certain embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In certain embodiments, the heterocycloalkyl moiety is monocyclic. In certain embodiments, the heterocycloalkyl moiety is C 2-7 It is a monocyclic heterocycloalkyl group.

[0186] The term "aryl" as used herein, alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety, including, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, the aryl group has 6-10 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.

[0187] The term "arylalkyl," as used herein, alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In certain embodiments, the alkyl moiety has 1-4, 1-3, 1-2, or 1 carbon atoms. In certain embodiments, the alkyl moiety is methylene. In certain embodiments, the aryl moiety is phenyl. In certain embodiments, the aryl group is a monocyclic or bicyclic group. In certain embodiments, the arylalkyl group is benzyl.

[0188] The term "heteroaryl," as used herein, 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 certain embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. Carbon atoms or heteroatoms of the ring of a heteroaryl group can be oxidized to form carbonyl, N-oxide or sulfonyl groups (or other oxidized bonds) or nitrogen atoms can be quaternized, provided that the aromatic character of the ring is retained. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0189] The term "heteroarylalkyl" as used herein, alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In certain embodiments, the alkyl moiety has 1-4, 1-3, 1-2, or 1 carbon atoms. In certain embodiments, the alkyl moiety is methylene. In certain 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 certain embodiments, the heteroaryl moiety has 5-10 carbon atoms.

[0190] The compounds described herein can be asymmetric (e.g., have one or more stereoisomeric centers). Stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention can be isolated as isomeric mixtures or as separate isomeric forms.

[0191] The compounds described herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms in which a proton may occupy more than one position of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0192] The compounds described herein also include all isotopes of atoms in intermediates or final compounds.Isotopes include 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.

[0193] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0194] All compounds and their pharma- ceutically acceptable salts may be found together with other substances such as water and solvents (eg, in the form of hydrates and solvates) or may be isolated.

[0195] In some embodiments, the compounds described herein or salts thereof are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched in the compounds of the present invention. Substantial separation can include compositions that contain at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present invention or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0196] The term "pharmacologically acceptable" as used herein refers to compounds, substances, compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0197] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0198] How to use It was found that genetic inactivation of poly(ADP-ribose) polymerase family member 14 (PARP14), also known as ADP-ribosyltransferase diphtheria toxin-like 8 (ARTD8) or B invasive lymphoma protein (BAL2), protected mice from allergen-induced airway disease (Mehrothra et al. 22841009, Cho et al. 23956424), inhibited the infiltration of immune cells such as eosinophils and neutrophils into the lungs, and reduced the release of inflammatory Th2 cytokines. Furthermore, treatment with a PARP14 inhibitor protected mice from severe asthma models induced by inhaled Alternaria alternata extract sensitization and recall exposure. PARP14 inhibitor-treated animals showed reduced airway mucus levels, serum IgE, infiltration of immune cells (eosinophils, neutrophils and lymphocytes), Th2 cytokines (IL-4, IL-5 and IL13) and alarmins (IL-33 and TSLP) (Ribon internal data).

[0199] Without being bound by theory, PARP14 has been shown to affect STAT6 and STAT3 signaling, signaling induced by Th2 and Th17 cytokines, M1 / M2 macrophage polarization, and signaling by lymphocytes. PARP14 has also been shown to be a regulator of Th2 / Th17 / THF T cell development, involved in B cell development, and involved in eosinophil / neutrophil recruitment / activation. Lymphocytes may be ILCs (e.g., ILC2 and ILC3) that are activated by alarmins (e.g., TSLP and IL-33) and are the main producers of downstream cytokines (e.g., IL-4, IL-5, and IL-13).

[0200] Not only does PARP14 inhibition affect the asthma phenotype at the level of secondary cytokines (e.g., IL-4, IL-5, and IL-13) and signaling to myeloid cells, but PARP14 inhibition also suppresses the alarmins TSLP and IL-33, which are important upstream drivers of asthma that are released in response to allergens.

[0201] The present invention relates, inter alia, to a method of treating or preventing an inflammatory disease in a patient comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as any of the compounds described herein or a pharma- ceutically acceptable salt thereof.

[0202] Examples of inflammatory diseases treatable by the disclosed method include, for example, asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloids, eosinophilic disorders, pulmonary fibrosis and other type 2 cytokine pathologies. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0203] Further examples of inflammatory diseases treatable by the disclosed methods include inflammatory bowel disease ("IBD"), including ulcerative colitis ("UC" or "colitis") and Crohn's disease. In some embodiments, the inflammatory disease is inflammatory bowel disease. In some embodiments, the inflammatory disease is ulcerative colitis. In some embodiments, the inflammatory disease is Crohn's disease.

[0204] In certain embodiments, the inflammatory disease is irritable bowel syndrome.

[0205] Eosinophilic disorders treatable by the disclosed methods include, for example, eosinophilic esophagitis (esophagus-EoE), eosinophilic gastritis (stomach-EG), eosinophilic gastroenteritis (stomach and small intestine-EGE), eosinophilic enteritis (small intestine-EE), eosinophilic colitis (colon-EC), and eosinophilic chronic rhinosinusitis.

[0206] The present invention further relates, inter alia, to a method for treating or preventing asthma in a patient, comprising administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as any of the compounds described herein or a pharma- ceutically acceptable salt thereof.

[0207] In some embodiments, asthma is steroid-insensitive asthma, steroid-refractory asthma, steroid-resistant asthma, atopic asthma, non-atopic asthma, persistent asthma, severe asthma or steroid-refractory severe asthma.In some embodiments, severe asthma is T2 high endotype, T2 low endotype or non-T2 endotype.In some embodiments, severe asthma is T2 high endotype.In some embodiments, severe asthma is T2 low endotype or non-T2 endotype.In some embodiments, severe asthma is T2 low endotype.In some embodiments, severe asthma is non-T2 endotype.

[0208] The present invention further relates to a method for treating or preventing fibrotic diseases, such as, but not limited to, pulmonary fibrosis, renal fibrosis, liver fibrosis (e.g., NASH and NAFLD), systemic fibrosis and idiopathic pulmonary fibrosis (IPF).In some embodiments, the fibrotic disease is systemic fibrosis.

[0209] The present invention further relates to methods of treating or preventing, inter alia, chronic obstructive pulmonary disease (COPD), emphysema and chronic bronchitis.

[0210] The present invention further relates to methods of treating or preventing inflammatory skin diseases, such as, inter alia, atopic dermatitis or rosacea.

[0211] The present invention further relates to a method for treating a patient having (a) reducing the level of airway mucus in lung tissue; (b) reduction in serum IgE; (c) reduced immune cell infiltration and activation in bronchoalveolar fluid; (d) reducing the levels of one or more inflammatory cytokines in bronchoalveolar fluid or lung tissue; or (e) reducing the levels of one or more alarmins in bronchoalveolar fluid or lung tissue. The method includes administering to the patient a therapeutically effective amount of a PARP14 inhibitor, such as a compound disclosed herein or a pharma- ceutically acceptable salt thereof.

[0212] In certain embodiments, the present invention provides a method of reducing the level of airway mucus in lung tissue in a patient.

[0213] In one embodiment, the present invention provides a method of reducing immune cell infiltration and activation in bronchoalveolar fluid in a patient. In one embodiment, the immune cells are eosinophils, neutrophils or lymphocytes.

[0214] In some embodiments, the present invention provides a method for reducing one or more inflammatory cytokines in bronchoalveolar fluid or lung tissue in a patient.In some embodiments, the inflammatory cytokine is a Th2 cytokine or a Th17 cytokine.In some embodiments, the inflammatory cytokine is a Th2 cytokine.In some embodiments, the inflammatory cytokine is IL-4, IL-5, IL13 or IL-17A.In some embodiments, the inflammatory cytokine is IL-4, IL-5 or IL-13.

[0215] In one embodiment, the present invention provides a method of reducing an alarmin in bronchoalveolar fluid or lung tissue in a patient. In one embodiment, the alarmin is IL-25, IL-33 or TSLP.

[0216] As used herein, the term "reduction" refers to a level in a patient prior to administration. More specifically, when a biomarker or symptom is reduced in a patient, the reduction refers to the level or severity of the biomarker or symptom in the patient prior to administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0217] As used herein, the terms "individual" or "patient" are used interchangeably and refer to mammals, and in particular humans. A patient may be in need of treatment.

[0218] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits 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.

[0219] As used herein, the term "treat" or "treatment" refers to 1) preventing a disease in an individual experiencing or exhibiting the pathology or symptomology of the disease (i.e., preventing further progression of the pathology and / or symptoms), or 2) alleviating a disease in an individual experiencing or exhibiting the pathology or symptomology of the disease (i.e., ameliorating the pathology and / or symptoms).

[0220] The terms "prevent" or "prevention" as used herein refer to the prevention of disease in individuals who may be predisposed to the disease but have not yet experienced or exhibited the pathology or symptomology of the disease.

[0221] Combination Therapy The compound of the present invention may be administered in combination with one or more additional medicines or treatment methods, which may be, for example, inhaled corticosteroids, inhaled long-acting beta antagonists or intravenously injected monoclonal antibodies.The compound of the present invention may also be administered in combination with other treatments or other targeted therapies.The drug may be combined with the compound in one dosage form, or the drug may be administered simultaneously or sequentially in separate dosage forms.

[0222] Suitable agents for use in combination with the compounds of the invention for the treatment of inflammatory diseases include corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone); disease-modifying antirheumatic drugs ("DMARDs", e.g., immunosuppressive or anti-inflammatory agents); antimalarials (e.g., hydroxychloroquine and chloroquine); immunosuppressants (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate); anti-inflammatory agents (e.g., aspirin, NSAIDs (e.g., ibuprofen, naproxen, indomethacin, nabumetone, celecoxib)); antihypertensive agents (e.g., calcium channel blockers, anti-CD20 (e.g., rituximab), anti-CD22; anti-B lymphocyte stimulators ("anti-BLyS", e.g., belimumab, blissibimod); type 1 interferon receptor antagonists (e.g., anifrolumab); T cell modulators (e.g., ligerimod); abatacept; anticoagulants (e.g., heparin, warfarin); and vitamin D supplements.

[0223] Further suitable agents for use in the combinations of the present invention for treating inflammatory diseases include, but are not limited to, sulfonylureas, meglitinides, biguanides, alpha-glucosidase inhibitors, peroxisome proliferator-activated receptor-gamma (i.e., PPAR-gamma) agonists, insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (e.g., fibrates, including fenofibrate, bezafibrate, gemfibrozil, clofibrate, and the like; bile acid sequestrants, including cholestyramine, colestipol, and the like; and niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists, including clopidogrel, ticlopidine, and the like), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and adiponectin.

[0224] Suitable drugs for use in the combination of the present invention for the treatment of asthma include beclomethasone (Cuvar). TM ), budesonide (Pulmicort Flexhaler TM ), budesonide / formoterol (Symbicort TM ), ciclesonide (Olvest TM ), flunisolide (Aerospan TM ), fluticasone (Flovent Diskus TM , flovent HFA TM , Annuity Ellipta TM ), fluticasone / salmeterol (Advair TM ), Mometasone (Azmanex TM ), mometasone / formoterol (Dulera TM ), albuterol sulfate (VoSpireER TM ), formoterol fumarate (Aerolizer TM ), salmeterol xinafoate (Serevent TM ), Arformoterol Tartrate (Brovana TM ), olodaterol (Striverdi TM ), fluticasone furoate / vilanterol (Breo Ellipta TM), fluticasone furoate / umeclidinium / vilanterol (Terilgy Ellipta TM ), Fluticasone Propionate / Salmeterol (AirDuo TM ), glycopyrrolate / formoterol fumarate (Bebespi Aerosphere TM ), Indacaterol / Glycopyrrolate (Utibron Neohaler TM ), tiotropium / olodaterol (Stiolto Respimat TM ), umeclidinium / vilanterol (Anoroellipta TM ), omalizumab (Xolair) TM ), mepolizumab (Nucala TM ), benralizumab (Fasenra TM ), reslizumab (Cinqair TM ), dupilumab, tralokinumab, lebrikizumab, etanercept, golimumab brodalumab, and tezepelumab.

[0225] Pharmaceutical Formulations and Dosage Forms When used as a pharmaceutical, the compounds of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a combination of the compounds of the present invention or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier. These compositions can be administered by methods well known in the pharmaceutical art, and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be oral, topical (mucosal, including ocular and intranasal, vaginal and rectal delivery), pulmonary (inhalation or insufflation of powders or aerosols, including, for example, by nebulizer; intratracheal, intranasal, epithelial and transdermal), ocular or parenteral.

[0226] The present invention also includes pharmaceutical compositions that contain one or more of the compounds of the present invention as active ingredients in combination with one or more pharma-ceutically acceptable carriers.When preparing the compositions of the present invention, the active ingredients are typically mixed with additives, diluted with additives or enclosed in such carriers, for example in the form of capsules, sachets, paper or other containers.When additives serve as diluents, they can be solid, semi-solid or liquid substances that act as a solvent, carrier or medium for the active ingredients.Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders that contain up to 10% by weight of the active compounds.

[0227] The compositions may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients.

[0228] The active compounds may be effective over a wide range of dosages and may generally be administered in a pharma- ceutical effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician depending on the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0229] In preparing solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, from 0.1 to about 500 mg of the active ingredient of the present invention.

[0230] The tablets or pills of the present invention can be coated or otherwise prepared to provide a dosage form with the advantage of long-acting action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of a coating over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact to the duodenum or to delay release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0231] Liquid forms into which the compounds and compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil 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.

[0232] Compositions for inhalation or insufflation include solutions and suspensions and powders in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described above. In some embodiments, compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by using inert gas. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be connected to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0233] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions are administered to a patient already suffering from a disease in an amount sufficient to cure the disease and its complications or at least partially halt the symptoms. The effective dose will depend on the disease state being treated and will be at the discretion of the clinician depending on factors such as the severity of the disease, the age, weight and general condition of the patient.

[0234] The compositions administered to patients can be in the form of the above-mentioned pharmaceutical compositions.These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.Aqueous solutions can be packaged or lyophilized for immediate use, and lyophilized preparations are combined with sterile aqueous carriers before administration.

[0235] The therapeutic dosage of the compounds of the invention may vary depending, for example, on the particular application for which the treatment is made, the method of administration of the compound, the health and condition of the patient, and the judgment of the treating physician. The proportion or concentration of the compound of the invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. One typical dosage range is about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage may depend on such variables as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the compound selected, the formulation of excipients, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0236] 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 immune enhancer, an immunosuppressant, an anti-inflammatory agent, or the like. EXAMPLES

[0237] Between-group deviations were statistically analyzed by one-way analysis of variance (ANOVA). When there were significant differences in the means between different levels of treatment, comparisons to the vehicle group were performed using Dunnett's test. p<0.05 was considered statistically significant.

[0238] Example A. Dose and efficacy testing of Compound 1 in an Alternaria-induced asthma model This was done to assess the effect of a PARP14 inhibitor, Compound 1, on pulmonary inflammation by assessing bronchoalveolar lavage (BAL) fluid cell counts, BAL fluid supernatant and lung tissue homogenate concentrations of TSLP, IL-4, IL-5, IL13 and IL-33, serum total IgE concentrations and airway mucus production in mice exposed to Alternaria. [ka] Dose-response evaluation of the effects of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one. This Alternaria-induced asthma model in mice is a recognized animal model for evaluating potential efficacy in treating asthma, including severe asthma. See U.S. Patent Publication US2019 / 0194174 for a description of Compound 1.

[0239] Animal welfare Throughout the study, all animals were maintained in the Biological Support Unit at the Pharmidex facility, European Knowledge Centre, Mosquito Way, Hatfield, AL10 9WN, United Kingdom. The facility operates under the UK Home Office Animal Scientific Procedures Act and therefore holds a valid facility licence (X07D13023) enabling it to carry out prescribed animal procedures at the facility. On arrival from the supplier, animals (55 male BalbC mice, 20-30g on arrival, Charles Rivers, UK) were housed in five cages as outlined below and the welfare of all animals was checked daily. Emergency care was provided by a designated veterinary surgeon if required, but this was not required during the study.

