Gpr52 modulator compounds

Abstract

The disclosure herein relates to novel compounds of Formula (1) or salts thereof and their use in treating, preventing, ameliorating, controlling or reducing the risk of diseases associated with the GPR52 receptor, wherein Q, V, L, W, R 1 and R 2 As defined herein:

Description

Technical Field

[0001] This application relates to novel compounds and their use as modulators of G protein-coupled receptor 52 (GPR52). The compounds described herein can be used to treat or prevent diseases involving the GPR52 receptor or diseases for which modulation of the GPR52 receptor may be beneficial. This application also relates to pharmaceutical compositions comprising these compounds, and the preparation of these compounds and compositions and their use in the prevention or treatment of such diseases involving the GPR52 receptor. Background Technology

[0002] G protein-coupled receptor 52 (GPR52) is a constitutively active Gs-coupled orphan receptor that is highly expressed in the striatum and cortex. In the striatum, GPR52 is expressed only on dopamine D2-expressing isospinal neurons, while 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 is thought to play a role in the regulation of dopamine in the frontostriatum and limbic system, and therefore may have practical applications in the treatment of neuropsychiatric disorders. GPR52 agonists are considered particularly relevant to the treatment of schizophrenia, presumably by indirectly improving cognition and negative symptoms through enhancing D1 signaling and alleviating positive symptoms by inhibiting D2-mediated signaling in the striatum.

[0003] GPR52 agonists can be used to treat mental illnesses associated with dysfunction of the mesolimbic and mesocortical pathways. Examples include 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. Neuropsychiatric symptoms (e.g., psychosis, anhedonia, mania) of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.) can also be treated with GPR52 agonists. The expression of GPR52 in the pituitary and hypothalamus suggests the applicability of GPR52 modulators in pituitary and hypothalamic disorders, and preclinical evidence (Xiong et al., 2016, WO2016 / 176571) indicates that GPR52 agonists can be used to treat hyperprolactinemia. Summary of the Invention

[0004] This invention provides compounds with G protein-coupled receptor 52 (GPR52) modulator activity.

[0005] The following are provided: a compound of formula (1) or a salt thereof:

[0006]

[0007] in;

[0008] R 1 C(O)C with H atoms, optionally substituted with 1 to 6 fluorine atoms 1-3 Alkyl groups, C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkyl groups, or C groups optionally substituted with 1 to 6 fluorine atoms. 3-6 Cycloalkyl; wherein any atom of the alkyl or cycloalkyl group may optionally be replaced by O;

[0009] R 2 It is H or CC, which is optionally substituted with 1 to 6 fluorine atoms. 1-3 alkyl;

[0010] Q is selected from -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-;

[0011] R 3 R 4 R 5 R 6 R 7 and R 8 Independently selected from H and C 1-3 alkyl;

[0012] V is a 6-membered aryl or heteroaryl ring that is meta-substituted by L, or optionally substituted.

[0013] L is selected from CH2, CHOH, and O;

[0014] Furthermore, W is an optionally substituted 6-membered aryl or heteroaryl ring.

[0015] The compounds of this invention can be used as GPR52 modulators. The compounds of this invention can be used as GPR52 agonists. The compounds of this invention can be used to manufacture pharmaceuticals. These compounds or pharmaceuticals can be used to treat, prevent, improve, control, or reduce the risk of diseases or conditions involving the GPR52 receptor. These compounds or pharmaceuticals can be used to treat, prevent, improve, control, or reduce the risk of diseases or conditions for which modulation of the GPR52 receptor may be beneficial. The compounds of this invention can be used to treat psychiatric disorders; neuropsychiatric disorders; neurodegenerative diseases; psychotic disorders; cognitive impairment; neurocognitive impairment; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depression; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depression; hypothalamic diseases; pituitary diseases; prolactin-related diseases; trauma or stressor-related disorders; disruptive, impulse control, or behavioral disorders; sleep-wake disorders; substance-related disorders; addiction disorders; behavioral disorders; frontal lobe dysfunction; tuberous-infundibular, mesolimbic, mesocortical, or substantia nigra-striatal pathway abnormalities; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction or related conditions or symptoms.

[0016] The compounds of this 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, anhedonia, mania, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, nonfunctional tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and related movements, choreoathetosis, ataxia, tetany, unilateral throwing disorder, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, dyskinesia induced by neuroleptics, myoclonus, mirror dyskinesia, paroxysmal kinesigenic dyskinesia, restless legs syndrome, spasticity, stereotyped dyskinesia. Obstacles, stereotyped disorders, tic disorders, tremors, Wilson's disease, schizotypal personality disorder, delusional disorder, short-term psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, substance or drug-induced psychotic disorders, delusions, hallucinations, thought disorder, severe disorder or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance or drug-induced bipolar disorder and related diseases, bipolar disorder and related diseases caused by other medical conditions, separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance or drug-induced anxiety disorder, anxiety disorder caused by other medical conditions, delirium, severe neurocognitive impairment, mild neurocognitive impairment, amnesia, dementia, developmental coordination disorder, stereotyped motor disorder, post-stroke effects, dentate nucleus, globus pallidus, hypothalamic nucleus atrophy, reduced emotional expression, lack of motivation, aphasia, and asocial behavior. Invention Details

[0018] This invention relates to novel compounds. It also relates to the use of these novel compounds as modulators of the GPR52 receptor. Furthermore, it relates to the use of these novel compounds in the manufacture of medicaments that function as GPR52 modulators. The compounds of this invention can be used as GPR52 agonists. These compounds or medicaments can be used to treat, prevent, improve, control, or reduce the risk of diseases or conditions involving the GPR52 receptor. These compounds or medicaments can be used to treat, prevent, improve, control, or reduce the risk of diseases or conditions for which modulation of the GPR52 receptor may be beneficial.

[0019] This invention also relates to compounds, compositions, and pharmaceuticals that can be used to treat the following conditions: mental illness; neuropsychiatric illness; neurodegenerative disease; psychotic disorder; cognitive impairment; neurocognitive impairment; extrapyramidal disorders; movement disorders; motor disorders; hyperkinesis; catatonia; mood disorders; depression; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depression; prolactin-related disorders; trauma or stressor-related disorders; disruptive, impulse control, or behavioral disorders; sleep-wake disorders; substance-related disorders; addiction disorders; behavioral disorders; frontal lobe dysfunction; tuberous-infundibular, mesolimbic, mesocortical, or substantia nigra-striatal pathway abnormalities; decreased striatal activity; cortical dysfunction; neurocognitive impairment or related conditions or symptoms.

[0020] The following are provided: a compound of formula (1) or a salt thereof:

[0021]

[0022] in;

[0023] R 1 C(O)C with H atoms, optionally substituted with 1 to 6 fluorine atoms 1-3 Alkyl groups, C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkyl groups or C atoms optionally substituted with 1 to 6 fluorine atoms 3-6 Cycloalkyl; wherein any atom of the alkyl or cycloalkyl group may optionally be replaced by O;

[0024] R 2 It is H, or C optionally substituted with 1 to 6 fluorine atoms. 1-3 alkyl;

[0025] Q is selected from -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 4O-;

[0026] R 3 R 4 R 5 R 6 R 7 and R 8 Independently selected from H and C 1-3 alkyl;

[0027] V is an optional substituted 6-membered aryl or heteroaryl ring that is meta-substituted by L;

[0028] L is selected from CH2, CHOH, and O;

[0029] Furthermore, W is an optionally substituted 6-membered aryl or heteroaryl ring.

[0030] Compounds of formula (1a) or salts thereof are also provided:

[0031]

[0032] in;

[0033] R 1 C(O)C with H atoms, optionally substituted with 1 to 6 fluorine atoms 1-3 Alkyl groups, C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkyl groups, or C groups optionally substituted with 1 to 6 fluorine atoms. 3-6 Cycloalkyl; wherein any atom of the alkyl or cycloalkyl group may optionally be replaced by O;

[0034] R 2 It is H, or C optionally substituted with 1 to 6 fluorine atoms. 1-3 alkyl;

[0035] Q is selected from -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-;

[0036] R 3 R 4 R 5 R 6 R 7 and R 8 Independently selected from H and C 1-3 alkyl;

[0037] L is selected from CH2, CHOH, and O;

[0038] Furthermore, W is an optionally substituted 6-membered aryl or heteroaryl ring.

[0039] Compounds of formula (1a) or salts thereof are also provided:

[0040]

[0041] in;

[0042] R 1 C(O)C with H atoms, optionally substituted with 1 to 6 fluorine atoms 1-3 Alkyl groups, C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkyl groups or C atoms optionally substituted with 1 to 6 fluorine atoms 3-6 Cycloalkyl; wherein any atom of the alkyl or cycloalkyl group may optionally be replaced by O;

[0043] R 2 It is H;

[0044] Q is selected from -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-;

[0045] R 3 R 4 R 5 R 6 R7 and R 8 Independently selected from H and C 1-3 alkyl;

[0046] L is selected from CH2, CHOH, and O;

[0047] Furthermore, W is an optionally substituted 6-membered aryl or heteroaryl ring.

[0048] In the compounds described in this article, R 1 It 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 oxetane. R 1 It can be selected from H, CH3, C(O)CH3, C(O)CH2CH3, C(O)CF2H, C(O)CF3, C(O)CFH2, CH2CH2OCH3, oxetane, and oxetane. R 1 It can be C(O)CH3.

[0049] In the compounds described in this paper, R 2 It can be selected from H, CH3, CF3, CHF2, and CH2F. R 2 It can be H.

