ALOX inhibitor and use thereof
By developing ALOX15 inhibitors, the treatment challenges of ALOX15-mediated chronic sinusitis with nasal polyps and other diseases have been solved, achieving effective inhibition of ALOX15 enzyme activity and providing a means of disease treatment and prevention.
Patent Information
- Application Number
- PCT/CN2025/108969
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-07-19
- Filing Date
- 2025-07-17
- Publication Date
- 2026-01-22
Smart Images
Figure CN2025108969_22012026_PF_FP_ABST
Abstract
Description
ALOX inhibitors and their uses Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to ALOX inhibitors and their use in the prevention and / or treatment of diseases related to or mediated by ALOX. This invention also relates to compounds that can be used to inhibit ALOX, etc., and particularly to ALOX15 inhibitors and their use in the prevention and / or treatment of diseases related to or mediated by ALOX15. Background Technology
[0002] Arachidonic acid 15-lipoxygenase (ALOX15) is a member of the arachidonic acid lipoxygenase (ALOX) family. It is an enzyme that catalyzes the oxidation of various unsaturated fatty acids, such as arachidonic acid and linoleic acid, and is thought to promote the pathophysiological processes of various immune and inflammatory diseases by producing various bioactive lipid mediators (Singh and Rao, 2019, Prog. Lipid Res., Vol. 73: p. 28). In humans, ALOX15 is constitutively expressed in immature erythrocytes, eosinophils, airway epithelial cells, resident macrophages, and other cells. Its expression is known to be strongly upregulated by the Th2 cytokines IL-4 and IL-13 (Singh and Rao, 2019, Prog. Lipid Res., Vol. 73: p. 28; Snodgrass and Brune, 2019, Front Pharmacol., Vol. 10: p. 719; Liu et al., 2009, Am J Physiol Lung Cell Mol Physiol., Vol. 297: p. L196; Zhao et al., 2011, Proc Natl Acad Sci US A., Vol. 108: p. 14246; Li et al., 2019, J Allergy Clin Immunol., Vol. 144: p. 1228; Wang et al., 2022, Nat Immunol., Vol. 23: p. 1484.
[0003] Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory form of sinusitis characterized by type 2 inflammation and eosinophilic infiltration (Stevens et al., 2019, J Allergy Clin Immunol Pract., Vol. 7: p. 2812). Large-scale GWAS studies have revealed that loss-of-function variants of ALOX15 are associated with a reduced risk of nasal polyps and chronic rhinosinusitis (CRS), and that these variants do not increase the risk of other diseases (Kristjansson et al., 2019, Nat Genet., Vol. 51: p. 267). ALOX15 expression in nasal polyp tissue has been reported to be increased in patients with eosinophilic CRSwNP and is associated with disease severity (Bangert et al., 2022, Front Immunol., Vol. 13: p. 850494; Liang et al., 2020, Allergy Asthma Clin Immunol., Vol. 16: p. 82). Studies have also shown an increase in the number of ALOX15-positive macrophages and dendritic cells in the nasal mucosa of patients with eosinophilic CRSwNP (Wang et al., 2022, Nat Immunol., Vol. 23: p. 1484). In vitro studies have shown that stimulation of human nasal epithelial cells with IL-13 increases ALOX15 expression, thereby promoting the expression and secretion of the eosinophilic chemokine CCL26 (Li et al., 2019, J Allergy Clin Immunol., Vol. 144: p. 1228). Stimulation of human macrophages with IL-4 or IL-13 has also been reported to promote the secretion of chemokines (such as CCL13, CCL17, CCL18, and CCL24), which are involved in the migration of eosinophils and T cells, and is associated with increased ALOX15 expression (Wang et al., 2022, Nat Immunol., Vol. 23: p. 1484). Therefore, ALOX15 inhibitors hold promise for the prevention and / or treatment of CRSwNP, as well as allergic asthma and eosinophilic esophagitis, with drugs targeting Th2 cytokines or their receptors being highly effective for these diseases (Kyriakopoulos et al., 2024, Eur Respir Rev., Vol. 33: 230-238; Nhu and Aceves, 2023, Ann Allergy Asthma Immunol., Vol. 130: 15). Furthermore, ALOX15 controls ferroptosis, a cell death caused by the accumulation of iron-dependent lipid oxidants (Hu et al., 2022, Cells, Vol. 11: 2040).Therefore, ALOX15 inhibitors hold promise for the prevention and / or treatment of diseases associated with ferroptosis, such as Friedreich ataxia, hereditary mitochondrial respiratory chain diseases, hereditary epilepsy, Leigh syndrome, Parkinson's disease, and amyotrophic lateral sclerosis. Summary of the Invention
[0004] One object of the invention is to provide a class of ALOX inhibitors, pharmaceutically acceptable salts thereof, or solvates thereof, particularly ALOX15 inhibitors, pharmaceutically acceptable salts thereof, or solvates thereof. The compounds of the present invention exhibit good ALOX15 inhibitory activity. Another object of the invention is to provide compounds that can be used to inhibit ALOX, etc. The compounds of the present invention are capable of treating or preventing ALOX-mediated diseases.
[0005] This invention provides the following technical solutions:
[0006] Scheme 1. An arachidonic acid lipoxygenase (ALOX) inhibitor, said ALOX inhibitor comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof.
[0007] in
[0008] R 1 Halogen, -CN, C 1-6 Alkyl (optionally C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 1-6 Alkyl ester, -OH, -NH2, 4-8 membered heterocyclic group, oxo group, -CO2H, -CN or 1-6 halogen substitutions), C 2-6 alkynyl group, C 2- 6-Haloacetylenic, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -OH, -NH2, -CO2H, -CN, 1-6 halogens, or C) 1-6 Alkyl groups), 4-8 membered heterocyclic groups (optionally C 1-6 (alkyl, oxo, or 1-6 halogen-substituted), -NR v R w C 1-6 Alkoxy groups (optionally replaced by -CN, C) 1-6 Alkoxy, C 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy;
[0009] R 2 H, halogen, -CN, C 1-6Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- 6-haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-6 cycloalkyl, -NR v R w -OH, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;
[0010] R 3 For H or -NR v R w ;
[0011] A is
[0012] X1 is CR b Or N;
[0013] R b H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, -NR v R w OR x ;
[0014] R x C 1-6 Alkyl groups (optionally -CN, C) 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, 4-8 membered heterocyclic group, 4-8 membered halocyclic group, C 1-6 (alkoxy or 1-6 halogenated), C 3-6 cycloalkyl, C 3-6 Halocycloalkyl, 4-8 membered heterocyclic group or 4-8 membered halocyclocyclic group;
[0015] R v and R w Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0016] X2 is CR c Or N;
[0017] R c H, halogen, C1-6 Alkyl groups (optionally substituted with -OH, -NH2, -CO2H, -CN, or 1-6 halogens), -OH, -NR y R z C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;
[0018] R y and R z Each is independently selected from H and C. 1-6 Alkyl groups (optionally substituted with -OH, -CO2H, -CN or 1-6 halogens) or 4-8 membered heterocyclic groups;
[0019] R 4 Halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;
[0020] R 5 It is H or halogen;
[0021] R 6 It is H or halogen;
[0022] X3 is either C or N;
[0023] X4 is either C or N;
[0024] R 7 It is H or halogen;
[0025] R 8 It is H or halogen;
[0026] R 9 H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;
[0027] B is a 5- or 6-membered heterocyclic group fused with X3 and X4 (optionally surrounded by 1-4 R groups). d (Substitute) or 5 or 6-membered heteroaryl (optionally replaced by 1-3 R) e replace);
[0028] R d and R e Each is independently selected from H, halogen, C 1-6 Alkyl, aryl, -NR v R w C 1-6 alkoxy, oxo, or thiocarbonyl groups;
[0029] m can be 0, 1, 2, or 3;
[0030] When m is 0, 1, or 2, X5 is CR f R g And when m is 3, X5 is CR. f R g Or O;
[0031] R 10 and R 11 Each is independently selected from H or C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogens);
[0032] When R 10 and R 11 Each independently is C 1-6 When the alkyl group (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogens) is R 10 and R 11 They can bond to form rings;
[0033] R 10 and R 11 They can form oxo groups together;
[0034] R 12 and R 13 Each is independently selected from H, halogen, -CN, C 1-6 Alkyl groups (optionally marked with -OH, C) 1-6 (alkoxy group or 1-6 halogen substituted) or -OH;
[0035] R f and R g Each is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0036] When R f and R g Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R f and R g They can bond to form rings;
[0037] When R 13 and R f Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R 13 and R f They can bond to form rings;
[0038] R 14 and R 15Each can be independently H or halogen;
[0039] R 16 and R 17 Each can be independently H or halogen;
[0040] R 18 and R 19 Each is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0041] When R 18 and R 19 Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R 18 and R 19 They can bond together to form rings.
[0042] Option 2. The inhibitor according to Option 1, wherein the arachidonic acid lipoxygenase (ALOX) is arachidonic acid-15-lipoxygenase (ALOX15).
[0043] Option 3. The inhibitor according to Option 1 or 2, wherein R 1 Halogen, -CN, C 1-6 Alkyl (optionally C 3-6 Cycloalkyl, oxo, -CO2H, -CN or 1-6 halogen substitutions), C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -CN, 1-6 halogens, or C) 1-6 Alkyl groups, 4-8 membered heterocyclic groups (optionally substituted with oxo groups), -NR v R w C 1-6 Alkoxy groups (optionally replaced by -CN, C) 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy, where R v and R w Each is independently selected from H or C 1-6 alkyl.
[0044] Option 4. An inhibitor according to any one of Options 1-3, wherein R 2 H, halogen, -CN, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6cycloalkyl, -NH2 or C 1-6 Alkyl group.
[0045] Option 5. An inhibitor according to any one of Options 1-4, wherein R c H, halogen, C 1-6 Alkyl groups (optionally substituted with 1-6 halogens), -OH, or -NR y R z , where R y and R z Each is independently selected from H and C. 1-6 alkyl.
[0046] Scheme 6. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof.
[0047] in
[0048] R 1 Halogen, -CN, C 1-6 Alkyl (optionally C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, oxo groups, -CO2H, -CN or 1-6 halogen substitutions), C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 2-6 alkenyl, C 2- 6-haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -CN, 1-6 halogens, or C) 1-6 Alkyl groups), 4-8 membered heterocyclic groups (optionally C 1-6 Alkyl, oxo, or 1-6 halogen-substituted groups), amino (optionally C-substituted) 1-6 Alkyl or C 1-6 (halogenated alkyl substitution), C 1-6 Alkoxy groups (optionally replaced by -CN, C) 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy;
[0049] R 2 H, halogen, -CN, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 cycloalkyl, -NR v R w C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;
[0050] R 3 For H;
[0051] A is
[0052] X 1 For CR b Or N;
[0053] R b H, halogen, -CN, -NR v R w OR x ;
[0054] R v and R w Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0055] R x C 1-6 Alkyl groups (optionally -CN, C) 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, 4-8 membered heterocyclic group, 4-8 membered halocyclic group, C 1-6 (alkoxy or 1-6 halogenated), C 3-6 cycloalkyl, C 3-6 Halocycloalkyl, 4-8 membered heterocyclic group or 4-8 membered halocyclocyclic group;
[0056] X2 is CR c Or N;
[0057] R c H, halogen, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, -CO2H, -CN, or 1-6 halogens), -OH, -NR y R z C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;
[0058] R y and R z Each is independently selected from H and C. 1-6 Alkyl groups (optionally substituted with -OH, -COOH, -CN or 1-6 halogens) or 4-8 membered heterocyclic groups;
[0059] R 4 Halogen, -CN, C 1-6 Alkyl, C1-6 Halogenated alkyl or C 3-6 cycloalkyl;
[0060] R 5 It is H or halogen;
[0061] R 6 It is H or halogen;
[0062] The condition is that,
[0063] When R 1 Halogen, C 1-6 Alkyne group, C substituted with -CN, -NH2, -OH or 4-8 membered heterocyclic groups 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted 4-8 membered heterocyclic group, or C-terminated 1-6 When an alkyl-substituted amino group is present, R 2 Not H;
[0064] When R 1 For unreplaced C 1-6 When alkyl, R 2 Not C 1-6 Alkyl groups (optionally substituted with -NH2 or 1-6 halogens);
[0065] When R 1 When it is -CN, R 2 Not H or -CN;
[0066] When R 1 When it is halogen, R 2 Not -NH2;
[0067] When X1 is CR b And X2 is CR c At that time, R b and R c They are not both H.
[0068] Scheme 7. The compound according to Scheme 6, its pharmaceutically acceptable salt or its solvate, wherein R c H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OH or -NR y R z , where R y and R z Each is independently selected from H or C 1-6 alkyl.
[0069] Scheme 8. An inhibitor or compound according to any one of Schemes 1-7, a pharmaceutically acceptable salt thereof, wherein R 6 For H.
[0070] Scheme 9. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof.
[0071] in
[0072] R 1 Halogen, -CN, C 1-6 Alkyl (optionally C 3-6 Cycloalkyl, -OH, 4-8 membered heterocyclic groups, oxo groups, -CO2H, -CN or 1-6 halogen substitutions), C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -CN, 1-6 halogens, or C) 1-6 Alkyl groups), 4-8 membered heterocyclic groups (optionally C 1-6 (alkyl, oxo, or 1-6 halogen-substituted), -NR v R w C 1-6 Alkoxy groups (optionally replaced by -CN, C) 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy;
[0073] R 2 H, halogen, -CN, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 cycloalkyl, -NR v R w Or C 1-6 Alkoxy;
[0074] R 3 It is H or -NH2;
[0075] A is
[0076] X3 is either C or N;
[0077] X4 is either C or N;
[0078] R 7 It is H or halogen;
[0079] R 8 It is H or halogen;
[0080] R 9 H, halogen, -CN, C 1-6 Alkyl, C1-6 Halogenated alkyl or C 3-6 cycloalkyl;
[0081] B is a 5- or 6-membered heterocyclic group fused with X3 and X4 (optionally surrounded by 1-4 R groups). d (Substitute) or 5 or 6-membered heteroaryl (optionally replaced by 1-3 R) e replace);
[0082] R d and R e Each is independently selected from H, halogen, C 1-6 Alkyl, aryl, -NR v R w C 1-6 alkoxy, oxo, or thiocarbonyl groups;
[0083] R v and R w Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.
[0084] Scheme 10. An inhibitor or compound according to any one of Schemes 1-5 and 9, wherein the structure containing B is any of the following structures:
[0085] In the above formula, R 7 R 8 R 9 R d R e And m is the same as schemes 1-5 and 9.
[0086] Scheme 11. The inhibitor or compound, a pharmaceutically acceptable salt thereof, or a solvation thereof, according to Schemes 1-5, 9, or 10, wherein the structure containing B is any of the following structures:
[0087] In the above formula, R 7 R 8 and R 9 Same as schemes 1-5 and 9-10.
[0088] Scheme 12. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvation thereof.
[0089] in,
[0090] R 1 Halogen, -CN, C 1-6 Alkyl (optionally C 3-6Cycloalkyl, 4-8 membered heterocyclic groups, oxo groups, -CO2H, -CN or 1-6 halogen substitutions), C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -CN, 1-6 halogens, or C) 1-6 Alkyl groups), 4-8 membered heterocyclic groups (optionally C 1-6 (alkyl, oxo, or 1-6 halogen-substituted), -NR v R w C 1-6 Alkoxy groups (optionally replaced by -CN, C) 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy;
[0091] R 2 H, halogen, -CN, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 cycloalkyl, -NR v R w Or C 1-6 Alkoxy;
[0092] R v and R w Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0093] R 3 It is H or -NH2;
[0094] A is
[0095] m can be 0, 1, 2, or 3;
[0096] When m is 0, 1, or 2, X5 is CR f R g And when m is 3, X5 is CR. f R g Or O;
[0097] R 10 and R 11 Each is independently selected from H or C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogens);
[0098] When R10 and R 11 Each independently is C 1-6 When the alkyl group (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogens) is R 10 and R 11 They can bond to form rings;
[0099] R 10 and R 11 They can form oxo groups together;
[0100] R 12 and R 13 Each is independently selected from H, halogen, -CN, C 1-6 Alkyl groups (optionally marked with -OH, C) 1-6 (alkoxy group or 1-6 halogen substituted) or -OH;
[0101] R f and R g Each is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0102] When R f and R g Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R f and R g They can bond to form rings;
[0103] When R 13 and R 14 Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R 13 and R 14 They can bond to form rings;
[0104] R 14 and R 15 Each is independently selected from H or halogen;
[0105] R 16 and R 17 Each is independently selected from H or halogen;
[0106] R 18 and R 19 Each is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;
[0107] When R 18 and R 19 Each independently is C 1-6 Alkyl or C1-6 When alkyl haloides are used, R 18 and R 19 They can bond to form rings;
[0108] The condition is that,
[0109] When A is m is 2, and R 1 Halogen, -CN, C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R 2 Not H;
[0110] When A is m is 2, and R 1 When it is -CN, R 2 Not halogen.
[0111] Scheme 13. The compound according to Scheme 12, its pharmaceutically acceptable salt or its solvate, wherein R 14 -R 17 Each is an independent halogen, and R 18 and R 19 Each independently is C 1-6 alkyl.
[0112] Option 14. An inhibitor or compound according to Options 1-4, 9, 12 or 13, a pharmaceutically acceptable salt or solvation thereof, wherein R 3 For H.
[0113] Scheme 15. A compound selected from the following, a pharmaceutically acceptable salt thereof, or a solvation thereof:
[0114] 3-Chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine;
[0115] 2-(2-Chloro-4-fluorophenyl)-5-methylpyrazine;
[0116] 2-(4-fluoro-2-isopropoxyphenyl)-5-methylpyrazine;
[0117] 3-Chloro-5-(2-Chloro-4-fluorophenyl)pyrazine-2-carboxylonitrile;
[0118] 3-Chloro-5-(2-Chloro-4-fluorophenyl)-2-methylpyrazine;
[0119] 2-(2-Chloro-4-fluorophenyl)-5-cyclopropylpyrazine;
[0120] 2-Chloro-5-(2-Chloro-4-fluorophenyl)pyrazine;
[0121] 2-(2-Chloro-4-fluorophenyl)-5-methoxypyrazine;
[0122] 3-Chloro-5-(4-fluoro-2-isopropoxyphenyl)-2-methylpyrazine;
[0123] 2-Bromo-5-(4-fluoro-2-isopropoxyphenyl)pyrazine;
[0124] 2-Bromo-5-(2-Chloro-4-fluorophenyl)pyrazine;
[0125] 2-Chloro-5-(4-fluoro-2-isopropoxyphenyl)pyrazine;
[0126] 2-Cyclopropyl-5-(4-fluoro-2-isopropoxyphenyl)pyrazine;
[0127] 2-Chloro-5-(2-Chloro-4-fluorophenyl)-3-methylpyrazine;
[0128] 2-Chloro-5-(4-fluoro-2-isopropoxyphenyl)-3-methylpyrazine;
[0129] 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine;
[0130] 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-5-chloropyrazine;
[0131] 6-(5-chloropyrazin-2-yl)-1H-indole;
[0132] 5-(2-chloro-4-fluorophenyl)-2,3-dimethylpyrazine;
[0133] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-fluoro-N-methylpyridin-2-amine;
[0134] 3-Chloro-5-(4-Chloro-2-isopropoxyphenyl)-2-methylpyrazine;
[0135] 3-Chloro-5-(2-Chloro-4-fluorophenyl)-2-(2,2-difluoroethoxy)pyrazine;
[0136] 3-Chloro-5-(4-Chloro-2-isopropoxyphenyl)-2-(2,2-difluoroethoxy)pyrazine;
[0137] 3-Chloro-5-(2-Chloro-4-fluorophenyl)-2-cyclopropylpyrazine;
[0138] 4-(5-Cyclopropylpyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0139] 1-(3-amino-5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)ethyl-1-one;
[0140] 7-Chloro-4-(5-Chloro-6-methylpyrazin-2-yl)-1H-indazole;
[0141] 7-Chloro-4-(6-Chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indazole;
[0142] 3-Chloro-5-(2-Chloro-4-fluorophenyl)-2-(difluoromethoxy)pyrazine;
[0143] 7-Chloro-4-(6-Chloro-5-(difluoromethoxy)pyrazin-2-yl)-1H-indazole;
[0144] 3-Chloro-5-(2,4-dichlorophenyl)-2-(difluoromethoxy)pyrazine;
[0145] 3-Chloro-5-(2-Chloro-4-fluorophenyl)-2-(difluoromethyl)pyrazine;
[0146] 3-Chloro-5-(2,4-dichlorophenyl)-2-(difluoromethyl)pyrazine;
[0147] 3-Chloro-5-(2,4-dichlorophenyl)pyrazine-2-carboxynitrile;
[0148] 3-Chloro-5-(7-Chloro-1H-indazol-4-yl)pyrazin-2-carboxylonitrile;
[0149] 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)-3-methylpyrazine;
[0150] 5-(2-Chloro-4-fluorophenyl)-2-(difluoromethoxy)-3-methylpyrazine;
[0151] 5-(2,4-Dichlorophenyl)-2-(difluoromethoxy)-3-methylpyrazine;
[0152] 3-Chloro-2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine;
[0153] 6-Chloro-3-(5-chloropyridin-2-yl)pyrazin-2-amine;
[0154] 2-(5-chloropyridin-2-yl)-5-(difluoromethyl)pyrazine;
[0155] 4-(5-(difluoromethoxy)-6-methylpyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0156] 7-(5-(difluoromethoxy)-6-methylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0157] 6-(2-chloro-4-fluorophenyl)-3-(difluoromethoxy)pyrazine-2-carboxylonitrile;
[0158] 4-(5-(difluoromethoxy)-6-methylpyrazin-2-yl)-7-fluorobenzo[d]thiazolyl-2-amine;
[0159] 3-(difluoromethoxy)-6-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine-2-carboxynitrile;
[0160] 4-Chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine;
[0161] 3-Chloro-5-(3-Chloro-4-fluorophenyl)-2-(difluoromethyl)pyrazine;
[0162] 3-Chloro-5-(4-Chloro-3-fluorophenyl)-2-(difluoromethyl)pyrazine;
[0163] 3-Chloro-2-(difluoromethyl)-5-(3,4-difluorophenyl)pyrazine;
[0164] 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0165] 2-(1,1-Difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine;
[0166] 4-(5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0167] 2-(2-Chloro-4-fluorophenyl)-5-((difluoromethoxy)methyl)pyrazine;
[0168] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2,3-bis(difluoromethyl)pyrazine;
[0169] 3-Chloro-5-(2-Chloro-4-fluorophenyl)-2-(1,1-difluoroethyl)pyrazine;
[0170] 3-Chloro-2-(1,1-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine;
[0171] 7-Chloro-4-(6-Chloro-5-(difluoromethoxy)pyrazin-2-yl)indoline-2-one;
[0172] 4-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0173] 7-Chloro-4-(6-Chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)indololin-2-one;
[0174] 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0175] 3-Chloro-2-(difluoromethyl)-5-(3,4,5-trifluorophenyl)pyrazine;
[0176] 3-Chloro-2-(difluoromethyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrazine;
[0177] 3-Chloro-2-(difluoromethoxy)-5-(3,4-difluorophenyl)pyrazine;
[0178] 7-Chloro-4-(5-(1,1-difluoroethyl)pyrazin-2-yl)indololin-2-one;
[0179] 4-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0180] 2-(difluoromethoxy)-5-(3,4-difluorophenyl)pyrazine;
[0181] 2-(difluoromethyl)-5-(3,4-difluorophenyl)pyrazine;
[0182] 2-(2-chloro-4-fluorophenyl)-5-(1,1-difluoroethyl)pyrazine;
[0183] 2-(1,1-difluoroethyl)-5-(3,4-difluorophenyl)pyrazine;
[0184] 4-(5-amino-6-chloropyrazin-2-yl)-7-chloroindololin-2-one;
[0185] 4-(6-amino-5-methoxypyrazin-2-yl)-7-chloroindololin-2-one;
[0186] 7-Chloro-4-(6-Chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)indololin-2-one;
[0187] 3-Chloro-2-(1,1-difluoroethyl)-5-(3,4-difluorophenyl)pyrazine;
[0188] 3-Chloro-5-(2-Chloro-3,4-difluorophenyl)-2-(difluoromethyl)pyrazine;
[0189] 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine;
[0190] 2-(2-(difluoromethoxy)-4-fluorophenyl)-5-(difluoromethyl)pyrazine;
[0191] 3-Chloro-2-(difluoromethyl)-5-(4-fluoro-2-(trifluoromethoxy)phenyl)pyrazine;
[0192] 4-Chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0193] 4-Chloro-7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0194] 4-Chloro-7-(6-Chloro-5-(difluoromethoxy)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0195] 3-Chloro-5-(4-Chloro-2-(difluoromethoxy)phenyl)-2-(1,1-difluoroethyl)pyrazine;
[0196] 3-Chloro-5-(4-Chloro-2-(difluoromethoxy)phenyl)-2-(difluoromethyl)pyrazine;
[0197] 2-(5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzonitrile;
[0198] 2-Chloro-5-(5-(difluoromethoxy)pyrazin-2-yl)aniline;
[0199] 4-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-7-chloroindololin-2-one;
[0200] 3-Chloro-2-(1,1-difluoroethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine;
[0201] 5-Chloro-3-(5-chloropyridin-2-yl)-6-(difluoromethyl)pyrazin-2-amine;
[0202] 3-Chloro-2-(difluoromethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine;
[0203] 3-Chloro-5-(5-chloropyridin-2-yl)-2-(difluoromethoxy)pyrazine;
[0204] 3-Chloro-5-(5-chloropyridin-2-yl)-2-(1,1-difluoroethyl)pyrazine;
[0205] 3-Chloro-2-(difluoromethoxy)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine;
[0206] 5-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-2-fluoroaniline;
[0207] 3-Chloro-5-(5-chloropyridin-2-yl)-2-(difluoromethyl)pyrazine;
[0208] 5-Chloro-3-(5-chloropyridin-2-yl)-6-(difluoromethoxy)pyrazin-2-amine;
[0209] 5-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-2-fluoroaniline;
[0210] 3-Chloro-2-(difluoromethyl)-5-(5-fluoropyridin-2-yl)pyrazine;
[0211] 3-Chloro-2-(1,1-difluoroethyl)-5-(5-fluoropyridin-2-yl)pyrazine;
[0212] 5-Chloro-6-(difluoromethyl)-3-(5-fluoropyridin-2-yl)pyrazin-2-amine;
[0213] 3-Chloro-2-(difluoromethoxy)-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)pyrazine;
[0214] 3-Chloro-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)-2-(difluoromethyl)pyrazine;
[0215] 3-Chloro-2-(1,1-difluoroethyl)-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)pyrazine;
[0216] 3-Chloro-2-(difluoromethoxy)-5-(5-fluoropyridin-2-yl)pyrazine;
[0217] 3-Chloro-2-(1,1-difluoroethyl)-5-(2-(difluoromethoxy)-4,5-difluorophenyl)pyrazine;
[0218] 3-Chloro-2-(1,1-difluoroethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)pyrazine;
[0219] 3-Chloro-2-(difluoromethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)pyrazine;
[0220] 2,3-Bis(difluoromethyl)-5-(5-fluoropyridin-2-yl)pyrazine;
[0221] 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-3-fluoropyridine-2-amine;
[0222] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-fluoropyridine-2-amine;
[0223] 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-fluoropyridine-2-amine;
[0224] 5-(5-chloropyridin-2-yl)-2,3-bis(difluoromethyl)pyrazine;
[0225] 3-Chloro-5-(5-fluoropyridin-2-yl)-2-(trifluoromethyl)pyrazine;
[0226] 3-Chloro-5-(5-chloropyridin-2-yl)-2-(trifluoromethyl)pyrazine;
[0227] 3-Chloro-6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)pyridin-2-amine;
[0228] 3-Chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(trifluoromethyl)pyrazine;
[0229] 3-Chloro-6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)pyridin-2-amine;
[0230] 3-Chloro-6-(6-Chloro-5-(difluoromethoxy)pyrazin-2-yl)pyridine-2-amine;
[0231] 2-(2,2-Difluoroethoxy)-3-(difluoromethyl)-5-(5-fluoropyridin-2-yl)pyrazine;
[0232] 5-(5-chloropyridin-2-yl)-2-(2,2-difluoroethoxy)-3-(difluoromethyl)pyrazine;
[0233] 2-(2,2-Difluoroethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazine;
[0234] 2-(1,1-Difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazine;
[0235] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-(trifluoromethyl)pyrazine;
[0236] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0237] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0238] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0239] 4-Chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0240] 4-Chloro-7-(6-Chloro-5-(fluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0241] 4-Chloro-7-(5-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0242] 4-Chloro-7-(5-(methylamino)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0243] 4-Chloro-7-(6-Chloro-5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0244] 4-Chloro-7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0245] 4-Chloro-7-(6-Chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0246] 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0247] 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0248] 4-Fluoro-7-(5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0249] 7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0250] 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0251] 7-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0252] 4-Chloro-7-(6-Chloro-5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0253] 7-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0254] 6-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-3-(difluoromethoxy)pyrazin-2-carboxynitrile;
[0255] 4-Chloro-7-(5-cyclopropoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0256] 4-Chloro-7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0257] 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)acetonitrile;
[0258] 4-Fluoro-7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0259] 4-Fluoro-7-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0260] 7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0261] 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0262] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0263] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0264] 4-Chloro-7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0265] 4-Chloro-7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0266] 7-(5-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0267] 7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0268] 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0269] 7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0270] 7-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0271] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0272] 7-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0273] 7-(6-chloro-5-cyclopropylpyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0274] 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0275] 4-Chloro-7-(5-cyclopropylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0276] 7-(5-Cyclopropylpyrazin-2-yl)-4,5-Difluorobenzo[d]oxazol-2(3H)-one;
[0277] 7-(5-Cyclopropoxypyrazin-2-yl)-4,5-Difluorobenzo[d]oxazol-2(3H)-one;
[0278] 4-Chloro-7-(6-Chloro-5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0279] 4-Chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0280] 7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0281] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-1H-indazole;
[0282] 7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0283] 7-(6-chloro-5-(1,1-difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0284] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one;
[0285] 7-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0286] 4-Chloro-7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0287] 4-Chloro-7-(6-Chloro-5-cyclopropylpyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0288] 4-Chloro-7-(6-Chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0289] 4,5-Difluoro-7-(5-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0290] 4-Chloro-5-fluoro-7-(5-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0291] 4-Chloro-7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0292] 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0293] 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0294] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0295] 7-(5-methoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0296] 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0297] 7-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0298] 4-Chloro-7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0299] 4-Chloro-7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0300] 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0301] 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one;
[0302] 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one;
[0303] 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0304] 4-Chloro-7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0305] 4-Chloro-7-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0306] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0307] 4-Chloro-7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0308] 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0309] 7-(5-chloropyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0310] 4-Chloro-7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0311] 7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0312] 7-(5-chloropyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0313] 4-Chloro-7-(5-chloropyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0314] 7-(5-(methylamino)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0315] 4-Chloro-5-fluoro-7-(5-methylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0316] 4,5-Difluoro-7-(5-methylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0317] 4-Chloro-7-(5-(2,2-difluorocyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0318] 7-(5-(2,2-difluorocyclopropyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0319] 4-Chloro-7-(5-(2,2-difluoro-1-methylcyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0320] 4-Fluoro-7-(5-(methylamino)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0321] 7-(5-(2,2-difluoro-1-methylcyclopropyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0322] 7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0323] 7-(5-(2,2-difluorocyclopropyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0324] 7-(5-chloropyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0325] 4-Chloro-7-(5-(1-methylcyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0326] 4-Fluoro-7-(5-(1-methylcyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0327] 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0328] 7-(5-ethoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0329] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0330] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0331] 4-Chloro-7-(5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0332] 4-Chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0333] 2-(difluoromethoxy)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine;
[0334] 2-(1,1-Difluoroethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine;
[0335] 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one;
[0336] 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-6-methylpyridin-3-yl)pyrazine;
[0337] 2-(difluoromethoxy)-5-(5-fluoro-6-methylpyridin-2-yl)pyrazine;
[0338] 5-(5-(difluoromethoxy)pyrazin-2-yl)-2-fluoroaniline;
[0339] 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)pyrazine;
[0340] 2-(difluoromethoxy)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)pyrazine;
[0341] 4-Fluoro-7-(5-(oxetane-2-ylmethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0342] 7-Chloro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)indoline-2-one;
[0343] 7-Chloro-4-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)indololin-2-one;
[0344] 3-Chloro-6-(5-(difluoromethoxy)pyrazin-2-yl)pyridine-2-amine;
[0345] 6-(5-(difluoromethoxy)pyrazin-2-yl)-3-fluoro-N-methylpyridine-2-amine;
[0346] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0347] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-chloro-5-fluorobenzo[d]oxazol-2(3H)-one;
[0348] 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0349] N-Cyclopropyl-6-(5-(difluoromethoxy)pyrazin-2-yl)-3-fluoropyridine-2-amine;
[0350] 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)pyrazine;
[0351] 7-(5-Cyclopropylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0352] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0353] 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0354] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0355] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one;
[0356] 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one;
[0357] 7-(5-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0358] 7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0359] 7-(5-Cyclopropylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0360] 7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0361] 7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0362] 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0363] 7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0364] 4-Chloro-7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0365] 7-(5-Cyclopropoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0366] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0367] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-(trifluoromethyl)-1H-indazole;
[0368] 4-(5-(1,1-difluoroethyl)pyrazin-2-yl)-6,7-difluoro-1H-indazole;
[0369] 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0370] 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0371] 4-(5-(1,1-difluoroethyl)pyrazin-2-yl)-7-(trifluoromethyl)-1H-indazole;
[0372] 4-(5-(difluoromethoxy)pyrazin-2-yl)-6,7-difluoro-1H-indazole;
[0373] 4-(5,6-bis(difluoromethyl)pyrazin-2-yl)-7-chloro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0374] 7-Chloro-4-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)indololin-2-one;
[0375] 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0376] 4-Chloro-7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0377] 6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-2-(methylamino)nicotinonitrile;
[0378] 6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-2-(dimethylamino)nicotinonitrile;
[0379] 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-2-(dimethylamino)nicotinonitrile;
[0380] 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-2-(methylamino)nicotinonitrile;
[0381] 4-Chloro-5-fluoro-7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0382] 3-(difluoromethyl)-5-(5-fluoropyridin-2-yl)-2-(2,2,2-trifluoroethoxy)pyrazine;
[0383] 6-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-2-(methylamino)nicotinonitrile;
[0384] 6-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-2-(methylamino)nicotinonitrile;
[0385] 7-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0386] 7-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;
[0387] 2-(difluoromethyl)-5-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)pyrazine;
[0388] 5-(5-chloropyridin-2-yl)-2-(difluoromethyl)-3-(trifluoromethyl)pyrazine;
[0389] 4-(5,6-bis(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0390] 4-(5,6-bis(difluoromethyl)pyrazin-2-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0391] 4-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0392] 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0393] 7-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0394] 5-Chloro-8-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine;
[0395] 7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0396] 2-((3-chloro-6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)pyridin-2-yl)amino)acetonitrile;
[0397] 2-(3-chloro-6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetonitrile;
[0398] 7-(5-methylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0399] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-chloropyrazolo[1,5-a]pyridine;
[0400] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine;
[0401] 2-((3-chloro-6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)amino)acetonitrile;
[0402] 2-((6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-3-chloropyridin-2-yl)amino)acetonitrile;
[0403] 2-(6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-3-chloropyridin-2-yl)acetonitrile;
[0404] 2-((6-(3-amino-5-(difluoromethoxy)pyrazin-2-yl)-3-chloropyridin-2-yl)amino)acetonitrile;
[0405] 4-(trifluoromethyl)-7-(5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-(5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0406] 7-(5-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0407] 2-(difluoromethoxy)-5-(2-methoxy-4-methylphenyl)pyrazine;
[0408] 2-(difluoromethoxy)-5-(2-methoxy-4-(trifluoromethyl)phenyl)pyrazine;
[0409] 7-(5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0410] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0411] 5-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0412] 5-Chloro-8-(5-(difluoromethoxy)pyrazin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine;
[0413] 7-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)pyrazolo[1,5-a]pyridine;
[0414] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)pyrazolo[1,5-a]pyridine;
[0415] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[c][1,2,5]thiadiazole;
