GPR52 Modulator Compounds

Abstract

The disclosure herein provides a compound of formula (1): TIFF2023501984000234.tif3761 and salts thereof [wherein R 1 , Q, X, Y, and Z are as defined herein] and their use for treating, preventing, ameliorating, controlling, or reducing the risk of disorders associated with the GPR52 receptor.

Description

[Technical field]

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

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

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

[0004] The present invention provides compounds which have activity as G protein-coupled receptor 52 (GPR52) modulators.

[0005] Formula (1):

[0006] [ka] or a salt thereof, wherein X is N or CR 2 and Y is N, NR 3 , or CR 2 and Z is N or NR 3 and where Y and Z are either NR, but not both. 3 and Q is -CR 4 R 5 -, -CR 4 R 5 CR 6 R7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 -,-OCR 4 R 5 CR 6 R 7 - and -CR 4 R 5 O-, R 1 is H, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, C optionally substituted with 1 to 6 fluorine atoms 3~6 Cycloalkyl, the group -C(R 14 )2C(R 18 )2OR 17 or a group -C(R 14 )2C(R 19 ) 2OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring, R 2 is H, halo, CN, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 C optionally substituted with alkyl, OH or 1 to 6 fluorine atoms 1~6Alkoxy, or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 cycloalkyl, where C 1~6 Alkyl, C 1~6 Alkoxy, or C 3~6 One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms; R 3 is the group -VLW, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 H and C 1~3 independently selected from alkyl, where V is the R 3 is a 6-membered optionally substituted aryl or heteroaryl ring substituted by L at the meta position relative to the attachment position of L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; W is an optionally substituted monocyclic or polycyclic ring system.

[0007] The compounds of the present invention can be used as GPR52 modulators. The compounds of the present invention can be used as GPR52 agonists. The compounds of the present invention can be used for the manufacture of medicines. The compounds or medicines can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders involving GPR52 receptors. The compounds or medicines can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders in which modulation of GPR52 receptors may be beneficial. The compounds of the invention may be useful for treating psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychiatric disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma or stressor-related disorders; disruptive, impulse-control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesencephalic or nigrostriatal pathways; reduced activity in the striatum; cortical dysfunction; neurocognitive dysfunction; or conditions or symptoms related thereto.

[0008] The compounds of the present invention are useful for treating schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumors, obesity, post traumatic stress disorder (PTSD), akathisia and related movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia, myoclonus, mirror movement disorder, paroxysmal kinesiogenic dyskinesia, and the like. kinesigenic dyskinesia, restless legs syndrome, spasms, stereotypy, sterotypy, tics, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or medication-induced psychosis, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or medication-induced bipolar and related disorders, bipolar and related disorders due to another medical condition, separation anxiety disorder, selective mutism mutism, specific phobia, social phobia, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder due to another medical condition, delirium, severe neurocognitive impairment, mild neurocognitive impairment, amnesia, dementia, developmental coordination disorder, stereotypy, post-stroke effects, dentatorubral-pallidoluysian atrophy, decreased emotional expressiveness, amotivation, allogy, and asociality. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention relates to novel compounds. The present invention also relates to the use of novel compounds as modulators of the GPR52 receptor. The present invention further relates to the use of novel compounds in the manufacture of medicaments for use as GPR52 modulators. The compounds of the present invention can be used as GPR52 agonists. The compounds or medicaments can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders in which the GPR52 receptor is involved. The compounds or medicaments can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders in which modulation of the GPR52 receptor may be beneficial.

[0010] The present invention further relates to compounds, compositions, and medicaments that may be useful in treating psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; movement disorders; hyperkinetic disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; prolactin-related disorders; trauma or stressor-related disorders; disruptive impulse control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesencephalic or nigrostriatal pathways; reduced activity in the striatum; cortical dysfunction; neurocognitive dysfunction; or conditions or symptoms related thereto.

[0011] Formula (1'):

[0012] [ka] or a salt thereof, wherein X is N or CR 2 and Y is N, NR 3 , or CR 2 and Z is N or NR 3 and where Y and Z are either NR, but not both. 3 and Q is -CR 4 R5 -, -CR 4 R 5 CR 6 R 7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 -,-OCR 4 R 5 CR 6 R 7 - and -CR 4 R 5 O-, R 1 is H, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, C optionally substituted with 1 to 6 fluorine atoms 3~6 Cycloalkyl, the group -C(R 14 )2C(R 18 )2OR 17 or a group -C(R 14 )2C(R 19 ) 2OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring, R 2 is H, halo, CN, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6C optionally substituted with alkyl, OH or 1 to 6 fluorine atoms 1~6 Alkoxy, or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 cycloalkyl, where C 1~6 Alkyl, C 1~6 Alkoxy, or C 3~6 One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms; R 3 is the group -VLW, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 H and C 1~3 independently selected from alkyl, where V is the R 3 is a 6-membered optionally substituted aryl or heteroaryl ring substituted by L at the meta position relative to the attachment position of L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; W is an optionally substituted monocyclic or polycyclic ring system.

[0013] Also, equation (1):

[0014] [ka] or a salt thereof, wherein X is N or CR 2 and Y is N, NR 3 , or CR 2 and Z is N or NR 3 and where Y and Z are either NR, but not both. 3 and Q is -CR 4 R 5-, -CR 4 R 5 CR 6 R 7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 - and - OCR 4 R 5 CR 6 R 7 - selected from R 1 is H, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, C optionally substituted with 1 to 6 fluorine atoms 3~6 Cycloalkyl, the group -C(R 14 )2C(R 18 )2OR 17 or a group -C(R 14 )2C(R 19 ) 2OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring, R 2 is H, halo, CN, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 C optionally substituted with alkyl, OH or 1 to 6 fluorine atoms 1~6Alkoxy, or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 cycloalkyl, where C 1~6 Alkyl, C 1~6 Alkoxy, or C 3~6 One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms; R 3 is the group -VLW, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 H and C 1~3 independently selected from alkyl, where V is the R 3 is a 6-membered optionally substituted aryl or heteroaryl ring substituted by L at the meta position relative to the attachment position of L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; W is an optionally substituted monocyclic or polycyclic ring system.

[0015] Also, equation (1a):

[0016] [ka] or a salt thereof, wherein X is N or CR 2 and Y is N, NR 3 , or CR 2 and Z is N or NR 3 and where Y and Z are either NR, but not both. 3 and Q is -CR 4 R 5 -, -CR 4 R 5 CR 6 R7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 -,-OCR 4 R 5 CR 6 R 7 - and -CR 4 R 5 O-, R 1 , H, C 1~3 Alkyl, or C 3~6 is cycloalkyl, R 2 H, halo, C 1~3 Alkyl, or C 3~6 is cycloalkyl, R 3 is the group -VLW, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 H and C 1~3 independently selected from alkyl, wherein V is a 6-membered optionally substituted aryl or heteroaryl ring substituted by L at the meta position; L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; W is an optionally substituted monocyclic or polycyclic ring system.

[0017] Also, equation (1b):

[0018] [ka] or a salt thereof, wherein Q, R 1 , R 2, and R 3 is as defined herein.

[0019] Also, equation (1b):

[0020] [ka] or a salt thereof, wherein Q is -CR 4 R 5 -, -CR 4 R 5 CR 6 R 7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 - and - OCR 4 R 5 CR 6 R 7 - selected from R 1 is H, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, C optionally substituted with 1 to 6 fluorine atoms 3~6 Cycloalkyl, the group -C(R 14 )2C(R 18 )2OR 17 or a group -C(R 14 )2C(R 19 ) 2OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring, R 2 is H, halo, CN, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 C optionally substituted with alkyl, OH or 1 to 6 fluorine atoms 1~6 Alkoxy, or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 cycloalkyl, where C 1~6 Alkyl, C 1~6 Alkoxy, or C 3~6 One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms; R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 H and C 1~3 independently selected from alkyl, R 3 is the expression:

[0021] [ka] where each A is independently N or CR 10 and L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; Each B is independently N, CR 11 , C.R. 12 , C.R. 13 , C.R. 15 , or CR 16 and R 10 is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, R11 , R 12 , R 13 , R 15 , and R 16 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon groups (where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S and their oxidized forms), OC optionally substituted with 1 to 6 fluorine atoms; 1~6 SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with 1 to 6 fluorine atoms or substituted with CF 3~6 cycloalkyl.

[0022] Also, equation (1b):

[0023] [ka] or a salt thereof, wherein Q is C 1~3 is an alkyl linker, R 1 is H or C 1~3 is alkyl, R 2 is CN, halo, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with OH or 1 to 6 fluorine atoms 1~6 alkoxy, wherein C 1~6 Alkyl or C 1~6 One atom of the alkoxy group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms; R 3 is the expression:

[0024] [ka] where A is N or CR10 and L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; B is N, CR 11 , C.R. 12 , or CR 13 and R 10 is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, R 11 , R 12 , and R 13 is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl and C optionally substituted with 1 to 6 fluorine atoms 1~6 alkoxy, wherein C 1~6 Alkyl or C 1~6 One atom of the alkoxy group may be replaced by a heteroatom selected from O, N, S and their oxidized forms.

[0025] In the compounds herein, X is N or CR 2 X may be N. X may be CR 2 It is possible.

[0026] In the compounds herein, Y is N, NR 3 , or CR 2 Y can be N. Y can be NR 3 Y can be CR 2 Y can be NR 3 Then Z is N.

[0027] In the compounds herein, Z is N or NR 3 Z can be N. Z can be NR 3 Z can be NR 3 If Y is N or CR 2 It is.

[0028] In the compounds herein, Y and Z may each be NR 3 Y is NR 3 and Z can be N. Z is NR 3 and Y can be N. Z is NR 3 and Y is CR 2 It is possible.

[0029] In the compounds herein, R 1 is H, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, C optionally substituted with 1 to 6 fluorine atoms 3~6 Cycloalkyl, the group -C(R 14 )2C(R 18 )2OR 17 or a group -C(R 14 )2C(R 19 ) 2OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring. 1 , H, C 1~3 Alkyl, or C 3~6 R may be cycloalkyl. 1 is H or C 1~3 R may be an alkyl group. 1 can be H. R 1 C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 1 C optionally substituted with 1 to 6 fluorine atoms 1~3R may be an alkyl group. 1 C optionally substituted with 1 to 6 fluorine atoms 3~6 R may be a cycloalkyl group. 1 is C 1~6 R may be an alkyl group. 1 is C 1~3 R may be an alkyl group. 1 is C 3~6 R may be a cycloalkyl group. 1 is -C(R 14 )2C(R 18 )2OR 17 or -C(R 14 )2C(R 19 ) 2OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring. 1 R can be H, methyl, -CH2CH2OCH3, -CH2CH2OH, CH(CH3)CH2OCH3, -CH(CH3)CH2OH, -CH2CH(CH3)OCH3, or -CH2CH(CH3)OH. 1 R can be H, methyl, -CHCHOCH, or -CHCHOH. 1 can be H or methyl. R 1 R can be methyl. 1 R can be an oxolane ring. 1 R can be a tetrahydrofuran ring. 1 can be an oxetane ring.

[0030] R1 teeth,

[0031] [ka] It is possible. R 1 teeth,

[0032] [ka] It is possible. R 1 teeth,

[0033] [ka] It is possible. R 1 teeth,

[0034] [ka] It is possible. R 1 teeth,

[0035] [ka] It is possible. R 1 teeth,

[0036] [ka] It is possible. R 1 teeth,

[0037] [ka] It is possible. R 1 teeth,

[0038] [ka] It is possible.

[0039] In the compounds herein, R 2 is H, halo, CN, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 C optionally substituted with alkyl, OH or 1 to 6 fluorine atoms 1~6 Alkoxy, or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 cycloalkyl, where C 1~6 Alkyl, C 1~6 Alkoxy, or C 3~6 One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S and their oxidized forms.

[0040] R 2 is H, halo, CN, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 C optionally substituted with alkyl, OH or 1 to 6 fluorine atoms 1~6 Alkoxy, or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 It may be a cycloalkyl.

[0041] R 2 H, halo, C 1~3 Alkyl, or C 3~6 R may be cycloalkyl. 2 is H or C 1~3 R may be an alkyl group. 2 can be H. R 2 can be a halo. R 2 is C 1~3 R may be an alkyl group. 2 is C 3~6 R may be a cycloalkyl group. 2 can be H or methyl. R 2 R can be methyl. 2 can be F. R 2 R can be Cl. 2 can be Br. 2is CN, halo, OH or C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with OH or 1 to 6 fluorine atoms 1~6 alkoxy, wherein C 1~6 Alkyl or C 1~6 One atom of the alkoxy group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 2 R may be selected from methyl, F, Cl, CN, CF3, and CH2OH. 2 C may be substituted with OH 1~6 R can be alkyl. 2 C optionally substituted with 1 to 6 fluorine atoms 1~6 R can be alkyl. 2 C may be substituted with OH 1~3 R can be alkyl. 2 C optionally substituted with 1 to 6 fluorine atoms 1~3 It can be alkyl.

[0042] In the compounds herein, R 3 can be a group -VLW.

[0043] In the compounds herein, V is an R bond to the remainder of the molecule. 3V may be a 6-membered optionally substituted aryl or heteroaryl ring substituted with L at the meta position relative to the point of attachment of V to Z or Y. V may be a 6-membered optionally substituted aryl or heteroaryl ring substituted with L at the meta position. V may be a 6-membered optionally substituted aryl ring substituted with L at the meta position. V may be a 6-membered optionally substituted heteroaryl ring substituted with L at the meta position. V may be a phenyl ring substituted with L at the meta position. V may be a pyridine ring substituted with L at the meta position. V may be a pyrimidine ring substituted with L at the meta position. V may be a pyridazine ring substituted with L at the meta position. The term "meta position" as used herein with respect to L means that the substituent -LW is substituted with respect to the point of attachment of ring V to Z or Y, i.e., R to the remainder of the molecule. 3 This should be interpreted as meaning that the ring V is located at the meta position (or 3-position) relative to the bonding position of the ring V.

[0044] In the compounds herein, L may be selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, or NH. L may be CH2. L may be CHD. L may be CD2. L may be CHF. L may be CF2. L may be C=O. L may be CHOH. L may be O. L may be NH.

[0045] In the compounds herein, W can be an optionally substituted monocyclic or polycyclic ring system. W can be an optionally substituted monocyclic ring system. W can be an optionally substituted polycyclic ring system. W can be a 6-membered optionally substituted aryl or heteroaryl ring. W can be a 6-membered optionally substituted aryl ring. W can be a 6-membered optionally substituted heteroaryl ring. W can be an optionally substituted phenyl ring. W can be an optionally substituted pyridine ring. W can be a 9-10 membered optionally substituted heterobicyclic ring system. W can be a 9-10 membered heterobicyclic ring system. W can be a 9-10 membered optionally substituted heterobicyclic ring system, where one or more rings are aromatic. W can be a 9-membered optionally substituted heterobicyclic ring system, where one or more rings are aromatic. W can be a 10 membered optionally substituted heterobicyclic ring system, where one or more rings are aromatic.

[0046] W is

[0047] [ka] It may be an optionally substituted 9-10 membered heterobicyclic ring system selected from:

[0048] W is

[0049] [ka] It may be an optionally substituted polycyclic ring selected from:

[0050] W can be an optionally substituted polycyclic ring system selected from quinoline, 3,4-dihydro-2H-1-benzopyran, 1-benzothiophene, bicyclo[1.1.1]pentane, cubane, and bicyclo[2.2.2]octane.

[0051] In the compounds herein, R3 is the expression:

[0052] [ka] where A is N or CR 10 and L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; R 10 is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, W is (i) a 6-membered optionally substituted aryl or heteroaryl ring; (ii) an optionally substituted 9-10 membered heterobicyclic ring system, wherein one or more rings are aromatic; or (iii)

[0053] [ka] an optionally substituted polycyclic ring system selected from Either:

[0054] In the compounds herein, R 3 is the expression:

[0055] [ka] where A is N or CR 10 and L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; B is N, CR 11 , C.R. 12 , or CR 13 and R 10 is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, R 11 , R 12 , and R 13 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon groups (where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms), OC optionally substituted with 1 to 6 fluorine atoms; 1~6 SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with 1 to 6 fluorine atoms or substituted with CF 3~6 cycloalkyl.

[0056] In the compounds herein, R 3 is the expression:

[0057] [ka] where each A is independently N or CR 10 and L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; Each B is independently N, CR 11 , C.R. 12 , C.R. 13 , C.R. 15 , or CR 16 and R 10 is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, R 11 , R 12 , R 13 , R 15 , and R 16 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon groups (where C 1~6One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S and their oxidized forms), OC optionally substituted with 1 to 6 fluorine atoms; 1~6 SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with 1 to 6 fluorine atoms or substituted with CF 3~6 cycloalkyl.

[0058] In the compounds herein, A is N or CR 10 A can be N. A can be CR 10 Each A can be independently N or CR 10 It is possible.

[0059] In the compounds herein, R 10 is H, halo, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 R can be alkyl. 10 can be H. R 10 can be a halo. R 10 can be F. R 10 R can be Cl. 10 can be Br. 10 C optionally substituted with 1 to 6 fluorine atoms 1~3 R may be an alkyl group. 10 is C 1~3 R may be an alkyl group. 10 R can be methyl. 10 can be CF3.

