GPR52 modulator compounds

Abstract

Disclosed herein is a compound of formula (1): JPEG2023539336000059.jpg6078 [where Q, V, L, W, R 1 and R 2 as defined herein] or a salt thereof and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with the GPR52 receptor.

Description

[Technical Field]

[0001] This application relates to novel compounds and their use as G protein-coupled receptor 52 (GPR52) modulators. The compounds described herein may be useful in the treatment or prevention of diseases in which the GPR52 receptor is involved or in which modulation of the GPR52 receptor may be beneficial. This application is also directed to pharmaceutical compositions comprising these compounds, as well as the manufacture and use of these compounds and compositions in the prevention or treatment of diseases in which the GPR52 receptor is involved. [Background technology]

[0002] G protein-coupled receptor 52 (GPR52) is a constitutively active, Gs-coupled orphan receptor highly expressed in the striatum and cortex. In the striatum, GPR52 is exclusively expressed on dopamine D2 medium spiny neurons, whereas in the cortex, it is found on cortical pyramidal neurons expressing dopamine D1 receptors (Komatsu et al., 2014, PLoS One 9:e90134). Based on its localization and functional coupling, GPR52 has been proposed to play a role in regulating frontal-striatal and limbic dopamine, and may therefore be useful in the treatment of neuropsychiatric disorders. GPR52 agonists are considered particularly relevant for the treatment of schizophrenia, hypothesizing that they indirectly improve cognition and negative symptoms by enhancing D1 signaling, while alleviating positive symptoms by inhibiting D2-mediated signaling in the striatum.

[0003] GPR52 agonists can be used to treat psychiatric disorders associated with dysfunction of the mesolimbic and mesocortical pathways. Examples include the treatment of positive, negative, and cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder, anxiety disorders (generalized anxiety disorder, obsessive-compulsive disorder, panic disorder), bipolar disorder, addiction / impulse control disorders, and autism spectrum disorders. GPR52 agonists can also be used to treat neuropsychiatric symptoms (e.g., psychosis, anhedonia, agitation, etc.) of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.). Expression of GPR52 in the pituitary gland and hypothalamus suggests the utility of GPR52 modulators in pituitary and hypothalamic disorders, and there is preclinical evidence suggesting that GPR52 agonists may be useful in treating hyperprolactinemia (Xiong et al., 2016, WO2016 / 176571). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Patent Publication No. WO2016 / 176571 [Non-patent literature]

[0005] [Non-Patent Document 1] Komatsu et al., 2014, PLoS One 9:e90134 Summary of the Invention

[0006] The present invention provides compounds that have activity as G protein-coupled receptor 52 (GPR52) modulators.

[0007] The formula provided is (1):

[0008] [ka] [In the formula, R 1is C(O)C optionally substituted with H or 1 to 6 fluorine atoms 1-3 alkyl, C optionally substituted with 1 to 6 fluorine atoms 1-6 C optionally substituted with alkyl or 1 to 6 fluorine atoms 3-6 cycloalkyl; any one atom of said alkyl or cycloalkyl group may be replaced with O; R 2 is H or C optionally substituted with 1 to 6 fluorine atoms 1-3 is alkyl; Q is -CR 3 R 4 -, -CR 3 R 4 CR 5 R 6 -, -CR 3 R 4 CR 5 R 6 CR 7 R 8 -, -CR 3 R 4 OCR 5 R 6 -, -CR 3 R 4 CR 5 R 6 O- and -CR 3 R 4 Selected from O-; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is H and C 1-3 independently selected from alkyl; V is a 6-membered, optionally substituted aryl or heteroaryl ring substituted at the meta position with L; L is selected from CH2, CHOH and O; and W is a 6-membered optionally substituted aryl or heteroaryl ring, or a salt thereof.

[0009] The compounds of the present invention can be used as GPR52 modulators. The compounds of the present invention can be used as GPR52 agonists. The compounds of the present invention can be used for the manufacture of a medicament. The compounds or medicaments can be for use in the treatment, prevention, amelioration, control, or reduction of risk of a disease or disorder in which the GPR52 receptor is involved. The compounds or medicaments can be for use in the treatment, prevention, amelioration, control, or reduction of risk of a disease or disorder in which modulation of the GPR52 receptor can be beneficial. The compounds of the invention may be useful for treating psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma or stress-related disorders; disruptive, impulse control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities of the infundibulopituitary, mesolimbic, mesocortical or nigrostriatal pathways; striatal hypoactivity; cortical dysfunction; neurocognitive dysfunction or a condition or symptom associated therewith.

[0010] The compounds of the present invention are useful for treating schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorders, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, disease with Lewy bodies, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and associative movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia, myoclonus, mirror movement disorder, and the like. disorder), paroxysmal exercise-induced dyskinesia, restless legs syndrome, convulsions, stereotypic movement disorder, stereotypies, tics, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or medication-induced psychotic disorder, delusions, hallucinations, disorganized thinking, severely disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or medication-induced bipolar disorder and related disorders, bipolar disorder and related disorders due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder due to another medical condition, delirium, dementia (major neurocognitive disorder) It may be useful in treating cognitive impairment, mild cognitive impairment, amnesia, dementia, developmental coordination disorder, stereotypy, post-stroke effects, dentatorubral-pallidoluysian atrophy, decreased emotional expression, amotivation, aphasia, and antisociality (social withdrawal). [Brief explanation of the drawings]

[0011] [Figure 1]Figure 1 shows the effect of acute treatment with Isomer 1 of Example 2 (0.3, 1, 3 and 10 mg / kg PO) on caffeine-induced hyperlocomotor activity. Significant differences relative to caffeine are represented as †p<0.05, ††p<0.01, †††p<0.001. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to novel compounds. The present invention also relates to the use of the novel compounds as modulators of the GPR52 receptor. The present invention further relates to the use of the novel compounds in the manufacture of a medicament for use as a GPR52 modulator. The compounds of the present invention can be used as GPR52 agonists. The compounds or medicaments may be for use in the treatment, prevention, amelioration, control, or reduction of risk of diseases or disorders in which the GPR52 receptor is involved. The compounds or medicaments may be for use in the treatment, prevention, amelioration, control, or reduction of risk of diseases or disorders in which modulation of the GPR52 receptor may be beneficial.

[0013] The present invention further relates to compounds, compositions and medicaments that may be useful in the treatment of psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; prolactin-related disorders; trauma or stress-related disorders; disruptive, impulse control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities of the infundibulopituitary, mesolimbic, mesocortical, or nigrostriatal pathways; striatal hypoactivity; cortical dysfunction; neurocognitive dysfunction or conditions or symptoms related thereto.

[0014] The formula provided is (1):

[0015] [ka] [In the formula, R 1 is C(O)C optionally substituted with H or 1 to 6 fluorine atoms 1-3 alkyl, C optionally substituted with 1 to 6 fluorine atoms 1-6 C optionally substituted with alkyl or 1 to 6 fluorine atoms 3-6 cycloalkyl; any one atom of said alkyl or cycloalkyl group may be replaced with O; R 2 is H or C optionally substituted with 1 to 6 fluorine atoms 1-3 is alkyl; Q is -CR 3 R 4 -, -CR 3 R 4 CR 5 R 6 -, -CR 3 R 4 CR 5 R 6 CR 7 R 8 -, -CR 3 R 4 OCR 5 R 6 -, -CR 3 R 4 CR 5 R 6 O- and -CR 3 R 4 Selected from O-; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is H and C 1-3 independently selected from alkyl; V is a 6-membered, optionally substituted aryl or heteroaryl ring substituted at the meta position with L; L is selected from CH2, CHOH and O; and W is a 6-membered optionally substituted aryl or heteroaryl ring, or a salt thereof.

[0016] Also provided is a compound of formula (1a):

[0017] [ka] [In the formula, R 1 is C(O)C optionally substituted with H or 1 to 6 fluorine atoms 1-3 alkyl, C optionally substituted with 1 to 6 fluorine atoms 1-6 C optionally substituted with alkyl or 1 to 6 fluorine atoms 3-6 cycloalkyl; any one atom of said alkyl or cycloalkyl group may be replaced with O; R 2 is H or C optionally substituted with 1 to 6 fluorine atoms 1-3 is alkyl; Q is -CR 3 R 4 -, -CR 3 R 4 CR 5 R 6 -, -CR 3 R 4 CR 5 R 6 CR 7 R 8 -, -CR 3 R 4 OCR 5 R 6 -, -CR 3 R 4 CR 5 R 6 O- and -CR 3 R 4 Selected from O-; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is H and C 1-3 independently selected from alkyl; L is selected from CH2, CHOH and O; and W is a 6-membered optionally substituted aryl or heteroaryl ring, or a salt thereof.

[0018] Also provided is a compound of formula (1a):

[0019] [ka] [In the formula, R 1 is C(O)C optionally substituted with H or 1 to 6 fluorine atoms 1-3 alkyl, C optionally substituted with 1 to 6 fluorine atoms 1-6 C optionally substituted with alkyl or 1 to 6 fluorine atoms 3-6 cycloalkyl; any one atom of said alkyl or cycloalkyl group may be replaced with O; R 2 is H; Q is -CR 3 R 4 -, -CR 3 R 4 CR 5 R 6 -, -CR 3 R 4 CR 5 R 6 CR 7 R 8 -, -CR 3 R 4 OCR 5 R 6 -, -CR 3 R 4 CR 5 R 6 O- and -CR 3 R 4 Selected from O-; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is H and C 1-3 independently selected from alkyl; L is selected from CH2, CHOH and O; and W is a 6-membered optionally substituted aryl or heteroaryl ring, or a salt thereof.

[0020] In the compounds described herein, R 1 R can be selected from H, CH3, CF3, CHF2, CH2F, C(O)CH3, C(O)CH2CH3, C(O)CF2H, C(O)CF3, C(O)CFH2, CH2CH2OCH3, oxetane and oxolane. 1 R can be selected from H, CH3, C(O)CH3, C(O)CH2CH3, C(O)CF2H, C(O)CF3, C(O)CFH2, CH2CH2OCH3, oxetane and oxolane. 1 can be C(O)CH3.

[0021] In the compounds described herein, R 2 can be selected from H, CH3, CF3, CHF2 and CH2F. 2 can be H.