[0050] In the compounds described in this paper, Q can be selected from -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-, where R 3 R 4 R 5 R 6 R 7 and R 8It is H. Q can be selected from CH2-, -CH2CH2-, CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, and -CH2O-. Q can be -CH2CH2-.

[0051] In the compounds described in this article, L can be CH2. L can be CHOH. L can be O.

[0052] In the compounds described herein, V can be an optionally substituted benzene ring or pyridine ring, which is substituted with L at the meta position.

[0053] V can be selected from the following group:

[0054]

[0055] V can be:

[0056]

[0057] In the compounds described in this article, W can be:

[0058]

[0059] Each B is independently selected from N and CR. 11 CR 12 or CR 13 ;

[0060] And R 11 R 12 and R 13 Independently selected from H, CN, halogens, and C atoms optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl groups and C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkoxy, wherein any atom of the alkyl or alkoxy group may optionally be replaced by a heteroatom selected from O, N, S and their oxidized forms.

[0061] W can be selected from the following:

[0062]

[0063] Where R 11 R 12 and R 13 Independently selected from H, CN, halogens, and C atoms optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl groups and C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkoxy, wherein any atom of the alkyl or alkoxy group may optionally be replaced by a heteroatom selected from O, N, S and their oxidized forms.

[0064] W can be selected from the following group:

[0065]

[0066] In the compounds described in this paper, R 11 R 12 and R 13 It can be independently H, CN, F, Cl, methyl, cyclopropyl, CF3, CF2H, OCF2H, OCF3, OMe, or SO2Me. 11 R 12 and R 13 It can be independently selected from H, F, CF3, CF2H, CFH2, and OCF2H. R 11 R 12 and R 13 It can be selected independently from H, F and CF3.

[0067] In the compounds described in this paper, R 11 It can be H. R 11 It can be CN. R 11 It can be halogen. R 11 It can be F or Cl. R 11 It can be F. R 11 C can be optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl, wherein C 1-6 One atom of the alkyl group may be optionally replaced by a heteroatom selected from O, N, S, and their oxidized forms. 11 C can be optionally replaced by 1 to 6 fluorine atoms. 1-6 Alkyl group. R 11 It can be C 1-6 Alkyl group. R 11 OCs can be optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl group. R 11 It can be OC 1-6 Alkyl group. R 11 It can be SO2C that is optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl group. R 11 It can be SO2C 1-6 Alkyl group. R 11 C can be optionally replaced by 1 to 6 fluorine atoms. 3-6 Cycloalkyl. R 11 It can be C 3-6 Cycloalkyl. R 11 It can be H. R 11 It can be CN. R 11 It can also be F. R 11 It can be Cl. R 11 It can be methyl. R 11 It can be cyclopropyl. R 11 It could be CF3. R11 It could be OCF2H. R 11 It could be SO2Me. R 11 It could be CF2H. R 11 It could be CH2F. R 11 It could be OMe. R 11 It can be H, F, CF3, CF2H, CFH2, or OCF2H. R 11 It can be H, F, or CF3.

[0068] In the compounds described in this paper, R 12 It can be H. R 12 It can be CN. R 12 It can also be halogen. R 12 It can be F or Cl. R 12 It can be F. R 12 C can be optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl, wherein C 1-6 One atom of the alkyl group may be optionally replaced by a heteroatom selected from O, N, S, and their oxidized forms. 12 C can be optionally replaced by 1 to 6 fluorine atoms. 1-6 Alkyl group. R 12 It can be C 1-6 Alkyl group. R 12 OCs can be optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl group. R 12 It can be OC 1-6 Alkyl group. R 12 It can be SO2C that is optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl group. R 12 It can be SO2C 1-6 Alkyl group. R 12 C can be optionally replaced by 1 to 6 fluorine atoms. 3-6 Cycloalkyl. R 12 It can be C 3-6 Cycloalkyl. R 12 It can be H. R 12 It can be CN. R 12 It can be F. R 12 It can be Cl. R 12 It can be methyl. R 12 It can be cyclopropyl. R 12 It could be CF3. R 12 It could be OCF2H. R 12 It could be SO2Me. R 12 It could be CF2H. R 12 It could be CH2F. R 12 It could be OMe. R 12It can be H, F, CF3, CF2H, CFH2, or OCF2H. R 12 It can be H, F, or CF3.

[0069] In the compounds described in this paper, R 13 It can be H. R 13 It can be CN. R 13 It can be halogen. R 13 It can be F or Cl. R 13 It can be F. R 13 C can be optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl, wherein C 1-6 One atom of the alkyl group may be optionally replaced by a heteroatom selected from O, N, S, and their oxidized forms. 13 C can be optionally replaced by 1 to 6 fluorine atoms. 1-6 Alkyl group. R 13 It can be C 1-6 Alkyl group. R 13 OCs can be optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl group. R 13 It can be OC 1-6 Alkyl group. R 13 It can be SO2C that is optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl group. R 13 It can be SO2C 1-6 Alkyl group. R 13 C can be optionally replaced by 1 to 6 fluorine atoms. 3-6 Cycloalkyl. R 13 It can be C 3-6 Cycloalkyl. R 13 It can be H. R 13 It can be CN. R 13 It can be F. R 13 It can be Cl. R 13 It can be methyl. R 13 It can be cyclopropyl. R 13 It could be CF3. R 13 It could be OCF2H. R 13 It could be SO2Me. R 13 It could be CF2H. R 13 It could be CH2F. R 13 It could be OMe. R 13 It can be H, F, CF3, CF2H, CFH2, or OCF2H. R 13 It can be H, F, or CF3.

[0070] Specific compounds include compounds of formula (2a), (2b) or (2c) or their salts:

[0071]

[0072] Among them, Q, L, R 1 R 2 R 11 R 12 and R 13 As defined above.

[0073] Specific compounds include compounds of formula (3a), (3b) or (3c) or their salts:

[0074]

[0075] Among them, L and R 1 R 2 R 11 R 12 and R 13 As defined above.

[0076] Specific compounds include compounds of formula (4a), (4b) or (4c) or their salts:

[0077]

[0078] Among them, L and R 11 R 12 and R 13 As defined above.

[0079] Specific compounds include compounds of formula (5) or their salts:

[0080]

[0081] Where R 1 and R 2 As defined above.

[0082] Specific compounds include compounds of formula (6a), (6b) or (6c) or their salts:

[0083]

[0084] Where R 1 R 2 R 11 R 12 and R 13 As defined above.

[0085] Specific compounds include compounds of formula (7a), (7b), (7c), (7d) or (7e) or their salts:

[0086]

[0087] Among them, Q, L, R 1 R 2 R 11 R 12 and R 13 As defined above.

[0088] It also includes compounds of formulas (1i) and (1ii) and their salts:

[0089]

[0090] Among them, Q, V, L, W, R 1 and R 2 As defined above.

[0091] It also includes compounds of formulas (1ai) and (1aii) and their salts:

[0092]

[0093] Among them, Q, L, W, R 1 and R 2 As defined above.

[0094] The compound may be selected from any one of Examples 1 to 21 shown in Table 1 or a salt thereof.

[0095] The compound may be selected from the group consisting of the following compounds or their salts:

[0096] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0097] N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0098] N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]propionamide;

[0099] 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;

[0100] 2-Fluoro-N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0101] N-(1-{4-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridin-2-yl}-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl)acetamide;

[0102] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-methyl-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0103] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0104] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxecyclobut-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0105] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxacyclopentan-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0106] N-[1-(4-{[3-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0107] N-[1-(4-{[3-(difluoromethoxy)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0108] N-[1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0109] N-[1-(4-{[3-fluoro-5-(fluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0110] 1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0111] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-1,4,5,6-tetrahydrocyclopentadien[d][1,2,3]triazol-4-amine;

[0112] N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-1,4,5,6-tetrahydrocyclopentadien[d][1,2,3]triazol-4-yl]acetamide;

[0113] 3-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,6,7,8-tetrahydro-3H-oxa [3,4-d][1,2,3]triazol-8-amine;

[0114] N-[3-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,6,7,8-tetrahydro-3H-oxa [3,4-d][1,2,3]triazol-8-yl]acetamide;

[0115] 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,7,8-tetrahydro-1H-oxa [4,5-d][1,2,3]triazol-4-amine;

[0116] N-[1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,7,8-tetrahydro-1H-oxa [4,5-d][1,2,3]triazol-4-yl]acetamide;

[0117] 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine;

[0118] 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine;

[0119] 1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine;

[0120] (4R)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0121] (4S)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine;

[0122] N-[(4R)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0123] N-[(4S)-1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0124] N-[(4R)-1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide;

[0125] N-[(4S)-1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-yl]acetamide.

[0126] Other embodiments of the present invention include 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 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 used to treat or prevent diseases for which regulation of the GPR52 receptor may be beneficial.

[0127] The compounds of this invention can be used to treat mental illnesses; neuropsychiatric illnesses; neurodegenerative diseases; psychotic disorders; cognitive impairments; neurocognitive impairments; extrapyramidal disorders; movement disorders; motor disorders; hyperkinesis; catatonia; mood disorders; depression; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depression; hypothalamic diseases; pituitary diseases; prolactin-related diseases; trauma or stressor-related disorders; disruptive, impulse control, or behavioral disorders; sleep-wake disorders; substance-related disorders; addiction disorders; behavioral disorders; frontal lobe dysfunction; tuberous-infundibular, mesolimbic, mesocortical, or substantia nigra-striatal pathway abnormalities; reduced striatal activity; cortical dysfunction; neurocognitive impairments or related conditions or symptoms.