[0240] Throughout the study, non-specific or unexpected adverse effects in animals undergoing regulated activities related to the method or administration of test compounds were evaluated using the following guidelines (Home Office Notice): Animals exhibiting two or more of any limiting clinical signs of a category equal to the protocol severity limit were removed from the study and sacrificed at the facility by Schedule 1 methods (cervical dislocation). When animals reached the limit of one or both of the first two signs with or without any other sign, they were removed from the study and sacrificed at the facility by Schedule 1 methods. Weight loss of more than 20% of the highest weight measured in an individual. Prominent piloerection accompanied by other signs of dehydration such as skin tenting. Unresponsive to activity and provocation. Persistently curled up (rigid). Distress-persistent crying. Persistent, copious eye and nasal discharge. forced breathing. Persistent tremors. Persistent convulsions.

[0241] Animals that sustained severe fighting injuries were also removed from the study and sacrificed by Schedule 1 methods at the facility. A 7-day acclimation period was allowed before the start of experimental procedures. Mice were housed on arrival in 5 cages based on body weight (animal weights were distributed evenly between each cage by the animal technician) with a 12-h light / dark cycle. Room temperature and humidity were maintained within Home Office guidelines (17-24°C and 40-70%, respectively). Environmental enrichment was provided in all cages. Mice had access to standard chow ad libitum and water was available ad libitum from bottles.

[0242] Allergen exposure Alternaria alternata was diluted in sterile phosphate-buffered saline (PBS) to 5 µg Alternaria per 40 µL. On days 1-5, Balb / c mice were exposed (intranasally) to isoflurane anesthesia. On days 23-25, Balb / c mice were exposed (intranasally) to isoflurane anesthesia 1 hour after the first dose of the day. PBS (group 1) or Alternaria (groups 2-6) were instilled dropwise into each nostril, alternating between the two, until 40 μl was delivered.

[0243] Formulations and treatment regimens 1-Aminobenzotriazole (1-ABT 25 mg / kg) and Compound 1 (150, 500 and 1500 mg / kg) were each independently formulated in a vehicle of 0.5% methylcellulose (MC) and 0.2% Tween in distilled water, and Compound 1 (150, 500 and 1500 mg / kg) was co-formulated in a vehicle of 0.5% methylcellulose (MC) and 0.2% Tween in distilled water. Group 1: On days 19-25, animals received vehicle (10 mL / kg, po, bid). On day 26, animals received vehicle 23 hours after PBS exposure on day 25. All mice were sacrificed 2 hours later. Group 2: On days 19-25, animals were administered vehicle (10 mL / kg, po, bid). On day 26, animals were administered vehicle 23 h after exposure to Alternaria on day 25. All mice were sacrificed 2 h later. Groups 3, 4, and 5: On days 19-25, animals were administered Compound 1 vehicle (10 mL / kg, po, bid). On day 26, animals were administered Compound 1 vehicle 23 h after Alternaria exposure on day 25. All mice were sacrificed 2 h later. Group 6: On day 19, animals were administered 1-ABT vehicle (10 mL / kg) followed 2 h later by Compound 1 vehicle (10 mL / kg). 12 h after Compound 1 vehicle administration, animals were administered 1-ABT and Compound 1 vehicle. On days 20-25, 1-ABT and Compound 1 vehicle were administered (po, bid). On day 26, 1-ABT and Compound 1 vehicle were administered 23 h after day 25 Alternaria exposure. All mice were sacrificed 2 h later.

[0244] Blood sample collection On day 19, animals 1-5 in groups 3-6 collected blood samples (15-20 μL) by venipuncture from the lateral tail vein 2 hours after the first dose of compound 1, and animals 6-10 in groups 3-6 collected blood samples (15-20 μL) by venipuncture from the lateral tail vein 30 minutes before the second dose of compound 1 (11.5 hours after the first dose). On day 26, blood samples were collected from all animals 30 minutes before the last dose of compound 1 and 2 hours after the last dose as the final blood draw. Each blood sample (15-20 μL) was placed in an EDTA tube, mixed gently, and then centrifuged (2000 g, 15 minutes, 4°C) from which the resulting supernatant was extracted, aliquoted, and stored at -80°C. On day 26, a final blood sample was collected from the lateral tail vein and placed into serum tubes. Each serum sample was kept at room temperature for 45 min to allow for clotting, then centrifuged (2000 g, 15 min, 4°C), from which the resulting supernatant was extracted, aliquoted, and stored at -80°C until analysis of IgE concentration.

[0245] Bronchoalveolar lavage (BAL) Immediately after the last blood sample collection, the animals were sacrificed by an overdose of pentobarbital. The trachea was then isolated by a midline incision in the neck and separation of the muscle layers. A small incision was made in the trachea and a plastic cannula was inserted and fixed in place with sutures. The airway was then lavaged by flushing the lungs using 0.5 mL of phosphate-buffered saline. This process was repeated until a volume of 1.6 mL was collected. The isolated BAL fluid was then centrifuged at 1500 rpm for 10 minutes at 4°C and the supernatant was aliquoted (400 μL) at -80°C for cytokine analysis. The cell pellet was then resuspended in 1.6 mL of phosphate-buffered saline and the BAL cells were then analyzed for total and differential counts.

[0246] Lung tissue collection After BAL fluid collection, the thoracic cavity was opened to expose the lungs and dissected from the animal. The left lung lobe was sliced ​​into equal halves along the midline. One half was placed in a sterile container filled with RNAlater and the other half was placed in another sterile container with 10% neutral buffered formalin and transferred to 70% ethanol for tissue processing and mucus scoring after 48 hours. The right lung lobe was placed in a sterile container, flash frozen, and then stored at -80°C before being processed and analyzed for cytokine concentrations. After fixation and processing of left lobe tissue in paraffin wax, sections (5 μM) were cut transversely, mounted on slides, stained with Periodic Acid Schiff (PAS), and then analyzed for airway mucus production using digital imaging.

[0247] Airway mucus production Airway mucus production was quantified as the percentage of mucus-covered surface from the ratio of mucus-positive epithelium to total epithelium using an area quantification algorithm (Halo image analysis software). Compound 1 reduced airway mucus levels. Figure 1 shows bar graphs representing the area of ​​PAS positive mucin in the airway mucosa of mouse lung tissue after treatment with Compound 1 (150-1500 mg / kg, po, bid, days 19-25), Compound 1 (500 mg / kg, po, bid, days 19-25) and 1-ABT treatment (25 mg / kg, po, bid, days 19-25) and vehicle (10 mL / Kg, po, bid, days 19-25) in Alternaria-sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Vehicle and Alternaria exposure (group 2) were compared to all other groups by ANOVA followed by Dunnett's test. *** P<0.001. Compound 1 reduced airway mucus in lung tissue in a dose-dependent manner.

[0248] IgE assay Serum supernatants were assessed for IgE concentration using an ELISA kit (Invitrogen, UK) according to the manufacturer's instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). IgE concentrations were determined using SoftMax Pro v. 6.4 (Molecular Devices). FIG. 2 shows plots depicting IgE levels in serum following treatment with vehicle, Compound 1, and Compounds 1 and 1-AB in Alternaria-sensitized mice exposed to PBS or Alternaria. Compound 1 reduced serum IgE levels in a dose-dependent manner.

[0249] number of cells Total and differential cell counts of BAL fluid samples were measured using an XT-2000iV analyzer (Sysmex). Differentially classified cell types were neutrophils, eosinophils, lymphocytes or macrophages. FIG. 3 shows plots depicting the relative abundance of neutrophils, eosinophils, lymphocytes and macrophages in BAL fluid following treatment with vehicle, Compound 1, and Compound 1 and 1-ABT in Alternaria-sensitized mice exposed to PBS or Alternaria. Compound 1 dose-dependently suppressed eosinophil, neutrophil and lymphocyte infiltration in bronchoalveolar lavage fluid. The total numbers of both eosinophils and neutrophils were significantly decreased by compound 1 treatment, suggesting the suppression of Th2 / TH17 signaling. The total number of lymphocytes was decreased at the highest dose of compound 1. There was no change in the number of macrophages. Compound 1 (500 mg / kg) and 1-ABT showed similar effects compared to compound 1 (500 mg / kg).

[0250] Cytokine analysis Cytokine concentrations (TSLP, IL-4, IL-5, IL-13 and IL-33) in BAL fluid supernatants and lung homogenates (all groups) were measured using ELISA kits (Biotechne, UK) according to the manufacturer's instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). Cytokine concentrations were determined using SoftMax Pro v. 6.4 (Molecular Devices). FIG. 4 shows bar graphs representing concentrations of TSLP, IL-4, IL-5, IL-13, and IL-33 in BAL fluid supernatants following treatment with vehicle, Compound 1, and Compound 1 and 1-ABT in Alternaria-sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Vehicle exposed Alternaria (group 2) was compared with all other groups ( * ) compared with * P < 0.05, ** P < 0.01 and *** *P<0.001. Figure 5 shows bar graphs representing concentrations of TSLP, IL-4, IL-5, IL-13 and IL-33 in lung homogenates following vehicle, Compound 1 and Compound 1-ABT treatment in Alternaria-sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Alternaria-exposed vehicle (group 2) was compared with all other groups ( * ) compared with * P < 0.05, ** P < 0.01 and *** P<0.001. Compound 1 dose-dependently reduced Th2 cytokine (IL-4, IL-5, and IL-13) and alarmin (IL-33 and TSLP) levels in BAL fluid and lung homogenates.

[0251] Example B. Efficacy Test of Compound 1 and Compound 2 in an Alternaria-Induced Asthma Model The study assessed the efficacy and safety of a PARP14 inhibitor, Compound 1: [ka] 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one and compound 2: [ka] 7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one Dose-response evaluation of the effect on pulmonary inflammation by assessment of bronchoalveolar lavage (BAL) fluid cell counts, BAL fluid supernatant concentrations of IL-4, IL-5, IL13, and IL-33, total IgE concentrations, and airway mucus production in mice exposed to Alternaria for 10 min. See U.S. Patent Publication US2019 / 0194174 for description of compounds 1 and 2.

[0252] Animal welfare Throughout the study, all animals were maintained in the Biological Support Unit at the Pharmidex facility, European Knowledge Centre, Mosquito Way, Hatfield, AL10 9WN, United Kingdom. The facility operates under the UK Home Office Animal Scientific Procedures Act and therefore holds a valid facility licence (X07D13023) enabling it to carry out prescribed animal procedures at the facility. On arrival from the supplier, animals (35 male BalbC mice, 20-30 g on arrival, Charles Rivers, UK) were housed in five cages as outlined below and the welfare of all animals was checked daily. If necessary, emergency care was provided by a designated veterinary surgeon but this was not required during the study.

[0253] Throughout the study, non-specific or unexpected adverse effects in animals undergoing regulated activities related to the method or administration of test compounds were evaluated using the following guidelines (Home Office Notice): Animals exhibiting two or more of any limiting clinical signs of a category equal to the protocol severity limit were removed from the study and sacrificed at the facility by Schedule 1 methods (cervical dislocation). When animals reached the limit of one or both of the first two signs with or without any other sign, they were removed from the study and sacrificed at the facility by Schedule 1 methods. Weight loss of more than 20% of the highest weight measured in an individual. Prominent piloerection accompanied by other signs of dehydration such as skin tenting. Unresponsive to activity and provocation. Persistently curled up (rigid). Distress-persistent crying. Persistent, copious eye and nasal discharge. forced breathing. Persistent tremors. Persistent convulsions.

[0254] Animals that sustained severe fighting injuries were also removed from the study and sacrificed by Schedule 1 methods at the facility. A 7-day acclimation period was allowed before the start of experimental procedures. Mice were housed on arrival in 5 cages based on body weight (animal weights were distributed evenly between each cage by the animal technician) with a 12-h light / dark cycle. Room temperature and humidity were maintained within Home Office guidelines (17-24°C and 40-70%, respectively). Environmental enrichment was provided in all cages. Mice had access to standard chow ad libitum and water was available ad libitum from bottles.

[0255] Allergen exposure Alternaria alternata was diluted in sterile PBS to 5 μg Alternaria per 40 μL. On days 1-5, Balb / c mice were exposed (intranasally) to isoflurane anesthesia. On days 23-25, Balb / c mice were exposed (intranasally) to isoflurane anesthesia 1 hour after the first dose of the day. PBS (group 1) or Alternaria (groups 2-4) were instilled dropwise into each nostril, alternating between the two, until 40 μl was delivered.

[0256] Formulations and treatment regimens 1-aminobenzotriazole (1-ABT, 25 mg / kg), compound 2 (500 mg / kg) and compound 1 (500 mg / kg) were each formulated in a vehicle of 0.5% methylcellulose (MC) and 0.2% Tween in distilled water, and 1-aminobenzotriazole (1-ABT, 25 mg / kg) and compound 1 (500 mg / kg) were co-formulated in a vehicle of 0.5% methylcellulose (MC) and 0.2% Tween in distilled water. Group 1: On days 19-25, animals received 1-ABT vehicle (10 mL / kg) bid. On day 26, animals received 1-ABT vehicle 23 hours after PBS exposure on day 25. All mice were sacrificed 2 hours later. Group 2: On days 19-25, animals received 1-ABT vehicle (10 mL / kg) bid. On day 26, animals received 1-ABT vehicle 23 h after Alternaria exposure on day 25. All mice were sacrificed 2 h later. Group 3: On days 19-25, animals were administered Compound 2 vehicle (10 mL / kg) bid. On day 26, animals were administered Compound 2 vehicle 23 hours after Alternaria exposure on day 25. All mice were sacrificed 2 hours later. Group 4: On day 19, animals were administered 1-ABT vehicle (10 mL / kg) followed 2 h later by Compound 1 vehicle (10 mL / kg). 12 h after Compound 1 vehicle administration, animals were administered 1-ABT and Compound 1 vehicle. On days 20-25, 1-ABT and Compound 1 vehicle were administered (po, bid). On day 26, 1-ABT and Compound 1 vehicle were administered 23 h after day 25 Alternaria exposure. All mice were sacrificed 2 h later.

[0257] Blood collection On day 19, animals 1-5 in groups 3 and 4 collected blood samples (15-20 μL) by venipuncture from the lateral tail vein 2 hours after the first dose of compound 2 or compound 1, and animals 6-10 in groups 3 and 4 collected blood samples (15-20 μL) by venipuncture from the lateral tail vein 30 minutes before the second dose of compound 2 or compound 1 (11.5 hours after the first dose). On day 26, blood samples were collected from all animals 30 minutes before the last dose of compound 2 or compound 1 and 2 hours after the last dose as the final blood draw. Each blood sample (15-20 μL) was placed in an EDTA tube, mixed gently, and then centrifuged (2000 g, 15 minutes, 4°C) from which the resulting supernatant was extracted, aliquoted, and stored at -80°C. On day 26, a final blood sample was collected from the lateral tail vein and placed into serum tubes. Each serum sample was kept at room temperature for 45 min to allow for clotting, then centrifuged (2000 g, 15 min, 4°C), from which the resulting supernatant was extracted, aliquoted, and stored at -80°C until analysis of IgE concentration.

[0258] Bronchoalveolar lavage (BAL) Immediately after the last blood sample collection, the animals were sacrificed by an overdose of pentobarbital. The trachea was then isolated by a midline incision in the neck and separation of the muscle layers. A small incision was made in the trachea and a plastic cannula was inserted and fixed in place with sutures. The airway was then lavaged by flushing the lungs using 0.5 mL of phosphate-buffered saline. This process was repeated until a volume of 1.6 mL was collected. The isolated BAL fluid was then centrifuged at 1500 rpm for 10 minutes at 4°C and the supernatant was aliquoted (400 μL) at -80°C for cytokine analysis. The cell pellet was then resuspended in 1.6 mL of phosphate-buffered saline and BAL cells BAL cells were analyzed for total and differential counts.

[0259] Lung and spleen tissue collection After BAL fluid collection, the thoracic cavity was opened to expose the lungs. The right and left lung lobes were placed in separate sterile containers containing 10% neutral buffered formalin for 48 hours and then transferred to 70% ethanol for tissue processing and mucus scoring. Lung tissue was analyzed for cytokine concentrations. Each animal also had a spleen removed after lung extraction. The spleen was cut into two pieces and each piece was weighed. One piece was flash frozen and stored at -80°C while the second piece was placed in RNAlater. After fixation and processing of left lobe tissue in paraffin wax, sections (5 μM) were cut transversely, mounted on slides, stained with Periodic Acid Schiff (PAS), and then analyzed for airway mucus production using digital imaging.