[0022] In the compounds described herein, Q is -CR 3 R 4 -, -CR 3 R 4 CR 5 R 6 -, -CR 3 R 4 CR 5 R 6 CR 7 R 8 -, -CR 3 R 4 OCR 5 R 6 -, -CR 3 R 4 CR 5 R 6 O- and -CR 3 R 4 O-, wherein R 3 , R 4 , R 5 , R 6 , R 7 and R8 is H. Q can be selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2OCH2- and -CH2O-. Q can be -CH2CH2-.

[0023] In the compounds described herein, L can be CH. L can be CHOH. L can be O.

[0024] In the compounds described herein, V can be an optionally substituted phenyl or pyridyl ring substituted with L at the meta position.

[0025] V is

[0026] [ka] It can be selected from the group consisting of:

[0027] V is

[0028] [ka] It is possible.

[0029] In the compounds described herein, W is

[0030] [ka] In the above formula, each B can be N, CR 11 , C.R. 12 or CR 13 wherein R 11 , R 12 and R 13 is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms 1-6 C optionally substituted with alkyl and 1 to 6 fluorine atoms 1-6alkoxy, wherein any one atom of said alkyl or alkoxy group may be replaced with a heteroatom selected from O, N, S and their oxidized forms.

[0031] W is

[0032] [ka] In the above formula, R 11 , R 12 and R 13 is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms 1-6 C optionally substituted with alkyl and 1 to 6 fluorine atoms 1-6 alkoxy, wherein any one atom of said alkyl or alkoxy group may be replaced with a heteroatom selected from O, N, S and their oxidized forms.

[0033] W is

[0034] [ka] It can be selected from the group consisting of:

[0035] In the compounds described herein, R 11 , R 12 and R 13 R can independently be H, CN, F, Cl, methyl, cyclopropyl, CF, CFH, OCFH, OCF, OMe, or SOMe. 11 , R 12 and R 13 can be independently selected from H, F, CF, CFH, CFH, and OCFH. 11 , R 12 and R 13 can be independently selected from H, F and CF3.

[0036] In the compounds described herein, R 11 can be H. R 11can be CN. R 11 can be a halo. R 11 can be F or Cl. 11 can be F. R 11 is C optionally substituted with 1 to 6 fluorine atoms 1-6 alkyl group, 1-6 One atom of the alkyl group may be replaced with a heteroatom selected from O, N, S and their oxidized forms. 11 is C optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 11 is C 1-6 R can be an alkyl group. 11 is OC optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 11 OC 1-6 R can be an alkyl group. 11 is SO2C optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 11 is SO2C 1-6 R can be an alkyl group. 11 is C optionally substituted with 1 to 6 fluorine atoms 3-6 R can be a cycloalkyl group. 11 is C 3-6 R can be a cycloalkyl group. 11 can be H. R 11 can be CN. R 11 can be F. R 11 can be Cl. 11 R can be methyl. 11 R can be cyclopropyl. 11 can be CF3. 11 can be OCF2H. 11 can be SO2Me. R 11 can be CF2H. 11 can be CH2F. R 11 can be OMe. R 11 can be H, F, CF, CFH, CFH, or OCFH. 11 can be H, F or CF3.

[0037] In the compounds described herein, R 12 can be H. R 12 can be CN. R 12 can be a halo. R 12 can be F or Cl. 12 can be F. R 12 is C optionally substituted with 1 to 6 fluorine atoms 1-6 alkyl group, 1-6 One atom of the alkyl group may be replaced with a heteroatom selected from O, N, S and their oxidized forms. 12 is C optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 12 is C 1-6 R can be an alkyl group. 12 is OC optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 12 OC 1-6 R can be an alkyl group. 12 is SO2C optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 12 is SO2C 1-6 R can be an alkyl group. 12 is C optionally substituted with 1 to 6 fluorine atoms 3-6 R can be a cycloalkyl group. 12 is C 3-6 R can be a cycloalkyl group. 12 can be H. R 12 can be CN. R 12 can be F. R 12 can be Cl. 12 R can be methyl. 12 R can be cyclopropyl. 12 can be CF3. 12 can be OCF2H. 12 can be SO2Me. R 12 can be CF2H. 12 can be CH2F. R 12can be OMe. R 12 can be H, F, CF, CFH, CFH, or OCFH. 12 can be H, F or CF3.

[0038] In the compounds described herein, R 13 can be H. R 13 can be CN. R 13 can be a halo. R 13 can be F or Cl. 13 can be F. R 13 is C optionally substituted with 1 to 6 fluorine atoms 1-6 alkyl group, 1-6 One atom of the alkyl group may be replaced with a heteroatom selected from O, N, S and their oxidized forms. 13 is C optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 13 is C 1-6 R can be an alkyl group. 13 is OC optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 13 OC 1-6 R can be an alkyl group. 13 is SO2C optionally substituted with 1 to 6 fluorine atoms 1-6 R can be an alkyl group. 13 is SO2C 1-6 R can be an alkyl group. 13 is C optionally substituted with 1 to 6 fluorine atoms 3-6 R can be a cycloalkyl group. 13 is C 3-6 R can be a cycloalkyl group. 13 can be H. R 13 can be CN. R 13 can be F. R 13 can be Cl. 13 R can be methyl. 13 R can be cyclopropyl. 13 can be CF3. 13 can be OCF2H.13 can be SO2Me. R 13 can be CF2H. 13 can be CH2F. R 13 can be OMe. R 13 can be H, F, CF, CFH, CFH, or OCFH. 13 can be H, F or CF3.

[0039] Particular compounds have the formula (2a), (2b) or (2c):

[0040] [ka] In the above formula, Q, L, R 1 , R 2 , R 11 , R 12 and R 13 is as defined above.

[0041] Particular compounds have the formula (3a), (3b) or (3c):

[0042] [ka] In the above formula, L, R 1 , R 2 , R 11 , R 12 and R 13 is as defined above.

[0043] Particular compounds have the formula (4a), (4b) or (4c):

[0044] [ka] In the above formula, L, R 11 , R 12 and R 13 is as defined above.

[0045] A particular compound has the formula (5):

[0046] [ka] In the above formula, R 1 and R 2 is as defined above.

[0047] Particular compounds have the formula (6a), (6b) or (6c):

[0048] [ka] In the above formula, R 1 , R 2 , R 11 , R 12 and R 13 is as defined above.

[0049] Particular compounds have the formula (7a), (7b), (7c), (7d) or (7e):

[0050] [ka] In the above formula, Q, L, R 1 , R 2 , R 11 , R 12 and R 13 is as defined above.

[0051] Also, the formulas (1i) and (1ii):

[0052] [ka] In the above formula, Q, V, L, W, R and their salts are also included. 1 and R 2 is as defined above.

[0053] Furthermore, the formulas (1ai) and (1aii):

[0054] [ka] In the above formula, Q, L, W, R and their salts are also included. 1 and R 2 is as defined above.

[0055] The compound can be selected from any one of Examples 1 to 21 as shown in Table 1, or a salt thereof.

[0056] The compound is 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]propanamide; 2,2-Difluoro-N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; 2-Fluoro-N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-(1-{4-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridin-2-yl}-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl)acetamide; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-methyl-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxolan-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; N-[1-(4-{[3-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-(difluoromethoxy)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-fluoro-5-(fluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; 1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-4-amine; N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-4-yl]acetamide; 3-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,6,7,8-tetrahydro-3H-oxepino[3,4-d][1,2,3]triazol-8-amine; N-[3-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,6,7,8-tetrahydro-3H-oxepino[3,4-d][1,2,3]triazol-8-yl]acetamide; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-d][1,2,3]triazol-4-amine; N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-d][1,2,3]triazol-4-yl]acetamide; 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine; 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine; 1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine; (4R)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; (4S)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; N-[(4R)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[(4S)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[(4R)-1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[(4S)-1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; or salts thereof.

[0057] A further aspect of the present invention includes the use of a compound of formula (1) or a salt thereof, or a pharmaceutical composition comprising a compound of formula (1), as a GPR52 receptor modulator or a GPR52 receptor agonist. The compounds of the present invention can be used as GPR52 modulators. The compounds of the present invention can be used as GPR52 agonists. The compounds of the present invention can be useful in the treatment or prevention of diseases in which modulation of the GPR52 receptor can be beneficial.

[0058] The compounds of the invention can be used to treat psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma or stress-related disorders; disruptive, impulse control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities of the infundibulopituitary, mesolimbic, mesocortical or nigrostriatal pathways; striatal hypoactivity; cortical dysfunction; neurocognitive dysfunction or a condition or symptom associated therewith.

[0059] The compounds of the present invention are useful for treating schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorders, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, disease with Lewy bodies, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and associative movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia, myoclonus, mirror movement disorder, and the like. disorder), paroxysmal exercise-induced dyskinesia, restless legs syndrome, convulsions, stereotypic movement disorder, stereotypies, tics, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or medication-induced psychotic disorder, delusions, hallucinations, disorganized thinking, severely disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or medication-induced bipolar disorder and related disorders, bipolar disorder and related disorders due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder due to another medical condition, delirium, dementia (major neurocognitive disorder) It can be used to treat: mild cognitive impairment, amnesia, dementia, developmental coordination disorder, stereotypic movement disorder, post-stroke effects, dentatorubral-pallidoluysian atrophy, decreased emotional expression, loss of motivation, aphasia, and antisociality (social withdrawal).

[0060] The compounds of the present invention can be used to treat schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, neurocognitive disorders, delirium, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD). The compounds of the present invention can be used to treat schizophrenia.

[0061] definition As used herein, the following definitions apply unless otherwise indicated.

[0062] As used herein, the term "GPR52 modulator" refers to any compound that binds to the GPR52 receptor and modulates its function. The term "modulator" should be interpreted to include modulation in a manner including, but not limited to, agonist, partial agonist, and inverse agonist.

[0063] In connection with the use of any of the compounds described herein, including compounds of Formula (1), the term "treatment" is used to describe any form of intervention in which a compound is administered to a subject suffering from, at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term "treatment" covers both preventative (prophylactic) treatment and treatment when measurable or detectable symptoms of the disease or disorder are present.

