ALOX inhibitor and use thereof

Abstract

The present invention belongs to the technical field of medicine, and specifically relates to an ALOX inhibitor compound represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof, and further relates to the use of the compound, wherein A, X1, Y and Z are as defined in the description. The compound can be used in the preparation of a drug for treating or preventing related ALOX-mediated diseases.

Description

ALOX inhibitors and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and specifically relates to ALOX inhibitors and their use in the prevention and / or treatment of diseases associated with or mediated by ALOX, and further relates to compounds useful for inhibiting ALOX, and in particular to ALOX15 inhibitors and their use in the prevention and / or treatment of diseases associated with or mediated by ALOX15. BACKGROUND

[0002] Arachidonate 15-lipoxygenase (ALOX15) is a member of the arachidonate lipoxygenase (ALOX) family, an enzyme that catalyzes the oxidation of various unsaturated fatty acids such as arachidonic acid and linoleic acid, and is believed to contribute to the pathophysiology 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 red blood cells, eosinophils, airway epithelial cells, resident macrophages, and other cells, and 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 USA., 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 sinusitis characterized mainly by type 2 inflammation and eosinophilic infiltration (Stevens et al., 2019, J Allergy Clin Immunol Pract, 7:2812). Large-scale GWAS studies revealed that loss-of-function variants in ALOX15 are associated with a reduced risk of nasal polyps and chronic rhinosinusitis (CRS), and the variant does not increase the risk of other diseases (Kristjansson et al., 2019, Nat Genet, 51:267). It has been reported that ALOX15 expression in nasal polyp tissue is increased in eosinophilic CRSwNP patients and is associated with the severity of the disease (Bangert et al., 2022, Front Immunol, 13:850494; Liang et al., 2020, Allergy Asthma Clin Immunol, 16:82). Studies have also shown that the number of ALOX15-positive macrophages and dendritic cells is increased in the nasal mucosa of eosinophilic CRSwNP patients (Wang et al., 2022, Nat Immunol, 23:1484). In vitro studies have shown that stimulation of human nasal epithelial cells with IL-13 increases the expression of ALOX15, thereby promoting the expression and secretion of the eosinophilic chemokine CCL26 (Li et al., 2019, J Allergy Clin Immunol, 144:1228). It has also been reported that stimulation of human macrophages with IL-4 or IL-13 promotes the secretion of chemokines such as CCL13, CCL17, CCL18, and CCL24, which are involved in the migration of eosinophils and T cells, associated with an increase in ALOX15 expression (Wang et al., 2022, Nat Immunol, 23:1484). Therefore, ALOX15 inhibitors are expected to be useful for the prevention and / or treatment of CRSwNP, as well as allergic asthma and eosinophilic esophagitis, for which drugs targeting Th2 cytokines or their receptors are highly effective (Kyriakopoulos et al., 2024, Eur Respir Rev, 33:230238; Nhu and Aceves, 2023, Ann Allergy Asthma Immunol, 130:15). Furthermore, ALOX15 controls ferroptosis, a form of cell death caused by the accumulation of iron-dependent lipid oxidants (Hu et al., 2022, Cells, 11:2040).Therefore, ALOX15 inhibitors are expected to be useful for preventing and / or treating diseases associated with ferroptosis, such as Friedreich's ataxia, inherited mitochondrial respiratory chain diseases, inherited epilepsy, Leigh syndrome, Parkinson's disease, and amyotrophic lateral sclerosis. SUMMARY

[0004] An object of the present application is to provide a class of ALOX inhibitors, particularly ALOX15 inhibitors, pharmaceutically acceptable salts thereof, or solvates thereof. The compounds of the present application have good ALOX15 inhibitory activity. Another object of the present application is to provide compounds useful for inhibiting ALOX, etc. The compounds of the present application can treat or prevent diseases associated with ALOX.

[0005] The present application provides the following technical solutions:

[0006] Scheme 1. An arachidonate lipoxygenase (ALOX) inhibitor comprising a compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0007] wherein,

[0008] a dashed line represents a single bond or a double bond;

[0009] X1is CR a , CR a R b , S, O, N, or NR c ;

[0010] Y is CH, C=O, O, N, or NR d ;

[0011] Z is CR e , O, or NR f ;

[0012] R a and R b are each independently selected from H, halogen, -CN, -NH2, C 1-6 alkyl, or C 1-6 haloalkyl;

[0013] R c and R d are each independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0014] R e is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C1-6 alkoxy or C 1-6 haloalkoxy;

[0015] R f is H, C 1-6 alkyl (optionally substituted by -CN, -C(O)O-C 1-6 alkyl, 4-8 membered heterocyclyl or 1-6 halo substituted), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0016] A is

[0017] X2is CR g or N;

[0018] R g is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, -NR v R w or OR x ;

[0019] R v and R w are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0020] R x is C 1-6 alkyl (optionally substituted by -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, 5 or 6 membered heteroaryl, C 1-6 alkoxy or 1-6 halo substituted), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0021] X3is CR h or N;

[0022] R h is H, halo, C 1-6 alkyl (optionally substituted by -OH, -NH2, -CO2H, -CN or 1-6 halo substituted), -OH, -NR yR z , C 1-6 alkyl or C 1-6 haloalkyl;

[0023] 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;

[0024] R 1 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

[0025] R 2 is H or halogen;

[0026] R 3 is H or halogen;

[0027] X4is C or N;

[0028] X5is C or N;

[0029] R 4 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3- 6 cycloalkyl;

[0030] R 5 is H or halogen;

[0031] R 6 is H or halogen;

[0032] B is a 6-membered aryl, 5- or 6-membered heterocyclyl (optionally substituted with 1-4 R i substituents) or 5- or 6-membered heteroaryl (optionally substituted with 1-3 R j substituents) fused to X4and X5;

[0033] R i and R j are each independently selected from H, halogen, C 1-6 alkyl, aryl, -NR v R w , C 1-6 alkoxy, oxo, or thiocarbonyl;

[0034] m is 0, 1, 2, or 3;

[0035] X6is CR when m is 0, 1, or 2 m R n X6is CR when m is 3 m R n or O;

[0036] R 7 and R 8 are each independently selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogen);

[0037] when R 7 and R 8 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogen), R 7 and R 8 may be bonded to form a ring;

[0038] R 7 and R 8 may together form an oxo group;

[0039] R 9 and R 10 are each independently selected from H, halogen, C 1-6 alkyl (optionally substituted with -OH, or 1-6 halogen), -OH, or -CN;

[0040] R m and R n are each independently selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl;

[0041] when R m and R n are each independently C 1-6 alkyl, or C 1-6 haloalkyl, R m and R n may be bonded to form a ring;

[0042] when R 10 and R m are each independently C 1-6 alkyl, or C 1-6 haloalkyl, R 10 and R m may be bonded to form a ring;

[0043] R 11 and R 12 are each independently H or halogen;

[0044] R 13 and R 14each independently H or halogen;

[0045] R 15 and R 16 each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0046] when R 15 and R 16 each independently is C 1-6 alkyl or C 1-6 haloalkyl, R 15 and R 16 may be bonded to form a ring.

[0047] Scheme 2. The inhibitor according to Scheme 1, wherein the arachidonic acid lipoxygenase (ALOX) is arachidonic acid-15-lipoxygenase (ALOX15).

[0048] Scheme 3. The inhibitor according to any one of Schemes 1-2, wherein,

[0049] A is

[0050] X2is CR g or N;

[0051] R g is H, halogen or OR x ;

[0052] R x is C 1-6 alkyl, optionally substituted with -CN or 1-6 halogens;

[0053] X3is CR h or N;

[0054] R h is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or -NR y R z ;

[0055] R y and R z each independently is selected from H, C 1-6 alkyl (optionally substituted with -OH, -CO2H, -CN or 1-6 halogens) or 4-8 membered heterocyclyl;

[0056] R 1 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;

[0057] R 2 is H;

[0058] R 3 is H;

[0059] X4is C;

[0060] X5is C;

[0061] R 4 is halo, C 1-6 haloalkyl or C 3-6 cycloalkyl;

[0062] R 5 is H or halo;

[0063] R 6 is H or halo;

[0064] B is a 6-membered aryl, 5-membered heterocyclyl (optionally substituted with 1-4 R i ) or 5-membered heteroaryl (optionally substituted with 1-3 R j ) fused to X4and X5;

[0065] R i and R j are each independently selected from H, halo, C 1-6 alkyl, aryl, -NR v R w , C 1-6 alkoxy, oxo or thiocarbonyl;

[0066] R v and R w are each independently selected from H or C 1-6 alkyl;

[0067] m is 1 or 2;

[0068] X6is CR m R n ;

[0069] R 7 and R 8 are each independently selected from H or C 1-6 alkyl;

[0070] when R 7 and R 8 are each independently C 1-6 alkyl, R 7 and R 8 may be bonded to form a ring;

[0071] R 7 and R 8 may together form an oxo group;

[0072] R 9 and R 10 are each independently selected from H, halogen, C 1-6 alkyl or -CN;

[0073] R m and R n are each independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0074] when R m and R n are each independently C 1-6 alkyl or C 1-6 haloalkyl, R m and R n may be bonded to form a ring;

[0075] when R 10 and R m are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 10 and R m may be bonded to form a ring.

[0076] Scheme 4. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0077] wherein,

[0078] the dashed line indicates a single or double bond;

[0079] X1is CR a , CR a R b , S, O, N, or NR c ;

[0080] Y is CH, C=0, O, N, or NR d ;

[0081] Z is CR e , O, or NR f ;

[0082] R a and R b are each independently selected from H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl;

[0083] R c and R d are each independently selected from H, C 1-6alkyl or C 1-6 haloalkyl;

[0084] R e is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogen), C 1-6 alkoxy or C 1-6 haloalkoxy;

[0085] R f is H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl or 1-6 halogen), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0086] A is

[0087] X2is CR g or N;

[0088] R g is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, -NR v R w or OR x ;

[0089] 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, 5 or 6 membered heteroaryl, C 1-6 alkoxy or 1-6 halogen), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0090] R v and R w are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0091] X3is CR h or N;

[0092] R h is 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;

[0093] 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;

[0094] R 1 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;

[0095] R 2 is H or halogen;

[0096] R 3 is H or halogen;

[0097] provided that,

[0098] when Z is NH, the bond between Y and X1is a double bond, Y is CH and X1is CH, R 1 is halogen and X2is CR g , wherein R 1 is not a fluorine atom or R g is not a bromine atom.

[0099] Scheme 5. A compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0100] wherein,

[0101] the dashed line represents a single or double bond;

[0102] X1is CR a , CR a R b , S, O, N, or NR c ;

[0103] Y is CH, C=O, O, N, or NR d ;

[0104] Z is CR e , O, or NR f ;

[0105] R a and R b are each independently selected from H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl;

[0106] R c and R d are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0107] R e is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogen), C 1-6 alkoxy or C 1-6 haloalkoxy;

[0108] R f is H, C 1-6 alkyl (optionally substituted with -CN, -C(O)O-C 1-6 alkyl, 4-8 membered heterocyclyl or 1-6 halogen), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0109] A is

[0110] X4is C or N;

[0111] X5is C or N;

[0112] R 4 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0113] R 5 is H or halogen;

[0114] R 6 is H or halogen;

[0115] B is a 6-membered aryl, 5 or 6-membered heterocyclyl (optionally substituted with 1-4 R i ) or 5 or 6-membered heteroaryl (optionally substituted with 1-3 R j ) fused to X4and X5;

[0116] R i and R jeach independently selected from H, halogen, C 1-6 alkyl, aryl, -NR v R w , C 1-6 alkyl, alkoxy, oxo, or thioxo;

[0117] R v and R w each independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0118] Scheme 6. A compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0119] wherein,

[0120] dashed lines represent single or double bonds;

[0121] X1is CR a , CR a R b , S, O, N, or NR c ;

[0122] Y is CH, C=0, O, N, or NR d ;

[0123] Z is CR e , O, or NR f ;

[0124] R a and R b each independently selected from H, halogen, -CN, -NH2, C 1-6 alkyl, or C 1-6 haloalkyl;

[0125] R c and R d each independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0126] R e is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0127] R f is H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl, or 1-6 halogens), C 3-6 cycloalkyl, C 3-6halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl;

[0128] A is

[0129] m is 0, 1, 2, or 3;

[0130] X6is CR m R n , when m is 3, is CR m R n or O;

[0131] R 7 and R 8 are each independently selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogen);

[0132] when R 7 and R 8 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogen), R 7 and R 8 may be bonded to form a ring;

[0133] R 7 and R 8 may together form an oxo group;

[0134] R 9 and R 10 are each independently selected from H, halogen, C 1-6 alkyl (optionally substituted with -OH or 1-6 halogen), -OH, or -CN;

[0135] R m and R n are each independently selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl;

[0136] when R m and R n are each independently C 1-6 alkyl or C 1-6 haloalkyl, R m and R n may be bonded to form a ring;

[0137] when R 10 and R m are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 10 and R mThey can bond together to form rings.

[0138] Option 7. An inhibitor or compound according to any one of Options 1-6, wherein,

[0139] X1 is CR a , O, N or NR c ;

[0140] R a It is H or halogen;

[0141] R c For H.

[0142] Scheme 8. An inhibitor or compound according to any one of Schemes 1-7, wherein,

[0143] Y represents CH, C=O, N, or NR. d ;

[0144] R d For H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0145] Scheme 9. An inhibitor or compound according to any one of Schemes 1-8, wherein,

[0146] Z is CR e or NR f ;

[0147] R e H, halogen, -CN, -NH2, oxo group, C 1-6 Alkyl groups (optionally substituted with carboxyl groups or 1-6 halogens), C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0148] R f For H, C 1-6 Alkyl groups (optionally substituted with 4-8-membered heterocyclic groups or 1-6 halogens) or 4-8-membered heterocyclic groups.

[0149] Scheme 10. An inhibitor or compound according to any one of Schemes 1-9, wherein the structure containing X, Y, and Z is any one of the following structures:

[0150] in,

[0151] R p For H, C 1-6 Alkyl groups (optionally prefixed with -CN, -C(O)OC) 1-6 Alkyl, 4-8 membered heterocyclic groups or 1-6 halogen-substituted groups), C 3-6 cycloalkyl, C 3-6haloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl;

[0152] R q is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogen), C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0153] R r is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogen), C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0154] R s is H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl, or 1-6 halogen), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl;

[0155] R t is H, halogen, -CN, -NH2, C 1-6 alkyl, or C 1-6 haloalkyl.

[0156] Scheme 11. The inhibitor or compound according to any one of Schemes 1-3, 5, wherein the structure containing B is any one of the following structures,

[0157] In the formula, R 4 , R 5 , and R 6 are the same as Schemes 1-3, 5.

[0158] Scheme 12. A compound selected from the following, a pharmaceutically acceptable salt thereof, or solvate thereof:

[0159] 1-(difluoromethyl)-5-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0160] 5-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0161] 2-(2-chloro-4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine;

[0162] 2-(4-fluoro-2-isopropoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine;

[0163] 5-(4-fluoro-2-isopropoxyphenyl)-lH-pyrazolo[3,4-b]pyrazine;

[0164] 5-(2,4-dichlorophenyl)-lH-pyrazolo[3,4-b]pyrazine;

[0165] 5-(4-fluoro-2-isopropoxyphenyl)-lH-pyrazolo[3,4-b]pyrazine;

[0166] 5-(4-chloro-2-isopropoxyphenyl)-lH-pyrazolo[3,4-b]pyrazine;

[0167] 5-(4-chloro-2-methoxyphenyl)-lH-pyrazolo[3,4-b]pyrazine;

[0168] 5-(4-chloronaphthalen-l-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0169] 2-(4-fluoro-2-isopropoxyphenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one;

[0170] 5-(4-fluoro-2-isopropoxyphenyl)-l,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;

[0171] 2-(4-chloro-2-isopropoxyphenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one;

[0172] 2-(7-chloro-lH-indazol-4-yl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one;

[0173] 5-(7-chloro-lH-indazol-4-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0174] 2-(5-chloro-2-(lH-pyrazolo[3,4-b]pyrazin-5-yl)phenoxy)acetonitrile;

[0175] 5-(2-(difluoromethoxy)-4-fluorophenyl)-lH-pyrazolo[3,4-b]pyrazine;

[0176] 2-(5-chloro-2-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenoxy)acetonitrile;

[0177] 2-(2-(difluoromethoxy)-4-fluorophenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one;

[0178] 2-(2,4-dichlorophenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one;

[0179] 5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0180] 5-(2-(difluoromethoxy)-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0181] 5-(2,4-dichlorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0182] 5-(4-chloro-2-(difluoromethoxy)phenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0183] 2-(2-(difluoromethoxy)-4-fluorophenyl)-5-(difluoromethyl)-5H-pyrrolo[2,3-b]pyrazine;

[0184] 2-(2-chloro-4-fluorophenyl)-5-(difluoromethyl)-5H-pyrrolo[2,3-b]pyrazine;

[0185] 1-(difluoromethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0186] 4-chloro-7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-1,3-dihydro-2H- benzo[d]imidazol-2-one;

[0187] 6-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0188] 6-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0189] 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0190] 1-(difluoromethyl)-5-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0191] 5-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-2-fluoroaniline;

[0192] 5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0193] 1 -(2,2-difluoroethyl)-5-(5-fluoropyridin-2-yl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0194] 1 -(2,2-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0195] 1 -(2,2-difluoroethyl)-5-(5-fluoropyridin-2-yl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0196] 5-(5-chloropyridin-2-yl)- 1 -(2,2-difluoroethyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0197] 1 -(2,2-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)- 1 H-[ 1,2,3 ]triazolo[4,5- b]pyrazine;

[0198] 5-(5-chloropyridin-2-yl)- 1 -(difluoromethyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0199] 1 -(2,2-difluoroethyl)-5-(2,4-difluorophenyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0200] 1 -(2,2-difluoroethyl)-5-(3,4-difluorophenyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0201] 6-( 1 -(difluoromethyl)- 1 H-pyrazolo[3,4-b]pyrazin-5-yl)-3 -fluoropyridin-2-amine;

[0202] 1 -(2,2-difluoroethyl)-5-(2,4-difluorophenyl)- 1 H-[ 1,2,3 ]triazolo[4,5-b]pyrazine;

[0203] 5-(3-chloro-4-fluorophenyl)- 1 -(difluoromethyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0204] 1 -(difluoromethyl)-5-(2,4,5-trifluorophenyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0205] 1 -(difluoromethyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0206] 1 -(difluoromethyl)-5-(4-fluorophenyl)- 1 H-pyrazolo[3,4-b]pyrazine;

[0207] 5-(3,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0208] 1-(difluoromethyl)-5-(2,4,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0209] 5-(2,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0210] 1-(difluoromethyl)-5-(3,4,5-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0211] 1-(difluoromethyl)-5-(2,3,4-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0212] (S)-5-(2,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0213] (R)-5-(2,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0214] 5-(4-chlorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0215] 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;

[0216] 4-chloro-7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0217] 4-chloro-7-(1H-pyrazolo[3,4-b]pyrazin-6-yl)benzo[d]oxazol-2(3H)-one;

[0218] 6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0219] 6-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0220] 4-fluoro-7-(1H-pyrazolo[3,4-b]pyrazin-6-yl)benzo[d]oxazol-2(3H)-one;

[0221] 7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;

[0222] 2-(5-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetic acid ethyl ester;

[0223] 7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;

[0224] 4-chloro-7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0225] 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;

[0226] 7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one;

[0227] 4-chloro-7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-5-fluorobenzo[d]oxazol-2(3H)-one;

[0228] 1-(difluoromethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0229] 4-chloro-7-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;

[0230] 4-fluoro-7-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzo[d]oxazol-2(3H)-one;

[0231] 4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one;

[0232] 4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-fluoroindolin-2-one;

[0233] 6-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-fluoropyridin-2-amine;

[0234] 4-fluoro-7-(1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)- one;

[0235] 4-fluoro-7-(1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0236] 4-chloro-7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluorobenzo[d]oxazol-2(3H)- one;

[0237] 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-fluoro-N-methylpyridin-2-amine;

[0238] 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one;

[0239] 5-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0240] 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one;

[0241] 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-(trifluoromethyl)pyridin-2-amine;

[0242] 2-amino-6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)nicotinonitrile;

[0243] 7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one;

[0244] 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-2-(methylamino)nicotinonitrile;

[0245] 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-methyl-3-(trifluoromethyl)pyridin-2- amine;

[0246] 5-(6,7-difluoro-lH-indol-4-yl)-l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazine;

[0247] 1-(difluoromethyl)-5-(7-(trifluoromethyl)-lH-indol-4-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0248] 4-(l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazin-5-yl)-2-(methylamino)benzonitrile;