[0416] 4-Chloro-7-(5-(difluoromethyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine;
[0417] 4-(5-(difluoromethoxy)pyrazin-2-yl)indoline-2-one;
[0418] 7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0419] 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0420] 4-(6-chloro-5-(1-fluorovinyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0421] 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0422] 3-Chloro-2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0423] 4-(5-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0424] (S)-2-(difluoromethyl)-5-(3-(difluoromethyl)pyrrolid-1-yl)pyrazine;
[0425] 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0426] 3-Chloro-2-(difluoromethyl)-5-(4-(difluoromethyl)piperidin-1-yl)pyrazine;
[0427] 3-Chloro-2-(difluoromethyl)-5-(3-(difluoromethyl)azacyclobutane-1-yl)pyrazine;
[0428] 3-Chloro-2-(1,1-difluoroethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0429] (S)-3-chloro-2-(difluoromethyl)-5-(3-(difluoromethyl)pyrrolid-1-yl)pyrazine;
[0430] 3-Chloro-2-cyclopropyl-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0431] 1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-ol;
[0432] 3-Chloro-2-(difluoromethyl)-5-(4-(trifluoromethyl)piperidin-1-yl)pyrazine;
[0433] 3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane;
[0434] 3-Chloro-5-(4,4-difluoro-3-methylpiperidin-1-yl)-2-(difluoromethyl)pyrazine;
[0435] 3-Chloro-2-(1,1-difluoroethyl)-5-(4-(difluoromethyl)piperidin-1-yl)pyrazine;
[0436] 3-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane;
[0437] cis-2-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-5,5-difluorooctahedral[c]pyrrole;
[0438] 3-Chloro-2-(difluoromethyl)-5-(4-fluoropiperidin-1-yl)pyrazine;
[0439] 3-Chloro-5-(4,4-difluoro-3-methylpiperidin-1-yl)-2-(1,1-difluoroethyl)pyrazine;
[0440] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0441] 3-Chloro-2-(1,1-difluoroethyl)-5-(4-fluoropiperidin-1-yl)pyrazine;
[0442] 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0443] 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-4-azaspiro[2.5]octane;
[0444] 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-4-azaspiro[2.5]octane;
[0445] 3-Chloro-2-(difluoromethyl)-5-(4-fluoro-2,2-dimethylpiperidin-1-yl)pyrazine;
[0446] 3-Chloro-5-(4,4-difluoro-2,2-dimethylpiperidin-1-yl)-2-(difluoromethyl)pyrazine;
[0447] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane;
[0448] 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane;
[0449] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1,1-difluoro-6-azaspiro[2.5]octane;
[0450] 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1,1-difluoro-6-azaspiro[2.5]octane;
[0451] 3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-3-azabicyclo[4.1.0]heptane;
[0452] 3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane;
[0453] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]oct-4-ol;
[0454] (1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-yl)methanol;
[0455] (1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-yl)methanol;
[0456] (1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoropiperidin-2-yl)methanol;
[0457] 8-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-8-azabispiro[2.1.2] 5 .3 3 ] Decane;
[0458] 8-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-8-azabispiro[2.1.2] 5 .3 3 ] Decane;
[0459] 8-(5,6-bis(difluoromethyl)pyrazin-2-yl)-8-azabispiro[2.1.2] 5 .3 3 ] Decane;
[0460] 4-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0461] 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1,4-oxazacycloheptane;
[0462] 8-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-8-azabispiro[2.1.2] 5 .3 3 ] Decane;
[0463] 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane;
[0464] 1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)azacycloheptane;
[0465] Methyl 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylic acid;
[0466] 6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0467] 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0468] 6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0469] 6-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0470] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylonitrile;
[0471] 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylon;
[0472] 6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylonitrile;
[0473] 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylonitrile;
[0474] 6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane;
[0475] 4-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-7-fluoro-4-azaspiro[2.5]octane;
[0476] 5-(4,4-Difluoro-2,2-dimethylpiperidin-1-yl)-2-(difluoromethyl)-3-(trifluoromethyl)pyrazine;
[0477] 2-(difluoromethyl)-5-(4-fluoro-2,2-dimethylpiperidin-1-yl)-3-(trifluoromethyl)pyrazine;
[0478] 5-(4,4-difluoro-2,2-dimethylpiperidin-1-yl)-2,3-bis(difluoromethyl)pyrazine;
[0479] 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylonitrile;
[0480] 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0481] 2-(2-Chloro-4-fluorophenyl)-5-(prop-1-en-2-yl)pyrazine;
[0482] 2-(2-Chloro-4-fluorophenyl)-5-vinylpyrazine;
[0483] 5-(2-Chloro-4-fluorophenyl)-3-methoxy-2-vinylpyrazine;
[0484] 2-Cyclopropyl-5-(2-Cyclopropyl-4-fluorophenyl)-3-methylpyrazine;
[0485] 3-(5-Fluoropyridin-2-yl)-6-vinylpyrazin-2-amine;
[0486] 5-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)-2-methylpyrazine;
[0487] 2-(2-chloro-4-fluorophenyl)-5-((trimethylsilyl)ethynyl)pyrazine;
[0488] 2-(2-Chloro-4-fluorophenyl)-5-ethynylpyrazine;
[0489] 5-(2-Chloro-4-fluorophenyl)-2-ethynyl-3-methylpyrazine;
[0490] 2-Ethynyl-5-(4-fluoro-2-isopropoxyphenyl)pyrazine;
[0491] 1-(5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)ethyl-1-one;
[0492] 1-(5-(2-chloro-4-fluorophenyl)-3-methylpyrazin-2-yl)ethyl-1-one;
[0493] 7-(5-acetyl-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0494] 2-(2-Chloro-4-fluorophenyl)-5-isopropylpyrazine;
[0495] 5-(2-Chloro-4-fluorophenyl)-2-ethyl-3-methoxypyrazine;
[0496] 5-(2-chloro-4-fluorophenyl)-2-(1,1-difluoroethyl)-3-methylpyrazine;
[0497] 2-(2-Chloro-4-fluorophenyl)-5-ethoxypyrazine;
[0498] 1-(5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)pyrazolidine-3-one;
[0499] 5-(2-Chloro-4-fluorophenyl)-2-ethoxy-3-methylpyrazine;
[0500] 1-(5-(2-chloro-4-fluorophenyl)-3-methylpyrazin-2-yl)pyrazolidine-3-one;
[0501] 5-(2-chloro-4-fluorophenyl)-2-(2,2-difluoroethoxy)-3-methylpyrazine;
[0502] 5-(2-Chloro-4-fluorophenyl)-2-(2-fluoroethoxy)-3-methylpyrazine;
[0503] 5-(2-Chloro-4-fluorophenyl)-3-methyl-2-propoxypyrazine;
[0504] 2-(2-chloro-4-fluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine;
[0505] 2-((5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)oxy)acetonitrile;
[0506] 3-(5-chloropyridin-2-yl)-6-(2,2-difluoroethoxy)pyrazin-2-amine;
[0507] 5-(2-Chloro-4-fluorophenyl)-2-iodo-3-methoxypyrazine;
[0508] 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)acetic acid;
[0509] 6-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylonitrile;
[0510] 6-(2-chloro-4-fluorophenyl)-3-methylpyrazine-2-carboxynitrile;
[0511] 6-(2-chloro-4-fluorophenyl)-3-(2,2-difluoroethoxy)pyrazine-2-carboxynitrile;
[0512] 6-(4-chloro-2-isopropoxyphenyl)-3-(2,2-difluoroethoxy)pyrazine-2-carboxynitrile;
[0513] 6-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxynitrile;
[0514] 3-(1,1-Difluoroethyl)-6-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine-2-carboxynitrile;
[0515] 3-(difluoromethyl)-6-(4,4-difluoropiperidin-1-yl)pyrazin-2-carboxynitrile;
[0516] 6-(4,4-difluoro-6-azaspiro[2.5]oct-6-yl)-3-(difluoromethyl)pyrazine-2-carboxylonitrile;
[0517] 6-(7,7-difluoro-4-azaspiro[2.5]oct-4-yl)-3-(1,1-difluoroethyl)pyrazine-2-carboxylonitrile;
[0518] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-methylpyrazine;
[0519] 5-(2-chloro-4-fluorophenyl)-3-methylpyrazine-2-carboxynitrile;
[0520] 5-(4-fluoro-2-isopropoxyphenyl)-3-methylpyrazine-2-carboxynitrile;
[0521] 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine;
[0522] 5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine-2-carboxynitrile;
[0523] 4-(5-(difluoromethyl)-6-methylpyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0524] 4-Chloro-7-(5-(difluoromethyl)-6-ethynylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0525] 4-(5-(1,1-difluoroethyl)-6-ethynylpyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0526] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-ethynylpyrazine;
[0527] 7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0528] 4-Chloro-7-(5-(trifluoromethyl)-6-vinylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0529] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-vinylpyrazine;
[0530] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0531] (6-(4,4-difluoro-6-azaspiro[2.5]oct-6-yl)-3-(difluoromethyl)pyrazin-2-yl)methanol;
[0532] 4-Chloro-7-(5-(difluoromethyl)-6-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0533] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-methoxypyrazine;
[0534] 3-Fluoro-5-(4-Fluoro-2-isopropoxyphenyl)-2-methylpyrazine;
[0535] 7-(6-amino-5-(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0536] 6-(4-chloro-2-isopropoxyphenyl)-3-methylpyrazine-2-amine;
[0537] 4-(6-amino-5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0538] 7-(6-amino-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0539] 6-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazine-2-amine;
[0540] 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0541] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0542] 4-Chloro-7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0543] 7-(6-(difluoromethyl)-5-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0544] 4-Chloro-7-(6-(difluoromethyl)-5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0545] 4-Chloro-7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0546] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine;
[0547] 3-Iodo-6-(6-azaspiro[2.5]oct-6-yl)pyrazin-2-carboxylonitrile;
[0548] 4-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0549] 5,6-Dichloro-3-(5-chloropyridin-2-yl)pyrazin-2-amine;
[0550] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyrazine;
[0551] 3-Chloro-5-(4-(difluoromethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrazine;
[0552] 3-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane;
[0553] 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0554] 6-(6-azaspiro[2.5]oct-6-yl)-3-(trifluoromethyl)pyrazine-2-carboxylonitrile;
[0555] 1-(3-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)ethyl-1-one;
[0556] 1-(3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)ethyl-1-one;
[0557] 5-(2-Chloro-4-fluorophenyl)-2-iodo-3-methylpyrazine;
[0558] 5-(2-chloro-4-fluorophenyl)-3-iodo-2-methylpyrazine;
[0559] 2-(2-Chloro-4-fluorophenyl)-5-iodopyrazine;
[0560] 6-(4-fluoro-2-isopropoxyphenyl)-3-iodopyrazine-2-carboxynitrile;
[0561] 5-(4-chloro-2-isopropoxyphenyl)-2-iodo-3-methylpyrazine;
[0562] 7-Chloro-4-(5-(2-fluoroprop-2-yl)pyrazin-2-yl)indoline-2-one;
[0563] 4-Chloro-7-(5-(2-fluoroprop-2-yl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0564] 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine;
[0565] 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine;
[0566] 4-(5,6-bis(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0567] 2-(1,1-difluoroethyl)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine;
[0568] 4-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0569] 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluorovinyl)pyrazine;
[0570] 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluoroethyl)pyrazine;
[0571] 4-Chloro-7-(5-(2,2-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0572] 7-(5-(2,2-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0573] 2-(2-chloro-4-fluorophenyl)-5-(2,2,2-trifluoroethyl)pyrazine;
[0574] 4-Chloro-7-(5-(2,2,2-trifluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0575] 3-Chloro-2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0576] 6-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-6-azaspiro[2.5]octane;
[0577] 2-Chloro-5-(2-Chloro-4-fluorophenyl)-3-(difluoromethyl)pyrazine;
[0578] 3-Chloro-2-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine;
[0579] 1-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)cyclopropane-1-carboxynitrile;
[0580] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-thione;
[0581] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1H-benzo[d][1,2,3]triazole;
[0582] 7-(5-(difluoromethoxy)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxynitrile;
[0583] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one;
[0584] 3-Chloro-2-(difluoromethyl)-5-(3,4,4-trifluoropiperidin-1-yl)pyrazine;
[0585] 3-Chloro-5-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl)-2-(1,1-difluoroethyl)pyrazine;
[0586] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-N-methylbenzo[d]oxazol-2-amine;
[0587] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-2-methoxybenzo[d]oxazole;
[0588] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2-amine;
[0589] 1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-2-one;
[0590] 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]oct-5-one;
[0591] 6-Chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0592] 5-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0593] 7-(5-(difluoromethyl)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxynitrile;
[0594] 4-(6-cyclopropyl-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0595] 3-Cyclopropyl-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine;
[0596] (6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]oct-4-yl)methanol;
[0597] 7-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0598] 7-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;
[0599] 4-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-7,7-Difluoro-4-azaspiro[2.5]octane;
[0600] 4-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2-yl)-7,7-Difluoro-4-azaspiro[2.5]octane;
[0601] 4-Cyclopropyl-7-(5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0602] 4-Cyclopropyl-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0603] 4-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane;
[0604] 7-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2-yl)-4-(Trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0605] 4-Chloro-7-(5-cyclopropyl-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;
[0606] 4-Cyclopropyl-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0607] 4-Chloro-7-(5-vinylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0608] 4-Chloro-7-(5-(prop-1-en-2-yl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0609] 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-N-(2,2-difluoroethyl)-3-fluoropyridine-2-amine;
[0610] 4-Chloro-7-(5-isopropylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0611] 7-(5-Cyclopropyl-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0612] 7-(5-methyl-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0613] 7-(5-(difluoromethyl)pyrazin-2-yl)-4-methylbenzo[d]oxazol-2(3H)-one;
[0614] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-methylbenzo[d]oxazol-2(3H)-one;
[0615] 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)-2,2-difluoroacetonitrile;
[0616] 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0617] 7-(5-chloro-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0618] 7-(5-(2-fluoroprop-2-yl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0619] 7-(6-(difluoromethyl)-5-(methylamino)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0620] 7-(6-(difluoromethyl)-5-methylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0621] 7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0622] 4-(1,1-difluoroethyl)-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0623] 7-(5-(difluoromethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0624] 4-Chloro-7-(6-methyl-5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0625] 7-(6-(difluoromethyl)-5-methoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0626] 7-(6-(difluoromethyl)-5-ethoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0627] 2-(2-bromo-4-fluorophenyl)-5-methylpyrazine;
[0628] 2-(4-chloro-2-methoxyphenyl)-5-methylpyrazine;
[0629] 2-(4-chloro-2-isopropoxyphenyl)-5-methylpyrazine;
[0630] 2-(2-(sec-butoxy)-4-chlorophenyl)-5-methylpyrazine;
[0631] 2-(5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)acetonitrile;
[0632] 2-(4-chloro-2-(oxetane-3-yloxy)phenyl)-5-methylpyrazine;
[0633] 2-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)oxazole;
[0634] 2-(4-chloro-2-(difluoromethoxy)phenyl)-5-methylpyrazine;
[0635] 2-(4-chloro-2-cyclobutoxyphenyl)-5-methylpyrazine;
[0636] 2-(4-chloro-2-(cyclopropylmethoxy)phenyl)-5-methylpyrazine;
[0637] 2-(4-chloro-2-(2-methoxyethoxy)phenyl)-5-methylpyrazine;
[0638] 2-(2-(but-2-yn-1-yloxy)-4-chlorophenyl)-5-methylpyrazine;
[0639] 2-(5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)propionitrile;
[0640] 2-(4-chloro-2-((tetrahydrofuran-3-yl)oxy)phenyl)-5-methylpyrazine;
[0641] 2-(4-chloro-2-(thionylbutane-3-yloxy)phenyl)-5-methylpyrazine;
[0642] 2-(4-chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-methylpyrazine;
[0643] 2-(4-chloro-2-(ethoxy)phenyl)-5-methylpyrazine;
[0644] 5-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)oxazole;
[0645] 2-(4-chloro-2-(cyclohexyloxy)phenyl)-5-methylpyrazine;
[0646] 3-(5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)propionitrile;
[0647] 3-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)isoxazole;
[0648] 4-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)oxazole;
[0649] 2-(4-chloro-2-ethoxyphenyl)-5-methylpyrazine;
[0650] 2-(4-chloro-2-propoxyphenyl)-5-methylpyrazine;
[0651] 2-(4-chloro-2-(difluoromethoxy)phenyl)-5-(difluoromethoxy)pyrazine;
[0652] 2-(4-chloro-2-(2,2-difluoroethoxy)phenyl)-5-(difluoromethoxy)pyrazine;
[0653] 2-(2,4-Dichlorophenyl)-5-(difluoromethoxy)pyrazine;
[0654] 7-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-1H-benzimidazole;
[0655] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)indoline-2-one;
[0656] 5-Chloro-8-(5-(difluoromethoxy)pyrazin-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
[0657] 2-(2,4-Dichlorophenyl)-5-(difluoromethyl)pyrazine;
[0658] 5-(4-Fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-carboxynitrile;
[0659] 6-(2,4-Dichlorophenyl)-3-(difluoromethyl)pyrazine-2-carboxynitrile;
[0660] 2-(3,4-Dichlorophenyl)-5-methylpyrazine;
[0661] 5-(7-chloro-2-oxoindololin-4-yl)pyrazine-2-onitrile;
[0662] 2-(2-(allyloxy)-4-fluorophenyl)-5-methylpyrazine;
[0663] 2-(4-fluoro-2-(prop-2-yn-1-yloxy)phenyl)-5-methylpyrazine;
[0664] 2-(5-fluoro-2-(5-methylpyrazin-2-yl)phenoxy)acetonitrile;
[0665] 2-(2-Cyclobutoxy-4-fluorophenyl)-5-methylpyrazine;
[0666] 2-(2-(sec-butoxy)-4-fluorophenyl)-5-methylpyrazine;
[0667] 2-(4-fluoro-2-propoxyphenyl)-5-methylpyrazine;
[0668] 2-(2-ethoxy-4-fluorophenyl)-5-methylpyrazine;
[0669] 7-Chloro-4-(6-Chloro-5-(difluoromethyl)pyrazin-2-yl)indololin-2-one;
[0670] 6-(7-chloro-2-oxoindoline-4-yl)-3-(difluoromethyl)pyrazine-2-onitrile;
[0671] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1H-indazole;
[0672] 5-(7-fluoro-1H-indazol-4-yl)pyrazin-2-carboxynitrile;
[0673] 5-Chloro-N-isopropyl-2-(5-methylpyrazin-2-yl)aniline;
[0674] 2-(2,4-Difluorophenyl)-5-methylpyrazine;
[0675] 2-(4-Chloro-2-fluorophenyl)-5-methylpyrazine;
[0676] 5-Fluoro-N-isopropyl-2-(5-methylpyrazin-2-yl)aniline;
[0677] 2-(6-chloro-2-methoxypyridin-3-yl)-5-methylpyrazine;
[0678] 7-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-1,3-dihydrobenzo[c]isothiazolium 2,2-dioxide;
[0679] 2-(2-Methoxy-4-fluorophenyl)-5-methylpyrazine;
[0680] 7-Chloro-4-(5-(difluoromethyl)pyrazin-2-yl)-1H-indazole;
[0681] 3,7-Dichloro-4-(5-(difluoromethyl)pyrazin-2-yl)-1H-indazole;
[0682] 5-((5-chloro-2-(5-(difluoromethoxy)pyrazin-2-yl)phenoxy)methyl)isoxazole;
[0683] 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7-fluoroindoline-2-one;
[0684] 2-(2-Chloro-4-fluorophenyl)-5-(difluoromethoxy)pyrazine;
[0685] 2-(4-chloro-2-methoxyphenyl)-5-(2,2,2-trifluoroethoxy)pyrazine;
[0686] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazole;
[0687] 6-Chloro-3-(5-(difluoromethoxy)pyrazin-2-yl)-2-fluorophenol;
[0688] 4-(5-(difluoromethyl)pyrazin-2-yl)-7-fluoroindoline-2-one;
[0689] 7-Chloro-4-(5-(difluoromethyl)pyrazin-2-yl)indololin-2-one;
[0690] 7-Chloro-4-(5-ethynylpyrazin-2-yl)-1H-indole;
[0691] 2-(6-chloro-2-isopropoxypyridin-3-yl)-5-methylpyrazine;
[0692] 5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-carboxynitrile;
[0693] 3-((5-chloro-2-(5-(difluoromethoxy)pyrazin-2-yl)phenoxy)methyl)isoxazole;
[0694] 2-(4-chloro-2-methoxyphenyl)-5-cyclopropylpyrazine;
[0695] 2-(2-Chloro-4-fluorophenyl)-5-(difluoromethyl)pyrazine;
[0696] (E)-2-(4-chloro-2-((1,2-dichlorovinyl)oxy)phenyl)-5-(difluoromethoxy)pyrazine;
[0697] 2-(4-chloro-2-isopropoxyphenyl)-5-(2,2-difluoroethoxy)pyrazine;
[0698] 7-Chloro-4-(5-methylpyrazin-2-yl)indololin-2-one;
[0699] 2-(4-chloro-2-(oxetane-3-yloxy)phenyl)-5-(2,2,2-trifluoroethoxy)pyrazine;
[0700] 2-(4-chloro-2-isopropoxyphenyl)-5-(2,2,2-trifluoroethoxy)pyrazine;
[0701] 2-(7-Chlorobenzofuran-4-yl)-5-methylpyrazine;
[0702] 7-Chloro-4-(5-methylpyrazin-2-yl)indoline;
[0703] 7-Chloro-1-methyl-4-(5-methylpyrazin-2-yl)-1H-indole;
[0704] 5-((5-chloro-2-(5-(difluoromethyl)pyrazin-2-yl)phenoxy)methyl)isoxazole;
[0705] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-(trifluoromethyl)indololin-2-one;
[0706] 7-Chloro-4-(5-methylpyrazin-2-yl)-3-phenyl-1H-indole;
[0707] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoroindoline-2-one;
[0708] 2-(4-chloro-2-isopropoxyphenyl)-5-cyclopropylpyrazine;
[0709] 7-Chloro-4-(5-methylpyrazin-2-yl)-1H-indazole;
[0710] 7-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-1H-indazole;
[0711] 7-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-3-fluoro-1H-indazole;
[0712] 7-Chloro-4-(5-Cyclopropylpyrazin-2-yl)-1H-indole;
[0713] 2-(4-chloro-2-(oxetane-3-yloxy)phenyl)-5-cyclopropylpyrazine;
[0714] 7-Chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)indoline-2-one;
[0715] 2-(4-chloro-2-methoxyphenyl)-5-(2,2-difluoroethoxy)pyrazine;
[0716] 2-(5-chloro-2-(5-(difluoromethoxy)pyrazin-2-yl)phenoxy)acetonitrile;
[0717] 5-(7-chloro-1H-indazol-4-yl)pyrazin-2-carboxynitrile;
[0718] 2-(4-chloro-2-(difluoromethoxy)phenyl)-5-(difluoromethyl)pyrazine;
[0719] 7-Chloro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indole;
[0720] 2-(4-chloro-2-(oxetane-3-yloxy)phenyl)-5-(2,2-difluoroethoxy)pyrazine;
[0721] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;
[0722] 7-Fluoro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indazole;
[0723] 2-(4-chloro-2-isopropoxyphenyl)-5-(difluoromethoxy)pyrazine;
[0724] 2-(4-chloro-2-methoxyphenyl)-5-(difluoromethoxy)pyrazine;
[0725] 7-Chloro-4-(5-(difluoromethyl)pyrazin-2-yl)-3-fluoro-1H-indazole;
[0726] 4-Chloro-7-(5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0727] 7-Chloro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indazole;
[0728] 2-(4-chloro-2-(oxetane-3-yloxy)phenyl)-5-(difluoromethoxy)pyrazine;
[0729] 7-Chloro-4-(5-chloropyrazin-2-yl)-1H-indole;
[0730] 4-Chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0731] 6-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-3-(difluoromethyl)pyrazine-2-carboxynitrile;
[0732] 3-(difluoromethyl)-6-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-carboxynitrile;
[0733] 6-Chloro-3-(6-Chloro-5-(difluoromethyl)pyrazin-2-yl)-2-fluorophenol;
[0734] 2-Chloro-5-(6-Chloro-5-(difluoromethyl)pyrazin-2-yl)phenol;
[0735] 8-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3,3-difluoro-8-azabicyclo[3.2.1]octane;
[0736] 7-Chloro-4-(6-Chloro-5-(difluoromethyl)pyrazin-2-yl)-1,3-dihydrobenzo[c]isothiazolium 2,2-dioxide;
[0737] 2-Fluoro-5-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)phenol;
[0738] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-methylindoline-2-one;
[0739] 7-(6-(butylamino)-5-(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0740] 4-Chloro-7-(5-(difluoromethyl)-6-(isobutylamino)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0741] 4-Chloro-7-(6-((cyclopropylmethyl)amino)-5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0742] 6-(7-chloro-2-oxoindololin-4-yl)-3-(1,1-difluoroethyl)pyrazine-2-onitrile;
[0743] 4'-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-b]pyridine];
[0744] 4'-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-b]pyridine];
[0745] 2-(4-fluorobenzofuran-7-yl)-5-methylpyrazine;
[0746] 2-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-5-methylpyrazine;
[0747] 7-Chloro-4-(5-methylpyrazin-2-yl)-1H-indole;
[0748] 7-Isopropoxy-6-(5-methylpyrazin-2-yl)-1H-indole;
[0749] 4-Chloro-7-(5-methylpyrazin-2-yl)-1H-indole;
[0750] 2-(4-Chlorobenzofuran-1-yl)-5-methylpyrazine;
[0751] 2-(2,4-Dichlorophenyl)-5-methylpyrazine;
[0752] 2-(2-Chloro-4-methylphenyl)-5-methylpyrazine;
[0753] 4-Chloro-7-(5-chloropyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0754] 4-Chloro-7-(5-(1,1-difluoroethyl)-6-ethynylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0755] 4-Chloro-7-(5,6-dichloropyrazin-2-yl)benzo[d]oxazol-2(3H)-one;
[0756] 7-(5-(tert-butyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0757] 7-(5-(tert-butyl)-6-chloropyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one;
[0758] 7-(5-(1,1-difluoroethyl)-6-ethynylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one;
[0759] 7-(5,6-Dichloropyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one.
[0760] Scheme 16. Use of the inhibitors or compounds described in any one of Schemes 1-15, their pharmaceutically acceptable salts, or their solvates in the preparation of a medicament for the prevention and / or treatment of any of the following diseases: eosinophilic airway diseases, eosinophilic airway diseases (e.g., eosinophilic chronic sinusitis, chronic sinusitis with nasal polyps, or asthma), other eosinophilic diseases (e.g., eosinophilic esophagitis), Friedreich ataxia, hereditary mitochondrial respiratory chain diseases, hereditary epilepsy, Leigh syndrome, stroke, diabetes (including diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy), obesity, glomerulonephritis, osteoporosis, periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, thrombosis, neurodegenerative or neuroinflammatory diseases (e.g., Parkinson's disease, Alzheimer's disease, dementia, amyotrophic lateral sclerosis, or cerebrovascular disease), cancer, brain injury. Diseases involving hypoxia or hypoxia, myocardial infarction, cardiovascular disease, heart failure (e.g., chronic or congestive heart failure), ischemic diseases (e.g., cerebral ischemia, retinal ischemia, myocardial ischemia, or postoperative cognitive impairment), inflammatory diseases (e.g., arteritis, inflammatory bowel disease, nephropathy, asthma, allergic rhinitis, gout, cardiopulmonary disease, rheumatoid arthritis, osteoarthritis, muscle fatigue, acne, dermatitis, or psoriasis), chronic bronchitis, excessive mucus secretion, chronic obstructive pulmonary disease, pulmonary fibrosis (including chemotherapy-induced fibrosis), idiopathic pulmonary fibrosis, cystic fibrosis, adult respiratory distress syndrome, CNS disorders, psychiatric disorders (e.g., anxiety or depression), peripheral neuropathy (e.g., diabetic peripheral neuropathy, spinal cord injury, head injury, or surgical trauma), allogeneic tissue or organ transplant rejection, autoimmune diseases (e.g., eczema), and diseases involving bone loss or bone formation.
[0761] Option 17. Use of the inhibitor or compound described in Option 16, a pharmaceutically acceptable salt thereof, or a solvation thereof in the preparation of a medicament for the prevention and / or treatment of any of the following diseases, wherein the eosinophilic airway diseases include eosinophilic chronic sinusitis, chronic sinusitis with nasal polyps, allergic rhinitis, asthma, or eosinophilic esophagitis, and the indications targeted by ALOX15-related competitors in clinical trials include Friedreich ataxia, hereditary mitochondrial respiratory chain diseases, hereditary epilepsy, Leigh syndrome, Parkinson's disease, or amyotrophic lateral sclerosis.
[0762] Invention Effects
[0763] The compounds of the present invention exhibit significant inhibitory effects on ALOX (such as ALOX15), indicating that the compounds of the present invention have greater potential for clinical application in the treatment of ALOX (such as ALOX15) mediated diseases.
[0764] Invention Details
[0765] The embodiments of the present invention will be described in more detail below with reference to specific implementation methods. However, those skilled in the art will understand that the specific embodiments described below are only for illustrating the present invention and should not be regarded as limiting the scope of protection of the present invention. On the contrary, the present invention is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the present invention as defined by the embodiments. Unless otherwise specified, the various embodiments of the present invention can be combined in any way, and the resulting transformations, modifications, and changes to the technical solutions are also included within the scope of the present invention.
[0766] definition
[0767] In this invention, "C" a-b The expression "group" (where a and b represent integers greater than 1, and a < b) indicates that the "group" has ab carbon atoms. For example, C 1-6 Alkyl groups, specifically those with 1-6 carbon atoms, C 1-6 Alkoxy groups, specifically those with 1-6 carbon atoms, are C... 3-6 Cycloalkyl refers to cycloalkyl groups with 3-6 carbon atoms, C 1-6 Alkoxy C 1-6 Alkyl groups are groups formed by the bonding of an alkoxy group with 1-6 carbon atoms to an alkyl group with 1-6 carbon atoms.
[0768] In this invention, "base" and "group" refer to monovalent groups or, as needed, groups with a valence of two or more. For example, "cycloalkyl" (also referred to as "cycloalkyl group") includes monovalent groups obtained by removing one hydrogen atom from a cycloalkane, and also includes groups with a valence of two or more obtained by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms of a cycloalkane. For example, when "cycloalkyl" is a terminal group, it is connected to other parts of the compound structure as a monovalent group when it does not carry substituents, and when it carries substituents, the cycloalkyl exhibits a corresponding valence number (number of substituents + 1) depending on the number of substituents carried. Those skilled in the art can determine the valence number represented by "base" and "group" without any doubt. In addition, in this invention, if "group" refers to a group with a valence of two or more, it is preferable that these bonds are connected to different atoms (carbon atoms, nitrogen atoms, etc., but not limited thereto) in the group.
[0769] In this invention, "halogen" or "halogen atom" refers to fluorine, chlorine, bromine, or iodine atoms. Fluorine and chlorine atoms are preferred.
[0770] In this invention, "amino" refers to the -NH2 group.
[0771] The "oxo group" mentioned in this invention refers to the =O group.
[0772] The "thio-group" or "thiocarbonyl group" mentioned in this invention refers to the =S group.
[0773] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group derived from an alkane moiety containing 1-6 carbon atoms by removing one hydrogen atom. It includes straight-chain C... 1-6 Alkyl and branched C 1-6 Alkyl groups. In fact, it is well known to those skilled in the art that C 1-6 Alkyl groups have branches (branched C) 1-6 In the case of alkyl groups, it has at least 3 carbon atoms. As "C 1-6 Examples of "alkyl" include, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 1-methyl-2-methylpropyl, etc. The "C"... 1-4 "Alkyl" refers to the above examples containing 1 to 4 carbon atoms.
[0774] The "C" described in this invention 1-6 "Halogenated alkyl" refers to a C-shaped alkyl group substituted with one or more halogen groups as defined above. 1-6 Alkyl group. Halogenated C 1-6 Examples of alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, bromomethyl, chloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropyl-2-yl, 3-bromo-2-fluoropropyl and 1,4,4-trifluorobutyl-2-yl.
[0775] The "C" described in this invention 1-6 "Alkoxy" refers to the "C" defined above. 1-6 An alkyl group is a group that is linked to other parts of a chemical structure via an oxygen atom, i.e., a C14 group. 1-6 Alkyl-O-" group, for example, the "C" group mentioned above can be listed 1-6 The groups listed in "alkyl" that are bonded to -O- include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, and n-hexoxy.
[0776] The "C" described in this invention 1-6 "Haloalkoxy" refers to a C-type compound substituted with one or more halogen groups as defined above. 1-6Alkoxy groups, examples of which include, but are not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.
[0777] The "C" described in this invention 1-6 "alkyl ester" refers to the above C 1-6 Esters formed from alkyl groups.
[0778] The "C" described in this invention 2-6 "Alkenyl" refers to a straight-chain or branched olefinic group derived from the removal of a hydrogen atom from an olefinic moiety containing at least one carbon-carbon double bond and 2-6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadi-1-enyl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, and 1,4-hexadien-1-yl. Preferably, "C 2-6 The "alkenyl" group contains a carbon-carbon double bond.
[0779] The "C" described in this invention 2-6 "Haloalkenyl" refers to a C-shaped group that has been substituted with one or more halogen groups as defined above. 2-6 Alkenyl group. Halogenated C 2-6 Examples of alkenyl groups include, but are not limited to, fluorovinyl, bromovinyl, and chlorovinyl.
[0780] The "C" described in this invention 2-6 "Alynyl" refers to a straight-chain or branched alkyne group derived from the removal of one hydrogen atom from a 2-6 carbon atom moiety containing at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, penynyl, hexynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyn-1-yl, 2-hexyn-1-yl, 3-hexyn-2-yl, 3-hexyn-1-yl, 3-hexyn-2-yl, etc.
[0781] “C 2-6 "Halogenated alkynyl" refers to a C group that is substituted with one or more halogen groups as defined above. 2-6 Alkyne group. Halogenated C 2-6 Examples of alkynyl groups include, but are not limited to, fluoroacetylene, bromoacetylene, and chloroacetylene.
[0782] The "C" described in this invention 3-6 "Cycloalkyl" refers to a monovalent group or (as needed) a divalent group derived from 3-6 membered cycloalkanes, C 3-6 Examples of cycloalkyl groups include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, etc.
[0783] The "C" described in this invention 3-6 "Halogenated cycloalkyl" refers to a C-shaped alkyl group that has been substituted with one or more halogen groups as defined above. 3-6 Cycloalkyl. Halogenated C 3-6 Examples of cycloalkyl groups include, but are not limited to, chlorocyclopropane, chlorocyclobutane, chlorocyclopentane, chlorocyclohexane, chlorocyclopentane-1,3-diyl, chlorocyclohexane-1,4-diyl, fluorocyclopropane, fluorocyclobutane, fluorocyclopentane, fluorocyclohexane, fluorocyclopentane-1,3-diyl, fluorocyclohexane-1,4-diyl, bromocyclopropane, bromocyclobutane, bromocyclopentane, and bromocyclohexane.
[0784] The "4-8 membered heterocyclic group" described in this invention refers to a monovalent group or (if necessary) a divalent group derived from a 4-8 membered heterocyclic alkane, i.e., a non-aromatic cyclic group in which at least one carbon atom of the 4-8 member is replaced by a heteroatom selected from O, S, S(O), S(O)2, C(O), and N, preferably containing one, two, or three heteroatoms. "4-8 membered heterocyclic groups" (e.g., 5-membered, 6-membered, and 7-membered heterocyclic groups) include monocyclic, bicyclic, or polycyclic systems, wherein one or more rings may be saturated or partially saturated, but excluding aromatic rings. Unless otherwise specified, this includes all possible monocyclic, fused (including fused in fused, spiro, or bridged forms), saturated, and partially saturated cases.
[0785] The monocyclic heterocyclic group can be a 4-8 member heterocyclic group, such as a 5-6 member heterocyclic group, a 5-7 member heterocyclic group, a 5-8 member heterocyclic group, a 4-6 member heterocyclic group, a 4-7 member heterocyclic group, or a 4-8 member heterocyclic group; a 4-8 member nitrogen-containing heterocyclic group, such as a 4-7 member nitrogen-containing heterocyclic group or a 5-6 member nitrogen-containing heterocyclic group; or a 4-8 member saturated heterocyclic group, such as a 5-6 member saturated heterocyclic group, etc. Examples include, but are not limited to, azacyclobutane, oxacyclobutane, thiohexacyclobutane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazoalkyl, pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazoalkyl, 1,3-thiazoalkyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiaranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxacyclohexane, 1,4-oxothiacyclohexane, 4,5-dihydroisooxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2, 3-Dihydrooxazolyl, 3,4-Dihydro-2H-pyrrolyl, 2,3-Dihydro-1H-pyrrolyl, 2,5-Dihydro-1H-imidazolyl, 4,5-Dihydro-1H-imidazolyl, 4,5-Dihydro-1H-pyrrolyl, 4,5-Dihydro-3H-pyrrolyl, 4,5-Dihydrothiazolyl, 2,5-Dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiaranyl, 4H-thiaranyl, 2,3,4,5-Tetrahydropyridyl, 1,2-isooxazinyl, 1,4-isooxazinyl or 6H-1,3-oxazinyl, etc.
[0786] Fused heterocyclic groups (such as 6-8 membered fused heterocyclic groups) include fused heterocyclic groups, spirocyclic groups, and bridged heterocyclic groups, which can be saturated, partially saturated, or unsaturated, but are not aromatic. Fused heterocyclic groups can be fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heterocyclic ring.
[0787] The heterocyclic group can be a 6-8 member heterocyclic group, such as a 6-membered heterocyclic group or a 7-membered heterocyclic group, a 6-membered saturated heterocyclic group, or a 6-membered nitrogen-containing heterocyclic group. Representative examples include, but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrol, octahydropyrrolo[3,4-b]pyrrol, and octahydropyrrolo[3,4-b][1,4]oxazinyl.
[0788] The spiroheterocyclic group can be a 6-8 member spiroheterocyclic group, such as a 7-8 member spiroheterocyclic group, a 7-8 member saturated spiroheterocyclic group, or a 7-8 member nitrogen-containing spiroheterocyclic group. Examples include, but are not limited to:
[0789] The bridged heterocyclic group can be a 6-8 member bridged heterocyclic group, such as a 6-8 member nitrogen-containing bridged heterocyclic group, a 7 member bridged heterocyclic group, or a 7 member nitrogen-containing bridged heterocyclic group. Examples include, but are not limited to:
[0790] The "4-8 membered halocyclic heterocyclic group" mentioned in this invention refers to a 4-8 membered heterocyclic group that is substituted with one or more halogen groups as defined above. Examples of halocyclic 4-8 membered heterocyclic groups include, but are not limited to, chlorinated 4-membered heterocyclic groups, chlorinated 5-membered heterocyclic groups, chlorinated 6-membered heterocyclic groups, chlorinated 7-membered heterocyclic groups, chlorinated 8-membered heterocyclic groups, fluorinated 4-8 membered heterocyclic groups, and brominated 4-8 membered heterocyclic groups.
[0791] The "C" described in this invention 3-6 "Cycloalkoxy" refers to C 3-6 cycloalkyl-O-,C 3-6 Examples of cycloalkoxy groups include, but are not limited to: cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, etc.
[0792] The "aryl" group referred to in this invention refers to a monovalent or divalent cyclic aromatic group derived from aromatic carbocyclic hydrocarbons containing 6-14 carbon atoms, including benzene, naphthyl, phenanthrene, etc.