[0064] The term "therapeutically effective amount" (e.g., in relation to treatment of a disease or condition) refers to an amount of a compound effective to produce a desired therapeutic effect. For example, when the condition is pain, an effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or a reduction in the severity of pain.

[0065] Terms such as "alkyl," "alkoxy," "aryl," "heteroaryl," and "cycloalkyl" are all used in their conventional sense (e.g., as defined in the IUPAC Gold Book) unless otherwise indicated. "Optionally substituted," as applied to any group, means that the group may be substituted, if desired, with one or more substituents, which may be the same or different.

[0066] Examples of the replacement of a carbon atom by a heteroatom are the replacement of a carbon atom in a -CH2-CH2-CH2- chain with oxygen or sulfur to give an ether -CH2-O-CH2- or a thioether -CH2-S-CH2-, the replacement of a carbon atom in a group CH2-C≡CH with nitrogen to give a nitrile (cyano) group CH2-C≡N, the replacement of a carbon atom in a group -CH2-CH2-CH2- with C=O to give a ketone -CH2-C(O)-CH2-, the replacement of a carbon atom in a group -CH2-CH=CH2 with C=O to give an aldehyde -CH2-C(O)H, the replacement of a carbon atom in a group -CH2-CH2-CH3 with O to give an alcohol -CH2-CH2-CH2OH, the replacement of a carbon atom in a group -CH2-CH2-CH3 with O to give an ether -CH2- O-CH, exchanging a carbon atom of the group -CH-CH-CH with S to give the thiol -CH-CH-CHSH, exchanging a carbon atom of the group -CH-CH-CH- with S=O or SO to give the sulfoxide -CH-S(O)-CH- or sulfone -CH-S(O)-CH-, exchanging a carbon atom of the -CH-CH-CH- chain with C(O)NH to give the amide -CH-CH-C(O)-NH-, exchanging a carbon atom of the -CH-CH-CH- chain with nitrogen to give the amine -CH-NH-CH-, and exchanging a carbon atom of the -CH-CH-CH- chain with C(O)O to give the ester (or carboxylic acid) -CH-CH-C(O)-O-, etc. In each such exchange, at least one carbon atom of the alkyl group must remain.

[0067] To the extent that any compound described contains a chiral center, the present invention extends to all optical isomers of such compounds, whether in the form of a racemate or resolved enantiomers. The invention described herein relates to all crystal forms, solvates, and hydrates of any of the disclosed compounds, however prepared. To the extent that any compound disclosed herein contains an acid or base center, such as a carboxylic acid or amino group, all salt forms of said compound are encompassed by the present invention. For pharmaceutical uses, the salts should be considered pharmaceutically acceptable salts.

[0068] Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound with one or more equivalents of the appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by lyophilization, or by filtration). Salts can also be prepared by exchanging the counterion of a compound in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0069] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral and organic acids, and salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0070] Examples of acid addition salts are acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphor- Sulfonic acids, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D- glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1- Includes acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0071] Any solvates of the compounds and their salts are also included. Suitable solvates are those formed by incorporating molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent) into the solid structure (e.g., crystalline structure) of the compounds of the present invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the present invention with a solvent or a mixture of solvents containing a solvating solvent. Whether a solvate has formed in any given case can be determined by analyzing the crystals of the compound using well-known standard techniques, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0072] Solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.For a more detailed description of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, 2nd Edition, published by SSCI, Inc., West Lafayette, Indiana, USA, 1999, ISBN 0-967-06710-3.

[0073] In the context of the present invention, the term "pharmaceutical composition" refers to a composition comprising an active agent and, in addition, one or more pharmaceutically acceptable carriers. The composition may further comprise, depending on the mode of administration and the nature of the dosage form, ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersing agents. The composition may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, troches, emulsions, solutions, cachets, granules, capsules, and suppositories, as well as injectable liquid preparations including liposomal preparations.

[0074] The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope all isotopes of that element. 1 H, 2 H(D), and 3 H(T) within its scope. Similarly, references to carbon and oxygen are 12 C. 13 C and 14 C and 16 O and 18 O are included within their scope. Similarly, reference to particular functional groups also includes isotopic variations within their scope unless the context dictates otherwise. For example, reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms within the group are in the form of a deuterium or tritium isotope, such as an ethyl group in which all five hydrogen atoms are in the deuterium isotope form (perdeuteroethyl) or a methoxy group in which all three hydrogen atoms are in the deuterium isotope form (trideuteromethoxy). Isotopes may be radioactive or non-radioactive.

[0075] Treatment dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound being used.Determining the appropriate dosage for a particular situation is within the skill of the art.Generally, treatment is initiated with a dosage that is less than the optimal dosage of the compound.Then, the dosage is gradually increased until the optimal effect under the circumstances is reached.For convenience, the total daily dosage can be divided and administered in divided doses throughout the day if desired.

[0076] The magnitude of an effective amount of a compound will, of course, vary depending on the nature of the severity of the condition being treated, as well as the particular compound and its route of administration. Selection of an appropriate dosage is within the ability of one of ordinary skill in the art without undue burden. Generally, the daily dose range can be about 10 μg to about 30 mg per kg of human and non-human animal body weight, preferably about 50 μg to about 30 mg per kg of human and non-human animal body weight, for example, about 50 μg to about 10 mg per kg of human and non-human animal body weight, for example, about 100 μg to about 30 mg per kg of human and non-human animal body weight, for example, about 100 μg to about 10 mg per kg of human and non-human animal body weight, and most preferably about 100 μg to about 1 mg per kg of human and non-human animal body weight.

[0077] Pharmaceutical preparations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, a formulation).

[0078] Thus, there is provided a pharmaceutical composition comprising at least one compound of formula (1) as defined above together with at least one pharmaceutically acceptable excipient.

[0079] The composition may be a tablet composition. The composition may be a capsule composition.

[0080] The pharmaceutically acceptable excipient(s) can be chosen from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g., release-retarding or delaying polymers or waxes), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity adjusters, thickeners, flavoring agents, sweeteners, dyes, plasticizers, taste-masking agents, stabilizers, or any other excipient conventionally used in pharmaceutical compositions.

[0081] As used herein, the term "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0082] Pharmaceutical compositions containing compounds of formula (1) can be formulated according to known techniques. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company (Easton, Pennsylvania, USA). The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, otic, rectal, vaginal, or transdermal administration.

[0083] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated (plain)), capsules (hard or soft shell), caplets, pills, troches, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal (mouth) patches.

[0084] The tablet composition may contain, together with a unit dose of active compound, an inert diluent or carrier, e.g., a sugar or sugar alcohol, such as lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar-derived diluent, e.g., sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivative, e.g., microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, such as corn starch. Tablets may also contain standard ingredients, such as binders and granulating agents, e.g., polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, e.g., citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein.

[0085] Tablets can be designed to release drug immediately upon contact with gastric fluids (immediate-release tablets) or in a controlled manner over an extended period of time or in specific areas of the GI tract (controlled-release tablets).

[0086] A pharmaceutical composition typically comprises approximately 1% (w / w) to approximately 95%, preferably % (w / w), of the active ingredient and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. Preferably, the composition comprises approximately 20% (w / w) to approximately 90% (w / w) of the active ingredient and 80% (w / w) to 10% (w / w) of a pharmaceutically acceptable excipient or a combination of excipients. A pharmaceutical composition comprises approximately 1% to approximately 95%, preferably approximately 20% to approximately 90%, of the active ingredient. A pharmaceutical composition according to the present invention may be in unit dosage form, for example, in the form of an ampule, vial, suppository, pre-filled syringe, dragee, powder, tablet, or capsule.

[0087] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid, and / or 0-99% (w / w) filler or extender (depending on dosage). They may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, and 0-5% (w / w) pigment. Sustained-release tablets will also typically contain 0-99% (w / w) release-controlling (e.g., retarding) polymer (depending on dosage). The film coat of a tablet or capsule typically contains 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer.

[0088] Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent, and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and if lyophilized). Intramuscular depot formulations may also contain 0-99% (w / w) oil.

[0089] Pharmaceutical formulations may be presented to patients in "patient packs" containing an entire course of treatment in a single package, usually a blister pack.

[0090] The compounds of formula (1) are generally provided in unit dosage forms and thus typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of compound are 0.1 milligram to 2 grams of active ingredient (more usually 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 milligram to 2 milligrams of active ingredient).

[0091] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram, of active compound.

[0092] The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The precise amount of compound to be administered can be determined by the attending physician according to standard procedures. [Example]

[0093] The present invention will now be described, but not limited to, with reference to the following examples shown in Table 1. NMR and LCMS characteristics are given in Table 3. Intermediates used are listed in Table 2.

[0094] Table 1 - Examples

[0095] [Table 1-1]

[0096] [Table 1-2]

[0097] [Table 1-3] Examples 1, 2, and 13 were obtained as single enantiomers (Isomer 1 and Isomer 2) after chiral separation. Data for each individual enantiomer are provided in Tables 3 and 4. However, the absolute stereochemistry of the isolated species was not assigned. All other example compounds were obtained as mixtures of enantiomers and were not subjected to chiral separation. When the structure of an example is depicted without showing the absolute stereochemistry, both enantiomers are included within the scope of the disclosure.

[0098] Thus, Example 1 - one of Isomers 1 and 2 is

[0099] [ka] and the other is,

[0100] [ka] is.

[0101] Example 2 - One of Isomers 1 and 2

[0102] [ka] and the other is,

[0103] [ka] is.

[0104] Example 13 - One of Isomers 1 and 2

[0105] [ka] and the other is,

[0106] [ka] is.

[0107] Preparation of the Compounds of the Invention Compounds of formula (1) can be prepared according to synthetic methods known to those skilled in the art. The present invention also provides methods for preparing compounds defined in formula (1) above. When intermediates are commercially available, they are identified by Chemical Abstracts Service (CAS) registry numbers in Table 3. When not commercially available, the synthesis of intermediates using standard transformations is detailed herein. Commercially available reagents were used without further purification.