[0249] 6-(l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazin-5-yl)-2-methoxynicotinonitrile;

[0250] 5-(6-chloro-5-fluoropyridin-2-yl)-l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazine;

[0251] 1-(difluoromethyl)-5-(5-methylpyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0252] 1-(difluoromethyl)-5-(5-(difluoromethyl)pyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0253] 2-(3-chloro-6-(l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazin-5-yl)pyridin-2-yl)acetonitrile;

[0254] 2-((3-chloro-6-(l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazin-5-yl)pyridin-2-yl)amino)acetonitrile;

[0255] 1-(2,2-difluoroethyl)-5-(7-(trifluoromethyl)-lH-indol-4-yl)-lH-[l,2,3]triazolo[4,5-b]pyrazine;

[0256] 1-(difluoromethyl)-5-(pyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0257] 1-(difluoromethyl)-5-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0258] (R)-5-(5-fluoropyridin-2-yl)-l-(oxetan-2-ylmethyl)-lH-pyrazolo[3,4-b]pyrazine;

[0259] 1-(difluoromethyl)-5-(4,5-difluoropyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine;

[0260] (R)-4-chloro-5-fluoro-7-(1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0261] 1-(difluoromethyl)-5-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0262] 2-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-(difluoromethyl)-5H-pyrrolo[2,3-b]pyrazine;

[0263] 1-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0264] 5-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0265] 5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0266] 6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0267] 3-iodo-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0268] 6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0269] 6-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0270] 6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0271] 6-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0272] 5-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0273] 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-6-azaspiro[2.5]octane-4- carbonitrile;

[0274] 5-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4- b]pyrazine;

[0275] 8-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane;

[0276] 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane;

[0277] 5-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazine;

[0278] 3,5-dibromo-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0279] 3-chloro-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0280] 3-chloro-6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0281] 3,5-dichloro-6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0282] 3-chloro-6-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0283] 3-chloro-6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0284] 3-chloro-6-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine;

[0285] 3-chloro-5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyrazine;

[0286] 3-chloro-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4- b]pyrazine;

[0287] 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4- b]pyrazine;

[0288] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-1-(difluoromethyl)-1H- pyrazolo[3,4-b]pyrazine;

[0289] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H- pyrazolo[3,4-b]pyrazine;

[0290] 6-(4-fluoro-2-isopropoxyphenyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one;

[0291] 5-(2-chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine;

[0292] 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4- b]pyrazine;

[0293] 2-(2-chloro-4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-b]pyrazine;

[0294] 5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyrazine;

[0295] 5-(5-fluoropyridin-2-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyrazine;

[0296] 1-cyclopropyl-5-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0297] 3-bromo-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4- b]pyrazine;

[0298] 5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-3-methyl-1H-pyrazolo[3,4- b]pyrazine;

[0299] 6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile;

[0300] 6-(4,4-difluoropiperidin-1-yl)isoxazolo[4,5-b]pyrazin-3-amine;

[0301] 6-(6-azaspiro[2.5]octan-6-yl)isoxazolo[4,5-b]pyrazin-3-amine;

[0302] 6-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyrazin-3-amine;

[0303] 6-(7-chloro-1H-indazol-4-yl)isoxazolo[4,5-b]pyrazin-3-amine;

[0304] 6-(2,4-dichlorophenyl)isoxazolo[4,5-b]pyrazin-3-amine;

[0305] 7-(3-aminoisoxazolo[4,5-b]pyrazin-6-yl)-4-fluorobenzo[d]oxazol-2(3H)-one;

[0306] 6-(4,4-difluoropiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-amine;

[0307] 3-(difluoromethyl)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0308] 2-(6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-difluoroacetic acid;

[0309] 3-(difluoromethoxy)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0310] 6-(2-chloro-4-fluorophenyl)-3-methylisoxazolo[4,5-b]pyrazine;

[0311] 7-chloro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one;

[0312] 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0313] 4-chloro-7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0314] 7-chloro-4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one;

[0315] 5-(2-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine;

[0316] 1-(2,2-difluoroethyl)-5-(6-azaspiro[2.5]oct-6-yl)-1H-pyrazolo[3,4-b]pyrazine;

[0317] 7-chloro-4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one;

[0318] 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0319] 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0320] 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1H-pyrazolo[3,4-b]pyrazin-1- yl)acetonitrile.

[0321] 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3,5-difluoro-N-methylpyridin-2- amine;

[0322] 2-(methylamino)-6-(1H-pyrazolo[3,4-b]pyrazin-6-yl)nicotinonitrile;

[0323] 4-chloro-7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0324] 4-chloro-7-(1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one;

[0325] 7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)- one.

[0326] Scheme 13. Use of an inhibitor or compound, a pharmaceutically acceptable salt thereof, or solvate thereof, of any one of schemes 1-12 in the manufacture of a medicament for the prevention and / or treatment of any one of: an eosinophilic airway disease, an eosinophilic airway disease (e.g., an eosinophilic chronic rhinosinusitis, a chronic rhinosinusitis with nasal polyps, or asthma), another eosinophilic disease (e.g., an eosinophilic esophagitis), Friedreich’s ataxia, a genetic 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.

[0327] Scheme 14. Use of an inhibitor or compound, a pharmaceutically acceptable salt thereof, or solvate thereof, according to scheme 13 in the manufacture of a medicament for the prevention and / or treatment of any one of: an eosinophilic airway disease, wherein the eosinophilic airway disease comprises an eosinophilic chronic rhinosinusitis, a chronic rhinosinusitis with nasal polyps, allergic rhinitis, asthma, or an eosinophilic esophagitis, and the indication targeted in the clinical trial for the ALOX15-related competitor comprises Friedreich’s ataxia, a genetic mitochondrial respiratory chain disease, a genetic epileptic disorder, Leigh syndrome, Parkinson’s disease, or amyotrophic lateral sclerosis.

[0328] Inventive Effects

[0329] The compounds of the present application exhibit significant inhibition of ALOX (e.g., ALOX15), which indicates that the compounds of the present application have better potential for clinical application in treating ALOX (e.g., ALOX15)-mediated diseases.

[0330] DETAILED DESCRIPTION

[0331] The embodiments of the present application will be described in more detail with reference to specific embodiments, but those skilled in the art will understand that the specific embodiments described below are only for the purpose of illustrating the present application and should not be construed as limiting the scope of the present application. On the contrary, the present application is intended to encompass all alternatives, modifications and equivalents that can be included within the scope of the present application defined by the claims. The embodiments of the present application can be combined in any manner unless specifically stated otherwise, and the conversion, modification and change of the technical solutions obtained by the combination are also included in the scope of the present application.

[0332] Definitions

[0333] In the present application, the expression "C a-b group" (a and b represent an integer of 1 or more, and a < b) means that the "group" has a carbon atom number of a to b, for example, C 1-6 alkyl group" means an alkyl group having a carbon atom number of 1 to 6, C 1-6 alkoxy group" means an alkoxy group having a carbon atom number of 1 to 6, C 3-6 cycloalkyl group" means a cycloalkyl group having a carbon atom number of 3 to 6, C 1-6 alkoxy C 1-6 alkyl group" means a group in which an alkoxy group having a carbon atom number of 1 to 6 and an alkyl group having a carbon atom number of 1 to 6 are bonded.

[0334] In the present application, "group" and "groups" mean a monovalent group or a divalent or more group according to the valence as needed, for example, "cycloalkyl group" (also expressed as cycloalkyl groups) includes a monovalent group obtained by removing one hydrogen atom from a cycloalkane and also includes a divalent or more group 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 group" is a terminal group, it is connected to the other part of the structural formula of the compound as a monovalent group without carrying a substituent thereon, and when it carries a substituent thereon, the cycloalkyl group exhibits a corresponding valence number (the number of substituents + 1) according to the number of the substituents carried thereon. The valence number represented by "group" and "groups" can be determined without any doubt by those skilled in the art. In addition, in the present application, if "group" means a group having a valence of two or more, it is preferred that these bonding bonds are connected to different atoms (carbon atom, nitrogen atom, etc., but not limited thereto) in the group.

[0335] In the present application, "halogen" or "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. It is preferred that the fluorine atom and the chlorine atom.

[0336] In the present application, "oxo group" means a =0 group.

[0337] "Sulfenyl" or "sulfinyl" as used herein refers to a =S group.

[0338] "C 1-6 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C 1-6 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C 1-6 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C 1-6 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C 1-6 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C 1-6 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C 1-4 Alkyl" refers to a straight or branched chain alkyl group derived by the removal of one hydrogen atom from a straight or branched chain alkane moiety containing from 1 to 6 carbon atoms, and includes straight chain C

[0339] "C 1-6 Haloalkyl" refers to a C 1-6 Alkyl group substituted with one or more halogen groups as defined above. Examples of haloC 1-6 Alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, bromomethyl, chloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0340] "C 1-6 Alkoxy" refers to a group of the formula "C 1-6 Alkyl" as defined above attached to the remainder of the chemical structure through an oxygen atom, i.e., a "C 1-6 Alkyl-O-" group. For example, groups in which a group recited in the above "C 1-6 Alkyl" is bonded to -O- include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, neopentoxy, and n-hexoxy.

[0341] "C 1-6 Haloalkoxy" refers to a C 1-6 Alkoxy group substituted with one or more halogen groups as defined above. Examples of haloC

[0342] "C 2-6 "Alkenyl" means a straight or branched chain hydrocarbon group derived from an alkene containing from 2 to 6 carbon atoms by removal of one hydrogen atom, containing at least one carbon-carbon double bond, such as ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 1,3-butanedi- 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, 1,4-hexadien-1 -yl. Preferably, "alkenyl" contains one carbon-carbon double bond. 2-6 "Alkenyl" means a straight or branched chain hydrocarbon group derived from an alkene containing from 2 to 6 carbon atoms by removal of one hydrogen atom, containing at least one carbon-carbon double bond, such as ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 1,3-butanedi- 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, 1,4-hexadien-1 -yl. Preferably, "alkenyl" contains one carbon-carbon double bond.

[0343] "C 2-6 "Haloalkenyl" means a C 2-6 alkenyl group substituted by one or more halogen groups as defined above. HaloC 2-6 Examples of haloalkenyl include, but are not limited to, fluorovinyl, bromovinyl, chlorovinyl.

[0344] "C 2-6 "Akynyl" means a straight or branched chain hydrocarbon group derived from an alkyne containing from 2 to 6 carbon atoms by removal of one hydrogen atom, containing at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, pentynyl, 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, and the like.

[0345] "C 2-6 "Haloalkynyl" means a C 2-6 alkynyl group substituted by one or more halogen groups as defined above. HaloC 2-6 Examples of haloalkynyl include, but are not limited to, fluorovinyl, bromovinyl, chlorovinyl.

[0346] "C 3-6 "Cycloalkyl" means a monovalent or (as necessary) divalent radical derived from a 3- to 6-membered cycloalkane, C 3-6 Examples of cycloalkyl include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, and the like.

[0347] "C 3-6 "Halocycloalkyl" means a C 3-6 cycloalkyl group substituted by one or more halogen groups as defined above. HaloC 3-6Examples of cycloalkyl groups include, but are not limited to, chlorocyclopropanyl, chlorocyclobutanyl, chlorocyclopentanoyl, chlorocyclohexanoyl, chlorocyclopentane-1,3-diyl, chlorocyclohexane-1,4-diyl, fluorocyclopropanoyl, fluorocyclobutanoyl, fluorocyclopentanoyl, fluorocyclohexanoyl, fluorocyclopentane-1,3-diyl, fluorocyclohexane-1,4-diyl, bromocyclopropanoyl, bromocyclobutanoyl, bromocyclopentanoyl, bromocyclohexanoyl, and the like.

[0348] As used herein, the term "4-8 membered heterocyclyl" refers to a monovalent or (as necessary) divalent radical derived from a 4-8 membered heterocycloalkane, i.e., a nonaromatic ring-containing group of from 4 to 8 ring carbon atoms in which at least one ring carbon atom is replaced with a heteroatom selected from O, S, S(O), S(O)2, C(O), N, and which preferably contains 1, 2, or 3 heteroatoms. "4-8 membered heterocyclyl" (e.g., 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl) includes monocyclic, bicyclic, or polycyclic ring systems in which one or more rings can be saturated or partially saturated, but not aromatic. Unless specifically indicated otherwise, all single-, fused (including fused in the form of a bicycle, spiro, bridge), saturated and partially saturated cases are included.

[0349] The monocyclic heterocyclyl group can be a 4-8 membered heterocyclyl group such as a 5-6 membered heterocyclyl group, a 5-7 membered heterocyclyl group, a 5-8 membered heterocyclyl group, a 4-6 membered heterocyclyl group, a 4-7 membered heterocyclyl group, or a 4-8 membered heterocyclyl group, a 4-8 membered nitrogen-containing heterocyclyl group such as a 4-7 membered nitrogen-containing heterocyclyl group or a 5-6 membered nitrogen-containing heterocyclyl group, a 4-8 membered saturated heterocyclyl group such as a 5-6 membered saturated heterocyclyl group, and the like. Examples thereof include, but are not limited to, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathianyl, 4,5-dihydroisoxazolyl, 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-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl, 6H-1,3-oxazinyl, and the like.

[0350] Fused heterocyclyl groups (e.g., 6-8 membered fused heterocyclyl groups) include spirocyclyl groups, bridged cyclyl groups, and fused cyclyl groups, which can be saturated, partially saturated, or unsaturated, but not aromatic. Fused heterocyclyl 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 heterocyclyl group, or a 5-6 membered monocyclic heterocyclyl ring.

[0351] The spirocyclyl groups can be 6-8 membered spirocyclyl groups, e.g., 7-8 membered spirocyclyl groups, 7-8 membered saturated spirocyclyl groups, 7-8 membered nitrogen-containing spirocyclyl groups, examples of which include, but are not limited to:

[0352] The bridged cyclyl groups can be 6-8 membered bridged cyclyl groups, e.g., 6-8 membered nitrogen-containing bridged cyclyl groups, 7 membered bridged cyclyl groups, 7 membered nitrogen-containing bridged cyclyl groups, examples of which include, but are not limited to:

[0353] The bridged cyclyl groups can be 6-8 membered bridged cyclyl groups, e.g., 6-8 membered nitrogen-containing bridged cyclyl groups, 7 membered bridged cyclyl groups, 7 membered nitrogen-containing bridged cyclyl groups, examples of which include, but are not limited to:

[0354] The "4-8 membered halogenated heterocyclyl" group as used herein refers to a 4-8 membered heterocyclyl group as defined above substituted with one or more halogen groups as defined above. Examples of halogenated 4-8 membered heterocyclyl groups include, but are not limited to, chlorinated 4 membered heterocyclyl groups, chlorinated 5 membered heterocyclyl groups, chlorinated 6 membered heterocyclyl groups, chlorinated 7 membered heterocyclyl groups, chlorinated 8 membered heterocyclyl groups, fluorinated 4-8 membered heterocyclyl groups, brominated 4-8 membered heterocyclyl groups.

[0355] The "aryl" group as used herein refers to a monovalent or, as necessary, divalent cyclic aromatic group derived from an aromatic carbocyclic hydrocarbon containing 6-14 carbon atoms, including benzene, naphthyl, phenanthryl, and the like.

[0356] The "heteroaryl" group described in the present application can be a 5- or 6-membered heteroaryl group, and refers to a monovalent or divalent cyclic group having aromaticity with 5 or 6 ring-forming atoms, at least one of which is a heteroatom selected from O, S, and N. Preferably, 1 to 3 ring-forming heteroatoms are present. In addition, the heteroaryl group also includes cases in which a carbon atom, a sulfur atom, is oxidized, or a nitrogen atom is replaced, for example, cases in which a carbon atom is replaced with C(=O), S(=O), S(=O)2, S(=O)(=NH). Examples thereof include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridinone, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.

[0357] The "pharmaceutically acceptable salt" described in the present application refers to a pharmaceutically acceptable acid and base addition salt and solvate. Such a pharmaceutically acceptable salt includes a salt of an acid 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, alkanecarboxylic acids (such as acetic acid, HOOC-(CH2)n-COOH (where n = 0 to 4)), and the like. Such a pharmaceutically acceptable salt also includes a salt of a base such as sodium, potassium, calcium, ammonium, and the like. A person skilled in the art knows various non-toxic pharmaceutically acceptable addition salts.

[0358] All numerical ranges described in the present application represent the range including both the end points of the range, all integers within the range, and sub-ranges formed from the integers. For example, "3-6" includes 3, 4, 5, 6; "1-6" includes 1, 2, 3, 4, 5, 6; "4-8" includes 4, 5, 6, 7, 8.

[0359] The term "optionally" or "optionally" means that the situation described thereafter can or can not occur, and the description includes both the occurrence of the described situation and the non-occurrence of the described situation.

[0360] In the present application, the term "optionally substituted" or "optionally substituted by" means that any of the moieties which can be substituted by the skilled person can be unsubstituted or substituted by the substituents described in the present application, wherein each substituent can be selected independently if there is more than one substituent. In case of substitution, the number of substituents is determined by the number of positions which can be substituted on the substituted group and can be 1 substitution, 2 substitutions, 3 substitutions, 4 substitutions, 5 substitutions, 6 substitutions, 7 substitutions, 8 substitutions or more, as long as the number of substituents does not exceed the number of positions which can be substituted on the substituted group. In case of substituents, "one or more" substituents means that there is more than one substituent, the number of substituents being different depending on the substituted group and can be 1 substitution, 2 substitutions, 3 substitutions, 4 substitutions, 5 substitutions, 6 substitutions, 7 substitutions, 8 substitutions or more, as long as the number of substituents does not exceed the number of positions which can be substituted on the substituted group.

[0361] In the present application, "optionally substituted" or "optionally substituted by" preceding a group means that all subgroups comprised in the group can be optionally substituted.

[0362] In the present application, the substituents in "optionally substituted by" can be "substituents" as described in the present application. The number of substituents is determined by the number of positions which can be substituted on the substituted group and can be 1 substitution, 2 substitutions, 3 substitutions, 4 substitutions, 5 substitutions, 6 substitutions, 7 substitutions, 8 substitutions or more.

[0363] In the chemical configuration of the compounds of the present application, the bond represents unspecified configuration, i.e. if there are chiral isomers in the chemical structure, the bond may be or both configurations can be included. In the chemical structure of the compounds of the present application. is a single bond or a double bond.

[0364] In one embodiment of the present application, X1is CR a , CR a R b , S, O, N or NR c .

[0365] In one embodiment of the present application, X1is preferably CR a , O, N or NR c .

[0366] In one embodiment of the present application, Y is CH, C=O, O, N or NR d .

[0367] In one embodiment of the application, Y is preferably CH, C=0, N or NR d .

[0368] In one embodiment of the application, Z is CR e , O or NR f ;

[0369] In one embodiment of the application, Z is preferably CR e or NR f ;

[0370] In one embodiment of the application, R a and R b are each independently selected from H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl;

[0371] In one embodiment of the application, R c and R d are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0372] In one embodiment of the application, R e is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy;

[0373] In one embodiment of the application, R e is H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens) or C 1-6 haloalkoxy;

[0374] In one embodiment of the application, R f is H, C 1-6 alkyl (optionally substituted with -CN, -C(O)O-C 1-6 alkyl, 4-8 membered heterocyclyl or 1-6 halogens), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0375] In one embodiment of the application, R f is preferably H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl or 1-6 halogens), C 3-6 cycloalkyl, C3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl;

[0376] In one embodiment of the application, R f more preferably H, C 1-6 alkyl (optionally substituted by 4-8 membered heterocyclyl or 1-6 halogen), or 4-8 membered heterocyclyl.