[0793] The "heteroaryl" described in this invention can be a 5- or 6-membered heteroaryl, referring to an aromatic monovalent or divalent cyclic group having at least one heteroatom selected from O, S, or N and having 5 or 6 cyclic atoms. Preferably, it has 1-3 cyclic heteroatoms. Furthermore, heteroaryl also includes cases where the carbon or sulfur atom, as a cyclic atom, is oxidized or nitrogenized, for example, the carbon atom is replaced by C(=O), S(=O), S(=O)₂, or S(=O)(=NH). Examples include, but are not limited to, furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridonel, pyridazinyl, pyrazinyl, pyrazolyl, pyrroleyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophene, triazolyl, and triazinyl.
[0794] The "pharmaceutically acceptable salts" described in this invention refer to pharmaceutically acceptable addition salts and solvates of acids and bases. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and alkanonic acids (such as acetic acid, HOOC-(CH2)n-COOH (where n = 0–4)). Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, and ammonium. Those skilled in the art are familiar with a variety of non-toxic pharmaceutically acceptable addition salts.
[0795] All numerical ranges described in this invention refer to the range including its two endpoints, all integers within the range, and subranges formed by these integers. For example, "3-6" includes 3, 4, 5, and 6; "1-6" includes 1, 2, 3, 4, 5, and 6; and "4-8" includes 4, 5, 6, 7, and 8.
[0796] The terms “optional” or “optionally” mean that the situation described below may or may not occur, including both the occurrence and non-occurrence of the situation.
[0797] In this invention, the terms "optionally substituted" or "optionally substituted with..." mean that any portion of the substitutable part known to those skilled in the art can be unsubstituted or substituted by the substituents described in this invention, wherein if more than one substituent is present, each substituent can be selected independently. In the case of substitution, the number of substituents depends on the number of positions that can be substituted on the substituted group, and can be 1-substituted, 2-substituted, 3-substituted, 4-substituted, 5-substituted, 6-substituted, 7-substituted, 8-substituted, or more, as long as it does not exceed the number of positions that can be substituted on the substituted group. In the presence of substituents, "one or more" substituents indicate the presence of more than one substituent, and the specific number of substituents varies depending on the substituted group, and can be 1-substituted, 2-substituted, 3-substituted, 4-substituted, 5-substituted, 6-substituted, 7-substituted, 8-substituted, or more, as long as it does not exceed the number of positions that can be substituted on the substituted group.
[0798] In this invention, the phrase "optionally substituted" or "optionally replaced by..." preceding a group indicates that all subgroups contained in that group may be optionally substituted.
[0799] In this invention, the substituent in "optionally substituted by a substituent" can be the "substituent" as described in this invention. The number of substituents is determined according to the number of positions that can be substituted on the substituted group, and can be 1-substituted, 2-substituted, 3-substituted, 4-substituted, 5-substituted, 6-substituted, 7-substituted, 8-substituted, or more.
[0800] In the chemical configuration of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. The chemical structure of the compound described in this invention. It can be a single bond or a double bond.
[0801] In one embodiment of the present invention, R 1 Halogen, -CN, C 1-6 Alkyl (optionally C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 1-6 Alkyl ester, -OH, -NH2, 4-8 membered heterocyclic group, oxo group, -CO2H, -CN or 1-6 halogen substitutions), C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -OH, -NH2, -CO2H, -CN, 1-6 halogens, or C) 1-6 Alkyl groups), 4-8 membered heterocyclic groups (optionally C 1-6 (alkyl, oxo, or 1-6 halogen-substituted), -NR v R w C 1-6 Alkoxy groups (optionally replaced by -CN, C) 1-6 Alkoxy, C 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy group.
[0802] In one embodiment of the present invention, R 1 Preferred halogens, -CN, C 1-6 Alkyl groups (optionally substituted with oxo groups, -CO2H, -CN, or 1-6 halogens), C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl groups (optionally substituted with -CN, 1-6 halogens, or C) 1-6 Alkyl groups, 4-8 membered heterocyclic groups (optionally substituted with oxo groups), -NR v R w C 1- 6-alkoxy group (optionally replaced by -CN, C) 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy, where R v and R w Each is independently selected from H or C 1-6 alkyl.
[0803] In one embodiment of the present invention, R 1 More preferably halogen, -CN, C 1-6 Alkyl (optionally C 3-6 (cycloalkyl, oxo, or 1-6 halogen-substituted), C 3-6 Cycloalkyl groups (optionally substituted with 1-6 halogens or C) 1-6Alkyl), C 1-6 Alkoxy (optionally C 3-6 (cycloalkyl, 4-8 membered heterocyclic or 1-6 halogenated) or C 3-6 Cycloalkoxy group.
[0804] In one embodiment of the present invention, R 2 H, halogen, -CN, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-6 cycloalkyl, -NR v R w -OH, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.
[0805] In one embodiment of the present invention, R 2 Preferably, H, halogen, -CN, or C are preferred. 1-6 Alkyl groups (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -NH2 or C 1-6 Alkyl group.
[0806] In one embodiment of the present invention, R 2 More preferably, H, halogen, -CN, C 1-6 Alkyl (optionally substituted with 1-6 halogens), vinyl, ethynyl, cyclopropyl, -NH2 or C 1-6 Alkyl group.
[0807] In one embodiment of the present invention, R 3 For H or -NR v R w .
[0808] In one embodiment of the present invention, R 3 H or -NH2 is preferred.
[0809] In one embodiment of the present invention, R 3 H is preferred.
[0810] In one embodiment of the present invention, A is...
[0811] In one embodiment of the present invention, A is preferably...
[0812] In one embodiment of the present invention, A is...
[0813] In one embodiment of the present invention, A is...
[0814] In one embodiment of the present invention, A is...
[0815] In one embodiment of the present invention, X1 is CR b Or N.
[0816] In one embodiment of the present invention, R b H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, -NR v R w OR x .
[0817] In one embodiment of the present invention, R b Preferably, H, halogen, -CN, or -NR are preferred. v R w OR x .
[0818] In one embodiment of the present invention, R b More preferably, it is H, halogen, or OR. x .
[0819] In one embodiment of the present invention, R x C 1-6 Alkyl groups (optionally -CN, C) 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, 4-8 membered heterocyclic group, 4-8 membered halocyclic group, C 1-6 (alkoxy or 1-6 halogenated), C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, 4-8 membered heterocyclic group or 4-8 membered halocyclic group.
[0820] In one embodiment of the present invention, R x C is preferred 1-6 Alkyl groups (optionally -CN, C) 2-6 alkenyl, C 2-6Haloalkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, C 1-6 (alkoxy or 1-6 halogenated), C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups.
[0821] In one embodiment of the present invention, R x More preferably C 1-6 Alkyl groups (optionally -CN, C) 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, C 1-6 (alkoxy or 1-6 halogenated), C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups. In one embodiment of the invention, R v and R w Each is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.
[0822] In one embodiment of the present invention, R v and R w Preferably, each is independently selected from H or C 1-6 alkyl.
[0823] In one embodiment of the present invention, X2 is CR c Or N.
[0824] In one embodiment of the present invention, R c H, halogen, C 1-6 Alkyl groups (optionally substituted with -OH, -NH2, -CO2H, -CN, or 1-6 halogens), -OH, -NR y R z C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.
[0825] In one embodiment of the present invention, R c Preferably, H, halogen, or C 1-6 Alkyl groups (optionally substituted with 1-6 halogens), -OH, or -NR y R z , where R y and R z Each is independently selected from H and C. 1-6 alkyl.
[0826] In one embodiment of the present invention, R y and R z Each is independently selected from H and C. 1-6 Alkyl groups (optionally substituted with -OH, -CO2H, -CN or 1-6 halogens) or 4-8 membered heterocyclic groups.
[0827] In one embodiment of the present invention, R y and R z Preferably, each is independently selected from H and C. 1-6 alkyl.
[0828] In one embodiment of the present invention, R 4 Halogen, -CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.
[0829] In one embodiment of the present invention, R 4 Preferred halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.
[0830] In one embodiment of the present invention, R 5 It is H or halogen.
[0831] In one embodiment of the present invention, R 5 H is preferred.
[0832] In one embodiment of the present invention, R 6 It is H or halogen.
[0833] In one embodiment of the present invention, R 6 H is preferred.
[0834] In one embodiment of the present invention, X3 is C or N.
[0835] In one embodiment of the present invention, X4 is C or N.
[0836] In one embodiment of the present invention, R 7 It is H or halogen.
[0837] In one embodiment of the present invention, R 8 It is H or halogen.
[0838] In one embodiment of the present invention, R 9 H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.
[0839] In one embodiment of the present invention, R 9 Preferably, H, halogen, -CN, or C are preferred. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3- 6-Cycloalkyl.
[0840] In one embodiment of the invention, B is a 5- or 6-membered heterocyclic group fused with X3 and X4 (optionally surrounded by 1-4 R groups). d (Substitute) or 5 or 6-membered heteroaryl (optionally replaced by 1-3 R) e replace).
[0841] In one embodiment of the invention, B is preferably a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group (optionally surrounded by 1-3 R groups) fused with X3 and X4. e replace).
[0842] In one embodiment of the present invention, R d and R e Each is independently selected from H, halogen, C 1-6 Alkyl, aryl, -NR v R w C 1-6 Alkoxy, oxo, or thiocarbonyl groups.
[0843] In one embodiment of the present invention, m is 0, 1, 2 or 3.
[0844] In one embodiment of the present invention, m is preferably 0, 1 or 2.
[0845] In one embodiment of the present invention, B is preferably configured as follows:
[0846] In one embodiment of the present invention, B is more preferably a structure as follows:
[0847] In one embodiment of the present invention, R 10 and R 11 Each is independently selected from H or C 1-6 Alkyl group (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogens).
[0848] In one embodiment of the present invention, R 10 and R 11 Preferably, each is independently selected from H or C 1-6 Alkyl group (optionally substituted with -OH).
[0849] In one embodiment of the present invention, when R 10 and R 11 Each independently is C 1-6 When the alkyl group (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogens) is R 10 and R 11 They can bond together to form rings.
[0850] In one embodiment of the present invention, R10 and R 11 They can form oxo groups together.
[0851] In one embodiment of the present invention, R 12 and R 13 Each is independently selected from H, halogen, -CN, C 1-6 Alkyl groups (optionally marked with -OH, C) 1-6 (Alkoxy or 1-6 halogenated) or -OH.
[0852] In one embodiment of the present invention, R f and R g Each is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.
[0853] In one embodiment of the present invention, when R f and R g Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R f and R g They can bond together to form rings.
[0854] In one embodiment of the present invention, when R 13 and R f Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R 13 and R f They can bond together to form rings.
[0855] In one embodiment of the present invention, R 14 and R 15 Each is independently H or halogen.
[0856] In one embodiment of the present invention, R 14 and R 15 Each is preferably an independent halogen.
[0857] In one embodiment of the present invention, R 16 and R 17 Each is independently H or halogen.
[0858] In one embodiment of the present invention, R 16 and R 17 H is preferred to be independent of each other.
[0859] In one embodiment of the present invention, R 18 and R 19 Each is independently selected from H, halogen, C 1-6Alkyl or C 1-6 Halogenated alkyl groups.
[0860] In one embodiment of the present invention, R 18 and R 19 Preferably, each is independently selected from C 1-6 alkyl.
[0861] In one embodiment of the present invention, when R 18 and R 19 Each independently is C 1-6 Alkyl or C 1-6 When alkyl haloides are used, R 18 and R 19 They can bond together to form rings.
[0862] The compounds of this invention also include isotopically labeled compounds. Such isotopic elements include hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine isotopes.
[0863] The isotope-labeled compounds described above can be prepared uniformly by performing the same procedure as disclosed in the following examples, except that readily available isotope-labeled reagents are used instead of non-isotope-labeled reagents.
[0864] The compounds of the present invention can also be used in the form of prodrugs. Prodrugs are compounds that can be converted into the compounds of the present invention under physiological conditions in vivo by, for example, enzymes or gastric acid reactions, such as compounds that are enzymatically oxidized, reduced, or hydrolyzed to the compounds of the present invention, or compounds that are hydrolyzed to the compounds of the present invention by gastric acid.
[0865] Therapeutic or prophylactic medicines containing compounds of the present invention or their pharmaceutically acceptable salts or solvates as active ingredients may be prepared into pharmaceutical compositions using carriers, bases, and excipients, as well as other additives commonly used in pharmaceutical manufacturing processes. Such carriers, bases, and excipients may be solids or liquids. Specific examples include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, triglycerides of medium-chain fatty acids, and other commonly used substances.
[0866] The compounds or pharmaceutical compositions of the present invention can be administered orally in the form of, for example, tablets, pills, capsules, soft capsules, granules, dispersants or liquids, or by injection such as intravenous or intramuscular injection, parenteral administration, suppository, transdermal or intranasal administration, etc.
[0867] While depending on factors such as the route of administration, the patient's age, sex, and the severity of the disease, as well as the frequency of administration, the therapeutically effective dose of the active ingredient in therapeutic agents, preventative agents, pharmaceutical compositions, and activators containing the compounds of the present invention as active ingredients can generally be from 1 mg / day to 1500 mg / day, and the frequency of administration can generally be from once / day to three times / day or from once / week to three times / week. Formulations that meet these conditions are preferred.
[0868] However, since dosage can vary depending on various conditions, a dosage lower than the above may be sufficient in some cases, while a dosage exceeding the above range may be required in others.
[0869] The inhibitors and compounds of the present invention have ALOX inhibitory activity, preferably ALOX15 inhibitory activity. Example
[0870] General synthesis methods
[0871] The compounds of formula (I) of the present invention and their pharmaceutically acceptable salts (hereinafter collectively referred to as the compounds of the present invention) can be synthesized by a combination of methods known in the art, including the synthetic methods described below. The reagents or solvents described in the chemical formulas are merely examples as described in the specification. If desired, each substituent can be protected with a suitable protecting group and can be protected or deprotected in appropriate steps. For suitable protecting groups and methods for removing protecting groups, protective groups for each substituent and known methods widely used in the art can be employed and described, for example, in "PROTECTIVE GROUPS in ORGANIC SYNTHESIS", 3rd edition, John Wiley & Sons, Inc. Furthermore, intermediates generated in the synthetic methods described below can be separated and purified by column chromatography, recrystallization, distillation, etc., or can be used directly in the next step without separation.
[0872] The following describes representative synthetic methods for the compounds of the present invention represented by general formula (I). The synthetic methods for the compounds of the present invention are not limited to these. The symbols in the formulas are as defined in formula (I).
[0873] Suzuki-Miyaura Coupling Reaction:
[0874] The palladium catalyst is preferably tetra(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) dichloride, or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate. There are no particular limitations on the solvent, including, for example, aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), ethers (such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc.), alcohols (such as methanol, ethanol, 2-propanol, butanol, etc.), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, and mixtures thereof. The reaction temperature is preferably 50°C to 150°C, and particularly preferably 80°C to 120°C.
[0875] Yuda-Kosugi-Stille coupling reaction:
[0876] Tin reagents include hexamethyldistin and bis(tributyltin). Preferred palladium catalysts include, for example, tetra(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. There are no particular limitations on the solvents used, including, for example, aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), ethers (such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc.), alcohols (such as methanol, ethanol, 2-propanol, butanol, etc.), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably from 50°C to 150°C, and particularly preferably from 70°C to 120°C.
[0877] Buchwald-Hartwig amination reaction:
[0878] The palladium catalyst is preferably tris(dibenzylacetone)dipalladium, palladium acetate, etc. The ligand is preferably 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, etc. The base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide, etc. There are no particular restrictions on the solvent, including, for example, aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), ethers (such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc.), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably 50°C to 150°C, and more preferably 80°C to 150°C.
[0879] Aromatic nucleophilic substitution reactions:
[0880] Preferred bases include, for example, organic bases (such as triethylamine and N,N-diisopropylethylamine) and inorganic bases (such as potassium carbonate and cesium carbonate). There are no particular limitations on the solvent, which includes, for example, ethers (such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, etc.), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The reaction temperature is preferably room temperature to 150°C.
[0881] The present invention will be described in more detail below through specific embodiments, but the present invention is not limited to these embodiments.
[0882] The abbreviations used in this invention have the following meanings:
[0883] ACN: Acetonitrile
[0884] aq: water
[0885] Boc: tert-butoxycarbonyl
[0886] eq: equivalent
[0887] DAST: (diethylamino)sulfur trifluoride
[0888] DBU: 1,8-diazabicyclo[5.4.0]-7-undecene
[0889] DCM: Dichloromethane
[0890] DIAD: Diisopropyl azodicarbonate
[0891] DIBAL-H: Diisobutylaluminum hydride
[0892] DIEA or DIPEA: N,N-Diisopropylethylamine
[0893] DMA: N,N-dimethylethylamine
[0894] DME: Dimethyl ether
[0895] DMF: N,N-Dimethylformamide
[0896] DMP: Dys-Martin Oxidant
[0897] DMSO: Dimethyl sulfoxide
[0898] EA or EtOAc: Ethyl acetate
[0899] EtOH: Ethanol
[0900] h: hours
[0901] HPLC: High Performance Liquid Chromatography
[0902] LDA: Lithium diisopropylamino
[0903] m-CPBA: m-chloroperoxybenzoic acid
[0904] MeOH: Methanol
[0905] MS: Mass spectrometry analysis
[0906] NBS: N-bromosuccinimide
[0907] NCS: N-chlorosuccinimide
[0908] NMP: 1-Methyl-2-pyrrolidone
[0909] NMR: Nuclear Magnetic Resonance Spectroscopy Analysis
[0910] PE: Petroleum ether
[0911] SEM: 2-(trimethylsilyl)ethoxymethyl
[0912] TFA: Trifluoroacetic acid
[0913] THF: Tetrahydrofuran
[0914] TLC: Thin-layer chromatography
[0915] The structure of the isolated new compound was obtained through 1 Identification can be performed by 1H-NMR and / or mass spectrometry using a single quadrupole instrument equipped with an electron spray source, or by other suitable analytical methods.
[0916] For measurement 1 1H-NMR spectra (400 MHz, DMSO-d6, CDCl3, or CD3OD) are shown, illustrating chemical shifts (δ: ppm) and coupling constants (J: Hz). For the results of mass spectrometry analysis, the observed values at M... + +H represents the measured value, that is, the mass of the proton (H). + The value is obtained by adding the molecular mass (M) of the compound to the molecular mass. The abbreviations used are as follows:
[0917] s = singlet, d = doublet, t = triplet, q = quartet, quintet, brs = broad singlet, m = multiplet.
[0918] Specific Implementation
[0919] [Refer to Example 1]
[0920] 5-Bromo-3-chloro-2-(2,2-difluoroethoxy)pyrazine (Reference Example 1)
[0921] Diisopropyl azodicarbonate (705 μL, 3.58 mmol) was added dropwise to a stirred THF solution of 5-bromo-3-chloropyrazine-2(1H)-one (500 mg, 2.39 mmol), 2,2-difluoroethane-1-ol (255 mg, 3.10 mmol), and triphenylphosphine (939 mg, 3.58 mmol). The mixture was stirred at room temperature for 3 days. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 2%–23%) to give the title compound (594 mg, 2.17 mmol, 91%) as a yellow oil.
[0922] 1 H-NMR (DMSO-d6) δ: 8.49 (1H, d, J = 1.4Hz), 6.57-6.28 (1H, m), 4.71-4.63 (2H, m).
[0923] [Refer to Example 2]
[0924] 5-Bromo-3-chloro-2-(difluoromethoxy)pyrazine (Reference Example 2)
[0925] Difluoromethyl trifluoromethanesulfonate (3.73 g, 18.6 mmol) was added to a stirred solution of 5-bromo-3-chloropyrazine-2(1H)-one (2.00 g, 9.55 mmol) and potassium hydroxide (6.43 g, 115 mmol) in MeCN (19 mL) / H₂O (19 mL). The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give the title compound (320 mg, 1.24 mmol, 13%) as a colorless oil.
[0926] 1 H-NMR (CD3OD) δ: 8.26 (1H, s), 7.42 (1H, t, J = 71.1Hz).
[0927] [Refer to Example 3]
[0928] 5-Bromo-2-(difluoromethoxy)-3-methylpyrazine (Ref. Example 3)
[0929] Sodium 2-chloro-2,2-difluoroacetate (807 mg, 5.29 mmol) was added to a stirred solution of 5-bromo-3-methylpyrazine-2(1H)-one (500 mg, 2.65 mmol) and potassium carbonate (1.10 g, 7.94 mmol) in DMF (5 mL). The mixture was stirred at 100 °C for 1 hour. After cooling to ambient temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–10%) to give the title compound (182 mg, 764 μmol, 29%) as a colorless oil.
[0930] 1 H-NMR (CD3OD) δ: 8.09 (1H, s), 7.39 (1H, t, J = 71.8Hz), 2.40 (3H, s).
[0931] [Refer to Example 4]
[0932] 2-(difluoromethoxy)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazine (Ref. Example 4)
[0933] A mixture of 5-bromo-2-(difluoromethoxy)-3-methylpyrazine (1.54 g, 6.44 mmol), bis(pinacol)diboron (2.45 g, 9.66 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (471 mg, 644 μmol), and potassium acetate (1.58 g, 16.1 mmol) in 1,4-dioxane (16 mL) was heated at 100 °C for 1 hour. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 65%–86%) to give the title compound (1.95 g, 6.80 mmol) containing impurities.
[0934] MS: m / z 205.10 (boric acid + H) + .
[0935] [Refer to Example 5]
[0936] 6-Bromo-3-(difluoromethoxy)pyrazine-2-carboxylonitrile (Ref. Example 5)
[0937] 6-Bromo-3-(difluoromethoxy)pyrazine-2-carboxamide (Intermediate 5)
[0938] Sodium 2-chloro-2,2-difluoroacetate (2.80 g, 18.3 mmol) was added to a stirred solution of 6-bromo-3-oxo-3,4-dihydropyrazine-2-carboxamide (2.00 g, 9.17 mmol) and potassium carbonate (3.80 g, 27.5 mmol) in DMF (40 mL). The mixture was stirred at 100 °C for 2 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth filter. 1 N HCl was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 40%–61%) to give the title compound (115 mg, 427 μmol, 5%) as a brown solid.
[0939] MS:m / z 267.90(M+H) + .
[0940] 6-Bromo-3-(difluoromethoxy)pyrazine-2-carboxylonitrile (Ref. Example 5)
[0941] 2,2,2-trifluoroacetic anhydride (89.0 μL, 641 μmol) was added to a stirred solution of 6-bromo-3-(difluoromethoxy)pyrazin-2-carboxamide (115 mg, 427 μmol) and triethylamine (180 μL, 1.28 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of NaHCO3 was added to the mixture, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[0942] MS: m / z 249.90 (M+H) + .
[0943] [Refer to Example 6]
[0944] 3,5-Dichloro-2-(1,1-difluoroethyl)pyrazine (Reference Example 6)
[0945] At 0 °C, (diethylamino)sulfur trifluoride (14.1 mL, 108 mmol) was added to a stirred solution of 1-(3,5-dichloropyrazin-2-yl)ethyl-1-one (4.11 g, 21.5 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 3 days. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–21%) to give the title compound (3.85 g, 18.1 mmol, 84%) as a pale yellow oil.
[0946] 1 H-NMR (CDCl3) δ: 8.50 (1H, s), 2.09 (3H, t, J=18.8Hz).
[0947] [Refer to Example 7]
[0948] 6-Chloro-3-(difluoromethoxy)pyrazine-2-amine (Ref. Example 7)
[0949] Sodium 2-chloro-2,2-difluoroacetate (300 mg, 1.97 mmol) was added to a stirred solution of 3-amino-5-chloropyrazine-2(1H)-one (125 mg, 857 μmol) and potassium carbonate (296 mg, 2.14 mmol) in DMF (4 mL) / H₂O (0.4 mL). The mixture was stirred at 100 °C for 15 hours. After cooling to ambient temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–40%) to give the title compound (37.6 mg, 192 μmol, 22%) as a white solid.
[0950] 1 H-NMR (CDCl3) δ: 7.42 (1H, s), 7.35 (1H, t, J = 72.4Hz), 5.02 (2H, s).
[0951] [Refer to Example 8]
[0952] 3,5-Dichloro-6-(difluoromethyl)pyrazine-2-amine (Ref. Example 8)
[0953] Ethyl 2-(6-amino-3,5-dichloropyrazin-2-yl)-2,2-difluoroacetate (intermediate 8A)
[0954] A mixture of 6-bromo-3-chloropyrazine-2-amine (2.59 g, 12.4 mmol), ethyl bromodifluoroacetate (3.22 mL, 24.8 mmol), and copper (3.15 g, 49.6 mmol) in DMSO (21 mL) was stirred at room temperature for 4 days. The mixture was filtered through a diatomaceous earth mat, and 1 N HCl was added to the filtrate. The mixture was extracted with ethyl acetate. The organic layer was washed with 1 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 18%–39%) to give the title compound (1.66 g, 6.58 mmol, 53%) as a yellow solid.
[0955] MS:m / z 252.00(M+H) + .
[0956] Ethyl 2-(6-amino-5-chloropyrazin-2-yl)-2,2-difluoroacetate (intermediate 8B)
[0957] A mixture of ethyl 2-(6-amino-3,5-dichloropyrazin-2-yl)-2,2-difluoroacetate (1.66 g, 6.58 mmol) and N-chlorosuccinimide (879 mg, 6.58 mmol) in DMF (10 mL) was stirred overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 22%–43%) to give the title compound (1.42 g, 4.98 mmol, 76%) as a yellow oil.
[0958] MS: m / z 285.90 (M+H) + .
[0959] 3,5-Dichloro-6-(difluoromethyl)pyrazine-2-amine (Ref. Example 8)
[0960] A mixture of ethyl 2-(6-amino-5-chloropyrazin-2-yl)-2,2-difluoroacetate (1.31 g, 4.59 mmol) and magnesium chloride hexahydrate (1.87 g, 9.19 mmol) in NMP (10 mL) was stirred under microwave irradiation at 180 °C for 0.5 h. Water was added to the mixture and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 14%–35%) to give the title compound (259 mg, 1.21 mmol, 26%) as a yellow solid.
[0961] MS:m / z 214.00(M+H)+ .
[0962] [Refer to Example 9]
[0963] 3-Bromo-5-chloro-6-(difluoromethoxy)pyrazine-2-amine (Ref. Example 9)
[0964] 2-Bromo-3-chloro-5-(difluoromethoxy)pyrazine (Intermediate 9A)
[0965] A mixture of 5-bromo-6-chloropyrazine-2-ol (4.00 g, 19.1 mmol), ethyl bromodifluoroacetate (4.94 mL, 38.2 mmol), and sodium carbonate (8.10 g, 76.4 mmol) in MeCN (50 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was passed through a short silica gel column and eluted with EtOAc to give the title compound (4.63 g, 17.8 mmol, 93%) as a deep yellow oil.
[0966] 1 H-NMR(CDCl3)δ:8.12(1H,s),7.32(1H,t,J=71.2Hz).
[0967] 3-Bromo-6-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)pyrazine-2-amine (Intermediate 9B)
[0968] A mixture of 2-bromo-3-chloro-5-(difluoromethoxy)pyrazine (4.43 g, 17.1 mmol), (2,4-dimethoxyphenyl)methylamine (2.57 mL, 17.1 mmol), and DIEA (8.7 mL, 51.2 mmol) in DMF (43 mL) was stirred at 60 °C for 1 hour. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 14%–35%) to give the title compound (3.80 g, 9.73 mmol, 57%) as a yellow oil.
[0969] MS:m / z 390.00(M+H) + .
[0970] 3-Bromo-6-(difluoromethoxy)pyrazine-2-amine (intermediate 9C)
[0971] A mixture of 3-bromo-6-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)pyrazin-2-amine (3.80 g, 9.73 mmol) and TFA (20 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 17%–38%) to give the title compound (2.07 g, 8.62 mmol, 89%) as a yellow solid.
[0972] MS:m / z 240.00(M+H) + .
[0973] 3-Bromo-5-chloro-6-(difluoromethoxy)pyrazine-2-amine (Ref. Example 9)
[0974] A mixture of 3-bromo-6-(difluoromethoxy)pyrazin-2-amine (180 mg, 750 μmol) and N-chlorosuccinimide (100 mg, 750 μmol) in DMF (2 mL) was stirred overnight at room temperature. The mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 16%–37%) to give the title compound (205 mg, 748 μmol, quantitative yield) as a yellow oil.
[0975] MS: m / z 273.90 (M+H) + .
[0976] [Refer to Example 10]
[0977] 5-Chloro-2,3-bis(difluoromethyl)pyrazine (Reference Example 10)
[0978] 2-Bromo-5-chloro-3-(difluoromethyl)pyrazine (Intermediate 10A)
[0979] At 0 °C, (diethylamino)sulfur trifluoride (4.48 mL, 33.9 mmol) was added to a stirred solution of 3-bromo-6-chloropyrazine-2-carboxaldehyde (2.50 g, 11.3 mmol) in DCM (70 mL). The mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / hexane = 0%–1%) to give the title compound (1.8 g, 65%) as a pale yellow oil.
[0980] 1H-NMR (DMSO-d6) δ: 8.50 (1H, s), 6.83 (1H, t, J = 53.1Hz).
[0981] Ethyl 2-(5-chloro-3-(difluoromethyl)pyrazin-2-yl)-2,2-difluoroacetate (intermediate 10B)
[0982] A mixture of ethyl bromodifluoroacetate (395 μL, 3.08 mmol) and Cu powder (392 mg, 6.16 mmol) in DMSO (5 mL) was stirred at room temperature for 1 hour. Then, 2-bromo-5-chloro-3-(difluoromethyl)pyrazine (500 mg, 2.05 mmol) was added to the solution, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of NH4Cl was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / hexane = 1%–2%) to give the title compound (140 mg, 24%).
[0983] 1 H-NMR (DMSO-d6) δ: 8.69 (1H, s), 7.02 (1H, t, J = 53.2Hz), 4.44-4.38 (2H, q, J = 7.1Hz), 1.35 (3H, t, J = 7.2Hz).
[0984] 5-Chloro-2,3-bis(difluoromethyl)pyrazine (Reference Example 10)
[0985] A mixture of ethyl 2-(5-chloro-3-(difluoromethyl)pyrazin-2-yl)-2,2-difluoroacetate (550 mg, 1.92 mmol) and magnesium chloride hexahydrate (1.95 g, 9.56 mmol) in NMP (8 mL) was stirred at 160 °C for 4 hours. Water was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / hexane = 1%–2%) to give the title compound (195 mg, 47%).
[0986] 1 H-NMR (CDCl3) δ: 8.78 (1H, s), 6.95 (1H, t, J = 53.2Hz), 6.89 (1H, t, J = 53.2Hz).
[0987] [Refer to Example 11]
[0988] 5-Chloro-2-(2,2-difluoroethoxy)-3-(trifluoromethyl)pyrazine (Ref. Example 11)
[0989] 5-Chloro-3-(trifluoromethyl)pyrazine-2(1H)-one (Intermediate 11)
[0990] Sodium nitrite (349 mg, 5.06 mmol) was added to a stirred solution of 5-chloro-3-(trifluoromethyl)pyrazin-2-amine (1.00 g, 5.06 mmol) in sulfuric acid (8 mL). The mixture was stirred at the same temperature for 0.5 h. Then 50 g of ice was added to the mixture and stirred for 0.5 h. A 2 M NaOH aqueous solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc) to give the title compound (871 mg, 4.39 mmol, 87%) as a pale yellow solid.
[0991] MS:m / z 199.00(M+H) + .
[0992] 5-Chloro-2-(2,2-difluoroethoxy)-3-(trifluoromethyl)pyrazine (Ref. Example 11)
[0993] Diisopropyl azodicarbonate (408 μL, 2.11 mmol) was added dropwise to a stirred solution of 5-chloro-3-(trifluoromethyl)pyrazin-2(1H)-one (322 mg, 1.62 mmol), 2,2-difluoroethane-1-ol (173 mg, 2.11 mmol), and triphenylphosphine (638 mg, 2.43 mmol) in THF (4 mL). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–10%) to give the title compound (48.3 mg, 184 μmol, 11%) as a colorless oil.
[0994] 1 H-NMR (CDCl3) δ: 8.34 (1H, s), 6.13 (1H, tt, J = 54.9, 4.1 Hz), 4.67 (2H, td, J = 13.0, 4.1 Hz).
[0995] [Refer to Example 12]
[0996] 5-Bromo-2-(1,1-difluoroethyl)-3-(difluoromethyl)pyrazine (Reference Example 12)
[0997] 6-Chloro-5-(1,1-difluoroethyl)-N-(2,4-dimethoxybenzyl)pyrazin-2-amine (Intermediate 12A)
[0998] A mixture of 3,5-dichloro-2-(1,1-difluoroethyl)pyrazine (2.50 g, 11.7 mmol), (2,4-dimethoxyphenyl)methylamine (1.76 mL, 11.7 mmol), and DIEA (3.07 mL, 17.6 mmol) in DMF (20 mL) / MeCN (20 mL) was stirred at room temperature for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / hexane = 20%) to give the title compound (2.20 g, 55%).
[0999] 1 H-NMR(DMSO-d6)δ:8.17-8.14(1H,m),7.88(1H,s),7.16(1H,d,J=8.2Hz),6.58-6.57(1H,m) ,6.48(1H,d,J=8.3Hz),4.35(2H,d,J=5.4Hz),3.80(3H,s),3.74(3H,s),2.01-1.92(3H,m).
[1000] 5-(1,1-Difluoroethyl)-N-(2,4-Dimethoxybenzyl)-6-vinylpyrazine-2-amine (Intermediate 12B)
[1001] A mixture of 6-chloro-5-(1,1-difluoroethyl)-N-(2,4-dimethoxybenzyl)pyrazin-2-amine (1.00 g, 2.91 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (493 μL, 2.91 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane adduct (237 mg, 291 μmol), and tripotassium phosphate (1.24 g, 5.82 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 4 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / hexane = 20%-22%) to give the title compound (850 mg, 87%).
[1002] 1H-NMR(DMSO-d6)δ:7.82(1H,s),7.76-7.74(1H,m),7.18(1H,d,J=8.2Hz),7.12-7.05(1H,m),6.56(1H,s),6. 47-6.38(2H,m),5.54(1H,d,J=10.4Hz),4.43(2H,d,J=5.4Hz),3.80(3H,s),3.73(3H,s),2.01-1.92(3H,m).
[1003] 3-(1,1-Difluoroethyl)-6-((2,4-Dimethoxybenzyl)amino)pyrazine-2-carboxaldehyde (intermediate 12C)
[1004] A mixture of 5-(1,1-difluoroethyl)-N-(2,4-dimethoxybenzyl)-6-vinylpyrazine-2-amine (2.20 g, 6.56 mmol), potassium osmium tetroxide (VI) dihydrate (1.19 g, 0.328 mmol), and sodium periodate (5.61 g, 26.2 mmol) in acetone (32 mL) / H₂O (3 mL) was stirred overnight at room temperature. A saturated aqueous solution of Na₂S₂O₃ was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography to give the title compound (1.80 g, 81%).
[1005] 1 H-NMR(DMSO-d6)δ:10.22(1H,s),8.11-8.07(2H,m),7.21(1H,d,J=8.2Hz),6.57(1H,s),6 .45(1H,d,J=7.1Hz), 4.42(2H,d,J=5.1Hz), 3.80(3H,s), 3.73(3H,s), 2.08-1.98(3H,m).
[1006] 5-(1,1-Difluoroethyl)-6-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrazine-2-amine (intermediate 12D)
[1007] At 0 °C, (diethylamino)sulfur trifluoride (5.58 mL, 42.2 mmol) was added to a stirred solution of 3-(1,1-difluoroethyl)-6-((2,4-dimethoxybenzyl)amino)pyrazin-2-carboxaldehyde (4.75 g, 14.1 mmol) in DCM (150 mL). The mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography to give the title compound (5.06 g, 61%).
[1008] 1 H-NMR(DMSO-d6)δ:8.12-8.10(1H,m),8.05(1H,s),7.21(1H d,J=8.3Hz),7.18-6.91(1H,m),6.578-6.573(1H,m),6.48-6.45(1H,dd,J=2.2, 8.3Hz), 4.41 (2H, d, J = 5.3Hz) 3.80 (3H, s), 3.70 (3H, s), 1.99 (3H, t, J = 19.3Hz).
[1009] 5-(1,1-Difluoroethyl)-6-(difluoromethyl)pyrazine-2-amine (intermediate 12E)
[1010] A mixture of 5-(1,1-difluoroethyl)-6-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrazin-2-amine (1.20 g, 3.34 mmol) and cerium ammonium nitrate (IV) (3.66 g, 6.68 mmol) in MeCN (24 mL) / H₂O (12 mL) was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / hexane = 0%–2%) to give the title compound (500 mg, 72%).
[1011] 1 H-NMR (DMSO-d6) δ: 7.96 (1H, s), 7.35 (2H, s), 7.04 (1H, t, J = 53.5Hz), 2.00 (3H, t, J = 19.3Hz).
[1012] 5-Bromo-2-(1,1-difluoroethyl)-3-(difluoromethyl)pyrazine (Reference Example 12)
[1013] CuBr2 (801 mg, 3.59 mmol) was added to a stirred solution of 5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-amine (500 mg, 2.39 mmol) in DMF (18 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was then cooled to 0 °C, and amyl nitrite (0.525 mL, 3.59 mmol) was added. The reaction mixture was then heated at 65 °C for 2 hours. Water was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography to give the title compound (463 mg, 71%).
[1014] 1 H-NMR (CDCl3) δ: 8.77 (1H, s), 7.08 (1H, t, J = 53.2 Hz), 2.10 (3H, t, J = 19.3 Hz).
[1015] [Refer to Example 13]
[1016] 2-(difluoromethyl)-5-(trimethyltinyl)pyrazine (Reference Example 13)
[1017] To a solution of 2-chloro-5-(difluoromethyl)pyrazine (150 mg, 911 μmol) in 1,4-dioxane (5 mL), hexamethyldistin (448 mg, 1.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (52.7 mg, 45.6 μmol) were added. The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.
[1018] MS:m / z 295.00(M+H) + .