[0108] General Procedure Room temperature (rt) refers to approximately 20 to 27°C. 1H NMR spectra were typically recorded at 400 MHz at ambient temperature unless otherwise noted. Chemical shift values ​​are expressed in parts per million (ppm), i.e., (δ) values. Standard abbreviations or combinations thereof are used for NMR signal multiplicities. For example, s = singlet, br = broad, d = doublet, t = triplet, q = quartet, quin = quintet or p = pentet, h = septet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet. Coupling constants are reported as J values ​​measured in Hz. NMR and mass spectrometry results were corrected for background peaks. Chromatography was performed using silica or C18 silica and refers to column chromatography performed under positive pressure (flash chromatography) conditions.

[0109] LCMS method LCMS experiments were performed using electrospray conditions under the following conditions (solvents: A1 = 2 mM ammonium acetate and 0.1% formic acid in HO; A2 = 5 mM ammonium acetate in HO; A3 = 2.5 L HO + 2.5 mL 28% ammonia solution in HO; A5 = 10 mM NH4HCO3 in HO; A6 = 0.2% 28% ammonia solution in HO; A7 = 0.1% TFA in HO; A8 = 5 mM NH4HCO3 in HO; A9 = 10 mM ammonium acetate in HO; B1 = 0.1% formic acid in MeCN; B2 = MeCN; B3 = 2.5 L MeCN + 135 mL HO + 2.5 mL 28% ammonia solution in HO). LCMS data are presented in the format: mass ion, electrospray mode (positive or negative), retention time (experimental text and Table 2); mass ion, electrospray mode (positive or negative), retention time, approximate purity (Table 3).

[0110] Method 1Instrument: Hewlett Packard 1100 with G1315A DAD, Micromass ZQ; Column: Phenomenex Gemini-NX C18, 3 micron, 2.0 × 30 mm; Gradient [time (min) / solvent A3 in B3 (%)]: 0.00 / 2, 0.10 / 2, 8.40 / 95, 10.00 / 95; Injection volume 1 μL; UV detection 230–400 nM; Column temperature 45 °C; Flow rate 1.5 mL / min.

[0111] Method 2 Instrumentation: Agilent Technologies 1260 LC with Chemstation software, diode array detector, Agilent 6120 quadrupole MS with APCI and ES sources; Column: Phenomenex Gemini-NX C18, 3 micron, 2 x 30 mm; Gradient [time (min) / solvent B3 in A3 (%)]: 0.00 / 2, 0.10 / 2, 8.40 / 95, 10.0 / 95, 10.1 / 2, 12.0 / 2; Injection volume 0.5 μL; UV detection 190-400 nm; Column temperature 40°C; Flow rate 1.5 mL / min.

[0112] Method 3 Instrument: Waters Acquity UPLC, Waters 3100 PDA detector, SQD; Column: Acquity HSS-T3, 1.8 micron, 2.1 x 100 mm; Gradient [time (min) / solvent B2 in A7 (%)]: 0.0 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 10.00 / 10; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL / min.

[0113] Method 4Instrumentation: Agilent Technologies 1260 LC with Chemstation software, diode array detector, Agilent 6120 quadrupole MS with APCI and ES sources; Column: Phenomenex Gemini-NX C18, 3 micron, 2 x 30 mm; Gradient [time (min) / solvent B3 in A3 (%)]: 0.00 / 5, 2.00 / 95, 2.50 / 95, 2.60 / 5, 3.00 / 5; Injection volume 0.5 μL; UV detection 190-400 nm; Column temperature 40 °C; Flow rate 1.5 mL / min.

[0114] Method 5 Instrument: Waters Acquity UPLC, Waters 3100 PDA detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 100 mm; Gradient [time (min) / solvent B2 in A2 (%)]: 0.00 / 2, 2.00 / 2, 7.00 / 50, 8.50 / 80, 9.50 / 2, 10.0 / 2; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL / min.

[0115] Method 6 Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax XDB C18, 5 micron; Gradient [time (min) / solvent B2 in A4 (%)]: 0.00 / 5, 2.50 / 95, 4.00 / 95, 4.50 / 5, 6.00 / 5; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 °C; Flow rate 1.5 mL / min.

[0116] Method 7 Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Waters XBridgeC8 3.5 micron, 4.6 x 50 mm; Gradient [time (min) / solvent A1 in B1 (%)]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25 °C; 1.5 mL / min.

[0117] Method 8 Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax extend C18, 5 micron, 4.6 x 50 mm; Gradient [time (min) / solvent A9 in B2 (%)]: 0.0 / 10, 4.0 / 95, 5.0 / 95, 5.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 °C; Flow rate 1.2 mL / min.

[0118] Method 9 Instrument: Waters Acquity UPLC, Waters 3100 PDA detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 100 mm; Gradient [time (min) / solvent B2 in A2 (%)]: 0.00 / 5, 0.25 / 5, 1.50 / 35, 2.50 / 95, 3.20 / 95, 3.60 / 5, 4.00 / 5; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 35 °C; Flow rate 0.6 mL / min until 3.20 min, then 0.8 mL / min.

[0119] Method 10 Instrument: Waters Acquity H Class, Waters PDA detector. SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 50 mm; Gradient [time (min) / % B1 in A1]: 0.00 / 5, 0.60 / 70, 0.8 / 90, 1.1 / 100, 1.70 / 100, 1.71 / 5, 2.00 / 5; Injection volume: 1 μL; Detection wavelength: 200-400 nm; Column temperature: RT; Flow rate: 0.55 mL / min until 0.60 min, then 0.60 mL / min until 0.80 min, then 0.65 mL / min until 1.71 min, then 0.55 mL / min thereafter.

[0120] GCMS method GCMS data is presented in the format of mass ion, electrospray mode (positive or negative), and retention time.

[0121] Method 1Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30m x 250μm x 0.25μm); Inlet temperature: 250°C; Split ratio: 75:1; Oven temperature: 50°C, hold time 3 min; Ramp 1: 40°C / min to 300°C, hold time 2 min; Detector temperature: 310°C; Column flow: 2mL / min; Air flow: 300mL / min; H2 flow: 40mL / min; Makeup flow (He): 25mL / min; Source temperature: 230°C.

[0122] Method 2 Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30m x 250μm x 0.25μm); Inlet temperature: 250°C; Split ratio: 75:1; Oven temperature: 120°C, hold time 1 min; Ramp 1: 40°C / min to 300°C, hold time 4 min; Detector temperature: 310°C; Column flow: 2mL / min; Air flow: 300mL / min; H2 flow: 40mL / min; Makeup flow (He): 25mL / min; Source temperature: 230°C.

[0123] MS method Method 1 Data were acquired on either a Waters QDA or Waters SQD instrument after running the UPLC column with buffer for 4-6 minutes.

[0124] Preparative HPLC method See LCMS Method section for solvent conditions.

[0125] Method 1 Equipment: Waters 2767 autopurification; Column: X-Bridge Shield C18 10 micron 19 x 250 mm; Gradient 20 min, solvent B2 (%) in A2 varied on an experimental basis (see exemplified procedure for details).

[0126] Method 2Equipment: Gilson semi-preparative HPLC system - 321 pump / 171 diode array detector / GX-271 liquid handler; Column: Phenomenex Gemini-NX C18 5 micron 30 x 100 mm; Gradient 12.5 min, solvent B2 (%) in A6 varied on an experimental basis (see exemplified procedure for details).

[0127] Method 3 Equipment: Waters 2767 autopurification; Column: Xtimate hexylphenyl 10 micron 19 x 250 mm; Gradient 18 min, solvent B2 (%) in A7 varied on an experimental basis (see exemplified procedure for details).

[0128] Method 4 Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD; Column: Waters XBridge C8 5 micron 19 x 150 mm; Gradient [time (min) / solvent A5 in B2 (%)]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0129] Chiral SFC method Method 1 Instrument: Sepiatec Prep SFC 100 with Prep SFC 100 control software and UV / Vis detector; Column: Lux C1 5 micron, 21.2 x 250 mm; Co-solvent: EtOH; Column temperature: 40°C; 50 mL / min.

[0130] Method 2 Instrument: Sepiatec Prep SFC 100 with Prep SFC 100 control software and UV / Vis detector; Column: Lux A1 5 micron, 21.2 x 250 mm; Co-solvent: 0.2% NH3 in IPA; Column temperature: 40°C; 50 mL / min.

[0131] Method 3Instrument: Waters Acquity UPC2, Masslynx software, equipped with PDA detector and QDa mass detector; Column: Lux A1 3 micron, 2 x 50 mm; Co-solvent: EtOH; Column temperature: 45°C; 1.5 mL / min.

[0132] Method 4 Instrument: Waters Acquity UPC2, Masslynx software with PDA detector and QDa mass detector; Column: Lux A1 3 micron, 2 x 50 mm; Co-solvent: IPA; Column temperature: 45°C; 1.5 mL / min.

[0133] Method 5 Instrument: Sepiatec Prep SFC 100 with Prep SFC 100 control software and UV / Vis detector; Column: Lux C1 5 micron, 21.2 x 250 mm; Co-solvent: 0.2% NH3 in MeOH; Column temperature: 40°C; 50 mL / min.

[0134] Method 6 Instrument: Waters Acquity UPC2, Masslynx software, equipped with PDA detector and QDa mass detector; Column: Lux C1 3 micron, 2 x 50 mm; Co-solvent: 0.1% NH3 in MeOH; Column temperature: 45°C; 1.5 mL / min.

[0135] Abbreviation aq = aqueous Boc = tert-butoxycarbonyl DAST = (diethylamino)sulfur trifluoride DavePhos = 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl dba = dibenzylideneacetone DCM = dichloromethane Dess-Martin = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIPEA = N,N-diisopropylethylamine DMSO = dimethyl sulfoxide dppf = 1,1'-ferrocenediyl-bis(diphenylphosphine) ES = electrospray EtOAc = ethyl acetate EtOH = ethanol h=time HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate IPA = i-propyl alcohol L = liters LC = liquid chromatography LCMS = Liquid Chromatography Mass Spectrometry LiAlH4 = lithium aluminum hydride MeCN = acetonitrile MeOH = methanol min = minutes MS= mass spectrometry NMP = 1-methyl-2-pyrrolidinone NMR = nuclear magnetic resonance Pet-ether = Petroleum ether pin=Pinacolato RT=room temperature SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran Ts = para-toluenesulfonyl The prefixes n-, s-, i-, t- and tert- have their usual meanings, ie, normal, secondary, iso and tertiary.