[0128] The compounds of this 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, anhedonia, mania, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, nonfunctional tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and related movements, choreoathetosis, ataxia, tetany, unilateral throwing disorder, chorea, choreoathetosis, movement disorders, tardive dyskinesia, depressant-induced movement disorders, myoclonus, mirror dyskinesia, paroxysmal kinesigenic dyskinesia, restless legs syndrome, spasticity, stereotyped dyskinesia, stereotyped disorder. Tic disorders, tremors, Wilson's disease, schizotypal personality disorder, paranoid disorders, short-term psychotic disorders, schizophrenia-like disorders, schizoaffective disorders, substance or drug-induced psychotic disorders, delusions, hallucinations, thought disorder, severe disorder or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance or drug-induced bipolar disorder and related disorders, bipolar disorder and related disorders caused by other medical conditions, separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance or drug-induced anxiety disorder, anxiety disorder caused by other medical conditions, delirium, severe neurocognitive impairment, mild neurocognitive impairment, amnesia, dementia, developmental coordination disorder, stereotyped motor disorder, post-stroke effects, atrophy of the dentate nucleus, globus pallidus, and hypothalamus, reduced emotional expression, lack of motivation, aphasia, and asocial behavior.

[0129] The compounds of this 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 disorder, delirium, anhedonia, mania, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD). The compounds of this invention can also be used to treat schizophrenia.

[0130] definition

[0131] In this application, unless otherwise stated, the following definitions apply.

[0132] 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 through means including, but not limited to, agonists, partial agonists, and inverse agonists.

[0133] The term “treatment” in connection with the use of any compound described herein (including compounds of formula (1)) is used to describe any form of intervention in which a compound is administered to a subject who has, may have, or is potentially likely to have the disease or condition in question. Thus, the term “treatment” includes both preventative (preventive) treatment and treatment that manifests measurable or detectable symptoms of a disease or condition.

[0134] The term "effective therapeutic amount" (e.g., in relation to a method of treating a symptom, disease, or condition) refers to the amount of a compound that effectively produces the desired therapeutic effect. For example, if the symptom is pain, then the effective therapeutic amount is an amount sufficient to provide the desired level of pain relief. The desired level of pain relief could be, for example, complete elimination of pain or reduction of the severity of pain.

[0135] Unless otherwise stated, the terms “alkyl,” “alkoxy,” “aryl,” “heteroaryl,” and “cycloalkyl” are used in their conventional sense (as defined in the IUPAC Gold Book). “Optional substitution” applied to any group means that, if desired, the group may be substituted with one or more identical or different substituents.

[0136] Examples of replacing carbon atoms with heteroatoms include replacing carbon atoms in the -CH2-CH2-CH2- chain with oxygen or sulfur to obtain ethers -CH2-O-CH2- or thioethers -CH2-S-CH2-; replacing carbon atoms in the CH2-C≡CH group with nitrogen to obtain nitrile (cyano) groups CH2-C≡N; replacing carbon atoms in the -CH2-CH2-CH2- group with C=O to obtain ketones CH2-C(O)-CH2-; replacing carbon atoms in the -CH2-CH=CH2 group with C=O to obtain aldehydes CH2-C(O)H; replacing carbon atoms in the -CH2-CH2-CH3 group with O to obtain alcohols CH2-CH2-CH2OH; and replacing carbon atoms in the -CH2-CH2-CH3 group with O to obtain ethers CH2. -O-CH3, replacing a carbon atom in the -CH2-CH2-CH3 group with S to obtain the thiol CH2-CH2-CH2SH, replacing a carbon atom in the -CH2-CH2-CH2- group with S=O or SO2 to obtain sulfoxide -CH2-S(O)-CH2- or sulfone -CH2-S(O)2-CH2-, replacing a carbon atom in the -CH2-CH2-CH2- chain with C(O)NH to obtain the amide -CH2-CH2-C(O)-NH-, replacing a carbon atom in the -CH2-CH2-CH2- chain with nitrogen to obtain the amine -CH2-NH-CH2-, and replacing a carbon atom in the -CH2-CH2-CH2- chain with C(O)O to obtain the ester (or carboxylic acid) CH2-CH2-C(O)-O-. In each of these substitutions, at least one carbon atom must be retained in the alkyl group.

[0137] Where any of the compounds described have a chiral center, the invention extends to all optical isomers of these compounds, whether racemic or enantiomerically separated. Regardless of the preparation method, the invention herein relates to all crystalline forms, solvates, and hydrates of any disclosed compound. Where any of the compounds disclosed herein have an acidic or basic center, such as a carboxylate or amino group, this invention includes all salt forms of the compound. In the case of pharmaceutical use, the salt should be considered a pharmaceutically acceptable salt.

[0138] Salts that may be mentioned, or pharmaceutically acceptable salts, include acid addition salts and base addition salts. Such salts can be formed by conventional methods, such as by reacting the free acid or free base form of the compound with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by freeze-drying, or by filtration). Salts can also be prepared by exchanging the counterion of the compound in its salt form with another counterion, for example using a suitable ion exchange resin.

[0139] Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0140] Examples of acid addition salts include those formed with the following acids: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, 1,2-ethanedisulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (… Examples include D-glucuronic acid, glutamic acid (e.g., L-glutamic acid), α-ketoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic 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-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-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanate, undecenoic acid, and valeric acid.

[0141] This also includes any solvates of these compounds and their salts. Preferred solvates are solvation products formed by introducing molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid-state structure (e.g., crystal structure) of the compounds of the 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 invention with a solvent containing a solvating solvent or a mixture of solvents containing a solvating solvent. Whether a solvate has been formed in any given case can be determined by analyzing the crystals of the compound using known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0142] Solvates can be stoichiometric or non-stoichiometric. Specific solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and their preparation and characterization methods, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0143] In the context of this invention, the term "pharmaceutical composition" refers to a composition comprising an active agent and additionally comprising one or more pharmaceutically acceptable carriers. Depending on the manner of administration and the nature of the dosage form, the composition may further comprise ingredients selected from: for example, diluents, adjuvants, excipients, carriers, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. The composition may take the form of, for example, tablets, sugar-coated pills, powders, elixirs, syrups, liquid formulations including suspensions, sprays, inhalers, tablets, lozenges, emulsions, solutions, capsules, granules, capsules, and suppositories, as well as liquid formulations for injection, including liposome formulations.

[0144] The compounds of this invention may contain one or more isotopic substitutions, and when a particular element is mentioned, all isotopes of that element are included within its scope. For example, when hydrogen is mentioned, all isotopes of that element are included within its scope. 1 H, 2 H(D) and 3 H(T). Similarly, when referring to carbon and oxygen, their respective ranges include... 12 C 13 C and 14 C and 16 O and 18 Similarly, unless the context otherwise indicates otherwise, references to a particular functional group also include isotopic variants within its scope. For example, references to alkyl (e.g., ethyl) or alkoxy (e.g., methoxy) also encompass variants in which one or more hydrogen atoms in the group are in deuterium or tritium isotopic form, such as in ethyl where all five hydrogen atoms are in deuterium isotopic form (all-deuterium ethyl group) or in methoxy where all three hydrogen atoms are in deuterium isotopic form (trideuterium methoxy group). Isotopes can be radioactive or non-radioactive.

[0145] The therapeutic dose can vary depending on the patient's requirements, the severity of the condition being treated, and the compound being used. Determining the appropriate dose for a specific situation is within the scope of the art. Typically, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect for that situation is achieved. For convenience, the total daily dose can be divided into several doses administered throughout the day if desired.

[0146] Of course, the effective dose of a compound will vary depending on the severity of the disease to be treated and the nature of the specific compound and its route of administration. The selection of an appropriate dose is within the capabilities of a person skilled in the art without undue burden. Typically, the daily dose range can be from about 10 μg to about 30 mg per kilogram of body weight for humans and non-human animals, preferably from about 50 μg to about 30 mg per kilogram of body weight for humans and non-human animals, for example from about 50 μg to about 10 mg per kilogram of body weight for humans and non-human animals, for example from about 100 μg to about 30 mg per kilogram of body weight for humans and non-human animals, for example from about 100 μg to about 10 mg per kilogram of body weight for humans and non-human animals, and most preferably from about 100 μg to about 1 mg per kilogram of body weight for humans and non-human animals.

[0147] pharmaceutical preparations

[0148] Although the active compound can be administered alone, it is preferred to provide it as a pharmaceutical composition (e.g., a formulation).

[0149] Therefore, a pharmaceutical composition is provided comprising at least one compound of formula (1) as defined above and at least one pharmaceutically acceptable excipient.

[0150] The composition may be a tablet composition. The composition may be a capsule composition.

[0151] Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents, such as fillers or fillers; and liquid diluents, such as solvents and co-solvents), granulators, binders, flow aids, coating agents, controlled-release agents (e.g., sustained-release or delayed-release polymers or waxes), adhesives, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tension modifiers, thickeners, flavoring agents, sweeteners, colorants, plasticizers, taste maskers, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0152] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic reactions, or other problems or complications, and have a reasonable benefit / risk ratio. Excipients must also be "acceptable," meaning they are compatible with other components of the formulation.

[0153] Pharmaceutical compositions containing compounds of formula (1) can be prepared according to known techniques, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, intraocular, intraauricular, rectal, vaginal, or transdermal administration.

[0154] Drug dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers, or patches, such as oral patches.