[0377] In one embodiment of the application, A is

[0378] In one embodiment of the application, A is

[0379] In one embodiment of the application, A is

[0380] In one embodiment of the application, A is

[0381] In one embodiment of the application, A is

[0382] In one embodiment of the application, A is

[0383] In one embodiment of the application, X2is CR g or N;

[0384] In one embodiment of the application, R g is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, -NR v R w or OR x ;

[0385] In one embodiment of the application, R g is preferably H, halogen, or OR x ;

[0386] In one embodiment of the application, R v and R w are each independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0387] In one embodiment of the application, R v and R w are preferably each independently selected from H or C 1-6 alkyl;

[0388] In one embodiment of the application, 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, 5 or 6 membered heteroaryl, C 1-6 alkoxy or 1-6 halo; 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl;

[0389] In one embodiment of the application, R x is preferably C 1-6 alkyl, optionally substituted with -CN or 1-6 halo;

[0390] In one embodiment of the application, R x is more preferably C 1-6 alkyl, optionally substituted with -CN;

[0391] In one embodiment of the application, X3is CR h or N;

[0392] In one embodiment of the application, R h is H, halo, C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, -CN or 1-6 halo), -OH, -NR y R z , C 1-6 alkoxy or C 1-6 haloalkoxy;

[0393] In one embodiment of the application, R h is H, halo, C 1-6 alkyl, C 1-6 haloalkyl or -NR y R z ;

[0394] In one embodiment of the application, R y and R z are each independently selected from H, C 1-6 alkyl (optionally substituted with -OH, -CO2H, -CN or 1-6 halo) or 4-8 membered heterocyclyl;

[0395] In one embodiment of the present application, R y and R z are each independently selected from the group consisting of H, C 1-6 alkyl;

[0396] In one embodiment of the present application, R 1 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0397] In one embodiment of the present application, R 1 is preferably halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0398] In one embodiment of the present application, R 2 is H or halogen;

[0399] In one embodiment of the present application, R 2 is preferably H;

[0400] In one embodiment of the present application, R 3 is H or halogen;

[0401] In one embodiment of the present application, R 3 is preferably H;

[0402] In one embodiment of the present application, X4is C or N

[0403] In one embodiment of the present application, X4is preferably C;

[0404] In one embodiment of the present application, X5is C or N;

[0405] In one embodiment of the present application, X5is preferably C;

[0406] In one embodiment of the present application, R 4 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1- 6alkoxy or C 1-6 haloalkoxy;

[0407] In one embodiment of the present application, R 4 is preferably halogen, C 1-6 haloalkyl or C 3-6 cycloalkyl;

[0408] In one embodiment of the application, R 5 is H or halogen;

[0409] In one embodiment of the application, R 6 is H or halogen;

[0410] In one embodiment of the application, B is a 6-membered aryl, 5- or 6-membered heterocyclyl (optionally substituted with 1-4 R i ) or 5- or 6-membered heteroaryl (optionally substituted with 1-3 R j ) fused to X4and X5;

[0411] In one embodiment of the application, B is preferably a 6-membered aryl, 5-membered heterocyclyl (optionally substituted with 1-4 R i ) or 5-membered heteroaryl (optionally substituted with 1-3 R j ) fused to X4and X5;

[0412] In one embodiment of the application, R i and R j are each independently selected from H, halogen, C 1-6 alkyl, aryl, -NR v R w , C 1-6 alkoxy, oxo or thiocarbonyl;

[0413] In one embodiment of the application, R i and R j are each independently selected from H or oxo;

[0414] In one embodiment of the application, m is 0, 1, 2 or 3;

[0415] In one embodiment of the application, m is preferably 1 or 2;

[0416] In one embodiment of the application, X6is CR m R n when m is 0, 1 or 2, and CR m R n or O when m is 3;

[0417] In one embodiment of the application, X6is preferably CR m R n ;

[0418] In one embodiment of the application, R 7 and R 8 are each independently selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H or 1-6 halogen).

[0419] In one embodiment of the application, when R 7 and R 8 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens), R 7 and R 8 may be bonded to form a ring;

[0420] In one embodiment of the application, R 7 and R 8 may together form an oxo group;

[0421] In one embodiment of the application, R 9 and R 10 are each independently selected from H, halogen, C 1-6 alkyl (optionally substituted with -OH or 1-6 halogens), -OH, or -CN;

[0422] In one embodiment of the application, R 9 and R 10 are each independently selected from H, halogen, or C 1-6 alkyl;

[0423] In one embodiment of the application, R m and R n are each independently selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl;

[0424] In one embodiment of the application, when R m and R n are each independently C 1-6 alkyl or C 1-6 haloalkyl, R m and R n may be bonded to form a ring;

[0425] In one embodiment of the application, when R 10 and R m are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 10 and R m may be bonded to form a ring;

[0426] In one embodiment of the application, R 11 and R 12 are each independently H or halogen;

[0427] In one embodiment of the application, R 13 and R14 each independently H or halogen;

[0428] In one embodiment of the present application, R 15 and R 16 each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0429] In one embodiment of the present application, when R 15 and R 16 each independently is C 1-6 alkyl or C 1-6 haloalkyl, R 15 and R 16 may be bonded to form a ring.

[0430] The compounds of the present application also include isotopically-labeled compounds. Such isotopically-labeled compounds are identified by the presence of an additional radioactive atom, such as for example, tritium (3H), carbon- 13 (13C), nitrogen- 15 (15N), oxygen- 17 (17O), fluorine- 18 (18F), and chlorine- 36 (36C1).

[0431] The above isotopically-labeled compounds can be prepared by uniformly following the same procedures as disclosed in the following Examples, except for using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents.

[0432] The compounds of the present application can also be used in the form of prodrugs. Prodrugs are compounds that can be converted under physiological conditions or by solvolytic, enzymatic or chemical processes to the compounds of the present application, such as enzymatic oxidation, reduction, hydrolysis, etc., or hydrolysis by gastric acid, etc., to the compounds of the present application.

[0433] Therapeutic or prophylactic drugs containing the compounds of the present application or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient can be prepared into the form of a pharmaceutical composition using carriers, bases and excipients and other additives commonly used in pharmaceutical formulation processes. Such carriers, bases and excipients can be solid or liquid. Specific examples include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, triglycerides of medium-chain fatty acids and other commonly used substances.

[0434] The administration of the compounds or pharmaceutical compositions of the present application can be performed orally in the form of, for example, tablets, pills, capsules, soft capsules, granules, dispersions or liquids, or parenterally by injection such as intravenous injection or intramuscular injection, using suppositories, transdermally or intranasally, etc.

[0435] The therapeutically effective dose of the active ingredient in the therapeutic agent, prophylactic agent, pharmaceutical composition, and activator containing the compound of the present application as the active ingredient can generally be 1 mg / day to 1500 mg / day, and the administration frequency can generally be 1 time / day to 3 times / day or 1 time / week to 3 times / week, although depending on, for example, the administration route, the age, sex, and severity of disease of the patient, and the administration frequency. A preparation satisfying these conditions is preferably prepared.

[0436] However, since the dose can also vary depending on various conditions, a dose smaller than the above dose can be sufficient in some cases, and a dose exceeding the above range can be required in other cases.

[0437] The inhibitors and compounds of the present application have ALOX inhibitory action, preferably ALOX15 inhibitory action. Examples

[0438] <General synthesis method>

[0439] The compounds of the formula (I) of the present application and their pharmaceutically acceptable salts (hereinafter, they will be collectively referred to as the compounds of the present application) can be synthesized by a combination of methods known in the art including the following synthetic methods. The reagents or solvents described as conditions in the chemical formula are merely examples as described in the specification. If necessary, each substituent can be protected with a suitable protecting group, and can be protected or deprotected in an appropriate step. For the appropriate protecting group and the method of removing the protecting group, the protecting group of each substituent widely used in the art and the well-known method can be employed, and are described in the section of protective groups in "Organic Synthesis" (3rd edition, John Wiley & Sons, Inc.), for example. In addition, the intermediates produced in the following synthetic methods can be isolated and purified by column chromatography, recrystallization, distillation, or the like, or can be used directly in the next step without isolation.

[0440] The following describes representative synthetic methods of the compounds of the present application represented by the general formula (I). The synthetic methods of the compounds of the present application are not limited to these. The symbols in each formula are defined as in the formula (I).

[0441] Suzuki-Miyaura coupling reaction:

[0442] The palladium catalyst is preferably tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, or the like, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tri- potassium phosphate, or the like. The solvent is not particularly limited here, and includes, for example, aromatic hydrocarbons (e.g., benzene, toluene, xylene, or the like), ethers (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or the like), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, or the like), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvents thereof, or the like. The reaction temperature is preferably from 50°C to 150°C, and particularly preferably from 80°C to 120°C.

[0443] Buchwald-Hartwig amination reaction:

[0444] The tin reagent includes hexamethylditin, bis(tri-n-butyltin), or the like. The preferred palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, or the like. The solvent is not particularly limited here, and includes, for example, aromatic hydrocarbons (e.g., benzene, toluene, xylene, or the like), ethers (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or the like), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, or the like), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or the like. The reaction temperature is preferably from 50°C to 150°C, and particularly preferably from 70°C to 120°C.

[0445] Buchwald-Hartwig amination reaction:

[0446] The palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like. The ligand is preferably 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, or the like. The base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tri-potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, or the like. The solvent is not particularly limited here, and includes, for example, aromatic hydrocarbons (e.g., benzene, toluene, xylene, or the like), ethers (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or the like), N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or the like. The reaction temperature is preferably from 50°C to 150°C, and particularly preferably from 80°C to 150°C.

[0447] Aromatic nucleophilic substitution reaction:

[0448] Preferred bases include, for example, organic bases (e.g., triethylamine and N,N- diisopropylethylamine), inorganic bases (e.g., potassium carbonate and cesium carbonate), and the like. The solvent is not particularly limited here, and includes, for example, ethers (e.g., tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like), N,N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, and the like. The reaction temperature is preferably room temperature to 150°C.

[0449] The present application will be described in more detail by specific examples below, but the present application is not limited to these examples.

[0450] The abbreviations used in the present application have the following meanings:

[0451] ACN: acetonitrile

[0452] aq: of water

[0453] eq: equivalent

[0454] DCM: dichloromethane

[0455] DIEA: N,N-diisopropylethylamine

[0456] DMA: N,N-dimethylacetamide

[0457] DMF: N,N-dimethylformamide

[0458] DMSO: dimethyl sulfoxide

[0459] dppf: [1,1'-bis(diphenylphosphino)ferrocene EA or EtOAc: ethyl acetate

[0460] EtOH: ethanol

[0461] H: hour

[0462] HPLC: high performance liquid chromatography

[0463] MeOH: methanol

[0464] MS: mass spectrometry NMP: 1-methyl-2-pyrrolidinone

[0465] NMR: nuclear magnetic resonance spectroscopy

[0466] PE: petroleum ether

[0467] SEM: 2-(trimethylsilyl)ethoxymethyl

[0468] TFA: trifluoroacetic acid

[0469] THF: tetrahydrofuran

[0470] TLC: thin layer chromatography

[0471] The structure of the new compounds isolated was identified by 1 H-NMR and / or mass spectrometry using a single quadrupole instrument equipped with an electrospray source or by other suitable analytical methods.

[0472] To measure 1 H-NMR spectra (400 MHz, DMSO-d6, CDCl3or CD3OD) show chemical shifts (δ: ppm) and coupling constants (J: Hz). For the results of mass spectrometric analyses, the observed values are indicated in M + + H, i.e. the value obtained by adding the mass of a proton (H + ) to the molecular mass (M) of the compound. The abbreviations used are as follows:

[0473] s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br s = broad singlet, m = multiplet.

[0474] Specific embodiments

[0475] [Reference Example 1]

[0476] 5-Bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (1)

[0477] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyrazine (2.00 g, 10.0 mmol), sodium chloro(difluoro)acetate (3.06 g, 20.1 mmol) and potassium carbonate (4.17 g, 30.1 mmol) in DMF (25 mL) was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. To the filtrate was added EtOAc (100 mL) and 2 N HCI (20 mL). The mixture was extracted with EtOAc, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 9% to 30%) to give 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (512.2 mg, 2.057 mmol, 20.5%) as a light yellow solid.

[0478] 1 H-NMR (CDCI3) δ: 8.66 (1H, s), 8.38 (1H, s), 7.62 (1H, t, J = 57.9 Hz).

[0479] MS: m / z 250.90 (M+H) + .

[0480] [Reference Example 2]

[0481] 5-bromo-l-(2,2-difluoroethyl)-lH-pyrazolo[3,4-b]pyrazine (2)

[0482] A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (500 mg, 2.51 mmol), 2,2- difluoroethan-l-ol (268 mg, 3.27 mmol) and triphenylphosphine (989 mg, 3.77 mmol) was suspended in THF (8 mL), then diisopropyl azodicarboxylate (660 mg, 3.27 mmol) was added dropwise to the suspension and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 12% - 33%) to give the title compound (548.7 mg, 2.086 mmol, 83.0%) as a yellow oil.

[0483] MS: m / z 262.90 (M+H) + .

[0484] [Reference Example 3]

[0485] 2-(5-bromo-lH-pyrazolo[3,4-b]pyrazin-l-yl)acetic acid ethyl ester (3)

[0486] A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (200 mg, 1.01 mmol), ethyl glycolate (136 mg, 1.31 mmol) and triphenylphosphine (395 mg, 1.51 mmol) was suspended in THF (3 mL). Then diisopropyl azodicarboxylate (264 mg, 1.31 mmol) was added dropwise to the suspension and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 14% - 35%) to give the title compound (189.8 mg, 0.666 mmol, 66.2%) as a light yellow solid.

[0487] MS: m / z 285.00 (M+H) + .

[0488] [Reference Example 4]

[0489] 5-bromo-l-(2,2-difluoroethyl)-lH-[l,2,3]triazolo[4,5-b]pyrazine (4)

[0490] 5-bromo-3-chloro-N-(2,2-difluoroethyl)pyrazin-2-amine (Intermediate 4A)

[0491] A mixture of 5-bromo-3-chloropyrazin-2-amine (2.00 g, 9.60 mmol) and sodium hydride (422 mg, 10.6 mmol) in DMF (20 mL) was stirred at room temperature for 10 minutes. To the mixture was added 2,2-difluoroethyl trifluoromethanesulfonate (2.26 g, 10.6 mmol) at 0 °C and the mixture was stirred at room temperature for 2 hours. Saturated aqueous NH4Cl 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 column chromatography on silica gel (EtOAc / heptane = 7% to 28%) to give the title compound (2.27 g, 8.34 mmol, 86.9%) as a yellow oil.

[0492] MS: m / z 271.90 (M+H) + .

[0493] 5-bromo-N 2 -(2,2-difluoroethyl)-N 3 -(2,4-dimethoxybenzyl)pyrazine-2,3-diamine (Intermediate 4B)

[0494] A mixture of 5-bromo-3-chloro-N-(2,2-difluoroethyl)pyrazin-2-amine

[0495] (2.27 g, 8.34 mmol), (2,4-dimethoxyphenyl)methanamine (1.67 g, 10.0 mmol) and DIEA (3.23 g, 25.0 mmol) in DMF (20 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 9% to 30%) to give the title compound (818 mg, 2.03 mmol, 24.3%) as a yellow oil.

[0496] MS: m / z 403.10 (M+H) + .

[0497] 5-bromo-N 2 -(2,2-difluoroethyl)pyrazine-2,3-diamine (Intermediate 4C)

[0498] A mixture of 5-bromo-N 2 -(2,2-difluoroethyl)-N 3A mixture of (2,4-dimethoxybenzyl)pyrazine-2,3-diamine (818 mg, 2.03 mmol) and TFA (8 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The concentrated residue was dissolved in ethyl acetate and filtered through aminosilica gel. The filtrate was concentrated under reduced pressure without further purification.

[0499] MS: m / z 253.00 (M+H) + .

[0500] 5-bromo-l-(2,2-difluoroethyl)-lH-[l,2,3]triazolo[4,5-b]pyrazine (4)

[0501] A mixture of 5-bromo-N 2 A mixture of (2,2-difluoroethyl)pyrazine-2,3-diamine (200 mg, 0.788 mmol) and sodium nitrite (272 mg, 3.94 mmol) in acetic acid (4 mL) was stirred at room temperature for 1 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 used in the next reaction without further purification.

[0502] MS: m / z 263.90 (M+H) + .

[0503] [Reference Example 5]

[0504] 5-bromo-l-(oxetan-2-ylmethyl)-lH-pyrazolo[3,4-b]pyrazine (5)

[0505] A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (200 mg, 1.01 mmol), oxetan-2- ylmethanol (115 mg, 1.31 mmol) and triphenylphosphine (395 mg, 1.51 mmol) was suspended in THF (2 mL). Then diisopropyl azodicarboxylate (264 mg, 1.31 mmol) was added dropwise to the suspension and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 23% - 44%) to give the title compound (218.8 mg, 0.666 mmol, 80.9%) as a yellow oil.

[0506] MS: m / z 269.00 (M+H) + .

[0507] [Reference Example 6]

[0508] 5-bromo-1 -(oxetan-3-yl)-1 H-pyrazolo[3,4-b]pyrazine (6)

[0509] A mixture of 5-bromo-1 H-pyrazolo[3,4-b]pyrazine (200 mg, 1.01 mmol), 3- hydroxyoxetane (96.8 mg, 1.31 mmol) and triphenylphosphine (395 mg, 1.51 mmol) was suspended in THF (2 mL). Diisopropyl azodicarboxylate (264 mg, 1.31 mmol) was then added dropwise to the suspension and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / Heptane = 23%-44%) to give the title compound (131.3 mg, 0.515 mmol, 51.2%) as a yellow oil.

[0510] MS: m / z 255.10 (M+H) + .

[0511] [Reference Example 7]

[0512] 7-bromo-4-chlorobenzo[d]oxazol-2(3H)-one (7)

[0513] 3-bromo-6-chloro-2-hydroxybenzoic acid tert-butyl ester (Intermediate 7A)

[0514] To a cooled solution of tert-butyl 2-bromo-5-chlorophenyl carbonate (15.4 g, 50.0 mmol) in THF (115 mL) at -78°C was added dropwise lithium diisopropylamide (30.0 mL, 60.0 mmol, 2M) over 15 minutes under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 hour, then allowed to warm gradually to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous NH4CI solution and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue was passed through a short silica gel column eluting with EtOAc to give tert-butyl 3-bromo-6-chloro-2-hydroxybenzoate (10.9 g, 35.5 mmol, 70.9%) as a brown oil.

[0515] 1 H-NMR (CDCI3) δ: 11.69 (1 H, s), 7.52 (1 H, d, J = 8.7 Hz), 6.86 (1 H, d, J = 8.7 Hz), 1.64 (9H, s).

[0516] 3-bromo-6-chloro-2-hydroxybenzoic acid (Intermediate 7B)

[0517] To a solution of 3-bromo-6-chloro-2-hydroxybenzoic acid tert-butyl ester (10.9 g, 35.5 mmol) in dichloromethane (82 mL) was added TFA (27 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, 68.2%) as a white solid.

[0518] 1 H-NMR (CDCI3) δ: 11.90 (1H, s), 7.63 (1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 8.7 Hz).

[0519] 7-bromo-4-chlorobenzo[d]oxazole-2(3H)-one (7)

[0520] To a solution of 3-bromo-6-chloro-2-hydroxybenzoic acid (6.08 g, 24.2 mmol) in toluene (122 mL) was added triethylamine (4.04 mL, 29.0 mmol) and diphenyl phosphorazide (5.46 mL, 25.4 mmol). The mixture was heated at 110 °C for 15.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water and a small amount of DCM were added and the resulting precipitate was collected by filtration. The filter cake was washed with DCM and dried under high vacuum to give 7-bromo-4-chlorobenzo[d]oxazole-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 MgS04, filtered and concentrated under reduced pressure. The residue was suspended in DCM and the solid was collected by filtration. The resulting solid was dried under high vacuum to give 7-bromo-4-chlorobenzo[d]oxazole-2(3H)-one (1.05 g, 4.22 mmol, 17.4%) as a white solid.

[0521] 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).

[0522] [Reference Example 8]

[0523] 4-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazole-2(3H)-one (8)

[0524] 7-bromo-4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 8)

[0525] To a 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) in DMF (16 mL) was added 2-(chloromethoxy)ethyltrimethylsilane (2.01 g, 12.1 mmol) and 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 MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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 light yellow oil.

[0526] 1 H-NMR (CD3OD) δ: 7.35 (1H, d, J = 9.1 Hz), 7.20 (1H, d, J = 8.7 Hz), 5.52 (2H, s), 3.74 (2H, t, J = 8.0 Hz), 0.94 (2H, t, J = 7.3 Hz), 0.00 (9H, s).

[0527] 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (8)

[0528] A mixture of 7-bromo-4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (2.22 g, 5.87 mmol), pinacol diborane (1.64 g, 6.46 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (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 pad of celite. The filtrate was poured into water and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to give 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as a dark brown syrup which was used in the next step without further purification.

[0529] [Reference Example 9]

[0530] 4-Fluoro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (9)

[0531] 7-Bromo-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 9)

[0532] To a 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) in DMF (32 mL) was added 2- (chloromethoxy)ethyltrimethylsilane (3.23 g, 19.4 mmol) and stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over MgS04, 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.

[0533] 1 H-NMR (CDC13) δ: 7.24 (1H, dd, J = 9.1, 4.6 Hz), 6.92 (1H, t, J = 9.6 Hz), 5.35 (2H, s), 3.70 (2H, t, J = 8.2 Hz), 0.97 (2H, t, J = 8.2 Hz), 0.00 (9H, s).