[0136] Synthesis of intermediates Intermediate 1: 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one

[0137] [ka] Step 1. (2-Chloropyridin-4-yl)boronic acid (24.5 g, 156 mmol) was added to a solution of 1-(bromomethyl)-3-(trifluoromethyl)benzene (40.0 g, 156 mmol) in 1,4-dioxane (450 mL) / water (150 mL), and the reaction mixture was purged with N for 10 minutes. Potassium carbonate (64.5 g, 467 mmol) and PdCl(dppf).DCM (6.35 g, 7.70 mmol) were added, and the resulting reaction mixture was heated at 90 °C for 4 hours. The reaction mixture was filtered through Celite, which was then rinsed with EtOAc (400 mL). The filtrate was washed with water (400 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 200 mL), and the combined organic layers were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-10% EtOAc in hexanes to give 2-chloro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a colorless oil (34.5 g, 77%). LCMS (Method 10): m / z 290.3, 292.3 (ES+), 1.39 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 8.34 (d, J = 5.2 Hz, 1H), 7.63-7.53 (m, 4H), 7.37 (d, J = 4.8 Hz, 1H), 4.13 (s, 2H).

[0138] Step 2. 2-Chloro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (25.0 g, 86.3 mmol) was added to a stirred solution of 3-aminocyclohex-2-en-1-one (11.5 g, 104 mmol) in THF (250 mL). The reaction mixture was purged with N for 10 minutes, and Pd(dba) (3.95 g, 4.30 mmol), DavePhos (3.39 g, 8.63 mmol), and CsCO (70.3 g, 216 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated at 80 °C for 8 hours and then filtered through Celite. The filtrate was partitioned between EtOAc (500 mL) and water (400 mL). The organic layer was separated, and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in hexanes to give 3-((4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)amino)cyclohex-2-en-1-one as a brown solid (13.5 g, 43%). LCMS (Method 10): m / z 365.3 (ES+), 1.26 min. 1 H NMR: (400 MHz, CDCl3) δ: 8.27 (d, J = 5.2 Hz, 1H), 7.36-7.22 (m, 2H), 7.09 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 10.2 Hz, 2H), 6.79 (d, J = 5.2 Hz, 1H), 6.39 (s, 1H), 4.04 (s, 2H), 2.60 (t, J = 6.2 Hz, 2H), 2.45 (t, J = 6.5 Hz, 2H), 2.11 (dd, J = 13.0, 6.6 Hz, 2H).

[0139] Step 3. 3-((4-(3-Fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)amino)cyclohex-2-en-1-one (10.0 g, 27.5 mmol) was added to a suspension of sodium tert-butoxide (3.96 g, 41.2 mmol) in MeCN (350 mL) at RT. A solution of tosyl azide (5.42 g, 36.6 mmol) in MeCN (50 mL) was added dropwise. The reaction mixture was stirred at RT for 12 h, and water (600 mL) was added. The aqueous layer was extracted with EtOAc (3 x 600 mL), the combined organic layers were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in hexanes to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one as an off-white solid (5.6 g, 52%). Data shown in Table 2.

[0140] Intermediate 2: 2-Fluoro-4-(3-(trifluoromethyl)benzyl)pyridine

[0141] [ka] 1-(Bromomethyl)-3-(trifluoromethyl)benzene (0.14 mL, 0.88 mmol) was added to a suspension of 2-fluoropyridine-4-boronic acid (150 mg, 1.06 mmol), potassium carbonate (146 mg, 1.06 mmol), and PdCl(dppf).DCM (129 mg, 0.18 mmol) in 1,4-dioxane (4 mL) / water (0.4 mL), and the resulting reaction mixture was heated at 80 °C for 2 h. The reaction mixture was partitioned between water (6 mL) and EtOAc (6 mL), and the organic layer was removed. The aqueous layer was extracted with EtOAc (2 × 6 mL), and the combined organic layers were dried (phase separator), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0–50% EtOAc in i-hexane to give 2-fluoro-4-(3-(trifluoromethyl)benzyl)pyridine as a yellow liquid (167 mg, 74%). Data are in Table 2.

[0142] Intermediate 3: 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one

[0143] [ka] Step 1. Iodine (0.260 g, 1 mmol) was added to a stirred mixture of cyclohexanone (2 g, 20 mmol) and 1,2-diphenyldisulfane (1.7 g, 80 mmol) in DMSO (12 mL), and the reaction mixture was heated at 80° C. for 12 h. The reaction was quenched by the addition of water (100 mL), and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried (NaSO), and the solvent removed in vacuo to give 2-(phenylthio)cyclohex-2-en-1-one as a yellow liquid (4.5 g, crude). This crude product was used in the next step without further purification. MS (method 1): m / z 205 (ES+).

[0144] Step 2. Sodium periodate (9.39 g, 40 mmol) was added to a stirred solution of 2-(phenylthio)cyclohex-2-en-1-one (4.5 g, 22 mmol) in MeOH (1.2 mL) and HO (12 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried (NaSO), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 30–35% EtOAc in hexane to give 2-(phenylsulfinyl)cyclohex-2-en-1-one as an orange gum (2.1 g, 43%). MS (Method 1): m / z 221 (ES+).

[0145] Step 3. Sodium azide (324 mg, 4 mmol) was added to a stirred solution of 2-(phenylsulfinyl)cyclohex-2-en-1-one (1 g, 4 mmol) in HO (17 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 2 using 1 N HCl (19 mL), and water (100 mL) was added. The aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried (NaSO), and the solvent was removed in vacuo to give 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one as an off-white solid (220 mg, 35%). Data are shown in Table 2.

[0146] Intermediate 4: tert-butyl (1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate

[0147] [ka] Step 1. KOtBu (47.7 g, 426.0 mmol) was added to a stirred solution of 4-bromo-2-fluoropyridine (25 g, 142 mmol) and 3-aminocyclohex-2-en-1-one (23.6 g, 213 mmol) in NMP (300 mL), and the resulting reaction mixture was heated at 140° C. for 12 h. The reaction mixture was partitioned between water (4×500 mL) and EtOAc (2×200 mL). The combined organic layers were washed with brine (300 mL), dried (NaSO), and the solvent was removed in vacuo to give 3-((4-bromopyridin-2-yl)amino)cyclohex-2-en-1-one (5.1 g, 13%) as an off-white solid. LCMS (Method 6): m / z 267.0 (ES+), 1.38 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 9.33 (s, 1H), 8.19 (d, J= 5.6 Hz, 1H), 7.25-7.20 (m, 2H), 6.86 (s, 1H), 2.70-2.50 (m, 2H), 2.34-2.19 (m, 2H), 2.00-1.58 (m, 2H).

[0148] Step 2. TsN3 (1.7 mL, 11.23 mmol) and NaOtBu (2.15 mg, 22.4 mmol) were added to a stirred solution of 3-((4-bromopyridin-2-yl)amino)cyclohex-2-en-1-one (2 g, 7.49 mmol) in MeCN (40 mL), and the resulting reaction mixture was stirred at RT for 1 h. The reaction mixture was partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine (100 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-25% EtOAc in petroleum ether to afford 1-(4-bromopyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (1.1 g, 50%) as a yellow solid. LCMS (Method 6): m / z 293.0 (ES+), 1.74 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 8.58-8.56 (m, 1H), 8.35 (d, J = 1.2 Hz, 1H), 7.92-7.90 (m, 1H), 3.37-3.33 (m, 2H), 2.68-2.58 (m, 2H), 2.19-2.12 (m, 2H).

[0149] Step 3. NHOAc (2.62 g, 34.1 mmol) and molecular sieves (2.62 g) were added to a stirred solution of 1-(4-bromopyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (1 g, 3.41 mmol) in MeOH (50 mL), followed by NaBHCN (0.641 g, 10.2 mmol), and the resulting reaction mixture was heated at 70 °C for 16 h. The reaction mixture was filtered through Celite, which was rinsed with EtOAc (50 mL). The filtrate was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine (50 mL), dried (NaSO), and the solvent removed in vacuo to give 1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (1.01 g, crude) as a brown gum, which was used in the next step without further purification. LCMS (Method 6): m / z 294.0 (ES+), 1.03 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 8.51-8.49 (m, 1H), 8.26-8.23 (m, 1H), 7.82-7.80 (m, 1H), 4.05 (t, J = 5.6 Hz, 1H), 3.10-2.95 (m, 2H), 2.20-1.89 (m, 6H).

[0150] Step 4. TEA (1.42 mL, 10.23 mmol) was added to a stirred solution of 1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (1 g, 3.41 mmol) in DCM (30 mL), followed by (Boc)2O (1.48 mL, 6.82 mmol) and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in petroleum ether to give tert-butyl (1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (750 mg, 56%) as a white solid. Data shown in Table 2.

[0151] Intermediate 5: 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene

[0152] [ka] Step 1. LiAlH4 (1.0 M in THF, 7.0 mL, 7.0 mmol) was added to a stirred solution of dimethyl 5-fluoroisophthalate (3 g, 14.1 mmol) in THF (10 mL) at 0 °C, and the resulting reaction mixture was stirred at RT for 3 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH ∼7, and the reaction mixture was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent removed in vacuo to give methyl 3-fluoro-5-(hydroxymethyl)benzoate (1.12 g, 43%) as a colorless liquid. GCMS (Method 1): m / z 184.0 (ES+), 7.34 min. 1H NMR: (400 MHz, DMSO-d6) δ: 7.79 (s, 1H), 7.55 (d, J = 12.8 Hz, 1H), 7.43 (d, J = 12.8 Hz, 1H), 5.49 (t, J = 7.6 Hz, 1H), 4.58 (d, J = 7.6 Hz, 2H), 3.87 (d, J = 2.4 Hz, 3H).

[0153] Step 2. Dess-Martin periodinane (2.3 g, 5.54 mmol) was added to a stirred solution of methyl 3-fluoro-5-(hydroxymethyl)benzoate (510 mg, 2.77 mmol) in DCM (10 mL), and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in hexane to afford methyl 3-fluoro-5-formylbenzoate (410 mg, 81%) as a white solid. GCMS (Method 1): m / z 182.0 (ES+), 6.76 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 10.08 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.05-8.04 (m, 2H), 3.92 (s, 3H).