[0060] In the compounds herein, B is N, CR 11 , C.R. 12 , or CR 13 B can be N. B can be selected from CR 11 B can be CR 12 B can be CR 13 Each B can be independently N, CR 11 , C.R. 12, or CR 13 B can be N, CR 11 , C.R. 12 , C.R. 13 , C.R. 15 , or CR 16 B can be N. B can be selected from CR 11 B can be CR 12 B can be CR 13 B can be CR 15 B can be CR 16 Each B can be independently N, CR 11 , C.R. 12 , C.R. 13 , C.R. 15 , or CR 16 It is possible.

[0061] In the compounds herein, R 3 teeth,

[0062] [ka] may be selected from the group consisting of:

[0063] In the compounds herein, the group:

[0064] [ka] teeth,

[0065] [ka] may be selected from the group consisting of:

[0066] In the compounds herein, the group:

[0067] [ka] teeth,

[0068] [ka] may be selected from the group consisting of:

[0069] In the compounds herein, W is

[0070] [ka] may be selected from the group consisting of:

[0071] In the compounds herein, W is

[0072] [ka] may be selected from the group consisting of:

[0073] In the compounds herein, R 11 , R 12 , and R 13 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon groups (where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms), OC optionally substituted with 1 to 6 fluorine atoms; 1~6 SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with 1 to 6 fluorine atoms or substituted with CF 3~6 cycloalkyl. R 11 , R 12 , and R 13 are each independently H, CN, halo, or C optionally substituted with 1 to 6 fluorine atoms. 1~6 Alkyl (where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms), OC, which may be substituted with 1 to 6 fluorine atoms; 1~6SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 Alkyl and C optionally substituted with 1 to 6 fluorine atoms 3~6 R may be cycloalkyl. 11 , R 12 , and R 13 is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl and C optionally substituted with 1 to 6 fluorine atoms 1~6 alkoxy, wherein C 1~6 Alkyl or C 1~6 One atom of the alkoxy group may be replaced by a heteroatom selected from O, N, S and their oxidized forms. 11 , R 12 , and R 13 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon group or OC optionally substituted with 1 to 6 fluorine atoms 1~6 alkyl.

[0074] In the compounds herein, R 11 , R 12 , R 13 , R 15 , and R 16 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon groups (where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S and their oxidized forms), OC optionally substituted with 1 to 6 fluorine atoms; 1~6 SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 Alkyl, and C optionally substituted with 1 to 6 fluorine atoms or substituted with CF 3~6 cycloalkyl. R 11 , R 12 , R 13 , R 15 , and R16 are each independently H, CN, halo, or C optionally substituted with 1 to 6 fluorine atoms. 1~6 Alkyl (where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms), OC, which may be substituted with 1 to 6 fluorine atoms; 1~6 SO2C optionally substituted with alkyl or 1 to 6 fluorine atoms 1~6 C optionally substituted with alkyl and 1 to 6 fluorine atoms 3~6 R may be cycloalkyl. 11 , R 12 , R 13 , R 15 , and R 16 is H, CN, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl and C optionally substituted with 1 to 6 fluorine atoms 1~6 alkoxy, wherein C 1~6 Alkyl or C 1~6 One atom of the alkoxy group may be replaced by a heteroatom selected from O, N, S and their oxidized forms. 11 , R 12 , R 13 , R 15 , and R 16 is H, CN, SF5, halo, C optionally substituted with 1 to 6 fluorine atoms 1~6 Saturated hydrocarbon group or OC optionally substituted with 1 to 6 fluorine atoms 1~6 alkyl.

[0075] In the compounds herein, R 11 , R 12 , and R 13 can be independently H, CN, SF, F, Cl, methyl, ethyl, isopropyl, cyclopropyl, CF, CFH, OCFH, OMe, and SOMe. 11 , R 12 , and R 13 may be independently selected from H, F, and CF3.

[0076] In the compounds herein, R 11 , R 12 , R 13 , R 15 , and R 16 can be independently H, CN, SF, F, Cl, methyl, ethyl, isopropyl, cyclopropyl, CF, CFH, OCFH, OMe, and SOMe. 11 , R 12 , R 13 , R 15 , and R 16 may be independently selected from H, F, and CF3.

[0077] In the compounds herein, R 11 can be H. R 11 can be CN. 11 can be a halo. R 11 can be F or Cl. 11 can be F. R 11 can be SF5. 11 C optionally substituted with 1 to 6 fluorine atoms 1~6 is a saturated hydrocarbon group, where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 11 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkyl group, where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 11 C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 11 is C 1~6 R may be an alkyl group. 11 is OC optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 11 is O.C. 1~6 R may be an alkyl group. 11C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkoxy group, R 11 is C 1~6 R may be an alkoxy group. 11 is SO2C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 11 is SO2C 1~6 R may be an alkyl group. 11 is optionally substituted with 1 to 6 fluorine atoms or optionally substituted with CF 3~6 R may be a cycloalkyl group. 11 is C 3~6 R may be a cycloalkyl group. 11 can be H. R 11 can be CN. 11 can be F. R 11 R can be Cl. 11 R can be methyl. 11 R can be ethyl. 11 R can be isopropyl. 11 R can be cyclopropyl. 11 can be CF3. 11 can be OCF2H. 11 can be SO2Me. R 11 R can be CF2H. 11 can be OMe. R 11 teeth,

[0078] [ka] It is possible.

[0079] In the compounds herein, R 12 can be H. R 12 can be CN. 12 can be a halo. R 12 can be F or Cl. 12 can be F. R 12 can be SF5. 12C optionally substituted with 1 to 6 fluorine atoms 1~6 is a saturated hydrocarbon group, where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 12 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkyl group, where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 12 C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 12 is C 1~6 R may be an alkyl group. 12 is OC optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 12 is O.C. 1~6 R may be an alkyl group. 12 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkoxy group, R 12 is C 1~6 R may be an alkoxy group. 12 is SO2C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 12 is SO2C 1~6 R may be an alkyl group. 12 is optionally substituted with 1 to 6 fluorine atoms or optionally substituted with CF 3~6 R may be a cycloalkyl group. 12 is C 3~6 R may be a cycloalkyl group. 12 can be H. R 12 can be CN. 12 can be F. R 12 R can be Cl. 12 R can be methyl. 12 R can be ethyl. 12 R can be isopropyl. 12R can be cyclopropyl. 12 can be CF3. 12 can be OCF2H. 12 can be SO2Me. R 12 R can be CF2H. 12 can be OMe. R 12 teeth,

[0080] [ka] It is possible.

[0081] In the compounds herein, R 13 can be H. R 13 can be CN. 13 can be a halo. R 13 can be F or Cl. 13 can be F. R 13 can be SF5. 13 C optionally substituted with 1 to 6 fluorine atoms 1~6 is a saturated hydrocarbon group, where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 13 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkyl group, where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 13 C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 13 is C 1~6 R may be an alkyl group. 13 is OC optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 13 is O.C. 1~6 R may be an alkyl group. 13 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkoxy group, R13 is C 1~6 R may be an alkoxy group. 13 is SO2C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 13 is SO2C 1~6 R may be an alkyl group. 13 is optionally substituted with 1 to 6 fluorine atoms or optionally substituted with CF 3~6 R may be a cycloalkyl group. 13 is C 3~6 R may be a cycloalkyl group. 13 can be H. R 13 can be CN. 13 can be F. R 13 R can be Cl. 13 R can be methyl. 13 R can be ethyl. 13 R can be isopropyl. 13 R can be cyclopropyl. 13 can be CF3. 13 can be OCF2H. 13 can be SO2Me. R 13 R can be CF2H. 13 can be OMe. R 13 teeth,

[0082] [ka] It is possible.

[0083] In the compounds herein, R 15 can be H. R 15 can be CN. 15 can be a halo. R 15 can be F or Cl. 15 can be F. R 15 can be SF5. 15 C optionally substituted with 1 to 6 fluorine atoms 1~6 is a saturated hydrocarbon group, where C 1~6One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 15 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkyl group, where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 15 C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 15 is C 1~6 R may be an alkyl group. 15 is OC optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 15 is O.C. 1~6 R may be an alkyl group. 15 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkoxy group, R 15 is C 1~6 R may be an alkoxy group. 15 is SO2C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 15 is SO2C 1~6 R may be an alkyl group. 15 is optionally substituted with 1 to 6 fluorine atoms or optionally substituted with CF 3~6 R may be a cycloalkyl group. 15 is C 3~6 R may be a cycloalkyl group. 15 can be H. R 15 can be CN. 15 can be F. R 15 R can be Cl. 15 R can be methyl. 15 R can be ethyl. 15 R can be isopropyl. 15 R can be cyclopropyl. 15 can be CF3. 15 can be OCF2H.15 can be SO2Me. R 15 R can be CF2H. 15 can be OMe. R 15 teeth,

[0084] [ka] It is possible.

[0085] In the compounds herein, R 16 can be H. R 16 can be CN. 16 can be a halo. R 16 can be F or Cl. 16 can be F. R 16 can be SF5. 16 C optionally substituted with 1 to 6 fluorine atoms 1~6 is a saturated hydrocarbon group, where C 1~6 One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 16 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkyl group, where C 1~6 One atom of the alkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms. 16 C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 16 is C 1~6 R may be an alkyl group. 16 is OC optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 16 is O.C. 1~6 R may be an alkyl group. 16 C optionally substituted with 1 to 6 fluorine atoms 1~6 is an alkoxy group, R 16 is C 1~6 R may be an alkoxy group. 16is SO2C optionally substituted with 1 to 6 fluorine atoms 1~6 R may be an alkyl group. 16 is SO2C 1~6 R may be an alkyl group. 16 is optionally substituted with 1 to 6 fluorine atoms or optionally substituted with CF 3~6 R may be a cycloalkyl group. 16 is C 3~6 R may be a cycloalkyl group. 16 can be H. R 16 can be CN. 16 can be F. R 16 R can be Cl. 16 R can be methyl. 16 R can be ethyl. 16 R can be isopropyl. 16 R can be cyclopropyl. 16 can be CF3. 16 can be OCF2H. 16 can be SO2Me. R 16 R can be CF2H. 16 can be OMe. R 16 teeth,

[0086] [ka] It is possible.

[0087] In the compounds herein, each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 R can be alkyl. 14 is H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 R can be alkyl. 14 can be H. R 14 can be F. R 14 can be methyl. 14 is R 17Together with R, they can form an oxolane or oxetane ring. 14 is R 17 together can form an oxolane or oxetane ring.

[0088] In the compounds herein, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 R can be alkyl. 17 R can be methyl. 17 is one R 14 Together with R, they can form an oxolane or oxetane ring. 17 is R 14 together can form an oxolane or oxetane ring.

[0089] In the compounds herein, each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 R can be alkyl. 18 is H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 R can be alkyl. 18 can be H. R 18 can be F. R 18 can be methyl.

[0090] In the compounds herein, each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 R can be alkyl. 19 is H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 R can be alkyl. 19 can be H. R 19 can be methyl.

[0091] In the compounds herein, R 3 teeth,

[0092] [ka]

[0093] [ka]

[0094] [ka] may be selected from the group consisting of:

[0095] In the compounds herein, Q is -CR 4 R 5 -, -CR 4 R 5 CR 6 R 7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 -,-OCR 4 R 5 CR 6 R 7 - and -CR 4 R 5 Q may be selected from -CR 4 R 5 -, -CR 4 R 5 CR 6 R 7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR 4 R 5 CR 6 R 7 O-, -OCR 4 R 5 - and - OCR 4 R 5 CR6 R 7 Q may be selected from -CR 4 R 5 Q can be -CR 4 R 5 CR 6 R 7 Q can be -CR 4 R 5 CR 6 R 7 CR 8 R 9 Q can be -CR 4 R 5 CR 6 R 7 Q can be -OCR 4 R 5 Q can be -OCR 4 R 5 CR 6 R 7 Q can be -CR 4 R 5 It can be O-.

[0096] In the compounds herein, Q can be selected from -CH2CH2-, -CH2CH2CH2-, -CH2-, -OCH2-, -CHO-, -CH2CH2O-, -OCH2CH2-, -CH(CH3)CH2-, and -CH2CH(CH3)-. Q can be selected from the group consisting of -CH2CH2-, -CH2CH2CH2-, -CH2-, -OCH2-, -CH2CH2O-, -CH(CH3)CH2-, and -CH2CH(CH3)-. Q can be -CH2CH2-. Q can be -CH2CH2CH2-. Q can be -CH2-. Q can be -OCH2-. Q can be -CHO-. Q can be -CH2CH2O-. Q can be CH2CH(CH3)-. Q can be -OCH2CH2-. Q can be -CH(CH3)CH2-. Q can be C 1~3 It may be an alkyl linker. Q may be selected from -CH2-, -CH2CH2-, and -CH2CH2CH2-. Q may be -CH2--. Q may be -CH2CH2-. Q may be -CH2CH2CH2-.

[0097] In the compounds herein, R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently H or C 1~3 R may be an alkyl group. 4 , R 5 , R 6 , R 7 , R 8 , and R 9 may independently be H or methyl.

[0098] In the compounds herein, R 4 can be H. R 4 is C 1~3 R may be an alkyl group. 4 can be methyl.

[0099] In the compounds herein, R 5 can be H. R 5 is C 1~3 R may be an alkyl group. 5 can be methyl.

[0100] In the compounds herein, R 6 can be H. R 6 is C 1~3 R may be an alkyl group. 6 can be methyl.

[0101] In the compounds herein, R 7 can be H. R 7 is C 1~3 R may be an alkyl group. 7 can be methyl.

[0102] In the compounds herein, R 8 can be H. R 8 is C 1~3 R may be an alkyl group. 8 can be methyl.

[0103] In the compounds herein, R 9 can be H. R 9 is C 1~3 R may be an alkyl group. 9 can be methyl.

[0104] Specific compounds include those of formulas (2a), (2b), (2c), (2d), (2e), (2f), and (2g):

[0105] [ka] or a salt thereof, wherein R 1 , R 3 and Q is as defined above.

[0106] Specific compounds include those of formulas (3a), (3b), (3c), (3d), (3e), (3f), and (3g):

[0107] [ka] or a salt thereof, wherein R 1 and R 3 is as defined above.

[0108] Particular compounds include those having formula (4a), (4b), (4c), (4d), (4e), (4f), (4g), (4h), (4i), or (4j):

[0109] [ka] or a salt thereof, wherein R 11 , R 12 , and R 13 is as defined above.

[0110] Particular compounds include those of formula (5a):

[0111] [ka] or a salt thereof, wherein R 2 and R 3 is as defined above.

[0112] The compound may have the formula (6a), (6b), (6c), (6d), (6e), (6f), (6g), (6h), (6i), or (6j):

[0113] [ka] or a salt thereof, wherein R 2 , R 11 , R 12 , and R 13 is as defined above.

[0114] The compound has the formula (6a):

[0115] [ka] or a salt thereof, wherein R 2 , R 11 , R 12 , and R 13 is as defined above.

[0116] The compound has the formula (8a), (8b), or (8c):

[0117] [ka] or a salt thereof, wherein R 3 is as defined above.

[0118] Particular compounds include those having formula (9a), (9b), (9c), (9d), (9e), (9f), (9g), (9h), (9i), or (9j):

[0119] [ka] or a salt thereof, wherein R 11 , R 12 , R 13 , R 15 , and R 16 is as defined above.

[0120] The compound may have the formula (10a), (10b), (10c), (10d), (10e), (10f), (10g), (10h), (10i), or (10j):

[0121] [ka] or a salt thereof, wherein R 2 , R 11 , R 12 , R 13 , R 15 , and R 16 is as defined above.

[0122] The compound has the formula (10a):

[0123] [ka] or a salt thereof, wherein R 2 , R 11 , R 12 , R 13 , R 15 , and R 16 is as defined above.

[0124] Particular compounds include those of formulae (11a), (11b), and (11c):

[0125] [ka] or a salt thereof, wherein R 1 , R 2 , R3 and Q is as defined above.

[0126] Specific compounds include those of formulae (12a), (12b), and (12c):

[0127] [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 is as defined above.

[0128] The compound may have the formula (13a), (13b), (13c), (13d), (13e), (13f), (13g), (13h), (13i), or (13j):

[0129] [ka] or a salt thereof, wherein R 1 , R 2 , R 11 , R 12 , R 13 , R 15 , and R 16 is as defined above.

[0130] The compound may have the formula (14a), (14b), (14c), (14d), (14e), (14f), (14g), (14h), (14i), or (14j):

[0131] [ka] or a salt thereof, wherein R 2 , R 11 , R 12 , R 13 , R 15 , and R 16 is as defined above.

[0132] The compound may be selected from any one of Examples 1-118 shown in Table 1, or a salt thereof.

[0133] The compound is 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 5-methyl-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-5-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one, 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridazin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridazin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-{4-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridin-2-yl}-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chlorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,5-difluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-fluoro-3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,4,5-trifluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-methylbenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-methyl-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(2-fluoro-3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(2-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,5-dichlorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-((4-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)-5-(trifluoromethyl)benzonitrile, 1-(2-(3,5-bis(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(fluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(difluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)methyl-d2)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-6-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 5-methyl-2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(2H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,7-dihydropyrazolo[4,3-d][1,2]oxazin-4(5H)-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)methyl-d)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-7-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-cyclopropyl-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-methoxy-3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyrimidin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-methoxy-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3,5-difluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(benzo[b]thiophen-5-ylmethyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-methoxy-4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(pentafluoro-λ 6 -sulfanyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-(difluoromethoxy)-3-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,4-difluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4,5-difluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(quinolin-3-ylmethyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(benzo[b]thiophen-2-ylmethyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,5-difluoro-4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-isopropylbenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((5-fluoro-6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(1-(trifluoromethyl)cyclopropyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-methyl-1-(2-(3,4,5-trifluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-methyl-1-(2-(3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-5-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-(difluoromethoxy)-3-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-3-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4,5-difluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-fluoro-5-((4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)benzonitrile, 1-(2-(3,4-difluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3,5-difluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((5-fluoro-6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-(difluoromethoxy)pyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-fluoro-5-((4-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)benzonitrile, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one, 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(5-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-methoxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-methoxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(3-(3-fluoro-5-(trifluoromethyl)benzyl)phenyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(hydroxymethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, or its salt may be selected from the group consisting of:

[0134] Further 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. Throughout this specification, a general reference to formula 1 includes all compounds of formula (1x), including (1'), (1a), (1b).