[0155] Tablet compositions may contain a unit dose of the active compound and an inert diluent or carrier, such as sugars or sugar alcohols, for example, lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starch, such as corn starch. Tablets may also contain standard ingredients such as binders and granulators, such as polyvinylpyrrolidone, disintegrants (such as swellable cross-linked polymers, such as cross-linked carboxymethyl cellulose), lubricants (such as stearates), preservatives (such as parabens), antioxidants (such as BHT), buffers (such as phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well-known and do not need to be discussed in detail here.

[0156] Tablets can be designed to release the drug upon contact with gastric juices (i.e., release tablets) or to release the drug in a controlled manner over a longer period of time or in a specific area of ​​the gastrointestinal tract (controlled-release tablets).

[0157] Pharmaceutical compositions typically comprise from about 1% (w / w) to about 95% (w / w) of a preferred active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g., as described above) or a combination of such excipients. Preferably, the composition comprises from about 20% (w / w) to about 90% (w / w) of an active ingredient and from 80% (w / w) to 10% (w / w) of a pharmaceutical excipient or a combination of excipients. The pharmaceutical composition comprises from about 1% to about 95%, preferably from about 20% to about 90%, of the active ingredient. Pharmaceutical compositions according to the invention may be in, for example, unit-dose form, such as ampoules, vials, suppositories, pre-filled syringes, sugar-coated pills, powders, tablets, or capsules.

[0158] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% glidants, and / or 0-99% (w / w) fillers / or fillers (depending on the drug dosage). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, and 0-5% colorants. Furthermore, sustained-release tablets typically contain 0-99% (w / w) controlled-release (e.g., delayed-release) polymers (depending on the dosage). Film coatings of tablets or capsules typically contain 0-10% (w / w) polymers, 0-3% (w / w) colorants, and / or 0-2% (w / w) plasticizers.

[0159] Parenteral preparations typically contain 0-20% (w / w) buffer, 0-50% (w / w) co-solvent, and / or 0-99% (w / w) water for injection (WFI) (depending on the dosage and whether it is lyophilized). Intramuscular reservoir preparations may also contain 0-99% (w / w) oil.

[0160] Drug formulations can be provided to patients in the form of "patient packages," which contain the entire course of treatment in a single package, typically blister packs.

[0161] Compounds of formula (1) are typically present in unit dose form and therefore usually contain sufficient amount of compound to provide the desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, such as 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligrams to 2 grams of active ingredient (more typically 10 milligrams to 1 gram, such as 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (such as 1 microgram to 10 milligrams, such as 0.1 milligrams to 2 milligrams of active ingredient).

[0162] For oral compositions, the unit dosage form may contain 1 mg to 2 g, more typically 10 mg to 1 g, such as 50 mg to 1 g, such as 100 mg to 1 mg of the active compound.

[0163] The active compound will be administered to the patient in need (e.g., human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective dose). The precise amount of compound administered can be determined by the supervising physician according to standard procedures. Example

[0164] The invention will now be described, and not limited, by reference to the following examples shown in Table 1. NMR and LCMS properties are shown in Table 3. The intermediates used are listed in Table 2.

[0165] Table 1 - Examples

[0166]

[0167]

[0168] 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 separated substances has not been determined. All other example compounds were obtained as mixtures of enantiomers without chiral separation. Both enantiomers are included within the scope of this disclosure unless the absolute stereochemistry is indicated by drawing the structures of the examples.

[0169] Therefore, one of the embodiments 1-isomers 1 and 2 is:

[0170]

[0171] The other one is:

[0172]

[0173] Example 2 - One of isomers 1 and 2 is:

[0174]

[0175] The other one is:

[0176]

[0177] Example 13 - One of isomers 1 and 2 is:

[0178]

[0179] The other one is:

[0180]

[0181] Preparation of the compounds of the present invention

[0182] 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 as defined in formula (1) above. If an intermediate is commercially available, it is identified by its Chemical Abstracts Service (CAS) number in Table 3; if it is not commercially available, the method for synthesizing the intermediate using standard conversion is described in detail herein. Commercially available reagents are used without further purification.

[0183] General Procedure

[0184] The room temperature (rt) is approximately 20-27℃. 1 ¹H NMR spectra are typically recorded at 400 MHz at ambient temperature unless otherwise specified. Chemical shift values ​​are expressed in parts per million (ppm), i.e., the (δ) value. Standard abbreviations or combinations thereof are used for the multiplicity of NMR signals, such as: s = singlet, br = broad peak, d = doublet, t = triplet, q = quartet, quin = quintet or p = quintet, h = septet, dd = doubletet, dt = doubletet, m = multiplet. Coupling constants are listed in J values ​​in Hz. NMR and mass spectrometry results are corrected to account for background peaks. Chromatography refers to column chromatography using silica or C18 silica, performed under positive pressure (rapid chromatography) conditions.

[0185] LCMS method

[0186] LCMS experiments were conducted using electrospray ionization under the following conditions (solvents: A1 = 2 mM ammonium acetate and 0.1% formic acid in H2O; A2 = 5 mM sodium acetate in H2O; A3 = 2.5 L H2O + 2.5 mL 28% ammonia in H2O; A5 = 10 mM NH4HCO3 in H2O; A6 = 0.2% 28% ammonia solution in water; A7 = 0.1% TFA in H2O; A8 = 5 mM NH4HCO3 in H2O; A9 = 10 mM ammonium acetate in H2O; B1 = 0.1% formic acid in MeCN; B2 = MeCN; B3 = 2.5 L MeCN + 135 mL H2O + 2.5 mL... A solution of 28% ammonia in H2O. LCMS data are given in the following formats: mass ions, electrospray mode (positive or negative), retention time (experimental text and Table 2); mass ions, electrospray mode (positive or negative), retention time, approximate purity (Table 3).

[0187] Method 1. Instruments: Hewlett-Packard 1100 with G1315A DAD, Micromass ZQ; Column: Phenomenex Gemini-NX C18, 3 μm, 2.0 x 30 mm; Gradient [time (min) / B3 (%) in solvent A3]: 0.00 / 2, 0.10 / 2, 8.40 / 95, 10.00 / 95; Injection volume 1 μL; UV detection 230 to 400 nM; Column temperature 45 °C; Flow rate 1.5 mL / min.

[0188] Method 2. Instruments: Agilent Technologies 1260 LC with Chemstation software, DiodeArray Detector, Agilent 6120 Quadrupole MS with APCI and ES Source; Column: Phenomenex Gemini-NX C18, 3 μm, 2 x 30 mm; Gradient [time (min) / B3 (%) in solvent 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.

[0189] Method 3. Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity HSS-T3, 1.8 μm, 2.1 x 100 mm; Gradient [time (min) / B2 (%) in solvent 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.

[0190] Method 4. Instruments: Agilent Technologies 1260 LC with Chemstation software, DiodeArray Detector, Agilent 6120 Quadrupole MS with APCI and ES Source; Column: Phenomenex Gemini-NX C18, 3 μm, 2 x 30 mm; Gradient [time (min) / B3 (%) in solvent 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.

[0191] Method 5. Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 μm, 2.1 x 100 mm; Gradient [time (min) / B2 (%) in solvent 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.

[0192] Method 6. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax XDB C18, 5 μm; Gradient [time (min) / B2 (%) in solvent 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.

[0193] Method 7. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Waters XBridge C8 3.5 μm, 4.6 x 50 mm; Gradient [time (min) / B1 (%) in solvent A1]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210 to 400 nM; Column temperature 25 °C; 1.5 mL / min.

[0194] Method 8. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax extend C18, 5 μm, 4.6 x 50 mm; Gradient [time (min) / B2 (%) in solvent A9]: 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.

[0195] Method 9. Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 μm, 2.1 x 100 mm; Gradient [time (min) / B2 (%) in solvent 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 to 3.20 min, then 0.8 mL / min.

[0196] Method 10. Instruments: Waters Acquity H Class, Waters PDA Detector, SQD; Column: AcquityBEH C-18, 1.7 μm, 2.1 x 50 mm; Gradient [time (min) / B1 (%) in solvent 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 to 0.60 min, then 0.60 mL / min to 0.80 min, then 0.65 mL / min to 1.71 min, then 0.55 mL / min.

[0197] GCMS method

[0198] GCMS data are provided in the following ways: mass ions, electrospray mode (positive or negative), and retention time.

[0199] Method 1. Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30m x 250μm x 0.25μm); Inlet temperature: 250℃; Split ratio: 75:1; Oven temperature: 50℃, hold time 3 min; Heating rate 1: 40℃ / min to 300℃, hold time 2 min; Detector temperature: 310℃; Column flow rate: 2 mL / min; Air flow rate: 300 mL / min; H2 flow rate: 40 mL / min; Make-up flow rate (He): 25 mL / min; Source temperature: 230℃.

[0200] Method 2. Instruments: Agilent GCMS 7890B; Column: HP-5ms UI (30m x 250μm x 0.25μm); Inlet temperature: 250℃; Split ratio: 75:1; Oven temperature: 120℃, hold time 1 min; Heating rate 1: 40℃ / min to 300℃, hold time 4 min; Detector temperature: 310℃; Column flow rate: 2 mL / min; Air flow rate: 300 mL / min; H2 flow rate: 40 mL / min; Make-up flow rate (He): 25 mL / min; Source temperature: 230℃.

[0201] MS method

[0202] Method 1. Data obtained on a Waters QDA or Waters SQD instrument after running the UPLC column with buffer for 4-6 minutes.

[0203] Preparative HPLC method

[0204] For information on solvent conditions, please refer to the LCMS method section.