[0154] Step 3. DAST (0.44 mL, 3.37 mmol) was added to a stirred solution of methyl 3-fluoro-5-formylbenzoate (410 mg, 2.25 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was neutralized with 10% aqueous NaHCO (20 mL) to pH 7, and the reaction mixture was partitioned between water (100 mL) and DCM (50 mL). The organic layer was separated, dried (Na SO ), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in hexane to afford methyl 3-(difluoromethyl)-5-fluorobenzoate (400 mg, 87%) as a colorless liquid. GCMS (Method 2): m / z 204.0 (ES+), 2.36 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 7.99 (s, 1H), 7.89 (d, J = 11.2 Hz, 1H), 7.80 (d, J = 11.2 Hz, 1H), 7.35-6.98 (m, 1H), 3.91 (s, 3H).

[0155] Step 4. LiAlH (2.0 M in THF, 0.45 mL, 0.90 mmol) was added to a stirred solution of methyl 3-(difluoromethyl)-5-fluorobenzoate (390 mg, 1.81 mmol) in THF (10 mL) at 0 °C, and the resulting reaction mixture was stirred at RT for 1 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH 7 and then partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (NaSO), and the solvent removed in vacuo to give (3-(difluoromethyl)-5-fluorophenyl)methanol (230 mg, 72%) as a colorless liquid. GCMS (Method 2): m / z 176.0 (ES+), 6.36 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 7.39 (s, 1H), 7.32-7.29 (m, 3H), 5.46 (d, J = 6.4 Hz, 1H), 4.57 (t, J = 6.4 Hz, 2H).

[0156] Step 5. Thionyl chloride (3 mL, 43.2 mmol) was added to a stirred solution of (3-(difluoromethyl)-5-fluorophenyl)methanol (170 mg, 0.96 mmol) in chloroform (10 mL) at RT, and the resulting reaction mixture was heated at 65° C. for 12 h. The reaction mixture was neutralized with 10% aqueous NaHCO (20 mL) to pH 7 and then partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (NaSO), and the solvent removed in vacuo to give 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (170 mg, crude) as a colorless liquid. This crude material was used in the next step without further purification. Data are shown in Table 2.

[0157] Intermediate 6: 1-(chloromethyl)-3-fluoro-5-(fluoromethyl)benzene

[0158] [ka] The title compound (220 mg, 19%) was prepared in four steps from dimethyl 5-fluoroisophthalate (2.68 g, 12.6 mmol) using the methods of steps 1, 3, 4, and 5 of Intermediate 5. After completion of step 4, the title compound was isolated as a colorless oil by partitioning between DCM (50 mL) and 10% aqueous NaHCO (25 mL). The organic layer was separated, dried (NaSO), and the solvent removed in vacuo. Data are shown in Table 2.

[0159] Synthesis of Examples Typical procedures for the preparation of the Examples are as illustrated by Procedures 1-9 of the Preparation of the Examples below.

[0160] Step 1: Example 1, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine

[0161] [ka] Ammonium acetate (1.18 g, 15.4 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (Intermediate 1, 400 mg, 1.02 mmol) in MeOH (10 mL), and the reaction mixture was stirred at RT for 16 h. NaBHCN (193 mg, 3.07 mmol) was then added, and the reaction mixture was heated at 70 °C for 16 h. The solvent was removed in vacuo, and the residue was quenched with aqueous NaHCO (30 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried (NaSO), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 3-6% MeOH in DCM to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (200 mg, 47%) as a brown semi-solid. A small amount (30 mg) was further purified by preparative HPLC (Method 2 - 40 to 70% gradient) to give the title compound (11 mg). Data are shown in Table 3.

[0162] Step 2 : Example 2, N-(1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide

[0163] [ka] Pyridine (0.15 mL, 1.9 mmol) and AcO (0.1 mL) were added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (Example 1, 75 mg, 0.19 mmol) in DCM (3 mL), and the reaction mixture was stirred at 0° C. for 3 h. The solvent was removed in vacuo, and the residue was purified by trituration with EtO and hexanes to give N-(1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide (21 mg, 25%) as a white solid. Data are shown in Table 3.

[0164] Step 3: Example 3, N-(1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)propionamide

[0165] [ka] 1-(4-(3-Fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (Example 1, 50 mg, 0.13 mmol), HATU (58 mg, 0.15 mmol), propionic acid (0.01 mL, 0.14 mmol), and DIPEA (0.03 mL, 0.15 mmol) were added to DCM (5 mL), and the reaction mixture was stirred at RT for 3 h. The reaction mixture was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO (30 mL). The organic layer was separated, dried (MgSO), and the solvent was removed in vacuo. The residue was triturated with EtO to give N-(1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)propionamide (32 mg, 56%). Data shown in Table 3.

[0166] Step 4: Example 6, N-(1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide

[0167] [ka] Step 1. 3-Aminocyclohex-2-en-1-one (632 mg, 5.68 mmol) was added to a stirred solution of 2-bromo-4-fluoropyridine (1.00 g, 5.68 mmol) in 1,4-dioxane (3.00 mL). The reaction mixture was degassed with argon for 10 minutes, and PdCl(dppf) (371 mg, 0.455 mmol), KPO (3.62 g, 17 mmol), and SPhos (117 mg, 0.284 mmol) were added to the reaction mixture. The reaction mixture was heated at 120 °C for 16 hours, then quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-5% MeOH in DCM to give 3-((4-fluoropyridin-2-yl)amino)cyclohex-2-en-1-one (400 mg, 32%) as a white solid. LCMS (Method 9): m / z 207.1 (ES+), 1.18 min.

[0168] Step 2. A solution of 3-((4-fluoropyridin-2-yl)amino)cyclohex-2-en-1-one (300 mg, 1.45 mmol) in MeCN (8 mL) was added dropwise to a suspension of sodium tert-butoxide (212 mg, 2.18 mmol) in MeCN (9 mL). After stirring at RT for 30 min, a solution of tosyl azide (373 mg, 1.89 mmol) in MeCN (3 mL) was added dropwise. The reaction mixture was stirred at RT for 1 h, and water (20 mL) was added. The aqueous layer was extracted with EtOAc (2 × 30 mL), the combined organic layers were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 30-40% EtOAc in hexanes to give 1-(4-fluoropyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (200 mg, 57%) as a brown solid. LCMS (Method 9): m / z 233.2 (ES+), at 1.38 min.

[0169] Step 3. K2CO3 (143 mg, 1.03 mmol) was added to a stirred solution of 3-fluoro-5-(trifluoromethyl)phenol (155 mg, 0.86 mmol) in MeCN (4 mL), and the reaction mixture was stirred at RT for 10 min. 1-(4-fluoropyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (200 mg, 0.86 mmol) was then added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was poured into water (20 mL), and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried (NaSO) and the solvent removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (230 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (Method 9): m / z 393.0 (ES+), 2.36 min.

[0170] Step 4. Ammonium acetate (147 mg, 1.9 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (75 mg, 0.19 mmol) in MeOH (3 mL), and the reaction mixture was stirred at RT for 16 h. Then, NaBHCN (36 mg, 0.57 mmol) was added at 0 °C, and the reaction mixture was heated at 65 °C for 16 h. The solvent was removed in vacuo, and the residue was quenched with aqueous NaHCO (20 mL). The aqueous layer was extracted with 10% MeOH in DCM (2 × 30 mL). The organic layers were combined, dried (NaSO), and the solvent was removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (Example 22) (73 mg, crude) as a brown gum, which was used in the next step without further purification. LCMS: Not recorded Step 5. Pyridine (0.07 mL, 0.91 mmol) and AcO (0.05 mL, 0.54 mmol) were added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (72 mg, 0.18 mmol) in DCM (4 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo and the residue was purified by gradient flash column chromatography eluting with 70-80% EtOAc in hexanes to give N-(1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide (15 mg, 19%) as a white solid. Data shown in Table 3.

[0171] Step 5: Example 7, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine

[0172] [ka] Ti(OiPr)4 (155 mg, 0.53 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (Intermediate 1, 70 mg, 0.18 mmol) and methylamine hydrochloride (33 mg, 1.08 mmol) in DCM (2.9 mL), and the reaction mixture was stirred at 0 °C for 4 h. Na(OAc)3BH (113 mg, 0.53 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (7.2 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Method 1 - 10 to 75% gradient) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (47 mg, 65%) as a white semi-solid. Data shown in Table 3.

[0173] Step 6: Example 9, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine

[0174] [ka] 10% Palladium on carbon (13 mg) and acetic acid (0.02 mL) were added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (Intermediate 1, 100 mg, 0.26 mmol) and 3-oxetanamine (112 mg, 1.54 mmol) in EtOH (0.78 mL). The reaction mixture was stirred under H at RT for 16 h. The reaction mixture was filtered through a pad of Celite, which was washed twice with EtOH. The solvent was removed in vacuo. The residue was purified by preparative HPLC (Method 1 - 10 to 85% gradient) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (19 mg, 17%) as a colorless semi-solid. Data shown in Table 3.

[0175] Step 7: Example 11, N-(1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide

[0176] [ka] Step 1. 2-Fluoro-4-(3-(trifluoromethyl)benzyl)pyridine (Intermediate 2, 465 mg, 1.82 mmol) was added to 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (Intermediate 3, 250 mg, 1.82 mmol), and the reaction mixture was heated at 135 ° C. for 16 hours. The reaction mixture was dissolved in 5% MeOH / DCM (10 mL), and the solvent was removed in vacuo to give 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (100 mg, crude). This crude material was used in the next step without further purification. MS (method 1): m / z 373 (ES+).

[0177] Step 2. ZnCl (493 mg, 3.62 mmol) was added to a stirred solution of 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (450 mg, 1.20 mmol) and ammonium acetate (924 mg, 12 mmol) in MeOH (12 mL), and the reaction mixture was stirred at RT for 7 h. NaBHCN (224 mg, 3.62 mmol) was added, and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with aqueous NaHCO (30 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried (NaSO), and the solvent was removed in vacuo to give 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (Example 23) (400 mg, crude) as a brown gel, which was used in the next step without further purification. MS (method 1): m / z 374 (ES+).