[0135] The compounds of the invention may be used to treat psychiatric disorders; neuropsychiatric disorders; neurodegenerative disorders; psychiatric disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; movement disorders; hyperkinetic disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma or stressor-related disorders; disruptive impulse control or conduct disorders; sleep-wake disorders; substance-related disorders; addictive disorders; behavioral disorders; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesencephalic or nigrostriatal pathways; reduced activity in the striatum; cortical dysfunction; neurocognitive dysfunction; or conditions or symptoms related thereto.

[0136] The compounds of the present invention are useful for treating schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharynx, and the like. Cephalomatosis, Cushing's disease, Diabetes insipidus, Nonfunctioning tumors, Obesity, Post-traumatic stress disorder (PTSD), Akathisia and related movements, Athetosis, Ataxia, Ballismus, Hemiballismus, Chorea, Choreoathetosis, Dyskinesia, Tardive dyskinesia, Neuroleptic-induced dyskinesia, Myoclonus, Mirror movement disorder, Paroxysmal kinesigenic dyskinesia, Restless legs syndrome, Spasms, Stereotypic movements, Sterotypy, Chiropractic dyscrasia, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or medication-induced psychosis, delusions, hallucinations, disorganized thinking, severely disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or medication-induced bipolar and related disorders, bipolar and related disorders caused by another medical condition It may be used to treat associated disorders, separation anxiety disorder, selective mutism, specific phobia, social phobia, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder caused by another medical condition, delirium, severe neurocognitive disorder, mild neurocognitive disorder, amnesia, dementia, developmental coordination disorder, stereotypy, post-stroke effects, dentatorubral-pallidoluysian atrophy, decreased emotional expressiveness, amotivation, allogy, and antisociality.

[0137] The compounds of the present invention can be used to treat schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, neurocognitive disorder, delirium, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD).The compounds of the present invention can be used to treat schizophrenia.

[0138] Aspects of the present invention also include the following. Aspect 1 Formula (1): [ka] or a salt thereof [wherein X is N or CR 2 and Y is N, NR 3 , or CR 2 and Z is N or NR 3 and where Y and Z are either NR, but not both. 3 and Q is -CR 4 R 5 -, -CR 4 R 5 CR 6 R 7 -, -CR 4 R 5 CR 6 R 7 CR 8 R 9 -, -CR4 R 5 CR 6 R 7 O-, -OCR 4 R 5 - and - OCR 4 R 5 CR 6 R 7 - selected from R 1 is H, C optionally substituted with 1 to 6 fluorine atoms 1~6 Alkyl, C optionally substituted with 1 to 6 fluorine atoms 3~6 Cycloalkyl, the group -C(R 14 ) 2 C(R 18 ) 2 OR 17 or a group -C(R 14 ) 2 C(R 19 ) 2 OH, where each R 14 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 is alkyl, R 17 C optionally substituted with 1 to 6 fluorine atoms 1~3 alkyl, and each R 18 are each independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; 1~3 alkyl, and each R 19 are each independently H or C optionally substituted with 1 to 6 fluorine atoms. 1~3 is alkyl, R 17 and one R 14 may be taken together to form an oxolane or oxetane ring, R 2 is H; halo; CN; OH or C optionally substituted with 1 to 6 fluorine atoms. 1~6 Alkyl; C optionally substituted with OH or 1 to 6 fluorine atoms 1~6 alkoxy; or C optionally substituted with OH or 1 to 6 fluorine atoms 3~6 cycloalkyl; 1~6 Alkyl, C 1~6 Alkoxy, or C 3~6 One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and their oxidized forms; R 3 is the group -VLW, R 4 、R 5 、R 6 、R 7 、R 8 , and R 9 H and C 1~3 independently selected from alkyl, where V is the R 3 is a 6-membered optionally substituted aryl or heteroaryl ring substituted by L at the meta position relative to the attachment position of L is CH 2 , C.H.D., C.D. 2 , CHF, CF 2 , C═O, CHOH, O, and NH; W is an optionally substituted monocyclic or polycyclic ring system. Aspect 2 R 3 But the formula:

change

[0023] A compound according to embodiment 1, wherein Aspect 3 The compound according to embodiment 1 or 2, wherein W is a 6-membered optionally substituted aryl or heteroaryl ring. Aspect 4 Formula (1b):

change

change

change

change

change

change

change

change

change

change

change

[0139] The term "GPR52 modulator" as used herein refers to any compound that binds to the GPR52 receptor and modulates the function of the GPR52 receptor. The term "modulator" should be interpreted to include modulation by modalities including, but not limited to, agonists, partial agonists, and inverse agonists.

[0140] The term "treatment", in relation to the use of any of the compounds described herein, including those of formula (1), (1'), (1a), (1b), is used to describe any form of intervention in which a compound is administered to a subject suffering from, at risk of suffering from, or potentially at risk of suffering from, a disease or disorder in question. Thus, the term "treatment" encompasses both preventative (prophylactic) treatment and treatment in which a measurable or detectable symptom of a disease or disorder is manifested.

[0141] The term "effective therapeutic amount" (e.g., with respect to a method of treating a disease or condition) refers to an amount of a compound that is effective to produce a desired therapeutic effect. For example, if the condition is pain, an effective therapeutic amount is an amount sufficient to produce a desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain, or a reduction in the severity of pain.

[0142] The terms "alkyl," "hydrocarbon," "alkoxy," "halo," "aryl," "heteroaryl," "monocyclic," "polycyclic," and "cycloalkyl" are all used in their conventional sense (e.g., as defined in the IUPAC Gold Book) unless otherwise indicated. "Optionally substituted," when applied to any group, means that the group can be substituted, if desired, with one or more substituents which can be the same or different.

[0143] Examples of heteroatom exchange of carbon atoms include the exchange of a carbon atom in a -CH-CH-CH- chain with oxygen or sulfur to give an ether -CH-O-CH- or a thioether -CH-S-CH-; the exchange of a carbon atom in a group CH-C≡CH with nitrogen to give a nitrile (cyano) group CH-C≡N; the exchange of a carbon atom in a group -CH-CH-CH- with C=O to give a ketone -CH-C(O)-CH-; the exchange of a carbon atom in a group -CH-CH=CH with C=O to give an aldehyde -CH-C(O)H; the exchange of a carbon atom in a group -CH-CH-CH with O to give an alcohol -CH-CH-CHOH; the exchange of a carbon atom in a group -CH-CH-CH with O to give an ether -CH-O These include exchanging a carbon atom in the group -CH-CH-CH to S to give a thiol -CH-CH-CHSH, exchanging a carbon atom in the group -CH-CH-CH- to S=O or SO to give a sulfoxide -CH-S(O)-CH- or sulfone -CH-S(O)-CH-, exchanging a carbon atom in the -CH-CH-CH- chain to C(O)NH to give an amide -CH-CH-C(O)-NH-, exchanging a carbon atom in the -CH-CH-CH- chain to nitrogen to give an amine -CH-NH-CH-, and exchanging a carbon atom in the -CH-CH-CH- chain to C(O)O to give an ester (or carboxylic acid) -CH-CH-C(O)-O-. In each such exchange, at least one carbon atom of the alkyl group must remain.

[0144] To the extent that any of the compounds described have chiral centers, the present invention covers all optical isomers of such compounds, whether in the form of racemates or split enantiomers.The invention described herein relates to all crystal forms, solvates, and hydrates of any of the compounds disclosed, even if so prepared.To the extent that any of the compounds disclosed herein have acid or basic centers, such as carboxylates or amino groups, all salt forms of said compounds are included herein.In the case of pharmaceutical use, salts should be considered as pharmaceutically acceptable salts.

[0145] The salt or pharma-ceutically acceptable salt that can be mentioned includes acid addition salt and base addition salt.Such salt can be formed by conventional methods, for example, by reacting the free acid or free base form of the compound with one or more equivalents of suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing said solvent or said medium using standard techniques (for example, under vacuum, by freeze-drying or by filtration).Salt can also be prepared by replacing the counterion of the compound in salt form with another counterion, for example, by using a suitable ion exchange resin.

[0146] Examples of pharma- ceutically acceptable salts include acid addition salts derived from mineral and organic acids, and salts derived from metals, such as sodium, magnesium, potassium, and calcium.

[0147] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphoric acid, Sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1- Included are the acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0148] Also included are any solvates of the compounds and their salts.Preferred solvates are those formed by incorporating non-toxic, pharma-ceutically acceptable solvent molecules (hereinafter referred to as solvating solvent) into the solid structure (e.g., crystalline structure) of the compounds of the present invention.Examples of such solvents include water, alcohol (e.g., ethanol, isopropanol and butanol), and dimethylsulfoxide.Solvates can be prepared by recrystallizing the compounds of the present invention with a solvent or mixture of solvents that contains a solvating solvent.Whether or not a solvate is formed in any given case can be determined by subjecting the crystals of the compound to analysis using well-known standard techniques, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0149] Solvate can be stoichiometric or non-stoichiometric solvate.Particular solvate can be hydrate, and examples of hydrate include hemihydrate, monohydrate and dihydrate.For more detailed discussion of solvate and the methods used to make and characterize them, 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.

[0150] The term "pharmaceutical composition" in the context of the present invention means a composition that contains an active agent and additionally contains one or more pharma-ceutically acceptable carriers.The composition may further contain, depending on the mode of administration and the nature of the dosage form, a component selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents.The composition may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, and injectable liquid preparations including liposome preparations.

[0151] The compounds of the invention may contain one or more isotopic substituents, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope all isotopes of the element. 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope: 12 C. 13 C and 14 C, and 16 O and 18 Each of the groups includes 0. Similarly, reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group, such as an ethyl group, or an alkoxy group, such as a methoxy group, also encompasses variations in which one or more hydrogen atoms in the group are in the form of a deuterium or tritium isotope, such as an ethyl group in which all five hydrogen atoms are in the form of a deuterium isotope (perdeuteroethyl group), or a methoxy group in which all three hydrogen atoms are in the form of a deuterium isotope (trideuteroethoxy group). Isotopes can be radioactive or non-radioactive.

[0152] Treatment dosage can vary according to the requirements of the patient, the severity of the condition being treated, and the compound being used.The determination of the correct dosage for a particular situation is within the skill of the art.Generally, treatment is started with a smaller dosage that is less than the optimal dosage of the compound.Then, dosage is increased by small increments until the optimal effect for the patient under the circumstances is achieved.For convenience, the total daily dosage can be divided and administered in small portions throughout the day if desired.

[0153] The magnitude of an effective dose of a compound will, of course, vary depending on the nature of the severity of the condition being treated, the particular compound, and its route of administration. Selection of an appropriate dosage is within the ability of one of ordinary skill in the art without incurring undue burden. In general, the range of daily doses may be about 10 μg to about 30 mg per kg of body weight of human and non-human animals, preferably about 50 μg to about 30 mg per kg of body weight of human and non-human animals, for example, about 50 μg to about 10 mg per kg of body weight of human and non-human animals, for example, about 100 μg to about 30 mg per kg of body weight of human and non-human animals, for example, about 100 μg to about 10 mg per kg of body weight of human and non-human animals, most preferably about 100 μg to about 1 mg per kg of body weight of human and non-human animals.

[0154] Pharmaceutical preparations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation).

[0155] Thus, in one embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound of formula (1), (1'), (1a), (1b) as defined above, together with at least one pharma- ceutically acceptable excipient.

[0156] The composition may be a tablet composition.The composition may be a capsule composition.

[0157] Pharmaceutically acceptable excipients may be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents, such as fillers or bulking agents, and liquid diluents, such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g., release-slowing or delaying polymers, or waxes), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, isotonicity agents, thickening agents, flavoring agents, sweetening agents, pigments, plasticizers, taste-masking agents, stabilizers, or any other excipients customarily used in pharmaceutical compositions.

[0158] The term "pharmacologically acceptable" as used herein means a compound, substance, composition, and / or dosage form that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0159] Pharmaceutical compositions containing compounds of formula (1), (1'), (1a), (1b) may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, otic, rectal, vaginal, or transdermal administration.

[0160] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, troches, syrups, liquids, powders, granules, elixirs and suspensions, sublingual tablets, wafers, or patches, such as buccal patches.

[0161] The tablet composition can contain a unit dose of the active compound together with an inert diluent or carrier, such as sugar or sugar alcohol, such as lactose, sucrose, sorbitol or mannitol, and / or non-sugar derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, such as corn starch.The tablet can also contain standard ingredients such as binders and granulating agents, such as polyvinylpyrrolidone, disintegrants (e.g., expanding cross-linked polymers, such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures.Such excipients are well known and need not be discussed in detail here.

[0162] Tablets can be designed to release drug upon contact with gastric fluids (immediate release tablets) or for controlled release over an extended period of time or in specific areas of the GI tract (controlled release tablets).

[0163] A pharmaceutical composition typically comprises from about 1% (w / w) to about 95%, preferably % (w / w) of an active ingredient, and from 99% (w / w) to 5% (w / w) of a pharma- ceutically acceptable excipient (e.g. as defined 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 pharma- ceutically acceptable excipient or a combination of such excipients. A pharmaceutical composition comprises from about 1% to about 95%, preferably from about 20% to about 90%, of an active ingredient. A pharmaceutical composition according to the invention may, for example, be in unit dose form, for example, in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets, or capsules.

[0164] Tablets and capsules may contain, for example, 0-20% (w / w) disintegrants, 0-5% lubricants, 0-5% flow aids, and / or 0-99% (w / w) fillers and / or extenders (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, and 0-5% (w / w) pigments. Slow release tablets additionally typically contain 0-99% (w / w) release-controlling (e.g., retarding) polymers (depending on dose). Film coats for tablets or capsules typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0165] Parenteral formulations 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 dose, if freeze-dried). Intramuscular depot formulations may also contain 0-99% (w / w) oil.

[0166] Pharmaceutical formulations may be presented to the patient in a "patient pack", usually a blister pack, which contains the entire course of treatment in a single package.

[0167] The compounds of formula (1), (1'), (1a), (1b) are generally presented in unit dosage form, which typically contains sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligram to 2 grams of active ingredient (more usually 10 milligram to 1 gram, e.g., 50 milligram to 500 milligram), or 1 microgram to 20 milligram (e.g., 1 microgram to 10 milligram, e.g., 0.1 milligram to 2 milligrams of active ingredient).

[0168] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram, of active compound.

[0169] The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The exact amount of the compound to be administered can be determined by the attending physician according to standard procedures. EXAMPLES

[0170] The invention will now be illustrated with reference to the following non-limiting examples shown in Table 1. NMR and LCMS characteristics are given in Table 3. Intermediates used are listed in Table 2.

[0171] [Table 1-1]

[0172] [Table 1-2]

[0173] [Table 1-3]

[0174] [Table 1-4]

[0175] [Table 1-5]

[0176] [Table 1-6]

[0177] [Table 1-7]

[0178] [Table 1-8] Methods for preparing compounds of formula (1), (1'), (1a) and (1b) Compounds of formula (1), (1'), (1a), (1b) can be prepared according to synthetic methods well known to those skilled in the art. Processes for preparing compounds defined in formula (1) above are provided. Compounds of formula (1) and related intermediates can be prepared according to procedures and schemes described herein. Intermediates disclosed may be applicable to the synthesis of one or more compounds of formula (1). Procedures described herein may be applicable to the synthesis of one or more intermediates or compounds of formula (1). Compounds of formula (1) can be prepared by the reaction of another compound of formula (1). An intermediate can be used in subsequent synthetic steps without isolation or full characterization itself. Certain compounds of the invention can be prepared according to the following general schemes.

[0179] [ka] Certain compounds of the present invention can be prepared according to the following general schemes.

[0180] [ka] Where intermediates are commercially available, they are identified by Chemical Abstracts Service (CAS) reference number in Table 3; where not commercially available, the synthesis of intermediates using standard transformations is detailed herein. Commercially available reagents were utilized without further purification.

[0181] General Procedure Room temperature (RT) refers to approximately 20 to 27°C. 1 H NMR spectra were typically recorded at ambient temperature at 400 MHz unless otherwise specified. Chemical shift values ​​are expressed in parts per million (ppm), i.e. (δ) values. Standard abbreviations, or combinations thereof, are used for the multiplicity of NMR signals, e.g., s=singlet, br=broadband, d=doublet, t=triplet, q=quartet, quin=quintet or p=pentet, h=sextet, dd=doublet of doublet, dt=doublet of triplet, m=multiplet. Coupling constants are listed as J values ​​measured in Hz. NMR and mass spectrometry results were corrected to account for background peaks. Chromatography refers to column chromatography performed using silica or C18 silica and run under positive pressure (flash chromatography) conditions.