[0205] Method 1. Instrument: Waters 2767 Auto purification; Column: X-Bridge Shield C18 10 μm 19 x 250 mm; Gradient 20 min, B2 (%) in solvent A2 varied on an independent run (see exemplary procedure for details).

[0206] Method 2. Instrument: Gilson Semi Preparative HPLC System-321 Pump / 171 Diode Array Detector / GX-271 Liquid Handler; Column: Phenomenex Gemini-NX C18 5 μm 30 x 100 mm; gradient 12.5 min, B2 (%) in solvent A6 varied on an independent run (see exemplary procedure for details).

[0207] Method 3. Instrument: Waters 2767 automated purification; Column: Ultimate hexyl phenyl 10 μm 19 x 250 mm; gradient 18 min, B2 (%) in solvent A7 varied on an independent run (see exemplary procedure for details).

[0208] Method 4. Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD; Column: Waters XBridge C8 5 μm 19 x 150 mm; Gradient [time (min) / B2 (%) in solvent A5]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0209] Chiral SFC method

[0210] Method 1. Instrument: Sepiatec Prep SFC 100 with Prep SFC 100 control software and UV / Vis detector; Column: Lux C1 5 μm, 21.2 x 250 mm; Co-solvent: EtOH; Column temperature: 40 °C; 50 mL / min.

[0211] Method 2. Instrument: Sepiatec Prep SFC 100 with Prep SFC 100 control software and UV / Vis detector; Column: Lux A1 5 μm, 21.2 x 250 mm; co-solvent IPA with 0.2% NH3; column temperature 40 °C; 50 mL / min.

[0212] Method 3. Instruments: Waters Acquity UPC2 with Masslynx software, PDA detector and QDa mass detector; Column: Lux Al 3 μm, 2 x 50 mm; Co-solvent EtOH; Column temperature 45℃; 1.5 mL / min.

[0213] Method 4. Instruments: Waters Acquity UPC2 with Masslynx software, PDA detector and QDa mass detector; Column: Lux A1 3 μm, 2 x 50 mm; co-solvent IPA; column temperature 45 °C; 1.5 mL / min.

[0214] Method 5. Instruments: Sepiatec Prep SFC 100 with Prep SFF 100 control software and UV / Vis detector; Column: Lux C1 5 μm, 21.2 x 250 mm; Co-solvent: 0.2% NH3 in MeOH; Column temperature: 40 °C; 50 mL / min.

[0215] Method 6. Instruments: Waters Acquity UPC2 with Masslynx software, PDA detector and QDa mass detector; Column: Lux C1 3 μm, 2 x 50 mm; Co-solvent: 0.1% NH3 in MeOH; Column temperature: 45 °C; 1.5 mL / min.

[0216] abbreviation

[0217] aq = containing water

[0218] Boc = tert-Butoxycarbonyl

[0219] DAST = (diethylamino)sulfur trifluoride

[0220] DavePhos=2-Dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl

[0221] dba = Dibenzylideneacetone

[0222] DCM = dichloromethane

[0223] Dess-Martin = 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzoyl-3-(1H)-one

[0224] DIPEA = N,N-Diisopropylethylamine

[0225] DMSO = dimethyl sulfoxide

[0226] dppf = 1,1-bis(diphenylphosphine)ferrocene

[0227] ES = Electrospray

[0228] EthOAc = Ethyl acetate

[0229] EtOH = ethanol

[0230] h = hours

[0231] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0232] IPA = Isopropyl alcohol

[0233] L = Liter

[0234] LC = Liquid Chromatography

[0235] LCMS = Liquid Chromatography-Mass Spectrometry

[0236] LiAlH4 = Lithium aluminum hydride

[0237] MeCN = Acetonitrile

[0238] MeOH = methanol

[0239] min = minutes

[0240] MS = Mass Spectrometry

[0241] NMP = 1-Methyl-2-pyrrolidone

[0242] NMR = Nuclear Magnetic Resonance

[0243] Pet-ether = petroleum ether

[0244] pin = pinacol

[0245] RT = room temperature

[0246] SPhos = 2-Dicyclohexylphosphine-2′,6′-Dimethoxybiphenyl

[0247] TEA = Trimethylamine

[0248] TFA = Trifluoroacetic acid

[0249] THF = Tetrahydrofuran

[0250] Ts = p-Toluenesulfonyl group

[0251] The prefixes n-, s-, i-, t-, and tert- have their usual meanings: positive, middle, different, and uncle.

[0252] Synthesis of intermediates

[0253] 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

[0254]

[0255] Step 1. Add (2-chloropyridin-4-yl)boric acid (24.5 g, 156 mmol) to a solution of 1-(bromomethyl)-3-(trifluoromethyl)benzene (40.0 g, 156 mmol) in 1,4-dioxane (450 mL) / water (150 mL), and purge the reaction mixture with N2 for 10 min. Add potassium carbonate (64.5 g, 467 mmol) and PdCl2 (dppf). Add DCM (6.35 g, 7.70 mmol), and heat the resulting reaction mixture at 90 °C for 4 h. Filter the reaction mixture through Celite and then wash with EtOAc (400 mL). Wash the filtrate with water (400 mL) and separate the organic layer. Extract the aqueous layer with EtOAc (3 x 200 mL), dry the combined organic layers (Na2SO4), and remove the solvent under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0-10% hexane solution of EtOAc to give 2-chloro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (34.5 g, 77%) as a colorless oil.

[0256] LCMS (Method 10): m / z 290.3, 292.3 (ES+), at 1.39 minutes.

[0257] 1 H NMR: (400MHz, 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).

[0258] 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-aminocyclohexane-2-en-1-one (11.5 g, 104 mmol) in THF (250 mL). The reaction mixture was purged with N2 for 10 min, and Pd2(dba)3 (3.95 g, 4.30 mmol), DavePhos (3.39 g, 8.63 mmol), and Cs2CO3 (70.3 g, 216 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated at 80 °C for 8 h, and then filtered through a Celite filter. The filtrate was partitioned between EtOAc (500 mL) and water (400 mL). The organic layer was separated, and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluted with 0-100% EtOAc in hexane, to give 13.5 g, 43%, a brown solid 3-((4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)amino)cyclohex-2-en-1-one.

[0259] LCMS (Method 10): m / z 365.3 (ES+), at 1.26 minutes.

[0260] 1 H NMR: (400MHz, CDCl3)δ:8.27(d,J=5.2Hz,1H),7.36-7.22(m,2H),7.09(d,J=9.2Hz,1H),6.94(d,J=10.2Hz,2H),6.79( d,J=5.2Hz,1H),6.39(s,1H),4.04(s,2H),2.60(t,J=6.2Hz,2H),2.45(t,J=6.5Hz,2H),2.11(dd,J=13.0,6.6Hz,2H).

[0261] Step 3. At room temperature, 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). A solution of p-toluenesulfonyl azide (5.42 g, 36.6 mmol) in MeCN (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours, and water (600 mL) was added. The aqueous layer was extracted with EtOAc (3 x 600 mL), the combined organic layers were dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0-50% EtOAc in hexane to give 5.6 g (52%) 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 as a grayish-white solid. Data are shown in Table 2.

[0262] Intermediate 2,2-fluoro-4-(3-(trifluoromethyl)benzyl)pyridine

[0263]

[0264] 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 PdCl2 (dppf). A solution of DCM (129 mg, 0.18 mmol) in 1,4-dioxane (4 mL) / water (0.4 mL) and the resulting reaction mixture were heated at 80 °C for 2 hours. 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 x 6 mL), and the combined organic layers were dried (phase separator) and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0-50% EtOAc in isohexane to give 2-fluoro-4-(3-(trifluoromethyl)benzyl)pyridine (167 mg, 74%) as a yellow liquid. Data are shown in Table 2.

[0265] Intermediate 3,1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one

[0266]

[0267] Step 1. Iodine (0.260 g, 1 mmol) was added to a stirred mixture of cyclohexanone (2 g, 20 mmol) and 1,2-diphenyldithionane (1.7 g, 80 mmol) in DMSO (12 mL), and the reaction mixture was heated at 80 °C for 12 hours. The reaction was quenched by adding water (100 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried (Na₂SO₄), and the solvent was removed under vacuum to give a yellow liquid of 2-(phenylthio)cyclohexyl-2-en-1-one (4.5 g crude product). The crude product was used in the next step without further purification.

[0268] MS (Method 1): m / z 205 (ES+).

[0269] Step 2. Sodium periodate (9.39 g, 40 mmol) was added to a stirred solution of 2-(phenylthio)cyclohexyl-2-en-1-one (4.5 g, 22 mmol) in MeOH (1.2 mL) and H₂O (12 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried (Na₂SO₄), and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluting with a 30–35% hexane solution of EtOAc, to give an orange gel-like 2-(phenylsulfinyl)cyclohexyl-2-en-1-one (2.1 g, 43%).

[0270] MS (Method 1): m / z 221 (ES+).

[0271] Step 3. Sodium azide (324 mg, 4 mmol) was added to a stirred solution of 2-(phenylsulfinyl)cyclohexyl-2-en-1-one (1 g, 4 mmol) in H2O (17 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 2 with 1N 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 (Na2SO4), and the solvent was removed under vacuum to give 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (220 mg, 35%) as a grayish-white solid. Data are shown in Table 2.

[0272] Intermediate 4, (1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl) tert-butyl carbamate

[0273]

[0274] 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-aminocyclohexyl-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 hours. The reaction mixture was partitioned between water (4 x 500 mL) and EtOAc (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried (Na2SO4), and the solvent was removed under vacuum to give 3-(((4-bromopyridin-2-yl)amino)cyclohexyl-2-en-1-one (5.1 g, 13%) as a grayish-white solid.