[0534] 4-Fluoro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (9)

[0535] 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(pinacolato)diboron (3.61 g, 14.2 mmol), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (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 h. After cooling to ambient temperature, the mixture was filtered through a pad of celite. 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-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as a brownish paste, which was used in the next step without further purification.

[0536] 1 H-NMR (CDCI3) δ: 7.51 (1H, dd, J = 8.7, 5.5 Hz), 6.99 (1H, dd, J = 10.1, 8.7 Hz), 5.38 (2H, s), 3.69 (2H, t, J = 8.2 Hz), 1.30 (12H, s), 0.97 (2H, t, J = 8.2 Hz), 0.00 (9H, s).

[0537] [Reference Example 10]

[0538] 2-(Difluoromethoxy)-6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (10)

[0539] A mixture of 3-bromo-2-(difluoromethoxy)-6-(difluoromethyl)pyridine (447 mg, 1.63 mmol), bis(pinacolato)diboron (621 mg, 2.45 mmol), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (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 h. After cooling to ambient temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and used without further purification.

[0540] MS: m / z 240.10 (boronic acid + H) + .

[0541] [Reference Example 11]

[0542] 8-azadispiro[2.1.2 5 .3 3 ]decane hydrochloride (11)

[0543] 8-azadispiro[2.1.2 5 .3 3 ]decane-8-carboxylic acid tert-butyl ester (intermediate 11)

[0544] Diethylzinc (13.4 mL, 13.4 mmol) was added dropwise to dry DCM (10 mL) at -40 °C under argon atmosphere. CH2I2(2.16 mL, 26.9 mmol) was then added dropwise to the reaction mixture. The reaction was then stirred at the same temperature for 30 minutes. 7-Methylene-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester was dissolved in dry DCM (5 mL) and added dropwise to the reaction mixture at the same temperature. The mixture was then gradually warmed to 4 °C and stirred for 20 hours. The reaction mixture was then quenched with saturated aqueous NH4Cl solution and extracted with 5% MeOH in DCM. The organic phase was dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by Combi flash column chromatography (eluted with 2-3% ethyl acetate in hexane) to give the desired product (250 mg, 39.2%).

[0545] 1 H-NMR (CDCI3) δ: 3.48 (2H, br s), 1.45 (9H, s), 1.32-1.21 (4H, m), 0.84 (2H, bs), 0.60 (2H, s), 0.31-0.24 (4H, m).

[0546] 8-azadispiro[2.1.2 5 .3 3 ]decane hydrochloride (11)

[0547] To a stirred solution of 8-azadispiro[2.1.2 5 .3 3 ]decane-8-carboxylic acid tert-butyl ester (300 mg, 1.26 mmol) in DCM (6 mL) was added 4N HCI in dioxane (6 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and triturated with n-pentane to give the desired compound (150 mg, 68.3%) as a yellow solid in the form of a hydrochloride salt.

[0548] The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and triturated with n-pentane to give the desired compound (150 mg, 68.3%) as a yellow solid in the form of a hydrochloride salt.

[0549] MS: m / z 137.98 (M+H) + .

[0550] MS: m / z 137.98 (M+H)1 H-NMR (CDC13) D: 9.27 (2H, br s), 3.10 (2H, br s), 1.58 (2H, br s), 1.51 (2H, br s), 0.99 (2H, t, J = 6.08 Hz), 0.68 (2H, t, J = 6.12 Hz), 0.38 (4H, s).

[0551] [Reference Example 12]

[0552] 3-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (12)

[0553] A mixture of 6-bromo-3-fluoropyridin-2-amine (200 mg, 1.05 mmol), bis(pinacolato)diboron (399 mg, 1.57 mmol), [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (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 h. After cooling to ambient temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and used without further purification.

[0554] [Reference Example 13]

[0555] 7-Bromo-4,5-difluorobenzo[d]oxazole-2(3H)-one (13)

[0556] 3-Bromo-5,6-difluoro-2-hydroxybenzoic acid tert-butyl ester (Intermediate 13A)

[0557] To a cooled solution of tert-butyl 2-bromo-4,5-difluorophenyl carbonate (4.00 g, 12.9 mmol) in THF (30 mL) at -78 °C was added dropwise lithium diisopropylamide (7.12 mL, 14.2 mmol, 2 M) over 5 min under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 h, then allowed to warm gradually to room temperature and stirred for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / heptane = 0% to 19%) to give tert-butyl 3-bromo-5,6-difluoro-2-hydroxybenzoate (3.22 g, 10.4 mmol, 80.6%) as a light yellow solid.

[0558] 1H-NMR (CDC13) δ: 11.85 (1H, s), 7.56 (1H, dd, J = 9.4, 8.0 Hz), 1.63 (9H, s).

[0559] 3-bromo-5,6-difluoro-2-hydroxybenzoic acid tert-butyl ester (intermediate 13B)

[0560] To a solution of 3-bromo-5,6-difluoro-2-hydroxybenzoic acid tert-butyl ester (3.22 g, 10.4 mmol) in dichloromethane (10 mL) was added TFA (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, 56.3%) as a white solid.

[0561] MS: m / z 252.90 (M+H) + .

[0562] 7-bromo-4,5-difluorobenzo[d]oxazole-2(3H)-one (13)

[0563] To a solution of 3-bromo-5,6-difluoro-2-hydroxybenzoic acid (1.49 g, 5.88 mmol) in toluene (30 mL) was added triethylamine (0.981 mL, 7.05 mmol) and diphenyl phosphorazide (1.33 mL, 6.17 mmol). 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 column chromatography on silica gel (EtOAc / heptane = 19% - 40%) to give 7-bromo-4,5-difluorobenzo[d]oxazole-2(3H)-one (1.26 g, 5.03 mmol, 85.6%) as a light yellow solid.

[0564] MS: m / z 249.90 (M+H) + .

[0565] [Reference Example 14]

[0566] 4,5-difluoro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazole-2(3H)-one (14)

[0567] 7-bromo-4,5-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazole- 2(3H)-one (intermediate 14)

[0568] To a 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) in DMF (15 mL) was added 2-(chloromethoxy)ethyltrimethylsilane (1.26 g, 7.54 mmol) and 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 column chromatography on silica gel (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.

[0569] 1 H-NMR (DMSO-d6) δ: 7.70 (1H, dd, J = 11.4, 6.9 Hz), 5.25 (2H, s), 3.65 (2H, t, J = 8.0 Hz), 0.87 (2H, t, J = 8.0 Hz), -0.04 (9H, s).

[0570] 4,5-Difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (14)

[0571] 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), pinacol diborane (1.46 g, 5.74 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (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 pad of celite. 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 4,5-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as a brown syrup which was used in the next step without further purification.

[0572] [Reference Example 15]

[0573] 4-Chloro-5-fluoro-7-iodobenzo[d]oxazol-2(3H)-one (15)

[0574] (5-chloro-4-fluoro-2-iodophenyl) tert-butyl carbonate (Intermediate 15A)

[0575] 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) was added di-tert-butyl dicarbonate (2.05 g, 9.38 mmol) and the mixture was stirred at room temperature overnight. 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 column chromatography on silica gel (EtOAc / heptane = 0% - 4%) to give the title compound (2.48 g, 6.64 mmol, 85.0%) as a colorless oil.

[0576] 1 H-NMR (CDCI3): 7.59 (1 H, d, J = 7.8 Hz), 7.24 (1 H, d, J = 6.9 Hz), 1.58 (9 H, s).

[0577] 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid tert-butyl ester (Intermediate 15B)

[0578] To a cooled solution of (5-chloro-4-fluoro-2-iodophenyl) tert-butyl carbonate (2.48 g, 6.64 mmol) in THF (19 mL) at -78°C under a nitrogen atmosphere was added dropwise lithium diisopropylamide (3.65 mL, 7.31 mmol, 2 M) over 5 minutes. The resulting mixture was stirred at the same temperature for 1 hour, then allowed to warm up to room temperature and stirred for 2 hours. The reaction was quenched by the addition of a saturated aqueous NH4C1 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / heptane = 0% - 4%) to give 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid tert-butyl ester (1.63 g, 4.37 mmol, 65.8%) as a light yellow oil.

[0579] 1 H-NMR (CDCI3) δ: 11.69 (1 H, s), 7.71 (1 H, d, J = 7.8 Hz), 1.64 (9 H, s).

[0580] 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid (Intermediate 15C)

[0581] To a solution of tert-butyl 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoate (1.63 g, 4.37 mmol) in dichloromethane (10 mL) was added TFA (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, 95.5%) as a brown solid which was used in the next step without further purification.

[0582] MS: m / z 316.90 (M+H) + .

[0583] 4-Chloro-5-fluoro-7-iodobenzo[d]oxazole-2(3H)-one (15)

[0584] To a solution of 2-chloro-3-fluoro-6-hydroxy-5-iodobenzoic acid (1.32 g, 4.18 mmol) in toluene (26 mL) was added triethylamine (0.698 mL, 5.01 mmol) and diphenyl phosphorazide (0.943 mL, 4.39 mmol). 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 column chromatography on silica gel (EtOAc / heptane = 17% - 38%) to give 4-chloro-5-fluoro-7-iodobenzo[d]oxazole-2(3H)-one (964 mg, 3.08 mmol, 73.7%) as a white solid.

[0585] MS: m / z 313.90 (M+H) + .

[0586] [Reference Example 16]

[0587] 7-Bromo-4-(trifluoromethyl)benzo[d]oxazole-2(3H)-one (16)

[0588] tert-Butyl 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoate (Intermediate 16A)

[0589] To a cooled solution of tert-butyl 2-bromo-5-(trifluoromethyl)phenyl carbonate (3.00 g, 8.79 mmol) in THF (23 mL) at -78 °C under nitrogen was added dropwise lithium diisopropylamide (4.84 mL, 9.67 mmol, 2 M) over 5 min. The resulting mixture was stirred at the same temperature for 1 h, then allowed to warm up to rt gradually and stirred for 2 h. The reaction was quenched with the addition of saturated aqueous NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / heptane = 7% to 28%) to give tert-butyl 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoate (2.48 g, 7.28 mmol, 82.8%) as a light yellow oil.

[0590] 1 H-NMR (CDCI3) δ: 11.15 (1H, s), 7.73 (1H, d, J = 8.7 Hz), 7.17 (1H, d, J = 8.4 Hz), 1.61 (9H, s).

[0591] 3-Bromo-2-hydroxy-6-(trifluoromethyl)benzoic acid (Intermediate 16B)

[0592] To a solution of tert-butyl 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoate (2.48 g, 7.28 mmol) in dichloromethane (20 mL) was added TFA (10 mL) and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to give 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoic acid as a light yellow solid which was used in the next step without further purification.

[0593] MS: m / z 284.90 (M+H) + .

[0594] 7-Bromo-4-(trifluoromethyl)benzo[d]oxazole-2(3H)-one (16)

[0595] To a solution of 3-bromo-2-hydroxy-6-(trifluoromethyl)benzoic acid (2.07 g, 7.28 mmol) in toluene (41 mL) was added triethylamine (1.22 mL, 8.73 mmol) and diphenyl phosphorazide (1.64 mL, 7.64 mmol). The mixture was heated at 110 °C overnight. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / heptane = 7% to 28%) to give 7-bromo-4-(trifluoromethyl)benzo[d]oxazole-2(3H)-one (1.25 g, 4.45 mmol, 61.1%) as a white solid.

[0596] MS: m / z 282.00 (M+H) + .

[0597] 1 H-NMR (DMSO-d6) δ: 12.63 (1H, s), 7.48 (1H, d, J = 8.7 Hz), 7.40 (1H, d, J = 8.7 Hz).

[0598] [Reference Example 17]

[0599] 4-Chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (17)

[0600] A mixture of 4-bromo-7-chloro-l,3-dihydro-2H-benzo[d]imidazol-2-one (200 mg, 808 μmol), bis(pinacolato)diboron (308 mg, 1.21 mmol), [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (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 h. After cooling to ambient temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound which was used in the next step without further purification.

[0601] MS: m / z 295.10 (M+H) + .

[0602] [Reference Example 18]

[0603] 6-Bromo-3-fluoro-N-methylpyridin-2-amine (18)

[0604] 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 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / heptane = 8% to 29%) to give 6-bromo-3-fluoro-N-methylpyridin-2-amine (29.2 mg, 142 μmol, 6.0%) as a colorless oil.

[0605] MS: m / z 205.00 (M+H) + .

[0606] [Reference Example 19]

[0607] 7-bromo-4,6-difluorobenzo[d]oxazol-2(3H)-one (19)

[0608] To a solution of 3-bromo-4,6-difluoro-2-hydroxybenzoic acid (417 mg, 1.65 mmol) in toluene (8 mL) was added triethylamine (275 μL, 1.98 mmol) and diphenyl phosphorazide (372 μL, 1.73 mmol). 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 column chromatography on silica gel (EtOAc / heptane = 21% - 42%) to give 7-bromo-4,6-difluorobenzo[d]oxazol-2(3H)-one (320 mg, 1.28 mmol, 77.7%) as a light yellow solid.

[0609] MS: m / z 249.90 (M+H) + .

[0610] [Reference Example 20]

[0611] (S)-5-bromo-l-(oxetan-2-ylmethyl)-lH-pyrazolo[3,4-b]pyrazine (20)

[0612] A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (500 mg, 2.51 mmol), (S)-oxetan-2-ylmethanol (288 mg, 3.27 mmol) and triphenylphosphine (988 mg, 3.77 mmol) was suspended in THF (10 mL). Diisopropyl azodicarboxylate (660 mg, 3.27 mmol) was then added dropwise to the suspension and the mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgS04and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 23% - 44%) to give the title compound (675 mg, 2.51 mmol, 100%) as a light yellow solid.

[0613] MS: m / z 269.00 (M+H) + .

[0614] [Reference Example 21]

[0615] (R)-5-bromo-l-(oxetan-2-ylmethyl)-lH-pyrazolo[3,4-b]pyrazine (21)

[0616] A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (500 mg, 2.51 mmol), (R)-oxetan-2- ylmethanol (288 mg, 3.27 mmol) and triphenylphosphine (988 mg, 3.77 mmol) was suspended in THF (10 mL). Diisopropyl azodicarboxylate (660 mg, 3.27 mmol) was then added dropwise to the suspension and the mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgS04and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / Heptane = 23% - 44%) to give the title compound (675 mg, 2.51 mmol, 100%) as a light yellow solid.

[0617] MS: m / z 269.00 (M+H) + .

[0618] [Reference Example 22]

[0619] 6-chloro-2-(methylamino)nicotinonitrile (22)

[0620] To a solution of 2-amino-6-chloronicotinonitrile (200 mg, 1.30 mmol) and sodium hydride (62.5 mg, 60 wt%, 1.56 mmol) in DMF (3 mL) was added iodomethane (89.6 μί, 1.43 mmol) at room temperature. 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 MgS04and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 9% - 30% EtOAc in heptane) to give the title compound (44.3 mg, 264 μιηοΐ, 20%).

[0621] MS: m / z 168.00 (M+H) + .

[0622] [Reference Example 23]

[0623] 2-(6-bromo-3-chloropyridin-2-yl)acetonitrile (23)

[0624] tert-butyl 2-(6-bromo-3-chloropyridin-2-yl)-2-cyanoacetate (Intermediate 23)

[0625] To a solution of sodium hydride (143 mg, 60 wt%, 3.56 mmol) in DMF (5 mL) was added tert-butyl cyanoacetate (242 mg, 1.71 mmol). After stirring at room temperature for 30 min, 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 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgS04and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with 0-7% EtOAc in heptane) to give the desired compound (413 mg, 1.25 mmol, 87%) as a yellow oil.

[0626] MS: m / z 274.90 (M+H) + -tBu.

[0627] 2-(6-bromo-3-chloropyridin-2-yl)acetonitrile (23)

[0628] 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) was added TFA (2 mL) at room temperature. The mixture was stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with 19-39% EtOAc in heptane) to give the title compound (150 mg, 648 pmol, 52%) as a colorless oil.

[0629] MS: m / z 230.90 (M+H) + .

[0630] [Reference Example 24]

[0631] 2-((6-bromo-3-chloropyridin-2-yl)amino)acetonitrile (24)

[0632] A mixture of 6-bromo-3-chloro-2-fluoropyridine (350 mg, 1.66 mmol), aminoacetonitrile hydrochloride (185 mg, 2.00 mmol) and DIEA (869 pL, 4.99 mmol) in DMSO (3 mL) was stirred at 100 °C for 3 h. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgS04and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with 25-46% EtOAc in heptane) to give 2-((6-bromo-3-chloropyridin-2-yl)amino)acetonitrile (272 mg, 1.10 mmol, 66%) as a white solid.

[0633] MS: m / z 245.90 (M+H) + .

[0634] [Reference Example 25]

[0635] 6-azaspiro[2.5]octane-4-carbonitrile (25)

[0636] 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-4-carboxylic acid (Intermediate 25A)

[0637] To a stirred solution of 6-(tert-butyl) 4-methyl 6-azaspiro[2.5]octane-4,6- dicarboxylate (873 mg, 3.24 mmol) in methanol (5 mL) and THF (5 mL) was added 2 M aqueous NaOH (10 mL). The mixture was stirred at room temperature for 20 h. The mixture was neutralized with 1 N aqueous HC1 and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The crude product was used in the next reaction without further purification.

[0638] MS: m / z 200.10 (M+H) + -tBu.

[0639] 4-aminocarbonyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (Intermediate 25B)

[0640] A mixture of the above crude, ammonium chloride (347 mg, 6.48 mmol), O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 h. To the mixture was added water and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 100% EtOAc) to give the semi-pure desired compound (824 mg, 3.24 mmol, 100%) as a light yellow gum.

[0641] MS: m / z 199.10 (M+H) + -tBu.

[0642] 4-cyano-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (Intermediate 25C)

[0643] To a solution of 4-aminocarbonyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (824 mg, 3.24 mmol) and triethylamine (2.26 mL, 16.2 mmol) in DCM (20 mL) was added trifluoroacetic anhydride (1.13 mL, 8.10 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. To the mixture was added water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was used in the next reaction without further purification.

[0644] MS: m / z 181.10 (M+H) + -tBu.

[0645] 6-azaspiro[2.5]octane-4-carbonitrile (25)

[0646] To the above crude mixture in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (10 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was filtered through SCX to give 6-azaspiro[2.5]octane-4-carbonitrile crude. The crude product was used in the next reaction without further purification.

[0647] [Example A-1]

[0648] 1-(difluoromethyl)-5-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine (A-1)

[0649] A mixture of 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (39.0 mg, 157 μmol), 2,4-difluorophenylboronic acid (32.2 mg, 204 μmol), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (11.5 mg, 15.7 μmol), and sodium carbonate (33.2 mg, 313 μmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the target compound (28.0 mg, 99.2 μmol, 63.3%) as an off-white solid.

[0650] MS: m / z 283.08 (M+H) + .

[0651] 1H-NMR (DMSO-d6) δ: 9.11 (1H, d, J = 2.3 Hz), 8.92 (1H, s), 8.33 (1H, t, J = 57.2 Hz), 8.02 (1H, td, J = 8.8, 6.7 Hz), 7.56-7.51 (1H, m), 7.35 (1H, td, J = 8.5, 2.6 Hz).

[0652] Compounds A-2 to A-56 shown in Table 1 below were synthesized according to the synthetic method described in Example A-1. Analytical data are shown in Table 2 below.

[0653] Table 1

[0654] Table 2

[0655] [Example B-1]

[0656] 7-(1-(Difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (B-1)

[0657] 7-(1-(Difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluoro-3-((2- (Trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate B-1)

[0658] A mixture of 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (50.0 mg, 201 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 (82.2 mg, 201 μmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (14.7 mg, 20.1 μmol), and sodium carbonate (42.6 mg, 402 μmol) in a 1,4-dioxane (1 mL) / water (0.1 mL) solution was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered through an anhydrous MgSO4 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 (27.6 mg, 61.1 μmol, 30.4%) as a colorless oil.

[0659] MS:m / z 452.10(M+H) + .

[0660] 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one (B-1)

[0661] A mixture of 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (27.6 mg, 61.1 μmol) and TFA (1 mL) was stirred at room temperature for 30 minutes and 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 and concentrated under reduced pressure. DCM (5 mL) was added to the crude residue and sonicated. The precipitate was collected by filtration. The collected solid was washed with DCM and dried under high vacuum to give the title compound (18.9 mg, 58.8 μmol, 96.2%) as a white solid.

[0662] MS:m / z 322.00(M+H) + .

[0663] 1 H-NMR (DMSO-d6) δ: 9.28 (1H, s), 8.92 (1H, s), 8.33 (1H, t, J = 56.9 Hz), 7.80 (1H, dd, J = 9.1, 5.0 Hz), 7.30 (1H, t, J = 9.4 Hz).