[0182] LCMS method LCMS experiments were performed using electrospray conditions under the following conditions (Solvents: A1 = 0.1% TFA:MeCN (95:5) in H2O; A2 = 5 mM ammonium acetate in H2O; A3 = 2.5 L H2O + 2.5 mL 28% aqueous ammonia in H2O; A4 = 0.1% HCOH:MeCN (95:5) in H2O; A5 = 10 mM NH4HCO3 in H2O; A6 = 0.2% 28% aqueous ammonia in H2O; A7 = 0.1% TFA in H2O; A8 = 5 mM NH4HCO3 in H2O; A9 = 10 mM ammonium acetate in H2O; B1 = 0.1% TFA in MeCN; B2 = MeCN; B3 = 2.5 L MeCN + 135 mL H2O + 2.5 mL 28% aqueous ammonia in H2O). LCMS data are presented in the format: mass ion, electrospray mode (positive or negative), retention time (experimental text and Table 2); mass ion, electrospray mode (positive or negative), retention time, approximate purity (Table 3).

[0183] Method 1. Instrument: Hewlett Packard 1100 with G1315A DAD, Micromass ZQ; Column: Phenomenex Gemini-NX C18, 3 micron, 2.0 x 30 mm; Gradient [time (min) / solvent B3 (%) in A3]: 0.00 / 2, 0.10 / 2, 8.40 / 95, 10.00 / 95; Injection volume 1 μL; UV detection 230-400 nM; Column temperature 45 °C; Flow rate 1.5 mL / min.

[0184] Method 2. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Waters XBridgeC8 3.5 micron, 4.6 x 50 mm; Gradient [time (min) / solvent B1 (%) in A1]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25 °C; 1.5 mL / min.

[0185] Method 3. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax XDB C18, 5 micron; Gradient [time (min) / solvent B2 (%) in A4]: 0.00 / 5, 2.50 / 95, 4.00 / 95, 4.50 / 5, 6.00 / 5; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25 °C; Flow rate 1.5 mL / min.

[0186] Method 4. Instrumentation: Agilent Technologies 1260 LC with Chemstation software, Agilent 6120 Quadrupole MS with Diode Array Detector, APCI and ES sources; Column: Phenomenex Gemini-NX C18, 3 micron, 2 x 30 mm; Gradient [time (min) / solvent B3 (%) in A3]: 0.00 / 5, 2.00 / 95, 2.50 / 95, 2.60 / 5, 3.00 / 5; Injection volume 0.5 μL; UV detection 190-400 nm; Column temperature 40 °C; Flow rate 1.5 mL / min.

[0187] Method 5. Instrument: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 100 mm; Gradient [time (min) / % B2 in A2]: 0.00 / 2, 2.00 / 2, 7.00 / 50, 8.50 / 80, 9.50 / 2, 10.0 / 2; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL per minute.

[0188] Method 6. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Waters XBridgeC8 3.5 micron, 4.6 x 50 mm; Gradient [time (min) / solvent B2 (%) in A5]: 0.0 / 10, 4.0 / 95, 5.0 / 95, 5.5 / 10, 7.0 / 10; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25 °C; Flow rate 1.2 mL / min.

[0189] Method 7. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax eclipse plus C18, 1.8 micron, 2.1 x 50 mm; Gradient [time (min) / solvent B2 (%) in A4]: 0.0 / 5, 0.25 / 5, 2.5 / 100, 3.0 / 100, 3.1 / 5, 4.0 / 5; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 °C; Flow rate 0.8 mL / min.

[0190] Method 8. Instrument: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity HSS-T3, 1.8 micron, 2.1 x 100 mm; Gradient [time (min) / % B2 in A7]: 0.0 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 10.00 / 10; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30 °C; Flow rate 0.3 mL per minute.

[0191] Method 9. Instrument: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1 x 100 mm; Gradient [time (min) / % B2 in A2]: 0.00 / 5, 0.25 / 5, 1.50 / 35, 2.50 / 95, 3.20 / 95, 3.60 / 5, 4.00 / 5; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 35°C; Flow rate 0.6 mL per min for 3.20 min then 0.8 mL per min.

[0192] Method 10. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax extend C18, 5 micron, 4.6 × 50 mm; Gradient [time (min) / solvent B2 (%) in 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.

[0193] Method 11. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Acquity BEH C18, 1.7 micron, 2.1 x 50 mm; Gradient [time (min) / solvent B2 (%) in A9]: 0.0 / 5, 0.25 / 5, 2.5 / 100, 3.0 / 100, 3.1 / 5, 4.0 / 5; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 °C; Flow rate 0.8 mL / min.

[0194] Method 12. Instrument: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Atlantis dC18, 5 micron, 4.6 x 50 mm; Gradient [time (min) / solvent B2 (%) in A4]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 °C; Flow rate 1.5 mL / min.

[0195] GCMS method GCMS data is presented in the format of mass ion, electrospray mode (positive or negative), and retention time.

[0196] Method 1. Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30m x 250μm x 0.25μm); Inlet temperature: 250°C; Split ratio: 75:1; Oven temperature: 50°C, hold time 3 min; Ramp 1: 40°C / min to 300°C, hold time 2 min; Detector temperature: 310°C; Column flow: 2mL / min; Air flow: 300mL / min; H2 flow: 40mL / min; Make up flow (He): 25mL / min; Source temperature: 230°C.

[0197] Method 2. Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30 m × 250 μm × 0.25 μm); Inlet temperature: 250 °C; Split ratio: 75:1; Oven temperature: 120 °C, hold time 1 min; Ramp 1: 40 °C / min to 300 °C, hold time 4 min; Detector temperature: 310 °C; Column flow: 2 mL / min; Air flow: 300 mL / min; H2 flow: 40 mL / min; Make-up flow (He): 25 mL / min; Source temperature: 230 °C.

[0198] MS method Method 1. Data was obtained from a Waters QDA or Waters SQD instrument after a 4-6 minute run on a UPLC column using buffer.

[0199] Preparative HPLC method Please see LCMS methods section for solvent conditions.

[0200] Method 1. Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD; Column: Waters XBridge C8 5 micron 19×150 mm; Gradient [time (min) / solvent B2 (%) in A5]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0201] Method 2. Equipment: Gilson Semi Preparative HPLC System-321 Pump / 171 Diode Array Detector / GX-271 Liquid Handler; Column: Phenomenex Gemini-NX C18 5 micron 30×100 mm; Gradient 12.5 min, Solvent B2 (%) in A6 varies for individual runs (see Exemplary Procedures for details).

[0202] Method 3. Instrument: Waters 2767 Auto purification; Column: Reprosil Gold C18 5 micron 19×250 mm; Gradient 15 min, Solvent B2 (%) in A2 varies for each individual run (see Exemplary Procedures for details).

[0203] Method 4. Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD; Column: Waters XBridge C8 5 micron 19×150 mm; Gradient [time (min) / solvent B2 (%) in A7]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0204] Method 5. Instrument: Waters 2767 Auto purification; Column: Xtimate hexylphenyl 10 micron 19×250 mm; Gradient 18 min, Solvent B2 (%) in A8 varies for individual runs (see Exemplary Procedures for details).

[0205] Method 6. Instrument: Waters 2767 Auto purification; Column: X Select C18 10 micron 19×250 mm; Gradient 20 min, Solvent B2 (%) in A8 varies for individual runs (see Exemplary Procedures for details).

[0206] Chiral SFC Method Method 1. Equipment: PIC solutions PIC-100, PIC-150, PIC-175, and PIC-400; Column: Lux A1 5 micron, 21.2 x 250 mm; Co-solvent 0.5% isopropylamine in MeOH; Column temperature 35°C; 20 mL / min.

[0207] Method 2. Instrument: Sepiatec Prep SFC 100 equipped with Prep SFC 100 control software and UV / Vis detector; Column: Lux C1 5 micron, 21.2 x 250 mm; Co-solvent 0.2% NH3 in IPA; Column temperature 40°C; 50 mL / min.

[0208] Method 3. Equipment: PIC solutions PIC 10-20 and PIC-10; Column: Lux A1 3 micron, 2 x 50 mm; Co-solvent 0.5% isopropylamine in MeOH; Column temperature 35°C; 3 mL / min.

[0209] Method 4. Instrument: Waters Acquity UPC2 equipped with Masslynx software, PDA detector and QDa mass detector; Column: Lux C1 3 micron, 2 x 50 mm; Co-solvent IPA; Column temperature 45°C; 1.5 mL / min.

[0210] Method 5. Equipment: PIC solutions PIC-100, PIC-150, PIC-175, and PIC-400; Column: Lux A1 5 micron, 21.2 x 250 mm; Co-solvent MeOH / MeCN (1:1); Column temperature 35°C; 30 mL / min.

[0211] Method 6. Equipment: PIC solutions PIC10-20 and PIC-10; Column: Lux A1 3 micron, 2 x 50 mm; Co-solvent MeOH / MeCN (1:1); Column temperature 35°C; 3 mL / min.

[0212] Method 7. Equipment: PIC solutions PIC-100, PIC-150, PIC-175, and PIC-400; Column: Chiralpak AS-H, 30 x 250 mm; Co-solvent 0.5% isopropylamine in MeOH; Column temperature 35°C; 30 mL / min.

[0213] Abbreviation aq = aqueous Boc = tert-butoxycarbonyl DAST = (Diethylamino)sulfuric acid trifluoride Davis Reagent = 2-(phenylsulfonyl)-3-phenyl-oxaziridine dba = dibenzylideneacetone DCM = dichloromethane Dess-Martin = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one DIPEA = N,N-diisopropylethylamine DMA = N,N-Dimethylacetamide DMAP = 4-(dimethylamino)pyridine DME = 1,2-dimethoxyethane DMF = N,N-dimethylformamide DMF-DMA = N,N-Dimethylformamide Dimethyl Acetal DMS = dimethyl sulfide DMSO = dimethyl sulfoxide dppf = 1,1'-ferrocenediyl-bis(diphenylphosphine) EDCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ES = electrospray EtOAc = ethyl acetate EtOH = ethanol h=time HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HMDS = hexamethyldisilazane IPA = i-propyl alcohol L = liters LC = Liquid Chromatography LCMS = Liquid Chromatography Mass Spectrometry LiAlH4 = Lithium Aluminum Hydride MeCN = acetonitrile MeOH = methanol min=minutes MS=mass spectrometry NMP = 1-methyl-2-pyrrolidinone MMR = Nuclear Magnetic Resonance MTBE = methyl tert-butyl ether NIS=N-iodosuccinimide Pet-ether = Petroleum ether pin=pinacol RT=room temperature RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl SFC = Supercritical Fluid Chromatography Sphos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMSI = iodotrimethylsilane TrixiePhos = rac-2-(di-tert-butylphosphino)-1,1'-binaphthyl Ts = para-toluenesulfonyl XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl The prefixes n-, s-, i-, t- and tert- have their usual meanings, linear, secondary, iso, and tertiary.

[0214] Synthesis of intermediates Preparation of substituted (dimethylamino)methylene intermediates Exemplary Procedure 1: Illustrated by the preparation of intermediate 1, (E)-3-((dimethylamino)methylene)piperidine-2,4-dione

[0215] [ka] A solution of piperidine-2,4-dione (10 g, 88.5 mmol) in DMF-DMA (100 mL) was stirred at 100° C. for 3 h and then at room temperature for 15 h. The precipitated solid was filtered, rinsed with EtO (2×30 mL) and dried under vacuum to give (E)-3-((dimethylamino)methylene)piperidine-2,4-dione as a brown solid (5 g, 33%). Data in Table 2.

[0216] Intermediate 2 2-((dimethylamino)methylene)cyclohexane-1,3-dione

[0217] [ka] The title compound (1.3 g, 88%) was prepared using the method of Intermediate 1 by heating cyclohexane-1,3-dione (1 g, 8.8 mmol) in DMF-DMA (10 mL) at 100° C. for 3 h. Data in Table 2.

[0218] Intermediate 17 (E)-3-((dimethylamino)methylene)-6-methylpiperidine-2,4-dione

[0219] [ka] The title compound (390 mg, 91%) was prepared using the method of Intermediate 1 by stirring 6-methylpiperidine-2,4-dione (300 mg, 2.36 mmol) in DMF-DMA (0.5 mL) and toluene (5 mL) at room temperature for 2 h. Data in Table 2.

[0220] Intermediate 20 (E)-3-((dimethylamino)methylene)-5-methylpiperidine-2,4-dione

[0221] [ka] The title compound (257 mg, 90%) was prepared using the method of Intermediate 1 by stirring 5-methylpiperidine-2,4-dione (200 mg, 1.56 mmol) in DMF-DMA (0.3 mL) and toluene (2 mL) at room temperature for 2 h. Data in Table 2.

[0222] Typical Procedure 2: exemplified by the preparation of intermediate 19, ethyl (Z)-4-(tert-butoxy)-2-((dimethylamino)methylene)-3-oxobutanoate

[0223] [ka] Step 1. Ethyl 4-chloro-3-oxobutanoate (2.00 g, 12.2 mmol) and t-BuOH (1.80 g, 24.3 mmol) were added to a suspension of sodium hydride (60% in mineral oil, 1.46 g, 36.5 mmol) in DMF (5 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with 1N HCl (20 mL) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried (Na2SO4) and the solvent removed under vacuum to yield ethyl 4-(tert-butoxy)-3-oxobutanoate as a yellow liquid (1.60 g, 65%).

[0224]

number

[0225] Preparation of substituted dihydropyridinones and equivalent intermediates Exemplary Procedure 3: exemplified by the preparation of intermediate 35, 3-acetyl-1-(2,4-dimethoxybenzyl)-4-hydroxy-5,6-dihydropyridin-2(1H)-one

[0226] [ka] Step 1. 4 Å molecular sieves (10 g) were added to a suspension of 2,4-dimethoxybenzaldehyde (5 g, 30.1 mmol) and methyl 3-aminopropanoate hydrochloride (5.38 g, 38.7 mmol) in DCM (100 mL) at room temperature, followed by triethylamine (15 mL, 107 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was filtered through Celite and washed with DCM (100 mL). The filtrate was washed with 10% NaHCO3 solution (100 mL) and brine (100 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was dissolved in MeOH (50 mL), cooled to -40 °C, NaBH4 (1.71 g, 45.2 mmol) was added in small portions and the reaction mixture was stirred at -40 °C for 1 h. The solvent was removed in vacuo and the resulting residue was dissolved in EtOAc (200 mL) and washed with H2O (200 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo to yield methyl 3-((2,4-dimethoxybenzyl)amino)propanoate as a pale yellow gum (6.8 g, 89%). LCMS (Method 3): m / z 254.1 (ES+), 1.02 min.

[0227]

number

[0228] Step 2. A solution of methyl 3-((2,4-dimethoxybenzyl)amino)propanoate (6.8 g, 26.8 mmol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (7.6 g, 53.7 mmol) in ο-xylene (100 mL) was stirred at 130 °C for 4 h. The solvent was removed under vacuum and the residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in petroleum ether to afford methyl 3-(N-(2,4-dimethoxybenzyl)-3-oxobutanamido)propanoate as a yellow gum (6.0 g, 66%). LCMS (Method 7): m / z 338.2 (ES+), 1.82 min.

[0229]

number

[0230] Typical Procedure 4: exemplified by the preparation of intermediate 44, tert-butyl 3-(2-methoxyacetyl)-2,4-dioxopiperidine-1-carboxylate

[0231] [ka] N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.180 g, 0.94 mmol) and DMAP (0.126 g, 1.03 mmol) were added to a stirred solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (0.2 g, 0.94 mmol) and 2-methoxyacetic acid (0.084 g, 0.94 mmol) in DCM (10 mL) at 0°C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water (30 mL) and DCM (2 x 30 mL). The combined organic layers were washed with brine solution (30 mL), dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-20% EtOAc in petroleum ether to afford tert-butyl 3-(2-methoxyacetyl)-2,4-dioxopiperidine-1-carboxylate as a yellow liquid (0.2 g, 75%). Data in Table 2.

[0232] Preparation of substituted fluoropyridine intermediates Exemplary Procedure 5: Illustrated by the preparation of intermediate 3, 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

[0233] [ka] Step 1. A solution of 2-bromo-4-fluoropyridine (4.0 g, 22.7 mmol) in 1,4-dioxane (60 mL) was degassed with argon for 10 min and bis(tributyltin) (17.3 mL, 34.0 mmol), LiCl (2.88 g, 68.1 mmol), and Pd(PPh3)4 (1.31 g, 1.13 mmol) were added. The reaction mixture was heated at 120 °C for 16 h. The reaction was quenched with water (100 mL) and the aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried (Na2SO4), and the solvent was removed under vacuum to yield 4-fluoro-2-(tributylstannyl)pyridine as a yellow liquid (14.3 g, crude material). The crude product was used in the next step without further purification. MS (method 1): m / z 388 (ES+) Step 2. 1-(Bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.33 g, 5.18 mmol) was added to a solution of 4-fluoro-2-(tributylstannyl)pyridine (14.3 g, 5.18 mmol) in 1,4-dioxane (30 mL). The reaction mixture was degassed with argon for 10 min and CuI (98 mg, 0.51 mmol), Pd(PPh3)4 (299 mg, 0.26 mmol) were added. The reaction mixture was heated at 120 °C for 16 h. The reaction was quenched with water (30 mL) and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 5-10% EtOAc in hexanes to afford 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a light yellow liquid (400 mg, 6.4% for two steps). Data in Table 2.

[0234] Exemplary Procedure 6: Illustrated by the preparation of intermediate 4, 2-fluoro-4-(3-(trifluoromethyl)benzyl)pyridine

[0235] [ka] 1-(Bromomethyl)-3-(trifluoromethyl)benzene (0.14 mL, 0.88 mmol) was added to a suspension of 2-fluoropyridine-4-boronic acid (150 mg, 1.06 mmol), K2CO3 (146 mg, 1.06 mmol), and PdCl2(dppf).DCM (129 mg, 0.18 mmol) in 1,4-dioxane (4 mL) / water (0.4 mL) and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was partitioned between water (6 mL) and EtOAc (6 mL) and the organic layer was removed. The aqueous layer was extracted with EtOAc (2 x 6 mL), the combined organic layers were dried (phase separator) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in i-hexane to afford 2-fluoro-4-(3-(trifluoromethyl)benzyl)pyridine as a yellow liquid (167 mg, 74%). Data in Table 2.