[1019] [Refer to Example 14]
[1020] 2-(difluoromethoxy)-5-(trimethyltinyl)pyrazine (Reference Example 14)
[1021] To a solution of 2-bromo-5-(difluoromethoxy)pyrazine (494 mg, 2.20 mmol) in 1,4-dioxane (5 mL), hexamethyldistin (1.08 g, 3.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (127 mg, 110 μmol) were added. The mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1022] 1 H-NMR (CDCl3) δ: 8.56 (1H, d, J = 1.2Hz), 8.15 (1H, d, J = 2.0Hz), 7.41 (1H, t, J = 72.4Hz), 0.39 (9H, s).
[1023] [Refer to Example 15]
[1024] 4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole-1-carboxylic acid tert-butyl ester (Reference Example 15)
[1025] A mixture of tert-butyl 7-bromo-4-chloro-1H-indazole-1-carboxylic acid (120 mg, 362 μmol), bis(pinacol)diboron (110 mg, 434 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (13.2 mg, 18.1 μmol), and potassium acetate (71.0 mg, 724 μmol) in 1,4-dioxane (2 mL) was heated at 100 °C for 3 hours. After cooling to ambient temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–93%) to give the title compound (81.0 mg, 214 μmol) as a white amorphous substance.
[1026] 1 H-NMR (CDCl3) δ: 8.23 (1H, s), 7.46 (1H, d, J = 8.0 Hz), 7.07 (1H, d, J = 7.6 Hz), 1.26 (21 H, s).
[1027] [Refer to Example 16]
[1028] 7-Bromo-4-chlorobenzo[d]oxazol-2(3H)-one (Reference Example 16)
[1029] 3-Bromo-6-chloro-2-hydroxybenzoate tert-butyl ester (intermediate 16A)
[1030] Under a nitrogen atmosphere and at -78°C, lithium diisopropylamino (30.0 mL, 60.0 mmol, 2 M) was added dropwise over 15 minutes to a THF (115 mL) coolant containing 15.4 g (50.0 mmol) of 2-bromo-5-chlorophenyl tert-butyl carbonate. The resulting mixture was stirred at the same temperature for 1 hour, then gradually heated to room temperature and stirred overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through a short silica gel column and eluted with EtOAc to give tert-butyl 3-bromo-6-chloro-2-hydroxybenzoate (10.9 g, 35.5 mmol, 71%) as a brown oil.
[1031] 1 H-NMR (CDCl3) δ: 11.69 (1H, s), 7.52 (1H, d, J = 8.7Hz), 6.86 (1H, d, J = 8.7Hz), 1.64 (9H, s).
[1032] 3-Bromo-6-chloro-2-hydroxybenzoic acid (intermediate 16B)
[1033] TFA (27 mL) was added to a solution of tert-butyl 3-bromo-6-chloro-2-hydroxybenzoate (10.9 g, 35.5 mmol) in dichloromethane (82 mL), and the mixture was stirred at room temperature for 1.5 hours. Heptane was added, and the precipitate was collected by filtration. The collected solid was washed with heptane and dried under high vacuum to give 3-bromo-6-chloro-2-hydroxybenzoic acid (6.08 g, 24.2 mmol, 68%) as a white solid.
[1034] 1 H-NMR (CDCl3) δ: 11.90 (1H, s), 7.63 (1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 8.7 Hz).
[1035] 7-Bromo-4-chlorobenzo[d]oxazol-2(3H)-one (Reference Example 16)
[1036] Triethylamine (4.04 mL, 29.0 mmol) and diphenyl azidophosphate (5.46 mL, 25.4 mmol) were added to a mixture of 3-bromo-6-chloro-2-hydroxybenzoic acid (6.08 g, 24.2 mmol) in toluene (122 mL). The mixture was heated at 110 °C for 15.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water and a small amount of DCM were added, and the precipitate was collected by filtration. The filter cake was washed with DCM and dried under high vacuum to give 7-bromo-4-chlorobenzo[d]oxazol-2(3H)-one (3.56 g, 14.3 mmol, 59.2%) as a white solid. The filtrate was separated, and the aqueous layer was extracted with EtOAc (40 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in DCM and collected by filtration. The obtained solid was dried under high vacuum to give 7-bromo-4-chlorobenzo[d]oxazol-2(3H)-one (1.05 g, 4.22 mmol, 17%), which was a white solid.
[1037] 1 H-NMR (DMSO-d6) δ: 12.54 (1H, s), 7.30 (1H, d, J = 9.2 Hz), 7.19 (1H, d, J = 8.8 Hz).
[1038] [Refer to Example 17]
[1039] 4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Ref. Example 17)
[1040] 7-Bromo-4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 17)
[1041] To a DMF (16 mL) suspension of 7-bromo-4-chlorobenzo[d]oxazol-2(3H)-one (2 g, 8.05 mmol) and potassium carbonate (2.23 g, 16.1 mmol), 2-(chloromethoxy)ethyltrimethylsilane (2.01 g, 12.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give 7-bromo-4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (3.09 g, 8.18 mmol, quantitative yield) as a pale yellow oil.
[1042] 1 H-NMR (CD3OD) δ: 7.35 (1H, d, J = 9.1Hz), 7.20 (1H, d, J = 8.7Hz), 5.52 (2H, s), 3.74 (2H, t, J = 8.0Hz), 0.94 (2H, t, J = 7.3Hz), 0.00 (9H, s).
[1043] 4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Ref. Example 17)
[1044] A mixture of 7-bromo-4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (2.22 g, 5.87 mmol), bis(pinacol)diboron (1.64 g, 6.46 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (215 mg, 294 μmol), and potassium acetate (1.15 g, 11.7 mmol) in 1,4-dioxane (29 mL) was heated at 90 °C for 4 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was poured into water and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one, a dark brown paste, which was used in the next step without further purification.
[1045] [Refer to Example 18]
[1046] 4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (Ref. Example 18)
[1047] A mixture of 7-bromo-4-chloropyrazolo[1,5-a]pyridine (100 mg, 432 μmol), bis(pinacol)diboron (143 mg, 562 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (31.6 mg, 43.2 μmol), and potassium acetate (106 mg, 1.08 mmol) in 1,4-dioxane (1.4 mL) was heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.
[1048] MS: m / z 230.90 (boric acid + H) + .
[1049] [Refer to Example 19]
[1050] 7-Chloro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indoline-2-one (Ref. Example 19)
[1051] A mixture of 4-bromo-7-chloroindololin-2-one (631 mg, 2.56 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (209 mg, 256 μmol), bis(pinacol)diboron (780 mg, 3.071 mmol), and potassium acetate (754 mg, 7.68 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 2 hours. After cooling, the reaction mixture was diluted with water and EtOAc and passed through a diatomaceous earth mat. The filtrate was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with toluene and heptane, and the precipitate was collected by filtration. The resulting solid was dried under high vacuum to give the title compound (468 mg, 1.60 mmol, 62%) as a light brown solid. The filtrate was concentrated under reduced pressure. The residue was ground with EtOH and water to give another batch of the title compound (270 mg, 919 μmol, 36%) as a light brown solid.
[1052] 1 H-NMR (CDCl3) δ: 7.37 (1H, d, J = 8.4Hz), 7.21 (1H, d, J = 8.4Hz), 3.78 (2H, s), 1.33 (12H, s).
[1053] [Refer to Example 20]
[1054] 2-(4-fluoro-2-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (Reference Example 20)
[1055] A mixture of 1-bromo-4-fluoro-2-(trifluoromethoxy)benzene (250 mg, 965 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (70.6 mg, 96.5 μmol), bis(pinacol)diboron (368 mg, 1.45 mmol), and potassium acetate (237 mg, 2.41 mmol) in 1,4-dioxane (4 mL) was heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.
[1056] [Refer to Example 21]
[1057] 4-Chloro-7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphane-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Reference Example 21)
[1058] A mixture of 4-bromo-7-chloro-1,3-dihydro-2H-benzo[d]imidazol-2-one (200 mg, 808 μmol), bis(pinacol)diboron (308 mg, 1.21 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (59.1 mg, 80.8 μmol), and potassium acetate (198 mg, 2.02 mmol) in 1,4-dioxane (4 mL) was heated at 100 °C for 4 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.
[1059] MS: m / z 295.10 (M+H) + .
[1060] [Refer to Example 22]
[1061] 2-(difluoromethoxy)-6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (Ref. Example 22)
[1062] A mixture of 3-bromo-2-(difluoromethoxy)-6-(difluoromethyl)pyridine (447 mg, 1.63 mmol), bis(pinacol)diboron (621 mg, 2.45 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (119 mg, 163 μmol), and potassium acetate (400 mg, 4.08 mmol) in 1,4-dioxane (4 mL) was stirred at 100 °C for 2.5 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and used without further purification.
[1063] MS: m / z 240.10 (boric acid + H) + .
[1064] [Refer to Example 23]
[1065] (4,4-Difluoropiperidin-2-yl)methanol hydrochloride (Reference Example 23)
[1066] A mixture of 144 mg (573 μmol) of 4,4-difluoro-2-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester and 4N HCl in dioxane (5 mL) was stirred at room temperature for 1.5 hours. The mixture was then concentrated under reduced pressure and used without further purification.
[1067] [Refer to Example 24]
[1068] 8-azabispirol [2.1.2] 5 .3 3 Decane hydrochloride (Reference Example 24)
[1069] 8-azabispirol [2.1.2] 5 .3 3 ]Decane-8-carboxylic acid tert-butyl ester (intermediate 24)
[1070] Diethylzinc (13.4 mL, 13.4 mmol) was added dropwise to anhydrous DCM (10 mL) under an argon atmosphere and at -40 °C. Then, CH₂I₂ (2.16 mL, 26.9 mmol) was added dropwise to the reaction mixture. The mixture was then stirred at the same temperature for 30 min. 7-Methylene-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester was dissolved in anhydrous DCM (5 mL) and added dropwise to the reaction mixture at the same temperature. The mixture was then gradually heated to 4 °C and stirred for 20 h. The reaction mixture was then quenched with a saturated aqueous NH₄Cl solution and extracted with a 5% MeOH solution in DCM. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by Combi rapid column chromatography (eluting with 2%–3% ethyl acetate in hexane) to give the desired product (250 mg, 39%).
[1071] 1 H-NMR(CDCl3)δ:3.48(2H,brs),1.45(9H,s),1.32-1.21(4H,m),0.84(2H,bs),0.60(2H,s),0.31-0.24(4H,m).
[1072] 8-azabispirol [2.1.2] 5 .3 3 Decane hydrogen chloride (Ref. Example 24)
[1073] Under a nitrogen atmosphere and at 0°C, a solution of dioxane in 4N HCl (6 mL) was added to a stirred solution of 300 mg (1.26 mmol) of 8-azabispiro[2.1.25.33]decane-8-carboxylic acid tert-butyl ester (DCM) in 6 mL of precipitate. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and ground with n-pentane to give the desired compound (150 mg, 68%) as a yellow solid.
[1074] MS: m / z 137.98 (M+H) + .
[1075] 1 H-NMR (CDCl3) δ: 9.27 (2H, brs), 3.10 (2H, brs), 1.58 (2H, brs), 1.51 (2H, brs), 0.99 (2H, t, J = 6.08 Hz), 0.68 (2H, t, J = 6.12 Hz), 0.38 (4H, s).
[1076] [Refer to Example 25]
[1077] 2-(2-(difluoromethoxy)-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (Reference Example 25)
[1078] A mixture of 1-bromo-2-(difluoromethoxy)-4,5-difluorobenzene (495 mg, 1.91 mmol), bis(pinacol)diboron (534 mg, 2.10 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (69.9 mg, 95.6 μmol), and potassium acetate (375 mg, 3.82 mmol) in 1,4-dioxane (4 mL) was stirred overnight at 100 °C. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure. The residue was passed through a short silica gel column and eluted with EtOAc to give a semi-pure compound as a yellow oil.
[1079] 1 H-NMR (CDCl3) δ: 7.55 (1H, t, J = 9.8Hz), 7.02 (1H, dd, J = 11.0, 6.4Hz), 6.48 (1H, t, J = 74.8Hz), 1.34 (12H, s).
[1080] [Refer to Example 26]
[1081] 7-Bromo-4,5-difluorobenzo[d]oxazol-2(3H)-one (Reference Example 26)
[1082] 3-Bromo-5,6-difluoro-2-hydroxybenzoate tert-butyl ester (intermediate 26A)
[1083] Under a nitrogen atmosphere and at -78°C, lithium diisopropylamino (7.12 mL, 14.2 mmol, 2 M) was added dropwise over 5 minutes to a THF (30 mL) coolant containing 4.00 g (12.9 mmol) of 2-bromo-4,5-difluorophenyl tert-butyl carbonate. The resulting mixture was stirred at the same temperature for 1 hour, then gradually heated to room temperature and stirred for 2 hours. The reaction was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 0%–19%) to give tert-butyl 3-bromo-5,6-difluoro-2-hydroxybenzoate (3.22 g, 10.4 mmol, 81%) as a pale yellow solid.
[1084] 1 H-NMR (CDCl3) δ: 11.85 (1H, s), 7.56 (1H, dd, J = 9.4, 8.0 Hz), 1.63 (9H, s).
[1085] 3-Bromo-5,6-difluoro-2-hydroxybenzoic acid (intermediate 26B)
[1086] TFA (10 mL) was added to a solution of tert-butyl 3-bromo-5,6-difluoro-2-hydroxybenzoate (3.22 g, 10.4 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration. The collected solid was washed with dichloromethane and dried under high vacuum to give 3-bromo-5,6-difluoro-2-hydroxybenzoic acid (1.49 g, 5.88 mmol, 56%) as a white solid.
[1087] MS: m / z 252.90 (M+H) + .
[1088] 7-Bromo-4,5-difluorobenzo[d]oxazol-2(3H)-one (Reference Example 26)
[1089] Triethylamine (0.981 mL, 7.05 mmol) and diphenyl azide phosphate (1.33 mL, 6.17 mmol) were added to a mixture of 3-bromo-5,6-difluoro-2-hydroxybenzoic acid (1.49 g, 5.88 mmol) in toluene (30 mL). The mixture was heated at 110 °C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 19%–40%) to give 7-bromo-4,5-difluorobenzo[d]oxazol-2(3H)-one (1.26 g, 5.03 mmol, 86%) as a pale yellow solid.
[1090] MS: m / z 249.90 (M+H) + .
[1091] [Refer to Example 27]
[1092] 4,5-Difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (27)
[1093] 7-Bromo-4,5-Difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 27)
[1094] To a DMF (15 mL) suspension of 7-bromo-4,5-difluorobenzo[d]oxazol-2(3H)-one (1.26 g, 5.03 mmol) and potassium carbonate (1.39 g, 10.1 mmol), 2-(chloromethoxy)ethyltrimethylsilane (1.26 g, 7.54 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give 7-bromo-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (1.98 g, 5.21 mmol, quantitative yield) as a colorless oil.
[1095] 1 H-NMR (DMSO-d6) δ: 7.70 (1H, dd, J = 11.4, 6.9Hz), 5.25 (2H, s), 3.65 (2H, t, J = 8.0Hz), 0.87 (2H, t, J = 8.0Hz), -0.04 (9H, s).
[1096] 4,5-Difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 27)
[1097] A mixture of 7-bromo-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (1.98 g, 5.21 mmol), bis(pinacol)diboron (1.46 g, 5.74 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (191 mg, 261 μmol), and potassium acetate (1.02 g, 10.4 mmol) in 1,4-dioxane (13 mL) was heated at 100 °C for 2.5 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4,5-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one, a brown slurry, which was used in the next step without further purification.
[1098] [Refer to Example 28]
[1099] 7-Bromo-4,6-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 28)
[1100] 7-Bromo-4,6-difluorobenzo[d]oxazol-2(3H)-one (Intermediate 28)
[1101] Triethylamine (275 μL, 1.98 mmol) and diphenyl azide phosphate (372 μL, 1.73 mmol) were added to a mixture of 3-bromo-4,6-difluoro-2-hydroxybenzoic acid (417 mg, 1.65 mmol) in toluene (8 mL). The mixture was heated at 110 °C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 21%–42%) to give the title compound (320 mg, 1.28 mmol, 78%) as a pale yellow solid.
[1102] MS: m / z 249.90 (M+H) + .
[1103] 7-Bromo-4,6-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 28)
[1104] To a DMF (10 mL) suspension of 7-bromo-4,6-difluorobenzo[d]oxazol-2(3H)-one (320 mg, 1.28 mmol) and potassium carbonate (354 mg, 2.56 mmol), 2-(chloromethoxy)ethyltrimethylsilane (321 mg, 1.92 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give the title compound (384 mg, 1.01 mmol, 79%) as a colorless oil.
[1105] [Refer to Example 29]
[1106] 2-(difluoromethyl)-3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (Reference Example 29)
[1107] A mixture of 6-bromo-2-(difluoromethyl)-3-fluoropyridine (100 mg, 551 μmol), bis(pinacol)diboron (210 mg, 826 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (40.3 mg, 55.1 μmol), and potassium acetate (108 mg, 1.10 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 2.5 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and used without further purification.
[1108] [Refer to Example 30]
[1109] 3-Fluoro-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine-2-amine (Reference Example 30)
[1110] A mixture of 6-bromo-3-fluoropyridine-2-amine (200 mg, 1.05 mmol), bis(pinacol)diboron (399 mg, 1.57 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (76.6 mg, 105 μmol), and potassium acetate (206 mg, 2.09 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C for 4.5 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and used without further purification.
[1111] [Refer to Example 31]
[1112] 6-Bromo-3-fluoro-N-methylpyridin-2-amine (Reference Example 31)
[1113] A mixture of 6-bromo-2-chloro-3-fluoropyridine (500 mg, 2.38 mmol), methylamine hydrochloride (160 mg, 2.38 mmol), and DIEA (1.2 mL, 7.13 mmol) in DMSO (5 mL) was heated at 80 °C for 3 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 8%–29%) to give 6-bromo-3-fluoro-N-methylpyridine-2-amine (29.2 mg, 142 μmol, 6%) as a colorless oil.
[1114] MS:m / z 205.00(M+H) + .
[1115] [Refer to Example 32]
[1116] 4-Chloro-5-fluoro-7-iodobenzo[d]oxazol-2(3H)-one (Reference Example 32)
[1117] (5-Chloro-4-fluoro-2-iodophenyl)tert-butyl carbonate (intermediate 32A)
[1118] To a mixture of 5-chloro-4-fluoro-2-iodophenol (2.13 g, 7.81 mmol) and 4-dimethylaminopyridine (47.7 mg, 391 μmol) in dichloromethane (43 mL), di-tert-butyl dicarbonate (2.05 g, 9.38 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–4%) to give the title compound (2.48 g, 6.64 mmol, 85%) as a colorless oil.
[1119] 1 H-NMR(CDCl3): 7.59(1H,d,J=7.8Hz), 7.24(1H,d,J=6.9Hz), 1.58(9H,s).
[1120] 2-Chloro-3-fluoro-6-hydroxy-5-iodobenzoate tert-butyl ester (intermediate 32B)
[1121] Under a nitrogen atmosphere and at -78°C, lithium diisopropylamino (3.65 mL, 7.31 mmol, 2 M) was added dropwise over 5 minutes to a THF (19 mL) coolant containing 2.48 g (6.64 mmol) of (5-chloro-4-fluoro-2-iodophenyl) tert-butyl carbonate. The resulting mixture was stirred at the same temperature for 1 hour, then gradually heated to room temperature and stirred for 2 hours. The reaction was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 0%–4%) to give tert-butyl 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoate (1.63 g, 4.37 mmol, 66%) as a pale yellow oil.
[1122] 1 H-NMR (CDCl3) δ: 11.69 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 1.64 (9H, s).
[1123] 2-Chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid (intermediate 32C)
[1124] TFA (10 mL) was added to a solution of tert-butyl 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoate (1.63 g, 4.37 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid (1.32 g, 4.18 mmol, 96%) as a brown solid, which was used in the next step without further purification.
[1125] MS: m / z 316.90 (M+H) + .
[1126] 4-Chloro-5-fluoro-7-iodobenzo[d]oxazol-2(3H)-one (Reference Example 32)
[1127] Triethylamine (0.698 mL, 5.01 mmol) and diphenyl azide phosphate (0.943 mL, 4.39 mmol) were added to a mixture of 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid (1.32 g, 4.18 mmol) in toluene (26 mL). The mixture was heated at 110 °C for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 17%–38%) to give 4-chloro-5-fluoro-7-iodobenzo[d]oxazol-2(3H)-one (964 mg, 3.08 mmol, 74%) as a white solid.
[1128] MS: m / z 313.90 (M+H) + .
[1129] [Refer to Example 33]
[1130] 4-Chloro-5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 33)
[1131] A mixture of 4-chloro-5-fluoro-7-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (265 mg, 597 μmol), bis(pinacol)diboron (227 mg, 896 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (43.7 mg, 59.7 μmol), and potassium acetate (117 mg, 1.19 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 5 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure and used without further purification.
[1132] [Refer to Example 34]
[1133] 3-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine-2-amine (Ref. Example 34)
[1134] A mixture of 6-bromo-3-chloropyridin-2-amine (900 mg, 4.34 mmol), bis(pinacol)diboron (1.65 g, 6.51 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (317 mg, 434 μmol), and potassium acetate (852 mg, 8.68 mmol) in 1,4-dioxane (11 mL) was stirred at 100 °C for 4 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. Water was added to the filtrate, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1135] MS: m / z 255.10 (M+H) + .
[1136] [Refer to Example 35]
[1137] 7-Bromo-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (Reference Example 35)
[1138] 3-Bromo-2-hydroxy-6-(trifluoromethyl)benzoate tert-butyl ester (intermediate 35A)
[1139] Under a nitrogen atmosphere and at -78°C, lithium diisopropylamino (4.84 mL, 9.67 mmol, 2 M) was added dropwise over 5 minutes to a THF (23 mL) coolant containing 3.00 g (8.79 mmol) of 2-bromo-5-(trifluoromethyl)phenyl tert-butyl carbonate. The resulting mixture was stirred at the same temperature for 1 hour, then gradually heated to room temperature and stirred for 2 hours. The reaction was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give tert-butyl 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoate (2.48 g, 7.28 mmol, 83%) as a pale yellow oil.
[1140] 1 H-NMR (CDCl3) δ: 11.15 (1H, s), 7.73 (1H, d, J = 8.7Hz), 7.17 (1H, d, J = 8.4Hz), 1.61 (9H, s).
[1141] 3-Bromo-2-hydroxy-6-(trifluoromethyl)benzoic acid (intermediate 35B)
[1142] TFA (10 mL) was added to a solution of tert-butyl 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoate (2.48 g, 7.28 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoic acid as a pale yellow solid, which was used in the next step without further purification.
[1143] MS: m / z 284.90 (M+H) + .
[1144] 7-Bromo-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (Reference Example 35)
[1145] Triethylamine (1.22 mL, 8.73 mmol) and diphenyl azide phosphate (1.64 mL, 7.64 mmol) were added to a mixture of 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoic acid (2.07 g, 7.28 mmol) in toluene (41 mL). The mixture was heated at 110 °C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give 7-bromo-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (1.25 g, 4.45 mmol, 61%) as a white solid.
[1146] MS:m / z 282.00(M+H) + .
[1147] 1 H-NMR (DMSO-d6) δ: 12.63 (1H, s), 7.48 (1H, d, J = 8.7Hz), 7.40 (1H, d, J = 8.7Hz).
[1148] [Refer to Example 36]
[1149] 6-Bromo-N-cyclopropyl-3-fluoropyridine-2-amine (Reference Example 36)
[1150] A mixture of 6-bromo-2-chloro-3-fluoropyridine (500 mg, 2.38 mmol), cyclopropylamine (136 mg, 2.38 mmol), and DIEA (1.2 mL, 7.13 mmol) in DMSO (5 mL) was heated at 100 °C for 4 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 7%–28%) to give the title compound (444 mg, 1.92 mmol, 81%) as a white solid.
[1151] MS:m / z 230.90(M+H) + .
[1152] [Refer to Example 37]
[1153] 4-Fluoro-7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 37)
[1154] 7-Bromo-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 37)
[1155] To a DMF (32 mL) suspension of 7-bromo-4-fluorobenzo[d]oxazol-2(3H)-one (3.00 g, 12.9 mmol) and potassium carbonate (3.57 g, 25.9 mmol), 2-(chloromethoxy)ethyltrimethylsilane (3.23 g, 19.4 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 8%–29%) to give 7-bromo-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (4.79 g, 13.2 mmol, quantitative yield) as a colorless oil.
[1156] 1 H-NMR (CDCl3) δ: 7.24 (1H, dd, J = 9.1, 4.6Hz), 6.92 (1H, t, J = 9.6Hz), 5.35 (2H, s), 3.70 (2H, t, J = 8.2Hz), 0.97 (2H, t, J = 8.2Hz), 0.00 (9H, s).
[1157] 4-Fluoro-7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 37)
[1158] A mixture of 7-bromo-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (4.68 g, 12.9 mmol), bis(pinacol)diboron (3.61 g, 14.2 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (473 mg, 647 μmol), and potassium acetate (2.54 g, 25.9 mmol) in 1,4-dioxane (32 mL) was heated at 100 °C for 3.5 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one, a brown paste, which was used in the next step without further purification.
[1159] 1 H-NMR(CDCl3)δ:7.51(1H,dd,J=8.7,5.5Hz),6.99(1H,dd,J=10.1,8.7Hz),5.38 (2H,s),3.69(2H,t,J=8.2Hz),1.30(12H,s),0.97(2H,t,J=8.2Hz),0.00(9H,s).
[1160] [Refer to Example 38]
[1161] 7-Bromo-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one (Reference Example 38)
[1162] Triethylamine (166 μL, 1.20 mmol) and diphenyl azidophosphate (225 μL, 1.05 mmol) were added to a mixture of 3-bromo-6-(difluoromethyl)-2-hydroxybenzoic acid (265.9 mg, 996 μmol) in toluene (5 mL). The mixture was heated at 110 °C for 2 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 23% to 44%) to give 7-bromo-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one (81.1 mg, 307 μmol, 31%) as a pale yellow solid.
[1163] MS: m / z 263.90 (M+H) + .
[1164] [Refer to Example 39]
[1165] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-4-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 39)
[1166] 7-Bromo-4-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 39)
[1167] To a DMF (7 mL) suspension of 7-bromo-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (814 mg, 2.89 mmol) and potassium carbonate (798 mg, 5.77 mmol), 2-(chloromethoxy)ethyltrimethylsilane (722 mg, 4.33 mmol) was added and the mixture was stirred at room temperature for 2.5 h. Water was added to the mixture and it was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 1%–22%) to give the title compound (464 mg, 1.13 mmol, 39%) as a colorless oil.
[1168] 1H-NMR (CDCl3) δ: 7.42 (1H, d, J = 9.2Hz), 7.39 (1H, d, J = 9.2Hz), 5.42 (2H, s), 3.69 (2H, t, J = 8.0Hz), 0.95 (2H, t, J = 8.0Hz), 0.00 (9H, s).
[1169] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-4-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 39)
[1170] A mixture of 7-bromo-4-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (157 mg, 381 μmol), pinacol diboronate (145 mg, 571 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride CH2Cl2 adduct (31.1 mg, 38.1 μmol), and potassium acetate (74.7 mg, 762 μmol) in 1,4-dioxane (1 mL) was heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.
[1171] [Refer to Example 40]
[1172] 5-Chloro-2-(2,2-difluoroethoxy)-3-(difluoromethyl)pyrazine (Reference Example 40)
[1173] 3-Bromo-5-chloro-2-(2,2-difluoroethoxy)pyrazine (Intermediate 40A)
[1174] Under a nitrogen atmosphere and at 0 °C, DIAD (1.50 mL, 3.10 mmol) was added dropwise to a stirred mixture of 3-bromo-5-chloropyrazine-2-ol (500 mg, 2.38 mmol), 2,2-difluoroethane-1-ol (392 mg, 4.77 mmol), and PPh3 (814 mg, 3.10 mmol) in 10 mL of THF. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography (EtOAc / hexane = 0%–1%) to give the desired compound (500 mg, 76%) as a colorless liquid.
[1175] 1 H-NMR (DMSO-d6) δ: 8.43 (1H, s), 6.42 (1H, tt, J = 54.0, 3.2Hz), 4.71-4.61 (2H, m).
[1176] 5-Chloro-2-(2,2-difluoroethoxy)-3-vinylpyrazine (Intermediate 40B)
[1177] Cs₂CO₃ (1.19 g, 3.65 mmol) was added to a stirred solution of 1,4-dioxane (5 mL) of 3-bromo-5-chloro-2-(2,2-difluoroethoxy)pyrazine (500 mg, 1.83 mmol) and pinacol ester of vinylboronate (844 mg, 3.65 mmol). The reaction mixture was degassed under argon for 10 min. The Pd(dppf)Cl₂-CH₂Cl₂ adduct was added to the reaction mixture, and the mixture was heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated to dryness. The crude product was purified by column chromatography (EtOAc / hexane = 0%–1%) to give the desired compound (380 mg, 94%) as a pale yellow liquid.
[1178] 1 H-NMR(DMSO-d6)δ:8.30(1H,s),6.91(1H,dd,J=16.0,12.0Hz),6.60-6.32(1H,m),6.11-5.75(2H,m),4.70-4.61(2H,m).
[1179] 6-Chloro-3-(2,2-difluoroethoxy)pyrazine-2-carboxaldehyde (intermediate 40C)
[1180] To a stirred solution of 5-chloro-2-(2,2-difluoroethoxy)-3-vinylpyrazine (500 mg, 2.26 mmol) in acetone-H₂O (10:1, 10 mL), NaIO₄ (1.90 g, 9.06 mmol) and K₂O₅SO₄·2H₂O (41.8 mg, 0.11 mmol) were added, respectively. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with Na₂S₂O₃ solution and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water and brine, dried over Na₂SO₄, and evaporated to dryness. The crude product was purified by column chromatography (EtOAc / hexane = 5%–7%) to give the desired compound (120 mg, 24%) as a pale yellow liquid.
[1181] 1 H-NMR(DMSO-d6)δ:10.04(1H,s),8.71(1H,s),6.57-6.31(1H,m),4.78-4.70(2H,m).
[1182] 5-Chloro-2-(2,2-difluoroethoxy)-3-(difluoromethyl)pyrazine (Reference Example 40)
[1183] DAST (500 μL, 3.59 mmol) was added to a stirred solution of 6-chloro-3-(2,2-difluoroethoxy)pyrazine-2-carboxaldehyde (400 mg, 1.79 mmol) in CH₂Cl₂ (7 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with CH₂Cl₂, slowly poured into ice-cold water, and extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated. The crude product was purified by column chromatography (using hexane as eluent) to give the title compound (300 mg, 68%) as a pale yellow liquid.
[1184] 1 H-NMR (DMSO-d6) δ: 8.64 (1H, s), 7.07 (1H, t, J = 52.0 Hz), 6.55-6.28 (1H, m), 4.76-4.68 (2H, m).
[1185] [Refer to Example 41]
[1186] 5-Chloro-2-(difluoromethyl)-3-(trifluoromethyl)pyrazine (Reference Example 41)
[1187] 2-Bromo-5-chloro-3-(trifluoromethyl)pyrazine (Intermediate 41A)
[1188] CuBr2 (6.78 g, 30.4 mmol) was added to a stirred solution of 5-chloro-3-(trifluoromethyl)pyrazin-2-amine (4.00 g, 20.3 mmol) in DMF (30 mL) at room temperature, and the reaction mixture was stirred for 10 minutes. The reaction mixture was then cooled to 0 °C, and isoamyl nitrite (4.09 mL, 30.4 mmol) was added dropwise. The reaction mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was then stirred at 65 °C for another 4 hours. The reaction mixture was diluted with ethyl acetate and washed with cold water and brine. The organic layer was collected, dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by column chromatography (eluent: hexane) to give the desired compound as a colorless oil (3.20 g, 60%).
[1189] 1 H-NMR (CDCl3) δ: 8.57 (1H, s).
[1190] 5-Chloro-3-(trifluoromethyl)-2-vinylpyrazine (Intermediate 41B)
[1191] A solution of 1,4-dioxane (30 mL) of vinylboronic acid pinacol ester (1.95 mL, 11.5 mmol) and Cs₂CO₃ (6.22 g, 19.1 mmol) was degassed for 5 min. 2-Bromo-5-chloro-3-(trifluoromethyl)pyrazine (2.50 g, 9.56 mmol) and Pd(dppf)Cl₂-CH₂Cl₂ adduct (470 mg, 0.570 mmol) were added to the mixture, and the mixture was stirred at 80 °C for 3.5 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried over Na₂SO₄, and evaporated to give the crude product. The crude product was purified by column chromatography (eluent: hexane) to give the desired compound as a colorless oil (1.00 g, 50%).
[1192] 1 H-NMR (CDCl3) δ: 8.70 (1H, s), 7.09-7.03 (1H, m), 6.65 (1H, d, J = 16.8Hz), 5.78 (1H, d, J = 10.8Hz).
[1193] 5-Chloro-3-(trifluoromethyl)pyrazine-2-carboxaldehyde (intermediate 41C)
[1194] To a stirred solution of 5-chloro-3-(trifluoromethyl)-2-vinylpyrazine (1.40 g, 6.71 mmol) in acetone-H₂O (10:1, 30 mL), NaIO₄ (5.74 g, 26.9 mmol) and K₂O₅SO₄·2H₂O (0.12 g, 0.34 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with an aqueous solution of Na₂S₂O₃ and extracted with diethyl ether. The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude material was purified by column chromatography (eluent: 15% EtOAc / hexane) to give the desired compound as a pale yellow oil (800 mg, 56%).
[1195] 1 H-NMR(CDCl3)δ:10.28(1H,s,),8.95(1H,s).
[1196] 5-Chloro-2-(difluoromethyl)-3-(trifluoromethyl)pyrazine (Reference Example 41)
[1197] DAST (1.53 mL, 11.4 mmol) was added dropwise to a stirred solution of 5-chloro-3-(trifluoromethyl)pyrazine-2-carboxaldehyde (800 mg, 3.80 mmol) in DCM (10 mL) at 0 °C, and the reaction mixture was stirred from 0 °C to room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution under ice-cold conditions and extracted with diethyl ether. The organic layer was collected, washed with water and brine, dried over Na2SO4 and evaporated to give the crude product. The crude product was purified by column chromatography (eluent: hexane) to give the title compound as a pale yellow oil (300 mg, 34%).
[1198] 1 H-NMR(CDCl3)δ:8.87(1H,s),6.94(1H,t,J=53.2Hz).
[1199] [Refer to Example 42]
[1200] 5-Chloro-2-(1,1-difluoroethyl)-3-(trifluoromethyl)pyrazine (Reference Example 42)
[1201] 1-(5-chloro-3-(trifluoromethyl)pyrazin-2-yl)ethyl-1-one (intermediate 42)
[1202] Tributyl(1-ethoxyvinyl)stanane (2.56 g, 7.08 mmol) was added to a stirred solution of 1,4-dioxane (15 mL) containing 1-bromo-5-chloro-3-(trifluoromethyl)pyrazine (1.85 g, 7.08 mmol), and the reaction mixture was degassed for 5 min. Pd(PPh3)2Cl2 (0.25 g, 0.35 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated to give the crude product. The crude product was purified by column chromatography (eluent: hexane) to give an intermediate (1.2 g).
[1203] The intermediate was diluted with 1,4-dioxane (10 mL) and 2N HCl (15 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and evaporated to give the crude product. The crude product was purified by column chromatography (eluent: 10% EtOAc / hexane) to give the desired compound as a colorless oil (1.0 g, 62%).
[1204] 1 H-NMR(CDCl3)δ:8.76(1H,s),2.69(3H,s).
[1205] 5-Chloro-2-(1,1-difluoroethyl)-3-(trifluoromethyl)pyrazine (Reference Example 42)
[1206] A mixture of 1-(5-chloro-3-(trifluoromethyl)pyrazin-2-yl)ethyl-1-one (1.00 g, 4.45 mmol) and DAST (15 mL) was stirred at 40 °C for 20 hours. The reaction mixture was cooled to 0 °C and poured into a saturated NaHCO3 solution under ice-cold conditions. The mixture was extracted with diethyl ether and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to give the crude product. The crude product was purified by column chromatography (eluent: hexane) to give the title compound as a pale yellow oil (500 mg, 45%).
[1207] 1 H-NMR (CDCl3) δ: 8.77 (1H, s), 2.07 (3H, t, J=18.6Hz).
[1208] [Refer to Example 43]
[1209] 2-Bromo-5-(cyclopropyldifluoromethyl)pyrazine (Reference Example 43)
[1210] (5-Bromopyrazin-2-yl)(cyclopropyl)methyl ketone (intermediate 43)
[1211] Under a nitrogen atmosphere and at 0 °C, cyclopropylmagnesium bromide (0.5 M THF solution, 54.0 mL, 27.1 mmol) was added to a stirred solution of 5-bromopyrazine-2-carboxynitrile (1.00 g, 5.43 mmol) in anhydrous THF (15 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na₂SO₄ and evaporated to give the crude product. The crude product was purified by column chromatography (EtOAc / hexane = 10%–12%) to give the desired compound (450 mg, 37%).
[1212] 1 H-NMR(CDCl3)δ:8.95(1H,s),8.75(1H,s),3.35-3.28(1H,m),1.30-1.27(2H,m),1.16-1.13(2H,m).
[1213] 2-Bromo-5-(cyclopropyldifluoromethyl)pyrazine (Reference Example 43)
[1214] In a sealed tube under a nitrogen atmosphere, DAST (3.10 mL, 19.9 mmol) was added to (5-bromopyrazin-2-yl)(cyclopropyl) methyl ketone (450 mg, 1.98 mmol). The reaction mixture was heated at 45 °C for 2 days. The reaction mixture was slowly poured into ice-cold water and extracted with EtOAc (2 × 60 mL). The combined organic layers were washed with brine (2 × 60 mL), dried over Na₂SO₄, and evaporated. The crude product was purified by column chromatography (EtOAc / hexane = 1%–2%) to give the title compound as a pale yellow liquid (300 mg, 60%).
[1215] 1 H-NMR(CDCl3)δ:8.72(1H,s),8.61(1H,s),1.75-1.68(1H,m),0.83-0.82(2H,m),0.72-0.70(2H,m).