[0260] Airway mucus production Airway mucus production was quantified as the percentage of mucus-covered surface from the ratio of mucus-positive epithelium to total epithelium using an area quantification algorithm (Halo image analysis software). FIG. 6 shows a bar graph representing the area of ​​PAS-positive mucin in the airway mucosa of mouse lung tissue after vehicle and 1-ABT, compound 2, and compound 1 and 1-ABT treatment in Alternaria-sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Alternaria-exposed vehicle and 1-ABT (group 2) were compared with all other groups ( * ) compared with *** P<0.001. Compound 2 and Compound 1 reduced airway mucus in lung tissue.

[0261] IgE assay Serum supernatants were assessed for IgE concentration using an ELISA kit (Invitrogen, UK) according to the manufacturer's instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). IgE concentrations were determined using SoftMax Pro v. 6.4 (Molecular Devices). Data are presented as IgE (pg / mL), mean ± SEM (standard error of the mean). FIG. 7 shows bar graphs representing IgE concentrations in serum after treatment with vehicle and 1-ABT, compound 2, and compound 1 and 1-ABT in Alternaria-sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Alternaria-exposed vehicle and 1-ABT (group 2) were compared with all other groups ( * ) compared with ** P < 0.01, *** P<0.001. Compound 2 and Compound 1 reduced IgE serum levels.

[0262] number of cells Total and differential cell counts of BAL fluid samples were measured using an XT-2000iV analyzer (Sysmex). Results are expressed as cells / mL (total and differential). Differentially classified cell types were neutrophils, eosinophils, lymphocytes, and macrophages. FIG. 8 shows bar graphs representing the number of neutrophils, eosinophils, lymphocytes and macrophages per mL in bronchoalveolar lavage fluid following vehicle and 1-ABT, compound 2 and compound 1 and 1-ABT treatments in Alternaria sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Alternaria exposed vehicle and 1-ABT (group 2) were compared with all other groups ( * ) compared with *** P<0.001. Compound 2 and Compound 1 reduced the levels of neutrophils and eosinophils, but not lymphocytes or macrophages, in BAL fluid.

[0263] Cytokine analysis Cytokine concentrations (IL-4, IL-5, IL-13 and IL-33) in BAL fluid supernatants and lung homogenates (all groups) were measured using a magnetic multiplex assay (Biotechne, UK) according to the manufacturer's instructions. Levels were measured using the Magpix system (Luminex Corp). Data are reported as cytokines (pg / mL), mean ± SEM (standard error of the mean). FIG. 9 shows bar graphs representing IL4, IL-5, IL-13 and IL-33 in BAL fluid supernatants following vehicle and 1-ABT, compound 2 and compound 1 and 1-ABT treatment in Alternaria sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Alternaria exposed vehicle and 1-ABT (group 2) were compared with all other groups ( * ) compared with ** P < 0.01 and *** *P<0.001. Figure 10 shows bar graphs of IL4, IL-5, IL-13 and IL-33 in lung homogenates after vehicle and 1-ABT, compound 2 and compound 1 and 1-ABT treatments in Alternaria sensitized mice exposed to PBS or Alternaria. Each column represents the mean and each bar represents the se mean of n=5-10. Alternaria exposed vehicle and 1-ABT (group 2) were compared with all other groups ( * ) compared with ** P < 0.01 and *** P<0.001. Compound 2 and Compound 1 show reduced levels of IL4, IL-5, IL-13 and IL-33 in BAL fluid and lung tissue.

[0264] Example C. PARP14 IHC Assay Staining procedures for immunohistochemistry ("IHC") analysis of PARP14 (rabbit clone 15B10-1) with DAB chromogen were performed using automated detection on a Leica Bond Rx (Leica Biosystems). All steps were performed at room temperature unless otherwise noted.

[0265] Preprocessing and Pretreatment FFPE specimens were sectioned at 4 microns thickness, mounted on positively charged glass slides, dried, and baked at 60°C for 30 minutes in an oven for offline deparaffinization and rehydration according to standard techniques. Tissue slides were then mounted on a Leica Bond RX autostainer and pretreated with Epitope Retrieval Solution 2 (ER2, Catalog# AR9640, Leica) starting with two rinses in ER2, followed by incubation in ER2 for 40 minutes at 100°C, followed by rinsing in ER2. Tissue slides were then rinsed four times, followed by a 3 minute incubation in Bond Wash Solution (Catalog# AR9590, Leica Biosystems).

[0266] staining method The staining protocol for PARP14 (rabbit clone 15B10-1) and negative control reagent (NCR) was started. Tissue slides were incubated with Peroxide Block (Bond Polymer Refine Detection, Catalog# DS9800, Leica Biosystems) for 5 minutes, followed by rinsing 3 times with Bond Wash Solution. Tissue slides were rinsed with ISH / IHC Super Blocking (Catalog# PV6122, Leica Biosystems) for 10 minutes. Tissue slides were then incubated with primary antibodies or NCR diluted in ISH / IHC Super Blocking (Leica Biosystems) for 30 minutes, followed by rinsing 3 times with Bond Wash Solution. Tissue slides were incubated with Post Primary (Bond Polymer Refine Detection) for 8 minutes, followed by washing 3x2 minutes with Bond Wash Solution. Tissue slides were incubated with Polymer (Bond Polymer Refine Detection) for 8 minutes, followed by washing 3x2 minutes with Bond Wash Solution, followed by rinsing twice with distilled water. The tissue slides were rinsed with Mixed DAB Refine (Bond Polymer Refine Detection) and then incubated with Mixed DAB Refine for 10 minutes, followed by 4 rinses with distilled water. After the staining procedure was completed, the tissue slides were counterstained online with Hematoxylin (Bond Polymer Refine Detection) for 5 minutes, followed by a rinse with distilled water, a rinse with Bond Wash Solution, and a final rinse with distilled water.

[0267] Post Processing Tissue slides were removed from the autostainer, dehydrated and cleared offline according to standard techniques, and coverslipped using an automated tape coverslipper (Sakura Finetek, Torrance, Calif.) or glass coverslipper (Leica).

[0268] Micrograph H&E and PARP14 (rabbit clone 15B10-1) stained slides were scanned using an Aperio AT Turbo or ScanScope CS system (Aperio, Vista, CA) to generate whole-slide images.

[0269] Human systemic sclerosis study PARP14 (rabbit clone 15B10-1) IHC staining was performed on 11 human systemic sclerosis tissues. Tissues were evaluated by pathologist review. One human systemic sclerosis tissue (ML2007935) was not evaluable due to tissue stripping. NCR staining was negative for all human systemic sclerosis tissues. Positive staining was scored on a scale of 1+ to 3+, with 3 being the most intense. Endothelial staining was observed as 1+ (cytoplasmic) for three human systemic sclerosis tissues and 1+ (membrane and cytoplasmic) for one human systemic sclerosis tissue. Smooth muscle staining was not observed in any of the enhanceable human systemic sclerosis tissues. Fibroblast staining was not observed in any of the enhanceable human systemic sclerosis tissues. Stromal staining was not observed in any of the enhanceable human systemic sclerosis tissues. Inflammatory cell staining was observed for all evaluable human systemic sclerosis tissues as 3+ (cytoplasmic, 3 tissues), 2+ (cytoplasmic, 3 tissues) or 1+ (cytoplasmic, 4 tissues). No neuronal staining was observed in any of the evaluable human systemic sclerosis tissues.

[0270] PARP14 (rabbit clone 15B10-1)-human normal tissue TMA Specificity analysis was performed using the optimized PARP14 (rabbit clone 15B10-1) IHC assay on normal TMA slides of 20 unique tissue cores purchased from USBiomax (ML2011751). The normal TMA cores were evaluated by pathologist review.

[0271] Normal cell expression Across 20 normal tissue cores, expression of PARP14 was observed in prostate tissue (80%; H-score 80) and adjacent normal endometrial tissue (35%; H-score 38). All other normal tissue cores were negative for PARP14 expression (0%; H-score 0). FIG. 11A is an immunohistochemical image (20x) of normal human skin. Figure 11B is an immunohistochemistry image (20x) of skin from a patient with systemic sclerosis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain. Based on the above IHC images, PARP14 was determined to be highly expressed in chronically inflamed skin from human systemic sclerosis patients, but not in normal skin tissue.

[0272] Example D. DNCB-induced atopic dermatitis model A study was conducted to investigate compound 1 in a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis model. Female BALB / c mice were exposed to two cycles of DNCB to induce atopic dermatitis. Animals were treated with vehicle or compound 1 twice daily (BID) for two weeks. Dexamethasone (DEX) was included as a comparator. The details of the study are provided below.

[0273] Formulation of Compound 1 Compound 1 was formulated in a vehicle of sesame oil. Each formulation was prepared by adding the required volume of sesame oil for the calibrated amount of Compound 1 and stirring the solution overnight at room temperature until a homogenously distributed suspension. Prior to each animal administration, the formulation was inverted several times to create a more homogenously distributed suspension. Formulations were prepared fresh each day. All vehicle and Compound 1 administrations were administered by oral gavage (PO) at 10 mL / kg. All BID (twice daily) administrations were based on a 12-hour cycle with a calculated schedule.

[0274] DNCB solution DNCB was weighed (50 mg) and dissolved in 10 ml of 4:1 (v / v) acetone / olive oil solution to make a 0.5% DNCB solution. DNCB was weighed (100 mg) and dissolved in 10 ml of 4:1 (v / v) acetone / olive oil solution to make a 1% DNCB solution, freshly prepared before each application.

[0275] animal Details of the mice used in the study are provided below. [Table 1]

[0276] Device The following equipment was used: Electronic balance: Changzhou Tianzhiping, YH2000 Small volume balance:Mettler-Toledo ML203 / 02 Micrometer: Digimatic QuantuMike Micrometer, 293-185 Thermometer: Omron IR thermometer, MC-872 Anesthesia machine: Raymain, HSIV-μ Quad, 4 channels Tevameter: MEDELINK, TM300

[0277] Grouping Eight-week-old female BALB / c mice (n=28) were used and divided into four groups. One day before the start of the study, the backs of all mice were shaved with a pet clipper to an area of ​​2×3 cm. On days 0-4 and 12-15, DNCB was applied topically to the shaved backs (dorsal area) of mice. The dose regimen and group assignments are shown in the table below. Test articles were prepared daily. Compound 1 was administered orally on days 9-23. Dexamethasone (DEX) was applied on days 9-23. Commercially available cream was weighed (70 mg onto the back skin) for each mouse in group 3. [Table 2] Abbreviations: BID = twice daily; DEX = dexamethasone; PO = oral; QD = once daily.

[0278] DNCB sensitization and treatment For groups 2 to 4, the dorsal (back) skin of the mice was sensitized with 0.1 ml 0.5% DNCB on days 1 and 2; and 0.12 ml 1% DNCB on days 3 and 4 (approximately 15:30, all days indicated). This cycle was repeated on days 12 to 15. From days 9 to 23, test compounds and vehicle were administered according to the regimen shown in the table above (approximately 9:30 and 21:30 for BID administration, daily). DEX was given at approximately 9:30 daily.

[0279] result Body temperatures of the vehicle and compound 1 groups were measured with an Omron IR thermometer in forehead measurement mode on the face before dosing and at 2, 4, 8 and 11.5 hours after dosing for the first 3 days of treatment. Body temperatures ranged from 31°C to 37°C for the first 3 days. The body temperature curves of both groups were similar. Figure 12 shows the body temperature curves of groups 1 and 4 up to 60 hours after dosing. The following clinical score parameters were used to assess the severity of back skin inflammation: [Table 3] Dorsal (back) skin was scored daily for erythema, scabbing and thickness. The cumulative score (erythema + thickness + scabbing) is shown as the total score. DNCB exposure-induced erythema, thickness and scabbing of the back skin and total clinical score peaked on day 17 with a value of 11.9. The DEX treatment group significantly inhibited inflammation with high clinical scores ranging from 6 to 7. Compound 1 treatment showed significant efficacy from days 11 to 23 with a peak clinical score of 10.8 on day 17. Figure 13A shows plots of the clinical scores for each group 9 to 24 days after the first DNCB exposure. Based on the total clinical score curve of each animal in each group, AUC was calculated and shown in Figure 13B. The inhibition rate was calculated by [AUC(vehicle)-AUC(treatment)] / AUC(vehicle) x 100. The DEX group significantly inhibited clinical scoring by 43.5% (P<0.0001) compared with vehicle. Compound 1 administered at an oral dose of 500 mg / kg BID significantly inhibited clinical scoring by 22.9% (P<0.0001) compared with vehicle. Transepidermal water loss (TEWL) of the dorsal skin was monitored daily using a Tevameter and expressed as g / h / m 2 Water was lost after dorsal skin induction by DNCB exposure and recovered after the exposure cycle was stopped. DEX treatment increased dorsal skin water loss compared to vehicle. Compound 1 treatment showed a trend to reduce water loss, with a significant reduction on day 21 compared to vehicle. Figure 14 shows a plot of transepidermal water loss over time. Body weight was also monitored daily throughout the study. Body weight of vehicle and Compound 1 treated animals was not significantly affected. DEX treatment reduced body weight as expected. There was no statistically significant difference in body weight between Compound 1 and vehicle groups. Body weight plots over time are provided in Figure 15.

[0280] Example E. Imiquimod (IMQ)-induced psoriasis model A study was conducted to explore the efficacy of Compound 1 in an imiquimod (IMQ)-induced psoriasis model. Female BALB / C mice were administered 5% IMQ cream topically on the shaved back and ears daily for 7 consecutive days. Animals were treated with vehicle or Compound 1 twice daily (BID) for a total of 9 days. Dexamethasone (DEX) was included as a comparator. Details of the study are provided below.

[0281] Formulation of Compound 1 Compound 1 was formulated in a vehicle of sesame oil. Each formulation was prepared by adding the required volume of sesame oil for the calibrated amount of Compound 1 and stirring the solution overnight at room temperature until a homogenously distributed suspension. Prior to each animal administration, the formulation was inverted several times to create a more homogenously distributed suspension. Formulations were prepared fresh each day. All vehicle and Compound 1 administrations were administered by oral gavage (PO) at 10 mL / kg. All BID (twice daily) administrations were based on a 12-hour cycle with a calculated schedule.

[0282] Device The following equipment was used: Electronic balance: Changzhou Tianzhiping, YH2000 Small volume balance: Sartorius, CPA225D Micrometer: Digimatic QuantuMike Micrometer, 293-185 Thermometer: Omron IR thermometer, MC-872

[0283] animal Details of the mice used in the study are provided below. [Table 4]

[0284] Grouping Eight-week-old female BALB / c mice were used (n=28) and divided into four groups. IMQ was applied topically to one ear and the shaved (dorsal) back of each mouse on days 0-6. The dose regimen and group assignments are shown in the table below. Test articles were prepared daily. Compound 1 was administered on days -2-6. DEX was applied on days 0-6. [Table 5] Abbreviations: BID = twice daily; DEX = dexamethasone; PO = oral; QD = once daily.

[0285] IMQ Sensitization and Treatment From days 0 to 6, mice in groups 2 to 4 received daily topical application of IMQ cream on the ears and shaved (dorsal) backs (approximately 13:30 each day). From day -2 to day 6, test compounds and vehicle were administered according to the regimen shown in the table above (approximately 9:30, approximately 21:30 and daily for BID administration). From day 0 to day 6, DEX was administered according to the regimen shown in the table above (at around 9:30 every day).

[0286] result Body temperatures of the vehicle and compound 1 groups were measured with an Omron IR thermometer in forehead measurement mode on the face before dosing, and 2, 4, 8, and 11.5 hours after dosing for the first 3 days of treatment and on the last day of treatment. Body temperature dropped to 30°C after the first dose on day -2 and recovered within 24 hours. On days -1 and 0, administration of compound 1 and vehicle resulted in body temperatures ranging from 32 to 36°C, which recovered faster than on day -2. On day 7, administration of compound 1 and vehicle did not affect body temperature. The body temperature curves of both groups were similar. The body temperature curves of both groups are shown in Figure 16. Ear thickness was recorded by micrometer every other day. Application of IMQ to the ears significantly increased ear thickness from day 3 onwards. DEX treatment potently inhibited ear thickness (days 3-7, P<0.0001). Compound 1 also inhibited the increase in ear thickness starting from day 5, especially on day 7. Plots of ear thickness before and after dosing are shown in Figure 17. The following clinical scoring parameters were used to assess back erythema, crust formation and thickness: [Table 6] Dorsal (back) skin was scored daily for erythema, scabbing and thickness. The cumulative score (erythema + thickness + scabbing) is shown as the total score. The DEX treatment group significantly inhibited inflammation starting on day 1 (P<0.0001). Compound 1 treatment showed significant efficacy on days 2-7 (P<0.001) and days 2-7 (P<0.001). A plot of the total clinical score on the days after the first IMQ exposure is shown in Figure 18A. Based on the total clinical score curve of each animal in each group, AUC was calculated and shown in Figure 18B. The inhibition rate was calculated by [AUC(vehicle)-AUC(treatment)] / AUC(vehicle) x 100. DEX group significantly inhibited clinical scoring by 87.7% (P<0.0001). Compound 1 at an oral dose of 500mg / kg BID significantly inhibited clinical scoring by 35.1% (P<0.001). Body weight was monitored daily throughout the study. Continuous treatment with IMQ and medication reduced the average body weight of vehicle and Compound 1 animals. DEX treatment also reduced body weight as expected. There was no statistically significant difference between Compound 1 and vehicle groups. A plot of the body weight of the various treatment groups is shown in Figure 19.