[0236] Intermediate 5 2-Fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

[0237] [ka] The title compound (1.8 g, 86%) was prepared using the method of Intermediate 4 by heating (2-fluoropyridin-4-yl)boronic acid (1.3 g, 7.77 mmol), 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.3 g, 9.30 mmol), PdCl2(dppf).DCM (284 mg, 0.38 mmol), and K2CO3 (3.2 g, 22.3 mmol) in 1,4-dioxane (20 mL) / water (5 mL) at 90 °C for 1 h. The title compound was isolated as a brown oil by partitioning between EtOAc (100 mL) and water (70 mL). The organic layer was separated, washed with brine (50 mL), dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in petroleum ether. Data in Table 2.

[0238] Intermediate 18 2-Chloro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

[0239] [ka] The title compound (3.00 g, 88%) was prepared using the method of Intermediate 4 by heating (2-chloropyridin-4-yl)boronic acid (1.84 g, 11.7 mmol), 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (3.00 g, 11.7 mmol), PdCl2(dppf).DCM (476 mg, 0.58 mmol), and K2CO3 (4.84 g, 35.0 mmol) in 1,4-dioxane (33.7 mL) / water (11.3 mL) at 90 °C for 2 h. The title compound was isolated as a colorless oil by partitioning between EtOAc (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 10-12% EtOAc in hexanes. Data in Table 2.

[0240] Preparation of substituted hydrazinoyl intermediates Typical Procedure 7: exemplified by the preparation of intermediate 6, 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine

[0241] [ka] Step 1. A pinch of iodine was added to a stirred solution of activated zinc (35 g, 583 mmol) in DMF (300 mL) and the solution was heated at 50 °C for 5 min, followed by the addition of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (32 g, 124 mmol) in DMF (50 mL). The reaction mixture was heated at 50 °C for 1 h and then cooled to room temperature. The residual zinc was allowed to settle and the supernatant pale green DMF layer was cannulated into a degassed suspension of 2-bromo-4-chloropyridine (16 g, 83.3 mmol) and RuPhos (2.3 g, 4.99 mmol) in DMF (50 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (3.8 g, 4.16 mmol). The reaction mixture was heated at 70° C. for 16 h, then filtered through Celite and washed with EtOAc (600 mL). The filtrate was washed with brine (3×300 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-5% EtOAc in petroleum ether to afford 4-chloro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a yellow semi-solid (8 g, 33%). LCMS (Method 3): m / z 290.1 ​​(ES+), 2.65 minutes.

[0242]

number

[0243] Intermediate 7 2-Hydrazineyl-4-(3-(trifluoromethyl)benzyl)pyridine

[0244] [ka] The title compound (486 mg, 80%) was prepared in two steps using the methods of Intermediate 4 and Intermediate 6, Step 2, by heating (2-chloropyridin-4-yl)boronic acid (3.6 g, 23.2 mmol), 1-(bromomethyl)-3-(trifluoromethyl)benzene (5 g, 21.09 mmol), PdCl(dppf).DCM (3.4 g, 4.21 mmol, 20 mol%), and KCO (3.4 g, 25.3 mmol) in 1,4-dioxane (40 mL) at 100 °C for 1 h and the product of Step 1 (500 mg, 1.84 mmol), hydrazine hydrate (0.45 mL, 9.20 mmol) in EtOH (4 mL) at 150 °C for 12 h. After completion of step 2, the title compound was isolated as an orange oil by partitioning between EtOAc (6 mL) and water (6 mL). The aqueous layer was washed with EtOAc (2×6 mL), dried (phase separator) and the solvent removed under vacuum. Data from Table 2.

[0245] Intermediate 39 4-(3-(difluoromethyl)-5-fluorobenzyl)-2-hydrazinylpyridine

[0246] [ka] The title compound (110 mg, crude) was prepared in two steps using the methods of Intermediate 4 and Intermediate 6, Step 2: (2-fluoropyridin-4-yl)boronic acid (145 mg, 1.03 mmol), 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (Intermediate 26, 200 mg, 1.03 mmol), PdCl(dppf).DCM (84 mg, 0.103 mmol), and KCO (426 mg, 3.09 mmol) in 1,4-dioxane (8 mL) / water (2 mL) heated at 110 °C for 16 h and hydrazine hydrate (0.5 mL, 9.77 mmol) in IPA (10 mL) heated at 100 °C for 48 h. After completion of step 2, the title compound was partitioned between EtOAc (10 mL) and water (10 mL) and isolated as a yellow gum. The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine solution (10 mL), dried (Na2SO4) and the solvent was removed under vacuum. The crude product was used in the next step without further purification. Data in Table 2.

[0247] Intermediate 8 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine

[0248] [ka] The title compound (350 mg, 100%) was prepared using the method of Intermediate 6, Step 2 by heating 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 5, 300 mg, 1.17 mmol) and hydrazine hydrate (0.17 mL, 3.52 mmol) in EtOH (10 mL) at 60° C. for 16 h. The title compound was isolated as a brown oil by partitioning between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine (50 mL), dried (Na2SO4) and the solvent removed in vacuo. Data from Table 2.

[0249] Typical Procedure 8: exemplified by the preparation of intermediate 9, 5-(3-fluoro-5-(trifluoromethyl)benzyl)-3-hydrazinylpyridazine

[0250] [ka] Step 1. A pinch of iodine was added to a stirred solution of activated zinc (1.49 g, 23.0 mmol) in anhydrous DMF (30 mL) and heated to 50° C. for 5 min, followed by the addition of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.19 g, 4.61 mmol) in DMF (10 mL). The reaction mixture was heated at 50° C. for 1 h and then cooled to room temperature. Residual zinc was allowed to settle, and the supernatant pale green DMF layer was transferred via cannula to a degassed suspension of 5-chloropyridazin-3(2H)-one (200 mg, 1.53 mmol), RuPhos (70 mg, 0.15 mmol), and tris(dibenzylideneacetone)dipalladium(0) (140 mg, 0.15 mmol) in DMF (10 mL), and the reaction mixture was heated to 100 °C for 16 h, then filtered through Celite and washed with EtOAc (2 × 50 mL). The filtrate was washed with water (2 × 70 mL). The organic layer was separated, dried (Na2SO4), and the solvent removed under vacuum. The residue was purified by gradient flash chromatography eluting with 0–20% EtOAc in petroleum ether to afford 5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridazin-3(2H)-one as a pale yellow liquid (95 mg, 21%). LCMS (Method 3): m / z 273.1 (ES+), 1.77 min.

[0251]

number

[0252] Step 3. Hydrazine hydrate (0.2 ml, 0.68 mmol) was added to a stirred solution of 3-chloro-5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridazine (100 mg) in ethanol (20 mL) and the reaction mixture was heated at 80° C. for 16 h. The solvent was removed in vacuo and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine (20 mL), dried (Na2SO4) and the solvent removed in vacuo to yield 5-(3-fluoro-5-(trifluoromethyl)benzyl)-3-hydrazinylpyridazine as a pale yellow liquid (90 mg, crude). The crude product was used in the next step without further purification. Data in Table 2.

[0253] Typical Procedure 9: Exemplary for the preparation of intermediate 42, tert-butyl 2-(3-(3-fluoro-5-(trifluoromethyl)benzyl)phenyl)hydrazine-1-carboxylate

[0254] [ka] Step 1. (3-Chlorophenyl)boronic acid (188 mg, 1.2 mmol), 3-fluoro-5-(trifluoromethyl)benzyl bromide (0.16 mL, 1.00 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and sodium carbonate (223 mg, 2.1 mmol) were dissolved in DME / water (2 mL:1 mL) and the reaction mixture was degassed with N2 for 5 min. The reaction mixture was then heated at 100 °C by microwave for 3 h. The reaction mixture was diluted with water (3 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were dried (phase separator) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0–100% Et2O in i-hexane to give 1-[(3-chlorophenyl)methyl]-3-fluoro-5-(trifluoromethyl)benzene as a clear oil (303 mg, quantitative). LCMS (Method 1): no m / z ionization observed (ES+), 6.15 min.

[0255]

number

[0256] Preparation of 1-substituted 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one intermediates and 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one intermediates Exemplary Procedure 10: Illustrated by the preparation of intermediate 10, 1-(6-chloropyridazin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0257] [ka] Step 1. Et3N (2 mL) was added to a suspension of 5-chloropyridazin-3(2H)-one (5 g, 38.3 mmol) in POCl3 (50 mL) at 0 °C and the reaction mixture was heated at 100 °C for 12 h. The solvent was removed under vacuum and the residue was purified by gradient flash chromatography eluting with 0-20% EtOAc in petroleum ether to afford 3,5-dichloropyridazine as an off-white solid (2 g, 35%). LCMS (method 3): m / z 149.0 (ES+), 1.24 min.

[0258]

number

[0259] Step 3. AcOH (0.1 mL) was added to a stirred solution of 3-chloro-5-hydrazinylpyridazine (200 mg, 1.39 mmol) and (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 278 mg, 1.66 mmol) in EtOH (20 mL) and the reaction mixture was heated at 80° C. for 12 h. The solvent was removed under vacuum and the residue was purified by preparative HPLC (Method 1) to yield 1-(6-chloropyridazin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (60 mg, 17%). Data in Table 2.

[0260] Intermediate 11 1-(5-bromopyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0261] [ka] The title compound (200 mg, 98%) was prepared in two steps using the method of Intermediate 10, steps 2 and 3: heating 3-bromo-5-fluoropyridine (700 mg, 4.0 mmol) and hydrazine hydrate (1.92 g, 60 mmol) in EtOH (10 mL) at 90 °C for 12 h, and (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 402 mg, 2.39 mmol) and acetic acid (0.01 mL) in EtOH (20 mL) at 80 °C for 15 h. After completion of step 2, the title compound was isolated as a yellow solid by filtering the precipitated solid, washing it with EtOH (2 x 10 mL), and drying under vacuum. Data in Table 2.

[0262] Intermediate 40 1-(5-fluoropyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0263] [ka] The title compound (370 mg, 37%) was prepared in two steps using the method of Intermediate 10, steps 2 and 3: heating 3,5-difluoropyridine (500 mg, 4.34 mmol) and hydrazine hydrate (3.29 g, 65.17 mmol) in IPA (50 mL) at 100 °C for 12 h, and (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 1.37 g, 8.18 mmol) and acetic acid (0.05 mL) in EtOH (50 mL) at 80 °C for 16 h. After completion of step 2, the title compound was isolated as a yellow solid by removing the solvent under vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (150 mL). The organic layer was separated, washed with brine solution (2 x 100 mL), dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by gradient flash chromatography eluting with 0-10% MeOH in DCM. Data in Table 2.

[0264] Intermediate 12 1-(4-bromopyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0265] [ka] The title compound (410 mg, 78%) was prepared using the method of Intermediate 10, Step 3 by heating 4-bromo-2-hydrazinylpyridine (300 mg, 1.78 mmol) and (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 332 mg, 1.78 mmol) in EtOH (5 mL) and AcOH (0.01 mL) at 100 °C for 10 h. The title compound was isolated as a yellow solid by trituration with EtO. Data in Table 2.

[0266] Exemplary Procedure 11: exemplified by the preparation of intermediate 13, 1-(2-bromopyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0267] [ka] Step 1. NaNO2 (4.7 g, 69.4 mmol) in water (30 mL) was added to a stirred solution of 2-bromopyridin-4-amine (10 g, 57.8 mmol) in 20% aqueous H2SO4 (300 mL) at 0 °C and stirred for 1 h, followed by addition of SnCl2 (21.8 g, 116 mmol) in 20% aqueous H2SO4 (100 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was basified to pH ∼8 with ammonium hydroxide solution (200 mL) and the reaction mixture was filtered through Celite. The filtrate was partitioned between water (200 mL) and 10% MeOH in DCM (400 mL). The organic layer was separated, washed with brine (50 mL), dried (Na2SO4) and the solvent was removed under vacuum to yield 2-bromo-4-hydrazinylpyridine as a brown solid (7.0 g, 64%). LCMS (method 3): m / z 188.0 (ES+), 0.37 min.

[0268]

number

[0269] Intermediate 37 1-(5-bromopyridin-3-yl)-5-(2,4-dimethoxybenzyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0270] [ka] The title compound (400 mg, 38%) was prepared in two steps using the method of Intermediate 13 by stirring 5-bromopyridin-3-amine (1 g, 5.78 mmol) in 6N HCl (10 mL) and NaNO2 (590 mg, 8.67 mmol) in water (20 mL) at 0 °C for 15 min, followed by addition of SnCl2 (2.1 g, 11.56 mmol) in 6N HCl (20 mL) and stirring at room temperature for 3 h, and heating 3-acetyl-1-(2,4-dimethoxybenzyl)-4-hydroxy-5,6-dihydropyridin-2(1H)-one (Intermediate 35, 700 mg, 2.29 mmol) and acetic acid (14 mg, 0.229 mmol) in EtOH (20 mL) at 90 °C for 15 h. After completion of Step 2, the title compound was isolated as a yellow solid by removing the solvent under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in petroleum ether. Data in Table 2.

[0271] Exemplary Procedure 12 exemplified by the preparation of intermediate 14, tert-butyl 1-(2-bromopyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0272] [ka] NaH (368 mg, 15.3 mmol) and Boc anhydride (3.34 g, 15.3 mmol) were added to a stirred solution of 1-(2-bromopyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Intermediate 13, 3 g, 10.2 mmol) in DMF (20 mL) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was partitioned between ice-cold water (500 mL) and EtOAc (250 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-80% EtOAc in hexanes to afford tert-butyl 1-(2-bromopyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as a white solid (2.6 g, 64%). Data in Table 2.

[0273] Exemplary Procedure 13: exemplified by the preparation of intermediate 21, tert-butyl 1-(2-bromopyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate

[0274] [ka] Step 1. Molecular sieves (3 g) were added to a stirred solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (3 g, 14.1 mmol) in toluene (50 mL) followed by 2,2-dimethoxyethan-1-amine (1.53 mL, 14.1 mmol). The reaction mixture was heated at 70° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. The residue was dissolved in DCM (30 mL) and cooled to 0° C. TFA (30 mL) was added and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-4% MeOH in DCM to afford 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one as an off-white solid. LCMS (Method 7): m / z 137.2 (ES+), 0.53 min.

[0275] Step 2. NEt3 (11.2 mL, 79.3 mmol) and DMAP (0.242 g, 1.98 mmol) were added to a stirred solution of 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.4 g, 13.23 mmol) in MeCN (50 mL), followed by the addition of Boc anhydride (15.9 mL, 69.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by flash column chromatography eluting with 0-25% EtOAc in petroleum ether to afford di-tert-butyl 4-oxo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-1,5(4H)-dicarboxylate as a yellow solid (2.91 g, 65%). LCMS (Method 7): m / z 281.2 (ES+), 2.56 min.

[0276]

number

[0277]

number

[0278] Exemplary Procedure 14: exemplified by the preparation of intermediate 23, tert-butyl 1-(6-chloropyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0279] [ka] Step 1. Hydrazine hydrate (3 g, 60.39 mmol) was added to a stirred solution of 4,6-dichloropyrimidine (3 g, 20.1 mmol) in IPA (50 mL) and the reaction mixture was heated at 80° C. for 16 h. The solvent was removed under vacuum and the residue was azeotroped with toluene to afford 4-chloro-6-hydrazineylpyrimidine as a pale yellow solid (2.5 g, 86%). LCMS (Method 10): m / z 145.1 (ES+), 0.86 min.

[0280]

number

[0281]

number

[0282] Exemplary Procedure 15: exemplified by the preparation of intermediate 36, 1-(2-bromopyridin-4-yl)-5-(2,4-dimethoxybenzyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0283] [ka] Step 1. Hydrazine hydrate (26 g, 521 mmol) was added to a stirred solution of 2-bromo-4-chloropyridine (20 g, 104 mmol) in IPA (100 mL) and the reaction mixture was heated at 110° C. for 16 h. The solvent was removed under vacuum and the residue was dissolved in EtOAc (500 mL) and washed with water (500 mL). The organic layer was separated, washed with brine solution (500 mL), dried (Na2SO4) and the solvent was removed under vacuum to yield 2-bromo-4-hydrazinylpyridine as a white solid (15 g, 77%). LCMS (Method 10): m / z 188.2 (ES+), 1.06 min.

[0284]

number

[0285] Intermediate 38 1-(4-bromopyridin-2-yl)-5-(2,4-dimethoxybenzyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0286] [ka] The title compound (700 mg, 25%) was prepared in two steps using the method of Intermediate 36 by heating 4-bromo-2-fluoropyridine (2 g, 11.4 mmol) and hydrazine hydrate (5.6 g, 114 mmol) in IPA (20 mL) at 85° C. for 12 h and stirring 4 Å molecular sieves (1 g) and 3-acetyl-1-(2,4-dimethoxybenzyl)-4-hydroxy-5,6-dihydropyridin-2(1H)-one (Intermediate 35, 1.6 g, 5.31 mmol) in EtOH (20 mL) at room temperature for 12 h followed by addition of acetic acid (0.1 mL) and heating at 90° C. for 12 h. After completion of Step 2, the title compound was isolated as a yellow solid by filtering, rinsing with EtOAc (2×50 mL) and removing the solvent under vacuum. The residue was dissolved in EtOAc (50 mL) and washed with 10% NaHCO3 solution (50 mL). The organic layer was separated, washed with brine solution (20 mL), dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-70% EtOAc in petroleum ether. Data in Table 2.