[1216] [Refer to Example 44]
[1217] 5-Chloro-3-(difluoromethyl)-2-(2,2,2-trifluoroethoxy)pyrazine (Reference Example 44)
[1218] 3-Bromo-5-chloro-2-(2,2,2-trifluoroethoxy)pyrazine (Intermediate 44A)
[1219] To a stirred solution of 3-bromo-5-chloropyrazine-2-ol (3.00 g, 14.33 mmol) in CH3CN (20 mL), Cs2CO3 (11.6 g, 35.8 mmol) and ethyl trifluoromethanesulfonate (4.13 mL, 28.7 mmol) were added, respectively. The reaction mixture was stirred at 50 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by column chromatography (EtOAc / hexane = 0%–1%) to give the desired compound (1.60 g, 38%) as a colorless liquid.
[1220] 1 H-NMR (DMSO-d6) δ: 8.47 (1H, s), 5.08 (2H, q, J = 8.8Hz).
[1221] 5-Chloro-2-(2,2,2-trifluoroethoxy)-3-vinylpyrazine (Intermediate 44B)
[1222] Cs₂CO₃ (4.47 g, 13.7 mmol) was added to a stirred solution of 3-bromo-5-chloro-2-(2,2,2-trifluoroethoxy)pyrazine (2.00 g, 6.86 mmol) and pinacol ester of vinylboronate (2.10 g, 13.7 mmol) in 1,4-dioxane (25 mL). The mixture was degassed under argon for 10 min. The Pd(dppf)Cl₂CH₂Cl₂ adduct was added and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated to dryness to give a crude product. The crude product was purified by column chromatography (with hexane as eluent) to give the desired compound (1.40 g, 87%) as a pale yellow liquid.
[1223] 1 H-NMR (DMSO-d6) δ: 8.33 (1H, s), 6.91 (1H, dd, J = 17.7, 10.1Hz), 6.41 (1H, d, J = 17.4Hz), 5.79 (1H, d, J = 11.0Hz), 5.07 (2H, q, J = 9.0Hz).
[1224] 6-Chloro-3-(2,2,2-trifluoroethoxy)pyrazin-2-carboxaldehyde (intermediate 44C)
[1225] At room temperature, NaIO4 (5.01 g, 23.5 mmol) was added to a stirred solution of 5-chloro-2-(2,2,2-trifluoroethoxy)-3-vinylpyrazine (1.40 g, 5.87 mmol) in acetone-H2O (10:1, 15 mL), followed by K2OsO4·2H2O (108 mg, 0.290 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with Na2S2O3 solution and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness to give the crude product. The crude product was purified by column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (650 mg, 46%) as a pale yellow liquid.
[1226] 1 H-NMR (DMSO-d6) δ: 10.02 (1H, s), 8.75 (1H, s), 5.15 (2H, q, J = 8.8Hz).
[1227] 5-Chloro-3-(difluoromethyl)-2-(2,2,2-trifluoroethoxy)pyrazine (Reference Example 44)
[1228] DAST (700 μL, 5.40 mmol) was added to a stirred solution of 6-chloro-3-(2,2,2-trifluoroethoxy)pyrazine-2-carboxaldehyde (650 mg, 2.70 mmol) in CH₂Cl₂ (8 mL). The reaction mixture was stirred at 0 °C for 1 hour. The mixture was diluted with CH₂Cl₂, slowly poured into ice-cold water, and extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated to dryness to give the crude product. The crude product was purified by column chromatography (using hexane as eluent) to give the title compound (550 mg, 77%) as a colorless oil.
[1229] 1 H-NMR (CDCl3) δ: 8.67 (1H, s), 7.08 (1H, t, J = 52.7Hz), 5.14 (2H, q, J = 8.8Hz).
[1230] [Refer to Example 45]
[1231] 2-Bromo-5-(2,2-difluorocyclopropyl)pyrazine (Reference Example 45)
[1232] 5-Bromo-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (Intermediate 45A)
[1233] NaH (2.86 g, 71.8 mmol) was added to a stirred solution of 5-bromopyrazin-2-amine (5.00 g, 28.7 mmol) in DMF (35 mL) at 0 °C under a nitrogen atmosphere, and the resulting solution was stirred for 15 min. PMB-Cl (9.74 mL, 71.8 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice-cold water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (11.1 g, 93%).
[1234] 1 H-NMR (DMSO-d6) δ: 8.14 (1H, s), 7.68 (1H, s), 7.11 (4H, d, J = 8.4Hz), 6.83 (4H, d, J = 8.5Hz), 4.66 (4H, s), 3.78 (6H, s).
[1235] N,N-bis(4-methoxybenzyl)-5-vinylpyrazine-2-amine (intermediate 45B)
[1236] PdCl2(dppf)-CH2Cl2 adduct (1.60 g, 2.05 mmol) was added to a degassed mixture of 5-bromo-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (8.50 g, 20.5 mmol), vinylboronic acid pinacol ester (3.64 g, 24.6 mmol), and Cs2CO3 (20.1 g, 61.6 mmol) in dioxane-H2O (90 mL, 4:1). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (7.56 g, 60%).
[1237] 1 H-NMR(DMSO-d6)δ:8.14(1H,s),8.01(1H,s),7.17(4H,d,J=8.5Hz),6.87(4H,d,J=8.5Hz),6. 67(1H,dd,J=17.3,10.8Hz),5.94-5.89(1H,m),5.20-5.17(1H,m),4.75(4H,s),3.71(6H,s).
[1238] 5-(2,2-Difluorocyclopropyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (intermediate 45C)
[1239] In a sealed tube, under a nitrogen atmosphere and at 0°C, NaI (98.9 mg, 0.660 mmol) was added to a THF (5 mL) solution of N,N-bis(4-methoxybenzyl)-5-vinylpyrazine-2-amine (600 mg, 1.60 mmol), followed by the addition of (trifluoromethyl)trimethylsilane (0.960 mL, 6.64 mmol). The mixture was heated to 110°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (400 mg, 58%).
[1240] 1H-NMR(DMSO-d6)δ:8.13(1H,s),7.95(1H,s),7.17(4H,d,J=8.4Hz),6.87(4H,d,J=8.5H z),4.72(4H,s),3.71(6H,s),3.05-2.97(1H,m),2.05-2.01(1H,m),1.92-1.87(1H,m).
[1241] 5-(2,2-Difluorocyclopropyl)pyrazin-2-amine (intermediate 45D)
[1242] A solution of 5-(2,2-difluorocyclopropyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (1.10 g, 2.67 mmol) in TFA-DCM (1:1, 50 mL) was stirred for 16 hours under a nitrogen atmosphere and at room temperature. TFA (10 mL) was added to the mixture and stirring was continued for another 16 hours. The reaction mixture was evaporated, cooled to 0 °C, alkalized with 1 M NaOH aqueous solution, and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 35%–40%) to give the desired compound (1.82 g, 88%).
[1243] 1 H-NMR(DMSO-d6)δ:7.93(1H,s),7.81(1H,s),6.36(2H,s),3.00-2.92(1H,m),2.04-2.00(1H,m),1.92-1.85(1H,m).
[1244] 2-Bromo-5-(2,2-difluorocyclopropyl)pyrazine (Reference Example 45)
[1245] Under a nitrogen atmosphere and at room temperature, CuBr2 (586 mg, 2.62 mmol) was added to a stirred solution of 5-(2,2-difluorocyclopropyl)pyrazin-2-amine (300 mg, 1.75 mmol) in DMF (3 mL), and the mixture was stirred for 10 min. The reaction mixture was then cooled to 0 °C, and isoamyl nitrite (0.350 mL, 2.62 mmol) was added dropwise, followed by further stirring for 10 min. The reaction mixture was heated to 65 °C and stirred for 16 h. The mixture was cooled to room temperature, diluted with cold water, and extracted with Et2O (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 0%–1%) to give the title compound as a light brown gel (80 mg, 19%).
[1246] 1 H-NMR(CDCl3)δ:8.60(1H,s),8.32(1H,s),2.90-2.83(1H,m),2.26-2.20(1H,m),1.95-1.89(1H,m).
[1247] [Refer to Example 46]
[1248] 2-Bromo-5-(2,2-difluoro-1-methylcyclopropyl)pyrazine (Reference Example 46)
[1249] N,N-bis(4-methoxybenzyl)-5-(prop-1-en-2-yl)pyrazin-2-amine (intermediate 46A)
[1250] PdCl2 (dppf) (1.50 g, 2.05 mmol) was added to a degassed solution of 5-bromo-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (8.50 g, 20.5 mmol), potassium isopropenyltrifluoroborate (3.64 g, 24.6 mmol), and Cs2CO3 (20.1 g, 61.6 mmol) in toluene-THF-H2O (90 mL, 2.5:2.5:1). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 × 120 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (7.10 g, 92%) as a pale yellow viscous oil.
[1251] 1 H-NMR(CDCl3)δ:8.30(1H,s),7.94(1H,s),7.13(4H,d,J=8.4Hz),6.84(4H,d ,J=8.4Hz),5.70(1H,s),5.09(1H,s),4.72(4H,s),3.78(6H,s),2.14(3H,s).
[1252] 5-(2,2-Difluoro-1-methylcyclopropyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (intermediate 46B)
[1253] In a sealed tube, under a nitrogen atmosphere and at 0°C, NaI (240 mg, 1.59 mmol) was added to a stirred solution of N,N-bis(4-methoxybenzyl)-5-(prop-1-en-2-yl)pyrazin-2-amine (1.50 g, 3.99 mmol) in THF (8 mL), followed by (trifluoromethyl)trimethylsilane (2.36 mL, 16.0 mmol). The reaction mixture was stirred at 110°C for 16 hours. The mixture was cooled to room temperature, quenched with water, and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (1.50 g, 90%) as a pale yellow, viscous oil.
[1254] 1 H-NMR (CDCl3) δ: 8.12 (1H, s), 7.90 (1H, s), 7.13 (4H, d, J = 8.4Hz), 6.84 (4H, d, J = 8. 5Hz),4.69(4H,s),3.78(6H,s),2.06-1.99(1H,m),1.56(3H,s),1.39-1.33(1H,m).
[1255] 5-(2,2-Difluoro-1-methylcyclopropyl)pyrazine-2-amine (intermediate 46C)
[1256] A mixture of 5-(2,2-difluoro-1-methylcyclopropyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (3.00 g, 7.05 mmol) in TFA-CH₂Cl₂ (1:1, 50 mL) was stirred at room temperature for 16 hours. TFA (10 mL) was then added, and the reaction continued for another 24 hours. The reaction mixture was evaporated, quenched with 1 M NaOH aqueous solution, and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 35%–40%) to give the desired compound (1.00 g, 76%) as a viscous oil.
[1257] 1 H-NMR(DMSO-d6)δ:7.98(1H,s),7.82(1H,s),6.40(2H,s),2.18-2.12(1H,m),1.56-1.51(1H,s),1.48(3H,s).
[1258] 2-Bromo-5-(2,2-difluoro-1-methylcyclopropyl)pyrazine (Reference Example 46)
[1259] Under a nitrogen atmosphere and at room temperature, CuBr2 (1.80 g, 8.10 mmol) was added to a stirred solution of 5-(2,2-difluoro-1-methylcyclopropyl)pyrazin-2-amine (1.00 g, 5.40 mmol) in DMF (10 mL), and the mixture was stirred for 10 min. The reaction mixture was then cooled to 0 °C, and isoamyl nitrite (1.07 mL, 8.10 mmol) was added dropwise, followed by further stirring for 10 min. The resulting mixture was heated at 65 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with cold water, and extracted with Et2O (3 × 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 0%–1%) to give the title compound (627 mg, 46%) as a pale yellow oil.
[1260] 1 H-NMR(CDCl3)δ:8.61(1H,s),8.39(1H,s),2.28-2.21(1H,m),1.64(3H,s),1.53-1.46(1H,m).
[1261] [Refer to Example 47]
[1262] 2-Bromo-5-(1-Methylcyclopropyl)pyrazine (Reference Example 47)
[1263] N,N-bis(4-methoxybenzyl)-5-(1-methylcyclopropyl)pyrazine-2-amine (intermediate 47A)
[1264] Under an argon atmosphere and at 0°C, Et₂Zn (1M hexane solution, 24.0 mL) was added to CH₂Cl₂ (20 mL), followed by the dropwise addition of CH₂I₂ (3.20 mL, 40.0 mmol). The reaction mixture was stirred for 30 minutes. N,N-bis(4-methoxybenzyl)-5-(prop-1-en-2-yl)pyrazin-2-amine (3.00 g, 7.99 mmol), dissolved in CH₂Cl₂ (25 mL), was added dropwise to the reaction mixture. The reaction mixture was stirred at 0°C for 2.5 hours. The reaction mixture was quenched with water and extracted with CH₂Cl₂ (3 × 75 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 8%–10%) to give the desired compound (2.30 g, 73%) as a pale yellow viscous oil.
[1265] 1H-NMR(CDCl3)δ:8.09(1H,s),7.85(1H,s),7.12(4H,d,J=8.4Hz),6.82(4H,d,J= 8.4Hz),4.67(4H,s),3.77(6H,s),1.46(3H,s),1.04(2H,s),0.71-0.69(2H,m).
[1266] 5-(1-Methylcyclopropyl)pyrazin-2-amine (Intermediate 47B)
[1267] A mixture of N,N-bis(4-methoxybenzyl)-5-(1-methylcyclopropyl)pyrazin-2-amine (3.00 g, 7.70 mmol) in TFA-CH2Cl2 (1:1, 60 mL) was stirred from 0 °C to room temperature for 16 hours. The reaction mixture was evaporated, cooled to 0 °C, and quenched with 1 N NaOH aqueous solution, followed by extraction with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 25%–40%) to give the desired compound (1.00 g, 87%) as a viscous oil.
[1268] 1 H-NMR(DMSO-d6)δ:7.86(1H,s),7.76(1H,s),6.07(2H,s),1.39(3H,s),0.94(2H,d,J=1.7Hz),0.65-0.63(2H,m).
[1269] 2-Bromo-5-(1-Methylcyclopropyl)pyrazine (Reference Example 47)
[1270] CuBr2 was added to a stirred solution of 5-(1-methylcyclopropyl)pyrazin-2-amine (1.30 g, 8.71 mmol) in DMF (10 mL) under a nitrogen atmosphere and at room temperature, and the mixture was stirred for 10 min. The reaction mixture was then cooled to 0 °C, and isoamyl nitrite (1.70 mL, 13.1 mmol) was added dropwise, followed by further stirring for 10 min. The reaction mixture was then heated to room temperature at 65 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with cold water, and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography (EtOAc / hexane = 0%–1%) to give the title compound (720 mg, 38%) as a pale yellow oil.
[1271] 1H-NMR(CDCl3)δ:8.47(1H,s),8.31(1H,s),1.52(3H,s),1.24(2H,s),0.95-0.88(2H,m).
[1272] [Refer to Example 48]
[1273] 4,6-Difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Reference Example 48)
[1274] A mixture of 7-bromo-4,6-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (732 mg, 1.93 mmol), bis(pinacol)diboron (587 mg, 2.31 mmol), PdCl2(dppf)-CH2Cl2 adduct (157 mg, 193 μmol), and potassium acetate (378 mg, 3.85 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 4 hours. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.
[1275] [Refer to Example 49]
[1276] 4-Bromo-7-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Reference Example 49)
[1277] 2-Amino-3-bromo-6-(trifluoromethyl)benzoic acid (intermediate 49)
[1278] A mixture of 2-amino-6-(trifluoromethyl)benzoic acid (1.00 g, 4.87 mmol) and N-bromosuccinimide (954 mg, 5.36 mmol) in acetic acid (10 mL) was stirred at room temperature for 15 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with a saturated aqueous solution of NaHCO3 and brine, dried over MgSO4, and concentrated under vacuum. Heptane was added to the residue, and the mixture was sonicated. The precipitate was collected by filtration, and the solid was dried under high vacuum to give the desired compound and the unwanted isomer (724 mg).
[1279] MS:m / z 283.90(M+H) + .
[1280] 4-Bromo-7-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Reference Example 49)
[1281] Triethylamine (533 μL, 3.82 mmol) and diphenyl azide phosphate (604 μL, 2.80 mmol) were added to a stirred solution of the above mixture (724 mg, 2.55 mmol) in toluene (10 mL). The mixture was heated at 110 °C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 58%–79%) to give the title compound (172 mg, 0.612 mmol, 24% yield in two steps) as a yellow solid.
[1282] MS:m / z 280.90(M+H) + .
[1283] [Refer to Examples 50 and 51]
[1284] 6-Chloro-2-(methylamino)nicotinonitrile (Reference Example 50)
[1285] 6-Chloro-2-(dimethylamino)nicotinonitrile (Reference Example 51)
[1286] Iodomethane (89.6 μL, 1.43 mmol) was added to a DMF (3 mL) solution of 2-amino-6-chloronicotinonitrile (200 mg, 1.30 mmol) and sodium hydride (62.5 mg, 60 wt%, 1.56 mmol). The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 9%–30% EtOAc / heptane) to give 6-chloro-2-(methylamino)nicotinonitrile (44.3 mg, 264 μmol, 20%) and 6-chloro-2-(dimethylamino)nicotinonitrile (58.1 mg, 320 μmol, 25%).
[1287] MS:m / z 168.00(M+H) + (See Example 50)
[1288] MS:m / z 182.00(M+H) + (See Example 51)
[1289] [Refer to Example 52]
[1290] 2-((6-bromo-3-chloropyridin-2-yl)amino)acetonitrile (Reference Example 52)
[1291] A mixture of 6-bromo-3-chloro-2-fluoropyridine (350 mg, 1.66 mmol), aminoacetonitrile hydrochloride (185 mg, 2.00 mmol), and DIEA (869 μL, 4.99 mmol) in DMSO (3 mL) was stirred at 100 °C for 3 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The solution was purified directly by column chromatography (silica gel, eluted with 25%–46% EtOAc / heptane) to give 2-((6-bromo-3-chloropyridin-2-yl)amino)acetonitrile (272 mg, 1.10 mmol, 66%) as a white solid.
[1292] MS: m / z 245.90 (M+H) + .
[1293] [Refer to Example 53]
[1294] 2-(6-bromo-3-chloropyridin-2-yl)acetonitrile (Reference Example 53)
[1295] 2-(6-bromo-3-chloropyridin-2-yl)-2-cyanoacetic acid tert-butyl ester (intermediate 53)
[1296] 2-Methyl-2-propylcyanoacetate (242 mg, 1.71 mmol) was added to a 5 mL solution of sodium hydride (143 mg, 60 wt%, 3.56 mmol) in DMF. After stirring at room temperature for 30 minutes, 6-bromo-3-chloro-2-fluoropyridine (300 mg, 1.43 mmol) was added to the reaction mixture. The mixture was stirred at 60 °C for 16 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 0%–7% EtOAc / heptane) to give the desired compound (413 mg, 1.25 mmol, 87%) as a yellow oil.
[1297] MS: m / z 274.90 (M+H) + -tBu.
[1298] 2-(6-bromo-3-chloropyridin-2-yl)acetonitrile (Reference Example 53)
[1299] TFA (2 mL) was added to a stirred solution of tert-butyl 2-(6-bromo-3-chloropyridin-2-yl)-2-cyanoacetate (413 mg, 1.25 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was then concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 19%–39% EtOAc / heptane) to give the title compound (150 mg, 648 μmol, 52%) as a colorless oil.
[1300] MS:m / z 230.90(M+H) + .
[1301] [Refer to Example 54]
[1302] 6-Zazaspiro[2.5]octane-4-carboxylonitrile (Reference Example 54)
[1303] 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-4-carboxylic acid (intermediate 54A)
[1304] To a stirred solution of 6-(tert-butyl)-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylic acid ester (873 mg, 3.24 mmol) in methanol (5 mL) and THF (5 mL), 10 mL of 2 M NaOH aqueous solution was added. The mixture was stirred at room temperature for 20 hours. The mixture was neutralized with 1 N HCl aqueous solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was used in the next reaction without further purification.
[1305] MS:m / z 200.10(M+H) + -tBu.
[1306] 4-Carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (intermediate 54B)
[1307] The mixture of crude ammonium chloride (347 mg, 6.48 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.84 g, 4.86 mmol), and triethylamine (1.81 mL, 13.0 mmol) in DMF (10 mL) was stirred at room temperature for 1.5 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 100% EtOAc) to give a semi-pure desired compound (824 mg, 3.24 mmol, 100%) as a pale yellow gel.
[1308] MS:m / z 199.10(M+H) + -tBu.
[1309] 4-Cyano-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (intermediate 54C)
[1310] At 0 °C, trifluoroacetic anhydride (1.13 mL, 8.10 mmol) was added to a 20 mL solution of 4-carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (824 mg, 3.24 mmol) and triethylamine (2.26 mL, 16.2 mmol). The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was used in the next step of the reaction without further purification.
[1311] MS:m / z 181.10(M+H) + -tBu.
[1312] 6-Zazaspiro[2.5]octane-4-carboxylonitrile (Reference Example 54)
[1313] At room temperature, a 10 mL solution of 1,4-dioxane in 4 M HCl was added to a 2 mL solution of the crude product mixture. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum. The residue was filtered through an SCX filter to obtain the crude product 6-azaspiro[2.5]octane-4-carboxylonitrile. This crude product was used in the next step of the reaction without further purification.
[1314] [Example 1-1]
[1315] 3-Chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine (1-1)
[1316] A mixture of 3,5-dichloro-2-(difluoromethyl)pyrazine (2.33 g, 11.7 mmol), 2-(2-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (3.37 g, 11.7 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (428 mg, 585 μmol), and sodium carbonate (2.48 g, 23.4 mmol) in 1,4-dioxane (30 mL) / water (6 mL) was stirred at 100 °C for 6 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–14%) to give the title compound (1.67 g, 5.15 mmol, 44%) as a white solid.
[1317] MS:m / z 325.00(M+H) + .
[1318] 1 H-NMR (CDCl3) δ: 9.04 (1H, s), 7.97 (1H, dd, J = 8.7, 6.4Hz), 7.12 (1H, ddd, J = 9.5, 7.0, 1.7Hz), 7.06-6.80 (2H, m), 6.57 (1H, t, J = 72.5Hz).
[1319] Compounds 1-2 to 1-122 shown in Table 1 below were synthesized according to the synthetic method described in Examples 1-1. Analytical data are shown in Table 2 below.
[1320] Table 1
[1321] Table 2
[1322] [Example 2-1]
[1323] 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one (2-1)
[1324] A mixture of 5-chloro-2,3-bis(difluoromethyl)pyrazine (50.0 mg, 233 μmol), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (99.2 mg, 233 μmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (17.1 mg, 23.3 μmol), and sodium carbonate (49.4 mg, 466 μmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was stirred at 100 °C for 1.5 h. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure.
[1325] The crude product and TFA (1 mL) were stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. 2 M NH3 / methanol (2 mL) was added to the residue, and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (31.0 mg, 89.1 μmol, 38%, step 2) as a brown solid.
[1326] MS: m / z 348.07 (M+H) + .
[1327] 1 H-NMR (DMSO-d6) δ: 12.68 (1H, s), 9.47 (1H, s), 7.87 (1H, d, J = 8.7Hz), 7.48 (1H, d, J = 8.8Hz), 7.40 (1H, t, J = 52.8Hz), 7.39 (1H, t, J = 52.8Hz).
[1328] Compounds 2-2 to 2-93 shown in Table 3 were synthesized according to the synthetic method described in Example 2-1. Analytical data are shown in Table 4 below.
[1329] Table 3
[1330] Table 4
[1331] [Example 3-1]
[1332] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (3-1)
[1333] To a solution of 2-bromo-5-(difluoromethoxy)pyrazine (50.0 mg, 222 μmol) and 7-bromo-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (62.7 mg, 222 μmol) in 1,4-dioxane (1 mL), hexamethyldistin (109 mg, 333 μmol) and tetrakis(triphenylphosphine)palladium(O) (25.7 mg, 22.2 μmol) were added. The mixture was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (19.0 mg, 54.7 μmol, 25%) as a grayish-white solid.
[1334] MS: m / z 348.09 (M+H) + .
[1335] 1 H-NMR (DMSO-d6) δ: 12.59 (1H, s), 8.94 (1H, d, J = 1.4Hz), 8.78 (1H, d, J = 1.4Hz), 7.80 (1H, t, J = 71.6Hz), 7.87 (1H, d, J = 8.2Hz), 7.62 (1H, d, J = 8.7Hz).
[1336] Compounds 3-2 to 3-77 shown in Table 5 were synthesized according to the synthetic method described in Example 3-1. Analytical data are shown in Table 6 below.
[1337] Table 5
[1338] Table 6
[1339] [Example 4-1]
[1340] 4-(5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4-1)
[1341] To a solution of 2-(difluoromethyl)-5-(trimethyltinyl)pyrazine (89.0 mg, 304 μmol) and 4-bromo-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (70.2 mg, 304 μmol) in 1,4-dioxane (1 mL), tetra(triphenylphosphine)palladium(0) (17.6 mg, 15.2 μmol) was added. The mixture was stirred at 100 °C for 6 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (8.10 mg, 28.9 μmol, 10%) as a pale yellow solid.
[1342] MS:m / z 281.01(M+H) + .
[1343] 1 H-NMR(DMSO-d6)δ:11.51(1H,s),11.05(1H,s),9.36(1H,s),8.94(1H,s),7.78(1H,dd,J=8.9,4.8Hz),7.18(1H,t,J=54.4Hz),7.08-7.03(1H,m).
[1344] Compounds 4-2 to 4-14 shown in Table 7 were synthesized according to the synthetic method described in Example 4-1. Analytical data are shown in Table 8 below.
[1345] Table 7
[1346] Table 8
[1347] [Examples 5-1, 5-2]
[1348] 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane (5-1)
[1349] 4-(6-chloro-5-(1-fluorovinyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane (5-2)
[1350] A mixture of 3,5-dichloro-2-(1,1-difluoroethyl)pyrazine (1.03 g, 4.82 mmol), 7,7-difluoro-4-azaspiro[2.5]octane hydrochloride (885 mg, 4.82 mmol), and DIEA (3.3 mL, 19.3 mmol) in DMSO (10 mL) was stirred at 150 °C for 6 hours. After cooling to room temperature, the crude mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 0%–19%) to give 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane (5–1) (872 mg, 2.69 mmol, 56%) as a pale yellow oil. The portion containing byproducts was purified by HPLC to obtain 4-(6-chloro-5-(1-fluorovinyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane (5-2) (3.26 mg, 10.7 μmol, 0.2%), which is a light yellow solid.
[1351] MS:m / z 324.00(M+H) + [5-1]
[1352] MS:m / z 304.06(M+H) + [5-2]
[1353] 1 H-NMR (CDCl3) δ: 8.31 (1H, s), 2.05 (3H, t, J = 18.5 Hz), 2.00 (3H, s), 1.26 (2H, s), 1.04 (4H, s), 0.87 (1H, d, J = 6.9 Hz). [5-1]
[1354] 1H-NMR (DMSO-d6) δ: 8.48 (1H, s), 5.28 (1H, dd, J = 38.0, 3.6 Hz), 5.20 (1H, dd, J = 10.0, 3.6 Hz), 2.04-1.98 (4H, m), 0.99 (4H, m). [5-2]
[1355] Compounds 5-3 to 5-61 shown in Table 9 were synthesized according to the synthetic method described in Example 5-1. Analytical data are shown in Table 10.
[1356] Table 9
[1357] Table 10
[1358] [Examples 5-62]
[1359] 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine (5-62)
[1360] A mixture of 2-bromo-5-(difluoromethoxy)pyrazine (100 mg, 444 μmol), 4,4-difluoropiperidine hydrochloride (91.1 mg, 578 μmol), tris(dibenzylacetone)dipalladium(0) (20.4 mg, 22.2 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (38.6 mg, 66.7 μmol), and cesium carbonate (507 mg, 1.56 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (13.0 mg, 49.1 μmol, 11%) as a yellow oil.
[1361] MS:m / z 266.10(M+H) + .
[1362] [Example 6-1]
[1363] 2-(2-Chloro-4-fluorophenyl)-5-(prop-1-en-2-yl)pyrazine (6-1)
[1364] 2-Chloro-5-(2-Chloro-4-fluorophenyl)pyrazine (1-7)
[1365] A mixture of 2-bromo-5-chloropyrazine (1.00 g, 5.17 mmol), (2-chloro-4-fluorophenyl)boronic acid (992 mg, 5.69 mmol), tetrakis(triphenylphosphine)palladium(0) (299 mg, 258 μmol), and sodium carbonate (1.10 g, 10.3 mmol) in 1,4-dioxane (13 mL) / water (2.6 mL) was stirred at 100 °C for 2 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Heptane was added to the crude residue, and the mixture was sonicated. The precipitate was collected by filtration. The collected solid was washed with heptane and dried under high vacuum to give the title compound (778 mg, 3.20 mmol, 62%) as a pale yellow solid.
[1366] MS: m / z 242.50 (M+H) + .
[1367] 1 H-NMR (DMSO-d6) δ: 8.94 (1H, d, J = 1.4Hz), 8.81 (1H, d, J = 1.4Hz), 7.73 (1H, dd, J = 8.7, 5.9Hz), 7.67 (1H, dd, J = 8.9, 2.5Hz), 7.42 (1H, td, J = 8.5, 2.4Hz).
[1368] 2-(2-Chloro-4-fluorophenyl)-5-(prop-1-en-2-yl)pyrazine (6-1)
[1369] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)pyrazine (50.0 mg, 206 μmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhexacyclopentane (51.8 mg, 309 μmol), tetra(triphenylphosphine)palladium(0) (11.9 mg, 10.3 μmol), and potassium carbonate (56.9 mg, 411 μmol) in 1,4-dioxane (1 mL) / water (0.2 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (8.20 mg) as a yellow solid.
[1370] MS: m / z 248.75 (M+H) + .
[1371] 1 H-NMR(DMSO-d6)δ:9.05(1H,d,J=1.4Hz),8.88(1H,d,J=1.4Hz),7.73(1H,dd,J=8.7,6.4Hz),7.65( 1H,dd,J=8.9,2.5Hz), 7.41(1H,td,J=8.6,2.6Hz), 6.12(1H,s), 5.51(1H,d,J=1.6Hz), 2.21(3H,s).
[1372] Compounds 6-2 to 6-6 shown in Table 11 were synthesized using the appropriate reagents according to the synthetic method described in Example 6-1. Analytical data are shown in Table 12 below.
[1373] Table 11
[1374] Table 12
[1375] [Examples 6-7, 6-8]
[1376] 2-(2-Chloro-4-fluorophenyl)-5-((trimethylsilyl)ethynyl)pyrazine (6-7)
[1377] 2-(2-Chloro-4-fluorophenyl)-5-ethynylpyrazine (6-8)
[1378] 2-(2-Chloro-4-fluorophenyl)-5-((trimethylsilyl)ethynyl)pyrazine (6-7)
[1379] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)pyrazine (100 mg, 411 μmol), trimethylsilylacetylene (52.5 mg, 535 μmol), bis(triphenylphosphine)palladium(II) dichloride (14.4 mg, 20.6 μmol), cuprous iodide (7.8 mg, 41.1 μmol), and triethylamine (172 μL, 1.23 mmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 6 hours. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 0%–21%) to give the title compound (104 mg, 342 μmol, 83%) as a pale yellow oil.
[1380] MS:m / z 305.10(M+H) + .
[1381] 1 H-NMR (CDCl3) δ: 8.91 (1H, d, J = 1.8Hz), 8.75 (1H, dd, J = 4.3, 1.6Hz), 7.64 (1H, dd, J = 8.7, 5.9Hz), 7.30-7.26 (1H, m), 7.17-7.12 (1H, m), 0.31 (9H, s).
[1382] 2-(2-Chloro-4-fluorophenyl)-5-ethynylpyrazine (6-8)
[1383] A mixture of 2-(2-chloro-4-fluorophenyl)-5-((trimethylsilyl)ethynyl)pyrazine (84.7 mg, 278 μmol) and potassium carbonate (115 mg, 834 μmol) in methanol (5 mL) was stirred at room temperature for 2 hours. The mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 10%–31%) to give the title compound (30.0 mg, 129 μmol, 46%) as a pale yellow solid.
[1384] MS:m / z 233.10(M+H) + .
[1385] 1 H-NMR(DMSO-d6)δ:8.94(1H,d,J=1.4Hz),8.92(1H,d,J=1.4Hz),7.74(1H,dd,J=8 .7, 5.9Hz), 7.67 (1H, dd, J = 8.9, 2.5Hz), 7.42 (1H, td, J = 8.5, 2.7Hz), 4.76 (1H, s).
[1386] Compounds 6-9 and 6-10, as shown in Table 13 below, were synthesized according to the synthetic methods described in Examples 6-8. Analytical data are shown in Table 14 below.
[1387] Table 13
[1388] Table 14
[1389] [Examples 6-11]
[1390] 1-(5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)ethyl-1-one (6-11)
[1391] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)pyrazine (50.0 mg, 206 μmol), tributyl(1-ethoxyvinyl)tin (96.6 mg, 267 μmol), bis(triphenylphosphine)palladium(II) dichloride (7.2 mg, 10.3 μmol), and cuprous iodide (3.9 mg, 20.6 μmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure.
[1392] 6N HCl (0.4 mL) was added to a 2 mL THF solution of the crude residue, and the mixture was stirred at room temperature for 2 hours. Then, 5 M NaOH (0.5 mL) was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (3.10 mg, 12.0 μmol, 6%) as a grayish-white solid.
[1393] MS:m / z 251.10(M+H) + .
[1394] Compounds 6-12 shown in Table 15 were synthesized according to the synthetic methods described in Examples 6-11. Analytical data are shown in Table 16.
[1395] Table 15
[1396] Table 16
[1397] [Examples 6-13]
[1398] 7-(5-acetyl-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (6-13)
[1399] 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 6-13)
[1400] A mixture of 2,5-dibromo-3-(difluoromethyl)pyrazine (200 mg, 695 μmol), 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (284 mg, 695 μmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (25.4 mg, 34.7 μmol), and sodium carbonate (147 mg, 1.39 mmol) in 1,4-dioxane (2 mL) / water (0.2 mL) was stirred at 80 °C for 4 hours. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 4%-25%) to give the title compound (35.5 mg, 72.4 μmol, 10%) as a colorless oil.
[1401] MS:m / z 490.10(M+H) + .
[1402] 7-(5-acetyl-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (6-13)
[1403] A mixture of 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (35.5 mg, 72.4 μmol), tributyl(1-ethoxyvinyl)tin (78.4 mg, 217 μmol), and [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.3 mg, 7.24 μmol) in 1,4-dioxane (1 mL) was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure.
[1404] Add 1 mL of TFA to the crude residue and stir the mixture at room temperature for 1 hour. Concentrate the mixture under reduced pressure. Add 2 mL of 2 M NH3 / methanol to the residue and stir the mixture at room temperature for 30 minutes. Concentrate the mixture under reduced pressure. Purify the crude mixture by silica gel column chromatography (EtOAc / heptane = 37%–58%) to give the title compound (4.9 mg, 15 μmol, 21%) as a pale yellow solid.
[1405] MS:m / z 324.01(M+H) + .
[1406] [Example 6-14]
[1407] 2-(2-Chloro-4-fluorophenyl)-5-isopropylpyrazine (6-14)
[1408] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)pyrazine (122 mg, 502 μmol), 1 M isopropyl magnesium chloride THF solution (602 μL, 602 μmol), and tris(2,4-pentanedione)ferric(III) (17.7 mg, 50.2 μmol) in THF (3 mL) / NMP (1 mL) was stirred at room temperature for 5 hours. 1 N HCl was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–10%) to give the title compound (24.9 mg, 99.3 μmol, 20%) as a white solid.
[1409] MS:m / z 251.15(M+H) + .
[1410] 1 H-NMR(DMSO-d6)δ:8.82(1H,s),8.71(1H,s),7.69(1H,dd,J=8.7,6.4Hz),7.63(1H,dd ,J=8.9,2.5Hz),7.38(1H,td,J=8.5,2.3Hz),3.21-3.14(1H,m),1.30(6H,d,J=6.9Hz).
[1411] [Example 6-15]
[1412] 5-(2-Chloro-4-fluorophenyl)-2-ethyl-3-methoxypyrazine (6-15)
[1413] 2-Chloro-5-(2-Chloro-4-fluorophenyl)-3-methoxypyrazine (Intermediate 6-15)
[1414] A mixture of 5-bromo-2-chloro-3-methoxypyrazine (500 mg, 2.24 mmol), (2-chloro-4-fluorophenyl)boronic acid (468 mg, 2.69 mmol), tetrakis(triphenylphosphine)palladium (0) (129 mg, 112 μmol), and potassium carbonate (619 mg, 4.48 mmol) in 1,4-dioxane (5.6 mL) / water (1.1 mL) was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure. Ethanol was added to the crude residue and the mixture was sonicated. The precipitate was collected by filtration. The collected solid was washed with ethanol and dried under high vacuum to give the title compound (500 mg, 1.83 mmol, 82%) as a white solid.
[1415] MS:m / z 272.70(M+H) + .
[1416] 5-(2-Chloro-4-fluorophenyl)-3-methoxy-2-vinylpyrazine (6-3)
[1417] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)-3-methoxypyrazine (50 mg, 183 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (41.0 μL, 238 μmol), tetrakis(triphenylphosphine)palladium(0) (10.6 mg, 9.15 μmol), and potassium carbonate (50.6 mg, 366 μmol) in 1,4-dioxane (1 mL) / water (0.2 mL) was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (18.7 mg, 70.5 μmol, 38%) as a pale yellow solid.
[1418] MS:m / z 264.70(M+H) + .
[1419] 5-(2-Chloro-4-fluorophenyl)-2-ethyl-3-methoxypyrazine (6-15)
[1420] Add 10% palladium on carbon (5.00 mg) to a stirred solution of 5-(2-chloro-4-fluorophenyl)-3-methoxy-2-vinylpyrazine (17.0 mg, 64.2 μmol) in ethyl acetate (2 mL). Purge the solution with H₂ and stir at room temperature for 7 hours. Filter the mixture through a diatomaceous earth mat. Concentrate the filtrate under reduced pressure. Purify the residue by HPLC to give the title compound (4.30 mg, 16.1 μmol, 25%) as a white solid.