[0287] Example F. Human IL-23-induced psoriasis model A study was conducted to investigate Compound 1 in a human IL-23-induced psoriasis model. Female C57BL / 6J mice were injected intradermally with recombinant hIL-23 protein daily for 7 consecutive days to induce ear hyperplasia. Animals were treated with vehicle or Compound 1 twice daily (BID) for a total of 9 days.

[0288] Formulation of Compound 1 Compound 1 was formulated in a vehicle of sesame oil. Each formulation was prepared by adding the required volume of sesame oil for the calibrated amount of Compound 1 and stirring the solution overnight at room temperature until a homogenously distributed suspension. Prior to each animal administration, the formulation was inverted several times to create a more homogenously distributed suspension. Formulations were prepared fresh each day. All vehicle and Compound 1 administrations were administered by oral gavage (PO) at 10 mL / kg. All BID (twice daily) administrations were based on a 12-hour cycle with a calculated schedule.

[0289] animal Details of the mice used in the study are provided below. [Table 7]

[0290] Device The following equipment was used: Electronic balance: Changzhou Tianzhiping, YH2000 Small volume balance:Mettler-Toledo ML203 / 02 Micrometer: Digimatic QuantuMike Micrometer, 293-185 Thermometer: Omron IR thermometer, MC-872 Anesthesia machine, Raymain, HSIV-μ Quad, 4 channels

[0291] Grouping Female C57BL / 6J mice, 7-8 weeks old (n=20), were divided into 3 groups based on body weight and ear thickness on day -2. Compound 1 and vehicle only administration began on day -2. On days 0-6, mice were anesthetized with isoflurane and received intradermal injections of 1 μg of hIL-23 in 20 μL PBS or 20 μL PBS (group 1) in the right ear. The dose regimen and group configuration are shown in the table below. [Table 7] BID = twice daily. Exactly 12 hours apart for BID administration.

[0292] hIL-23 sensitization and treatment hIL-23 protein was diluted to 0.05 mg / mL in PBS immediately prior to intradermal injection. From days 0 to 6 (approximately 13:30), mice in groups 1 to 3 were anesthetized with isoflurane and received daily intradermal injections of 20 μL of hIL-23 in PBS in the right ear. Mice in group 1 received PBS only. From day -2 to day 6, Compound 1 and vehicle were administered according to the regimen shown in the table above (approximately 9:30 and 21:30, daily for BID administration).

[0293] result The body temperatures of the vehicle and Compound 1 animals were measured with an Omron IR thermometer on the face in forehead measurement mode before dosing for the first 3 days of treatment, 2 hours, 4 hours, 8 hours, and 11.5 hours after dosing for the first 3 days of treatment, and on the final day of treatment. The body temperatures of the vehicle and Compound 1 treated animals are shown in Figure 20. Administration of sesame oil vehicle caused a rapid decrease in body temperature 2 hours after administration on day 0. At subsequent time points, body temperatures in both vehicle and Compound 1 treatment groups remained in the normal range for the first 3 days. Body temperatures were relatively low on day 7, ranging from 32.6 to 34.6°C at 24 hours. The body temperature curves of both groups were similar. Ear thickness was recorded by micrometer every other day. Intradermal injection of hIL-23 into the right ear increased ear thickness. Plots of ear thickness for naive, vehicle and compound 1 groups are shown in Figure 21A. Percent inhibition or area under the curve (AUC) for a particular day was calculated by [(thickness vehicle-thickness naive)-(thickness treated-thickness naive)] / [thickness vehicle-thickness naive] x 100. Graphs of normalized ear thickness AUC for naive, vehicle and compound 1 groups are shown in Figure 21B. Compound 1 group showed inhibition of ear thickness increase by 60% (P<0.05) on day 5 and 60% (P<0.01) on day 7, with compound 1 reducing AUC by 72% (P<0.05). On day 7, a portion of the ear (8 mm diameter) was taken from each mouse. Ear weights were recorded and weight gain was calculated by [weight (treated)-weight (naive) average]. A graph of ear thickness for naive, vehicle and compound 1 groups is shown in Figure 22A. A graph of ear weight gain for naive, vehicle and compound 1 groups is shown in Figure 22B. Consistent with the ear thickness data, ear weight for the vehicle group was significantly higher than that of the naive group. Compound 1 group showed a trend towards decreased ear weight compared to vehicle controls. Body weight was monitored daily throughout the study. There was no statistically significant difference between the Compound 1 and vehicle groups. A plot of body weight for the naive, vehicle and Compound 1 groups is shown in FIG.

[0294] Example G: Bleomycin (BLM)-induced pulmonary fibrosis model A study was conducted to evaluate the efficacy of Compound 1 in a bleomycin (BLM)-induced pulmonary fibrosis model. BLM-induced pulmonary fibrosis is an established disease model for IPF. In this model, alveolar injury and interstitial inflammation / fibrosis are induced by tracheal BLM administration.

[0295] Test sample preparation Compound 1: Compound 1 was weighed out and diluted to the required concentration appropriate for the study using sesame oil. For example, Compound 1 (4821 mg) was added to sesame oil (80 mL) with grinding to obtain a suspension of Compound 1 at a concentration of 60 mg / mL. The formulation was then sonicated for 30 minutes using a water bath sonicator. Just before administration to each animal, the formulation was vortexed to ensure that Compound 1 was uniformly dispersed in the suspension. The formulation (50 μL / vial) was stored for dose verification on the first and last administration days (2 vials each, total of 4 vials).

[0296] Tofacitinib: Tofacitinib (25 mg) was added to 5 mL of 0.5% methylcellulose / 0.025% Tween 20 in water with vortexing and sonicated to obtain a suspension of tofacitinib at a concentration of approximately 5 mg / mL.

[0297] animal Forty-five 6-week-old female C57BL / 6 mice were obtained from Japan SLC Co., Ltd. (Japan). The animals were housed under controlled conditions and fed a normal diet (CE-2; Nippon Clea, Japan). All animals used in the study were housed and cared for in accordance with the Japanese Pharmacological Society guidelines for animal experiments. The animals were maintained in an SPF facility under controlled conditions of temperature (23 ± 3 °C), humidity (50 ± 20%), lighting (12-h artificial light and dark cycle; lights on 08:00–20:00) and air exchange. The experimental room was maintained at hyperbaric pressure to prevent contamination of the facility. The animals were housed in TPX cages (CLEA Japan) with a maximum of 5 mice per cage. Sterile Pepper Clean (SLC Japan) bedding was used and changed once a week. Sterile regular food was provided in a metal lid on top of the cage and was available ad libitum. RO water was available ad libitum from a water bottle equipped with a rubber stopper and a water inlet. Water bottles were changed, cleaned, sterilized by autoclaving, and reused once a week. Mice treated with Compound 1 had access to food pellets and hydrogel on the bottom of the cage. Mice were identified by ear punches. Each cage was also given a unique identification code.

[0298] Study Group Group 1: Sham Five control mice were maintained without any treatment until sacrifice after a single intratracheal phosphate-buffered saline (PBS) administration.

[0299] Group 2: Medium Fifteen BLM-induced pulmonary fibrosis model mice were orally administered vehicle (sesame oil) at a volume of 10 mL / kg twice daily from days 1 to 14.

[0300] Group 3: Compound 1 Fifteen BLM-induced pulmonary fibrosis model mice were orally administered vehicle (sesame oil) supplemented with compound 1 at a dose of 500 mg / kg in a volume of 10 mL / kg twice daily (total 1000 mg / kg / day) from days 1 to 14.

[0301] Group 4: Tofacitinib free base Ten BLM-induced pulmonary fibrosis model mice were orally administered tofacitinib free base at a dose of 50 mg / kg in a volume of 10 mL / kg in vehicle (0.5% methylcellulose / 0.025% Tween 20) twice daily (total 100 mg / kg / day) from days 1 to 14.

[0302] The study design and treatment schedule are summarized in the table below. [Table 8] BLM=bleomycin; PO=oral; BID=twice daily The 45 mice were divided into one group of 5 mice, one group of 10 mice, and two groups of 15 mice based on their relative body weights before BLM or / saline administration on day 0.

[0303] Induction of BLM-induced pulmonary fibrosis model On day 0, 40 mice were anesthetized with a mixture of medetomidine (0.75 mg / kg), midazolam (4 mg / kg) and butorphanol (5 mg / kg) administered intraperitoneally in a volume of 10 mL / kg using a microsprayer. (登録商標) The development of pulmonary fibrosis was induced by a single intratracheal administration of bleomycin hydrochloride (BLM, Nippon Kayaku, Japan) in PBS at a dose of 3.0 mg / kg in a volume of 50 μL per animal using a 50 μL PBS-based endotracheal catheter (Penn-Century, USA). After BLM administration, atipamezole hydrochloride (0.75 mg / kg) was administered intraperitoneally at a volume of 10 mL / kg, and mice were placed on a heat pad until they recovered from the effects of anesthesia. Five mice were administered PBS instead of BLM intratracheally and used as the sham group.

[0304] Route and Dosage of Drug Administration Compound 1 was administered orally at a dose of 500 mg / kg twice daily in a volume of 10 mL / kg (total 1000 mg / kg / day). Tofacitinib was administered orally at a dose of 50 mg / kg twice daily in a volume of 10 mL / kg (total 100 mg / kg / day).

[0305] Animal Monitoring and Sacrifice Viability, clinical signs and behavior were monitored daily. Body weights were recorded daily from day 0. Dose volumes were adjusted based on most recent body weights. Mice were observed for significant clinical signs of toxicity, moribundity and death for approximately 60 minutes after each dose. Animals were sacrificed on day 14 by exsanguination from the abdominal vena cava under anesthesia with a mixture of medetomidine, midazolam and butorphanol. Times of dosing and cessation were recorded. Left and inferior vena cava lobe weights were recorded for all mice. Animals showing more than 40% weight loss compared to day 0 were sacrificed before the end of the study by abdominal aorta and vena cava section under anesthesia with a mixture of medetomidine (0.75 mg / kg), midazolam (4 mg / kg) and butorphanol (5 mg / kg) administered intraperitoneally in a volume of 10 mL / kg. Samples were taken from sacrificed animals.

[0306] PK and PD Plasma Sample Preparation (Groups 3 and 4) Blood (50 μL) was collected from the facial vein 2 hours after the first administration (surviving mice, mice 1–7 / group 3, mice 1–5 / group 4) and 30 minutes before the second administration (surviving mice, mice 8–15 / group 3, mice 6–10 / group 4), and K2EDTA (Greiner Bio-One, Austria) plasma was prepared. Thirty minutes before the final administration at the time of sacrifice (while alive, mice 1-15 / group 3, mice 1-10 / group 4), blood (50 μL) was collected from the facial vein to prepare K2EDTA plasma. Two hours after the last dose (final, mice 1-15 / group 3, mice 1-10 / group 4), non-fasted blood was drawn from the inferior vena cava at the time of sacrifice using a pre-chilled syringe. Collected blood was transferred to polypropylene tubes containing anticoagulant (K2EDTA, Greiner Bio-One) and stored on ice until centrifugation. Blood samples were centrifuged at 6,000×g for 5 min at 4°C. Supernatants were collected in two separate tubes, 100 μL for PD analysis and the remaining plasma for PK analysis, and stored at -80°C until transport.

[0307] Preparation of PD plasma samples At the time of sacrifice, non-fasted blood was drawn from the inferior vena cava of animals in groups 1 and 2 using a pre-chilled syringe. Collected blood was transferred to polypropylene tubes containing anticoagulant (K2EDTA, Greiner Bio-One) and stored on ice until centrifugation. Blood samples were centrifuged at 6,000×g for 5 min at 4° C. A minimum of 100 μL of supernatant was collected for PD analysis and stored at −80° C. until transport.

[0308] Preparation of BALF samples For group 1, BALF samples were collected at the time of sacrifice by flushing the lungs through the trachea with sterile PBS (0.8 mL) under anesthesia with a mixture of medetomidine, midazolam and butorphanol. BALF was centrifuged at 3,000 × g for 5 min at 4°C, and the supernatant was collected and stored at -80°C. For groups 2-4, BALF samples were collected at the time of sacrifice by flushing the lungs through the trachea with sterile PBS three times (first, second and third BALF, 0.8 mL each) under anesthesia with a mixture of medetomidine, midazolam and butorphanol. The first BALF was centrifuged at 3,000 × g for 5 min at 4 °C, and the supernatant was collected and stored at -80 °C. The cell pellet from the first fraction (first BALF) was resuspended and added to the remaining fractions of the lavage fluid (second and third BALF). The total BALF was centrifuged at 1,000 × g for 5 min at 4 °C, and the supernatant was removed. Ammonium-chloride-potassium (ACK) lysis buffer was added to the pellet and washed to lyse red blood cells. After the addition of cold PBS, the fluid was centrifuged at 1,000 × g for 3 min at 4 °C, and the supernatant was removed. The cells were resuspended in PBS, and the total number of cells in the BALF was counted using a hemocytometer (C-Chip disposable hemocytometer, Digital Bio). After counting the total cells, the cell suspension was resuspended in PBS at 5 × 10 5 The cells were resuspended at 100 cells / mL. Smear samples were then prepared by spotting 100 μL of the cell suspension onto a slide and air drying using a hair dryer set on the cold air setting.

[0309] Preparation of lung samples The left lobe, inferior vena cava lobe and right lower lobe bronchus were ligated to avoid leakage of fixative. An indwelling needle was inserted into the trachea and connected to the injection line of a syringe. The syringe was filled with 10% neutral buffered formalin and maintained at a height of 20 cm. The upper and middle lobes were then injected with 10% neutral buffered formalin and ligated after expansion. Two fixed lobes (for histological analysis), unfixed left lung (for biochemistry) and unfixed right lower and inferior vena cava lobes (for transport) were collected. The three unfixed lobes were washed with cold saline and wet weights were measured. Two fixed lobes were fixed in 10% neutral buffered formalin for 24 hours. After fixation, these specimens were embedded in paraffin for Masson's trichrome staining. The right inferior and inferior vena cava lobes were flash frozen in liquid nitrogen and stored at −80°C until transport. For all groups, the right lower lobe (minimum 30 mg) was snap frozen in RNAlater. For all groups, the remaining right lower lobe and inferior vena cava lobe (approximately 50 mg) were directly placed into one 500–750 μL homogenizer tube containing MAR lysis buffer and flash frozen in liquid nitrogen. The left lung was snap frozen in liquid nitrogen and stored at −80°C for hydroxyproline analysis.

[0310] Measurement of lung hydroxyproline content (all groups) For lung hydroxyproline content quantification, frozen left lung samples were treated with the acid hydrolysis method as follows: Lung samples were acid-hydrolyzed with 200 μL of 6N HCl at 121°C for 20 min and neutralized with 200 μL of 4N NaOH containing 10 mg / mL activated charcoal. AC buffer (2.2 M acetic acid / 0.48 M citric acid, 200 μL) was added to the samples, followed by centrifugation and collection of the supernatant. A standard curve for hydroxyproline was constructed with trans-4-hydroxy-L-proline (Sigma-Aldrich Co. LLC., USA Code: 54409) at 16 μg / mL, 8 μg / mL, 4 μg / mL, 2 μg / mL, 1 μg / mL and 0.5 μg / mL. The prepared samples and standards (300 μL each) were mixed with 300 μL Chloramine T solution (Nacalai Tesque, Inc., Japan, Code: 08005-52) and incubated at room temperature for 25 min. The samples were then mixed with Ehrlich's solution (300 μL) and heated at 65°C for 20 min to develop color. Samples were collected on ice and centrifuged to remove precipitates, after which the optical density of each supernatant was measured at 560 nm. Hydroxyproline concentrations were calculated from a hydroxyproline standard curve. Lung hydroxyproline levels were expressed as μg per left lung.