[0275] LCMS (Method 6): m / z 267.0 (ES+), at 1.38 minutes.

[0276] 1 H NMR: (400MHz, DMSO-d6)δ:9.33(s,1H),8.19(d,J=5.6Hz,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).

[0277] 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)cyclohexyl-2-en-1-one (2 g, 7.49 mmol) in MeCN (40 mL), and the resulting reaction mixture was stirred at RT for 1 hour. 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 under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0–25% EtOAc in pet-ether solution, to give 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.

[0278] LCMS (Method 6): m / z 293.0 (ES+), at 1.74 minutes.

[0279] 1 H NMR: (400MHz, DMSO-d6) δ: 8.58-8.56 (m, 1H), 8.35 (d, J = 1.2Hz, 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).

[0280] Step 3. 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), add NH4OAc (2.62 g, 34.1 mmol) and molecular sieve (2.62 g), followed by NaBH3CN (0.641 g, 10.2 mmol). Heat the resulting reaction mixture at 70 °C for 16 h. Filter the reaction mixture through Celite and wash with EtOAc (50 mL). Partition the filtrate between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine (50 mL), dried (Na₂SO₄), and the solvent was removed under vacuum to give a brown, gelatinous 1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine (1.01 g, crude product). The crude product was used in the next step without further purification.

[0281] LCMS (Method 6): m / z 294.0 (ES+), at 1.03 minutes.

[0282] 1 H NMR: (400MHz, 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 = 5.6Hz, 1H), 3.10-2.95 (m, 2H), 2.20-1.89 (m, 6H).

[0283] 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 the addition of (Boc)₂O (1.48 mL, 6.82 mmol). The resulting reaction mixture was stirred at RT for 16 hours. 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 under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0-30% EtOAc pet-ether solution 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 are shown in Table 2.

[0284] Intermediate 5,1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene

[0285]

[0286] Step 1. At 0 °C, LiAlH4 (1.0 M THF solution, 7.0 mL, 7.0 mmol) was added to a THF (10 mL) stirred solution of dimethyl 5-fluoroisophthalate (3 g, 14.1 mmol), and the resulting reaction mixture was stirred at RT for 3 hours. The reaction mixture was neutralized to pH ~7 with 1.5 N HCl (50 mL), and the reaction mixture was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum to give methyl 3-fluoro-5-(hydroxymethyl)benzoate (1.12 g, 43%) as a colorless liquid.

[0287] GCMS (Method 1): m / z 184.0 (ES+), at 7.34 minutes.

[0288] 1H NMR: (400MHz, DMSO-d6) δ: 7.79 (s, 1H), 7.55 (d, J = 12.8 Hz, 1H), 7.43 (d, J = 12. 8Hz, 1H), 5.49 (t, J = 7.6Hz, 1H), 4.58 (d, J = 7.6Hz, 2H), 3.87 (d, J = 2.4Hz, 3H).

[0289] Step 2. Dess-Martin periodine (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 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0–30% EtOAc in hexane to give methyl 3-fluoro-5-formylbenzoate (410 mg, 81%) as a white solid.

[0290] GCMS (Method 1): m / z 182.0 (ES+), at 6.76 minutes.

[0291] 1 H NMR: (400MHz, 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).

[0292] Step 3. At 0°C, DAST (0.44 mL, 3.37 mmol) was added to a stirred solution of methyl 3-fluoro-5-carboxymethyl benzoate (410 mg, 2.25 mmol), and the resulting reaction mixture was stirred at RT for 2 hours. The reaction mixture was neutralized to pH ~7 with 10% NaHCO3 aqueous solution (20 mL), and the reaction mixture was partitioned between water (100 mL) and DCM (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0-30% EtOAc in hexane to give methyl 3-(difluoromethyl)-5-fluorobenzoate (400 mg, 87%) as a colorless liquid.

[0293] GCMS (Method 2): m / z 204.0 (ES+), at 2.36 minutes.

[0294] 1H NMR: (400MHz, DMSO-d6) δ: 7.99 (s, 1H), 7.89 (d, J = 11.2Hz, 1H), 7.80 (d, J = 11.2Hz, 1H), 7.35-6.98 (m, 1H), 3.91 (s, 3H).

[0295] Step 4. LiAlH4 (2.0 M solution in THF, 0.45 mL, 0.90 mmol) was added at 0 °C to a stirred solution of methyl 3-(difluoromethyl)-5-fluorobenzoate (390 mg, 1.81 mmol) in THF (10 mL), and the resulting reaction mixture was stirred at RT for 1 hour. The reaction mixture was neutralized to pH ~7 with 1.5 N HCl (50 mL), and then partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum to give a colorless liquid of (3-(difluoromethyl)-5-fluorophenyl)methanol (230 mg, 72%).

[0296] GCMS (Method 2): m / z 176.0 (ES+), at 6.36 minutes.

[0297] 1 H NMR: (400MHz, DMSO-d6) δ: 7.39 (s, 1H), 7.32-7.29 (m, 3H), 5.46 (d, J = 6.4Hz, 1H), 4.57 (t, J = 6.4Hz, 2H).

[0298] Step 5. At room temperature, 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), and the resulting reaction mixture was heated at 65 °C for 12 hours. The reaction mixture was neutralized to pH ~7 with 10% NaHCO3 aqueous solution (20 mL), and then partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum to give 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (170 mg, crude product) as a colorless liquid. The crude product was used in the next step without further purification. Data are shown in Table 2.

[0299] Intermediate 6,1-(chloromethyl)-3-fluoro-5-(fluoromethyl)benzene

[0300]

[0301] The title compound (220 mg, 19%) was prepared in four steps from dimethyl 5-fluoroisophthalate (2.68 g, 12.6 mmol) using steps 1, 3, 4, and 5 of intermediate 5. After step 4, the title compound was separated into a colorless oil by partitioning between DCM (50 mL) and a 10% aqueous solution of NaHCO3 (25 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. Data are shown in Table 2.

[0302] Synthesis of the Implementation Examples

[0303] Typical procedures for preparation of the examples are shown in the following examples in procedures 1-9.

[0304] Program 1:

[0305] 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

[0306] 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 hours. Then, NaBH3CN (193 mg, 3.07 mmol) was added, and the reaction mixture was heated at 70 °C for 16 hours. The solvent was removed under vacuum, and the residue was quenched with an aqueous solution of NaHCO3 (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 3–6% MeOH in DCM solution 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 fraction (30 mg) was further purified by preparative HPLC (Method 2–40–70% gradient) to give the title compound (11 mg). Data are shown in Table 3.

[0307] Program 2:

[0308] 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

[0309]

[0310] Pyridine (0.15 mL, 1.9 mmol) and Ac₂O (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 hours. The solvent was removed under vacuum, and the residue was purified by grinding with Et₂O and hexane 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.

[0311] Program 3:

[0312] 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

[0313]

[0314] 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 hours. The reaction mixture was partitioned between EtOAc (30 mL) and a saturated aqueous solution of NaHCO3 (30 mL). The organic layer was separated, dried (MgSO4), and the solvent was removed under vacuum. The residue was prepared using Et2O to obtain 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 are shown in Table 3.

[0315] Program 4:

[0316] 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

[0317]

[0318] Step 1. 3-Aminocyclohexyl-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 mol) in 1,4-dioxane (3.00 mL). The reaction mixture was degassed with argon for 10 min, and PdCl2 (dppf) (371 mg, 0.455 mmol), K3PO4 (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 h, then quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluted with 0-5% MeOH in DCM solution, to give 3-((4-fluoropyridin-2-yl)amino)cyclohexyl-2-en-1-one (400 mg, 32%) as a white solid.

[0319] LCMS (Method 9): m / z 207.1 (ES+), at 1.18 minutes.

[0320] Step 2. A solution of 3-((4-fluoropyridin-2-yl)amino)cyclohexyl-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 p-toluenesulfonyl azide (373 mg, 1.89 mmol) in MeCN (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, and water (20 mL) was added. The aqueous layer was extracted with EtOAc (2 x 30 mL), and the combined organic layers (Na2SO4) were dried and the solvent was removed under vacuum. The residue was purified by gradient rapid column chromatography, eluting with a 30-40% EtOAc hexane solution 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.

[0321] LCMS (Method 9): m / z 233.2 (ES+), at 1.38 minutes.

[0322] 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. Then 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 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 (Na₂SO₄) and the solvent was removed under vacuum to give a yellow solid, 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 product). The crude product was used in the next step without further purification.

[0323] LCMS (Method 9): m / z 393.0 (ES+), at 2.36 minutes.

[0324] 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 hours. Then, NaBH3CN (36 mg, 0.57 mmol) was added at 0 °C, and the reaction mixture was heated at 65 °C for 16 hours. The solvent was removed under vacuum, and the residue was quenched with an aqueous solution of NaHCO3 (20 mL). The aqueous layer was extracted with a solution of 10% MeOH in DCM (2 x 30 mL). The organic layers were combined, dried (Na₂SO₄), and the solvent was removed under vacuum to give a brown, gel-like 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 product). The crude product was used in the next step without further purification.

[0325] LCMS: Not recorded.

[0326] Step 5. At 0 °C, pyridine (0.07 mL, 0.91 mmol) and Ac₂O (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). The reaction mixture was stirred at RT for 16 hours. The solvent was removed under vacuum, and the residue was purified by gradient rapid column chromatography, eluting with 70-80% EtOAc in hexane 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 are shown in Table 3.