[1421] MS: m / z 267.05 (M+H) + .
[1422] [Example 6-16]
[1423] 5-(2-Chloro-4-fluorophenyl)-2-(1,1-difluoroethyl)-3-methylpyrazine (6-16)
[1424] 1-(5-(2-chloro-4-fluorophenyl)-3-methylpyrazin-2-yl)ethyl-1-one (intermediate 6-16)
[1425] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)-3-methylpyrazine (433 mg, 1.68 mmol), tributyl(1-ethoxyvinyl)tin (1.83 g, 5.05 mmol), tetrakis(triphenylphosphine)palladium(0) (97.3 mg, 84.2 μmol), and cuprous iodide (48.1 mg, 253 μmol) in toluene (4 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure.
[1426] Add 1 mL of 6N HCl to a 5 mL THF solution of the crude product with stirring. Stir the mixture at room temperature for 2 hours. Add 5 M NaOH aqueous solution to the mixture and extract with EtOAc. Wash the combined organic layers with brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the crude product mixture by silica gel column chromatography (EtOAc / heptane = 0%–19%) to give the title compound (436 mg, 1.65 mmol, 98%) as a white solid.
[1427] MS:m / z 265.00(M+H) + .
[1428] 5-(2-Chloro-4-fluorophenyl)-2-(1,1-difluoroethyl)-3-methylpyrazine (6-16)
[1429] At 0 °C, 505 μL (3.85 mmol) of (diethylamino)sulfur trifluoride was added to a stirred solution of 1-(5-(2-chloro-4-fluorophenyl)-3-methylpyrazin-2-yl)ethyl-1-one (340 mg, 1.28 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 3 days. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (9.56 mg, 33.3 μmol, 3%) as a pale yellow solid.
[1430] MS: m / z 287.05 (M+H) + .
[1431] [Example 7-1]
[1432] 2-(2-Chloro-4-fluorophenyl)-5-ethoxypyrazine (7-1)
[1433] A mixture of 2-chloro-5-(2-chloro-4-fluorophenyl)pyrazine (50.0 mg, 206 μmol) and sodium ethoxide (42.0 mg, 617 μmol) in DMF (1 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, 1 N HCl was added to the mixture, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (22.7 mg, 44%) as a pale yellow solid.
[1434] MS: m / z 252.70 (M+H) + .
[1435] 1 H-NMR(DMSO-d6)δ:8.45(1H,d,J=1.4Hz),8.39(1H,d,J=1.4Hz),7.65(1H,dd,J=8.5,6.4Hz),7.60 (1H, dd, J = 8.7, 2.7Hz), 7.36 (1H, td, J = 8.5, 2.7Hz), 4.40 (2H, q, J = 7.0Hz), 1.37 (3H, t, J = 7.1Hz).
[1436] Compounds 7-2 to 7-10 shown in Table 17 were synthesized using the appropriate reagents according to the synthetic method described in Example 7-1. Analytical data are shown in Table 18 below.
[1437] Table 17
[1438] Table 18
[1439] [Examples 7-11]
[1440] 5-(2-Chloro-4-fluorophenyl)-2-iodo-3-methoxypyrazine (7-11)
[1441] Acetyl chloride (19.4 μL, 274 μmol) and sodium iodide (274 mg, 1.83 mmol) were added to a stirred solution of 2-chloro-5-(2-chloro-4-fluorophenyl)-3-methoxypyrazine (50.0 mg, 183 μmol) in acetonitrile (1 mL). The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, a saturated aqueous solution of NaHCO3 was carefully added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (21.8 mg, 59.8 μmol, 33%) as a pale yellow solid.
[1442] MS: m / z 364.85 (M+H) + .
[1443] 1 H-NMR (CDCl3) δ: 8.27 (1H, s), 7.60 (1H, dd, J = 8.7, 5.9 Hz), 7.26-7.23 (1H, m), 7.10 (1H, td, J = 8.2, 2.4 Hz), 4.04 (3H, s).
[1444] [Examples 7-12]
[1445] 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)acetic acid (7-12)
[1446] 1-(tert-butyl)-3-ethyl ester of 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)malonic acid (intermediate 7-12A)
[1447] A mixture of tert-butyl ethyl malonate (285 μL, 1.51 mmol) and sodium hydride (66.0 mg, 1.65 mmol) in DMF (3 mL) was stirred at room temperature for 30 minutes. 2-chloro-5-(4-fluoro-2-isopropoxyphenyl)pyrazine (367 mg, 1.38 mmol) was added to the mixture, and the mixture was stirred overnight at 50 °C, then heated to 80 °C and stirred for 16 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1448] MS:m / z 419.20(M+H) + .
[1449] 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)ethyl acetate (intermediate 7-12B)
[1450] Add 2 mL of TFA to a 2 mL solution of dichloromethane in the above crude product mixture and stir the mixture overnight at room temperature. Concentrate the mixture under reduced pressure. Purify the crude product mixture by silica gel column chromatography (EtOAc / heptane = 16%–37%) to give the title compound (72.3 mg, 227 μmol, 17%) as a yellow oil.
[1451] MS:m / z 319.10(M+H) + .
[1452] 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)acetic acid (7-12)
[1453] To a stirred solution of ethyl 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)acetate (72.3 mg, 227 μmol) in THF (1 mL) / methanol (1 mL), 0.4 mL of 2 M NaOH aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. 1 N HCl was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (47.4 mg, 163 μmol, 72%) as a yellow oil.
[1454] MS:m / z 291.10(M+H) + .
[1455] [Example 8-1]
[1456] 6-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylonitrile (8-1)
[1457] Under microwave irradiation, a mixture of 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine (205 mg, 631 μmol), Zn(CN)₂ (148 mg, 1.26 mmol), and [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (46.2 mg, 63.1 μmol) in DMF (3 mL) was stirred at 150 °C for 2 hours. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 11%–32%) to give the title compound (157 mg, 498 μmol, 79%) as a yellow solid.
[1458] MS:m / z 316.00(M+H) + .
[1459] 1H-NMR(CDCl3)δ:9.29(1H,s),8.03(1H,dd,J=8.7,6.4Hz),7.17(1H,ddd,J=9.3,7.0, 1.9Hz), 7.08 (1H, dd, J = 9.1, 2.7Hz), 6.91 (1H, t, J = 49.4Hz), 6.60 (1H, t, J = 68.2Hz).
[1460] Compounds 8-2 to 8-9 shown in Table 19 were synthesized according to the synthetic method described in Example 8-1. Analytical data are shown in Table 20.
[1461] Table 19
[1462] Table 20
[1463] [Example 9-1]
[1464] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-methylpyrazine (9-1)
[1465] A mixture of 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine (50.0 mg, 154 μmol), trimethylcycloboroxane (64.6 μL, 462 μmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (11.3 mg, 15.4 μmol), and potassium carbonate (42.6 mg, 308 μmol) in 1,4-dioxane (1 mL) was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (35.5 mg, 117 μmol, 76%) as a pale yellow solid.
[1466] MS: m / z 305.05 (M+H) + .
[1467] 1 H-NMR (DMSO-D6) δ: 8.88 (1H, s), 7.91 (1H, dd, J = 8.5, 6.6Hz), 7.53-7.09 (4H, m), 2.70 (3H, s).
[1468] Compounds 9-2 to 9-6 shown in Table 21 below were synthesized according to the synthetic method described in Example 9-1. Starting materials were synthesized using the above synthetic method. Analytical data are shown in Table 22 below.
[1469] Table 21
[1470] Table 22
[1471] [Example 10-1]
[1472] 4-Chloro-7-(5-(difluoromethyl)-6-ethynylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one (10-1)
[1473] 4-Chloro-7-(6-Chloro-5-(difluoromethyl)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 10-1A)
[1474] A mixture of 3,5-dichloro-2-(difluoromethyl)pyrazine (1.05 g, 5.25 mmol), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (3.35 g, 7.88 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (384 mg, 525 μmol), and sodium carbonate (1.11 g, 10.5 mmol) in 1,4-dioxane (13 mL) / water (1.3 mL) was stirred at 90 °C for 5 hours. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–21%) to give the title compound (858 mg, 1.86 mmol, 35%) as a white solid.
[1475] MS:m / z 462.10(M+H) + .
[1476] 4-Chloro-7-(5-(difluoromethyl)-6-((trimethylsilyl)ethynyl)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 10-1B)
[1477] A mixture of 4-chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (80.0 mg, 173 μmol), trimethylsilylacetylene (31 μL, 225 μmol), bis(triphenylphosphine)palladium(II) dichloride (12.1 mg, 17.3 μmol), cuprous iodide (3.3 mg, 17.3 μmol), and triethylamine (72.4 μL, 519 μmol) in 1,4-dioxane (2 mL) was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 10%–31%) to give the title compound (122 mg) containing impurities.
[1478] MS: m / z 524.20 (M+H) + .
[1479] 4-Chloro-7-(5-(difluoromethyl)-6-ethynylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one (10-1)
[1480] TFA (2 mL) was added to the obtained 4-chloro-7-(5-(difluoromethyl)-6-((trimethylsilyl)ethynyl)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (122 mg), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. 2 M NH3 / methanol (4 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (13.6 mg, 42.1 μmol, 18% yield in two steps) as a yellow solid.
[1481] MS:m / z 322.03(M+H) + .
[1482] 1 H-NMR (DMSO-d6) δ: 9.31 (1H, s), 7.62 (1H, d, J = 8.7Hz), 7.26 (1H, t, J = 53.2Hz), 7.23 (1H, d, J = 8.8Hz), 5.05 (1H, s).
[1483] Compounds 10-2 and 10-3 shown in Table 23 below were synthesized according to the synthesis method described in Example 10-1.
[1484] Table 23
[1485] [Example 11-1]
[1486] 7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one(11-1)
[1487] 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 11-1A)
[1488] A mixture of 3,5-dichloro-2-(1,1-difluoroethyl)pyrazine (300 mg, 1.41 mmol), 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (576 mg, 1.41 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (103 mg, 141 μmol), and sodium carbonate (299 mg, 2.82 mmol) in 1,4-dioxane (4 mL) / water (0.4 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 6%-27%) to give the title compound (210 mg, 456 μmol, 32%) as a pale yellow oil.
[1489] MS:m / z 460.10(M+H) + .
[1490] 7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 11-1B)
[1491] A mixture of 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (210 mg, 456 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (230 μL, 1.37 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (33.4 mg, 45.6 μmol), and potassium carbonate (189 mg, 1.37 mmol) in 1,4-dioxane (2 mL) / water (0.2 mL) was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–19%) to give the title compound (137 mg, 303 μmol, 66%) as a yellow oil.
[1492] MS: m / z 452.20 (M+H) + .
[1493] 7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one(11-1)
[1494] A mixture of 7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (21.9 mg, 48.5 μmol) and TFA (0.5 mL) was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. 1 M NH3 / methanol (2 mL) was added to the residue, and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (5.23 mg, 16.3 μmol, 34%) as a pale yellow solid.
[1495] MS: m / z 322.06 (M+H) + .
[1496] 1 H-NMR(DMSO-d6)δ:12.62(1H,s),9.12(1H,s),7.95(1H,dd,J=8.9,5.3Hz),7.34-7.26 (2H,m),6.73(1H,d,J=14.6Hz), 5.82(1H,dd,J=10.7,2.1Hz), 2.14(3H,t,J=19.7Hz).
[1497] Compounds 11-2 to 11-4 shown in Table 24 below were synthesized according to the synthetic method described in Example 11-1. Intermediates were synthesized using the above synthetic method.
[1498] Table 24
[1499] [Example 12-1]
[1500] (6-(4,4-difluoro-6-azaspiro[2.5]oct-6-yl)-3-(difluoromethyl)pyrazin-2-yl)methanol(12-1)
[1501] A mixture of 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane (90.0 mg, 291 μmol), potassium (acetoxymethyl)trifluoroborate (105 mg, 581 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (24.7 mg, 29.1 μmol), and sodium carbonate (92.4 mg, 872 μmol) in 1,4-dioxane (4 mL) / water (0.4 mL) was stirred at 110 °C for 4 days. After cooling to room temperature, the mixture was filtered through an anhydrous magnesium sulfate pad. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 28%-49%) to give the title compound (7.06 mg, 23.1 μmol, 8%) as a yellow oil.
[1502] MS:m / z 306.10(M+H) + .
[1503] [Example 13-1]
[1504] 4-Chloro-7-(5-(difluoromethyl)-6-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one (13-1)
[1505] 4-Chloro-7-(5-(difluoromethyl)-6-methoxypyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 13-1)
[1506] Potassium tert-butoxide (29.1 mg, 260 μmol) was added to a stirred methanol (2 mL) solution of 4-chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (60.0 mg, 130 μmol). The mixture was stirred overnight at 100 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1507] MS:m / z 458.10(M+H) + .
[1508] 4-Chloro-7-(5-(difluoromethyl)-6-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one (13-1)
[1509] The mixture of the crude product and TFA (1 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. 2 M NH3 / methanol (1 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (3.80 mg, 11.6 μmol, 9% yield in two steps) as a white solid.
[1510] MS: m / z 328.03 (M+H) + .
[1511] Compound 13-2 in Table 25 was synthesized according to the synthetic method described in Example 13-1. Analytical data are shown in Table 26 below.
[1512] Table 25
[1513] Table 26
[1514] [Example 13-3]
[1515] 3-Fluoro-5-(4-Fluoro-2-isopropoxyphenyl)-2-methylpyrazine (13-3)
[1516] A mixture of 3-chloro-5-(4-fluoro-2-isopropoxyphenyl)-2-methylpyrazine (40.0 mg, 142 μmol), CsF (65.0 mg, 427 μmol), 18-crown-6 ether (3.2 μL, 14.2 μmol), and tetramethylammonium chloride (1.6 mg, 14.2 μmol) in MeCN (1 mL) was stirred overnight at 60 °C. The mixture was then heated overnight at 90 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (0.85 mg, 3.2 μmol, 2%) as a colorless oil.
[1517] MS: m / z 265.15 (M+H) + .
[1518] [Example 14-1]
[1519] 7-(6-amino-5-(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one (14-1)
[1520] 4-Chloro-7-(5-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 14-1)
[1521] A mixture of 4-chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (77.5 mg, 168 μmol), (2,4-dimethoxyphenyl)methylamine (30.3 μL, 201 μmol), and DIEA (86 μL, 503 μmol) in DMF (1 mL) was stirred overnight at 100 °C. After cooling to room temperature, the mixture was passed directly through a short silica gel column and eluted with 30% EtOAc / heptane to give a semi-pure product.
[1522] MS: m / z 593.20 (M+H) + .
[1523] 7-(6-amino-5-(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one (14-1)
[1524] The mixture of semipure intermediate 14-1 and TFA (1 mL) was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. 2 M NH3 / methanol (2 mL) was added to the residue, and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (5.51 mg, 17.6 μmol, 11% yield in two steps) as a pale yellow solid.
[1525] MS: m / z 313.05 (M+H) + .
[1526] 1 H-NMR (DMSO-d6) δ: 12.53 (1H, s), 8.42 (1H, s), 7.74 (1H, d, J = 8.7Hz), 7.39 (1H, d, J = 8.7Hz), 7.05 (1H, t, J = 53.5Hz), 6.88 (2H, s).
[1527] Compounds 14-2 to 14-5 shown in Table 27 below were synthesized according to the synthetic method described in Example 14-1.
[1528] Table 27
[1529] [Example 15-1]
[1530] 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (15-1)
[1531] A mixture of 7-(5-(1,1-difluoroethyl)-6-vinylpyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (137 mg, 303 μmol), microencapsulated osmium tetroxide (38.5 mg), and sodium periodate (130 mg, 606 μmol) in 1,4-dioxane (3 mL) / H₂O (1 mL) was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth mat. Water was added to the filtrate, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
[1532] At 0°C, 119 μL (0.908 mmol) of (diethylamino)sulfur trifluoride was added to a stirred solution of the crude product in DCM (1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
[1533] Add 1 mL of TFA to the crude residue and stir the mixture at room temperature for 15 minutes. Concentrate the mixture under reduced pressure. Add 2 mL of 2 M NH3 / methanol to the residue and stir the mixture at room temperature for 15 minutes. Concentrate the mixture under reduced pressure. Purify the crude mixture by silica gel column chromatography (EtOAc / heptane = 21%–42%) to give the title compound (51.3 mg, 149 μmol, 49% yield in 3 steps) as a pale yellow solid.
[1534] MS:m / z 346.00(M+H) + .
[1535] 1 H-NMR (DMSO-d6) δ: 12.66 (1H, s), 9.39 (1H, s), 7.88 (1H, dd, J = 9.1, 5.0 Hz), 7.38 (1H, t, J = 53.6 Hz), 7.35 (1H, d, J = 9.6 Hz), 2.15 (3H, t, J = 19.7 Hz).
[1536] Compounds 15-2 to 15-6 in Table 28 below were synthesized according to the synthetic method described in Example 15-1. Starting materials were synthesized using the above synthetic method. Analytical data are shown in Table 29 below.
[1537] Table 28
[1538] Table 29
[1539] [Example 16-1]
[1540] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine (16-1)
[1541] 2-Chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine (intermediate 16-1)
[1542] DIEA (2.70 mL, 16.1 mmol) was added to an 11 mL DMF solution of 2,6-dichloropyrazine (800 mg, 5.37 mmol) and 4,4-difluoropiperidine hydrochloride (866 mg, 5.50 mmol) with stirring. The solution was stirred at 100 °C for 1 hour. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1543] MS:m / z 234.10(M+H) + .
[1544] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine (16-1)
[1545] The mixture of the above crude product and N-iodosuccinimide (1.33 g, 5.91 mmol) in acetonitrile (13 mL) was heated overnight at 80 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of Na₂S₂O₃ and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / heptane = 5%–26%) to give the title compound (832 mg, 2.31 mmol, 43% yield in two steps) as a grayish-white solid.
[1546] MS:m / z 360.00(M+H) + .
[1547] Compounds 16-2 and 16-3, as shown in Table 30 below, were synthesized using the appropriate reagents according to the synthetic method described in Example 16-1. Analytical data are shown in Table 31 below.
[1548] Table 30
[1549] Table 31
[1550] [Example 16-4]
[1551] 5,6-Dichloro-3-(5-chloropyridin-2-yl)pyrazin-2-amine (16-4)
[1552] A mixture of 6-chloro-3-(5-chloropyridin-2-yl)pyrazin-2-amine (50.0 mg, 207 μmol), acetic acid (0.2 mL), and N-chlorosuccinimide (30.5 mg, 228 μmol) in DMF (1 mL) was heated at 100 °C for 2 hours. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 14%–35%) to give the title compound (22.0 mg, 79.8 μmol, 38%) as a yellow solid.
[1553] MS:m / z 275.00(M+H) + .
[1554] 1 H-NMR (CDCl3) δ: 8.55 (1H, d, J = 2.7Hz), 8.43 (1H, d, J = 8.7Hz), 7.81 (1H, dd, J = 8.7, 2.3Hz).
[1555] [Example 17-1]
[1556] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyrazine (17-1)
[1557] A mixture of 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine (100 mg, 278 μmol) and trifluoromethyl(1,10-phenanthroline)copper(I) (261 mg, 334 μmol) in DMF (1 mL) was stirred at 100 °C for 3 days. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 26%–47%). The resulting semi-pure compound was then purified by HPLC to give the title compound (14.3 mg, 47.2 μmol, 17%) as a brown solid.
[1558] MS:m / z 302.00(M+H) + .
[1559] 1 H-NMR (CDCl3) δ: 8.02 (1H, s), 3.87 (4H, t, J = 5.7Hz), 2.15-2.05 (4H, m).
[1560] Compounds 17-2 to 17-5, as shown in Table 32 below, were synthesized according to the synthetic method described in Example 17-1. Starting materials were synthesized using the above synthetic method. Analytical data are shown in Table 33 below.
[1561] Table 32
[1562] Table 33
[1563] [Example 17-6]
[1564] 1-(3-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)ethyl-1-one (17-6)
[1565] A mixture of 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine (1.00 g, 2.78 mmol), tributyl(1-ethoxyvinyl)tin (1.21 g, 3.34 mmol), and [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (204 mg, 278 μmol) in 1,4-dioxane (9 mL) was stirred at 100 °C for 2 days. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure.
[1566] Add 2 mL of 6N HCl to a 10 mL THF solution of the crude product with stirring. Stir the mixture at room temperature for 0.5 h. Add 2 M NaOH aqueous solution to the mixture and extract with EtOAc. Wash the combined organic layers with brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the crude product mixture by silica gel column chromatography (EtOAc / heptane = 20%–41%) to give the title compound (360 mg, 1.31 mmol, 47%) as a yellow solid.
[1567] MS:m / z 276.10(M+H) + .
[1568] 1 H-NMR (DMSO-d6) δ: 8.43 (1H, s), 3.85 (4H, t, J = 5.9 Hz), 2.49 (3H, s), 2.13-2.03 (4H, m).
[1569] [Example 17-7]
[1570] 1-(3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)aceto-1-one (17-7)
[1571] 2-(difluoromethyl)-6-(4,4-difluoropiperidin-1-yl)pyrazine (intermediate 17-7A)
[1572] DIEA (0.89 mL, 5.26 mmol) was added to a stirred solution of 2-chloro-6-(difluoromethyl)pyrazine (289 mg, 1.75 mmol) and 4,4-difluoropiperidine hydrochloride (276 mg, 1.75 mmol) in DMF (4 mL). The solution was stirred at 80 °C for 3 days. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 26%–47%) to give the title compound (254 mg, 1.02 mmol, 58%) as a yellow oil.
[1573] MS:m / z 250.10(M+H) + .
[1574] 2-Chloro-3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine (intermediate 17-7B)
[1575] A mixture of 2-(difluoromethyl)-6-(4,4-difluoropiperidin-1-yl)pyrazine (254 mg, 1.02 mmol), N-chlorosuccinimide (150 mg, 1.12 mmol), and acetic acid (0.3 mL) in DMF (3 mL) was heated overnight at 80 °C. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 19%–40%) to give the title compound (144 mg, 508 μmol, 50%) as a colorless oil.
[1576] MS:m / z 284.00(M+H) + .
[1577] 1-(3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)aceto-1-one (17-7)
[1578] A mixture of 2-chloro-3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine (38.5 mg, 136 μmol), tributyl(1-ethoxyvinyl)tin (147 mg, 407 μmol), and [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (9.9 mg, 13.6 μmol) in 1,4-dioxane (1 mL) was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure.
[1579] Add 0.2 mL of 6N HCl to a 2 mL THF solution of the crude product with stirring. Stir the mixture at room temperature for 1 hour. Add a saturated aqueous solution of NaHCO3 to the mixture and extract the mixture with EtOAc. Wash the combined organic layers with brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the crude product mixture by HPLC to give the title compound (8.68 mg, 29.8 μmol, 22%) as a pale yellow solid.
[1580] MS: m / z 292.07 (M+H) + .
[1581] [Example 18-1]
[1582] 5-(2-Chloro-4-fluorophenyl)-2-iodo-3-methylpyrazine (18-1)
[1583] 5-(2-Chloro-4-fluorophenyl)-3-methylpyrazine-2-amine (Intermediate 18-1)
[1584] A mixture of 5-bromo-3-methylpyrazine-2-amine (250 mg, 1.33 mmol), (2-chloro-4-fluorophenyl)boronic acid (301 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium(0) (76.8 mg, 66.5 μmol), and potassium carbonate (368 mg, 2.66 mmol) in 1,4-dioxane (4 mL) / water (1 mL) was stirred at 100 °C for 5 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 49%–70%) to give the title compound (310 mg, 1.31 mmol, 98%) as a white solid.
[1585] MS: m / z 238.05 (M+H) + .
[1586] 5-(2-Chloro-4-fluorophenyl)-2-iodo-3-methylpyrazine (18-1)
[1587] At 0 °C, p-toluenesulfonic acid monohydrate (1.24 g, 6.53 mmol), sodium nitrite (270 mg, 3.92 mmol), and potassium iodide (867 mg, 5.22 mmol) were added to a stirred solution of 5-(2-chloro-4-fluorophenyl)-3-methylpyrazine-2-amine (310 mg, 1.31 mmol) in MeCN (6.5 mL) and H₂O (2.2 mL). The mixture was stirred at room temperature for 16 hours. An aqueous solution of Na₂S₂O₃ was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–17%). The resulting semi-pure compound was then purified by HPLC to give the title compound (16.3 mg, 46.6 μmol, 4%) as a white solid.
[1588] MS: m / z 348.89 (M+H) + .
[1589] 1 H-NMR (DMSO-d6) δ: 8.53 (1H, s), 7.70 (1H, dd, J = 8.7, 6.4 Hz), 7.64 (1H, dd, J = 8.9, 2.5 Hz), 7.40 (1H, td, J = 8.5, 2.6 Hz), 2.69 (3H, s).
[1590] Compounds 18-2 to 18-5, as shown in Table 34 below, were synthesized according to the synthetic method described in Example 18-1. Analytical data are shown in Table 35 below.
[1591] Table 34
[1592] Table 35
[1593] [Example 19-1]
[1594] 7-Chloro-4-(5-(2-fluoroprop-2-yl)pyrazin-2-yl)indoline-2-one (19-1)
[1595] 7-Chloro-4-(5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)indoline-2-one (Intermediate 19-1)
[1596] A mixture of 2-(5-chloropyrazin-2-yl)prop-2-ol (34.5 mg, 200 μmol), 7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)indoline-2-one (64.6 mg, 220 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (7.3 mg, 10.0 μmol), and potassium carbonate (55.3 mg, 400 μmol) in 1,4-dioxane (1 mL) / water (0.2 mL) was stirred overnight at 90 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 50%-80%) to give the title compound (35.7 mg, 118 μmol, 59%) as a pale yellow solid.
[1597] MS:m / z 304.00(M+H) + .
[1598] 7-Chloro-4-(5-(2-fluoroprop-2-yl)pyrazin-2-yl)indoline-2-one (19-1)
[1599] At 0 °C, 1 mL of (diethylamino)sulfur trifluoride (10.6 μL, 80.6 μmol) was added to a stirred solution of 7-chloro-4-(5-(2-hydroxypropyl-2-yl)pyrazin-2-yl)indoline-2-one (20.4 mg, 67.2 μmol) in DCM. The mixture was stirred at room temperature for 1 day. Then, 1 mL of THF and another 10.6 μL of (diethylamino)sulfur trifluoride (80.6 μmol) were added to the solution, and the mixture was stirred at room temperature for another day. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (3.70 mg, 12.1 μmol, 18%) as a grayish-white solid.
[1600] MS:m / z 306.10(M+H) + .
[1601] 1 H-NMR (DMSO-d6) δ: 10.96 (1H, s), 9.11 (1H, s), 8.91 (1H, s), 7.58 (1H, d, J = 8.4Hz), 7.44 (1H, d, J = 8.0Hz), 3.95 (2H, s), 1.73 (6H, d, J = 22.0Hz).
[1602] Compound 19-2, shown in Table 36, was synthesized according to the synthetic method described in Example 19-1 and by SEM deprotection. Analytical data are shown in Table 37.
[1603] Table 36
[1604] Table 37
[1605] [Example 20-1]
[1606] 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (20-1)
[1607] 2-(4,4-Difluoropiperidin-1-yl)-6-(trifluoromethyl)pyrazine (intermediate 20-1A)
[1608] DIEA (3.30 mL, 19.2 mmol) was added to a stirred solution of 2-chloro-6-(trifluoromethyl)pyrazine (1.00 g, 5.48 mmol) and 4,4-difluoropiperidine hydrochloride (863 mg, 5.48 mmol) in DMF (11 mL). The solution was stirred overnight at 100 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1609] MS:m / z 268.10(M+H) + .
[1610] 2-Chloro-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (intermediate 20-1B)
[1611] A mixture of 2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)pyrazine (810 mg, 3.03 mmol) and N-chlorosuccinimide (405 mg, 3.03 mmol) in DMF (6 mL) was heated at 80 °C for 3 days. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 16%–37%) to give the title compound (590 mg, 1.96 mmol, 65%) as a pale yellow solid.
[1612] MS:m / z 302.10(M+H) + .
[1613] 5-(4,4-Difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazin-2(1H)-one (intermediate 20-1C)
[1614] A mixture of 2-chloro-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (200 mg, 663 μmol) and acetoxyxamic acid (149 mg, 1.99 mmol) in DMSO (2 mL) was heated at 70 °C for 2 days. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat, and water was added to the filtrate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 60%–81%) to give the title compound (51.7 mg, 183 μmol, 28%) as a yellow solid.
[1615] MS:m / z 284.00(M+H) + .
[1616] 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (20-1)
[1617] Difluoromethyl trifluoromethanesulfonate (110 mg, 548 μmol) was added to a stirred solution of 5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazin-2(1H)-one (51.7 mg, 183 μmol) and potassium hydroxide (123 mg, 2.19 mmol) in MeCN (1 mL) / H₂O (1 mL). The mixture was stirred overnight at room temperature. Water was added to the mixture and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (13.1 mg, 39.2 μmol, 22%) as a pale yellow oil.
[1618] MS:m / z 334.10(M+H) + .
[1619] [Example 20-2]
[1620] 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (20-2)
[1621] 2-Bromo-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (intermediate 20-2A)
[1622] A mixture of 2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)pyrazine (1.42 g, 5.30 mmol) and N-bromosuccinimide (1.04 g, 5.83 mmol) in MeCN (18 mL) was stirred overnight at room temperature. An additional 500 mg of N-bromosuccinimide was added to the mixture, and the mixture was stirred again at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / heptane = 18%–39%) to give the title compound (1.21 g, 3.48 mmol, 66%) as a grayish-white solid.
[1623] MS:m / z 346.00(M+H) + .
[1624] 2-(5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazin-2-yl)-2,2-difluoroethyl acetate (intermediate 20-2B)
[1625] A mixture of ethyl bromodifluoroacetate (526 μL, 4.05 mmol) and Cu powder (514 mg, 8.09 mmol) in DMSO (4 mL) was stirred at room temperature for 1 hour. Then, 2-bromo-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (700 mg, 2.02 mmol) was added to the solution, and the mixture was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth mat. 1 N HCl was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 19%–40%) to give the title compound (439 mg, 1.13 mmol, 56%) as a yellow oil.
[1626] MS:m / z 390.10(M+H) + .
[1627] 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (20-2)
[1628] A mixture of ethyl 2-(5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazin-2-yl)-2,2-difluoroacetate (30.0 mg, 77.1 μmol) and magnesium chloride (7.3 mg, 77.1 μmol) in NMP (0.5 mL) was stirred at 180 °C for 2 hours under microwave irradiation. Water was added to the mixture and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (3.83 mg, 12.1 μmol, 16%) as a white solid.
[1629] MS: m / z 318.05 (M+H) + .
[1630] Compound 20-3 shown in Table 38 below was synthesized according to the synthesis method described in Example 20-2.
[1631] Table 38
[1632] [Example 20-4]
[1633] 2-(1,1-Difluoroethyl)-5-(4,4-Difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (20-4)
[1634] 2-(6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-2,2-difluoroethane-1-ol (intermediate 20-4A)
[1635] At 0 °C, NaBH4 (58.3 mg, 1.54 mmol) was added to a stirred solution of ethyl 2-(5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazin-2-yl)-2,2-difluoroacetate (400 mg, 1.03 mmol) in THF (2.5 mL) / MeOH. The solution was stirred at room temperature for 3 days. 1 N HCl was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / heptane = 26%–47%) to give the title compound (116 mg, 334 μmol, 33%) as a yellow oil.
[1636] MS:m / z 348.10(M+H) + .
[1637] 3-(1,1-Difluoro-2-iodoethyl)-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine (intermediate 20-4B)
[1638] At 0 °C, trifluoromethanesulfonic anhydride (113 mg, 401 μmol) was added to a stirred solution of 2 mL of DCM containing 2-(6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-2,2-difluoroethane-1-ol (116 mg, 334 μmol) and pyridine (53.8 μL, 668 μmol). The solution was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
[1639] Sodium iodide (250 mg, 1.67 mmol) was added to a stirred acetone (2 mL) solution of the crude product. The solution was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / heptane = 10%–31%) to give the title compound (79.7 mg, 174 μmol, 52%) as a white solid.
[1640] MS:m / z 458.00(M+H) + .
[1641] 2-(1,1-Difluoroethyl)-5-(4,4-Difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine (20-4)
[1642] A mixture of 3-(1,1-difluoro-2-iodoethyl)-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine (79.7 mg, 174 μmol) and tributyltin hydride (138 μL, 523 μmol) in THF (2 mL) was stirred overnight at 70 °C. The mixture was then heated at 100 °C for 2 hours under microwave irradiation. Water was added to the mixture, and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (15.9 mg, 48.0 μmol, 28%) as a white solid.
[1643] MS: m / z 332.08 (M+H) + .
[1644] Compounds 20-5 shown in Table 39 below were synthesized according to the synthesis method described in Examples 20-4.
[1645] Table 39
[1646] [Examples 21-1, 21-2]
[1647] 2-(2-Chloro-4-fluorophenyl)-5-(2,2-difluorovinyl)pyrazine (21-1)
[1648] 2-(2-Chloro-4-fluorophenyl)-5-(2,2-difluoroethyl)pyrazine (21-2)
[1649] (5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)methanol (intermediate 21-1A)
[1650] A mixture of (5-chloropyrazin-2-yl)methanol (300 mg, 2.08 mmol), (2-chloro-4-fluorophenyl)boronic acid (434 mg, 2.49 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (75.9 mg, 104 μmol), and sodium carbonate (440 mg, 4.15 mmol) in 1,4-dioxane (5 mL) / water (0.5 mL) was stirred at 120 °C for 1 hour. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / heptane = 59%–80%) to give the title compound (242 mg, 1.02 mmol, 49%) as a grayish-white solid.
[1651] MS:m / z 239.00(M+H) + .
[1652] 5-(2-Chloro-4-fluorophenyl)pyrazin-2-carboxaldehyde (Intermediate 21-1B)
[1653] To a stirred solution of (242 mg, 1.02 mmol) pyrazin-2-yl)methanol in 10 mL of dichloromethane, manganese oxide (IV) (706 mg, 8.13 mmol) was added. The resulting black, inhomogeneous mixture was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.
[1654] 1H-NMR(CDCl3)δ:10.22(1H,s),9.25(1H,d,J=0.9Hz),9.15(1H,d,J=1.4Hz),7.72 (1H, dd, J = 8.7, 5.9 Hz), 7.31 (1H, dd, J = 8.2, 2.3 Hz), 7.19 (1H, td, J = 8.1, 2.4 Hz).
[1655] 2-(2-Chloro-4-fluorophenyl)-5-(2,2-difluorovinyl)pyrazine (21-1)
[1656] The mixture of the crude product and triphenylphosphine (533 mg, 2.03 mmol) in DMF (5 mL) was stirred at 100 °C for 10 min. Then, sodium 2-chloro-2,2-difluoroacetate (310 mg, 2.03 mmol) was carefully added to the mixture, and the mixture was stirred at 100 °C for 1 h. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 0%–16%) to give the title compound (35.4 mg, 131 μmol, 13%) as a pale yellow solid.
[1657] MS:m / z 271.00(M+H) + .
[1658] 1 H-NMR(CDCl3)δ:8.91(1H,d,J=1.4Hz),8.75(1H,s),7.64(1H,dd,J=8.7,5.9Hz ), 7.27 (1H, dd, J = 8.7, 2.3 Hz), 7.17-7.12 (1H, m), 5.60 (1H, dd, J = 26.1, 3.2 Hz).
[1659] 2-(2-Chloro-4-fluorophenyl)-5-(2,2-difluoroethyl)pyrazine (21-2)
[1660] Add 10% palladium on carbon (29.0 mg) to a stirred solution of 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluorovinyl)pyrazine (29.2 mg, 108 μmol) in ethyl acetate (3 mL). Purge the solution with H₂ and stir at room temperature for 3 hours. Add another 10% palladium on carbon (29.0 mg) to the mixture. Purge the solution with H₂ and stir at room temperature for 2 hours. Filter the mixture through a diatomaceous earth mat. Concentrate the filtrate under reduced pressure. Purify the crude mixture by silica gel column chromatography (EtOAc / heptane = 10%–31%) to give the title compound (1.55 mg, 5.68 μmol, 5%) as a colorless oil.
[1661] MS: m / z 273.06 (M+H) + .
[1662] Compounds 21-3 and 21-4, as shown in Table 40 below, were synthesized according to the synthetic methods described in Examples 21-1 and 21-2. Analytical data are shown in Table 41 below.
[1663] Table 40
[1664] Table 41
[1665] [Example 22-1]
[1666] 2-(2-Chloro-4-fluorophenyl)-5-(2,2,2-trifluoroethyl)pyrazine (22-1)
[1667] A mixture of 5-(2-chloro-4-fluorophenyl)pyrazin-2-carboxaldehyde (300 mg, 1.27 mmol) and hydrazine monohydrate (246 μL, 5.07 mmol) in ethanol (13 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. The crude product was used without further purification.
[1668] A solution of 1-trifluoromethyl-1,2-benzyl-3(1H)-one (481 mg, 1.52 mmol) in DMSO (6 mL) was added to the stirred solution of the crude product, and the mixture was stirred overnight at 50 °C. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product mixture was purified by silica gel column chromatography (EtOAc / heptane = 9%–30%) to give the title compound (77.1 mg, 265 μmol, 21%) as a pale yellow oil.
[1669] MS:m / z 291.00(M+H) + .
[1670] 1 H-NMR(CDCl3)δ:8.96(1H,d,J=1.4Hz), 8.71(1H,d,J=0.9Hz), 7.65(1H,dd,J=8.7 ,5.9Hz),7.28(1H,dd,J=8.5,2.5Hz),7.18-7.13(1H,m),3.72(2H,q,J=10.5Hz).
[1671] Compound 22-2 shown in Table 42 was synthesized according to the synthesis method described in Example 22-1. Starting materials were synthesized using the above synthesis method.