[0311] Measurement of BALF IL-4, IL-6, IL-10 and IL-17 (groups 2 to 4) For groups 2–4, BALF IL-4, IL-6, IL-10 and IL-17 levels were quantified by Quantikine enzyme-linked immunosorbent assay kits (code. M4000B for IL-4, code. M6000B for IL-6, code. M1000B for IL-10, code. M1700 for IL-17, R&D systems) according to the manufacturer's instructions.

[0312] Blinding The samples were given a code number for blinded evaluation. Each number was generated using the RAND function in Excel software, sorted in ascending order, and assigned to a slide. The tissue slides were used for subsequent staining and evaluation by the experimenter.

[0313] Histological analysis For all groups, right lung tissue pre-fixed in 10% neutral buffered formalin was embedded in paraffin and sectioned at 4 μm (2 sections / slide). For Masson-Trichrome staining, sections were deparaffinized, rehydrated, and subsequently refixed in Bouin's solution for 15 min. Sections were stained with Weigert's iron hematoxylin working solution (Sigma-Aldrich), Biebrich's scarlet-acid fuchsin solution (Sigma-Aldrich), phosphotungstic / phosphomolybdic acid solution, aniline blue solution, and 1% acetic acid solution (Sigma-Aldrich). For quantitative analysis of pulmonary fibrosis area, bright-field images of Masson-Trichrome stained sections were randomly captured using a digital camera (DFC295; Leica, Germany) at 100x magnification, and the subpleural area in 20 fields / mouse was assessed according to the criteria for pulmonary fibrosis grading (Ashcroft, T., et al., J Clin Pathol, 1988; 41:467-70). All sections were analyzed blinded by the experimenters. Pulmonary fibrosis was graded using the following criteria: [Table 9] * If it is difficult to decide between the two odd categories, the field is given an intermediate even score. For groups 2-4, Diff-Quik (Sysmex Corporation) staining was performed on the prepared smear samples by immersion in the following order of fixation, staining solution I, and staining solution II as described in the Diff-Quik manual. Stained sections were used to perform blood cell morphology analysis (lymphocytes, monocytes, neutrophils, and eosinophils). Slides were observed at 200x magnification using a bright-field microscope (Leica Microsystems). Blood cells were counted to a total of 200, and the ratio of each blood cell type was calculated. The number of each blood cell type was then calculated by applying the ratio to the total cell number.

[0314] result Body weight was expressed as a percentage of body weight change from baseline (day 0). The mean body weight change in the Sham group was significantly higher than the vehicle group from days 6 to 14. The mean body weight change in the Compound 1 group was significantly higher than the vehicle group from days 8 to 12. The mean body weight change in the Tofacitinib free base group was significantly higher than the vehicle group from days 6 to 14. During the treatment period, mice died and were sacrificed before reaching day 14 as follows: 2 of 15 mice were sacrificed in the vehicle group. 2 of 15 mice died in the compound 1 group. No animals died in the tofacitinib free base group during the treatment period.

[0315] Body weight and lung weight measurements are shown in the table below. [Table 10] Figure 24A shows the body weight and lung weight of mice in each treatment group. Figure 24B shows the left lung weight of mice in each treatment group. Figure 24C shows the ascending vena cava lobe weight of mice in each treatment group. Figure 24D shows the right lower lobe weight of mice in each treatment group. There were no significant differences in survival curves between the vehicle and test groups. There was no significant difference in body weight on the day of sacrifice. The average body weight of the Sham group on the day of sacrifice tended to be increased compared to the Vehicle group. The sham group showed a significant decrease in mean left lung weight compared to the vehicle group. The mean left lung weights of the compound 1 and tofacitinib free base groups tended to decrease compared to the vehicle group. The sham group showed a significant decrease in mean inferior vena cava leaf weight compared to the vehicle group. The mean inferior vena cava leaf weight in the compound 1 and tofacitinib free base groups tended to decrease compared to the vehicle group. The sham group showed a significant decrease in mean right lower lobe weight compared to the vehicle group. Compound 1 and tofacitinib free base groups showed a significant decrease in mean inferior vena cava lobe weight compared to the vehicle group. Figure 25A shows the total number of immune cells in the bronchoalveolar lavage fluid of mice in each treatment group. Figure 25B shows the BALF monocyte ratio of mice in each treatment group. Figure 25C shows the BALF lymphocyte ratio of mice in each treatment group. Figure 25D shows the BALF neutrophil ratio of mice in each treatment group. Figure 26A shows BALF IL-6 concentrations in mice from each treatment group, and Figure 26B shows BALF IL-10 concentrations in mice from each treatment group.

[0316] The measurements of BALF are shown in the table below. [Table 11] * Vehicle (n=10), Compound 1 (n=6), Tofacitinib free base (n=1) The total cell count in BALF of the compound 1 group tended to decrease compared to the vehicle group. There was no significant difference in the total cell count in BALF between the vehicle group and the tofacitinib free base group. The compound 1 group showed a significant increase in the percentage of monocytes in BALF compared to the vehicle group. The percentage of monocytes in BALF in the tofacitinib free base group tended to increase compared to the vehicle group. The compound 1 group showed a significant decrease in the percentage of lymphocytes in BALF compared to the vehicle group. The percentage of lymphocytes in BALF in the tofacitinib free base group tended to decrease compared to the vehicle group. There was no significant difference in the percentage of neutrophils. The BALF IL-6 content in the tofacitinib free base group tended to be decreased compared with the vehicle group.

[0317] Lung hydroxyproline content is shown in the table below. [Table 12] FIG. 27 shows the lung hydroxyproline content for each treatment group. The sham group showed a significant decrease in lung hydroxyproline content compared to the vehicle group. The lung hydroxyproline content of the tofacitinib free base group tended to decrease compared to the vehicle group. There was no significant difference in lung hydroxyproline content between the vehicle group and the compound 1 group. Figure 28A shows photomicrographs of Masson's trichrome stained lung sections in the sham treated group, Figure 28B shows photomicrographs of Masson's trichrome stained lung sections in the vehicle treated group, Figure 28C shows photomicrographs of Masson's trichrome stained lung sections in the compound 1 treated group, and Figure 28D shows photomicrographs of Masson's trichrome stained lung sections in the tofacitinib free base treated group.

[0318] FIG. 29 shows the Ashcroft scores of mice in each treatment group. The Ashcroft scores for the various treatment groups are shown in the table below. [Table 13] The sham and compound 1 groups showed a significant decrease in Ashcroft scores compared to the vehicle group. The Ashcroft scores of the tofacitinib free base group tended to decrease compared to the vehicle group.

[0319] conclusion Treatment with Compound 1 showed significant decreases in mean right lower lobe weight, percentage of lymphocytes in BALF and Ashcroft score as well as significant increases in percentage of monocytes in BALF and a trend towards decreases in mean left lung weight, mean inferior vena cava lobe weight, total cell count in BALF and Ashcroft score compared to the vehicle group. Treatment with tofacitinib free base showed a significant decrease in mean right lower lobe weight, percentage of lymphocytes in BALF and a significant increase in percentage of monocytes in BALF, as well as a trend towards an increase in mean body weight on the day of sacrifice and a trend towards decreases in mean left lung weight, mean inferior vena cava lobe weight, BALF IL-6 content, lung hydroxyproline content and Ashcroft score compared to the vehicle group.

[0320] Example H. PARP14 IHC in Inflammation Assays Immunohistochemistry ("IHC") staining for PARP14 (rabbit clone 15B10-1) using DAB chromogen was performed using automated detection on a Leica Bond Rx (Leica Biosystems). All steps were performed at room temperature unless otherwise stated.

[0321] Preprocessing and Pretreatment FFPE specimens were sectioned at 4 microns thickness, mounted on positively charged glass slides, dried, and baked at 60°C for 30 minutes in an oven for offline deparaffinization and rehydration according to standard techniques. Tissue slides were then mounted on a Leica Bond RX autostainer and pretreated with Epitope Retrieval Solution 2 (ER2, Catalog# AR9640, Leica) starting with two rinses in ER2, followed by incubation in ER2 for 40 minutes at 100°C, followed by rinsing in ER2. Tissue slides were then rinsed four times, followed by a 3 minute incubation in Bond Wash Solution (Catalog# AR9590, Leica Biosystems).

[0322] staining method The staining protocol for PARP14 (rabbit clone 15B10-1) and negative control reagent (NCR) was started. Tissue slides were incubated with Peroxide Block (Bond Polymer Refine Detection, Catalog# DS9800, Leica Biosystems) for 5 minutes, followed by rinsing 3 times with Bond Wash Solution. Tissue slides were rinsed with ISH / IHC Super Blocking (Catalog# PV6122, Leica Biosystems) for 10 minutes. Tissue slides were then incubated with primary antibodies or NCR diluted in ISH / IHC Super Blocking (Leica Biosystems) for 30 minutes, followed by rinsing 3 times with Bond Wash Solution. Tissue slides were incubated with Post Primary (Bond Polymer Refine Detection) for 8 minutes, followed by washing 3x2 minutes with Bond Wash Solution. Tissue slides were incubated with Polymer (Bond Polymer Refine Detection) for 8 minutes, followed by washing 3x2 minutes with Bond Wash Solution, followed by rinsing twice with distilled water. The tissue slides were rinsed with Mixed DAB Refine (Bond Polymer Refine Detection) and then incubated with Mixed DAB Refine for 10 minutes, followed by 4 rinses with distilled water. After the staining procedure was completed, the tissue slides were counterstained online with Hematoxylin (Bond Polymer Refine Detection) for 5 minutes, followed by a rinse with distilled water, a rinse with Bond Wash Solution, and a final rinse with distilled water.

[0323] Post Processing Tissue slides were removed from the autostainer, dehydrated and cleared offline according to standard techniques, and coverslipped using an automated tape coverslipper (Sakura Finetek, Torrance, Calif.) or glass coverslipper (Leica).

[0324] Micrograph H&E and PARP14 (rabbit clone 15B10-1) stained slides were scanned using an Aperio AT Turbo or ScanScope CS system (Aperio, Vista, CA) to generate whole-slide images.

[0325] Atopic Dermatitis Test PARP14 (rabbit clone 15B10-1) IHC staining was performed on 12 human atopic dermatitis tissues obtained from commercial sources. Tissues were evaluated by pathologist review. One human atopic dermatitis tissue (ML2103082) was not evaluable due to tissue peeling. Positive staining was judged on a scale of 1+ to 3+, with 3 being the strongest intensity. Endothelial staining was observed as 1+ (cytoplasm) for three human atopic dermatitis tissues and 1+ (membrane and cytoplasm) for three human atopic dermatitis tissues and 1+ (membrane, cytoplasm and nucleus) for one human atopic dermatitis tissue. Smooth muscle staining was not observed in any of the evaluable human atopic dermatitis tissues. Fibroblast staining was observed in the cytoplasm of two human atopic dermatitis tissues (1+), and both cytoplasm and membrane staining was observed in seven human atopic dermatitis tissues (2+). Stromal staining was not observed in any of the evaluable human atopic dermatitis tissues. Inflammatory cell staining was observed as 3+ (cytoplasmic and membranous) in seven human atopic dermatitis tissue samples or 2+ (cytoplasmic and membranous) in three human atopic dermatitis tissue samples. Neuronal staining was not observed in any of the evaluable human atopic dermatitis tissues.

[0326] Psoriasis Test PARP14 (rabbit clone 15B10-1) IHC staining was performed on 12 human psoriatic tissues obtained from commercial sources. Tissues were evaluated by pathologist review. Three human psoriatic tissues were not evaluable for inflammatory areas due to tissue peeling. Positive staining was scored on a scale of 1+ to 3+, with 3 being the most intense. Endothelial staining was observed in one human psoriatic tissue as 1+ (cytoplasmic). Smooth muscle staining was not observed in any of the evaluable human psoriatic tissues. Fibroblast staining was observed in the cytoplasm of one human atopic dermatitis tissue (1+). Stromal staining was not observed in any of the evaluable human atopic dermatitis tissues. Inflammatory cell staining was observed in seven human psoriatic tissue samples as 1+ (cytoplasmic). Nerve staining was not observed in any of the evaluable human psoriatic tissues.

[0327] Normal Skin Test PARP14 (rabbit clone 15B10-1) IHC staining was performed on 10 human normal skin tissues obtained from commercial sources. Tissues were evaluated by pathologist review. One (1) human normal skin tissue (ML2103143) was not evaluable due to tissue peeling. Positive staining was scored on a scale of 1+ to 3+, with 3 being the most intense. Endothelial staining was not observed in any of the evaluable human normal skin tissues. Smooth muscle staining was not observed in any of the evaluable human normal skin tissues. Fibroblast staining was not observed in any of the evaluable human normal skin tissues. Stromal staining was not observed in any of the evaluable human normal skin tissues. Inflammatory cell staining was observed as 1+ (cytoplasmic) in one human normal skin tissue sample. Neuronal staining was not observed in any of the evaluable human normal skin tissues.

[0328] Idiopathic Pulmonary Fibrosis Trial PARP14 (rabbit clone 15B10-1) IHC staining was performed on 12 human idiopathic pulmonary fibrosis (IPF) tissues obtained from commercial sources. Tissues were evaluated by pathologist review. Positive staining was judged on a scale of 1+ to 3+, with 3 being the strongest intensity. Endothelial staining was observed as 1+ (membrane and cytoplasmic) in 4 human IPF tissues and 2+ (membrane and cytoplasmic) in 8 human IPF tissues. Smooth muscle staining was not observed in any of the evaluable human IPF tissues. Fibroblast staining was not observed in any of the evaluable human IPF tissues. Interstitial staining was not observed in any of the evaluable human IPF tissues. Inflammatory cell staining was observed as 1+ (cytoplasmic) in 1 human IPF tissue sample or 2+ (cytoplasmic and membrane) in 11 human IPF tissue samples. Neuronal staining was not observed in any of the evaluable human IPF tissues.

[0329] Normal Lung Tissue Test PARP14 (rabbit clone 15B10-1) IHC staining was performed on 10 human normal lung tissues obtained from a commercial source. Tissues were evaluated by pathologist review. Positive staining was determined on a scale of 1+ to 3+, with 3 being the strongest intensity. Endothelial staining was observed as 1+ (cytoplasmic and membranous) in 2 human normal lung tissues, 2+ (membranous) in 5 human normal lung tissues, 2+ (membranous and cytoplasmic) in 1 human normal lung tissue, and 3+ (membranous and cytoplasmic) in 1 human normal lung tissue. Smooth muscle staining was not observed in any of the evaluable human normal lung tissues. Fibroblast staining was not observed in any of the evaluable human normal lung tissues. Interstitial staining was not observed in any of the evaluable human normal lung tissues. Inflammatory cell staining was observed as 1+ (cytoplasmic and membranous) in 1 human normal lung tissue sample and 2+ (cytoplasmic and membranous) in 9 human normal lung tissue samples. No neural staining was observed in any of the evaluable human normal lung tissues.

[0330] result FIG. 30A is an immunohistochemical image (20x) of normal human skin. Figure 30B is an immunohistochemistry image (20x) of skin from a patient with atopic dermatitis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain. Figure 30C is an immunohistochemistry image (20x) of skin from a patient with psoriasis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain. FIG. 31A is an immunohistochemistry image (20x) of normal human lung tissue. Figure 31B is an immunohistochemistry image (20x) of bronchial epithelial cells from lung tissue of a patient with idiopathic pulmonary fibrosis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain. Figure 31C is an immunohistochemical image (20x) of inflammatory cells in lung tissue from a patient with idiopathic pulmonary fibrosis. PARP14 was visualized using DAB (brown chromogen) and hematoxylin counterstain. Based on the above IHC images, it was determined that PARP14 was observed to be present in inflammatory cells in atopic dermatitis and psoriasis skin samples compared to normal skin.Furthermore, PARP14 was observed to be more strongly expressed in inflammatory cells and bronchial epithelial cells in idiopathic pulmonary fibrosis lung samples compared to normal lung.

[0331] Example I: Oxazolone-induced colitis model A study was conducted to evaluate the efficacy of Compound 1 in an oxazolone (OXZ)-induced colitis model in mice.

[0332] Test sample preparation Compound 1 was stored at room temperature. Each formulation was prepared daily by adding the appropriate amount of Compound 1 to sesame oil, followed by vortexing and sonication to dissolve Compound 1.