[0327] Program 5:

[0328] 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

[0329]

[0330] 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). 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 a saturated aqueous solution of NaHCO3 (7.2 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The organic layers were combined, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by preparative HPLC (method 1–10–75% 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 are shown in Table 3.

[0331] Program 6:

[0332] Example 9, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(oxecyclobut-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-amine

[0333]

[0334] 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-oxacyclobutamine (112 mg, 1.54 mmol) in EtOH (0.78 mL). The reaction mixture was stirred at RT under H2 for 16 hours. The reaction mixture was filtered through a Celite pad and washed twice with EtOH. The solvent was removed under vacuum. The residue was purified by preparative HPLC (method 1–10–85% gradient) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(oxecyclobut-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 are shown in Table 3.

[0335] Program 7:

[0336] 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

[0337]

[0338] 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 under vacuum 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 product). The crude product was used in the next step without further purification.

[0339] MS (Method 1): m / z 373 (ES+).

[0340] Step 2. ZnCl2 (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 hours. NaBH3CN (224 mg, 3.62 mmol) was added, and the reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was quenched with an aqueous solution of NaHCO3 (30 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried (Na₂SO₄), and the solvent was removed under vacuum to give a brown gel-like 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 product). The crude product was used in the next step without further purification.

[0341] MS (Method 1): m / z 374 (ES+).

[0342] Step 3. Pyridine (0.8 mL, 10.7 mmol) and Ac₂O (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 hour. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (Method 3–40–50% 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.

[0343] Program 8:

[0344] 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

[0345]

[0346] Step 1. At room temperature, KOAc (264 mg, 2.69 mmol) and [B(pin)]2 (354 mg, 1.4 mmol) were added to a stirred solution of (1-(4-bromopyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate tert-butyl (425 mg, 1.07 mmol) in 1,4-dioxane (20 mL), followed by the addition of PdCl2(dppf)·DCM (44 mg, 0.053 mmol). The resulting reaction mixture was heated at 90 °C for 12 hours. The reaction mixture was filtered through a Celite filter and washed with 1,4-dioxane (40 mL). The filtrate was concentrated under vacuum to obtain (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 product), which was a brown gel. The crude product was used in the next step without further purification.

[0347] LCMS (Method 6): m / z 360.1 (ES+), at 1.70 minutes.

[0348] 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 product) and 1-(bromomethyl)-3-(difluoromethoxy)-5-fluorobenzene (99 mg, 0.389 mmol) in 1,4-dioxane (5 mL), followed by the addition of Pd(dppf)Cl₂·DCM (31 mg, 0.0389 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through a Celite filter and washed with 1,4-dioxane (10 mL). The filtrate was concentrated under vacuum. The residue was purified by gradient rapid column chromatography, eluting with 0-40% EtOAc pet-ether solution to give brown gel-like (1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate tert-butyl ester (80 mg, 42%).

[0349] LCMS (Method 6): m / z 490.1 (ES+), at 2.69 minutes.

[0350] 1H NMR: (400MHz, DMSO-d6)δ:8.49(d,J=6.4Hz,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).

[0351] Step 3. A suspension of (1-(4-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate tert-butyl (80 mg, 0.163 mmol) in 20% TFA in DCM (10 mL) was stirred at RT for 2 hours. The solvent was removed under vacuum, and the residue was partitioned between EtOAc (10 mL) and 10% NaHCO3 aqueous solution (10 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum to give a colorless, gel-like 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%).

[0352] LCMS (Method 7): m / z 390.0 (ES+), at 2.23 minutes.

[0353] 1 ¹H NMR: (400MHz, DMSO-d⁶)δ: 8.49 (d, J = 5.2Hz, 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). No two exchangeable protons were observed.

[0354] Step 4. At 0 °C, 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), 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 under vacuum, and the residue was purified by preparative HPLC (Method 4). The solvent was removed under vacuum, and the residue was partitioned between water (10 mL) and DCM (10 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum to obtain 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 a grayish-white solid. Data are shown in Table 3.

[0355] Program 9:

[0356] 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

[0357]

[0358] Steps 1 and 2. Using the methods of steps 1 and 2 of Procedure 8, tert-butyl carbamate (120 mg, 47%) was prepared from (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-fluorobenzyl (intermediate 5, 200 mg, 1.03 mmol).

[0359] LCMS (Method 6): m / z 474.1 (ES+), at 2.60 minutes.

[0360] 1¹H NMR: (400MHz, CDCl₃) δ: 8.43 (d, J = 5.2Hz, 1H), 7.99 (s, 1H), 7.17–7.13 (m, 3H), 7.06–7.02 (m, 1H), 6.63 (t, J = 56.0Hz, 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.

[0361] Step 3. A solution of 4N HCl in 1,4-dioxane (5 mL) was added to a suspension of (1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-yl)carbamate tert-butyl (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 under vacuum to give a colorless, gel-like 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%).

[0362] LCMS (Method 8): m / z 374.1 (ES+), at 1.35 minutes.

[0363] 1 H NMR: (300MHz, 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=55.2Hz,1H),4.65-4.55(m,1H),4.25(s,2H),3.70-3.50(m,2H),2.20-2.00(m,4H).

[0364] Step 4. Using the method in Step 4 of Procedure 8, 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-yl)acetamide (80 mg, 0.20 mmol). Data are shown in Table 3.

[0365] Other embodiments prepared by the above procedure are detailed in Table 3.

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] Bioactivity

[0372] GPR52 agonist functional cAMP assay

[0373] HEKf suspension cells were infected for 24 hours with BacMam virus expressing human GPR52 at 0.1% v / v. BacMam is a modified baculovirus designed for mammalian gene expression. Following BacMam infection, cells were pelleted by centrifugation (335 g, 5 min), resuspended in cell freezing medium (Sigma), and frozen at -150°C until needed. On the day of the experiment, 25 nL of GPR52 compound prepared in DMSO was diluted and hydraulically pressed onto microplates (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. Before centrifugation (335 g, 1 min), 10 μL of cells were added to the assay plate using a Multidrop Combi reagent dispenser (ThermoFisher). Cells were incubated with the compound at 37°C for 30 min before adding the cAMP assay kit (HiRange cAMP kit, Cisbio) prepared according to the manufacturer's instructions. Plates were shaken at room temperature for 1 h, after which readings were performed using a standard HTRF setting on a PHERAstar FS plate reader (BMG Labtech). The HTRF ratio was obtained by dividing the receptor 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]thiophene-7-yl)-N-(2-methoxyethyl)benzamide (compound 7m in J. Med. Chem., 2014, 572226) response (100%) and fitted to a 4-parameter logistic fit to generate agonist pEC. 50 The maximum response is shown in Table 4 below.

[0374] Table 4 – GPR52 pEC 50 data

[0375]

[0376]

[0377] Pharmacokinetic analysis

[0378] The pharmacokinetic characteristics of Example 2 were evaluated in male Sprague-Dawley rats via intravenous (IV) and oral (per os, PO) delivery routes. Pharmacokinetic data (mean ± standard deviation) for Example 2 of this invention are detailed in Table 5.

[0379] Methods: For pharmacokinetic analysis, single doses of Example 2 were administered via IV or PO route using the dosage, dose volume, and carrier specified in Table 5. Three male Sprague-Dawley rats weighing between 200 and 230 g were used in each group. Following administration, blood samples were collected at several time points (IV administration: 2 min, 5 min, 15 min, 30 min, 1 hour, 3 hour, 6 hour, 12 hour, and 24 hour before administration; PO administration: 5 min, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 8 hour, 12 hour, and 24 hour before administration) and plasma was centrifuged for LC-MS / MS analysis. Pharmacokinetic parameters were generated using WinNonlin v8.2 statistical software (Pharsight Corporation, California, USA) with a non-compartmental model.

[0380] brain penetration

[0381] Following IV administration, plasma and brain exposure were assessed to evaluate brain penetration in Example 2. After experimentally determining binding in rat plasma and brain tissue homogenates, the unbound brain-plasma ratio (K0.05) was calculated. p,uu As shown in Table 5.

[0382] Methods: For brain osmotic assessment, male Sprague-Dawley rats (n=3) were administered a single dose of 1 mg / kg via intravenous administration (prepared in 10% DMAC + 10% Solutol HS15 + 80% saline). Ten minutes post-administration, animals were sacrificed and the brain was extracted, homogenized in 2 volumes (w / v) of 50 mM sodium phosphate buffer (pH 7.4), and analyzed by LC-MS / MS. At the same time point, blood samples were collected via tail vein expulsion, centrifuged, and analyzed by LC-MS / MS.