[0178] Step 3. Pyridine (0.8 mL, 10.7 mmol) and AcO (1.01 mL, 10.7 mmol) were added to a stirred solution of 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (400 mg, 1.07 mmol) in DCM (6 mL), and the reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC (Method 3 - 40 to 50% gradient) to give N-(1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide (30 mg, 6%) as a white solid. Data are shown in Table 3.

[0179] Step 8: Example 12, N-(1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide

[0180] [ka] Step 1. KOAc (264 mg, 2.69 mmol) and [B(pin)] (354 mg, 1.4 mmol) were added to a stirred solution of tert-butyl (1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (425 mg, 1.07 mmol) in 1,4-dioxane (20 mL) at RT, followed by the addition of PdCl(dppf).DCM (44 mg, 0.053 mmol). The resulting reaction mixture was heated at 90° C. for 12 h. The reaction mixture was filtered through Celite, which was washed with 1,4-dioxane (40 mL). The filtrate was concentrated in vacuo to give (2-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-4-yl)boronic acid (900 mg, crude) as a brown gum, which was used in the next step without further purification. LCMS (Method 6): m / z 360.1 (ES+), 1.70 min.

[0181] Step 2. K2CO3 (161 mg, 1.167 mmol) was added to a degassed solution of (2-(4-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-4-yl)boronic acid (140 mg, crude) and 1-(bromomethyl)-3-(difluoromethoxy)-5-fluorobenzene (99 mg, 0.389 mmol) in 1,4-dioxane (5 mL), followed by Pd(dppf)Cl2·DCM (31 mg, 0.0389 mmol), and the resulting reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through Celite, which was washed with 1,4-dioxane (10 mL). The filtrate was concentrated in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-40% EtOAc in petroleum ether to give tert-butyl (1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (80 mg, 42%) as a brown gum. LCMS (Method 6): m / z 490.1 (ES+), 2.69 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 8.49 (d, J = 6.4 Hz, 1H), 7.97 (s, 1H), 7.48-7.45 (m, 1H), 7.29-7.00 (m, 5H), 4.82-4.76 (m, 1H), 4.02 (s, 2H), 3.06-2.90 (m, 2H), 1.99-1.75 (m, 4H), 1.43 (s, 9H).

[0182] Step 3. A suspension of tert-butyl (1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (80 mg, 0.163 mmol) in 20% TFA in DCM (10 mL) was stirred at RT for 2 hours. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (10 mL) and 10% aqueous NaHCO (10 mL). The organic layer was separated, dried (NaSO), and the solvent removed in vacuo to give 1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (Example 24) (55 mg, 87%) as a colorless gum. LCMS (Method 7): m / z 390.0 (ES+), 2.23 min. 1 H NMR: (400 MHz, DMSO-d6) δ: 8.49 (d, J = 5.2 Hz, 1H), 7.98 (s, 1H), 7.48-7.44 (m, 1H), 7.29 (s, 1H), 7.21-7.00 (m, 3H), 4.16 (s, 2H), 4.15-4.11 (m, 1H), 3.05-2.97 (m, 2H), 1.99-1.91 (m, 2H), 1.74-1.58 (m, 2H). Two exchangeable protons not observed.

[0183] Step 4. TEA (14 mg, 0.141 mmol) was added to a stirred solution of 1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (55 mg, 0.141 mmol) in DCM (5 mL) at 0° C., followed by the addition of acetyl chloride (11 mg, 0.141 mmol). The resulting reaction mixture was stirred at RT for 30 min. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Method 4). The solvent was removed in vacuo and the residue was partitioned between water (10 mL) and DCM (10 mL). The organic layer was separated, dried (Na2SO4), and the solvent removed in vacuo to give N-(1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide (14 mg, 23%) as an off-white solid. Data in Table 3.

[0184] Step 9: Example 13, N-(1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide

[0185] [ka] Steps 1 and 2. tert-Butyl (1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (120 mg, 47%) was prepared from tert-butyl (1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (Intermediate 4, 425 mg, 1.07 mmol) and 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (Intermediate 5, 200 mg, 1.03 mmol) using the method of Steps 1 and 2 of Procedure 8. LCMS (Method 6): m / z 474.1 (ES+), 2.60 min. 1H NMR: (400 MHz, CDCl) δ: 8.43 (d, J = 5.2 Hz, 1H), 7.99 (s, 1H), 7.17-7.13 (m, 3H), 7.06-7.02 (m, 1H), 6.63 (t, J = 56.0 Hz, 1H), 5.03-4.93 (m, 1H), 4.13 (s, 2H), 2.00-1.85 (m, 2H), 1.65-1.40 (m, 4H), 1.13 (s, 9H). No exchangeable protons were observed.

[0186] Step 3. 4N HCl in 1,4-dioxane (5 mL) was added to a suspension of tert-butyl (1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate (120 mg, 0.253 mmol) in 1,4-dioxane (5 mL), and the resulting reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated in vacuo to give 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine hydrochloride (Example 15) (80 mg, 77%) as a colorless gum. LCMS (Method 8): m / z 374.1 (ES+), 1.35 min. 1 H NMR: (300 MHz, DMSO-d6) δ: 8.55-8.45 (m, 3H), 8.03 (s, 1H), 7.51-7.45 (m, 4H), 7.34-7.31 (m, 1H), 7.03 (t, J = 55.2 Hz, 1H), 4.65-4.55 (m, 1H), 4.25 (s, 2H), 3.70-3.50 (m, 2H), 2.20-2.00 (m, 4H).

[0187] Step 4. N-(1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)acetamide (16 mg, 20%) was prepared from 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine hydrochloride (80 mg, 0.20 mmol) using the method in Procedure 8, Step 4. Data in Table 3.

[0188] Further details about examples prepared by the above procedure are provided in Table 3.

[0189] Table 2 - Intermediates

[0190] [Table 2-1]

[0191] [Table 2-2] Table 3 - Working Examples

[0192] [Table 3-1]

[0193] [Table 3-2]

[0194] [Table 3-3]

[0195] [Table 3-4]

[0196] [Table 3-5] biological activity GPR52 agonist functional cAMP assay HEKf suspension cells were infected with 0.1% v / v human GPR52-expressing BacMam virus (a modified baculovirus designed for mammalian gene expression) for 24 hours. After BacMam infection, cells were pelleted by centrifugation (335g, 5 min), resuspended in cell freezing medium (Sigma), and frozen at -150°C until needed. On the day of the experiment, GPR52 compound dilutions prepared in DMSO were stamped onto proxy plates (PerkinElmer) using a LabCyte ECHO acoustic dispenser. Frozen cells were thawed and resuspended in assay stimulation buffer (Cisbio) containing 0.5 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma) to achieve a density of 2000 cells per well. 10 μl of cells were added to the assay plate using a Multidrop Combi Reagent Dispenser (ThermoFisher) and then centrifuged (335g, 1 min). Cells were incubated with compounds for 30 minutes at 37°C, after which cAMP detection reagent (HiRange cAMP kit, Cisbio) prepared according to the manufacturer's instructions was added. Plates were shaken at room temperature for 1 hour and then read using standard HTRF settings on a PHERAstar FS plate reader (BMG Labtech). HTRF ratios were calculated by dividing the acceptor emission (665 nm) by the donor emission (620 nm) and multiplying by 10,000. Data were normalized to DMSO (0%) and the maximum 3-(2-(3-chloro-5-fluorobenzyl)benzo[b]thiophen-7-yl)-N-(2-methoxyethyl)benzamide (compound 7m, J. Med. Chem., 2014, 57, 5226) response (100%) and fitted to a four-parameter logistic fit to determine the pEC of the agonist. 50 and maximum responses were produced, which are shown in Table 4 below.

[0197] Table 4 - GPR52 pEC 50 data

[0198] [Table 4] Pharmacokinetic profile The pharmacokinetic profile of Example 2 was evaluated in male Sprague-Dawley rats via intravenous (IV) and oral (PO) delivery routes. Detailed pharmacokinetic data (mean ± standard deviation) for Example 2 of the present invention are shown in Table 5.

[0199] Methods: For pharmacokinetic analysis, groups of three male Sprague-Dawley rats weighing between 200 and 230 g were administered a single dose of Example 2 via either the IV or PO route, using the doses, dose volumes, and vehicle specified in Table 5. After administration, blood samples were collected via serial tail vein sampling at several time points (pre-dose, 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, and 24 hours for IV administration; pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours for PO administration), centrifuged to separate plasma, and analyzed by LC-MS / MS. Pharmacokinetic parameters were generated using noncompartmental analysis using WinNonlin v8.2 statistical software (Pharsight Corporation, California, USA).

[0200] Brain penetration To assess the brain penetration of Example 2 after IV administration, plasma and brain exposure were evaluated. After experimentally determining binding in rat plasma and brain homogenates, the unbound brain-to-plasma ratio (K p,uu ) was calculated. Details are shown in Table 5.

[0201] Methods: To assess brain penetration, male Sprague-Dawley rats (n=3) were administered a single 1 mg / kg dose (formulated in 10% DMAC + 10% Solutol HS15 + 80% saline) via the IV route. Ten minutes after administration, the animals were sacrificed, and the brains were removed, homogenized in 2 volumes (w / v) of 50 mM sodium phosphate buffer (pH 7.4), and analyzed by LC-MS / MS. Blood samples were drawn via tail vein at the same time points, and plasma was analyzed by LC-MS / MS.