[0664] Compounds B-2 to B-13 shown in Table 3 below were synthesized according to the synthetic method described in Example B-1. Analytical data are shown in Table 4 below.

[0665] Table 3

[0666] Table 4

[0667] [Example C-1]

[0668] 1-(Difluoromethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1H-pyrazolo[3,4- b]pyrazine (C-1)

[0669] To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (60.0 mg, 241 µmol) and 6-chloro-2-(difluoromethyl)-3-fluoropyridine (43.7 mg, 241 µmol) in 1,4-dioxane (1 mL) was added hexamethylditin (118 mg, 361 µmol) and tetrakis(triphenylphosphine)palladium(0) (27.8 mg, 24.1 µmol). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (20.5 mg, 65.0 µmol, 27.0%) as a white solid.

[0670] MS: m / z 316.03 (M+H) + .

[0671] 1 H-NMR (DMSO-d6) δ: 9.61 (1H, d, J = 0.9 Hz), 8.95 (1H, s), 8.65 (1H, dd, J = 8.7, 3.2 Hz), 8.36 (1H, t, J = 56.8 Hz), 8.22-8.17 (1H, m), 7.31 (1H, t, J = 53.1 Hz).

[0672] Compounds C-2 to C-33 shown in Table 5 below were synthesized according to the synthetic method described in Example C-1. Analytical data are shown in Table 6 below.

[0673] Table 5

[0674] Table 6

[0675] [Example D-1]

[0676] 1-(Difluoromethyl)-5-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (D-1)

[0677] To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (30.0 mg, 120 pmol) and 6-azaspiro[2.5]octane hydrochloride (26.7 mg, 181 pmol) in DMSO (1 mL) was added DIEA (82.0 pL, 482 pmol). The mixture was stirred at 150 °C for 3 hours under microwave irradiation. After cooling to room temperature, the mixture was directly purified by silica gel column chromatography (EtOAc / heptane = 9% - 30%) to give the title compound (21.8 mg, 78.1 pmol, 64.8%) as a yellow solid.

[0678] MS: m / z 280.10 (M+H) + .

[0679] 1 H-NMR (DMSO-d6) d: 8.59 (1H, s), 8.31 (1H, s), 8.07 (1H, t, J = 57.6 Hz), 3.71 (4H, dd, J = 6.4, 4.6 Hz), 1.42 (4H, dd, J = 6.4, 4.6 Hz), 0.36 (4H, s).

[0680] The compounds D-2 to D-13 shown in Table 7 below were synthesized according to the synthetic method described in Example D-1. Analytical data are shown in Table 8 below.

[0681] Table 7

[0682] Table 8

[0683] [Example E-1]

[0684] 5-(7,7-Difluoro-4-azaspiro[2.5]octan-4-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (E-1)

[0685] To a solution of 5-bromo-l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazine (39.0 mg, 157 pmol), 7,7-difluoro-4-azaspiro[2.5]octane hydrochloride (34.5 mg, 188 pmol) and cesium carbonate (153 mg, 470 pmol) in 1,4-dioxane (1 mL) was added palladium(II) acetate (3.5 mg, 15.6 pmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (14.6 mg, 31.3 pmol). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (4.29 mg, 13.6 pmol, 8.7%) as a light yellow solid.

[0686] MS: m / z 316.18 (M+H) + .

[0687] Compounds E-2 to E-4 shown in Table 9 below were synthesized according to the synthetic method described in Example E-1. Analytical data are shown in Table 10 below.

[0688] Table 9

[0689] Table 10

[0690] [Example F-1]

[0691] 3,5-dibromo-6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine (F-1)

[0692] 6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate F-1)

[0693] To a solution of 6-chloro-lH-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol) and 6-azaspiro[2.5]octane hydrochloride (344 mg, 2.33 mmol) in DMF (3 mL) was added DIEA (990 pL, 5.82 mmol). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was directly purified by column chromatography on silica gel (EtOAc / heptane = 58%-79%) to give the title compound (194 mg, 846 pmol, 43.6%) as a yellow solid.

[0694] MS: m / z 230.20 (M+H) + .

[0695] 3,5-dibromo-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (F-1)

[0696] A mixture of 6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (184 mg, 803 µmol) and N-bromosuccinimide (214 mg, 1.20 mmol) in DMF (2 mL) was heated at 100 °C for 1 h. After cooling to rt, the mixture was directly purified by column chromatography on silica gel (EtOAc / heptane = 28-49%) to give the title compound (76.3 mg, 197 µmol, 24.6%) as a yellow solid.

[0697] MS: m / z 385.90 (M+H) + .

[0698] 1 H-NMR (DMSO-d6) δ: 3.42 (4H, t, J = 5.3 Hz), 1.52 (4H, t, J = 5.3 Hz), 0.36 (4H, s).

[0699] [Example F-2]

[0700] 3-chloro-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (F-2)

[0701] 6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (Intermediate F-2)

[0702] To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol) and 6-azaspiro[2.5]octane hydrochloride (344 mg, 2.33 mmol) in DMF (3 mL) was added DIEA (990 µL, 5.82 mmol). The mixture was stirred at 100 °C overnight. After cooling to rt, the mixture was directly purified by column chromatography on silica gel (EtOAc / heptane = 58-79%) to give the title compound (194 mg, 846 µmol, 43.6%) as a yellow solid.

[0703] MS: m / z 230.20 (M+H) + .

[0704] 3-chloro-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (F-2)

[0705] A mixture of 6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine (15.0 mg, 65.4 pmol) and N-chlorosuccinimide (13.1 mg, 98.1 pmol) in DMF (1 mL) was heated at 100 °C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC to give the title compound (7.15 mg, 27.1 pmol, 41.4%) as a light yellow solid.

[0706] MS: m / z 264.11 (M+H) + .

[0707] 1 H-NMR (DMSO-d6) δ: 8.18 (1H, s), 3.40 (4H, t, J = 5.3 Hz), 1.52 (4H, t, J = 5.3 Hz), 0.36 (4H, s).

[0708] Compounds F-3 to F-5 shown in Table 11 below were synthesized according to the synthetic method described in Example F-2. Analytical data are shown in Table 12 below.

[0709] Table 11

[0710] Table 12

[0711] [Example F-6]

[0712] 3-chloro-6-(2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyrazine (F-6)

[0713] 6-(2,4-difluorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate F-6A)

[0714] A mixture of 6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyrazine (122 mg, 428 pmol), (2,4-difluorophenyl)boronic acid (87.9 mg, 557 pmol), [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (31.3 mg, 42.8 pmol) and sodium carbonate (90.8 mg, 857 pmol) in 1,4-dioxane (2 mL) / water (0.2 mL) was stirred at 100 °C for 2.5 h. After cooling to room temperature, the mixture was filtered through a pad of anhydrous MgS04. The filtrate was concentrated under reduced pressure to give a crude mixture which was used in the next step without further purification.

[0715] MS: m / z 363.10 (M+H) + .

[0716] 6-(2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate F-6B)

[0717] A mixture of the above crude mixture and TFA (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. To the residue was added 2 M NH3 / methanol (2 mL), the mixture was stirred at room temperature for 30 min, and the mixture was concentrated under reduced pressure. To the crude residue was added DCM and sonicated. The precipitate was collected by filtration. The collected solid was washed with DCM and dried under high vacuum to give the title compound (154 mg, 662 pmol, >100%) as a dark brown solid with impurities.

[0718] MS: m / z 233.00 (M+H) + .

[0719] 3-chloro-6-(2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyrazine (F-6)

[0720] A mixture of 6-(2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyrazine (11.4 mg, 49.1 pmol) and N-chlorosuccinimide (13.1 mg, 98.2 pmol) in DMF (0.5 mL) was heated at 100 °C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC to give the title compound (7.70 mg, 28.9 pmol, 58.8%) as a white solid.

[0721] MS: m / z 267.05 (M+H) + .

[0722] The compounds F-7 shown in Table 13 below were synthesized according to the synthetic method described in Example F-6. Analytical data are shown in Table 14 below.

[0723] Table 13

[0724] Table 14

[0725] [Example F-8]

[0726] 3-chloro-5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrazolo[3,4-b]pyrazine (F-8)

[0727] 3-chloro-5-(2-chloro-4-fluorophenyl)-1 H-pyrazolo[3,4-b]pyrazine (Intermediate F-8)

[0728] A mixture of 5-(2-chloro-4-fluorophenyl)-1 H-pyrazolo[3,4-b]pyrazine (32.4 mg, 130 μmol) and N-chlorosuccinimide (20.9 mg, 156 μmol) in DMF (0.6 mL) was heated at 60 °C for 2 h. After cooling to room temperature, water was added and the resulting precipitate was collected by filtration. The filter cake was washed with water and dried under high vacuum. The resulting solid was purified by HPLC to give the title compound (10.4 mg, 36.7 μmol, 28.2%).

[0729] MS: m / z 282.95 (M+H) + .

[0730] 3-chloro-5-(2-chloro-4-fluorophenyl)-1-methyl-1 H-pyrazolo[3,4-b]pyrazine (F-8)

[0731] To a mixture of 3-chloro-5-(2-chloro-4-fluorophenyl)-1 H-pyrazolo[3,4-b]pyrazine (17.8 mg, 62.9 μmol) and potassium carbonate (17.4 mg, 126 μmol) in DMF (0.3 mL) was added iodomethane (13.4 mg, 94.3 μmol). The mixture was stirred at room temperature for 30 min, then diluted with water and extracted with DCM (4 x 2 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (9.85 mg, 33.2 μmol, 52.7%) as a white solid.

[0732] MS: m / z 296.85 (M+H) + .

[0733] 1H-NMR (DMSO-d6) δ: 8.99 (1H, s), 7.76 (1H, dd, J = 8.5, 6.2 Hz), 7.69 (1H, dd, J = 9.1, 2.7 Hz), 7.44 (1H, td, J = 8.5, 2.6 Hz), 4.12 (3H, s).

[0734] [Examples F-9, F-10]

[0735] 3-chloro-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1 H-pyrazolo[3,4-b]pyrazine (F-9)

[0736] 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine (F-10)

[0737] To a mixture of 3-chloro-5-(2-chloro-4-fluorophenyl)-lH-pyrazolo[3,4- b]pyrazine (35.3 mg, 125 pmol), sodium 2-chloro-2,2-difluoroacetate (38.0 mg, 249 pmol) and potassium carbonate (51.7 mg, 374 pmol) in DMF (1 mL) was added. The reaction mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give 3-chloro-5-(2-chloro-4-fluorophenyl)-l-(difluoromethyl)-lH-pyrazolo[3,4- b]pyrazine (F-9, 4.33 mg, 13.0 pmol, 10.4%, light yellow solid) and 3-chloro-5-(2- chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine (F-10, 4.36 mg, 13.1 pmol, 10.5%, light yellow solid).

[0738] MS: m / z 332.98 (M+H) + [F-9]

[0739] MS: m / z 332.97 (M+H) + [F-10]

[0740] 1 H-NMR (DMSO-d6) δ: 9.16 (1H, s), 8.34 (1H, t, J = 56.7 Hz), 7.78 (1H, dd, J = 8.7, 6.4 Hz), 7.72 (1H, dd, J = 8.9, 2.5 Hz), 7.47 (1H, td, J = 8.5, 2.3 Hz). [F-9]

[0741] [Examples F-11, F-12]

[0742] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-l-(difluoromethyl)-lH-pyrazolo[3,4- b]pyrazine (F-11)

[0743] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4- b]pyrazine (F-12)

[0744] 5-bromo-l,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (Intermediate F-11A)

[0745] To a solution of 3,6-dibromopyrazine-2-carboxylic acid methyl ester (3.00 g, 10.1 mmol) in ethanol (25 mL) was added hydrazine monohydrate (558 mg, 11.2 mmol). The reaction mixture was stirred at reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. To the crude residue was added DCM (20 mL) and sonicated. The precipitate was collected by filtration. The collected solid was washed with DCM and dried under high vacuum to give the title compound (1.009 g, 4.69 mmol, 46.3%) as a light yellow solid.

[0746] MS: m / z 214.90 (M+H) + .

[0747] 5-bromo-3-chloro-lH-pyrazolo[3,4-b]pyrazine (Intermediate F-11B)

[0748] A mixture of 5-bromo-l,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (500 mg, 2.33 mmol, 100 mass) and phosphorus oxychloride (5 mL) was stirred at 110 °C overnight. The mixture was carefully basified with the addition of EtOAc and saturated aqueous NaHC03solution, then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc / heptane = 19% - 40%) to give the title compound (44.0 mg, 188 pmol, 8.1%) as a light yellow solid.

[0749] MS: m / z 233.10 (M+H) + .

[0750] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate F-11C)

[0751] To a solution of 5-bromo-3-chloro-lH-pyrazolo[3,4-b]pyrazine (44.0 mg, 188 μmol), 2-(4-fluoro-2-isopropoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (59.7 mg, 207 μmol) and sodium carbonate (40.0 mg, 377 μmol) in 1,4-dioxane (2 mL) / water (0.2 mL) was added [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (13.8 mg, 18.8 μmol). The reaction mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc / heptane = 16% to 37%) to give the title compound (33.4 mg, 106 μmol, 56.3%) as a light yellow solid.

[0752] MS: m / z 315.00 (M+H) + .

[0753] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-l-(difluoromethyl)-lH-pyrazolo[3,4- b]pyrazine (F-11)

[0754] 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4- b]pyrazine (F-12)

[0755] To a solution of 5-bromo-3-chloro-lH-pyrazolo[3,4-b]pyrazine (44.0 mg, 188 μmol), 2-(4-fluoro-2-isopropoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (59.7 mg, 207 μmol) and sodium carbonate (40.0 mg, 377 μmol) in 1,4-dioxane (2 mL) / water (0.2 mL) was added [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (13.8 mg, 18.8 μmol). The reaction mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc / heptane = 16% to 37%) to give the title compound (33.4 mg, 106 μmol, 56.3%) as a light yellow solid.

[0756] MS: m / z 365.05 (M+H) + . [F-11]

[0757] MS: m / z 365.04 (M+H)+ . [F-12]

[0758] 1 H-NMR (DMSO-d6) δ: 9.15 (1H, s), 8.33 (1H, t, J = 56.7 Hz), 7.89 (1H, dd, J = 8.7, 6.9 Hz), 7.40-7.34 (2H, m), 7.34 (1H, t, J = 78.4 Hz). [F-11]

[0759] [Example G-1]

[0760] 6-(4-Fluoro-2-isopropoxyphenyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (G-1)

[0761] 3-Chloro-5-(4-fluoro-2-isopropoxyphenyl)pyrazine-2-carboxylic acid methyl ester (Intermediate G-1)

[0762] To a solution of 3,5-dichloropyrazine-2-carboxylic acid methyl ester (882 mg, 4.26 mmol), 2-(4-fluoro-2-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (928 mg, 4.69 mmol) and sodium carbonate (903 mg, 8.52 mmol) in 1,4-dioxane (10 mL) / water (1 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (156 mg, 213 μmol). The reaction mixture was stirred at 80 °C for 5 hours. After cooling to room temperature, the mixture was filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc / heptane = 4% - 25%) to give the title compound (1.28 g, 3.94 mmol, 92.5%) as a white solid.

[0763] MS: m / z 325.10 (M+H) + .

[0764] 6-(4-Fluoro-2-isopropoxyphenyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (G-1)

[0765] To a solution of 3-chloro-5-(4-fluoro-2-isopropoxyphenyl)pyrazine-2-carboxylic acid methyl ester (110 mg, 339 pmol) in ethanol (2 mL) was added hydrazine monohydrate (18.7 mg, 373 pmol). After the reaction mixture was stirred at 85 °C for 4 h, additional hydrazine monohydrate (18.7 mg, 373 pmol) was added. The reaction mixture was stirred at 85 °C over the weekend. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (5.55 mg, 19.3 pmol, 5.7%) as a yellow solid.

[0766] MS: m / z 288.77 (M+H) + .

[0767] 1 H-NMR (DMSO-d6) δ: 12.58 (1H, s), 8.85 (1H, s), 7.76 (1H, dd, J = 8.5, 7.1 Hz), 7.15 (1H, dd, J = 11.4, 2.3 Hz), 6.95-6.91 (1H, m), 4.81-4.75 (1H, m), 1.29 (6H, t, J = 4.8 Hz).

[0768] [Example H-1]

[0769] 5-(2-Chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine (H-1)

[0770] A mixture of 5-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine (60.0 mg, 241 pmol), ethyl 2-bromo-2,2-difluoroacetate (58.8 mg, 290 pmol) and sodium carbonate (51.2 mg, 483 pmol) in MeCN (0.8 mL) was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 23% - 44%) then by HPLC to give the title compound (6.51 mg, 21.8 pmol, 9.0%) as a white solid with another isomer (4.29 mg, 14.4 pmol, 6.0%).

[0771] MS: m / z 298.97 (M+H) + .

[0772] 1H-NMR (DMSO-d6) δ: 9.46 (1H, s), 9.05 (1H, s), 8.24 (1H, t, J = 58.5 Hz), 7.78 (1H, dd, J = 8.7, 5.9 Hz), 7.70 (1H, dd, J = 8.7, 2.7 Hz), 7.45 (1H, td, J = 8.5, 2.4 Hz).

[0773] [Example H-2]

[0774] 5-(2-(Difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine (H-2)

[0775] A mixture of 5-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine (33.2 mg, 118 pmol), ethyl 2-bromo-2,2-difluoroacetate (28.9 mg, 142 pmol) and sodium carbonate (25.1 mg, 237 pmol) in MeCN (2 mL) was stirred at 100 °C for 2 days. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 19% - 40%) then by HPLC to give the title compound (3.60 mg, 10.9 pmol, 9.2%) as an off-white solid with another isomer (2.32 mg, 7.93 pmol, 6.7%).

[0776] MS: m / z 331.02 (M+H) + .

[0777] 1 H-NMR (DMSO-d6) δ: 9.44 (1H, s), 9.06 (1H, s), 8.23 (1H, t, J = 58.5 Hz), 7.86 (1H, dd, J = 8.5, 6.6 Hz), 7.40 - 7.32 (2H, m), 7.34 (1H, t, J = 70.0 Hz).

[0778] [Example H-3]

[0779] 2-(2-Chloro-4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-b]pyrazine (H-3)

[0780] To a mixture of 2-(2-chloro-4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (23.9 mg, 96.5 μmol) and NaH (5.8 mg, 145 μmol) in DMF (0.6 mL) was added iodomethane (27.4 mg, 193 μmol). The mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with EtOAc (3 x 3 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (14.00 mg, 53.5 μmol, 55.4%) as a white solid.

[0781] MS: m / z 261.65 (M+H) + .

[0782] 1 H-NMR (DMSO-d6) δ: 8.49 (1H, s), 7.99 (1H, d, J = 3.7 Hz), 7.68 (1H, dd, J = 8.5, 6.2 Hz), 7.61 (1H, dd, J = 9.1, 2.7 Hz), 7.37 (1H, td, J = 8.5, 2.6 Hz), 6.70 (1H, d, J = 3.7 Hz), 3.88 (3H, s).

[0783] [Example H-4]

[0784] 5-(2-Chloro-4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyrazine (H-4)

[0785] To a mixture of 5-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine (15.1 mg, 60.7 μmol) and potassium carbonate (16.8 mg, 121 μmol) in DMF (0.4 mL) was added iodomethane (12.9 mg, 91.1 μmol). The mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with EtOAc (4 x 2 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (8.95 mg, 34.1 μmol, 56.1%) as a white solid.

[0786] MS: m / z 262.95 (M+H) + .

[0787] 1H-NMR (DMSO-d6) δ: 8.87 (1H, s), 8.53 (1H, s), 7.74 (1H, dd, J = 8.5, 6.2 Hz), 7.67 (1H, dd, J = 8.9, 2.5 Hz), 7.42 (1H, td, J = 8.5, 2.6 Hz), 4.14 (3H, s).

[0788] [Example H-5]

[0789] 5-(5-Fluoropyridin-2-yl)-l-isopropyl-lH-pyrazolo[3,4-b]pyrazine (H-5)

[0790] 5-(5-Fluoropyridin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- b]pyrazine (Intermediate H-5A)

[0791] A mixture of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- b]pyrazine (300 mg, 911 μmol), 2-bromo-5-fluoropyridine (192 mg, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (105 mg, 91.1 μmol) and hexamethylditin (448 mg, 1.37 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 20 h. The crude solution was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with 5% to 26% EtOAc in heptane) to give the desired compound (211 mg, 609 μmol, 66.9%) as an off-white solid.

[0792] MS: m / z 346.10 (M+H) + .