[0287] Exemplary Procedure 16: exemplified by the preparation of intermediate 41, tert-butyl 1-(2-bromo-5-methylpyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0288] [ka] Step 1. Hydrazine hydrate (0.16 mL, 3.16 mmol) was added to a stirred solution of 2-bromo-4-fluoro-5-methylpyridine (200 mg, 1.05 mmol) in IPA (10 mL) at room temperature and the reaction mixture was heated at 100 °C for 16 h. The solvent was removed under vacuum. The residue was triturated with 10% NaHCO3 solution (5 mL) and the solid was filtered, washed with water (10 mL) and dried under vacuum to afford 2-bromo-4-hydrazinyl-5-methylpyridine as an off-white solid (130 mg, 61%). LCMS (method 2): m / z 201.7 (ES+), 1.07 min.

[0289]

number

[0290]

number

[0291] Exemplary Procedure 17: exemplified by the preparation of intermediate 45, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-iodo-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0292] [ka] Step 1. Hydrazine hydrate (297 mg, 5.95 mmol) was added to a stirred solution of (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 500 mg, 2.97 mmol) in 2-methoxyethanol (10 mL) and the reaction mixture was heated at 130 °C for 12 h. The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-15% MeOH in DCM to afford (1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one) as a brown solid (300 mg, 73%). LCMS (Method 6): m / z 138.2 (ES+), 0.63 min.

[0293]

number

[0294] Step 2. NIS (980 mg, 4.37 mmol) was added to a stirred solution of 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (300 mg, 2.18 mmol) in DMF (10 mL) at room temperature and the reaction mixture was heated at 80 °C for 12 h. The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-15% MeOH in DCM to afford 3-iodo-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as an off-white solid (290 mg, 51%). LCMS (method 3): m / z 263.9 (ES+), 0.61 min.

[0295]

number

[0296] Preparation of Substituted Triazole and Pyrazole Intermediates Exemplary Procedure 18: exemplified by the preparation of intermediate 15, 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one

[0297] [ka] Step 1. Iodine (0.26 g, 1 mmol) was added to a stirred mixture of cyclohexanone (2 g, 20 mmol) and 1,2-diphenyldisulfane (1.7 g, 80 mmol) in DMSO (12 mL) and the reaction mixture was heated at 80° C. for 12 h. The reaction was quenched by addition of water (100 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried (Na2SO4) and the solvent removed under vacuum to yield 2-(phenylthio)cyclohex-2-en-1-one as a yellow liquid (4.5 g, crude). The crude product was used in the next step without further purification. MS (method 1): m / z 205 (ES+).

[0298] Step 2. Sodium periodate (9.39 g, 40 mmol) was added to a stirred solution of 2-(phenylthio)cyclohex-2-en-1-one (4.5 g, 22 mmol) in MeOH (1.2 mL) and HO (12 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by addition of water (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried (NaSO) and the solvent removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 30-35% EtOAc in hexanes to afford 2-(phenylsulfinyl)cyclohex-2-en-1-one as an orange gum (2.1 g, 43%). MS (method 1): m / z 221 (ES+).

[0299] Step 3. Sodium azide (324 mg, 4 mmol) was added to a stirred solution of 2-(phenylsulfinyl)cyclohex-2-en-1-one (1 g, 4 mmol) in HO (17 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was acidified to pH 2 using 1N HCl (19 mL) and water (100 mL) was added. The aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried (NaSO) and the solvent removed under vacuum to yield 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one as an off-white solid (220 mg, 35%). Data in Table 2.

[0300] Exemplary Procedure 19: exemplified by the preparation of intermediate 16, 1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one

[0301] [ka] Step 1. Iso-amyl nitrite (1.41 mL, 10.48 mmol) was added to a solution of 2-chloropyridine-3,4-diamine (300 mg, 2.09 mmol) in EtOH (5 mL). The reaction mixture was heated at 85° C. for 16 h. The solvent was removed under vacuum to give 1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one as a brown solid (310 mg, crude). The crude product was used in the next step without further purification. MS (method 1): m / z 134.9 (ES-)

[0302]

number

[0303] Step 2. 10% Pd / C (50% w / w, 400 mg) was slowly added to a mixture of 1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one (300 mg, 2.20 mmol) in MeOH (35 mL) and the reaction mixture was heated at 135° C. under H2 atmosphere (150 psi) for 16 h. The reaction mixture was filtered through Celite and washed with MeOH (25 mL). The solvent was removed under vacuum to yield 1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one as an off-white solid (200 mg, crude). Data in Table 2.

[0304] Typical Procedure 20 exemplified by the preparation of intermediate 43, ethyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-1H-pyrazole-4-carboxylate

[0305] [ka] Step 1. Hydrazine hydrate (2.5 g, 48 mmol) was added to a suspension of diethyl 2-(ethoxymethylene)malonate (8.5 g, 40 mmol) in 25% aqueous ammonium hydroxide (11 mL, 320 mmol) at room temperature and the reaction mixture was heated at 60° C. for 4 h. The reaction mixture was diluted with water (200 mL), adjusted to pH ∼7 with 1.5 N HCl (30 mL) and extracted with EtOAc (500 mL). The organic layer was separated, washed with brine solution (100 mL), dried (Na2SO4) and the solvent removed under vacuum to yield ethyl 5-hydroxy-1H-pyrazole-4-carboxylate as an off-white solid (3 g, 48%). LCMS (Method 7): m / z 157.2 (ES+), 0.43 min.

[0306]

number

[0307]

number

[0308]

number

[0309] Preparation of substituted benzyl halide intermediates Typical Procedure 21 exemplified by the preparation of intermediate 22, 1-(chloromethyl)-3-cyclopropyl-5-fluorobenzene

[0310] [ka] Step 1. K2CO3 (1.0 g, 12.87 mmol) was added to a stirred solution of methyl 3-bromo-5-fluorobenzoate (1.0 g, 4.29 mmol) and cyclopropylboronic acid (401 mg, 4.72 mmol) in 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was degassed with N2 for 20 min, then Pd(dppf)2Cl2.DCM complex (350 mg, 0.429 mmol) was added. The reaction mixture was heated at 100 °C for 12 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (80 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by flash column chromatography eluting with 0-50% EtOAc in hexanes to afford methyl 3-cyclopropyl-5-fluorobenzoate as a yellow liquid (750 mg, 90%). GCMS (method 2): m / z 194.0 (ES+), 3.43 minutes.

[0311]

number

[0312]

number

[0313] Intermediate 31 1-Chloro-5-(chloromethyl)-2-fluoro-3-(trifluoromethyl)benzene

[0314] [ka] The title compound (70 mg, crude) was prepared in two steps using the method of Intermediate 22, steps 2 and 3: 3-chloro-4-fluoro-5-(trifluoromethyl)benzoic acid (0.5 g, 2.06 mmol) and LiAlH4 (2M in THF, 1.5 mL, 3.1 mmol) in THF (10 mL) stirred at room temperature for 1 h, and thionyl chloride (0.03 mL, 0.43 mmol) in chloroform (5 mL) stirred at room temperature for 1 h. After completion of step 2, the title compound was isolated as an off-white solid by quenching with 10% NaHCO3 solution (50 mL) followed by extraction with DCM (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed under vacuum. Data in Table 2.

[0315] Typical Procedure 22 exemplified by the preparation of intermediate 24, 4-(chloromethyl)-1-(difluoromethoxy)-2-fluorobenzene

[0316] [ka] Step 1. K2CO3 (2.95 g, 21.42 mmol) was added to a stirred solution of 3-fluoro-4-hydroxybenzaldehyde (1 g, 7.14 mmol) in MeCN:H2O (15 ml:2 mL) at room temperature followed by sodium 2-chloro-2,2-difluoroacetate (1.2 g, 8.57 mmol) and the reaction mixture was heated at 60 °C for 12 h. The solvent was removed under vacuum and the residue was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine solution (20 mL), dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in petroleum ether to afford 4-(difluoromethoxy)-3-fluorobenzaldehyde as a colorless liquid (400 mg, 30%). GCMS (method 2): m / z 190.0 (ES+), 2.19 minutes.

[0317]

number

[0318]

number

[0319] Typical Procedure 23 Illustrated by the preparation of intermediate 25, 5-(bromomethyl)-1,2-difluoro-3-(trifluoromethyl)benzene

[0320] [ka] Step 1. LiAlH4 (2 M in THF, 1.6 mL, 3.32 mmol) was slowly added dropwise to a suspension of 3,4-difluoro-5-(trifluoromethyl)benzoic acid (250 mg, 1.11 mmol) in THF (20 mL) at -40 °C and the reaction mixture was stirred at -40 °C for 3 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL) and the aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layer was separated, washed with brine solution (100 mL), dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-60% EtOAc in petroleum ether to afford (3,4-difluoro-5-(trifluoromethyl)phenyl)methanol as a colorless liquid (130 mg, 56%). GCMS (method 1): m / z 212.0 (ES+), 2.19 minutes.

[0321]

number

[0322] Typical Procedure 24 exemplified by the preparation of intermediate 26, 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene

[0323] [ka] Step 1. LiAlH4 (1.0 M in THF, 7.0 mL, 7.0 mmol) was added to a stirred solution of dimethyl 5-fluoroisophthalate (3 g, 14.1 mmol) in THF (10 mL) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH ∼7 and the reaction mixture was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed under vacuum to yield methyl 3-fluoro-5-(hydroxymethyl)benzoate as a colorless liquid (1.12 g, 43%). GCMS (method 1): m / z 184.0 (ES+), 7.34 minutes.

[0324]

number

[0325]

number

[0326]

number

[0327]

number

[0328] Typical Procedure 25 exemplified by the preparation of intermediate 27, 1-chloro-5-(chloromethyl)-2,3-difluorobenzene

[0329] [ka] Step 1. Borane dimethylsulfide complex (0.58 mL, 6.25 mmol) was added to a solution of 3-chloro-4,5-difluorobenzoic acid (400 mg, 2.08 mmol) in THF (6 mL) at 50 °C and the reaction mixture was heated at 70 °C for 2 h. The reaction mixture was cooled to 0 °C, quenched with methanol, and stirred at room temperature for 12 h. The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in hexanes to afford (3-chloro-4,5-difluorophenyl)methanol as a pink liquid (237 mg, 63%).

[0330] Step 2. Thionyl chloride (1.8 mL, 25.2 mmol) was added to a solution of (3-chloro-4,5-difluorophenyl)methanol (100 mg, 0.56 mmol) in chloroform (5 mL) and the reaction mixture was heated at 65 °C for 12 h. The reaction mixture was neutralized with 10% NaHCO3 solution (20 mL) to pH 7 and then partitioned between water (50 mL) and DCM (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed under vacuum to yield 1-chloro-5-(chloromethyl)-2,3-difluorobenzene as a colorless liquid (90 mg, crude). The crude product was used in the next step without further purification. Data in Table 2.

[0331] Intermediate 28 5-(chloromethyl)-1,3-difluoro-2-(trifluoromethyl)benzene

[0332] [ka] The title compound (128 mg, 25%) was prepared in two steps using the method of Intermediate 27 by stirring 3,5-difluoro-4-(trifluoromethyl)benzoic acid (500 mg, 2.21 mmol) and borane dimethylsulfide complex (1M in THF, 11.1 mL, 11.1 mmol) in THF (50 mL) at room temperature for 12 h and heating thionyl chloride (130 μL, 1.76 mmol) in chloroform (10 mL) at 70 °C for 12 h. After completion of step 2, the title compound was isolated as a brown oil by neutralizing with 10% NaHCO3 solution (20 mL) to pH 7 and then partitioning between water (50 mL) and DCM (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed under vacuum. Data in Table 2.

[0333] Intermediate 34 5-(Chloromethyl)-2-(difluoromethoxy)pyridine

[0334] [ka] The title compound (140 mg, 54%) was prepared in two steps using the method of intermediate 27: 6-(difluoromethoxy)nicotinic acid (250 mg, 1.32 mmol) and borane dimethylsulfide complex (2M in THF, 3.3 mL, 6.6 mmol) in THF (2 mL) heated at 85 °C for 16 h and thionyl chloride (0.2 mL, 2.4 mmol) in chloroform (2 mL) stirred at room temperature for 3 h. After completion of step 2, the title compound was isolated as a colorless liquid by quenching with ice water (50 mL) and extracting with DCM (2 x 50 mL). The combined organic layers were washed with brine solution (100 mL), dried (Na2SO4) and the solvent removed under vacuum. Data in Table 2.

[0335] Typical Procedure 26 exemplified by the preparation of intermediate 29, 1-(chloromethyl)-3-fluoro-5-isopropylbenzene

[0336] [ka] Step 1. In a sealed tube, Cs2CO3 (1.39 g, 4.29 mmol), Pd(dppf)Cl2.DCM (175 mg, 0.214 mmol), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxabromane (541 mg, 3.21 mmol) were added to a degassed suspension of methyl 3-bromo-5-fluorobenzoate (500 mg, 2.145 mmol) in 1,4-dioxane:H2O (10 mL:1 mL) and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine solution (50 mL), dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-20% EtOAc in petroleum ether to afford methyl 3-fluoro-5-(prop-1-en-2-yl)benzoate as a colorless liquid (380 mg, 91%). GCMS (method 1): m / z 194.0 (ES+), 6.89 minutes.

[0337]

number

[0338]

number

[0339]

number

[0340] Typical Procedure 27 exemplified by the preparation of intermediate 30, 1-(chloromethyl)-3-fluoro-5-(1-(trifluoromethyl)cyclopropyl)benzene

[0341] [ka] Step 1. K2CO3 (2.36 g, 17.14 mmol) was added to a solution of 2-bromo-3,3,3-trifluoroprop-1-ene (1.5 g, 8.57 mmol) and (3-fluoro-5-(methoxycarbonyl)phenyl)boronic acid (1.86 g, 9.43 mmol) in 1,4-dioxane:water (18 mL:2 mL). The reaction mixture was degassed with N2 for 10 min followed by the addition of Pd(dppf)2Cl2.DCM complex (351 mg, 0.43 mmol). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through a pad of Celite, washed with DCM (100 mL) and the filtrate was concentrated under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-15% EtOAc in petroleum ether to afford methyl 3-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzoate as a colorless liquid (1.2 g, 57%). GCMS (method 2): m / z 248.0 (ES+), 2.67 minutes.

[0342]

number

[0343] Step 3. NaBH4 (0.121 g, 3.2 mmol) was added in small portions followed by a solution of CaCl2 (0.711 g, 6.41 mmol) in EtOH (5 mL) dropwise to a solution of methyl 3-fluoro-5-(1-(trifluoromethyl)cyclopropyl)benzoate (0.28 g, 1.06 mmol) in EtOH (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with ice water (50 mL) and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum to yield (3-fluoro-5-(1-(trifluoromethyl)cyclopropyl)phenyl)methanol as a colorless liquid (130 mg, 52%). LCMS (Method 3): no m / z ionization observed (ES+), 2.13 min.

[0344]

number

[0345] Intermediate 32 5-(chloromethyl)-3-fluoro-2-methoxypyridine

[0346] [ka] The title compound (294 mg, 62%) was prepared in two steps using the method of intermediate 30, steps 3 and 4: methyl 5-fluoro-6-methoxynicotinate (0.5 g, 2.6 mmol) in EtOH (5 mL), and NaBH4 (0.15 g, 4.04 mmol) in EtOH (5 mL), and CaCl2 (0.44 g, 4.04 mmol) in EtOH (5 mL) stirred at room temperature for 1 h, and thionyl chloride (1.13 g, 9.54 mmol) in chloroform (10 mL) stirred at room temperature for 1 h. After completion of step 2, the title compound was isolated as a colorless gum by quenching the reaction mixture with 10% NaHCO3 solution (50 mL) and extracting with DCM (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent removed under vacuum. The residue was purified by gradient flash column chromatography eluting with a gradient of 0-10% EtOAc in petroleum ether. Data in Table 2.

[0347] Intermediate 33 5-(Chloromethyl)-2-methoxypyridine

[0348] [ka] The title compound (180 mg, 75%) was prepared in two steps using the method of intermediate 30, steps 3 and 4: methyl 6-methoxynicotinate (0.5 g, 2.99 mmol), NaBH4 (0.37 g, 8.97 mmol), and CaCl2 (0.49 g, 4.48 mmol) in EtOH (30 mL) stirred at room temperature for 16 h, and thionyl chloride (0.52 mL, 7.18 mmol) in chloroform (20 mL) stirred at room temperature for 2 h. After completion of step 2, the title compound was isolated as a colorless liquid by quenching the reaction mixture with 10% NaHCO3 solution (50 mL) and extracting with DCM (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried (Na2SO4), and the solvent was removed under vacuum. Data in Table 2.

[0349] Synthesis Example Typical Preparation Procedures The following preparation examples are illustrated by steps 1 to 27: Step 1: Example 1 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0350] [ka] A catalytic amount of acetic acid (1 mL) was added to a solution of 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine (Intermediate 6, 5 g, 17.5 mmol) in EtOH (250 mL) at room temperature, followed by (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 3.5 g, 21.1 mmol) and the reaction mixture was heated at 80° C. for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (100 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by gradient flash chromatography eluting with 0-10% MeOH in DCM to afford 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as an off-white solid (2.0 g, 30%). Data in Table 3.