[0333] animal Twenty-eight female BALB / c mice (8 weeks old, 18–20 g body weight) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Joint Venture of Charles River Laboratories in China) and housed in specific pathogen-free, individually ventilated cages (5 mice per cage) in a temperature-controlled (20 ± 2 °C) room with a 12-h light-dark cycle. Chow pellets and tap water were available ad libitum. All experimental protocols were approved by the Institutional Animal Care and Use Committee of the Wuxi AppTec. Mice were acclimated in the Wuxi animal facility for at least 3 days before the experiments.

[0334] OXZ induction of acute colitis in mice To induce colitis, mice were inoculated with 200 μL of 2% OXZ (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one) dissolved in a 4:1 mixture of acetone and olive oil onto 4 cm of the shaved back of the mouse. 2 The area was presensitized (day -5) followed by intracolonic injection of 100 μL of 1.5% oxazolone dissolved in 50% ethanol 5 days after presensitization (day 0). Mice in the sham-operated group were presensitized with 200 μL of a 4:1 mixture of acetone and olive oil on the shaved back of the mouse (day -5) followed by intracolonic injection of 100 μL of 50% ethanol on day 0. Before intracolonic perfusion of OXZ, mice were anesthetized with 0.3 mL of avertin (1.25%) and kept in a head-down position for 2 min after intracolonic administration.

[0335] Study Group Mice were assigned to 4 groups. 4 mice were assigned to the sham group and 8 mice were assigned to each of the remaining 3 groups. Animals in the tofacitinib group (group 3) received 10 mg / kg tofacitinib twice daily (BID) in 0.5% sodium carboxymethylcellulose at a dosing volume of 10 mL / kg body weight. Animals in the vehicle group (group 2) received sesame oil twice daily (BID) and animals in the compound 1 treatment group (group 4) received 1,000 mg / kg compound 1 in sesame oil twice daily (BID). All dosing was performed by oral gavage (PO) on days -2 to 4 (corresponding to days -2 and 4 for PK dosing and days -1 to 3 for dosing+assessment of efficacy endpoints). The dose regimens and groups are shown in the following table. [Table 14] OXZ = oxazolone; NA = not applicable; PO = oral gavage; BID = twice daily

[0336] Assessment of colitis severity Body weight and Disease Activity Index (DAI) scoring were recorded daily for colitis. DAI score was calculated as the sum of weight loss score, fecal score and bleeding score. A blinded scoring system was used for the assessment of colitis. DAI scorers were blinded to group information and animal ID and were responsible for fecal consistency and bleeding scoring (bloody stool) assessment. DAI scoring standards are listed in the table below. [Table 15]

[0337] Fecal occult blood test If no blood was visible to the naked eye, fecal occult blood (FOB) testing was performed with fecal occult blood test strips using a modified pyramidon method. FOB scores (0-2) were interpreted as follows: 0, no color after 2 minutes; 1, dull color appeared in 1-2 minutes; 2, dark color appeared in 1-2 minutes.

[0338] Colon collection and colon density measurement The colon was collected and the mesenteric and adipose tissue was carefully removed. The colon was placed on a lined photographic paper. The length of the colon was then measured, and the weight of the colon was then measured by removing the colon contents and rinsing with cold PBS.

[0339] Colon tissue collection for histological examination At the end of the study, whole colons were collected from the mice, rolled, and fixed in 10% buffered formalin for hematoxylin and eosin (H&E) staining and pathological scoring by a pathologist.

[0340] Blood collection Whole blood was collected by cardiac puncture and allowed to clot at room temperature for approximately 30 minutes, after which the blood was centrifuged at 8,000 rpm for 10 minutes at 4°C to separate the serum, which was frozen at -80°C and stored for future analysis.

[0341] Pharmacokinetics Plasma collection On day -2 (2 days before OXZ intracolonic injection) and day 4 (endpoint), mice were bled for evaluation of plasma Compound 1 concentrations. Blood was collected 2 and 11.5 hours after administration to determine Compound 1 plasma concentration levels.

[0342] Histopathological scoring Fixed colons were evaluated by a pathologist who reviewed and scored H&E stains blinded to animal grouping and animal ID. Pathology scores are listed in the table below. [Table 16]

[0343] statistical analysis Data between groups were compared using ANOVA test. If positive, the populations were evaluated with Dunnett's test or t-test against the vehicle control group (group 2) using Graph Pad Prism 6.0 software (San Diego, CA, USA). A P value of P<0.05 was considered as a statistically significant difference. Data are presented as mean ± standard error of the mean (SEM).

[0344] result A bioanalytical method for detection of Compound 1 in Balb / c mouse plasma (lower limit of quantification [LLOQ] of 2 ng / ml) was used. On days -2 and 4, Compound 1 plasma concentrations were highest 2 hours after dosing and lowest 11.5 hours after dosing. FIG. 32A shows in-life weight loss scoring of disease severity in an OXZ-induced colitis mouse model. FIG. 32B shows in-life DAI scoring of disease severity in an OXZ-induced colitis mouse model. FIG. 32C shows the in-life AUC of weight change scoring of disease severity in an OXZ-induced colitis mouse model. FIG. 32D shows the AUC of in-life DAI scoring of disease severity in an OXZ-induced colitis mouse model. Compound 1 was evaluated for disease severity reduction in an OXZ-induced model of colitis. Compared to the sham group (group 1), the vehicle group animals (group 2) showed weight loss and increased DAI scores after day 0 intracolonic OXZ administration (Figures 32A-32D). Compound 1-treated mice (group 4) showed significantly less weight loss when compared to the vehicle group mice (Figure 32A). The DAI scores of compound 1-treated mice were also improved compared to vehicle-treated mice (Figure 32B), as was the area under the curve (AUC) of the DAI scores of compound 1-treated mice (Figure 32D). As a comparator, mice in group 3 were treated with tofacitinib, which also inhibited weight loss (Figure 32A), DAI scores (Figure 32B), and AUC of DAI scores (Figure 32D) compared to the vehicle-treated control group. There was no significant difference in the AUC of body weight change between compound 1 and the vehicle group, but no statistical difference was observed in the AUC of body weight change between tofacitinib, comparator and vehicle groups (Figure 32C). These findings indicate that compound 1 reduces the severity of OXZ-induced colitis by reducing weight loss and improving DAI scores.

[0345] FIG. 33A shows a graph of colon density in an OXZ-induced colitis mouse model. FIG. 33B shows a graph of colon length in an OXZ-induced colitis mouse model. FIG. 33C shows a graph of colon weight in an OXZ-induced colitis mouse model. Compared to the sham group, intracolonic administration of OXZ to mice in the vehicle group caused colon shortening and increased colon weight and density, which can be used to indicate the severity of colitis (Figures 33A-33C). Compound 1-treated animals (group 4) showed suppression of the increase in colon density induced by OXZ treatment (Figure 33A). Compound 1 also suppressed the shortening of colon length (Figure 33B) and the increase in colon weight (Figure 33C) compared to those seen in the vehicle control group. As a comparator, mice in group 3 were treated with tofacitinib, which also suppressed the increase in colon density, shortening of colon length, and increase in colon weight (Figures 33A-C). These findings indicate that compound 1 can reduce colitis disease severity by suppressing the increase in colon weight and density and shortening of colon length induced by OXZ treatment.

[0346] FIG. 34A shows H&E (hematoxylin and eosin) stained photographs at 200x magnification of samples from the sham group of the OXZ-induced colitis mouse model. FIG. 34B shows an H&E stained photograph at 200x magnification of a sample from the vehicle group of the OXZ-induced colitis mouse model. FIG. 34C shows H&E stained photographs at 200x magnification of samples from the tofacitinib group of the OXZ-induced colitis mouse model. FIG. 34D shows an H&E stained photograph at 200x magnification of a sample from the compound 1 group of the OXZ-induced colitis mouse model. FIG. 35 shows the pathological scores of colitis severity in an OXZ-induced colitis mouse model. Treatment with OXZ induced extensive pathological changes in the colon histology of vehicle-treated mice (Figures 34A-34D), which was quantified by pathological scores (Figure 35). Compared to the vehicle group, the colons of mice treated with compound 1 or the comparator tofacitinib appeared similar to the sham group (Figures 34A-34D). Both groups showed increased crypt structural integrity, less inflammatory cell infiltration, less muscle thickening, and fewer crypt abscesses compared to the vehicle control group (Figure 35). Thus, compound 1 suppressed the severity of histological changes in the OXZ-induced colitis model.

[0347] conclusion Treatment with OXZ induced weight loss, increased colon density (length shortening and weight gain), elevated DAI scores, and significant alterations in colon histology (crypt structure, inflammatory cell infiltration, muscle thickening, and crypt abscesses). Compound 1 administered orally at a dose of 1,000 mg / kg twice daily inhibited the AUC of DAI scores by 70.3% (P<0.0001). Compound 1 administered orally at a dose of 1,000 mg / kg twice daily increased the AUC of body weight change by 64.7% (P<0.001). Compound 1 also inhibited OXZ-induced changes in colonic gross morphology and colonic histopathology. Taken together, these data indicate the efficacy of Compound 1 in this model.

[0348] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this specification, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

Claim 1: A pharmaceutical for treating or preventing an inflammatory disease, comprising a compound of formula I: 【Chemical 1】 [During the ceremony, W is CR Ｗ or N; X is CR Ｘ or N; Y is CR Ｙ or N; Z is CR Ｚ or N; wherein no more than two of W, X, Y and Z are simultaneously N; Ring A is a monocyclic or polycyclic C ３－１４ or Ring A is a monocyclic or polycyclic 4- to 18-membered heterocycloalkyl, where Ring A optionally has 1, 2, 3, or 4 R Ａ When ring A is polycyclic, ring A is substituted with -(L) of formula I via a non-aromatic ring. ｍ -bonded to the moiety; Lは-(CR ５ R ６ ) ｔ -、-(CR ５ R ６ ) ｐ -O-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ -S-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ -NR ３ -(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ -CO-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｒ -C(O)O-(CR ５ R ６ ) ｓ -、-(CR ５ R ６ ) ｒ -CONR ３ -(CR ５ R ６ ) ｓ -、-(CR ５ R ６ ) ｐ -SO-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ 2000 ２ -(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｒ -SONR ３ -(CR ５ R ６ ) ｓ -または-NR ３ CONR ４ - and; R １ and R ２ are each independently selected from H and methyl; R ３ and R ４ are each independently H and C １－４ alkyl; R ５ and R ６ are each independently H, halo, or C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, amino, C １－４ Alkylamino and C ２－８ dialkylamino; Each R Ａ is independently halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )R ｂ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ wherein R Ａ The C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ The alkyl is each optionally selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from: R Ｗ , R Ｘ , R Ｙ and R Ｚ are each independently H, halo, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ wherein R Ｗ , R Ｘ , R Ｙ or R Ｚ The C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is optionally Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from: W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ If so, then R Ｗ , R Ｘ , R Ｙ and R Ｚ at least one of is other than H; Each Cy １ is independently C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy ２ is independently C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ and R ｄ２ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ The alkyl may optionally be Cy ３ , Cy ３ -C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Each Cy ３ is C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each optionally containing halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ substituted with 1, 2, 3, or 4 substituents independently selected from R ａ３ , R ｂ３ , R ｃ３ and R ｄ３ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is optionally OH, CN, amino, halo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R ｃ１ and R ｄ１ together with the N atom to which they are attached, optionally halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: or R ｃ２ and R ｄ２ together with the N atom to which they are attached, optionally halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: Each R ｅ１ , R ｅ２ and R ｅ３ are independently H, C １－４ selected from alkyl and CN; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, where p+q is 0, 1 or 2; r is 0 or 1; s is 0 or 1, where r+s is 0 or 1; and t is 1, 2, or 3; wherein any of said heteroaryl or heterocycloalkyl groups contains 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups is optionally substituted with an oxo (=O) group; and One or more ring-forming S atoms of any of the above heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups. or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The pharmaceutical of claim 1, wherein the inflammatory disease is asthma.

3. W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ The pharmaceutical composition of claim 1 or 2,

4. W is N; X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ The pharmaceutical composition of claim 1 or 2,

5. W is CR Ｗ X is N; and Y is CR Ｙ and Z is CR Ｚ The pharmaceutical composition of claim 1 or 2,

6. W is CR Ｗ and X is CR Ｘ Y is N; and Z is CR Ｚ The pharmaceutical composition of claim 1 or 2,

7. W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is N.

8. Ring A optionally contains 1, 2, 3 or 4 R Ａ Monocyclic or polycyclic C substituted with ３－１４ cycloalkyl, wherein when ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. ｍ The pharmaceutical agent of any one of claims 1 to 7, which is bound to a - moiety.

9. Ring A optionally contains 1, 2, 3 or 4 R Ａ Monocyclic C substituted with ３－７ The pharmaceutical agent according to any one of claims 1 to 7, which is cycloalkyl.

10. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the aryl group is cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl substituted with

11. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the cyclohexyl is substituted with .

12. Ring A optionally contains 1, 2, 3 or 4 R Ａ and wherein when ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. ｍ The pharmaceutical agent of any one of claims 1 to 7, which is bound to a - moiety.

13. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the heterocycloalkyl is a monocyclic 4- to 7-membered heterocycloalkyl substituted with

14. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl or tetrahydrothiopyranyl is substituted with

15. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the aryl group is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl substituted with

16. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the compound is piperidinyl substituted with

17. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the compound is piperidin-4-yl substituted with

18. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the compound is tetrahydropyranyl substituted with

19. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 1 to 7, wherein the compound is tetrahydropyran-4-yl substituted with

20. L is -(CR ５ R ６ ) ｔ The pharmaceutical agent according to any one of claims 1 to 19, wherein

21. L is -(CR ５ R ６ ) ｔ - and t is 1.

22. L is -CH ２ The pharmaceutical agent according to any one of claims 1 to 19, wherein

23. The pharmaceutical agent according to any one of claims 1 to 22, wherein m is 0.

24. The pharmaceutical agent of any one of claims 1 to 22, wherein m is 1.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein n is 0.