[0383] To allow for the calculation of the unbound brain to plasma ratio (K0)p,uu The binding of the test compound was determined using rapid equilibration dialysis (RED) in rat plasma and brain tissue homogenates. The test compound (1 μM final, 0.2% DMSO) prepared in DMSO was added to (i) undiluted male Sprague Dawley rat plasma and (ii) rat brain tissue homogenized with 2 volumes (w / v) sodium phosphate buffer (pH 7.4), and dialyzed against phosphate buffer at 37°C for 5 hours. After incubation, the contents of each plasma / brain and buffer 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 adding acetonitrile containing the analytical internal standard (allowing for the determination of the test compound to the internal standard ratio), centrifuged, and the supernatant was removed for analysis by LC-MS / MS. The unbound fraction (F) in plasma and brain was calculated using the following formula. u This was then used to correct for total plasma and brain concentrations to arrive at K. p,uu :

[0384] Binding score = (Total plasma or brain ratio) - (Total buffer ratio) / Total plasma or brain ratio

[0385] Uncombined fractions (F) u (brain or plasma) = 1 - binding fraction

[0386] Used to correct dilution in brain binding assays:

[0387] Undiluted F u Brain = (1 / Dilution Factor) / ((1 / F) u Diluted ))-1)+(1 / dilution factor)

[0388] Where the dilution factor = 4

[0389] Table 5 - Pharmacokinetic data from Example 2

[0390]

[0391]

[0392] Inhibitory effect of caffeine on motor activity in rats

[0393] Caffeine is a non-selective adenosine receptor antagonist, which works primarily by blocking A... 2APsychostimulants that increase rodent locomotion activity via receptors (Br. J. Pharmacol., 2000, 129, 1465). These receptors are densely expressed at the terminals of GABAergic striatopallidal neurons via the indirect pathway in the basal ganglia, with co-expression of dopamine D2 receptors (J. Comp. Neurol., 1998, 401, 163; J. Comp. Neurol., 2001, 431, 331). A 2A Tetanic activation of the receptor reduces the affinity of the D2 receptor for dopamine. 2A Receptor antagonism promotes dopaminergic signaling (Curr. Pharm. Des., 2008, 14, 1468). Many antipsychotic drugs have been shown to block caffeine-induced hyperkinesis (Pharmacol. Biochem. Behav., 1994, 47, 89; Naunyn-Schmiedeberg's Arch. Pharmacol., 2016, 389, 11).

[0394] Male Sprague-Dawley rats (200-250g) were grouped and housed under a 12-hour light / dark cycle (light on at 07:00) at an ambient temperature of 21±2℃, fed a standard pellet diet, and given free access to water. Testing was conducted during the light phase. On the day of the experiment, animals were acclimatized to their exercise cages for 60 minutes. Subsequently, they were administered the carrier or isomer 1 of Example 2 (0.1, 0.3, 1, and 3 mg / kg) orally and returned to their appropriate exercise cages. Isomer 1 of Example 2 was formulated in a carrier of 10% DMAC, 10% solubilol (Kolliphor HS15), and 80% water (v / v / v). After 60 minutes, the animals were administered the carrier (physiological saline) or caffeine (15 mg / kg) subcutaneously. Motor activity was assessed within 2 hours following caffeine treatment. Data are inversely transformed averages, adjusted for differences in activity between treatment groups within 30 minutes prior to treatment with the test compound or carrier (n = 10⁻¹²). Analysis employed a general linear model with treatment, cohort, and rack as factors. SEM was calculated based on the residuals of the statistical model. Isomer 1 of Example 2 was compared with caffeine using the Williams test.

[0395] like Figure 1 As shown, treatment with isomer 1 of Example 2 reduced the dose-dependent nature of caffeine-induced hypermotor response, achieving statistically significant differences of 3 and 10 mg / kg at all time points. Attached Figure Description

[0396] Figure 1 Effect of acute treatment with isomer 1 (0.3, 1, 3, and 10 mg / kg, PO) from Example 2 on caffeine-induced hypermotor activity. Significant differences vs. caffeine are expressed as follows: p<0.05 p<0.01 p<0.001.

Claims

1. Compounds of formula (1a) or their salts: in; R 1 C(O)C with H atoms, optionally substituted with 1 to 6 fluorine atoms 1-3 Alkyl groups, C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkyl groups, or C groups optionally substituted with 1 to 6 fluorine atoms. 3-6 Cycloalkyl; wherein the alkyl group or any atom of the cycloalkyl group may optionally be replaced by O; R 2 It is H; Q is selected from -CR 3 R 4 -and-CR 3 R 4 CR 5 R 6 -; R 3 R 4 R 5 and R 6 Independently selected from H and C 1-3 alkyl; L is selected from CH2, CHOH, and O; And W is selected from the following: Where R 11 R 12 and R 13 Independently selected from H, CN, halogens, and C atoms optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl groups and C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkoxy group, wherein any atom of the alkyl group or the alkoxy group may optionally be replaced by a heteroatom selected from O, N, S and their oxidized forms.

2. The compound according to claim 1, wherein it is a compound of formula (2a) or a salt thereof: in; R 11 R 12 and R 13 Independently selected from H, CN, halogens, and C atoms optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl groups and C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkoxy group, wherein any atom of the alkyl group or the alkoxy group may optionally be replaced by a heteroatom selected from O, N, S and their oxidized forms.

3. The compound according to claim 1, wherein Q is selected from -CH2- and -CH2CH2-.

4. The compound according to claim 3, wherein Q is -CH2CH2-.

5. The compound according to claim 1, wherein it is a compound of formula (3a) or a salt thereof: in: R 11 R 12 and R 13 Independently selected from H, CN, halogens, and C atoms optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl groups and C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkoxy group, wherein any atom of the alkyl group or the alkoxy group may optionally be replaced by a heteroatom selected from O, N, S and their oxidized forms.

6. The compound according to claim 1, wherein R 1 Selected from H, CH3, C(O)CH3, C(O)CH2CH3, C(O)CF2H, C(O)CF3, C(O)CFH2, CH2CH2OCH3, oxacyclobutane and oxacyclopentane.

7. The compound according to claim 6, wherein R 1 It is C(O)CH3.

8. The compound according to claim 1, wherein it is a compound of formula (4a) or a salt thereof: in; R 11 R 12 and R 13 Independently selected from H, CN, halogens, and C atoms optionally substituted with 1 to 6 fluorine atoms. 1-6 Alkyl groups and C atoms optionally substituted with 1 to 6 fluorine atoms 1-6 Alkoxy group, wherein any atom of the alkyl group or the alkoxy group may optionally be replaced by a heteroatom selected from O, N, S and their oxidized forms.

9. The compound according to any one of claims 1 to 8, wherein L is CH2.

10. The compound according to any one of claims 1 to 8, wherein R 11 R 12 and R 13 It is independently selected from H, F, CF3, CF2H, CFH2 and OCF2H.

11. The compound according to claim 1, wherein W is selected from:

12. The compound according to claim 1, wherein it is a compound of formula (5) or a salt thereof:

13. The compound or a salt thereof according to claim 1, wherein the compound is selected from: 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]propionamide; 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-(oxecyclobut-3-yl)-4,5,6,7-tetrahydro-1H-benzotriazol-4-amine; 1-(4-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}pyridin-2-yl)-N-(oxacyclopentan-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.

14. The compound according to claim 1, wherein the compound is:

15. The compound according to claim 1, wherein the compound is:

16. The compound according to claim 1, wherein the compound is:

17. The compound according to claim 1, wherein the compound is:

18. The compound according to claim 1, wherein the compound is:

19. The compound according to claim 1, wherein the compound is:

20. The compound according to claim 1, wherein the compound is:

21. The compound according to claim 1, wherein the compound is:

22. The compound according to claim 1, wherein the compound is:

23. The compound according to claim 1, wherein the compound is:

24. The compound according to claim 1, wherein the compound is:

25. The compound according to claim 1, wherein the compound is:

26. A salt of the compound as defined in any one of claims 14 to 25.

27. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 26 and a pharmaceutically acceptable excipient.

28. Use of the compound according to any one of claims 1 to 26 or the composition according to claim 27 in the preparation of a medicament for treating or preventing diseases in which the regulation of the GPR52 receptor is beneficial.

29. Use of the compound according to any one of claims 1 to 26 or the composition according to claim 27 in the preparation of a medicament for treating mental illnesses; neuropsychiatric disorders; neurodegenerative diseases; psychotic disorders; cognitive impairments; extrapyramidal disorders; movement disorders; hyperkinesis; catatonia; mood disorders; depression; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; hypothalamic diseases; pituitary diseases; prolactin-related diseases; trauma or stressor-related disorders; Disruptive, impulse control, or behavioral disorders; Sleep-wake disorders; substance-related disorders; addiction disorders; behavioral disorders; frontal lobe dysfunction; tuberous-infundibular, mesolimbic, mesocortical, or substantia nigra-striatal pathway abnormalities; reduced striatal activity; cortical dysfunction; neurocognitive impairment or related conditions or symptoms.

30. The use according to claim 29, wherein the disease or symptom is selected from 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, mania, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, nonfunctional tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and related movements, choreoathetosis, ataxia, tetany, unilateral throwing disorder, chorea, choreoathetosis, movement disorder, mirror movement disorder, restless legs syndrome, spasticity, stereotyped disorder, tic disorder, tremor, Wilson's disease. Schizophrenia, schizotypal personality disorder, paranoid disorder, short-term psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, substance or drug-induced psychotic disorder, delusions, hallucinations, thought disorder, severe disorder or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance or drug-induced bipolar disorder and related diseases, bipolar disorder and related diseases caused by other medical conditions, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance or drug-induced anxiety disorder, anxiety disorder caused by other medical conditions, delirium, severe neurocognitive impairment, mild neurocognitive impairment, amnesia, dementia, developmental coordination disorder, post-stroke effects, dentate nucleus, globus pallidus, hypothalamic nucleus atrophy, reduced emotional expression, lack of motivation, aphasia, and asocial behavior.

31. The use according to claim 29, wherein the condition or symptom is selected from 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, mania, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD).

32. The use according to claim 29, wherein the condition or symptom is selected from neurocognitive disorders and motor disorders.

33. The use according to claim 29, wherein the condition or symptom is selected from positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, tardive dyskinesia, dyskinesia caused by neuroleptic inhibitors, myoclonus, paroxysmal motor evoked dyskinesia, and stereotyped dyskinesia.

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