[1672] Table 42
[1673] [Example 23-1]
[1674] 3-Chloro-2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine (23-1)
[1675] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-((4-methoxybenzyl)oxy)pyrazine (intermediate 23-1A)
[1676] A mixture of 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine (500 mg, 1.39 mmol), (4-methoxyphenyl)methanol (208 μL, 1.67 mmol), cuprous iodide (26.5 mg, 139 μmol), 1,10-phenanthroline (65.7 mg, 278 μmol), and cesium carbonate (1.13 g, 3.48 mmol) in toluene (5.6 mL) was stirred at 100 °C for 3 days. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 9%–30%) to give the title compound (510 mg, 1.38 mmol, 99%) as a white solid.
[1677] MS:m / z 370.10(M+H) + .
[1678] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-ol (Intermediate 23-1B)
[1679] A mixture of 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-((4-methoxybenzyl)oxy)pyrazine (510 mg, 1.38 mmol) and TFA (10 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the solution was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 30%–65%, with a small amount of triethylamine) to give the title compound (103 mg, 411 μmol, 30%) as a yellow solid.
[1680] MS:m / z 250.00(M+H) + .
[1681] 3-Chloro-2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine (23-1)
[1682] Difluoromethyl trifluoromethanesulfonate (247 mg, 1.23 mmol) was added to a stirred solution of 3-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-ol (103 mg, 411 μmol) and potassium hydroxide (277 mg, 4.94 mmol) in MeCN (2 mL) / H₂O (2 mL). The mixture was stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 14%–35%) to give the title compound (38.2 mg, 127 μmol, 31%) as a pale yellow oil.
[1683] MS:m / z 300.00(M+H) + .
[1684] 1 H-NMR (CDCl3) δ: 7.60 (1H, s), 7.18 (1H, dd, J = 88.3, 57.2Hz), 3.70 (4H, t, J = 5.7Hz), 2.11-2.01 (4H, m).
[1685] Compound 23-2, as shown in Table 43 below, was synthesized according to the synthetic method described in Example 23-1. Starting materials were synthesized using the above synthetic method. Analytical data are shown in Table 44 below.
[1686] Table 43
[1687] Table 44
[1688] [Example 24-1]
[1689] 2-Chloro-5-(2-Chloro-4-fluorophenyl)-3-(difluoromethyl)pyrazine (24-1)
[1690] 3-Chloro-6-(2-Chloro-4-fluorophenyl)pyrazine-2-carboxylic acid methyl ester (intermediate 24-1A)
[1691] A mixture of methyl 6-bromo-3-chloropyrazine-2-carboxylate (1.00 g, 3.98 mmol), (2-chloro-4-fluorophenyl)boronic acid (763 mg, 4.37 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (145 mg, 199 μmol), and sodium carbonate (843 mg, 7.95 mmol) in 1,4-dioxane (10 mL) / water (1 mL) was stirred at 80 °C for 4 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. Water was added to the filtrate, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 0%–18%) to give the title compound (1.03 g, 3.44 mmol, 87%) as a white solid.
[1692] MS:m / z 301.00(M+H) + .
[1693] (3-Chloro-6-(2-Chloro-4-fluorophenyl)pyrazin-2-yl)methanol (Intermediate 24-1B)
[1694] At 0 °C, 4 M lithium borohydride (0.946 mL, 3.78 mmol) was carefully added to a stirred solution of methyl 3-chloro-6-(2-chloro-4-fluorophenyl)pyrazine-2-carboxylate (1.03 g, 3.44 mmol) in tetrahydrofuran (34 mL) / methanol (3.4 mL). The reaction mixture was stirred at 0 °C for 10 minutes. Then, methanol (14 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reactants were slowly poured into 1 N HCl (20 mL) and...
[1695] The mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 11%–32%) to give the title compound (161 mg, 589 μmol, 17%) as a white solid.
[1696] MS:m / z 273.00(M+H) + .
[1697] 2-Chloro-5-(2-Chloro-4-fluorophenyl)-3-(difluoromethyl)pyrazine (24-1)
[1698] To a stirred solution of (3-chloro-6-(2-chloro-4-fluorophenyl)pyrazin-2-yl)methanol (161 mg, 589 μmol) in dichloromethane (12 mL), manganese oxide (IV) (512 mg, 5.88 mmol) was added. The resulting black, inhomogeneous mixture was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure.
[1699] At 0 °C, 233 μL (1.77 mmol) of (diethylamino)sulfur trifluoride was added to a stirred solution of crude product in DCM (3 mL). The mixture was stirred at room temperature for 2 days. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product mixture was purified by silica gel column chromatography (EtOAc / heptane = 8%–29%) to give the title compound (89.3 mg, 305 μmol, 52%) as a white solid.
[1700] MS:m / z 293.00(M+H) + .
[1701] 1 H-NMR (CDCl3) δ: 8.89 (1H, s), 7.68 (1H, dd, J = 8.7, 5.9 Hz), 7.27 (1H, dd, J = 8.5, 2.5 Hz), 7.17-7.13 (1H, m), 6.92 (1H, t, J = 53.5 Hz).
[1702] [Example 24-2]
[1703] 3-Chloro-2-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine (24-2)
[1704] 3,5-Dichloro-2-vinylpyrazine (Intermediate 24-2A)
[1705] A mixture of 2-bromo-3,5-dichloropyrazine (1.00 g, 4.39 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (830 μL, 4.83 mmol), tetrakis(triphenylphosphine)palladium(0) (254 mg, 219 μmol), and potassium carbonate (1.21 g, 8.78 mmol) in 1,4-dioxane (9 mL) / water (0.9 mL) was stirred overnight at 100 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / heptane = 0%–6%) to give the title compound (391 mg, 2.23 mmol, 51%) as a pale yellow oil.
[1706] 1 H-NMR (CDCl3) δ: 8.47 (1H, s), 7.13 (1H, dd, J = 17.2, 10.7Hz), 6.55 (1H, dd, J = 16.9, 1.4Hz), 5.74 (1H, dd, J = 10.7, 1.6Hz).
[1707] 3-Chloro-5-(4,4-difluoropiperidin-1-yl)-2-vinylpyrazine (Intermediate 24-2B)
[1708] DIEA (0.39 mL, 2.29 mmol) was added to a stirred solution of 3,5-dichloro-2-vinylpyrazine (100 mg, 571 μmol) and 4,4-difluoropiperidine hydrochloride (90.0 mg, 571 μmol) in DMF (2 mL). The solution was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 4%–25%) to give the title compound (29.7 mg, 114 μmol, 20%) as a pale yellow oil.
[1709] MS:m / z 260.10(M+H) + .
[1710] 3-Chloro-2-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine (24-2)
[1711] A mixture of 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-vinylpyrazine (29.7 mg, 114 μmol), (trifluoromethyl)trimethylsilane (82.0 μL, 555 μmol), and sodium iodide (41.6 mg, 277 μmol) in THF (1 mL) was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (3.46 mg, 11.2 μmol, 8%) as a yellow solid.
[1712] MS:m / z 310.10(M+H) + .
[1713] 1 H-NMR (DMSO-d6) δ: 8.35 (1H, d, J = 1.8Hz), 3.73 (4H, s), 3.14 (1H, dd, J = 19.7, 11.4Hz), 2.12-2.02 (6H, m).
[1714] [Example 24-3]
[1715] 1-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)cyclopropane-1-carboxylonitrile(24-3)
[1716] At 0 °C, 1,2-dibromoethane (32.1 μL, 371 μmol) was added to a stirred solution of 2-(5-(4-chloro-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)acetonitrile (129 mg, 309 μmol) and sodium hydride (30.9 mg, 774 μmol) in DMF. The mixture was stirred at room temperature for 5 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used without further purification.
[1717] The crude product and TFA (1 mL) were stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure. 2 M NH3 / methanol (2 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (13.1 mg, 42.0 μmol, 14% yield in two steps) as a pale yellow solid.
[1718] MS:m / z 313.07(M+H) + .
[1719] [Example 24-4]
[1720] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-thione (24-4)
[1721] 3-(5-(difluoromethoxy)pyrazin-2-yl)-6-fluorobenzene-1,2-diamine (intermediate 24-4)
[1722] A mixture of 2-(difluoromethoxy)-5-(trimethyltinyl)pyrazine (529 mg, 1.46 mmol), 3-bromo-6-fluorobenzene-1,2-diamine (200 mg, 975 μmol), and tetra(triphenylphosphine)palladium(0) (113 mg, 97.5 μmol) in 1,4-dioxane (3 mL) was stirred overnight at 100 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 18%–39%) to give the title compound (136 mg, 503 μmol, 52%) as a white amorphous substance.
[1723] MS:m / z 271.00(M+H) + .
[1724] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-thione (24-4)
[1725] A mixture of 3-(5-(difluoromethoxy)pyrazin-2-yl)-6-fluorobenzene-1,2-diamine (50.0 mg, 185 μmol) and 1,1'-thiocarbonyldiimidazole (46.2 mg, 259 μmol) in 1,4-dioxane (1 mL) was stirred overnight at 100 °C. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 23%–65%). EtOAc (2 mL) was added to the concentrated fraction, and the mixture was sonicated. The precipitate was collected by filtration. The filter cake was dried under high vacuum to give the title compound (20.8 mg, 66.6 μmol, 36%) as a white amorphous substance.
[1726] MS:m / z 313.00(M+H) + .
[1727] 1H-NMR (DMSO-d6) δ: 12.40 (1H, s), 8.91 (1H, s), 8.63 (1H, s), 7.76 (1H, t, J = 72.0Hz), 7.72 (1H, dd, J = 8.8, 4.8Hz), 7.18 (1H, t, J = 9.2Hz).
[1728] [Examples 24-5]
[1729] 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1H-benzo[d][1,2,3]triazole(24-5)
[1730] To a stirred solution of 3-(5-(difluoromethoxy)pyrazin-2-yl)-6-fluorophenyl-1,2-diamine (96.9 mg, 359 μmol) in acetic acid (1.4 mL) / water (0.7 mL), 1 M sodium nitrite aqueous solution (1.79 mL, 1.79 mmol) was carefully added. The mixture was stirred at room temperature for 30 min, then heated at 85 °C for 1 h. After cooling to room temperature, 1 M NaOH aqueous solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 15%–35%) to give the title compound (81.0 mg, 288 μmol, 80%).
[1731] MS:m / z 282.00(M+H) + .
[1732] 1 H-NMR (DMSO-d6) δ: 9.37 (1H, s), 8.74 (1H, s), 8.32 (1H, dd, J = 8.0, 4.0 Hz), 7.86 (1H, t, J = 72.0 Hz), 7.49 (1H, dd, J = 9.6, 8.8 Hz).
[1733] [Examples 24-6]
[1734] 7-(5-(difluoromethoxy)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxynitrile (24-6)
[1735] Under microwave irradiation, a mixture of 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one (125 mg, 399 μmol), Zn(CN)2 (140 mg, 1.20 mmol), palladium(II) acetate (8.9 mg, 39.9 μmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (38.0 mg, 79.7 μmol) in DMF (2 mL) was stirred at 150 °C for 2 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane = 44%–65%) to give the title compound (81.0 mg, 266 μmol, 67%) as a pale yellow solid.
[1736] MS:m / z 305.00(M+H) + .
[1737] 1 H-NMR (DMSO-D6) δ: 13.05 (1H, s), 8.92 (1H, d, J = 1.4 Hz), 8.77 (1H, d, J = 0.9 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.78 (1H, t, J = 71.2 Hz), 7.69 (1H, d, J = 8.0 Hz).
[1738] [Examples 24-7]
[1739] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one (24-7)
[1740] 7-(5-(difluoromethoxy)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxaldehyde (intermediate 24-7)
[1741] At -78 °C, 1.5 M diisobutylaluminum hydride (420 μL, 625 μmol) was added dropwise to a stirred solution of 7-(5-(difluoromethoxy)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxynitrile (76.0 mg, 250 μmol) in THF (5 mL). The mixture was stirred at the same temperature for 1 hour. The mixture was then heated to room temperature and stirred for 3 hours. 1 N HCl was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 49%–70%) to give the title compound (21.8 mg, 71.0 μmol, 28%) as a yellow solid.
[1742] MS:m / z 308.00(M+H) + .
[1743] 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one (24-7)
[1744] At 0 °C, 46.5 μL (355 μmol) of (diethylamino)sulfur trifluoride was added to a stirred solution of 7-(5-(difluoromethoxy)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxaldehyde (21.8 mg, 71.0 μmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (4.18 mg, 12.7 μmol, 18%) as a pale yellow solid.
[1745] MS:m / z 330.02(M+H) + .
[1746] 1 H-NMR(DMSO-d6)δ:12.36(1H,s),8.91(1H,d,J=1.4Hz),8.75(1H,d,J=1.4Hz),7.81(1 H, d, J = 8.4Hz), 7.78 (1H, t, J = 72.0Hz), 7.48 (1H, d, J = 8.7Hz), 7.19 (1H, t, J = 54.7Hz).
[1747] [Examples 24-8]
[1748] 3-Chloro-2-(difluoromethyl)-5-(3,4,4-trifluoropiperidin-1-yl)pyrazine (24-8)
[1749] At 0 °C, 19.2 μL (147 μmol) of (diethylamino)sulfur trifluoride was added to a stirred solution of 1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-ol (11.0 mg, 36.7 μmol) in DCM (1 mL). The mixture was stirred at room temperature for 2 days. The mixture was carefully poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 16%–37%) to give the title compound (0.60 mg, 2.00 μmol, 5%) as a colorless oil.
[1750] MS:m / z 302.00(M+H) + .
[1751] [Examples 24-9]
[1752] 3-Chloro-5-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl)-2-(1,1-difluoroethyl)pyrazine (24-9)
[1753] Iodomethane (15.6 μL, 250 μmol) was added to a stirred solution of (1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-yl)methanol (41.0 mg, 125 μmol) and potassium carbonate (51.9 mg, 375 μmol) in DMF (0.5 mL). The mixture was stirred overnight at room temperature and then heated overnight at 100 °C. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 11%–32%) to give the title compound (0.66 mg, 1.9 μmol, 2%) as a white solid.
[1754] MS:m / z 342.10(M+H) + .
[1755] [Example 24-10]
[1756] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-N-methylbenzo[d]oxazol-2-amine (24-10)
[1757] At 0 °C, trifluoromethanesulfonic anhydride (41.8 μL, 255 μmol) was added to a stirred solution of 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one (67 mg, 213 μmol) and triethylamine (59 μL, 426 μmol) in DCM (2 mL). The mixture was stirred at room temperature for 30 min. Then, 2 M methylamine solution (2.13 mL, 4.26 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 h. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC to give the title compound (11.5 mg, 35.2 μmol, 17% yield in two steps) as a pale yellow solid.
[1758] MS: m / z 326.98 (M+H) + .
[1759] Compounds 24-11 in Table 45 were synthesized using the corresponding reagents according to the synthesis methods described in Examples 24-10.
[1760] Table 45
[1761] [Example 24-12]
[1762] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2-amine (24-12)
[1763] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine (intermediate 24-12)
[1764] Trifluoromethanesulfonic anhydride (105 μL, 643 μmol) was added to a stirred solution of 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one (168 mg, 536 μmol) and triethylamine (149 μL, 1.07 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure.
[1765] 2,4-Dimethoxybenzylamine (80.7 μL, 536 μmol) was added to a stirred solution of crude product and DIEA (270 μL, 1.61 mmol) in DMF (3 mL). The mixture was stirred overnight at room temperature. EtOAc and a saturated aqueous solution of NH4Cl were added, and the precipitate was collected by filtration. The collected solid was washed with water and dried under high vacuum to give the title compound (70.5 mg, 152 μmol, 28%) as a white solid.
[1766] MS:m / z 463.10(M+H) + .
[1767] 4-Chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2-amine (24-12)
[1768] A mixture of 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine (67.0 mg, 145 μmol) and TFA (1 mL) was stirred at 130 °C for 5 min. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (31.1 mg, 99.5 μmol, 19%) as a white solid.
[1769] MS:m / z 313.03(M+H) + .
[1770] [Example 24-13]
[1771] 1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-2-one (24-13)
[1772] A mixture of 3-chloro-2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine (97.3 mg, 343 μmol), ruthenium oxide (IV) (13.7 mg, 103 μmol), and sodium periodate (293 mg, 1.37 mmol) in EtOAc (2 mL) / H2O (2 mL) was stirred at room temperature for 2 days. The mixture was filtered through a diatomaceous earth mat. The filtrate was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC to give the title compound (22.3 mg, 75.0 μmol, 22%) as a yellow oil.
[1773] MS: m / z 297.97 (M+H) + .
[1774] 1 H-NMR (DMSO-d6) δ: 9.19 (1H, s), 7.25 (1H, t, J = 52.8 Hz), 4.01 (2H, t, J = 6.4 Hz), 3.40-3.33 (2H, m), 2.57-2.49 (2H, m).
[1775] Compounds 24-14 in Table 46 below were synthesized according to the synthesis method described in Examples 24-13.
[1776] Table 46
[1777] [Examples 24-15]
[1778] 6-Chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (24-15)
[1779] A mixture of 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (50.0 mg, 169 μmol) and N-chlorosuccinimide (45.2 mg, 339 μmol) in acetic acid (1 mL) was heated at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (46.2 mg, 140 μmol, 83%) as a pale yellow solid.
[1780] MS: m / z 330.06 (M+H) + .
[1781] 1 H-NMR (DMSO-d6) δ: 12.74 (1H, s), 9.20 (1H, d, J = 1.4Hz), 9.02 (1H, d, J = 0.9Hz), 7.61 (1H, d, J = 10.1Hz), 2.12 (3H, t, J = 19.2Hz).
[1782] Compounds 24-16 shown in Table 47 were synthesized according to the synthetic methods described in Examples 24-15. Analytical data are shown in Table 48.
[1783] Table 47
[1784] Table 48
[1785] [Examples 24-17]
[1786] 7-(5-(difluoromethyl)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-carboxynitrile (24-17)
[1787] Under microwave irradiation, a mixture of 4-chloro-7-(5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one (100 mg, 336 μmol), Zn(CN)2 (78.9 mg, 672 μmol), palladium(II) acetate (7.5 mg, 33.6 μmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (32.0 mg, 67.2 μmol) in DMF (1 mL) was stirred at 150 °C for 3 hours. After cooling to room temperature, the mixture was purified directly by silica gel column chromatography (EtOAc / heptane = 49%–70%) to give the title compound (32.1 mg, 111 μmol, 33%) as a white solid.
[1788] MS: m / z 289.07 (M+H) + .
[1789] [Examples 24-18]
[1790] 4-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (24-18)
[1791] A mixture of 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (20.0 mg, 60.8 μmol), cyclopropylboronic acid (20.9 mg, 243 μmol), PdCl2(dppf)-CH2Cl2 adduct (5.0 mg, 6.08 μmol), and sodium carbonate (19.3 mg, 183 μmol) in 1,4-dioxane (0.5 mL) / water (50 μL) was stirred at 100 °C for 18 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (1.40 mg, 3.53 μmol, 6%) as a yellow solid.
[1792] MS: m / z 335.14 (M+H) + .
[1793] [Example 24-19]
[1794] 3-Cyclopropyl-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine (24-19)
[1795] A mixture of 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine (50.0 mg, 154 μmol), cyclopropylboronic acid (52.9 mg, 616 μmol), PdCl2(dppf)-CH2Cl2 adduct (12.6 mg, 15.4 μmol), and cesium carbonate (100 mg, 308 μmol) in 1,4-dioxane (0.5 mL) / water (50 μL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (22.3 mg, 67.4 μmol, 44%) as a light brown solid.
[1796] MS:m / z 331.12(M+H) + .
[1797] [Examples 24-20]
[1798] (6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]oct-4-yl)methanol(24-20)
[1799] Sodium borohydride (43.8 mg, 1.16 mmol) was added to a stirred solution of methyl 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylate (128 mg, 386 μmol) in THF (1 mL) and methanol (1 mL). The mixture was stirred at room temperature for 3 hours. The mixture was then heated at 60 °C for 2 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by HPLC to give the title compound (10.4 mg, 31.2 μmol, 8%) as a brown gel.
[1800] MS:m / z 304.13(M+H) + .
[1801] [Examples 24-21]
[1802] 7-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (24-21)
[1803] 7-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 24-21)
[1804] A mixture of 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (53.0 mg, 115 μmol), cyclopropylboronic acid (29.7 mg, 346 μmol), PdCl2(dppf)-CH2Cl2 adduct (9.4 mg, 11.5 μmol), and sodium carbonate (36.6 mg, 346 μmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was stirred at 100 °C for 18 hours. After cooling to room temperature, the mixture was filtered through a MgSO4 pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%-13% EtOAc / heptane) to give 7-(6-cyclopropyl-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (1.5 mg, 3.2 μmol, 3%) as a yellow gel.
[1805] MS:m / z 466.20(M+H) + .
[1806] 7-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (24-21)
[1807] A mixture of 7-(6-cyclopropyl-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (1.5 mg, 3.2 μmol) and TFA (0.2 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. 2 M NH3 / methanol (0.5 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 16%–37% EtOAc / heptane) to give the title compound (0.25 mg, 0.71 μmol, 22%) as a brown solid.
[1808] MS:m / z 336.10(M+H) + .
[1809] [Examples 24-22]
[1810] 7-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (24-22)
[1811] 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (intermediate 24-22A)
[1812] A mixture of 2,5-dibromo-3-(difluoromethyl)pyrazine (150 mg, 521 μmol), 4,5-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (267 mg, 625 μmol), PdCl2(dppf)-CH2Cl2 adduct (42.5 mg, 52.1 μmol), and sodium carbonate (110 mg, 1.04 mmol) in 1,4-dioxane (2 mL) / water (0.2 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was filtered through a MgSO4 pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%-8% EtOAc / heptane) to give 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (36.2 mg, 71.2 μmol, 14%), as a light yellow gel.
[1813] MS:m / z 508.00(M+H) + .
[1814] 7-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2-yl)-4-fluoro-3-((2-(Trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 24-22B)
[1815] A mixture of 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (36.2 mg, 71.2 μmol), cyclopropylboronic acid (30.6 mg, 356 μmol), PdCl2(dppf)-CH2Cl2 adduct (5.8 mg, 7.1 μmol), and potassium carbonate (29.5 mg, 214 μmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was stirred at 100 °C for 18 hours. After cooling to room temperature, the mixture was filtered through a MgSO4 pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%-8% EtOAc / heptane) to give 7-(5-cyclopropyl-6-(difluoromethyl)pyrazin-2-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (2.8 mg, 6.0 μmol, 8%) as a colorless gel.
[1816] MS:m / z 470.10(M+H) + .
[1817] 7-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (24-22)
[1818] A mixture of 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (2.8 mg, 6.0 μmol) and TFA (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. 2 M NH3 / methanol (1 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 19%–39% EtOAc / heptane) to give the title compound (1.96 mg, 5.78 μmol, 97%) as a white solid.
[1819] MS:m / z 340.00(M+H) + .
[1820] [Examples 24-23]
[1821] 4-(6-Cyclopropyl-5-(1,1-Difluoroethyl)pyrazin-2-yl)-7,7-Difluoro-4-azaspiro[2.5]octane (24-23)
[1822] A mixture of 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane (50.0 mg, 154 μmol), cyclopropylboronic acid (53.1 mg, 618 μmol), PdCl2(dppf)-CH2Cl2 adduct (12.6 mg, 15.4 μmol), and cesium carbonate (101 mg, 309 μmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was stirred at 100 °C for 3 days. After cooling to room temperature, the mixture was filtered through a MgSO4 pad. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (2.33 mg, 6.81 μmol, 4%) as a pale yellow solid.
[1823] MS:m / z 330.21(M+H) + .
[1824] [Examples 24-24]
[1825] 4-(5-Cyclopropyl-6-(Difluoromethyl)pyrazin-2...
Claims
An arachidonic acid lipoxygenase (ALOX) inhibitor, the ALOX inhibitor comprising a compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 1 halo, -CN, C 1-6 alkyl (optionally substituted with C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl ester, -OH, -NH2, 4-8 membered heterocyclyl, oxo, -CO2H, -CN, or 1-6 halo), C 2-6 alkynyl, C 2- haloalkynyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 3-6 cycloalkyl (optionally substituted with -OH, -NH2, -CO2H, -CN, 1-6 halo, or C 1-6 alkyl), 4-8 membered heterocyclyl (optionally substituted with C 1-6 alkyl, oxo, or 1-6 halo), -NR v R w , C 1-6 alkoxy (optionally substituted with -CN, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, or 1-6 halo), or C 3-6 cycloalkoxy; R 2 H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- alkynyl, C 2-6 haloalkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, -NR v R w , -OH, C 1-6 alkoxy, or C 1-6 haloalkoxy; R 3 R is H or -NR v R w ; A is X1is CR b or N; R b H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, -NR v R w or OR x ; R x is C 1-6 alkyl (optionally substituted with -CN, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, 4-8 membered haloheterocyclyl, C 1-6 alkoxy or 1-6 halo), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl; R v and R w each independently is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; X2 is CR c Or N; R c H, halogen, C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, -CN, or 1-6 halogens), -OH, -NR y R z , C 1-6 alkoxy or C 1-6 haloalkoxy; R y and R z are each independently selected from H, C 1-6 alkyl (optionally substituted with -OH, -CO2H, -CN, or 1-6 halogens) or 4-8 membered heterocyclyl; R 4 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; R 5 is H or halogen; R 6 is H or halogen; X3 is C or N; X4 is C or N; R 7 is H or halogen; R 8 is H or halogen; R 9 H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; B is a 5 or 6 membered heterocyclyl (optionally substituted with 1-4 R d substituents) or a 5 or 6 membered heteroaryl (optionally substituted with 1-3 R e substituents) fused to X3and X4; R d and R e are each independently selected from H, halogen, C 1-6 alkyl, aryl, -NR v R w , C 1-6 alkoxy, oxo, or thiocarbonyl; m is 0, 1, 2, or 3; X5is CR when m is 0, 1 or 2 f R g X5is CR when m is 0, 1 or 2 f R g or O; R 10 and R 11 each independently is selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens); when R 10 and R 11 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens), R 10 and R 11 may be bonded to form a ring; R 10 and R 11 may together form an oxo group; R 12 and R 13 each independently is selected from H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, C 1-6 alkoxy or 1-6 halogens) or -OH; R f and R g each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R f and R g are each independently C 1-6 alkyl or C 1-6 haloalkyl, R f and R g may be bonded to form a ring; when R 13 and R f are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 13 and R f may be bonded to form a ring; R 14 and R 15 each independently H or halogen; R 16 and R 17 each independently H or halogen; R 18 and R 19 each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R 18 and R 19 are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 18 and R 19 may be bonded to form a ring. The inhibitor of claim 1, wherein the arachidonic acid lipoxygenase (ALOX) is arachidonic acid-15-lipoxygenase (ALOX15). The inhibitor of claim 1 or 2, wherein R 1 is halogen, -CN, C 1-6 alkyl (optionally substituted by C 3-6 cycloalkyl, oxo, -CO2H, -CN, or 1-6 halogen), C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl (optionally substituted by -CN, 1-6 halogen, or C 1-6 alkyl), 4-8 membered heterocyclyl (optionally substituted by oxo), -NR v R w , C 1-6 alkoxy (optionally substituted by -CN, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, or 1-6 halogen), or C 3-6 cycloalkoxy, wherein R v and R w are each independently selected from H or C 1-6 alkyl. The inhibitor according to any one of claims 1-3, wherein R 2 is H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -NH2, or C 1-6 alkoxy. The inhibitor according to any one of claims 1-4, wherein R c is H, halogen, C 1-6 alkyl (optionally substituted with 1-6 halogens), -OH, or -NR y R z wherein R y and R z are each independently selected from H and C 1-6 alkyl. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein, R 1 halo, -CN, C 1-6 alkyl (optionally substituted by C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, oxo, -CO2H, -CN, or 1-6 halo), C 2-6 alkynyl, C 2-6 haloalkynyl, C 2-6 alkenyl, C 2- haloalkenyl, C 3-6 cycloalkyl (optionally substituted by -CN, 1-6 halo, or C 1-6 alkyl), 4-8 membered heterocyclyl (optionally substituted by C 1-6 alkyl, oxo, or 1-6 halo), amino (optionally substituted by C 1-6 alkyl or C 1-6 haloalkyl), C 1-6 alkoxy (optionally substituted by -CN, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, or 1-6 halo), or C 3-6 cycloalkoxy; R 2 H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- alkynyl, C 3-6 cycloalkyl, -NR v R w , C 1-6 alkoxy or C 1-6 haloalkoxy; R 3 is H; A is X 1 CR b or N; R b H, halogen, -CN, -NR v R w or OR x ; R v and R w are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; R x is C 1-6 alkyl (optionally substituted with -CN, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, 4-8 membered haloheterocyclyl, C 1-6 alkoxy or 1-6 halo), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl; X2is CR c or N; R c H, halogen, C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, -CN, or 1-6 halogens), -OH, -NR y R z , C 1-6 alkoxy or C 1-6 haloalkoxy; R y and R z each independently is selected from H, C 1-6 alkyl (optionally substituted with -OH, -COOH, -CN, or 1-6 halogens) or 4-8 membered heterocyclyl; R 4 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; R 5 is H or halogen; R 6 is H or halogen; provided that, R is not H when R 1 is halogen, C 1-6 alkynyl, C 1-6 alkyl, unsubstituted C 1-6 alkoxy, unsubstituted 4-8 membered heterocyclyl, or amino substituted with C 1-6 alkyl; and R 2 is not H. when R 1 is unsubstituted C 1-6 alkyl, R 2 is not C 1-6 alkyl (optionally substituted with -NH2or 1-6 halogens); when R 1 is -CN, R 2 is not H or -CN; when R 1 is halogen, R 2 is not -NH2; when X1is CR b and X2is CR c R b and R c are not both H. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein R c is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OH, or -NR y R z wherein R y and R z are each independently selected from H or C 1-6 alkyl. The inhibitor or compound, pharmaceutically acceptable salt, or solvate thereof, according to any one of claims 1-7, wherein R 6 is H. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein, R 1 halo, -CN, C 1-6 alkyl (optionally substituted by C 3-6 cycloalkyl, -OH, 4-8 membered heterocyclyl, oxo, -CO2H, -CN, or 1-6 halo), C 2-6 alkynyl, C 2-6 haloalkynyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 3-6 cycloalkyl (optionally substituted by -CN, 1-6 halo, or C 1-6 alkyl), 4-8 membered heterocyclyl (optionally substituted by C 1-6 alkyl, oxo, or 1-6 halo), -NR v R w , C 1-6 alkoxy (optionally substituted by -CN, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, or 1-6 halo), or C 3-6 cycloalkoxy; R 2 H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- 6alkynyl, C 3-6 cycloalkyl, -NR v R w or C 1-6 alkoxy; R 3 is H or -NH2; A is X3 is C or N; X4 is C or N; R 7 is H or halogen; R 8 is H or halogen; R 9 H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; B is a 5 or 6 membered heterocyclyl (optionally substituted with 1-4 R d substituents) or a 5 or 6 membered heteroaryl (optionally substituted with 1-3 R e substituents) fused to X3and X4; R d and R e are each independently selected from H, halogen, C 1-6 alkyl, aryl, -NR v R w , C 1-6 alkoxy, oxo, or thiocarbonyl; R v and R w each independently is selected from H, C 1-6 alkyl or C 1-6 haloalkyl. The inhibitor or compound of any one of claims 1-5, 9, wherein the structure containing B is any one of the following structures, In the formula, R 7 , R 8 , R 9 , R d , R e and m are the same as in claims 1-5, 9. The inhibitor or compound, the pharmaceutically acceptable salt thereof, or the solvate thereof according to claim 1-5, 9 or 10, wherein the structure containing B is any one of the following structures, In the formula, R 7 , R 8 and R 9 are the same as in claims 1-5, 9-10. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof; wherein R 1 halo, -CN, C 1-6 alkyl (optionally substituted by C 3-6 cycloalkyl, 4-8 membered heterocyclyl, oxo, -CO2H, -CN, or 1-6 halo), C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl (optionally substituted by -CN, 1-6 halo, or C 1-6 alkyl), 4-8 membered heterocyclyl (optionally substituted by C 1-6 alkyl, oxo, or 1-6 halo), -NR v R w , C 1-6 alkoxy (optionally substituted by -CN, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, or 1-6 halo), or C 3-6 cycloalkoxy; R 2 H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, -NH2, or 1-6 halogens), C 2-6 alkenyl, C 2- 6alkynyl, C 3-6 cycloalkyl, -NR v R w or C 1-6 alkoxy; R v and R w each independently is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; R 3 is H or -NH2; A is m is 0, 1, 2, or 3; X5is CR when m is 0, 1 or 2 f R g X5is CR when m is 0, 1 or 2 f R g or O; R 10 and R 11 are each independently selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens); when R 10 and R 11 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens), R 10 and R 11 may be bonded to form a ring; R 10 and R 11 may together form an oxo group; R 12 and R 13 each independently is selected from H, halogen, -CN, C 1-6 alkyl (optionally substituted with -OH, C 1-6 alkoxy or 1-6 halogens) or -OH; R f and R g each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R f and R g are each independently C 1-6 alkyl or C 1-6 haloalkyl, R f and R g may be bonded to form a ring; when R 13 and R 14 are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 13 and R 14 may be bonded to form a ring; R 14 and R 15 are each independently selected from H or halogen; R 16 and R 17 are each independently selected from H or halogen; R 18 and R 19 each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R 18 and R 19 are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 18 and R 19 may be bonded to form a ring; provided that, When A is m is 2 and R 1 halo, -CN, C 1-6 alkyl or C 1-6 haloalkyl, R 2 is not H; When A is m is 2, and R 1 is -CN, R 2 is other than halogen. The compound, the pharmaceutically acceptable salt thereof or the solvate thereof according to Claim 12, wherein R 14 -R 17 each independently is halogen, and R 18 and R 19 each independently is C 1-6 alkyl. The inhibitor or compound, pharmaceutically acceptable salt, or solvate thereof of claims 1-4, 9, 12, or 13, wherein R 3 is H. a compound selected from the group consisting of: 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-methylpyrazine; 2-(4-fluoro-2-isopropoxyphenyl)-5-methylpyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)pyrazine-2-carbonitrile; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-methylpyrazine; 2-(2-chloro-4-fluorophenyl)-5-cyclopropylpyrazine; 2-chloro-5-(2-chloro-4-fluorophenyl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-methoxypyrazine; 3-chloro-5-(4-fluoro-2-isopropoxyphenyl)-2-methylpyrazine; 2-bromo-5-(4-fluoro-2-isopropoxyphenyl)pyrazine; 2-bromo-5-(2-chloro-4-fluorophenyl)pyrazine; 2-chloro-5-(4-fluoro-2-isopropoxyphenyl)pyrazine; 2-cyclopropyl-5-(4-fluoro-2-isopropoxyphenyl)pyrazine; 2-chloro-5-(2-chloro-4-fluorophenyl)-3-methylpyrazine; 2-chloro-5-(4-fluoro-2-isopropoxyphenyl)-3-methylpyrazine; 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine; 2-(benzo[d][l,3]dioxol-5-yl)-5-chloropyrazine; 6-(5-chloropyrazin-2-yl)-lH-indole; 5-(2-chloro-4-fluorophenyl)-2,3-dimethylpyrazine; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-fluoro-N-methylpyridin-2-amine; 3-chloro-5-(4-chloro-2-isopropoxyphenyl)-2-methylpyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(2,2-difluoroethoxy)pyrazine; 3-chloro-5-(4-chloro-2-isopropoxyphenyl)-2-(2,2-difluoroethoxy)pyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-cyclopropylpyrazine; 4-(5-cyclopropylpyrazin-2-yl)-7-fluoro-l,3-dihydro-2H-benzo[d]imidazol-2-one; l-(3-amino-5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)ethan-l-one; 7-chloro-4-(5-chloro-6-methylpyrazin-2-yl)-lH-indazole; 7-chloro-4-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-lH-indazole; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(difluoromethoxy)pyrazine; 7-chloro-4-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-lH-indazole; 3-chloro-5-(2,4-dichlorophenyl)-2-(difluoromethoxy)pyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(difluoromethyl)pyrazine; 3-chloro-5-(2,4-dichlorophenyl)-2-(difluoromethyl)pyrazine; 3-chloro-5-(2,4-dichlorophenyl)pyrazine-2-carbonitrile; 3-chloro-5-(7-chloro-lH-indazol-4-yl)pyrazine-2-carbonitrile; 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)-3-methylpyrazine; 5-(2-chloro-4-fluorophenyl)-2-(difluoromethoxy)-3-methylpyrazine; 5-(2,4-dichlorophenyl)-2-(difluoromethoxy)-3-methylpyrazine; 3-chloro-2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine; 6-chloro-3-(5-chloropyridin-2-yl)pyrazin-2-amine; 2-(5-chloropyridin-2-yl)-5-(difluoromethyl)pyrazine; 4-(5-(difluoromethoxy)-6-methylpyrazin-2-yl)-7-fluoro-l,3-dihydro-2H- benzo[d]imidazol-2-one; 7-(5-(difluoromethoxy)-6-methylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)- one; 6-(2-chloro-4-fluorophenyl)-3-(difluoromethoxy)pyrazine-2-carbonitrile; 4-(5-(difluoromethoxy)-6-methylpyrazin-2-yl)-7-fluorobenzo[d]thiazol-2-amine; 3-(difluoromethoxy)-6-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine-2- carbonitrile; 4-chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)pyrazolo[l,5-a]pyridine; 3-chloro-5-(3-chloro-4-fluorophenyl)-2-(difluoromethyl)pyrazine; 3-chloro-5-(4-chloro-3-fluorophenyl)-2-(difluoromethyl)pyrazine; 3-chloro-2-(difluoromethyl)-5-(3,4-difluorophenyl)pyrazine; 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-l,3-dihydro-2H- benzo[d]imidazol-2-one; 2-(l,l-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine; 4-(5-(l,l-difluoroethyl)pyrazin-2-yl)-7-fluoro-l,3-dihydro-2H- benzo[d]imidazol-2-one; 2-(2-chloro-4-fluorophenyl)-5-((difluoromethoxy)methyl)pyrazine; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2,3-bis(difluoromethyl)pyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(l,l-difluoroethyl)pyrazine; 3-chloro-2-(l,l-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine; 7-chloro-4-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)indolin-2-one; 4-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H- benzo[d]imidazol-2-one; 7-chloro-4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)indolin-2-one; 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H- benzo[d]imidazol-2-one; 3-chloro-2-(difluoromethyl)-5-(3,4,5-trifluorophenyl)pyrazine; 3-chloro-2-(difluoromethyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrazine; 3-chloro-2-(difluoromethoxy)-5-(3,4-difluorophenyl)pyrazine; 7-chloro-4-(5-(1,1-difluoroethyl)pyrazin-2-yl)indolin-2-one; 4-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H- benzo[d]imidazol-2-one; 2-(difluoromethoxy)-5-(3,4-difluorophenyl)pyrazine; 2-(difluoromethyl)-5-(3,4-difluorophenyl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-(1,1-difluoroethyl)pyrazine; 2-(1,1-difluoroethyl)-5-(3,4-difluorophenyl)pyrazine; 4-(5-amino-6-chloropyrazin-2-yl)-7-chloroindolin-2-one; 4-(6-amino-5-methoxypyrazin-2-yl)-7-chloroindolin-2-one; 7-chloro-4-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)indolin-2-one; 