[0793] 5-(5-Fluoropyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate H-5B)

[0794] A mixture of 5-(5-fluoropyridin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-b]pyrazine (211 mg, 609 μmol) and TFA (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. To the residue was added 2 M NH3 / methanol (3 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The product was used in the next step without further purification.

[0795] MS: m / z 216.10 (M+H) + .

[0796] 5-(5-Fluoropyridin-2-yl)-l-isopropyl-lH-pyrazolo[3,4-b]pyrazine (H-5)

[0797] To a solution of the above crude (100 mg, 465 μmol) and potassium carbonate (193 mg, 1.39 mmol) in DMF (2 mL) was added isopropyl iodide (103 mg, 604 μmol). The mixture was stirred at 100 °C for 20 h. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by HPLC to give the title compound (9.03 mg, 35.0 μmol, 7.5%) as a light yellow solid.

[0798] MS: m / z 258.16 (M+H) + .

[0799] [Example H-6]

[0800] 1-Cyclopropyl-5-(5-fluoropyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine (H-6)

[0801] A mixture of 5-(5-fluoropyridin-2-yl)-lH-pyrazolo[3,4-b]pyrazine (18.4 mg, 85.5 μmol), cyclopropylboronic acid hydrate (35.5 mg, 342 μmol), copper acetate (15.5 mg, 85.5 μmol), 2,2'-bipyridine (13.4 mg, 85.5 μmol) and sodium carbonate (18.1 mg, 171 μmol) in 1,2-dichloroethane (0.5 mL) was stirred at 70 °C for 20 h. The crude solution was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified by HPLC to give the title compound (2.66 mg, 10.3 μmol, 12.1%) as an off-white solid.

[0802] MS: m / z 256.17 (M+H) + .

[0803] [Examples I-1, I-2]

[0804] 3-Bromo-5-(2-chloro-4-fluorophenyl)-l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazine (I-1)

[0805] 5-(2-Chloro-4-fluorophenyl)-l-(difluoromethyl)-3-methyl-lH-pyrazolo[3,4-b]pyrazine (I-2)

[0806] 5-bromo-l-(2,4-dimethoxybenzyl)-l,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (Intermediate 1-1A)

[0807] To a stirred solution of 3,6-dibromopyrazine-2-carboxylic acid methyl ester (2.00 g, 6.76 mmol) and (2,4-dimethoxybenzyl)hydrazine hydrochloride (1.48 g, 6.76 mmol) in ethanol (17 mL) was added triethylamine (2.83 mL, 20.3 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature and water was added to the mixture. 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. Ethanol (20 mL) was added to the crude residue and sonicated. The precipitate was collected by filtration. The collected solid was washed with ethanol and dried under high vacuum to give the title compound (739 mg, 2.02 mmol, 29.9%) as a yellow solid. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc / heptane = 9% to 30%) to give the title compound (225 mg, 616 μmol, 9.1%) as a yellow solid.

[0808] MS: m / z 365.00 (M+H) + .

[0809] 5-(2-chloro-4-fluorophenyl)-l-(2,4-dimethoxybenzyl)-l,2-dihydro-3H-pyrazolo[3,4- b]pyrazin-3-one (Intermediate 1-1B)

[0810] A mixture of 5-5-bromo-l-(2,4-dimethoxybenzyl)-l,2-dihydro-3H-pyrazolo[3,4- b]pyrazin-3-one (1.31 g, 3.59 mmol), 2-chloro-4-fluorophenylboronic acid (751 mg, 4.30 mmol), [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (78.7 mg, 108 μmol) and sodium carbonate (760 mg, 7.17 mmol) in 1,4-dioxane (9 mL) / water (0.9 mL) was stirred at 100 °C for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 63% to 84%) to give the title compound (847 mg, 2.04 mmol, 56.9%) as a yellow solid.

[0811] MS: m / z 415.00 (M+H) + .

[0812] 3-bromo-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4- b]pyrazine (I-1)

[0813] A mixture of 5-(2-chloro-4-fluorophenyl)-1-(2,4-dimethoxybenzyl)-1,2-dihydro-3H- pyrazolo[3,4-b]pyrazin-3-one (847 mg, 2.04 mmol) and phosphorus oxybromide (1.17 g, 4.08 mmol) in acetonitrile (20 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and water was added to the mixture. 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 column chromatography on silica gel (EtOAc / heptane = 18% - 39%) to give the title compound (60.7 mg, 185 pmol, 9.1%) as an off-white solid.

[0814] MS: m / z 326.90 (M+H) + .

[0815] 3-bromo-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4- b]pyrazine (I-1)

[0816] To a solution of 3-bromo-5-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine (97.3 mg, 297 pmol) and sodium carbonate (94.5 mg, 891 pmol) in DMF (2 mL) was added ethyl bromodifluoroacetate (77.2 pL, 594 pmol). The reaction mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 10% - 31%) to give the title compound (49.7 mg, 132 pmol, 44.3%) as a white solid.

[0817] MS: m / z 376.96 (M+H) + .

[0818] 5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-3-methyl-1H-pyrazolo[3,4- b]pyrazine (I-2)

[0819] A mixture of 3-bromo-5-(2-chloro-4-fluorophenyl)-l-(difluoromethyl)-lH- pyrazolo[3,4-b]pyrazine (49.7 mg, 132 μmol), trimethyl boroxine (49.6 mg, 395 μmol), [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (9.6 mg, 13.2 μmol) and potassium carbonate (36.4 mg, 263 μmol) in 1,4-dioxane (1 mL) was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC to give the title compound (1.98 mg, 6.33 μmol, 4.8%) as a white solid.

[0820] MS: m / z 313.00 (M+H) + .

[0821] [Example J-1]

[0822] 6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine-3-carbonitrile (J-1)

[0823] 3-iodo-6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate J-1)

[0824] To a stirred solution of 6-chloro-3-iodo-lH-pyrazolo[3,4-b]pyrazine (150 mg, 535 μmol) and 6-azaspiro[2.5]octane hydrochloride (94.8 mg, 642 μmol) in DMF (2 mL) was added DIEA (270 μL, 1.60 mmol). The solution was stirred at 100 °C overnight. After cooling to room temperature, the mixture was poured into water (20 mL) and stirred. The precipitate was collected by filtration. The collected solid was washed with water and dried under high vacuum to give the title compound (183 mg, 514 μmol, 96.1%) as a yellow solid.

[0825] MS: m / z 356.00 (M+H) + .

[0826] 6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine-3-carbonitrile (J-1)

[0827] To a stirred solution of 3-iodo-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4- b]pyrazine (180 mg, 507 pmol) in DMF (2 mL) was added zinc cyanide (119 mg, 1.01 mmol) and [1,1 -Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (37.1 mg, 50.7 pmol). The solution was stirred at 130 °C for 13 h. After cooling to rt, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 25% to 46%) to give the title compound (6.09 mg, 23.9 pmol, 4.7%) as a yellow solid.

[0828] MS: m / z 255.16 (M+H) + .

[0829] 1H-NMR (DMSO-d6) d: 8.59 (1H, s), 3.79 (4H, t, J = 5.5 Hz), 1.42 (4H, t, J = 5.3 Hz), 0.37 (4H, s).

[0830] [Example K-1]

[0831] 6-(4,4-difluoropiperidin-1-yl)isoxazolo[4,5-b]pyrazin-3-amine (K-1)

[0832] 3-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carbonitrile (Intermediate K-1)

[0833] A mixture of 3,5-dichloropyrazine-2-carbonitrile (200 mg, 1.15 mmol), 4,4- difluoropiperidine hydrochloride (199 mg, 1.26 mmol) and DIEA (780 pL, 4.60 mmol) in DMF (3 mL) was stirred at rt for 2 h. The mixture was directly purified by column chromatography on silica gel (EtOAc / heptane = 14% to 35%) to give the title compound (179 mg, 692 pmol, 60.2%) as a white solid.

[0834] MS: m / z 259.00 (M+H) + .

[0835] 6-(4,4-difluoropiperidin-1-yl)isoxazolo[4,5-b]pyrazin-3-amine (K-1)

[0836] A mixture of 3-chloro-5-(4,4-difluoropiperidin-l-yl)pyrazine-2-carbonitrile (54.0 mg, 209 μmol), acetoaldoxime (15.7 mg, 209 μmol) and potassium carbonate (29.0 mg, 209 μmol) in MeCN (696 μL) / H2O (174 μL) was stirred at room temperature overnight. 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 HPLC to give the title compound (16.4 mg, 64.4 μmol, 30.8%) as a light yellow solid.

[0837] MS: m / z 256.10 (M+H) + .

[0838] The compounds K-2 shown in Table 15 below were synthesized according to the synthetic method described in Example K-1. Analytical data are shown in Table 16 below.

[0839] Table 15

[0840] Table 16

[0841] [Example K-3]

[0842] 6-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyrazin-3-amine (K-3)

[0843] 3-chloro-5-(2-chloro-4-fluorophenyl)pyrazine-2-carbonitrile (Intermediate K-3)

[0844] A mixture of 3,5-dichloropyrazine-2-carbonitrile (500 mg, 2.87 mmol), (2-chloro-4-fluorophenyl)boronic acid (601 mg, 3.45 mmol), tetrakis(triphenylphosphine)palladium(0) (157 mg, 587 μmol) and potassium carbonate (794 mg, 5.75 mmol) in 1,4-dioxane (10 mL) / water (2 mL) 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 magnesium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (EtOAc / heptane = 13%-34%) to give the title compound (435.7 mg, 1.63 mmol, 56.6%) as a white solid.

[0845] MS: m / z 268.00 (M+H) + .

[0846] 1 H-NMR (DMSO-d6) D: 9.20 (1H, s), 7.80 (1H, dd, J = 8.7, 5.9 Hz), 7.74 (1H, dd, J = 8.7, 2.7 Hz), 7.48 (1H, td, J = 8.5, 2.3 Hz).

[0847] 6-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyrazin-3-amine (K-3)

[0848] A mixture of 3-chloro-5-(2-chloro-4-fluorophenyl)pyrazine-2-carbonitrile (73.0 mg, 272 μmol), acetoxyhydroxamic acid (20.4 mg, 272 μmol), and potassium carbonate (37.6 mg, 272 μmol) in MeCN (908 μL) / H2O (227 μL) was stirred at room temperature overnight. 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 HPLC to give the title compound (21.4 mg, 80.8 μmol, 29.7%) as an off-white solid.

[0849] MS: m / z 265.08 (M+H) + .

[0850] Compounds K-4 to K-6 shown in Table 17 below were synthesized according to the synthetic method described in Example K-3. Analytical data are shown in Table 18 below.

[0851] Table 17

[0852] Table 18

[0853] [Example K-7]

[0854] 6-(4,4-difluoropiperidin-l-yl)-lH-pyrazolo[3,4-b]pyrazin-3-amine (K-7)

[0855] A solution of 3-chloro-5-(4,4-difluoropiperidin-l-yl)pyrazine-2-carbonitrile (108 mg, 418 μmol) and hydrazine monohydrate (41.8 mg, 835 μmol) in ethanol (1 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the precipitate was collected by filtration. The collected solid was washed with ethanol and dried under high vacuum to give the title compound (86.4 mg, 340 μmol, 81.4%) as a yellow solid.

[0856] MS: m / z 255.10 (M+H)+ .

[0857] [Examples L-1, L-2]

[0858] 3-(Difluoromethyl)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (L-1)

[0859] 2-(6-(6-Azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazol-3-yl)-2,2-difluoroacetic acid (L-2)

[0860] Ethyl 2-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazol-3-yl)-2,2-difluoroacetate (Intermediate L-1A)

[0861] A mixture of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazine (689 mg, 1.678 mmol), ethyl bromodifluoroacetate (436 μL, 3.356 mmol) and copper (427 mg, 6.71 mmol) in DMSO (3 mL) was stirred at room temperature overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 11% to 32%) to give the title compound (122 mg, 301 μmol, 17.9%) as a light yellow oil.

[0862] MS: m / z 407.10 (M+H) + .

[0863] Ethyl 2-(6-(6-azaspiro[2.5]octan-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazol-3-yl)-2,2-difluoroacetate (Intermediate L-1B)

[0864] To a stirred solution of 2-(6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-b]pyrazin-3-yl)-2,2-difluoroacetic acid ethyl ester (122 mg, 301 pmol) and 6- azaspiro[2.5]octane hydrochloride (53.3 mg, 361 pmol) in DMF (2 mL) was added DIEA (150 pL, 902 pmol). The solution was stirred at 100 °C overnight. After cooling to room temperature, the mixture was directly purified by silica gel column chromatography (EtOAc / heptane = 12% - 33%) to give the title compound (58.3 mg, 121 pmol, 40.3%) as a light yellow oil.

[0865] MS: m / z 482.20 (M+H) + .

[0866] 3-(Difluoromethyl)-6-(6-azaspiro[2.5]octan-6-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyrazine (Intermediate L-1C)

[0867] A mixture of 2-(6-(6-azaspiro[2.5]octan-6-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-difluoroacetic acid ethyl ester (58.3 mg, 121 pmol) and magnesium chloride hexahydrate (49.2 mg, 242 pmol) in NMP (1 mL) was stirred at 180 °C for 1 h under microwave irradiation. To the mixture was added water 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 a crude mixture which was used in the next step without further purification.

[0868] MS: m / z 410.20 (M+H) + .

[0869] 3-(Difluoromethyl)-6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine (L-1)

[0870] 2-(6-(6-Azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-difluoroacetic acid (L-2)

[0871] A mixture of the above crude mixture and TFA (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. To the residue was added 2 M NH3 / methanol (2 mL), the mixture was stirred at room temperature for 30 min, and the mixture was concentrated under reduced pressure. The crude mixture was purified by HPLC to give 3-(difluoromethyl)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (1.80 mg, 6.44 µmol, 5.3% yield for two steps, brown solid) and 2-(6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-difluoroacetic acid (11.5 mg, 35.4 µmol, 29.3% yield for two steps, yellow solid).

[0872] MS: m / z 280.16 (M+H) + . [L-1]

[0873] MS: m / z 324.12 (M+H) + . [L-2]

[0874] [Example M-1]

[0875] 3-(difluoromethoxy)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine (M-1)

[0876] 6-chloro-1-(2,4-dimethoxybenzyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (Intermediate M-1A)

[0877] To a stirred solution of methyl 3,5-dichloropyrazine-2-carboxylate (1.00 g, 4.83 mmol) and (2,4-dimethoxybenzyl)hydrazine hydrochloride (1.06 g, 4.83 mmol) in ethanol (12 mL) was added triethylamine (2.02 mL, 14.5 mmol). The solution was stirred at reflux overnight. After cooling to room temperature, the mixture was poured into water (50 mL) and stirred. The precipitate was collected by filtration. The collected solid was washed with water and dried under high vacuum to give the title compound (1.19 g, 3.71 mmol, 76.7%) as a yellow solid.

[0878] MS: m / z 321.00 (M+H) + .

[0879] 1-(2,4-dimethoxybenzyl)-6-(6-azaspiro[2.5]octan-6-yl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one (Intermediate M-1B)

[0880] A mixture of 6-chloro-l-(2,4-dimethoxybenzyl)-l,2-dihydro-3H-pyrazolo[3,4- b]pyrazin-3-one (200 mg, 624 pmol), 6-azaspiro[2.5]octane hydrochloride (120 mg, 811 pmol) and DIEA (320 pL, 1.87 mmol) in DMF (2 mL) was stirred at 100 °C for 5 h. After cooling to rt, the mixture was directly purified by silica gel column chromatography (EtOAc / heptane = 49-70%) to give the title compound (54.8 mg, 139 pmol, 22.2%) as a brown oil.

[0881] MS: m / z 396.20 (M+H) + .

[0882] 3-(Difluoromethoxy)-l-(2,4-dimethoxybenzyl)-6-(6-azaspiro[2.5]octan-6-yl)-lH- pyrazolo[3,4-b]pyrazine (Intermediate M-1C)

[0883] To a solution of l-(2,4-dimethoxybenzyl)-6-(6-azaspiro[2.5]octan-6-yl)-l,2-dihydro-3H- pyrazolo[3,4-b]pyrazin-3-one (54.8 mg, 139 pmol) and potassium carbonate (57.5 mg, 416 pmol) in DMF (1 mL) was added sodium 2-chloro-2,2-difluoroacetate (42.3 mg, 277 pmol). The reaction mixture was stirred at 100 °C for 3 h. After cooling to rt, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give a crude mixture which was used in the next step without further purification.

[0884] MS: m / z 446.20 (M+H) + .

[0885] 3-(Difluoromethoxy)-6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4-b]pyrazine (M-1)

[0886] A mixture of the above crude mixture and TFA (1 mL) was stirred at rt overnight. The mixture was concentrated under reduced pressure. The crude mixture was purified by HPLC to give 3-(difluoromethoxy)-6-(6-azaspiro[2.5]octan-6-yl)-lH-pyrazolo[3,4- b]pyrazine (1.05 mg, 3.56 pmol, 2.6% over two steps) as a yellow solid.

[0887] MS: m / z 296.16 (M+H) + .

[0888] [Example N-1]

[0889] 6-(2-chloro-4-fluorophenyl)-3-methylisoxazolo[4,5-b]pyrazine (N-1)

[0890] 1-(3-chloro-5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)ethan-1-one (Intermediate N-1)

[0891] A mixture of 1-(3,5-dichloropyrazin-2-yl)ethan-1-one (60.0 mg, 314 μmol), (2-chloro-4-fluorophenyl)boronic acid (54.8 mg, 314 μmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (23.0 mg, 31.4 μmol) and sodium carbonate (66.6 mg, 628 μmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of anhydrous MgSO4. The filtrate was concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (EtOAc / heptane = 12% to 33%) to give the title compound (71.3 mg, 250 μmol, 79.6%) as a light yellow solid.

[0892] MS: m / z 285.00 (M+H) + .

[0893] 6-(2-chloro-4-fluorophenyl)-3-methylisoxazolo[4,5-b]pyrazine (N-1)

[0894] To a stirred solution of acetone oxime (54.8 mg, 750 μmol) and potassium tert-butoxide (84.2 mg, 750 μmol) in THF (2 mL) was added 1-(3-chloro-5-(2-chloro-4-fluorophenyl)pyrazin-2-yl)ethan-1-one (71.3 mg, 250 μmol). The resulting mixture was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl 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 the residue was added 2N hydrogen chloride (1 mL) and methanol (1 mL). The mixture was stirred at 100 °C for 3 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 HPLC to give the title compound (5.62 mg, 21.3 μmol, 8.5%) as a yellow solid.

[0895] MS: m / z 264.05 (M+H) + .

[0896] 1 H-NMR (DMSO-d6) δ: 9.15 (1H, s), 7.81 (1H, dd, J = 8.7, 5.9 Hz), 7.73 (1H, dd, J = 8.9, 2.5 Hz), 7.47 (1H, td, J = 8.5, 2.7 Hz), 2.67 (3H, s).

[0897] Example O-1 : 7-Chloro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one (O-1)

[0898] Step 1: Synthesis of 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazine

[0899] 5-bromo-1H-pyrazolo[3,4-b]pyrazine (1.00 g, 5.02 mmol, 1.0 eq), 1,1,1-trifluoro-2- iodoethane (2.10 g, 10.0 mmol, 2.0 eq) and K2CO3 (1.38 g, 10.0 mmol, 2.0 eq) were added into DMF (20 mL), heated to 80 °C, and reacted for 20 h. Cooled to room temperature, added water (50 mL), extracted with EA (50 mL), the organic phase was washed with saturated NaCl aqueous solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1) to obtain the product (345 mg, yield: 24.4%).

[0900] Step 2: Synthesis of 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0901] To a solution of 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (170 mg, 0.605 mmol, 1.0 eq), 7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (195 mg, 0.664 mmol, 1.1 eq), Pd(dppf)Cl2(44.3 mg, 0.0605 mmol, 0.1 eq) and NaHCO3(102 mg, 1.21 mmol, 2.0 eq) in 1,4-dioxane (10 mL) and water (3 mL) was heated to 110 °C under nitrogen protection for 2 hours. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with EA (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 50:1) to give the product (92.0 mg, yield: 41.1%).

[0902] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 10.97 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 5.55-5.48 (m, 2H), 4.00 (s, 2H).

[0903] Molecular Formula: C 15 H9ClF3N5O Exact Mass: 367.04 LC-MS (m / z): 366.05 [M-H] - .

[0904] Example O-2: 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one (O-2)

[0905] Step 1: Synthesis of 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0906] Into a flask, 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (170 mg, 0.605 mmol, 1.0 eq), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (283 mg, 0.665 mmol, 1.1 eq), Pd(dppf)Cl2(44.3 mg, 0.0605 mmol, 0.1 eq) and NaHCO3(102 mg, 1.21 mmol, 2.0 eq) were added into 1,4-dioxane (10 mL), water (3 mL) was added, heated to 110 °C under nitrogen protection, reacted for 2 hours. Cooled to room temperature, added water (30 mL), extracted with EA (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 20:1 ~ 5:1) to obtain the product (98.2 mg, yield: 32.5%).