[0351] Step 2: Example 3 5-Methyl-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0352] [ka] NaH (60% in mineral oil, 21 mg, 0.53 mmol) was added to a solution of 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 2, 100 mg, 0.26 mmol) in THF (4 mL) at 0° C. After stirring for 30 min, MeI (0.03 mL, 0.53 mmol) in THF (1 mL) was added slowly and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (15 mL) and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 27-29% EtOAc in hexanes to afford 5-methyl-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a colorless gel (43 mg, 43%). Data in Table 3.

[0353] Step 3: Example 6 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0354] [ka] Step 1. Bis(pinacolato)diboron (260 mg, 1.02 mmol) was added to a solution of 1-(4-bromopyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Intermediate 12, 200 mg, 0.68 mmol) in 1,4-dioxane (8 mL), the reaction mixture was degassed under argon for 25 min, then KOAc (201 mg, 2.05 mmol) and PdCl2(dppf).DCM (28 mg, 0.03 mmol) were added. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through Celite and washed with 5% MeOH in DCM (100 mL). The solvent was removed under vacuum and the residue was triturated with MTBE (20 mL) to give (2-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-4-yl)boronic acid as a brown solid (415 mg, crude). The crude product was used in the next step without further purification. MS (method 1): m / z 259.0 (ES+).

[0355] Step 2. 5-(Bromomethyl)-2-fluoro-3-methylpyridine (200 mg, 0.98 mmol) and K2CO3 (407 mg, 2.95 mmol) were added to a solution of (2-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-4-yl)boronic acid (432 mg, 1.67 mmol) in 1,4-dioxane:H2O (4:1). After degassing with argon for 25 min, PdCl2(dppf).DCM (40 mg, 0.04 mmol) was added and the reaction mixture was heated at 90 °C for 1 h. The reaction mixture was quenched by the addition of water (100 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. The residue was triturated with EtO, filtered and washed with 2% MeOH in DCM to give 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as an off-white solid (180 mg, 54%). Data in Table 3.

[0356] Step 4: Example 8 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0357] [ka] 2-Hydrazineyl-4-(3-(trifluoromethyl)benzyl)pyridine (Intermediate 7, 54 mg, 0.2 mmol) in THF (1 mL) was added to a suspension of piperidine-2,4-dione (22 mg, 0.2 mmol) in THF (1 mL) and the reaction mixture was stirred at room temperature for 2 h. DMF-DMA (0.08 mL, 0.6 mmol) was added and the reaction mixture was heated at 70 °C for 16 h. The solvent was removed under vacuum and the residue was purified by gradient flash chromatography eluting with 0-10% MeOH in DCM. The residue was further purified by preparative HPLC (Method 2 - 4-70% gradient) to afford 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (13 mg, 18%). Data in Table 3.

[0358] Step 5: Example 10 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one

[0359] [ka] Step 1. 2-((Dimethylamino)methylene)cyclohexane-1,3-dione (Intermediate 2, 3.37 g, 20.2 mmol) and acetic acid (2.7 mL) were added to a suspension of 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine (Intermediate 8, 5.82 g, 20.4 mmol) in EtOH (70 mL) and the reaction mixture was heated at 80 °C for 3 h. The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 12 to 100% EtOAc in i-hexane and the solvent was removed under vacuum to afford 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-indazol-4-one as a dark orange solid (5.55 g, 71% yield). LCMS (Method 4): m / z 390.4 (ES+), 1.63 min.

[0360]

number

[0361]

number

[0362]

number

[0363] Step 6: Example 13 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one

[0364] [ka] Step 1. K2CO3 (5.16 g, 37.45 mmol) was added to a solution of 2-hydrazinyl-4-(3-(trifluoromethyl)benzyl)pyridine (Intermediate 7, 4 g, 14.98 mmol) and diethyl 2-(ethoxymethylene)malonate (8.08 g, 37.45 mmol) in EtOH:H2O (85 mL:15 mL) and the reaction mixture was heated at 60 °C for 16 h. The reaction mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by gradient flash chromatography eluting with 0 to 5% MeOH in DCM to afford ethyl 5-hydroxy-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate as a yellow solid (1.5 g, 25%). LCMS (method 3): m / z 392.0 (ES+), 2.55 minutes.

[0365]

number

[0366] Step 2. K2CO3 (0.79 g, 5.75 mmol) was added to a solution of ethyl 5-hydroxy-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (1.5 g, 3.83 mmol) and tert-butyl (2-bromoethyl)carbamate (1.02 g, 4.59 mmol) in MeCN (30 mL) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo to yield ethyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate as a colorless liquid (500 mg, crude). LCMS (Method 3): m / z 535.0 (ES+), 3.03 min.

[0367] Step 3. HCl solution (4M in 1,4-dioxane, 0.4 mL) was added to a solution of ethyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (200 mg, 0.374 mmol) in 1,4-dioxane (2 mL) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum to yield ethyl 5-(2-aminoethoxy)-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate hydrochloride as a white solid (250 mg, crude). LCMS (Method 3): m / z 435.3 (ES+), 1.85 min.

[0368] Step 4. Cs2CO3 (169 mg, 0.518 mmol) was added to a solution of ethyl 5-(2-aminoethoxy)-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate hydrochloride (150 mg) in MeCN (1.5 mL) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by preparative HPLC (Method 1) to yield 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one as an off-white solid (39 mg, 29%). Data in Table 3.

[0369] Step 7: Example 16 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0370] [ka] A pinch of iodine was added to a solution of activated zinc (665 mg, 10.2 mmol) in DMF (10 mL) and heated to 50 °C for 5 min, followed by the addition of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (526 mg, 2.04 mmol) in DMF (5 mL). The reaction mixture was heated at 50 °C for 1 h and then cooled to room temperature. The supernatant DMF layer was transferred to a degassed suspension of 1-(5-bromopyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Intermediate 11, 200 mg, 0.68 mmol) and RuPhos (63 mg, 0.13 mmol) in DMF (10 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (63 mg, 0.06 mmol). The reaction mixture was heated to 70° C. for 16 h, then filtered through Celite and washed with EtOAc (2×50 mL). The filtrate was washed with water (2×50 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed under vacuum. The residue was purified by gradient flash chromatography eluting with 0-100% EtOAc in petroleum ether to afford 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as an off-white solid (170 mg, 64%). Data in Table 3.

[0371] Step 8: Example 18 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0372] [ka] Cs2CO3 (1.08 g, 3.33 mmol) was added to a solution of 3-fluoro-5-(trifluoromethyl)phenol (200 mg, 1.11 mmol) in NMP (5 mL) and the reaction mixture was stirred at room temperature for 10 min, followed by the addition of 1-(4-bromopyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Intermediate 12, 259 mg, 0.88 mmol). The reaction mixture was heated at 120° C. for 16 h. The reaction mixture was poured into water (30 mL) and the formed precipitate was filtered, washed with water (3×20 mL) and dried under vacuum. The residue was purified by preparative HPLC (Method 3 - 100% isocratic gradient) to give 1-(4-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (12 mg, 12%). Data in Table 3.

[0373] Step 9: Example 19 1-(2-(4-chlorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0374] [ka] Step 1. Hexamethylditin (1.24 g, 3.81 mmol) was added to a solution of tert-butyl 1-(2-bromopyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 14, 1 g, 2.54 mmol) in 1,4-dioxane (20 mL), followed by Pd(PPh3)4 (293 mg, 0.25 mmol) and the reaction mixture was heated at 100° C. for 2 h. The solvent was removed under vacuum to yield tert-butyl 4-oxo-1-(2-(trimethylstannyl)pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as a yellow gum (1.5 g, crude). LCMS (Method 3): m / z 479.1 (ES+), 1.47 min.

[0375] Step 2. 1-(Bromomethyl)-4-chlorobenzene (36 mg, 0.18 mmol) was added to a solution of tert-butyl 4-oxo-1-(2-(trimethylstannyl)pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (60 mg) in 1,4-dioxane (10 mL) followed by the addition of Pd(PPh3)4 (14 mg, 0.01 mmol) under argon and then the reaction mixture was heated at 100 °C for 12 h. The solvent was removed under vacuum and the residue was purified by gradient flash chromatography eluting with 0 to 50% EtOAc in petroleum ether to afford tert-butyl 1-(2-(4-chlorobenzyl)pyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as a colorless liquid (40 mg, 72%). LCMS (Method 3): m / z 439.2 (ES+), 2.40 min.

[0376] Step 3. HCl solution (4M in 1,4-dioxane, 5 mL) was added to a solution of tert-butyl 1-(2-(4-chlorobenzyl)pyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (40 mg, 0.09 mmol) in 1,4-dioxane (5 mL) at room temperature and the reaction mixture was stirred at room temperature for 2 h. 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 10% NaHCO3 solution (5 mL) and EtOAc (10 mL). The organic layer was separated, washed with saturated brine solution (5 mL), dried (Na2SO4) and the solvent removed in vacuo to give 1-(2-(4-chlorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (6 mg, 20%). Data in Table 3.

[0377] Step 10: Example 33 3-((4-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)-5-(trifluoromethyl)benzonitrile

[0378] [ka] Steps 1 and 2. tert-Butyl 1-(2-(3-bromo-5-(trifluoromethyl)benzyl)pyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (150 mg, 54%) was prepared from tert-butyl 1-(2-bromopyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 14, 200 mg, 0.50 mmol) and 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (322 mg, 1.01 mmol) using the method of Procedure 9, steps 1 and 2. LCMS (Method 2): m / z 450.9 (ES+), 2.63 min.

[0379]

number

[0380]

number

[0381] Step 11: Example 35 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one Example 36 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one Example 37 1-(2-(fluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0382] [ka] Step 1. Selenium dioxide (113 mg, 1.02 mmol) was added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 1, 600 mg, 1.53 mmol) in 1,4-dioxane (15 mL) and the reaction mixture was heated at 100° C. for 3 h. The solvent was removed under vacuum and the residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in petroleum ether to yield 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as an off-white solid (Example 35, 400 mg, 64%). Data in Table 3.

[0383] Step 2. Sodium borohydride (28 mg, 0.742 mmol) was added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (200 mg, 0.495 mmol) in EtOH:THF (1 mL:10 mL) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in petroleum ether to afford 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (Example 36, 135 mg, 68%). Data in Table 3.

[0384] Step 3. DAST (22 mg, 0.13 mmol) was added to a solution of 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (50 mg, 0.12 mmol) in DCM (10 mL) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between NaHCO3 solution (10 mL) and DCM (10 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in petroleum ether to afford 1-(2-(fluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (Example 37, 13 mg, 26%). Data in Table 3.

[0385] Step 12: Example 38 1-(2-(difluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0386] [ka] Step 1. NEt3 (0.2 ml, 1.48 mmol), DMAP (12 mg, 0.09 mmol), and Boc anhydride (128 mg, 0.15 mmol) were added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 35, 200 mg, 0.49 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was heated at 60° C. for 16 h. The solvent was removed under vacuum and the residue was purified by gradient flash column chromatography eluting with 0-80% EtOAc in petroleum ether to afford tert-butyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as an off-white solid (100 mg, 40%). LCMS (method 2): m / z 505.0 (ES+), 2.89 min.

[0387]

number

[0388] Step 3. tert-Butyl 1-(2-(difluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (70 mg) was dissolved in HCl solution (4M in 1,4-dioxane, 5 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was partitioned between 10% NaHCO3 solution (20 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by preparative HPLC (Method 4). The solvent was removed under vacuum and the residue was partitioned between 10% NaHCO3 solution (10 mL) and EtOAc (10 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo to give 1-(2-(difluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (6 mg, 10%). Data in Table 3.

[0389] Step 13: Example 39 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)methyl-d2)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0390] [ka] Step 1. NEt3 (0.155 mg, 1.53 mmol), DMAP (12 mg, 0.102 mmol), and Boc anhydride (134 mg, 0.615 mmol) were added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 1, 200 mg, 0.512 mmol) in CHCl3 (10 mL) and the reaction mixture was heated at 80 °C for 16 h. The solvent was removed under vacuum and the residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in petroleum ether to afford tert-butyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as an off-white solid (120 mg, 47%). LCMS (Method 7): m / z 491.0 (ES+), 2.46 min.

[0391]

number

[0392] Step 14: Example 41 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one Example 45 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(2H)-one

[0393] [ka] Step 1. 2-Fluoro-4-(3-(trifluoromethyl)benzyl)pyridine (Intermediate 4, 465 mg, 1.82 mmol) was added to 1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (Intermediate 15, 250 mg, 1.82 mmol) and the reaction mixture was heated at 135° C. for 16 h. The reaction mixture was dissolved in 5% MeOH / DCM (10 mL) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 35-40% EtOAc in hexanes to afford 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one as a white solid (peak 1, 24 mg, 4%) and 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one as a white solid (peak 2, 30 mg, 4%). Peak 1: MS (method 1): m / z 373 (ES+).

[0394]

number

[0395]

number

[0396] Step 2 (Peak 1). NaN3 (104 mg, 1.61 mmol) was added slowly to a solution of 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one (Step 1, Peak 1, 200 mg, 0.53 mmol) in DCM:MeSO3H (9 mL, 2:1) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 2N aqueous NaOH and the aqueous layer was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with MTBE to give 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(2H)-one as a white solid (Example 45, 75 mg, 36%). Data in Table 3.

[0397] Step 15: Example 42 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one Example 43 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one

[0398] [ka] 2-Fluoro-4-(3-(trifluoromethyl)benzyl)pyridine (Intermediate 4, 350 mg, 1.36 mmol) was added to 1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one (Intermediate 16, 190 mg, 1.36 mmol) and the reaction mixture was heated at 150° C. for 16 h. The reaction mixture was triturated with hexane (10 mL). The residue was purified by preparative HPLC (Method 5 - 35-50% gradient) to give 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one as a white solid (Example 42, peak 2, 14 mg, 3%) and 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one as a white solid (Example 43, peak 1, 42 mg, 8%). Data in Table 3.

[0399] Step 16: Example 46 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one

[0400] [ka] Step 1. 2-Chloro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 18, 2.61 g, 9.00 mmol) was added to a solution of 3-aminocyclohex-2-en-1-one (1.00 g, 9.00 mmol) in 1,4-dioxane (10 mL). The reaction mixture was degassed with argon for 10 min and PdCl2(dppf).DCM (367 mg, 0.45 mmol), SPhos (369 mg, 0.90 mmol) and K3PO4 (5.73 g, 27.0 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated at 120 °C for 16 h and then filtered through Celite and washed with EtOAc (300 mL). The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 3-5% MeOH in DCM to afford 3-((4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)amino)cyclohex-2-en-1-one as a brown solid (1.50 g, 43%). LCMS (Method 9): m / z 365.0 (ES+), 2.33 minutes.

[0401] Step 2. A solution of 3-((4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)amino)cyclohex-2-en-1-one (1.5 g, 4.11 mmol) in MeCN (45 mL) was added dropwise to a suspension of sodium tert-butoxide (600 mg, 6.20 mmol) in MeCN (45 mL). After stirring at room temperature for 30 min, a solution of tosyl azide (1.05 g, 6.50 mmol) in MeCN (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 min and water (60 mL) was added. The aqueous layer was extracted with EtOAc (3×50 mL), the combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. The residue was triturated with EtO (30 mL) to afford 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-benzo[d][1,2,3]triazol-4-one as an off-white solid (1.0 g, 63%). LCMS (Method 9): m / z 391.0 (ES+), 2.33 minutes.

[0402]

number

[0403] Step 17: Example 47 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,7-dihydropyrazolo[4,3-d][1,2]oxazin-4(5H)-one

[0404] [ka] Step 1. A solution of ethyl (Z)-4-(tert-butoxy)-2-((dimethylamino)methylene)-3-oxobutanoate (Intermediate 19, 500 mg, 1.94 mmol) and 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine (Intermediate 8, 554 mg, 1.94 mmol) in EtOH (10 mL) and acetic acid (0.5 mL) was heated at 80 °C for 16 h. The reaction mixture was concentrated under vacuum and the residue was purified by gradient flash column chromatography eluting with 15-16% EtOAc in hexanes to afford ethyl 5-(tert-butoxymethyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate as a light yellow solid (1.30 g, 71%). LCMS (Method 9): m / z 478.4 (ES+), 2.54 min.

[0405] Step 2. TFA (10 mL) was added to a solution of ethyl 5-(tert-butoxymethyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (500 mg, 1.04 mmol) in DCM (10 mL) at 0° C. and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under vacuum to give ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H-pyrazole-4-carboxylate as a brown semi-solid (400 mg, crude). The crude product was used in the next step without further purification. LCMS (Method 9): m / z 424.0 (ES+), 2.39 min.

[0406] Step 3. Tribromophosphane (0.27 mL, 2.83 mmol) was added to a solution of ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H-pyrazole-4-carboxylate (400 mg, 0.945 mmol) in THF (15 mL) and the reaction mixture was stirred at 0° C. for 3 h. The reaction was quenched with saturated NaHCO3 solution (5 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The organic layer was washed with brine, dried (Na2SO4) and the solvent was removed under vacuum to yield ethyl 5-(bromomethyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate as a liquid (450 mg, crude). The crude product was used in the next step without further purification.

[0407] Step 4. Ethyl 5-(bromomethyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (450 mg, 0.93 mmol) was added to a solution of 2-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione (302 mg, 1.85 mmol) and K2CO3 (389 mg, 2.78 mmol) in DMF (10 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated under vacuum. The residue was purified by gradient flash column chromatography eluting with 30-35% EtOAc in hexanes to afford ethyl 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate as a solid (180 mg, 34%). LCMS (Method 9): m / z 569.0 (ES+), 2.44 minutes.