3-chloro-2-(1,1-difluoroethyl)-5-(3,4-difluorophenyl)pyrazine; 3-chloro-5-(2-chloro-3,4-difluorophenyl)-2-(difluoromethyl)pyrazine; 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine; 2-(2-(difluoromethoxy)-4-fluorophenyl)-5-(difluoromethyl)pyrazine; 3-chloro-2-(difluoromethyl)-5-(4-fluoro-2-(trifluoromethoxy)phenyl)pyrazine; 4-chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1,3-dihydro-2H- benzo[d]imidazol-2-one; 4-chloro-7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1,3-dihydro-2H- benzo[d]imidazol-2-one; 4-chloro-7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-1,3-dihydro-2H- benzo[d]imidazol-2-one; 3-chloro-5-(4-chloro-2-(difluoromethoxy)phenyl)-2-(1,1-difluoroethyl)pyrazine; 3-chloro-5-(4-chloro-2-(difluoromethoxy)phenyl)-2-(difluoromethyl)pyrazine; 2-(5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzonitrile; 2-chloro-5-(5-(difluoromethoxy)pyrazin-2-yl)aniline; 4-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-7-chloroindolin-2-one; 3-chloro-2-(1,1 -difluoroethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine; 5-chloro-3-(5-chloropyridin-2-yl)-6-(difluoromethyl)pyrazin-2-amine; 3-chloro-2-(difluoromethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine; 3-chloro-5-(5-chloropyridin-2-yl)-2-(difluoromethoxy)pyrazine; 3-chloro-5-(5-chloropyridin-2-yl)-2-(1,1 -difluoroethyl)pyrazine; 3-chloro-2-(difluoromethoxy)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine; 5-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-2-fluoroaniline; 3-chloro-5-(5-chloropyridin-2-yl)-2-(difluoromethyl)pyrazine; 5-chloro-3-(5-chloropyridin-2-yl)-6-(difluoromethoxy)pyrazin-2-amine; 5-(6-chloro-5-(1,1 -difluoroethyl)pyrazin-2-yl)-2-fluoroaniline; 3-chloro-2-(difluoromethyl)-5-(5-fluoropyridin-2-yl)pyrazine; 3-chloro-2-(1,1 -difluoroethyl)-5-(5-fluoropyridin-2-yl)pyrazine; 5-chloro-6-(difluoromethyl)-3-(5-fluoropyridin-2-yl)pyrazin-2-amine; 3-chloro-2-(difluoromethoxy)-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3- yl)pyrazine; 3-chloro-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)-2- (difluoromethyl)pyrazine; 3-chloro-2-(1,1 -difluoroethyl)-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3- yl)pyrazine; 3-chloro-2-(difluoromethoxy)-5-(5-fluoropyridin-2-yl)pyrazine; 3-chloro-2-(1,1 -difluoroethyl)-5-(2-(difluoromethoxy)-4,5-difluorophenyl)pyrazine; 3-chloro-2-(1,1 -difluoroethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)pyrazine; 3-chloro-2-(difluoromethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)pyrazine; 2,3-bis(difluoromethyl)-5-(5-fluoropyridin-2-yl)pyrazine; 6-(6-chloro-5-(1,1 -difluoroethyl)pyrazin-2-yl)-3-fluoropyridin-2-amine; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3-fluoropyridin-2-amine; 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-fluoropyridin-2-amine; 5-(5-chloropyridin-2-yl)-2,3-bis(difluoromethyl)pyrazine; 3-chloro-5-(5-fluoropyridin-2-yl)-2-(trifluoromethyl)pyrazine; 3-chloro-5-(5-chloropyridin-2-yl)-2-(trifluoromethyl)pyrazine; 3-chloro-6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)pyridin-2-amine; 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(trifluoromethyl)pyrazine; 3-chloro-6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)pyridin-2-amine; 3-chloro-6-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)pyridin-2-amine; 2-(2,2-difluoroethoxy)-3-(difluoromethyl)-5-(5-fluoropyridin-2-yl)pyrazine; 5-(5-chloropyridin-2-yl)-2-(2,2-difluoroethoxy)-3-(difluoromethyl)pyrazine; 2-(2,2-difluoroethoxy)-5-(2-(difluoromethoxy)-4-fluorophenyl)-3- (difluoromethyl)pyrazine; 2-(1,1 -difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)-3- (difluoromethyl)pyrazine; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3- (trifluoromethyl)pyrazine; 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)- one; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)- one; 4-chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 4-chloro-7-(6-chloro-5-(fluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 4-chloro-7-(5-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(methylamino)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 4-chloro-7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 4-chloro-7-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)- one; 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)- one; 4-fluoro-7-(5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)- one; 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)- one; 4-chloro-7-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 6-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-3-(difluoromethoxy)pyrazine-2- carbonitrile; 4-chloro-7-(5-cyclopropyloxy-pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)acetonitrile; 4-fluoro-7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-fluoro-7-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 4-chloro-7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-cyclopropylpyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-cyclopropylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-cyclopropylpyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-cyclopropoxy-pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-1H-indazole; 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(1,1-difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-chloro-5-cyclopropylpyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-chloro-5-(2,2-difluoroethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4,5-difluoro-7-(5-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-5-fluoro-7-(5-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-methoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(6-amino-5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-Chloro-7-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-chloropyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-chloropyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-Chloro-7-(5-chloropyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(methylamino)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-Chloro-5-fluoro-7-(5-methylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4,5-Difluoro-7-(5-methylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(2,2-difluorocyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluorocyclopropyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(2,2-difluoro-1-methylcyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-fluoro-7-(5-(methylamino)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoro-1-methylcyclopropyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(cyclopropyldifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluorocyclopropyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-chloropyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(1-methylcyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-fluoro-7-(5-(1-methylcyclopropyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-ethoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one; 4-chloro-7-(5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-(difluoromethoxy)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine; 2-(1,1-difluoroethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)pyrazine; 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one; 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-6-methylpyridin-3-yl)pyrazine; 2-(difluoromethoxy)-5-(5-fluoro-6-methylpyridin-2-yl)pyrazine; 5-(5-(difluoromethoxy)pyrazin-2-yl)-2-fluoroaniline; 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)pyrazine; 2-(difluoromethoxy)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)pyrazine; 4-fluoro-7-(5-(oxetan-2-ylmethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-chloro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)indolin-2-one; 7-chloro-4-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)indolin-2-one; 3-chloro-6-(5-(difluoromethoxy)pyrazin-2-yl)pyridin-2-amine; 6-(5-(difluoromethoxy)pyrazin-2-yl)-3-fluoro-N-methylpyridin-2-amine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-chloro-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; N-cyclopropyl-6-(5-(difluoromethoxy)pyrazin-2-yl)-3-fluoropyridin-2-amine; 2-(difluoromethoxy)-5-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)pyrazine; 7-(5-cyclopropylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5,6-bis(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethoxy)pyrazin-2-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(5-cyclopropylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4- (trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)- one; 7-(5-cyclopropoxy-pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-(trifluoromethyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-(trifluoromethyl)-1H-indazole; 4-(5-(1,1-difluoroethyl)pyrazin-2-yl)-6,7-difluoro-1H-indazole; 7-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d] oxazol-2(3H)-one; 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d] oxazol-2(3H)-one; 4-(5-(1,1-difluoroethyl)pyrazin-2-yl)-7-(trifluoromethyl)-1H-indazole; 4-(5-(difluoromethoxy)pyrazin-2-yl)-6,7-difluoro-1H-indazole; 4-(5,6-bis(difluoromethyl)pyrazin-2-yl)-7-chloro-1,3-dihydro-2H-benzo[d]imidazol-2- one; 7-chloro-4-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)indolin-2-one; 7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4,5-difluorobenzo[d]oxazol- 2(3H)-one; 4-chloro-7-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d] oxazol-2(3H)-one; 6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-2-(methylamino)nicotinonitrile; 6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-2-(dimethylamino)nicotinonitrile; 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-2-(dimethylamino)nicotinonitrile; 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-2-(methylamino)nicotinonitrile; 4-chloro-5-fluoro-7-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 3-(difluoromethyl)-5-(5-fluoropyridin-2-yl)-2-(2,2,2-trifluoroethoxy)pyrazine; 6-(6-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)-2-(methylamino)nicotinonitrile; 6-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-2-(methylamino)nicotinonitrile; 7-(6-(di fluoromethyl)-5-(2,2,2-trif luoroethoxy)pyrazin-2-yl)-4- (trif luoromethyl)benzo[d]oxazol-2(3H)-one; 7-(6-(di fluoromethyl)-5-(2,2,2-trif luoroethoxy)pyrazin-2-yl)-4- (trif luoromethyl)benzo[d]oxazol-2(3H)-one; 2-(di fluoromethyl)-5-(5-fluoropyridin-2-yl)-3-(trif luoromethyl)pyrazine; 5-(5-chloropyridin-2-yl)-2-(di fluoromethyl)-3-(trif luoromethyl)pyrazine; 4-(5,6-bis(di fluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H- benzo[d]imidazol-2-one; 4-(5,6-bis(di fluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H- benzo[d]imidazol-2-one; 4-(5,6-bis(di fluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H- benzo[d]imidazol-2-one; 7-(5-(2,2-dif luoroethoxy)-6-(di fluoromethyl)pyrazin-2-yl)-4- fluorobenzo[d]oxazol-2(3H)-one; 7-(6-(di fluoromethyl)-5-(2,2,2-trif luoroethoxy)pyrazin-2-yl)-4- (trif luoromethyl)benzo[d]oxazol-2(3H)-one; 5-chloro-8-(5-(1,1-dif luoroethyl)-6-(di fluoromethyl)pyrazin-2-yl)- [1,2,4]triazolo[4,3-a]pyridine; 7-(5-(cyclopropyldif luoromethyl)pyrazin-2-yl)-4-(trif luoromethyl)benzo[d]oxazol- 2(3H)-one; 2-((3-chloro-6-(5-(1,1-dif luoroethyl)-6-(di fluoromethyl)pyrazin-2-yl)pyridin-2- yl)amino)acetonitrile; 2-(3-chloro-6-(5-(di fluoromethyl)-6-(trif luoromethyl)pyrazin-2-yl)pyridin-2- yl)acetonitrile; 7-(5-methylpyrazin-2-yl)-4-(trif luoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5,6-bis(di fluoromethyl)pyrazin-2-yl)-4-chloropyrazolo[1,5-a]pyridine; 4-chloro-7-(5-(1,1-dif luoroethyl)-6-(di fluoromethyl)pyrazin-2-yl)pyrazolo[1,5- a]pyridine; 2-((3-chloro-6-(5-(di fluoromethyl)-6-(trif luoromethyl)pyrazin-2-yl)pyridin-2- yl)amino)acetonitrile; 2-((6-(5,6-bis(di fluoromethyl)pyrazin-2-yl)-3-chloropyridin-2-yl)amino)acetonitrile; 2-(6-(5,6-bis(di fluoromethyl)pyrazin-2-yl)-3-chloropyridin-2-yl)acetonitrile; 2-((6-(3-amino-5-(di fluoromethoxy)pyrazin-2-yl)-3-chloropyridin-2-yl)amino)acetonitrile; 4-(trif luoromethyl)-7-(5-(trif luoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)- one; 4-(5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7-(5-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 2-(difluoromethoxy)-5-(2-methoxy-4-methylphenyl)pyrazine; 2-(difluoromethoxy)-5-(2-methoxy-4-(trifluoromethyl)phenyl)pyrazine; 7-(5-(difluoromethoxy)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 5-chloro-8-(5-(difluoromethoxy)pyrazin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine; 7-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)pyrazolo[1,5-a]pyridine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)pyrazolo[1,5-a]pyridine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[c][1,2,5]thiadiazole; 4-chloro-7-(5-(difluoromethyl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine; 4-(5-(difluoromethoxy)pyrazin-2-yl)indolin-2-one; 7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 4-(6-chloro-5-(1-fluorovinyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine; 3-chloro-2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine; 4-(5-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; (S)-2-(difluoromethyl)-5-(3-(difluoromethyl)pyrrolidin-1-yl)pyrazine; 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 3-chloro-2-(difluoromethyl)-5-(4-(difluoromethyl)piperidin-1-yl)pyrazine; 3-chloro-2-(difluoromethyl)-5-(3-(difluoromethyl)azetidin-1-yl)pyrazine; 3-chloro-2-(1,1-difluoroethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine; (S)-3-chloro-2-(difluoromethyl)-5-(3-(difluoromethyl)pyrrolidin-1-yl)pyrazine; 3-chloro-2-cyclopropyl-5-(4,4-difluoropiperidin-1-yl)pyrazine; 1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-ol; 3-chloro-2-(difluoromethyl)-5-(4-(trifluoromethyl)piperidin-1-yl)pyrazine; 3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane; 3-chloro-5-(4,4-difluoro-3-methylpiperidin-1-yl)-2-(difluoromethyl)pyrazine; 3-chloro-2-(1,1-difluoroethyl)-5-(4-(difluoromethyl)piperidin-1-yl)pyrazine; 3-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane; cis-2-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-5,5-difluorooctahydrocyclopenta[c]pyrrole; 3-chloro-2-(difluoromethyl)-5-(4-fluoropiperidin-1-yl)pyrazine; 3-chloro-5-(4,4-difluoro-3-methylpiperidin-1-yl)-2-(1,1-difluoroethyl)pyrazine; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 3-chloro-2-(1,1-difluoroethyl)-5-(4-fluoropiperidin-1-yl)pyrazine; 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-4-azaspiro[2.5]octane; 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-4-azaspiro[2.5]octane; 3-chloro-2-(difluoromethyl)-5-(4-fluoro-2,2-dimethylpiperidin-1-yl)pyrazine; 3-chloro-5-(4,4-difluoro-2,2-dimethylpiperidin-1-yl)-2-(difluoromethyl)pyrazine; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane; 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1,1-difluoro-6-azaspiro[2.5]octane; 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1,1-difluoro-6-azaspiro[2.5]octane; 3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-3-azabicyclo[4.1.0]heptane; 3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octan-4-ol; (1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoropiperidin-3-yl)methanol; (1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoropiperidin-2-yl)methanol; (1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-4,4-difluoropiperidin-2-yl)methanol; 8-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane; 8-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane; 8-(5,6-bis(difluoromethyl)pyrazin-2-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane; 4-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 4-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1,4-oxazepane; 8-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane; 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane; 1-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)azepane; 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carboxylic acid methyl ester; 6-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 6-(5-(1,1-difluoroethyl)-6-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carbonitrile; 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carbonitrile; 6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carbonitrile; 6-(5,6-bis(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carbonitrile; 6-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-4,4-difluoro-6-azaspiro[2.5]octane; 4-(5-(difluoromethyl)-6-(trifluoromethyl)pyrazin-2-yl)-7-fluoro-4-azaspiro[2.5]octane; 5-(4,4-difluoro-2,2-dimethylpiperidin-1-yl)-2-(difluoromethyl)-3-(trifluoromethyl)pyrazine; 2-(difluoromethyl)-5-(4-fluoro-2,2-dimethylpiperidin-1-yl)-3-(trifluoromethyl)pyrazine; 5-(4,4-difluoro-2,2-dimethylpiperidin-1-yl)-2,3-bis(difluoromethyl)pyrazine; 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane-4-carbonitrile; 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-(prop-1-en-2-yl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-vinylpyrazine; 5-(2-chloro-4-fluorophenyl)-3-methoxy-2-vinylpyrazine; 2-cyclopropyl-5-(2-cyclopropyl-4-fluorophenyl)-3-methylpyrazine; 3-(5-fluoropyridin-2-yl)-6-vinylpyrazin-2-amine; 5-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)-2-methylpyrazine; 2-(2-chloro-4-fluorophenyl)-5-((trimethylsilyl)ethynyl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-ethynylpyrazine; 5-(2-chloro-4-fluorophenyl)-2-ethynyl-3-methylpyrazine; 2-ethynyl-5-(4-fluoro-2-isopropoxyphenyl)pyrazine; 1-(5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)ethan-1-one; 1-(5-(2-chloro-4-fluorophenyl)-3-methylpyrazin-2-yl)ethan-1-one; 7-(5-acetyl-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 2-(2-chloro-4-fluorophenyl)-5-isopropylpyrazine; 5-(2-chloro-4-fluorophenyl)-2-ethyl-3-methoxypyrazine; 5-(2-chloro-4-fluorophenyl)-2-(1,1-difluoroethyl)-3-methylpyrazine; 2-(2-chloro-4-fluorophenyl)-5-ethoxypyrazine; 1-(5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)pyrazolidin-3-one; 5-(2-chloro-4-fluorophenyl)-2-ethoxy-3-methylpyrazine; 1-(5-(2-chloro-4-fluorophenyl)-3-methylpyrazin-2-yl)pyrazolidin-3-one; 5-(2-chloro-4-fluorophenyl)-2-(2,2-difluoroethoxy)-3-methylpyrazine; 5-(2-chloro-4-fluorophenyl)-2-(2-fluoroethoxy)-3-methylpyrazine; 5-(2-chloro-4-fluorophenyl)-3-methyl-2-propoxypyrazine; 2-(2-chloro-4-fluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine; 2-((5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)oxy)acetonitrile; 3-(5-chloropyridin-2-yl)-6-(2,2-difluoroethoxy)pyrazin-2-amine; 5-(2-chloro-4-fluorophenyl)-2-iodo-3-methoxypyrazine; 2-(5-(4-fluoro-2-isopropoxyphenyl)pyrazin-2-yl)acetic acid; 6-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carbonitrile; 6-(2-chloro-4-fluorophenyl)-3-methylpyrazine-2-carbonitrile; 6-(2-chloro-4-fluorophenyl)-3-(2,2-difluoroethoxy)pyrazine-2-carbonitrile; 6-(4-chloro-2-isopropoxyphenyl)-3-(2,2-difluoroethoxy)pyrazine-2-carbonitrile; 6-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carbonitrile; 3-(1,1-difluoroethyl)-6-(2-(difluoromethoxy)-4-fluorophenyl)pyrazine-2-carbonitrile; 3-(difluoromethyl)-6-(4,4-difluoropiperidin-1-yl)pyrazine-2-carbonitrile; 6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-3-(difluoromethyl)pyrazine-2-carbonitrile; 6-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-3-(1,1-difluoroethyl)pyrazine-2-carbonitrile; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-ethynylpyrazine; 5-(2-chloro-4-fluorophenyl)-3-methylpyrazine-2-carbonitrile; 5-(4-fluoro-2-isopropoxyphenyl)-3-methylpyrazine-2-carbonitrile; 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine; 5-(4,4-difluoropiperidin-1-yl)-3-methylpyrazine-2-carbonitrile; 4-(5-(difluoromethyl)-6-methylpyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 4-chloro-7-(5-(difluoromethyl)-6-ethynylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-(5-(1,1-difluoroethyl)-6-ethynylpyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-ethynylpyrazine; 7-(5-(1,1-difluoroethyl)-6-ethenylpyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(trifluoromethyl)-6-ethenylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-ethenylpyrazine; 4-chloro-7-(5-(1,1-difluoroethyl)-6-ethenylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one;(6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-3-(difluoromethyl)pyrazin-2-yl)methanol; 4-chloro-7-(5-(difluoromethyl)-6-methoxypyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-3-methoxypyrazine; 3-fluoro-5-(4-fluoro-2-isopropoxyphenyl)-2-methylpyrazine; 7-(6-amino-5-(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one; 6-(4-chloro-2-isopropoxyphenyl)-3-methylpyrazin-2-amine; 4-(6-amino-5-(difluoromethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7-(6-amino-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one; 6-(2-(difluoromethoxy)-4-fluorophenyl)-3-(difluoromethyl)pyrazin-2-amine; 7-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(6-(difluoromethyl)-5-(trifluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-(difluoromethyl)-5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-iodopyrazine; 3-iodo-6-(6-azaspiro[2.5]oct-6-yl)pyrazine-2-carbonitrile; 4-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 5,6-dichloro-3-(5-chloropyridin-2-yl)pyrazin-2-amine; 3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyrazine; 3-chloro-5-(4-(difluoromethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrazine; 3-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane; 6-(6-chloro-5-(trifluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octane; 6-(6-azaspiro[2.5]oct-6-yl)-3-(trifluoromethyl)pyrazine-2-carbonitrile; 1-(3-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)ethan-1-one; 1-(3-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)ethan-1-one; 5-(2-chloro-4-fluorophenyl)-2-iodo-3-methylpyrazine; 5-(2-chloro-4-fluorophenyl)-3-iodo-2-methylpyrazine; 2-(2-chloro-4-fluorophenyl)-5-iodopyrazine; 6-(4-fluoro-2-isopropoxyphenyl)-3-iodopyrazine-2-carbonitrile; 5-(4-chloro-2-isopropoxyphenyl)-2-iodo-3-methylpyrazine; 7-chloro-4-(5-(2-fluoropropan-2-yl)pyrazin-2-yl)indolin-2-one; 4-chloro-7-(5-(2-fluoropropan-2-yl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine; 2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine; 4-(5,6-bis(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 2-(1,1-difluoroethyl)-5-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyrazine; 4-(5-(1,1-difluoroethyl)-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluoroethenyl)pyrazine; 2-(2-chloro-4-fluorophenyl)-5-(2,2-difluoroethyl)pyrazine; 4-chloro-7-(5-(2,2-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(2,2-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 2-(2-chloro-4-fluorophenyl)-5-(2,2,2-trifluoroethyl)pyrazine; 4-chloro-7-(5-(2,2,2-trifluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 3-chloro-2-(difluoromethoxy)-5-(4,4-difluoropiperidin-1-yl)pyrazine; 6-(6-chloro-5-(difluoromethoxy)pyrazin-2-yl)-6-azaspiro[2.5]octane; 2-chloro-5-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)pyrazine; 3-chloro-2-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)pyrazine; 1-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazole-2-thione; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1H-benzo[d][1,2,3]triazole; 7-(5-(difluoromethoxy)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazole-4-carbonitrile; 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-(difluoromethyl)benzo[d]oxazol-2(3H)-one; 3-chloro-2-(difluoromethyl)-5-(3,4,4-trifluoropiperidin-1-yl)pyrazine; 3-chloro-5-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl)-2-(1,1-difluoroethyl)pyrazine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-N-methylbenzo[d]oxazol-2-amine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-2-methoxybenzo[d]oxazole; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2-amine; 1-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-4,4-difluoropiperidin-2-one; 6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]octan-5-one; 6-chloro-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 5-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7-(5-(difluoromethyl)pyrazin-2-yl)-2-oxo-2,3-dihydrobenzo[d]oxazole-4-carbonitrile; 4-(6-cyclopropyl-5-(1,1-difluoroethyl)pyrazin-2-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one; 3-cyclopropyl-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)pyrazine; (6-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-6-azaspiro[2.5]oct-4-yl)methanol; 7-(6-cyclopropyl-5-(1,1-difluoroethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 7-(5-cyclopropyl-6-(difluoromethyl)pyrazin-2-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-(6-cyclopropyl-5-(1,1-difluoroethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 4-(5-cyclopropyl-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 4-cyclopropyl-7-(5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-cyclopropyl-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-(5-(2,2-difluoroethoxy)-6-(difluoromethyl)pyrazin-2-yl)-7,7-difluoro-4-azaspiro[2.5]octane; 7-(5-cyclopropyl-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-cyclopropyl-6-(difluoromethyl)pyrazin-2-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 4-cyclopropyl-7-(5-(1,1-difluoroethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-vinylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(prop-1-en-2-yl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 6-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-N-(2,2-difluoroethyl)-3-fluoropyridin-2-amine; 4-chloro-7-(5-isopropylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-cyclopropyl-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-methyl-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethyl)pyrazin-2-yl)-4-methylbenzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethoxy)pyrazin-2-yl)-4-methylbenzo[d]oxazol-2(3H)-one; 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazin-2-yl)-2,2- difluoroacetonitrile; 7-(5-bromo-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one; 7-(5-chloro-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one; 7-(5-(2-fluoroprop-2-yl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(6-(difluoromethyl)-5-(methylamino)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol- 2(3H)-one; 7-(6-(difluoromethyl)-5-methylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one; 7-(5-(difluoromethoxy)-6-(difluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol- 2(3H)-one; 4-(1,1-difluoroethyl)-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(difluoromethoxy)-6-(trifluoromethyl)pyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol- 2(3H)-one; 4-chloro-7-(6-methyl-5-(trifluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(6-(difluoromethyl)-5-methoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one; 7-(6-(difluoromethyl)-5-ethoxypyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one; 2-(2-bromo-4-fluorophenyl)-5-methylpyrazine; 2-(4-chloro-2-methoxyphenyl)-5-methylpyrazine; 2-(4-chloro-2-isopropoxyphenyl)-5-methylpyrazine; 2-(2-(sec-butoxy)-4-chlorophenyl)-5-methylpyrazine; 2-(5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)acetonitrile; 2-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-methylpyrazine; 2-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)oxazole; 2-(4-chloro-2-(difluoromethoxy)phenyl)-5-methylpyrazine; 2-(4-chloro-2-cyclobutoxyphenyl)-5-methylpyrazine; 2-(4-chloro-2-(cyclopropylmethoxy)phenyl)-5-methylpyrazine; 2-(4-chloro-2-(2-methoxyethoxy)phenyl)-5-methylpyrazine; 2-(2-(but-2-yn-1-yloxy)-4-chlorophenyl)-5-methylpyrazine; 2-(5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)propanenitrile; 2-(4-chloro-2-(tetrahydrofuran-3-yl)oxy)phenyl)-5-methylpyrazine; 2-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-methylpyrazine; 2-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-methylpyrazine; 2-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-methylpyrazine; 5-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)oxazole; 2-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-methylpyrazine; 3-(5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)propanenitrile; 3-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)isoxazole; 4-((5-chloro-2-(5-methylpyrazin-2-yl)phenoxy)methyl)oxazole; 2-(4-chloro-2-ethoxyphenyl)-5-methylpyrazine; 2-(4-chloro-2-propoxyphenyl)-5-methylpyrazine; 2-(4-chloro-2-(difluoromethoxy)phenyl)-5-(difluoromethoxy)pyrazine; 2-(4-chloro-2-(2,2-difluoroethoxy)phenyl)-5-(difluoromethoxy)pyrazine; 2-(2,4-dichlorophenyl)-5-(difluoromethoxy)pyrazine; 7-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-1H-benzimidazole; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)indolin-2-one; 5-chloro-8-(5-(difluoromethoxy)pyrazin-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 2-(2,4-dichlorophenyl)-5-(difluoromethyl)pyrazine; 5-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazine-2-carbonitrile; 6-(2,4-dichlorophenyl)-3-(difluoromethyl)pyrazine-2-carbonitrile; 2-(3,4-dichlorophenyl)-5-methylpyrazine; 5-(7-chloro-2-oxoindolin-4-yl)pyrazine-2-carbonitrile; 2-(2-(allyloxy)-4-fluorophenyl)-5-methylpyrazine; 2-(4-fluoro-2-(prop-2-yn-1-yloxy)phenyl)-5-methylpyrazine; 2-(5-fluoro-2-(5-methylpyrazin-2-yl)phenoxy)acetonitrile; 2-(2-cyclobutoxy-4-fluorophenyl)-5-methylpyrazine; 2-(2-(sec-butoxy)-4-fluorophenyl)-5-methylpyrazine; 2-(4-fluoro-2-propoxyphenyl)-5-methylpyrazine; 2-(2-ethoxy-4-fluorophenyl)-5-methylpyrazine; 7-chloro-4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)indolin-2-one; 6-(7-chloro-2-oxoindolin-4-yl)-3-(difluoromethyl)pyrazine-2-carbonitrile; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoro-1H-indazole; 5-(7-fluoro-1H-indazol-4-yl)pyrazine-2-carbonitrile; 5-chloro-N-isopropyl-2-(5-methylpyrazin-2-yl)aniline; 2-(2,4-difluorophenyl)-5-methylpyrazine; 2-(4-chloro-2-fluorophenyl)-5-methylpyrazine; 5-fluoro-N-isopropyl-2-(5-methylpyrazin-2-yl)aniline; 2-(6-chloro-2-methoxypyridin-3-yl)-5-methylpyrazine; 7-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide; 2-(2-methoxy-4-fluorophenyl)-5-methylpyrazine; 7-chloro-4-(5-(difluoromethyl)pyrazin-2-yl)-1H-indazole; 3,7-dichloro-4-(5-(difluoromethyl)pyrazin-2-yl)-1H-indazole; 5-((5-chloro-2-(5-(difluoromethoxy)pyrazin-2-yl)phenoxy)methyl)isoxazole; 4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-7-fluoroindolin-2-one; 2-(2-chloro-4-fluorophenyl)-5-(difluoromethoxy)pyrazine; 2-(4-chloro-2-methoxyphenyl)-5-(2,2,2-trifluoroethoxy)pyrazine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)benzo[d]oxazole; 6-chloro-3-(5-(difluoromethoxy)pyrazin-2-yl)-2-fluorophenol; 4-(5-(difluoromethyl)pyrazin-2-yl)-7-fluoroindolin-2-one; 7-chloro-4-(5-(difluoromethyl)pyrazin-2-yl)indolin-2-one; 7-chloro-4-(5-ethynylpyrazin-2-yl)-1H-indole; 2-(6-chloro-2-isopropoxypyridin-3-yl)-5-methylpyrazine; 5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazine-2-carbonitrile; 3-((5-chloro-2-(5-(difluoromethoxy)pyrazin-2-yl)phenoxy)methyl)isoxazole; 2-(4-chloro-2-methoxyphenyl)-5-cyclopropylpyrazine; 2-(2-chloro-4-fluorophenyl)-5-(difluoromethyl)pyrazine; (E)-2-(4-chloro-2-((1,2-dichlorovinyl)oxy)phenyl)-5-(difluoromethoxy)pyrazine; 2-(4-chloro-2-isopropoxyphenyl)-5-(2,2-difluoroethoxy)pyrazine; 7-chloro-4-(5-methylpyrazin-2-yl)indolin-2-one; 2-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-(2,2,2-trifluoroethoxy)pyrazine; 2-(4-chloro-2-isopropoxyphenyl)-5-(2,2,2-trifluoroethoxy)pyrazine; 2-(7-chlorobenzofuran-4-yl)-5-methylpyrazine; 7-chloro-4-(5-methylpyrazin-2-yl)indoline; 7-chloro-1-methyl-4-(5-methylpyrazin-2-yl)-1H-indole; 5-((5-chloro-2-(5-(difluoromethyl)pyrazin-2-yl)phenoxy)methyl)isoxazole; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-(trifluoromethyl)indolin-2-one; 7-chloro-4-(5-methylpyrazin-2-yl)-3-phenyl-1H-indole; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-fluoroindolin-2-one; 2-(4-chloro-2-isopropoxyphenyl)-5-cyclopropylpyrazine; 7-chloro-4-(5-methylpyrazin-2-yl)-1H-indazole; 7-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-1H-indazole; 7-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)-3-fluoro-1H-indazole; 7-chloro-4-(5-cyclopropylpyrazin-2-yl)-1H-indole; 2-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-cyclopropylpyrazine; 7-chloro-4-(5-(difluoromethoxy)pyrazin-2-yl)indolin-2-one; 2-(4-chloro-2-methoxyphenyl)-5-(2,2-difluoroethoxy)pyrazine; 2-(5-chloro-2-(5-(difluoromethoxy)pyrazin-2-yl)phenoxy)acetonitrile; 5-(7-chloro-1H-indazol-4-yl)pyrazine-2-carbonitrile; 2-(4-chloro-2-(difluoromethoxy)phenyl)-5-(difluoromethyl)pyrazine; 7-chloro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indole; 2-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-(2,2-difluoroethoxy)pyrazine; 4-chloro-7-(5-(difluoromethoxy)pyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7-fluoro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indazole; 2-(4-chloro-2-isopropoxyphenyl)-5-(difluoromethoxy)pyrazine; 2-(4-chloro-2-methoxyphenyl)-5-(difluoromethoxy)pyrazine; 7-chloro-4-(5-(difluoromethyl)pyrazin-2-yl)-3-fluoro-1H-indazole; 4-chloro-7-(5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazole-2(3H)-one; 7-chloro-4-(5-(2,2-difluoroethoxy)pyrazin-2-yl)-1H-indazole; 2-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-(difluoromethoxy)pyrazine; 7-chloro-4-(5-chloropyrazin-2-yl)-1H-indole; 4-chloro-7-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazole-2(3H)-one; 6-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-3-(difluoromethyl)pyrazine-2-carbonitrile; 3-(difluoromethyl)-6-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)pyrazine-2-carbonitrile; 6-chloro-3-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-2-fluorophenol; 2-chloro-5-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)phenol; 8-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-3,3-difluoro-8-azabicyclo[3.2.1]octane; 7-chloro-4-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide; 2-fluoro-5-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)phenol; 4-(5-(difluoromethoxy)pyrazin-2-yl)-7-methylindolin-2-one; 7-(6-(butylamino)-5-(difluoromethyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(difluoromethyl)-6-(isobutylamino)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(6-((cyclopropylmethyl)amino)-5-(difluoromethyl)pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 6-(7-chloro-2-oxoindolin-4-yl)-3-(1,1-difluoroethyl)pyrazine-2-carbonitrile; 4'-(6-chloro-5-(difluoromethyl)pyrazin-2-yl)-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-b]pyridine]; 4'-(6-chloro-5-(1,1-difluoroethyl)pyrazin-2-yl)-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-b]pyridine]; 2-(4-fluorobenzofuran-7-yl)-5-methylpyrazine; 2-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-5-methylpyrazine; 7-chloro-4-(5-methylpyrazin-2-yl)-1H-indole; 7-isopropoxy-6-(5-methylpyrazin-2-yl)-1H-indole; 4-chloro-7-(5-methylpyrazin-2-yl)-1H-indole; 2-(4-chlorobenzofuran-1-yl)-5-methylpyrazine; 2-(2,4-dichlorophenyl)-5-methylpyrazine; 2-(2-chloro-4-methylphenyl)-5-methylpyrazine; 4-chloro-7-(5-chloropyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5-(1,1-difluoroethyl)-6-ethynylpyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(5,6-dichloropyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 7-(5-(tert-butyl)pyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one; 7-(5-(tert-butyl)-6-chloropyrazin-2-yl)-4-chlorobenzo[d]oxazol-2(3H)-one; 7-(5-(1,1-difluoroethyl)-6-ethynylpyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 7-(5,6-dichloropyrazin-2-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one. Use of the inhibitor or compound, pharmaceutically acceptable salt thereof, or solvate thereof of any one of claims 1-15, for the manufacture of a medicament for the prevention and / or treatment of any one of the following diseases: an eosinophilic airway disease, an eosinophilic granulocytic airway disease (e.g., eosinophilic chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, or asthma), another eosinophilic granulocytic disease (e.g., eosinophilic esophagitis), Friedreich’s ataxia, a hereditary mitochondrial respiratory chain disease, a genetic epileptic disorder, Leigh syndrome, stroke, diabetes (including diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy), obesity, glomerulonephritis, osteoporosis, periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, thrombosis, a neurodegenerative or neuroinflammatory disorder (e.g., Parkinson’s disease, Alzheimer’s disease, dementia, amyotrophic lateral sclerosis, or cerebrovascular disease), cancer, brain injury, a disease involving hypoxia or anoxia, myocardial infarction, a cardiovascular disease, heart failure (e.g., chronic or congestive heart failure), ischemia (e.g., cerebral ischemia, retinal ischemia, myocardial ischemia, or postoperative cognitive dysfunction), an inflammatory disease (e.g., arterial inflammation, inflammatory bowel disease, nephritis, asthma, allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue, acne, dermatitis, or psoriasis), chronic bronchitis, mucus hypersecretion, chronic obstructive pulmonary disease, pulmonary fibrosis (including chemotherapy-induced fibrosis), idiopathic pulmonary fibrosis, cystic fibrosis, adult respiratory distress syndrome, a CNS disorder, a psychiatric disorder (e.g., anxiety or depression), a peripheral neuropathy (e.g., diabetic peripheral neuropathy, spinal cord injury, head injury, or surgical trauma), rejection of allogeneic transplanted tissue or organ transplantation, an autoimmune disorder (e.g., eczema), and a disorder involving bone loss or bone formation. Use of the inhibitor or compound, pharmaceutically acceptable salt thereof, or solvate thereof of claim 16, for the manufacture of a medicament for the prevention and / or treatment of any one of the following diseases, wherein the eosinophilic granulocytic airway disease comprises eosinophilic chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, allergic rhinitis, asthma, or eosinophilic esophagitis, and the indication targeted in the clinical trial by the ALOX15-related competitor comprises Friedreich’s ataxia, a hereditary mitochondrial respiratory chain disease, a genetic epileptic disorder, Leigh syndrome, Parkinson’s disease, or amyotrophic lateral sclerosis.
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