[0907] Step 2: Synthesis of 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one

[0908] Into a flask, 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (98.0 mg, 0.196 mmol, 1.0 eq) was added into TFA (2 mL), concentrated after reaction at room temperature for 3 hours, added ammonia-methanol solution (3 mL), concentrated after stirring for 20 minutes, purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to obtain the product (40.0 mg, yield: 55.2%).

[0909] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 12.57 (s, 1H), 9.24 (s, 1H), 8.76 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.57-5.50 (m, 2H).

[0910] Molecular formula: C 14 H7ClF3N5O2Exact mass: 369.02 LC-MS (m / z): 368.03 [M-H] - .

[0911] Example O-3: 4-chloro-7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one (O-3)

[0912] Step 1: Synthesis of 4-chloro-7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0913] 5-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (60 mg, 0.228 mmol, 1.0 eq), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (107 mg, 0.251 mmol, 1.1 eq), Pd(dppf)Cl2(16.7 mg, 0.0228 mmol, 0.1 eq) and NaHCO3(38.3 mg, 0.456 mmol, 2.0 eq) were added into 1,4-dioxane (10 mL), water (3 mL) was added, heated to 110 °C under nitrogen protection, and reacted for 2 hours. Cooled to room temperature, added water (30 mL), extracted with EA (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 20:1 ~ 5:1) to obtain the product (42.0 mg, yield: 38.2%).

[0914] Step 2: Synthesis of 4-chloro-7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one

[0915] 4-chloro-7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (42.0 mg, 0.0871 mmol, 1.0 eq) was added to TFA (2 mL), reacted at room temperature for 3 hours, concentrated, and then added to an ammonia-methanol solution (3 mL), stirred for 20 minutes, and then concentrated, and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to obtain the product (12.5 mg, yield: 40.8%).

[0916] 1HNMR (400 MHz, DMSO-d6) δ (ppm): 12.56 (s, 1H), 9.22 (s, 1H), 8.70 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 6.69-6.40 (m, 1H), 5.07-4.99 (m, 1H).

[0917] Molecular Formula: C 14 HNMR (400 MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.69-6.40 (m, 1H), 5.06-4.97 (m, 2H), 4.00 (s, 2H). - .

[0918] Example O-4: 7-Chloro-4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one (O-4)

[0919] Step 1: Synthesis of 7-Chloro-4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one

[0920] To 5-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (200 mg, 0.760 mmol, 1.0 eq), 7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (245 mg, 0.835 mmol, 1.1 eq), Pd(dppf)Cl2(55.6 mg, 0.0760 mmol, 0.1 eq) and NaHCO3(128 mg, 1.52 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL), water (3 mL) was added, heated to 110 °C under nitrogen protection, and reacted for 2 hours. Cooled to room temperature, added water (30 mL), extracted with EA (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 40:1) to obtain the product (108 mg, yield: 40.6%).

[0921] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.69-6.40 (m, 1H), 5.06-4.97 (m, 2H), 4.00 (s, 2H).

[0922] Molecular Formula: C15 H 10 ClF2N5OExact Mass: 349.05 LC-MS (m / z): 348.08 [M-H] - .

[0923] Example O-5: 5-(2-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazine (O-5)

[0924] Step 1: Synthesis of 5-(2-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazine

[0925] 5-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (200 mg, 0.760 mmol, 1.0 eq), 2-chloro-4-fluorophenylboronic acid (146 mg, 0.837 mmol, 1.1 eq), Pd(dppf)Cl2(55.6 mg, 0.0760 mmol, 0.1 eq) and NaHCO3(128 mg, 1.52 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL), water (3 mL) was added, and the reaction was heated to 110 °C under nitrogen protection for 2 hours. Cooled to room temperature, added water (30 mL), extracted with EA (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (224 mg, yield: 94.2%) was obtained by purification on a silica gel column (PE:EA = 10:1).

[0926] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 8.93 (s, 1H), 8.67 (s, 1H), 7.80-7.76 (m, 1H), 7.71-7.68 (m, 1H), 7.47-7.42 (m, 1H), 6.70-6.41 (m, 1H), 5.07-4.99 (m, 2H).

[0927] Molecular Formula: C 13 H8ClF3N4Exact Mass: 312.04 LC-MS (m / z): 313.02 [M+H] + .

[0928] Example O-6: 1-(2,2-difluoroethyl)-5-(6-azaspiro[2.5]oct-6-yl)-1H-pyrazolo[3,4- b]pyrazine (O-6)

[0929] Step 1: Synthesis of 1-(2,2-difluoroethyl)-5-(6-azaspiro[2.5]octan-6-yl)-1H- pyrazolo[3,4-b]pyrazine

[0930] To a solution of 5-bromo-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (100 mg, 0.380 mmol, 1.0 eq), 6-azaspiro[2.5]octane hydrochloride (84.2 mg, 0.570 mmol, 1.5 eq) and DIPEA (147 mg, 1.14 mmol, 3.0 eq) in DMA (3 mL) was heated to 120 °C in microwave for 2 h. Cooled to room temperature, added water (20 mL), extracted with EA (20 mL), washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 50:1 ~ 10:1) to give the product (43.0 mg, yield: 38.6%).

[0931] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 8.54 (s, 1H), 8.07 (s, 1H), 6.59-6.30 (m, 1H), 4.88-4.79 (m, 2H), 3.70-3.68 (m, 4H), 1.45-1.42 (m, 4H), 1.37 (s, 4H).

[0932] Molecular Formula: C 14 H 17 F2N5Exact Mass: 293.15 LC-MS (m / z): 294.18 [M+H] + .

[0933] Example O-7: 7-chloro-4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2- one (O-7)

[0934] Step 1: Synthesis of 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine

[0935] To a solution of 5-bromo-lH-pyrazolo[3,4-b]pyrazine (2.00 g, 10.0 mmol, 1.0 eq), ethyl difluorobromoacetate (4.06 g, 20.0 mmol, 2.0 eq) and Na2C03(2.12 g, 20.0 mmol, 2.0 eq) in acetonitrile (50 mL) was heated to 100 °C for 24 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EA (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 20:1 ~ 5:1) to give the product (422 mg, yield: 16.9%).

[0936] Step 2: Synthesis of 7-chloro-4-(l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazin-5- yl)indolin-2-one

[0937] To a solution of 5-bromo-l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazine (120 mg, 0.482 mmol, 1.0 eq), 7-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (156 mg, 0.531 mmol, 1.1 eq), Pd(PPh3)4(55.7 mg, 0.0482 mmol, 0.1 eq) and K2C03(133 mg, 0.962 mmol, 2.0 eq) in 1,4-dioxane (10 mL) was added H20 (3 mL) and heated to 110 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched with water (30 mL) and filtered. The filter cake was washed with EA and slurried in methanol to give the product (118 mg, yield: 73.2%).

[0938] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 10.02 (s, 1H), 9.23 (s, 1H), 8.86 (s, 1H), 8.44-8.15 (m, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 3.99 (s, 2H).

[0939] Molecular Formula: C 14 H8ClF2N5O Exact Mass: 335.04 LC-MS (m / z) = 334.03 [M-H] - .

[0940] Example O-8: 4-chloro-7-(l-methyl-lH-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)- one (O-8)

[0941] Step 1: Synthesis of 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4- b]pyrazine

[0942] 5-bromo-lH-pyrazolo[3,4-b]pyrazine (500 mg, 2.51 mmol, 1.0 eq) was dissolved in THF (10 mL), PTSA (43.2 mg, 0.251 mmol, 0.1 eq) was added, then 3,4-dihydro-2H-pyran (422 mg, 5.02 mmol, 2.0 eq) was added, and the reaction was stirred at room temperature for 2 hours. Water (40 mL) was added to quench the reaction, and EA (30 mL) was used to extract the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 20:1) to obtain the product (652 mg, yield: 91.7%).

[0943] Step 2: Synthesis of 4-chloro-7-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4- b]pyrazin-5-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0944] 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-b]pyrazine (500 mg, 1.77 mmol, 1.0 eq), 4-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (829 mg, 1.95 mmol, 1.1 eq), Pd(dppf)Cl2(130 mg, 0.178 mmol, 0.1 eq), and NaHCO3(297 mg, 3.54 mmol, 2.0 eq) were sequentially added to 1,4-dioxane (20 mL), H2O (10 mL) was added, and the reaction was heated to 90°C under nitrogen protection for 2 hours. After cooling to room temperature, water (40 mL) was added, and EA (30 mL) was used to extract the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 50:1~5:1) to obtain the product (112 mg, yield: 12.6%).

[0945] Step 3: Synthesis of 4-chloro-7-(lH-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0946] Step 4: Synthesis of 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0947] Step 4: Synthesis of 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0948] Step 4: Synthesis of 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0949] Step 5: Synthesis of 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol- 2(3H)-one

[0950] Step 4: Synthesis of 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0951] 1 HNMR (400 MHz, DMSO-d6) d (ppm): 12.53 (s, 1H), 9.18 (s, 1H), 8.56 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 4.15 (s, 3H).

[0952] Molecular Formula: C 13 H8ClN5O2Exact Mass: 301.04 LC-MS (m / z) = 301.96 [M+H] + .

[0953] Example O-9: 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)- one (O-9)

[0954] Step 1: Synthesis of 5-bromo-1-ethyl-1H-pyrazolo[3,4-b]pyrazine

[0955] 5-bromo-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.00 mmol, 1.0 eq), iodoethane (312 mg, 2.00 mmol, 2.0 eq) and potassium carbonate (276 mg, 2.00 mmol, 2.0 eq) were added to acetonitrile (10 mL) and reacted at room temperature for 20 hours. Water (30 mL) was added and extracted with EA (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product (130 mg, yield: 57.0%).

[0956] Step 2: Synthesis of 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0957] Into a 10 mL sealed tube, 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (162 mg, 0.363 mmol, 1.0 eq) was added into TFA (2 mL), stirred at room temperature for 0.5 h, concentrated, then added ammonia-methanol solution (2 mL), stirred for 20 min, concentrated, purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to give the product (63.0 mg, yield: 54.9%).

[0958] Step 3: Synthesis of 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one

[0959] Into a 10 mL sealed tube, 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (162 mg, 0.363 mmol, 1.0 eq) was added into TFA (2 mL), stirred at room temperature for 0.5 h, concentrated, then added ammonia-methanol solution (2 mL), stirred for 20 min, concentrated, purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to give the product (63.0 mg, yield: 54.9%).

[0960] 1 HNMR (400 MHz, DMSO-d6) d (ppm): 12.55 (s, 1H), 9.18 (s, 1H), 8.59 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 4.60-4.55 (m, 2H), 1.52-1.48 (m, 3H).

[0961] Molecular Formula: C 14 H 10 ClN5O2Exact Mass: 315.05 LC-MS (m / z) = 315.99 [M+H] + .

[0962] Example O-10: 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1H- pyrazolo[3,4-b]pyrazin-1-yl)acetonitrile (O-10)

[0963] Step 1: Synthesis of 2-(5-bromo-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetonitrile

[0964] 5-bromo-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.00 mmol, 1.0 eq), bromoacetonitrile (240 mg, 2.00 mmol, 2.0 eq) and potassium carbonate (276 mg, 2.00 mmol, 2.0 eq) were added into acetonitrile (10 mL) and reacted at room temperature for 20 hours. Water (30 mL) was added and extracted with EA (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 10:1 ~ 5:1) to obtain the product (168 mg, yield: 70.2%).

[0965] Step 2: Synthesis of 2-(5-(4-chloro-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)- 2,3-dihydrobenzo[d]oxazol-7-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetonitrile

[0966] 2-(5-bromo-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetonitrile (168 mg, 0.706 mmol, 1.0 eq), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (331 mg, 0.777 mmol, 1.1 eq), Pd(dppf)Cl2(51.7 mg, 0.0707 mmol, 0.1 eq) and NaHCO3(119 mg, 1.42 mmol, 2.0 eq) were sequentially added into 1,4-dioxane (6 mL), H2O (3 mL) was added, and the mixture was heated to 110°C under nitrogen protection for 2 hours. After cooling to room temperature, water (20 mL) was added and extracted with EA (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 10:1 ~ 2:1) to obtain the product (194 mg, yield: 60.2%).

[0967] Step 3: Synthesis of 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1H- pyrazolo[3,4-b]pyrazin-1-yl)acetonitrile

[0968] To a solution of 2-(5-(4-chloro-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydrobenzo[d]oxazol-7-yl)-1H-pyrazol-3-yl)acetonitrile (194 mg, 0.425 mmol, 1.0 eq) in TFA (2 mL) was added and stirred at room temperature for 0.5 h, concentrated, then added ammonia-methanol solution (2 mL), stirred for 20 min, concentrated, purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 50:1) to give the product (82.5 mg, yield: 59.5%).

[0969] 1 HNMR (400 MHz, DMSO-d6) d (ppm): 12.56 (s, 1H), 9.25 (s, 1H), 8.76 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 5.90 (s, 1H).

[0970] Molecular Formula: C 14 H7ClN6O2Exact Mass: 326.03 LC-MS (m / z) = 324.01 [M+H] + .

[0971] [Example O-11]

[0972] 6-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-3,5-difluoro-N-methylpyridin-2-amine (O-11)

[0973] Step 1: Synthesis of 1-(Difluoromethyl)-5-(3,5,6-trifluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine

[0974] A mixture of 5-bromo-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine (100 mg, 402 µmol), 2-bromo-3,5,6-trifluoropyridine (85.1 mg, 402 µmol), tetrakis(triphenylphosphine)palladium(0) (46.4 mg, 40.2 µmol) and hexamethylditin (197 mg, 602 µmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 2 days. The crude solution was directly purified by silica gel column chromatography (EtOAc / heptane = 13% - 34%) to give the product (103 mg, 342 µmol, 85.2%) as a light yellow solid.

[0975] MS: m / z 302.00 (M+H) + .

[0976] Step 2: Synthesis of 6-(l-(difluoromethyl)-lH-pyrazolo[3,4-b]pyrazin-5-yl)-3,5- difluoro-N-methylpyridin-2-amine

[0977] A mixture of l-(difluoromethyl)-5-(3,5,6-trifluoropyridin-2-yl)-lH-pyrazolo[3,4- b]pyrazine (50 mg, 0.17 mmol), methylamine hydrochloride (13 mg, 0.20 mmol) and DIEA (87 μL, 0.50 mmol) in DMSO (0.5 mL) was stirred at 100 °C for 40 min. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgS04and concentrated in vacuo. The residue was purified by HPLC to give the title compound (22.4 mg, 71.6 μmol, 43%) as a yellow solid.

[0978] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (1H, s), 8.83 (1H, s), 8.29 (1H, t, J = 57.2 Hz), 7.14 (1H, dd, J = 12.3, 8.2 Hz), 6.88 (1H, d, J = 3.7 Hz), 2.82 (3H, d, J = 4.6 Hz).

[0979] MS: m / z 313.10 (M+H) + .

[0980] [Example O-12]

[0981] 2-(Methylamino)-6-(lH-pyrazolo[3,4-b]pyrazin-6-yl)nicotinonitrile (O-12)

[0982] Step 1: 2-(Methylamino)-6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- b]pyrazin-6-yl)nicotinonitrile

[0983] A mixture of 6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- b]pyrazine (50.0 mg, 176 μmol), 6-chloro-2-(methylamino)nicotinonitrile (29.4 mg, 176 μmol), tetrakis(triphenylphosphine)palladium(0) (20.3 mg, 17.6 μmol), and hexamethylditin (86.3 mg, 263 μmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 20 h. The crude solution was filtered through a pad of celite. The filtrate was concentrated in vacuo. The product was used in the next step without further purification.

[0984] MS: m / z 382.10 (M+H) + .

[0985] Step 2: Synthesis of 2-(methylamino)-6-(lH-pyrazolo[3,4-b]pyrazin-6-yl)nicotinonitrile

[0986] A mixture of the above crude residue and TFA (1 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. To the residue was added 2 M NH3 / methanol (2 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The crude product was purified by HPLC to give the title compound (2.9 mg, 11 μmol, 6.3%) as a yellow solid.

[0987] MS: m / z 252.14 (M+H) + .

[0988] [Example O-13]

[0989] 4-chloro-7-(l-cyclopropyl-lH-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one (O-13)

[0990] Step 1: Synthesis of 5-bromo-l-cyclopropyl-lH-pyrazolo[3,4-b]pyrazine

[0991] Into a 10 mL round-bottom flask, 5-bromo-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.00 mmol, 1.0 eq), cyclopropylboronic acid (172 mg, 2.00 mmol, 2.0 eq), Cu(OAc)2(200 mg, 1.00 mmol, 1.0 eq), bipyridine (156 mg, 1.00 mmol, 1.0 eq) and Na2CO3(212 mg, 2.00 mmol, 2.0 eq) were added into DCE (10 mL), heated to 70 °C, and reacted for 3 h. After cooling to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with DCM (20 mL x 2). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product (195 mg, yield: 81.2%).

[0992] Step 2: Synthesis of 4-chloro-7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

[0993] Into a 10 mL round-bottom flask, 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazine (195 mg, 0.816 mmol, 1.0 eq), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (382 mg, 0.897 mmol, 1.0 eq), Pd(dppf)Cl2(59.7 mg, 0.0816 mmol, 0.1 eq) and NaHCO3(137 mg, 1.63 mmol, 2.0 eq) were added into 1,4-dioxane (6 mL), H2O (3 mL) was added, and the mixture was heated to 110 °C under nitrogen protection for 2 h. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EA (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 50:1~10:1) to obtain the product (213 mg, yield: 57.0%).

[0994] Step 3: Synthesis of 4-chloro-7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol- 2(3H)-one

[0995] To 4-chloro-7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (213 mg, 0.465 mmol, 1.0 eq) was added TFA (2 mL), after reaction at room temperature for 30 minutes, concentrated, then added ammonia-methanol solution (2 mL), stirred for 20 minutes, concentrated, the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to obtain the product (121 mg, yield: 79.4%).

[0996] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 12.51 (s, 1H), 9.13 (s, 1H), 8.49 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.01-3.95 (m, 1H), 1.28-1.24 (m, 2H), 1.21-1.16 (m, 1H).

[0997] Molecular Formula: C 15 H 10 ClN5O2Exact Mass: 327.05 LC-MS (m / z) = 327.97 [M+H] + .

[0998] [Example O-14]

[0999] 4-chloro-7-(1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one (O-14)

[1000] Step 1: Synthesis of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazine

[1001] 5-bromo-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.00 mmol, 1.0 eq) was dissolved in DMF (4 mL), K2CO3 (207 mg, 1.50 mmol, 1.5 eq) was added, cooled to 0°C, then dropwise added SEMCl (200 mg, 1.20 mmol, 1.2 eq), reacted for 4 hours. Added water (30 mL), extracted with EA (20 mL), the organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the product (192 mg, yield: 58.0%).

[1002] Step 2: Synthesis of 4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-7-(1-((2- trimethylsilyl)ethoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one

[1003] To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- b]pyrazine (192 mg, 0.583 mmol, 1.0 eq), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (273 mg, 0.641 mmol, 1.0 eq), Pd(dppf)Cl2(42.7 mg, 0.584 mmol, 0.1 eq) and NaHCO3(98.0 mg, 1.17 mmol, 2.0 eq) in 1,4-dioxane (6 mL) was added H2O (3 mL) and heated to 110 °C under nitrogen protection for 2 h. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EA (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1 ~ 2:1) to give the product (112 mg, yield: 35.1%).

[1004] Step 3: Synthesis of 4-chloro-7-(1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)- one

[1005] To a solution of 4-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-7-(1-((2- trimethylsilyl)ethoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one (112 mg, 0.204 mmol, 1.0 eq) in TFA (2 mL) was added and stirred at room temperature for 30 min. After concentration, ammonia-methanol solution (2 mL) was added and stirred for 20 min. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give the product (26.0 mg, yield: 44.2%).

[1006] 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 14.38 (s, 1H), 12.60 (s, 1H), 9.16 (s, 1H), 8.56 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H).

[1007] Molecular Formula: C 12 H6ClN5O2Exact Mass: 287.02 LC-MS (m / z) = 288.14 [M+H] + .