[0202] Brain-plasma unbound concentration ratio (K p,uu To allow for the calculation of the β-amyloid ratio (F), binding of test compounds in rat plasma and brain homogenates was performed using Rapid Equilibrium Dialysis (RED). Test compounds prepared in DMSO (1 μM final, 0.2% DMSO) were added to (i) undiluted male Sprague-Dawley rat plasma and (ii) rat brain tissue homogenized in 2 volumes (w / v) of sodium phosphate buffer (pH 7.4) and dialyzed against phosphate buffer for 5 hours at 37°C. After incubation, the contents of each plasma / brain and buffer compartment were removed and mixed with an equal volume of control dialysis buffer or plasma / brain to maintain matrix similarity for analysis. Proteins were then precipitated by the addition of acetonitrile containing an analytical internal standard (allowing for the derivation of the test compound to internal standard ratio), centrifuged, and the supernatant was removed and analyzed by LC-MS / MS. The unbound fraction (F) of plasma and brain was determined. u ) was calculated using the following equation and then used to correct for total plasma and brain concentrations, K p,uu was derived. Bound fraction = (total plasma or brain ratio) - (total buffer ratio) / total plasma or brain ratio Uncombined fraction (F u , brain or plasma) = 1-bound fraction Correction for dilution in the brain binding assay: Undiluted F u , brain = (1 / dilution factor) / ((1 / F u Dilution))-1)+(1 / Dilution factor) Here, dilution factor = 4 Table 5 - Pharmacokinetic data for Example 2

[0203] [Table 5] Caffeine-induced reduction of locomotor activity in rats. Caffeine, a nonselective adenosine receptor antagonist, primarily acts on A 2A It is a psychostimulant that increases locomotor activity in rodents by blocking receptors (Br. J. Pharmacol., 2000, 129, 1465). These receptors are densely expressed on the terminals of GABAergic striatopallidal neurons in the indirect pathway of the basal ganglia, where dopamine D2 receptors are also co-expressed (J. Comp. Neurol., 1998, 401, 163; J. Comp. Neurol., 2001, 431, 331). 2A Tonic activation of the receptor reduces the affinity of D2 receptors for dopamine, 2A Receptor antagonism enhances dopaminergic signaling (Curr. Pharm. Des., 2008, 14, 1468). Some antipsychotic drugs have been shown to block caffeine-induced hyperlocomotion (Pharmacol. Biochem. Behav., 1994, 47, 89; Naunyn-Schmiedeberg's Arch. Pharmacol., 2016, 389, 11).

[0204] Male Sprague-Dawley rats (200-250 g) were divided into groups and maintained on a 12-hour light / dark cycle (lights on at 07:00), at an ambient temperature of 21 ± 2°C, with standard pelleted chow and free access to water. Testing was performed during the light phase of the light / dark cycle. On the day of the experiment, animals were habituated to locomotor cages for 60 minutes. Subsequently, animals were orally administered vehicle or Isomer 1 of Example 2 (0.1, 0.3, 1, or 3 mg / kg) and returned to the appropriate locomotor cage. Isomer 1 of Example 2 was formulated in a vehicle of 10% DMAC, 10% solutol (Kolliphor HS15), and 80% water (v / v / v). After 60 minutes, animals were administered vehicle (saline) or caffeine (15 mg / kg) subcutaneously. Locomotor activity was assessed for 2 hours after caffeine treatment. Data are back-transformed means, adjusted for differences between treatment groups in (locomotor) activity during the 30 min period prior to treatment with test compound or vehicle (n = 10-12). Analyses were performed using a general linear model with treatment, cohort, and rack as factors. SEM was calculated from the residuals of the statistical model. Isomer 1 from Example 2 was compared to caffeine using a Williams test.

[0205] As shown in Figure 1, treatment with Isomer 1 of Example 2 caused a dose-dependent reduction in the caffeine-induced hyperlocomotion response, reaching statistical significance at 3 and 10 mg / kg across all time points.

Claims

1. Formula (1a): 【Chemistry 1】 [In the formula, R １ represents H, C(O)C optionally substituted with 1 to 6 fluorine atoms １－３ alkyl, C optionally substituted with 1 to 6 fluorine atoms １－６ C optionally substituted with alkyl or 1 to 6 fluorine atoms ３－６ cycloalkyl; any one atom of said alkyl or cycloalkyl group may be replaced with O; R ２ is H; Q is -CR ３ R ４ -, -CR ３ R ４ CR ５ R ６ -, -CR ３ R ４ CR ５ R ６ CR ７ R ８ -, -CR ３ R ４ OCR ５ R ６ -, -CR ３ R ４ CR ５ R ６ O- and -CR ３ R ４ Selected from O-; R ３ , R ４ , R ５ , R ６ , R ７ and R ８ is H and C １－３ independently selected from alkyl; L is CH ２ , CHOH, and O; and W is a 6-membered optionally substituted aryl or heteroaryl ring, or a salt, hydrate, and / or solvate thereof.

2. W is, 【Chemistry 2】 [In the formula, R １１ , R １２ and R １３ is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms １－６ alkyl, and C optionally substituted with 1 to 6 fluorine atoms １－６ alkoxy, wherein any one atom of said alkyl or alkoxy group may be replaced with a heteroatom selected from O, N, S and their oxidized forms, or a salt, hydrate, and / or solvate thereof.

3. Formula (2a): 【Transformation 3】 [In the formula, R １１ , R １２ and R １３ is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms １－６ alkyl, and C optionally substituted with 1 to 6 fluorine atoms １－６ alkoxy, wherein any one atom of the alkyl or alkoxy group may be replaced with a heteroatom selected from O, N, S and their oxidized forms; or a salt, hydrate, and / or solvate thereof.

4. Q is -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ CH ２ O-, -CH ２ OCH ２ - and -CH ２ 4. The compound according to claim 1, or a salt, hydrate, and / or solvate thereof, selected from:

5. Q is -CH ２ CH ２ The compound according to any one of claims 1 to 4, or a salt, hydrate, and / or solvate thereof, wherein

6. Formula (3a): 【Chemistry 4】 [In the formula, R １１ , R １２ and R １３ is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms １－６ alkyl, and C optionally substituted with 1 to 6 fluorine atoms １－６ alkoxy, wherein any one atom of the alkyl or alkoxy group may be replaced with a heteroatom selected from O, N, S and their oxidized forms; or a salt, hydrate, and / or solvate thereof.

7. R １ But H, CH ３ , C(O)CH ３ , C(O)CH ２ CH ３ , C(O)CF ２ H, C(O)CF ３ , C(O)CFH ２ , C.H. ２ CH ２ OCH ３ 7. The compound according to claim 1, or a salt, hydrate, and / or solvate thereof, selected from the group consisting of oxetane and oxolane.

8. R １ is C(O)CH ３ 8. The compound of claim 7, or a salt, hydrate, and / or solvate thereof, wherein:

9. Formula (4a): 【Transformation 5】 [In the formula, R １１ , R １２ and R １３ is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms １－６ alkyl, and C optionally substituted with 1 to 6 fluorine atoms １－６ alkoxy, wherein any one atom of the alkyl or alkoxy group may be replaced with a heteroatom selected from O, N, S and their oxidized forms; or a salt, hydrate, and / or solvate thereof.

10. L is CH ２ The compound according to any one of claims 1 to 9, or a salt, hydrate, and / or solvate thereof, wherein

11. R １１ , R １２ and R １３ But H, F, CF ３ , C.F. ２ H, C.F.H. ２ and OCF ２ 11. The compound of any one of claims 1 to 10, or a salt, hydrate, and / or solvate thereof, wherein each of said compounds is independently selected from H.

12. W is 【Transformation 6】 2. The compound of claim 1, or a salt, hydrate, and / or solvate thereof, selected from the group consisting of:

13. Formula (5): 【Transformation 7】 9. The compound of claim 1, 7 or 8, wherein the compound is: or a salt, hydrate, and / or solvate thereof.

14. 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]propanamide; 2,2-difluoro-N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; 2-fluoro-N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-(1-{4-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridin-2-yl}-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl)acetamide; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-methyl-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxolan-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; N-[1-(4-{[3-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-(difluoromethoxy)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[1-(4-{[3-fluoro-5-(fluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine; 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine; 1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine; (4R)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; (4S)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; N-[(4R)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[(4S)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[(4R)-1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; N-[(4S)-1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide; 2. The compound of claim 1, selected from the group consisting of: or a salt, hydrate, and / or solvate thereof.

15. The compound of claim 1, 【Transformation 8】 2. The compound of claim 1, wherein:

16. The compound of claim 1, 【Chemistry 9】 2. The compound of claim 1, wherein:

17. The compound of claim 1 【Chemistry 10】 2. The compound of claim 1, wherein:

18. The compound of claim 17, 【Chemistry 11】 2. The compound of claim 1, wherein:

19. The compound of claim 1 【Chemistry 12】 2. The compound of claim 1, wherein:

20. The compound of claim 1, 【Chemistry 13】 2. The compound of claim 1, wherein:

21. The compound of claim 1, 【Chemistry 14】 2. The compound of claim 1, wherein:

22. The compound of claim 1, 【Chemistry 15】 2. The compound of claim 1, wherein:

23. The compound of claim 1, 【Chemistry 16】 2. The compound of claim 1, wherein:

24. The compound of claim 1, 【Chemistry 17】 2. The compound of claim 1, wherein:

25. The compound of claim 1, [Chemistry 18] 2. The compound of claim 1, wherein:

26. The compound of claim 1, 【Chemistry 19】 2. The compound of claim 1, wherein:

27. A salt of a compound defined in any one of claims 15 to 26.

28. A pharmaceutically acceptable salt of a compound defined in any one of claims 15 to 26.

29. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 28, or a salt, hydrate and / or solvate thereof, and a pharmaceutically acceptable excipient.

30. 30. The composition of claim 29 for use in medicine.

31. 30. The composition of claim 29 for use in treating psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma or stress-related disorders; disruptive, impulse control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities of the infundibulopituitary, mesolimbic, mesocortical, or nigrostriatal pathways; striatal hypoactivity; cortical dysfunction; neurocognitive dysfunction or a condition or symptom related thereto.

32. The disorder or symptom is schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, disease with Lewy bodies, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumor, obesity, post-traumatic stress disorder (PTSD), akathisia and associative movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia Diarrhea, myoclonus, mirror movement disorder, paroxysmal kinesigenic dyskinesia, restless legs syndrome, convulsions, stereotypic movement disorder, stereotypies, tics, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or medication-induced psychotic disorder, delusions, hallucinations, disorganized thinking, severely disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or medication-induced bipolar disorder and related disorders, bipolar disorder and related disorders due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder due to another medical condition, delirium, dementia 32. The composition for use according to claim 31, wherein the condition is selected from: cognitive impairment, cognitive impairment (cognitive disorder), mild cognitive impairment, amnesia, dementia, developmental coordination disorder, stereotypy, post-stroke effects, dentatorubral-pallidoluysian atrophy, decreased emotional expression, amotivation, aphasia and antisociality (social withdrawal).

33. 32. The composition for use according to claim 31, wherein the disorder or condition is selected from schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, neurocognitive disorder, delirium, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD).

Images