26. R １ and R ２ The pharmaceutical agent according to any one of claims 1 to 25, wherein both are H.

27. R １ is methyl, and R ２ The pharmaceutical agent of any one of claims 1 to 25, wherein is H.

28. Each R Ａ became independent and became C １－６ Alkyl, halo, C １－６ Haloalkyl, OR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , N.R. ｃ１ R ｄ１ , S(O) ２ R ｂ１ , 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl; wherein said C １－６ Alkyl, C １－６ haloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ Each alkyl is optionally Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ The pharmaceutical agent of any one of claims 1 to 27, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

29. Each R Ａ became independent and became C １－６ Alkyl, OR ａ１ , C(O)R ｂ１ , N.R. ｃ１ R ｄ１ and S(O) ２ R ｂ１ wherein said C １－６ Alkyl optionally is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ The pharmaceutical agent of any one of claims 1 to 27, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

30. Each R Ａ Halo, C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, OR ａ１ , N.R. ｃ１ R ｄ１ , C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , C(O)R ｂ１ , C(O)OR ａ１ and S(O) ２ R ｂ１ wherein the C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally halo, CN, OR ａ１ , N.R. ｃ１ R ｄ１ , C(O)R ｂ１ and N.R. ｃ１ C(O)R ｂ１ The pharmaceutical agent of any one of claims 1 to 27, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

31. Each R Ａ Halo, C １－６ Haloalkyl, OR ａ１ , C(O)NR ｃ１ R ｄ１ and C(O)OR ａ１ The pharmaceutical agent of any one of claims 1 to 27, independently selected from:

32. R Ａ is OR ａ１ The pharmaceutical agent according to any one of claims 1 to 27,

33. R ａ１ H, C １－６ Alkyl or C １－６ The pharmaceutical agent of any one of claims 1 to 32, which is haloalkyl.

34. Each R Ｗ , R Ｘ , R Ｙ and R Ｚ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, CN, OR ａ２ , C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ wherein R Ｗ , R Ｘ , R Ｙ and R Ｚ The C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C ６－１０ Aryl-C １－４ Each alkyl is optionally Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 1 to 33, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

35. Each R Ｗ , R Ｘ , R Ｙ and R Ｚ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, CN, OR ａ２ , C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ and N.R. ｃ２ C(O)R ｂ２ wherein R Ｗ , R Ｘ , R Ｙ and R Ｚ The C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C ６－１０ Aryl-C １－４ Each alkyl is optionally Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 1 to 33, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

36. W is CR Ｗ and R Ｗ The pharmaceutical of any one of claims 1 to 35, wherein is other than H.

37. W is CR Ｗ and R Ｗ The pharmaceutical agent of any one of claims 1 to 35, wherein is H.

38. R Ｗ is C １－６ Alkyl, C １－６ Haloalkyl, halo and OR ａ２ wherein said C １－６ Alkyl and C １－６ Each haloalkyl is optionally OR ａ２ 38. The pharmaceutical agent of any one of claims 1 to 37, substituted with:

39. R Ｗ is C １－６ Alkyl, C １－６ Haloalkyl, CN, halo and OR ａ２ wherein said C １－６ Alkyl and C １－６ Each haloalkyl is optionally OR ａ２ 38. The pharmaceutical agent of any one of claims 1 to 37, substituted with:

40. R Ｗ The pharmaceutical of any one of claims 1 to 37, wherein is halo.

41. R Ｗ The pharmaceutical agent according to any one of claims 1 to 37, wherein is F.

42. X is CR Ｘ and R Ｘ The pharmaceutical of any one of claims 1 to 41, wherein is other than H.

43. X is CR Ｘ and R Ｘ The pharmaceutical agent of any one of claims 1 to 41, wherein is H.

44. R Ｘ is C １－６ Alkyl, halo and OR ａ２ The pharmaceutical agent according to any one of claims 1 to 43, selected from the group consisting of:

45. Y is CR Ｙ and R Ｙ The pharmaceutical of any one of claims 1 to 44, wherein is other than H.

46. Y is CR Ｙ and R Ｙ The pharmaceutical agent of any one of claims 1 to 44, wherein is H.

47. Y is CR Ｙ and R Ｙ is C １－６ Alkyl, OR ａ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 1 to 44, independently selected from:

48. Y is CR Ｙ and R Ｙ is C １－６ Alkyl, C ３－７ Cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, halo, CN, OR ａ２ , S.R. ａ２ , C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ where R Ｙ The C １－６ Alkyl, C ３－７ Cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl each optionally include halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , N.R. ｃ２ R ｄ２ and S(O) ２ R ｂ２ The pharmaceutical agent of any one of claims 1 to 44, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

49. Y is CR Ｙ and R Ｙ NR ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 1 to 44, independently selected from:

50. Y is CR Ｙ and R Ｙ is C １－６ Alkyl and OR ａ２ The pharmaceutical agent of any one of claims 1 to 44, independently selected from:

51. R ａ２ H, C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally C １－４ Alkyl, C １－４ Haloalkyl, Halo, CN, OR ａ３ , C(O)R ｂ３ , C(O)OR ａ３ and S(O) ２ R ｂ３ 51. The pharmaceutical agent of any one of claims 1 to 50, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

52. Y is CR Ｙ and R Ｙ NR ｃ２ R ｄ２ and N.R. ｃ２ C(O)R ｂ２ The pharmaceutical agent of any one of claims 1 to 44, independently selected from:

53. R ｃ２ and R ｄ２ are H and C respectively １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally C １－４ Alkyl, C １－４ Haloalkyl, Halo, CN, OR ａ３ , C(O)R ｂ３ , C(O)OR ａ３ and S(O) ２ R ｂ３ 53. The pharmaceutical agent of any one of claims 1 to 52, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

54. Z is CR Ｚ and R Ｚ The pharmaceutical of any one of claims 1 to 53, wherein is other than H.

55. Z is CR Ｚ and R Ｚ The pharmaceutical of any one of claims 1 to 53, wherein is H.

56. Z is CR Ｚ and R Ｚ is C １－６ The pharmaceutical of any one of claims 1 to 53, which is alkyl.

57. Z is CR Ｚ and R Ｚ is C １－６ The pharmaceutical of any one of claims 1 to 53, which is alkyl, halo, or CN.

58. The compound of formula II: 【Chemistry 3】 The pharmaceutical composition of claim 1, which is a compound having the formula:

59. The compound of formula IIIA, IIIB, IIIC, IIID or IIIE: 【Chemistry 4】 The pharmaceutical composition of claim 1, which is a compound having the formula:

60. The compound of formula IVA or IVB: 【Chemistry 5】 The pharmaceutical composition of claim 1, which is a compound having the formula:

61. A compound 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 6-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 6-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)thio)ethyl)quinazolin-4(3H)-one; 5-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate; 8-methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one; 2-((azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile; 7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-methylpiperidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 7-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2-((((trans)-3-(benzyloxy)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-((oxetan-3-ylthio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 6-chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7,8-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 2-(((trans-3-hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-3-aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide; N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide; N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide; 4-oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide; 7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((4-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((3-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrazin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrimidin-5-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methyl-1H-imidazol-2-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(thiazol-2-ylamino)quinazolin-4(3H)-one; 7-((2-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((4-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((5-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(dimethylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-morpholino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(4-methylpiperazin-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(isopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-4-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-2-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(benzylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-phenylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)amino)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-3-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexyl(methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-[(1-benzyl-3-piperidyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one; 7-(3-piperidylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one; 7-((1-benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 7-((1-acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(4-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide; 2-(((1-(4-(dimethylamino)benzyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 4-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)benzonitrile; 2-(((1-((1H-pyrazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-((1-methyl-1H-indazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-quinazolin-4(3H)-one; 2-(((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((3-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-phenethylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((3-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(3-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide; 2-(((1-((1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(imidazo[1,2-a]pyridin-3-ylmethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-((1-benzyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenoxy)acetonitrile; 8-methyl-2-(((1-((2-oxoindolin-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-((5-methoxypyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; (S)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (R)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (S)-8-methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(2-aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; N-(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)picolinamide; 2-(((1-(3-aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(3-aminopropanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(3-(dimethylamino)propanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (R)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine; (S)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine; 2-(((1-(L-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(D-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-(3-(pyridin-2-yl)propanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; N-(((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl)acetamide; 7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-((((1R,4R)-4-(hydroxymethyl)cyclohexyl)thio)-methyl)quinazolin-4(3H)-one; 2-((((trans)-4-(2-aminoethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((3-(aminomethyl)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-3-(2-aminoethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one 7-(cyclopentylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; (S)-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 2-((azepan-4-ylthio)methyl)-7-(cyclopentylamino)quinazolin-4(3H)-one; 2-(((3-(aminomethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-((3-methylisoxazol-5-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1-(methylsulfonyl)azetidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((oxepan-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 7-isobutyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 5-chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; Methyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate; 2-((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; cis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid; trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid; trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 7-(cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide; 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; (R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; (S)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((((cis)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 2-(((trans-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 2-(((cis-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 6-fluoro-7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; (R)-5-fluoro-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-cyclopentylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2-difluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(3,3,3-trifluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(((2,2-difluorocyclopropyl)methyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2-difluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-((3,3-difluorocyclopentyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; (R)-2-(((1-acetylpiperidin-4-yl)thio)methyl)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; 5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((piperidin-4-ylthio)methyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(1,1-dioxidothietan-3-yl)piperidin-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((2-morpholinoethyl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-methylacetamide; 7-(((2,2-difluorocyclopropyl)methyl)amino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetonitrile; 2-(trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 5-fluoro-7-((2-morpholinoethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-6-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-6-fluoroquinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-(2,2-difluoropropyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-(2,2-difluoroethyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 5-fluoro-7-((trans-2-fluorocyclopentyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-isobutoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-((cyclohexylthio)methyl)-5-fluoroquinazolin-4(3H)-one; 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one; trans-4-(((7-(cyclobutylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 7-((1-(2,2-difluoroethyl)piperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one; 7-((3,3-difluorocyclobutyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; (R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; (S)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; (S)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; (R)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((S)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-(((cis)-3-ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((((trans)-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclobutylmethoxy)-5-fluoroquinazolin-4(3H)-one; 5-fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one 7-((cyclopropylmethyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one; 5-fluoro-7-(((trans)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(oxetan-3-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1,4-dioxan-2-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclohexyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-5,6-difluoro-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((R)-1-acetylpyrrolidin-3-yl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-4(3H)-one; 7-((5,5-dimethyltetrahydrofuran-3-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-(((4-methyltetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-2-hydroxycyclopentyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (trans)-4-((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile; (cis)-4-((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile; 5,6-difluoro-7-(((trans)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one; 5-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 2-(((4,4-difluorocyclohexyl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpyrrolidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(2-cyclohexylethyl)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)thio)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-4-fluoropyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-4-fluoro-1-methylpyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((trans)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((trans)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propionamide; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one; N-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-methylcyclohexyl)acetamide; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydro-2H-pyran-3-yl)amino)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazoline-5-carbonitrile; 5,6-difluoro-7-(neopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((cis)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide; 5-fluoro-7-(((cis)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-((1-(cyclopropanecarbonyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5-fluoro-4-oxo-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-4-(((7-(cyclobutylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide; 7-(1-cyclopentylethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)cyclopropanecarboxamide; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-isobutyrylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-propionylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(piperidin-4-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((cis)-3-(trifluoromethoxy)cyclobutyl)amino)quinazolin-4(3H)-one; 7-amino-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((((trans)-4-(dimethylamino)cyclohexyl)thio)methyl)-5-fluoro-7,8-dihydroquinazolin-4(3H)-one; 5-fluoro-2-((((cis)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((2-methoxy-2-methylpropyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((((cis)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one; Methyl 4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate; 5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((trans)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((4-methylmorpholin-2-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(neopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((cis)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(3,3,3-trifluoro-2,2-dimethylpropoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(2-methoxyacetyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((((trans)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; and 7-((3,3-difluoro-1-methylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one The pharmaceutical composition of claim 1, which is a compound selected from the following or a pharmaceutically acceptable salt thereof:

62. 62. The pharmaceutical of any one of claims 1 and 3 to 61, wherein the inflammatory disease is selected from asthma, atopic dermatitis, psoriasis, rhinitis, systemic sclerosis, keloids, eosinophilic disorders, pulmonary fibrosis and type 2 cytokine pathology.

63. 62. The pharmaceutical of any one of claims 1 and 3 to 61, wherein the inflammatory disease is atopic dermatitis.

64. The pharmaceutical of any one of claims 1 and 3 to 61, wherein the inflammatory disease is systemic sclerosis.

65. 63. The medicament of claim 2 or 62, wherein the asthma is steroid-insensitive asthma, steroid-refractory asthma, steroid-resistant asthma, atopic asthma, non-atopic asthma, persistent asthma, severe asthma or steroid-refractory severe asthma.

66. 66. The pharmaceutical of claim 65, wherein the severe asthma is T2 high endo type, T2 low endo type or non-T2 endo type.

67. 66. The pharmaceutical of claim 65, wherein the severe asthma is T2 low endotype or non-T2 endotype.

68. (a) reducing the level of airway mucus in lung tissue; (b) reduction of serum IgE; (c) reduced immune cell infiltration and activation in bronchoalveolar fluid; (d) reducing the levels of one or more inflammatory cytokines in bronchoalveolar fluid or lung tissue; or (e) reducing the level of one or more alarmins in bronchoalveolar fluid or lung tissue A medicament for treating a patient having a condition of formula I: 【Chemistry 6】 [During the ceremony, W is CR Ｗ or N; X is CR Ｘ or N; Y is CR Ｙ or N; Z is CR Ｚ or N; wherein no more than two of W, X, Y and Z are simultaneously N; Ring A is a monocyclic or polycyclic C ３－１４ or Ring A is a monocyclic or polycyclic 4- to 18-membered heterocycloalkyl, where Ring A optionally has 1, 2, 3, or 4 R Ａ When ring A is polycyclic, ring A is substituted with -(L) of formula I via a non-aromatic ring. ｍ -bonded to the moiety; Lは-(CR ５ R ６ ) ｔ -、-(CR ５ R ６ ) ｐ -O-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ -S-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ -NR ３ -(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ -CO-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｒ -C(O)O-(CR ５ R ６ ) ｓ -、-(CR ５ R ６ ) ｒ -CONR ３ -(CR ５ R ６ ) ｓ -、-(CR ５ R ６ ) ｐ -SO-(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｐ 2000 ２ -(CR ５ R ６ ) ｑ -、-(CR ５ R ６ ) ｒ -SONR ３ -(CR ５ R ６ ) ｓ -または-NR ３ CONR ４ - and; R １ and R ２ are each independently selected from H and methyl; R ３ and R ４ are each independently H and C １－４ alkyl; R ５ and R ６ are each independently H, halo, or C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, amino, C １－４ Alkylamino and C ２－８ dialkylamino; Each R Ａ is independently halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )R ｂ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ wherein R Ａ The C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from: R Ｗ , R Ｘ , R Ｙ and R Ｚ are each independently H, halo, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ wherein R Ｗ , R Ｘ , R Ｙ or R Ｚ The C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from: W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ If so, then R Ｗ , R Ｘ , R Ｙ and R Ｚ at least one of is other than H; Each Cy １ is independently C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy ２ is independently C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ and R ｄ２ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ The alkyl may optionally be Cy ３ , Cy ３ -C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Each Cy ３ is C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each optionally containing halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ substituted with 1, 2, 3, or 4 substituents independently selected from R ａ３ , R ｂ３ , R ｃ３ and R ｄ３ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is optionally OH, CN, amino, halo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or R ｃ１ and R ｄ１ together with the N atom to which they are attached, optionally halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: or R ｃ２ and R ｄ２ together with the N atom to which they are attached, optionally halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R. ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ )NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ R ｂ３ , N.R. ｃ３ S(O) ２ NR ｃ３ R ｄ３ and S(O) ２ NR ｃ３ R ｄ３ forming a 4- to 7-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: Each R ｅ１ , R ｅ２ and R ｅ３ are independently H, C １－４ selected from alkyl and CN; m is 0 or 1; n is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2, where p+q is 0, 1 or 2; r is 0 or 1; s is 0 or 1, where r+s is 0 or 1; and t is 1, 2, or 3; wherein any of said heteroaryl or heterocycloalkyl groups contains 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; one or more ring-forming C or N atoms of any of the above heterocycloalkyl groups is optionally substituted with an oxo (=O) group; and One or more ring-forming S atoms of any of the above heterocycloalkyl groups are optionally substituted with one or two oxo (=O) groups. or a pharmaceutically acceptable salt thereof as an active ingredient.

69. W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ The pharmaceutical of claim 68,

70. W is N; X is CR Ｘ and Y is CR Ｙ and Z is CR Ｚ The pharmaceutical of claim 68,

71. W is CR Ｗ X is N; and Y is CR Ｙ and Z is CR Ｚ The pharmaceutical of claim 68,

72. W is CR Ｗ and X is CR Ｘ Y is N; and Z is CR Ｚ The pharmaceutical of claim 68,

73. W is CR Ｗ and X is CR Ｘ and Y is CR Ｙ and Z is N.

74. Ring A optionally contains 1, 2, 3 or 4 R Ａ Monocyclic or polycyclic C substituted with ３－１４ cycloalkyl, wherein when ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. ｍ - A pharmaceutical agent according to any one of claims 68 to 73, which is linked to a moiety.

75. Ring A optionally contains 1, 2, 3 or 4 R Ａ Monocyclic C substituted with ３－７ The pharmaceutical of any one of claims 68 to 73, which is cycloalkyl.

76. Ring A optionally contains 1, 2, 3 or 4 R Ａ 74. The pharmaceutical of any one of claims 68 to 73, wherein the cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl is substituted with:

77. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical of any one of claims 68 to 73, wherein the cyclohexyl is substituted with .

78. Ring A optionally contains 1, 2, 3 or 4 R Ａ and wherein when ring A is polycyclic, ring A is connected to -(L) of formula I via a non-aromatic ring. ｍ - A pharmaceutical agent according to any one of claims 68 to 73, which is linked to a moiety.

79. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent of any one of claims 68 to 73, wherein the heterocycloalkyl is a monocyclic 4- to 7-membered heterocycloalkyl substituted with

80. Ring A optionally contains 1, 2, 3 or 4 R Ａ 74. The pharmaceutical agent of any one of claims 68 to 73, which is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl or tetrahydrothiopyranyl substituted with:

81. Ring A optionally contains 1, 2, 3 or 4 R Ａ 74. The pharmaceutical agent of any one of claims 68 to 73, which is oxetanyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl substituted with:

82. Ring A optionally contains 1, 2, 3 or 4 R Ａ 74. The pharmaceutical of any one of claims 68 to 73, which is piperidinyl substituted with:

83. Ring A optionally contains 1, 2, 3 or 4 R Ａ 74. The pharmaceutical agent of any one of claims 68 to 73, which is piperidin-4-yl substituted with:

84. Ring A optionally contains 1, 2, 3 or 4 R Ａ 74. The pharmaceutical of any one of claims 68 to 73, which is tetrahydropyranyl substituted with:

85. Ring A optionally contains 1, 2, 3 or 4 R Ａ The pharmaceutical agent according to any one of claims 68 to 73, which is tetrahydropyran-4-yl substituted with

86. L is -(CR ５ R ６ ) ｔ The pharmaceutical of any one of claims 68 to 85, wherein

87. L is -(CR ５ R ６ ) ｔ - and t is 1.

88. L is -CH ２ The pharmaceutical of any one of claims 68 to 85, wherein

89. The pharmaceutical of any one of claims 68 to 88, wherein m is 0.

90. The pharmaceutical of any one of claims 68 to 88, wherein m is 1.

91. The pharmaceutical of any one of claims 68 to 90, wherein n is 0.

92. R １ and R ２ The pharmaceutical of any one of claims 68 to 91, wherein both are H.

93. R １ is methyl, and R ２ The pharmaceutical of any one of claims 68 to 91, wherein is H.

94. Each R Ａ became independent and became C １－６ Alkyl, halo, C １－６ Haloalkyl, OR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , N.R. ｃ１ R ｄ１ , S(O) ２ R ｂ１ , 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl; wherein said C １－６ Alkyl, C １－６ haloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ Each alkyl is optionally Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ The pharmaceutical agent of any one of claims 68 to 93, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

95. Each R Ａ became independent and became C １－６ Alkyl, OR ａ１ , C(O)R ｂ１ , N.R. ｃ１ R ｄ１ and S(O) ２ R ｂ１ wherein said C １－６ Alkyl optionally is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R. ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ )NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S(O) ２ R ｂ１ , N.R. ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ and S(O) ２ NR ｃ１ R ｄ１ The pharmaceutical agent of any one of claims 68 to 93, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

96. Each R Ａ Halo, C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, OR ａ１ , N.R. ｃ１ R ｄ１ , C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , C(O)R ｂ１ , C(O)OR ａ１ and S(O) ２ R ｂ１ wherein the C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally halo, CN, OR ａ１ , N.R. ｃ１ R ｄ１ , C(O)R ｂ１ and N.R. ｃ１ C(O)R ｂ１ The pharmaceutical agent of any one of claims 68 to 93, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

97. Each R Ａ Halo, C １－６ Haloalkyl, OR ａ１ , C(O)NR ｃ１ R ｄ１ and C(O)OR ａ１ The pharmaceutical agent of any one of claims 68 to 93, independently selected from:

98. R Ａ is OR ａ１ The pharmaceutical of any one of claims 68 to 93,

99. R ａ１ H, C １－６ Alkyl or C １－６ The pharmaceutical agent of any one of claims 68 to 93, which is haloalkyl.

100. Each R Ｗ , R Ｘ , R Ｙ and R Ｚ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, CN, OR ａ２ , C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ wherein R Ｗ , R Ｘ , R Ｙ and R Ｚ The C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C ６－１０ Aryl-C １－４ Each alkyl is optionally Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ 94. The pharmaceutical agent of any one of claims 68 to 93, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

101. Each R Ｗ , R Ｘ , R Ｙ and R Ｚ are independently H, halo, C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, CN, OR ａ２ , C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ and N.R. ｃ２ C(O)R ｂ２ wherein R Ｗ , R Ｘ , R Ｙ and R Ｚ The C １－６ Alkyl, C １－６ haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C ６－１０ Aryl-C １－４ Each alkyl is optionally Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R. ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ , N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ and S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 68 to 93, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

102. W is CR Ｗ and R Ｗ The pharmaceutical of any one of claims 68 to 101, wherein is other than H.

103. W is CR Ｗ and R Ｗ The pharmaceutical of any one of claims 68 to 101, wherein is H.

104. R Ｗ is C １－６ Alkyl, C １－６ Haloalkyl, halo and OR ａ２ wherein said C １－６ Alkyl and C １－６ Each haloalkyl is optionally OR ａ２ The pharmaceutical agent of any one of claims 68 to 103, substituted with

105. R Ｗ is C １－６ Alkyl, C １－６ Haloalkyl, CN, halo and OR ａ２ wherein said C １－６ Alkyl and C １－６ Each haloalkyl is optionally OR ａ２ The pharmaceutical agent of any one of claims 68 to 103, substituted with

106. R Ｗ The pharmaceutical of any one of claims 68 to 103, wherein is halo.

107. R Ｗ The pharmaceutical agent of any one of claims 68 to 103, wherein is F.

108. X is CR Ｘ and R Ｘ The pharmaceutical of any one of claims 68 to 107, wherein is other than H.

109. X is CR Ｘ and R Ｘ The pharmaceutical of any one of claims 68 to 107, wherein is H.

110. R Ｘ is C １－６ Alkyl, halo and OR ａ２ The pharmaceutical agent according to any one of claims 68 to 109, selected from the group consisting of:

111. Y is CR Ｙ and R Ｙ The pharmaceutical of any one of claims 68 to 110, wherein is other than H.

112. Y is CR Ｙ and R Ｙ The pharmaceutical of any one of claims 68 to 110, wherein is H.

113. Y is CR Ｙ and R Ｙ is C １－６ Alkyl, OR ａ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 68 to 110, independently selected from:

114. Y is CR Ｙ and R Ｙ is C １－６ Alkyl, C ３－７ Cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, halo, CN, OR ａ２ , S.R. ａ２ , C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ where R Ｙ The C １－６ Alkyl, C ３－７ Cycloalkyl-C １－４ alkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl each optionally include halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ２ , N.R. ｃ２ R ｄ２ and S(O) ２ R ｂ２ The pharmaceutical agent of any one of claims 68 to 110, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

115. Y is CR Ｙ and R Ｙ NR ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ )R ｂ２ , C(=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ )NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S(O) ２ R ｂ２ and N.R. ｃ２ S(O) ２ NR ｃ２ R ｄ２ The pharmaceutical agent of any one of claims 68 to 110, independently selected from:

116. Y is CR Ｙ and R Ｙ is C １－６ Alkyl and OR ａ２ The pharmaceutical agent of any one of claims 68 to 110, independently selected from:

117. R ａ２ H, C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally C １－４ Alkyl, C １－４ Haloalkyl, Halo, CN, OR ａ３ , C(O)R ｂ３ , C(O)OR ａ３ and S(O) ２ R ｂ３ The pharmaceutical agent of any one of claims 68 to 116, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

118. Y is CR Ｙ and R Ｙ NR ｃ２ R ｄ２ and N.R. ｃ２ C(O)R ｂ２ The pharmaceutical agent of any one of claims 68 to 110, independently selected from:

119. R ｃ２ and R ｄ２ are H and C respectively １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, wherein said C １－６ Alkyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Each alkyl is optionally C １－４ Alkyl, C １－４ Haloalkyl, Halo, CN, OR ａ３ , C(O)R ｂ３ , C(O)OR ａ３ and S(O) ２ R ｂ３ The pharmaceutical agent of any one of claims 68 to 118, substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

120. Z is CR Ｚ and R Ｚ The pharmaceutical of any one of claims 68 to 119, wherein is other than H.

121. Z is CR Ｚ and R Ｚ The pharmaceutical of any one of claims 68 to 119, wherein is H.

122. Z is CR Ｚ and R Ｚ is C １－６ The pharmaceutical of any one of claims 68 to 119, which is alkyl.

123. Z is CR Ｚ and R Ｚ is C １－６ The pharmaceutical of any one of claims 68 to 119, which is alkyl, halo, or CN.

124. The compound of formula II: 【Chemistry 7】 69. The pharmaceutical of claim 68, which is a compound having the formula: or a pharmaceutically acceptable salt thereof. Claim 125. The compound of formula IIIA, IIIB, IIIC, IIID or IIIE: 【Chemistry 8】 69. The pharmaceutical of claim 68, which is a compound having the formula: or a pharmaceutically acceptable salt thereof. Claim 126. The compound of formula IVA or IVB: 【Chemistry 9】 69. The pharmaceutical of claim 68, which is a compound having the formula: or a pharmaceutically acceptable salt thereof.

127. A compound 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 6-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 6-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)thio)ethyl)quinazolin-4(3H)-one; 5-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-benzyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one trifluoroacetate; 8-methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one; 2-((azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-(dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-4-methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile; 7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-Methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-methylpiperidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 7-fluoro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2-((((trans)-3-(benzyloxy)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-((oxetan-3-ylthio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 6-chloro-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7,8-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 2-(((trans-3-hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-3-aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 5-fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-(aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-4-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((trans-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((cis-3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((cis)-3-((dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide; N-(4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide; N-methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide; 4-oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide; 7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((4-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((3-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-methoxyphenyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrazin-2-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyridin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrimidin-5-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methyl-1H-imidazol-2-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(thiazol-2-ylamino)quinazolin-4(3H)-one; 7-((2-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((4-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((5-methylpyridin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one; 2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(dimethylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-morpholino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(4-methylpiperazin-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(isopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-4-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-2-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(benzylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-phenylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)amino)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((pyridin-3-ylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexyl(methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-[(1-benzyl-3-piperidyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one; 7-(3-piperidylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one; 7-((1-benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one 7-((1-acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(4-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide; 2-(((1-(4-(dimethylamino)benzyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 4-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)benzonitrile; 2-(((1-((1H-pyrazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-((1-methyl-1H-indazol-3-yl)methyl)piperidin-4-yl)thio)methyl)-quinazolin-4(3H)-one; 2-(((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((3-methylpyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-phenethylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((1-methyl-1H-indazol-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-((3-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; N-(3-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenyl)acetamide; 2-(((1-((1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(imidazo[1,2-a]pyridin-3-ylmethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-((1-benzyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)phenoxy)acetonitrile; 8-methyl-2-(((1-((2-oxoindolin-6-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-((5-methoxypyridin-2-yl)methyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; (S)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (R)-2-(((1-(2,3-dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (S)-8-methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((1-(2-hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(2-aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; N-(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)picolinamide; 2-(((1-(3-aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(3-aminopropanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(3-(dimethylamino)propanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; (R)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine; (S)-1-(4-amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine; 2-(((1-(L-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((1-(D-lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 8-methyl-2-(((1-(3-(pyridin-2-yl)propanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; N-(((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl)acetamide; 7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-((((1R,4R)-4-(hydroxymethyl)cyclohexyl)thio)-methyl)quinazolin-4(3H)-one; 2-((((trans)-4-(2-aminoethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-(((3-(aminomethyl)cyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 2-((((trans)-3-(2-aminoethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one 7-(cyclopentylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; (S)-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 2-((azepan-4-ylthio)methyl)-7-(cyclopentylamino)quinazolin-4(3H)-one; 2-(((3-(aminomethyl)cyclopentyl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-((3-methylisoxazol-5-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1-(methylsulfonyl)azetidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 8-methyl-2-((oxepan-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-((((1R,4R)-4-hydroxycyclohexyl)thio)methyl)-5-(trifluoromethyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; (R)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 7-isobutyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; cis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 5-chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; Methyl 4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate; 2-((trans)-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; cis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid; trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylic acid; trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 7-(cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide; 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; (R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; (S)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((((cis)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 2-(((trans-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 2-(((cis-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one; 6-fluoro-7-((tetrahydro-2H-pyran-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; (R)-5-fluoro-7-((1-(methylsulfonyl)piperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylamino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-cyclopentylethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2-difluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(3,3,3-trifluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-(((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)methyl)-8-methylquinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(((2,2-difluorocyclopropyl)methyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(2,2-difluoropropyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-((3,3-difluorocyclopentyl)amino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; (R)-2-(((1-acetylpiperidin-4-yl)thio)methyl)-7-((1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; 5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-1-(methylsulfonyl)piperidin-3-yl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((piperidin-4-ylthio)methyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1-(1,1-dioxidothietan-3-yl)piperidin-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-5-fluoro-2-(((1-(oxetan-3-yl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((2-morpholinoethyl)amino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylmethoxy)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-N-methylacetamide; 7-(((2,2-difluorocyclopropyl)methyl)amino)-5-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 2-(4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)acetonitrile; 2-(trans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 5-fluoro-7-((2-morpholinoethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-one; 7-(cyclohexylamino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-6-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-6-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-6-fluoroquinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-(2,2-difluoropropyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-(2,2-difluoroethyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(oxetan-3-yl)piperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-6-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 5-fluoro-7-((trans-2-fluorocyclopentyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-isobutoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)methyl)-5-fluoroquinazolin-4(3H)-one; 7-(cyclobutylmethoxy)-2-((cyclohexylthio)methyl)-5-fluoroquinazolin-4(3H)-one; 2-((cyclohexylthio)methyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one; trans-4-(((7-(cyclobutylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide; 7-((1-(2,2-difluoroethyl)piperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5,6-difluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one; 7-((3,3-difluorocyclobutyl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; (R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; (S)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; (S)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; (R)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((S)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-(((cis)-3-ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 2-((((trans)-4-(aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclobutylmethoxy)-5-fluoroquinazolin-4(3H)-one; 5-fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one 7-((cyclopropylmethyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((cyclobutylmethyl)amino)-2-(((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one; 5-fluoro-7-(((trans)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(oxetan-3-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1,4-dioxan-2-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclohexyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (R)-5,6-difluoro-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((R)-1-acetylpyrrolidin-3-yl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((2,2-difluorocyclopentyl)amino)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-4(3H)-one; 7-((5,5-dimethyltetrahydrofuran-3-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-2-(((4-methyltetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-2-hydroxycyclopentyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; (trans)-4-((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile; (cis)-4-((5,6-difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile; 5,6-difluoro-7-(((trans)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one; 5-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 2-(((4,4-difluorocyclohexyl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpyrrolidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(2-cyclohexylethyl)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)thio)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-4-fluoropyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-4-fluoro-1-methylpyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((trans)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((trans)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propionamide; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one; N-(4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-methylcyclohexyl)acetamide; 5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydro-2H-pyran-3-yl)amino)quinazolin-4(3H)-one; 5-fluoro-2-((((trans)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazoline-5-carbonitrile; 5,6-difluoro-7-(neopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((cis)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(((trans)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((cis)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide; 5-fluoro-7-(((cis)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; 7-((1-(cyclopropanecarbonyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5-fluoro-4-oxo-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-4-(((7-(cyclobutylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; N-((trans)-3-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclobutyl)acetamide; 7-(1-cyclopentylethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one; N-((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)cyclopropanecarboxamide; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-isobutyrylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-propionylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(piperidin-4-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((cis)-3-(trifluoromethoxy)cyclobutyl)amino)quinazolin-4(3H)-one; 7-amino-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopropylmethoxy)-2-((((trans)-4-(dimethylamino)cyclohexyl)thio)methyl)-5-fluoro-7,8-dihydroquinazolin-4(3H)-one; 5-fluoro-2-((((cis)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 5,6-difluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((2-methoxy-2-methylpropyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((((cis)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one; Methyl 4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate; 5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((trans)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-(cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((4-methylmorpholin-2-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-(neopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((cis)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-(((1-acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(3,3,3-trifluoro-2,2-dimethylpropoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5-fluoro-7-((1-(2-methoxyacetyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; 5,6-difluoro-7-((((trans)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one; N-((trans)-4-(((5-fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide; and 7-((3,3-difluoro-1-methylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof 69. The pharmaceutical of claim 68, which is a compound selected from the group consisting of:

128. The pharmaceutical of any of claims 68 to 127, wherein the immune cells are eosinophils, neutrophils, or lymphocytes.

129. The pharmaceutical of any of claims 68 to 127, wherein the inflammatory cytokine is a Th2 cytokine or a Th17 cytokine.

130. The pharmaceutical of any one of claims 68 to 127, wherein the inflammatory cytokine is IL-4, IL-5, IL13 or IL-17A.

131. The pharmaceutical of any of claims 68 to 127, wherein the alarmin is IL-25, IL-33 or TSLP.

132. A pharmaceutical agent according to any one of claims 1 to 131, used in combination with a second therapeutic agent.

133. 62. The pharmaceutical of any one of claims 1 and 3 to 61, wherein the inflammatory disease is inflammatory bowel disease.

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