[1008] [Example O-15]

[1009] 7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (Example O-15)

[1010] Step 1: Synthesis of 7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4- (trifluoromethyl)benzo[d]oxazol-2(3H)-one

[1011] 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazine (152 mg, 0.636 mmol, 1.0 eq), 7-bromo-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (180 mg, 0.638 mmol, 1.0 eq), hexamethylditin (229 mg, 0.699 mmol, 1.1 eq) and Pd(PPh3)4 (73.5 mg, 0.0636 mmol, 0.1 eq) were added to 1,4-dioxane (5 mL) and heated to 100 °C under nitrogen protection for 48 h. Cooled to room temperature, added potassium fluoride aqueous solution, extracted with EA (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA = 20:1 ~ 5:1) to obtain the product (21.7 mg, yield: 9.4%). 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 12.59 (s, 1H), 9.24 (s, 1H), 8.57 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 4.04-3.98 (m, 1H), 1.28-1.26 (m, 2H), 1.22-1.19 (m, 2H).

[1012] Molecular Formula: C 11 H5Cl2N3O2Exact Mass: 361.08 LC-MS (m / z) = 362.16 [M+H] + .

[1013] Experimental Example

[1014] Experimental Example 1: In vitro hALOX15 enzyme activity assay

[1015] Method A

[1016] The enzymatic inhibitory activity of the compounds of the application on hALOX15 was determined using a fluorescence intensity assay.

[1017] Six μL of recombinant hALOX15 (in-house; His-tagged, purified soluble protein expressed in Expi293) diluted in PBS was added to a black 384-well plate (Corning; #3575) followed by the addition of 14 concentrations of compound (0.15 μL) in DMSO. The mixture was incubated for 15 minutes at room temperature before the addition of 6 μL of DPPP (TCI; #D2404) and 8 μL of arachidonic acid (Sigma; #A3611). The final assay conditions were 10 nM hALOX15, 70 μM arachidonic acid, 5 μM DPPP and multiple concentrations of compound in buffer (PBS). The assay plate was incubated for 15 minutes at room temperature in the dark before fluorescence was measured using a PHERAstar FS (BMG Labtech) at an excitation wavelength of 330 nm and an emission wavelength set to 410 nm. IC 50 values were calculated by non-linear regression using Dotmatics software.

[1018] Method B

[1019] The enzymatic inhibitory activity of the compounds of the application on hALOX15 was determined using an optimized RapidFire high-throughput mass spectrometry (RF / MS) assay format.

[1020] Six μL of recombinant hALOX15 (in-house; His-tagged, purified soluble protein expressed in Expi293) diluted in PBS was added to a black 384-well plate (Corning; #3575) followed by 16 concentrations of compound (0.225 μL) in DMSO. The mixture was incubated for 15 minutes at room temperature, then 10 μL of arachidonic acid (Sigma, #A3611) and 14 μL of PBS were added. The final assay conditions were 5 nM hALOX15, 100 μM arachidonic acid, and multiple concentrations of compound in buffer (PBS). The assay plate was incubated for 15 minutes at room temperature. The reaction was terminated by adding 10 μL of assay solution from each well of the compound-treated plate to 20 μL of acetonitrile containing 15(S)-HETE-d8 (Cayman; #334720; 50 ng / ml) as an internal standard. The 15(S)-HpETE concentration was analyzed by the RapidFire high-throughput mass spectrometry system (Agilent Technologies) using a 6495 triple quadrupole LC / MS (Agilent Technologies). IC 50 values were calculated by non-linear regression using Dotmatics software.

[1021] By using the above method, the inhibitory effect of the compounds of the present application on ALOX15 was evaluated, and the results are shown in Table 19. IC 50 < 50 nM; “+++”: 50 nM ≤ IC 50 < 100 nM; “++”: 100 nM ≤ IC 50 < 500 nM; “+”: 500 nM ≤ IC 50 ≤ 1000 nM. 50 < 500 nM; “+”: 500 nM ≤ IC

[1022] Table 19

[1023] As can be seen from the results in Table 19, the compounds of the present application exhibit a significant inhibitory effect on hALOX15, which indicates that the compounds of the present application are useful in the treatment of hALOX15-mediated diseases and have a good potential for clinical application.

[1024] The compounds of the present application have good selectivity, and it has been confirmed that a plurality of compounds have high selectivity for ALOX5, ALOX12, and ALOX15B.

[1025] A plurality of compounds of the present application, such as Compound A-1, etc., have high liver microsomal metabolic stability.

Claims

1. 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, Formula (I) ###0001### (I). wherein, dashed line represents a single or double bond; X1is CR a , CR a R b , S, O, N or NR c ; Y is CH, C=0, O, N or NR d ; Z is CR e , O or NR f ; R a and R b each independently is selected from the group consisting of H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl; R c and R d each independently is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; R e H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R f is H, C 1-6 alkyl (optionally substituted by -CN, -C(O)O-C 1-6 alkyl, 4-8 membered heterocyclyl or 1-6 halo substituted), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl; A is X2is CR g or N; R g is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, -NR v R w or OR x ; R v and R w each independently is 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, 5 or 6 membered heteroaryl, 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; X3is CR h or N; R h 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, -CO2H, -CN, or 1-6 halogens) or 4-8 membered heterocyclyl; R 1 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; R 2 is H or halogen; R 3 is H or halogen; X4is C or N; X5is C or N; R 4 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl; R 5 is H or halogen; R 6 is H or halogen; B is a 6-membered aryl, 5- or 6-membered heterocyclyl (optionally substituted with 1-4 R i substituents) or 5- or 6-membered heteroaryl (optionally substituted with 1-3 R j substituents) fused to X4and X5; R i and R j 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; X6is CR when m is 0, 1 or 2 m R n X6is CR when m is 3 m R n or O; R 7 and R 8 are each independently selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens); when R 7 and R 8 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens), R 7 and R 8 may be bonded to form a ring; R 7 and R 8 may together form an oxo group; R 9 and R 10 each independently is selected from H, halogen, C 1-6 alkyl (optionally substituted with -OH or 1-6 halogens), -OH, or -CN; R m and R n each independently is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R m and R n are each independently C 1-6 alkyl or C 1-6 haloalkyl, R m and R n may be bonded to form a ring; when R 10 and R m are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 10 and R m may be bonded to form a ring; R 11 and R 12 each independently H or halogen; R 13 and R 14 each independently H or halogen; R 15 and R 16 each independently is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R 15 and R 16 are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 15 and R 16 may be bonded to form a ring.

2. The inhibitor of any one of claims 1, wherein the arachidonic acid lipoxygenase (ALOX) is arachidonic acid-15-lipoxygenase (ALOX15).

3. The inhibitor of any one of claims 1-2, wherein, A is X2 is CR g Or N; R g R is H, halogen or OR x ; R x is C 1-6 alkyl, optionally substituted with -CN or 1-6 halogen; X3is CR h or N; R h H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or -NR y R z ; R y and R z each independently is selected from H, C 1-6 alkyl (optionally substituted with -OH, -CO2H, -CN, or 1-6 halogens) or 4-8 membered heterocyclyl; R 1 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; R 2 is H; R 3 is H; X4is C; X5is C; R 4 halogen, C 1-6 haloalkyl or C 3-6 cycloalkyl; R 5 is H or halogen; R 6 R is H or halogen; B is a 6-membered aryl, 5-membered heterocyclyl (optionally substituted with 1-4 R i substituents) or 5-membered heteroaryl (optionally substituted with 1-3 R j substituents) fused to X4and X5; R i and R j 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 are each independently selected from H or C 1-6 alkyl; m is 1 or 2; X6is CR m R n ; R 7 and R 8 are each independently selected from H or C 1-6 alkyl; when R 7 and R 8 are each independently C 1-6 alkyl, R 7 and R 8 may be bonded to form a ring; R 7 and R 8 may together form an oxo group; R 9 and R 10 each independently is selected from H, halogen, C 1-6 alkyl or -CN; R m and R n are each independently selected from the group consisting of halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R m and R n are each independently C 1-6 alkyl or C 1-6 haloalkyl, R m and R n may be bonded to form a ring; when R 10 and R m are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 10 and R m may be bonded to form a ring.

4. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein, dashed line represents a single or double bond; X1is CR a , CR a R b , S, O, N or NR c ; Y is CH, C=0, O, N or NR d ; Z is CR e , O or NR f ; R a and R b each independently is selected from H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl; R c and R d are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; R e H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R f is H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl, or 1-6 halogens), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl; A is X2is CR g or N; R g H, halogen, 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, 5 or 6 membered heteroaryl, 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; X3is CR h or N; R h 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, -CO2H, -CN, or 1-6 halogens) or 4-8 membered heterocyclyl; R 1 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; R 2 R is H or halogen; R 3 is H or halogen; provided that, When Z is NH, the bond between Y and X1 is a double bond, Y is CH and X1 is CH, R 1 It is halogen and X2 is CR g When, R 1 Not a fluorine atom or R g It is not a bromine atom.

5. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein, dashed line represents a single or double bond; X1is CR a , CR a R b , S, O, N or NR c ; Y is CH, C=0, O, N or NR d ; Z is CR e , O or NR f ; R a and R b are each independently selected from the group consisting of H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl; R c and R d are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; R e H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R f H, C 1-6 alkyl (optionally substituted by -CN, -C(O)O-C 1-6 alkyl, 4-8 membered heterocyclyl or 1-6 halo substituted), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl; A is X4is C or N; X5is C or N; R 4 halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R 5 R is H or halogen; R 6 R is H or halogen; B is a 6-membered aryl, 5- or 6-membered heterocyclyl (optionally substituted with 1-4 R i substituents) or 5- or 6-membered heteroaryl (optionally substituted with 1-3 R j substituents) fused to X4and X5; R i and R j 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.

6. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein, dashed line represents a single or double bond; X1is CR a , CR a R b , S, O, N or NR c ; Y is CH, C=0, O, N or NR d ; Z is CR e , O or NR f ; R a and R b each independently is selected from H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl; R c and R d each independently is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; R e H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R f is H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl, or 1-6 halogens), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl; A is m is 0, 1, 2, or 3; X6is CR when m is 0, 1 or 2 m R n X6is CR when m is 3 m R n or O; R 7 and R 8 are each independently selected from H or C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens); when R 7 and R 8 are each independently C 1-6 alkyl (optionally substituted with -OH, -NH2, -CO2H, or 1-6 halogens), R 7 and R 8 may be bonded to form a ring; R 7 and R 8 may together form an oxo group; R 9 and R 10 each independently is selected from H, halogen, C 1-6 alkyl (optionally substituted with -OH or 1-6 halogens), -OH, or -CN; R m and R n are each independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl; when R m and R n are each independently C 1-6 alkyl or C 1-6 haloalkyl, R m and R n may be bonded to form a ring; when R 10 and R m are each independently C 1-6 alkyl or C 1-6 haloalkyl, R 10 and R m may be bonded to form a ring.

7. The inhibitor or compound of any one of claims 1-6, wherein, X1is CR a , O, N or NR c ; R a R is H or halogen; R c is H.

8. The inhibitor or compound of any one of claims 1-7, wherein, Y is CH, C=0, N or NR d ; R d is H, C 1-6 alkyl or C 1-6 haloalkyl.

9. The inhibitor or compound of any one of claims 1-8, wherein, Z is CR e or NR f ; R e H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R f is H, C 1-6 alkyl (optionally substituted with 4-8 membered heterocyclyl or 1-6 halogen) or 4-8 membered heterocyclyl.

10. The inhibitor or compound of any one of claims 1-9, wherein the structure containing X, Y, and Z is any one of the following structures, wherein, R p H, C 1-6 alkyl (optionally substituted by -CN, -C(O)O-C 1-6 alkyl, 4-8 membered heterocyclyl or 1-6 halo substituted), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl or 4-8 membered haloheterocyclyl; R q H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R r H, halogen, -CN, -NH2, oxo, C 1-6 alkyl (optionally substituted with carboxy or 1-6 halogens), C 1-6 alkoxy or C 1-6 haloalkoxy; R s is H, C 1-6 alkyl (optionally substituted with -CN, 4-8 membered heterocyclyl, or 1-6 halogen), C 3-6 cycloalkyl, C 3-6 halocycloalkyl, 4-8 membered heterocyclyl, or 4-8 membered haloheterocyclyl; R t H, halogen, -CN, -NH2, C 1-6 alkyl or C 1-6 haloalkyl.

11. The inhibitor or compound of any one of claims 1-3, 5, wherein the structure containing B is any one of the following structures, In the formula, R 4 , R 5 and R 6 are the same as in claims 1-3, 5.

12. A compound selected from the group consisting of: 1-(difluoromethyl)-5-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 2-(2-chloro-4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine; 2-(4-fluoro-2-isopropoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine; 5-(4-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(2,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4-fluoro-2-isopropoxyphenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4-chloro-2-isopropoxyphenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4-chloro-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4-chloronaphthalen-1-yl)-1H-pyrazolo[3,4-b]pyrazine; 2-(4-fluoro-2-isopropoxyphenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one; 5-(4-fluoro-2-isopropoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one; 2-(4-chloro-2-isopropoxyphenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one; 2-(7-chloro-1H-indazol-4-yl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one; 5-(7-chloro-1H-indazol-4-yl)-1H-pyrazolo[3,4-b]pyrazine; 2-(5-chloro-2-(1H-pyrazolo[3,4-b]pyrazin-5-yl)phenoxy)acetonitrile; 5-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 2-(5-chloro-2-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenoxy)acetonitrile; 2-(2-(difluoromethoxy)-4-fluorophenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one; 2-(2,4-dichlorophenyl)-5,7-dihydro-6H-pyrrolo[2,3-b]pyrazin-6-one; 5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(2-(difluoromethoxy)-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(2,4-dichlorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4-chloro-2-(difluoromethoxy)phenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 2-(2-(difluoromethoxy)-4-fluorophenyl)-5-(difluoromethyl)-5H-pyrrolo[2,3-b]pyrazine; 2-(2-chloro-4-fluorophenyl)-5-(difluoromethyl)-5H-pyrrolo[2,3-b]pyrazine; 1-(difluoromethyl)-5-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 4-chloro-7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-1,3-dihydro-2H- benzo[d]imidazol-2-one; 6-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 6-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-2-fluoroaniline; 5-(2-(difluoromethoxy)-6-(difluoromethyl)pyridin-3-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 1-(2,2-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(2,2-difluoroethyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 5-(5-chloropyridin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(2,2-difluoroethyl)-5-(2-(difluoromethoxy)-4-fluorophenyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine; 5-(5-chloropyridin-2-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(2,2-difluoroethyl)-5-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(2,2-difluoroethyl)-5-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-fluoropyridin-2-amine; 1-(2,2-difluoroethyl)-5-(2,4-difluorophenyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine; 5-(3-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(2,4,5-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(3,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(2,4,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(2,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(3,4,5-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(2,3,4-trifluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; (S)-5-(2,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine; (R)-5-(2,4-difluorophenyl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4-chlorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(1H-pyrazolo[3,4-b]pyrazin-6-yl)benzo[d]oxazol-2(3H)-one; 6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 6-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 4-fluoro-7-(1H-pyrazolo[3,4-b]pyrazin-6-yl)benzo[d]oxazol-2(3H)-one; 7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 2-(5-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)ethyl acetate; 7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4,5-difluorobenzo[d]oxazol-2(3H)-one; 4-chloro-7-(1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 1-(difluoromethyl)-5-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 4-chloro-7-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-fluoro-7-(6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzo[d]oxazol-2(3H)-one; 4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one; 4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-fluoroindolin-2-one; 6-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-fluoropyridin-2-amine; 4-fluoro-7-(1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 4-fluoro-7-(1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluorobenzo[d]oxazol-2(3H)-one; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-fluoro-N-methylpyridin-2-amine; 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 5-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 7-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4,6-difluorobenzo[d]oxazol-2(3H)-one; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3-(trifluoromethyl)pyridin-2-amine; 2-amino-6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)nicotinonitrile; 7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-2-(methylamino)nicotinonitrile; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-methyl-3-(trifluoromethyl)pyridin-2-amine; 5-(6,7-difluoro-1H-indol-4-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(7-(trifluoromethyl)-1H-indol-4-yl)-1H-pyrazolo[3,4-b]pyrazine; 4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-2-(methylamino)benzonitrile; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-2-methoxynicotinonitrile; 5-(6-chloro-5-fluoropyridin-2-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(5-methylpyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(5-(difluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 2-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)pyridin-2-yl)acetonitrile; 2-((3-chloro-6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)pyridin-2-yl)amino)acetonitrile; 1-(2,2-difluoroethyl)-5-(7-(trifluoromethyl)-1H-indol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine; 1-(difluoromethyl)-5-(pyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; (R)-5-(5-fluoropyridin-2-yl)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(difluoromethyl)-5-(4,5-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; (R)-4-chloro-5-fluoro-7-(1-(oxetan-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 1-(difluoromethyl)-5-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 2-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-(difluoromethyl)-5H-pyrrolo[2,3-b]pyrazine; 1-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine; 5-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 3-iodo-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 6-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazolo[3,4-b]pyrazine; 6-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1H-pyrazolo[3,4-b]pyrazine; 5-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-6-azaspiro[2.5]octane-4-carbonitrile; 5-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 8-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane; 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-8-azaspiro[2.1.2 5 .3 3 ]decane; 5-(7,7-difluoro-4-azaspiro[2.5]octan-4-yl)-1-(2,2-difluoroethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine; 3,5-dibromo-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 3,5-dichloro-6-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-6-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-6-(2-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-5-(2-chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine; 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 3-chloro-5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine; 6-(4-fluoro-2-isopropoxyphenyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyrazin-3-one; 5-(2-chloro-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine; 5-(2-(difluoromethoxy)-4-fluorophenyl)-2-(difluoromethyl)-2H-pyrazolo[3,4-b]pyrazine; 2-(2-chloro-4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-b]pyrazine; 5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyrazine; 5-(5-fluoropyridin-2-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyrazine; 1-cyclopropyl-5-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazine; 3-bromo-5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazine; 5-(2-chloro-4-fluorophenyl)-1-(difluoromethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine; 6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile; 6-(4,4-difluoropiperidin-1-yl)isoxazolo[4,5-b]pyrazin-3-amine; 6-(6-azaspiro[2.5]octan-6-yl)isoxazolo[4,5-b]pyrazin-3-amine; 6-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyrazin-3-amine; 6-(7-chloro-1H-indazol-4-yl)isoxazolo[4,5-b]pyrazin-3-amine; 6-(2,4-dichlorophenyl)isoxazolo[4,5-b]pyrazin-3-amine; 7-(3-aminoisoxazolo[4,5-b]pyrazin-6-yl)-4-fluorobenzo[d]oxazol-2(3H)-one; 6-(4,4-difluoropiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-amine; 3-(difluoromethyl)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 2-(6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-2,2-difluoroacetic acid; 3-(difluoromethoxy)-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 6-(2-chloro-4-fluorophenyl)-3-methylisoxazolo[4,5-b]pyrazine; 7-chloro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one; 4-chloro-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 7-chloro-4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one; 5-(2-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine; 1-(2,2-difluoroethyl)-5-(6-azaspiro[2.5]octan-6-yl)-1H-pyrazolo[3,4-b]pyrazine; 7-chloro-4-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)indolin-2-one; 4-chloro-7-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 2-(5-(4-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetonitrile; 6-(1-(difluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)-3,5-difluoro-N-methylpyridin-2-amine; 2-(methylamino)-6-(1H-pyrazolo[3,4-b]pyrazin-6-yl)nicotinonitrile; 4-chloro-7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 4-chloro-7-(1H-pyrazolo[3,4-b]pyrazin-5-yl)benzo[d]oxazol-2(3H)-one; 7-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzo[d]oxazol-2(3H)-one.

13. Use of the inhibitor or compound, pharmaceutically acceptable salt thereof, or solvate thereof of any one of claims 1-12 in the manufacture of a medicament for the prevention and / or treatment of any one of: an eosinophilic airway disease, an eosinophilic airway disease (e.g., an eosinophilic chronic rhinosinusitis, a chronic rhinosinusitis with nasal polyps, or asthma), another eosinophilic disease (e.g., an eosinophilic esophagitis), Friedreich’s ataxia, a genetic 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 a cerebrovascular disease), cancer, a 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 transplants, an autoimmune disorder (e.g., eczema), and a disorder involving bone loss or bone formation.

14. Use of the inhibitor or compound, pharmaceutically acceptable salt thereof, or solvate thereof of claim 13 in the manufacture of a medicament for the prevention and / or treatment of any one of: an eosinophilic airway disease, wherein the eosinophilic airway disease comprises an eosinophilic chronic rhinosinusitis, a chronic rhinosinusitis with nasal polyps, allergic rhinitis, asthma, or an eosinophilic esophagitis, and the indication targeted in the clinical trial for the ALOX15-related competitor comprises Friedreich’s ataxia, a genetic mitochondrial respiratory chain disease, a genetic epileptic disorder, Leigh syndrome, Parkinson’s disease, or amyotrophic lateral sclerosis.

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