[0408] Step 5. Hydrazine hydrate (220 mg, 4.40 mmol) was added to a solution of ethyl 5-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (500 mg, 0.88 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction was filtered and the filtrate was concentrated under vacuum to afford ethyl 5-((aminooxy)methyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate as a semi-solid (280 mg, crude). The crude product was used in the next step without further purification. LCMS (Method 9): m / z 437.4 (ES+), 2.27 min.

[0409] Step 6. LiOH.H2O (77 mg, 1.83 mmol) and water (0.2 mL) were added to a solution of ethyl 5-((aminooxy)methyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (250 mg, 0.61 mmol) in MeOH (5 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc (10 mL). The solution was washed with brine (5 mL), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 30-35% EtOAc in hexanes to afford 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,7-dihydropyrazolo[4,3-d][1,2]oxazin-4(5H)-one as a white solid (25 mg, 10%). Data in Table 3.

[0410] Step 18: Example 48 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one

[0411] [ka] Steps 1, 2, and 3. Ethyl 5-(bromomethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate (165 mg, crude) was prepared from ethyl (Z)-4-(tert-butoxy)-2-((dimethylamino)methylene)-3-oxobutanoate (Intermediate 19, 433 mg, 0.56 mmol) and 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine (Intermediate 6, 160 mg, 0.56 mmol) using the method of Procedure 17, steps 1, 2, and 3. The crude product was used in the next step without further purification. LCMS (Method 9): m / z 486.2 (ES+), 2.46 min.

[0412] Step 4. Potassium 1,3-dioxo-2,3-dihydro-1H-isoindol-2-ide (63 mg, 0.34 mmol) was added to a solution of ethyl 5-(bromomethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate (160 mg, 0.34 mmol) in MeCN (4 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were concentrated under vacuum to afford ethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate as a white semi-solid (241 mg, crude material). The crude product was used in the next step without further purification. LCMS (Method 9): m / z 552.9 (ES+), 2.46 min.

[0413] Step 5. Ethyl 5-(aminomethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate (110 mg, crude) was prepared from ethyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate (241 mg, 0.44 mmol) and hydrazine hydrate (0.06 mL, 1.31 mmol) using the method of Procedure 17, step 5. The crude product was used in the next step without further purification. LCMS (Method 9): m / z 423.0 (ES+), 2.24 min.

[0414] Step 6. Trimethylaluminum (0.18 mL, 0.36 mmol) was added to a solution of ethyl 5-(aminomethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate (100 mg, 0.24 mmol) in toluene (4 mL) at 0° C. and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was quenched with water (2 mL), filtered through a pad of Celite, and washed with DCM (2×20 mL). The organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was washed with Et2O (10 mL) and dried under vacuum to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one as a white solid (38 mg, 43%). Data in Table 3.

[0415] Step 19: Example 49 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)methyl-d)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0416] [ka] Step 1. NaBD4 (16 mg, 0.37 mmol) was added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 35, 100 mg, 0.24 mmol) in CD3OD (10 mL) and the reaction mixture was heated at room temperature for 1 h. The reaction mixture was partitioned between saturated NH4Cl solution (20 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was triturated with petroleum ether (5 mL) and dried under vacuum to afford 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl-d)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a yellow solid (80 mg, 79%). LCMS (Method 7): m / z 408.2 (ES+), 1.80 min.

[0417]

number

[0418] Step 20: Example 105 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0419] [ka] Iodotrimethylsilane (223 mg, 1.12 mmol) was added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-methoxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 104, 100 mg, 0.223 mmol) in chloroform (10 mL) at room temperature and the reaction mixture was heated at 80° C. for 4 h. The reaction mixture was partitioned between water (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL) and the combined organic layers were washed with water (10 mL) and brine solution (10 mL), dried over anhydrous (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-10% MeOH in DCM to afford 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white gum (24 mg, 24%). Data in Table 3.

[0420] Step 21: Example 107 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0421] [ka] A solution of BBr3 (1.0M in DCM, 0.75 mL, 0.75 mmol) was added dropwise to a solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-methoxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 106, 65 mg, 0.15 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by preparative HPLC (Method 6 - 40 to 75% gradient) to afford 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (6 mg, 8%).

[0422] Step 22: Example 109 1-(3-(3-fluoro-5-(trifluoromethyl)benzyl)phenyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0423] [ka] tert-Butyl 2-(3-(3-fluoro-5-(trifluoromethyl)benzyl)phenyl)hydrazine-1-carboxylate (181 mg, 0.47 mmol) and (E)-3-((dimethylamino)methylene)piperidine-2,4-dione (Intermediate 1, 95 mg, 0.57 mmol) were dissolved in ethanol (5 mL) and acetic acid (0.03 mL, 0.57 mmol) was added. The reaction mixture was heated at 80° C. for 3 h. TFA (0.06 mL) was added and the reaction mixture was heated at 80° C. for 2 h. Further TFA (0.74 mL) was added and the reaction mixture was heated at 80° C. overnight. The solvent was removed in vacuo and the residue was partitioned between saturated NaHCO3 solution (5 mL) and EtOAc (5 mL). The organic layer was removed, the aqueous layer was extracted with EtOAc (2×5 mL), the combined organic layers were dried (phase separator) and the solvent was removed in vacuo. The residue was purified by gradient flash chromatography eluting with 2-7% MeOH in DCM. The residue was further purified by preparative HPLC (Method 2 - 40-70% gradient) to give 1-(3-(3-fluoro-5-(trifluoromethyl)benzyl)phenyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (35 mg, 19%). Data in Table 3.

[0424] Step 23: Example 111 1-(2-((6-difluoromethoxy)-5-fluoropyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0425] [ka] Step 1. 1-(2-((5-fluoro-6-hydroxypyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (100 mg, 55%) was prepared from 1-(2-((5-fluoro-6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 93, 0.19 g, 0.52 mmol) using the method of procedure 20. LCMS (Method 11): m / z 354.1 (ES+), 1.27 min.

[0426]

number

[0427] Step 24: Example 112 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one

[0428] [ka] Step 1. Potassium t-butoxide (150 mg, 1.336 mmol) was added to a solution of ethyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-1H-pyrazole-4-carboxylate (Intermediate 43, 200 mg, 0.67 mmol) and 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 3, 183 mg, 0.67 mmol) in NMP (10 mL) at room temperature and the reaction mixture was heated at 110° C. for 16 h. The solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-40% EtOAc in petroleum ether to afford ethyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylate as an off-white solid (200 mg, 54%). LCMS (Method 3): m / z 553.1 (ES+), 2.69 min.

[0429]

number

[0430]

number

[0431] Step 4. DIPEA (48 mg, 0.38 mmol) and HATU (143 mg, 0.38 mmol) were added to a solution of 3-(2-aminoethoxy)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxylic acid hydrochloride (80 mg, 0.17 mmol) in DMF (1.6 mL) and the reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine solution (50 mL), dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by preparative HPLC (Method 4). The residue was partitioned between 10% NaHCO3 solution (20 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo to give 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one as a white solid (30 mg, 42%). Data in Table 3.

[0432] Step 25: Example 116 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0433] [ka] CuBr (8.3 mg, 0.058 mmol) was added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-iodo-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (150 mg, 0.290 mmol) in DMA (8 mL) followed by the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (334 mg, 1.74 mmol). The reaction mixture was heated at 100° C. for 1 h in a microwave. The reaction mixture was partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by preparative HPLC (Method 4). The residue was partitioned between 10% NaHCO3 solution (5 mL) and EtOAc (10 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (14 mg, 10%). Data in Table 3.

[0434] Step 26: Example 117 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0435] [ka] Steps 1 and 2. 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (300 mg, 58%) was prepared from 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 75, 500 mg, 1.23 mmol) using the method of procedure 11, steps 1 and 2. LCMS (Method 3): m / z 421.1 (ES+), 1.80 min.

[0436]

number

[0437] Step 4 (Peak 1). K2CO3 (79 mg, 0.572 mmol) was added to a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl benzoate (Peak 1, 100 mg, 0.191 mmol) in MeOH (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (10 mL) and H2O (10 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by chiral SFC (Method 5 - run isocratically with 20% co-solvent) to afford 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Isomer 1) as an off-white solid (28 mg, 35%). Data in Table 3.

[0438] Step 4 (Peak 2). K2CO3 (87 mg, 0.629 mmol) was added to a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl benzoate (Peak 2, 110 mg, 0.210 mmol) in MeOH (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (10 mL) and H2O (10 mL). The organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by chiral SFC (Method 5 - run isocratically with 20% co-solvent) to afford 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (isomer 2) as an off-white solid (41 mg, 46%). Data in Table 3.

[0439] Step 27: Example 118 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0440] [ka] Step 1. A solution of LiHMDS (1M in THF, 3.71 mL, 3.71 mmol) was added to a solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Example 95, 500 mg, 1.23 mmol) in THF (5 mL) at -78 °C and stirred for 10 min, followed by the addition of Davis reagent (1 g, 3.71 mmol) at -20 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (40 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-100% EtOAc in petroleum ether. After the solvent was removed under vacuum, the residue was dissolved in MeOH (5 mL) and sodium borohydride (52 mg, 0.69 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by gradient flash column chromatography eluting with 0-80% EtOAc in petroleum ether to afford 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as an off-white solid (250 mg, 48%). LCMS (Method 6): m / z 421.1 (ES+), 2.12 min.

[0441]

number

[0442] Step 2. 4-Nitrobenzoyl chloride (105 mg, 0.571 mmol) and NEt3 (0.2 mL, 1.71 mmol) were added to a solution of 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (240 mg, 0.57 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Method 1). The resulting residue was dissolved in EtOAC (50 mL) and washed with water (50 mL). The organic layer was separated, dried (Na2SO4) and the solvent was removed in vacuo. The residue was subjected to chiral SFC (Method 7 - performed isocratically with 20% co-solvent). Upon evaporation of the chiral SFC fractions, the 4-nitrobenzoyl ester hydrolyzed, so both eluates were further purified by gradient flash column chromatography eluting with 0-80% EtOAc in petroleum ether to afford 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (isomer 1) as an off-white solid (25 mg, 11%) and 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (isomer 2) as an off-white solid (27 mg, 11%). Data in Table 3.

[0443] Further examples prepared by the above procedures are detailed in Table 3.

[0444] [Table 2-1]

[0445]

Table 2-2

[0446]

Table 2-3

[0447]

Table 2-4

[0448]

Table 2-5

[0449]

Table 2-6

[0450]

Table 2-7

[0451]

Table 2-8

[0452]

Table 2-9

[0453]

Table 3-1

[0454]

Table 3-2

[0455]

Table 3-3

[0456]

Table 3-4

[0457]

Table 3-5

[0458]

Table 3-6

[0459]

Table 3-7

[0460]

Table 3-8

[0461]

Table 3-9

[0462]

Table 3-10

[0463]

Table 3-11

[0464]

Table 3-12

[0465]

Table 3-13

[0466] [Table 3-14]

[0467] [Table 3-15]

[0468] [Table 3-16]

[0469] [Table 3-17]

[0470] [Table 3-18]

[0471] [Table 3-19]

[0472] [Table 3-20]

[0473] [Table 3-21]

[0474] [Table 3-22] biological activity Functional cAMP assay of GPR52 agonists HEKf suspension cells were infected for 24 hours with 0.1% v / v human GPR52 expressing BacMam virus, a modified baculovirus designed for mammalian gene expression. After BacMam infection, cells were pelleted by centrifugation (335g, 5 min), resuspended in cell freezing medium (Sigma), and frozen at -150°C until required. On the day of the experiment, 25 nL of GPR52 compound dilutions prepared in DMSO were stamped onto a proxiplate (PerkinElmer) with a LabCyte ECHO acoustic dispenser. Frozen cells were thawed and resuspended in assay stimulation buffer (Cisbio) containing 0.5 mM 3-iso-butyl-1-methylxanthine (IBMX, Sigma) to achieve a cell density of 2000 cells per well. 10 μl of cells were added to the assay plate using a Multidrop Combi Reagent Dispenser (ThermoFisher) before centrifugation (335g, 1 min). Cells were incubated with compounds for 30 min at 37 °C before adding cAMP detection reagent (HiRange cAMP kit, Cisbio) prepared according to the manufacturer's instructions. Plates were shaken for 1 h at room temperature before reading on a PHERAstar FS plate reader (BMG Labtech) using standard HTRF settings. HTRF ratios were obtained by dividing the acceptor emission (665 nm) by the donor emission (620 nm) and multiplying by 10,000. Data were normalized to DMSO (0%) and maximum 3-(2-(3-chloro-5-fluorobenzyl)benzo[b]thiophen-7-yl)-N-(2-methoxyethyl)benzamide (compound 7m from J. Med. Chem., 2014, 57, 5226) response (100%) and fitted with a 4-parameter logistical fit to obtain the pEC of the agonist. 50 The S and maximum responses were generated and are presented in Table 4 below.

[0475] [Table 4] Pharmacokinetic profile The pharmacokinetic profile of Example 1 was assessed in male Sprague-Dawley rats via intravenous (IV) and oral (per os, PO) delivery routes. The pharmacokinetic data (mean ± standard deviation) of Example 1 of the present invention are detailed in Table 5.

[0476] Methods: For pharmacokinetic analysis, groups of three male Sprague-Dawley rats, ranging in weight from 200 to 230 g, were administered a single dose of Example 1 via IV or PO route using the dose, dose volume, and vehicle specified in Table 5. After dosing, blood samples were collected by continuous tail vein bleeding at several time points (pre-dose, 2 min, 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, 12 h, and 24 h for IV administration; pre-dose, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h for PO administration), centrifuged, and plasma was separated for analysis by LC-MS / MS. Pharmacokinetic parameters were generated using non-compartmental analysis using WinNonlin v8.2 statistical software (Pharsight Corporation, California, USA).

[0477] Brain penetrant Plasma and brain exposure were evaluated to assess the brain penetration of Example 1 after IV administration. The unbound brain-to-plasma ratio (K p,uu ) was calculated after experimentally measuring binding in rat plasma and brain homogenates and is detailed in Table 5.

[0478] Methods: To assess brain penetrance, male Sprague-Dawley rats (n=3) were administered a single dose of 1 mg / kg (formulated in 10% DMAC+10% Solutol HS15+80% saline) via IV route. 10 min after dosing, animals were sacrificed and brains were extracted, homogenized in 2 volumes (w / v) of 50 mM sodium phosphate buffer (pH 7.4) and analyzed by LC-MS / MS. Blood samples were taken at the same time points by tail vein bleeding, centrifuged, and plasma was analyzed by LC-MS / MS.

[0479] Unbound brain / plasma ratio (K p,uu Binding of test compounds in rat plasma and brain homogenates was performed using Rapid Equilibrium Dialysis (RED) to allow calculation of the F. Test compounds prepared in DMSO (1 μM final, 0.2% DMSO) were added to (i) undiluted male Sprague-Dawley rat plasma and (ii) rat brain tissue homogenized in 2 volumes (w / v) of sodium phosphate buffer (pH 7.4) and dialyzed against phosphate buffer for 5 hours at 37°C. After incubation, the contents of each compartment of plasma / brain and buffer were removed and mixed with an equal volume of control dialysis buffer or plasma / brain to maintain similarity of the matrix for analysis. Proteins were then precipitated by addition of acetonitrile containing an analytical internal standard (allowing the ratio of test compound to internal standard to be derived), centrifuged, and the supernatant was removed for analysis by LC-MS / MS. The unbound fractions of plasma and brain (F u ) was calculated using the following formula, and then corrected for the total plasma and brain concentrations to obtain K p,uu was used to derive. Bound fraction = (total plasma or brain ratio) - (total buffer ratio) / total plasma or brain ratio Unbound fraction (F u Brain or plasma) = 1-bound fraction Correction of dilutions in the brain binding assay: Undiluted F u Brain = (1 / Dilution Factor) / ((1 / Dilution Factor u ))-1)+(1 / dilution factor) where the dilution factor=4.

[0480] [Table 5] Amphetamine-induced locomotor activity in rats. The rat amphetamine-induced hyperlocomotion test is used to model the increased mesolimbic dopaminergic activity that is believed to contribute to human psychosis.The effect of Example 1 and FTBMT (J.Pharmacol.Exp.Ther.,2017,363,253) was evaluated on amphetamine-induced hyperlocomotion in rats, using risperidone as a positive control.

[0481] Male Sprague-Dawley rats (200-250 g) were group housed with a 12-hour light / dark cycle (lights on at 07:00) at an ambient temperature of 21±2°C with standard pellet diet and water ad libitum. Testing was performed during the light phase. On the day of the experiment, animals were habituated to the locomotor cages for 60 minutes. They were then dosed with vehicle, Example 1 (1, 3, and 10 mg / kg), or FTBMT (10 mg / kg) by oral route or risperidone by subcutaneous route and returned to the appropriate locomotor cage. Example 1 was formulated in a vehicle of 10% DMAC, 10% solutol (Kolliphor HS15), and 80% water (v / v / v), FTBMT was formulated in 0.5% HPMC / 0.1% Tween 80 in deionized water, and risperidone was dissolved in acidified saline. Sixty minutes later, animals were dosed subcutaneously with vehicle (saline) or D-amphetamine. Locomotor activity was assessed 2 hours after D-amphetamine treatment. Data are back-transformed means adjusted for differences between treatment groups (n=10-12 animals) in activity during the 30 minutes prior to treatment with test compound or vehicle. Analysis was by general linear model with treatment, cohort and rack as functions. SEM was calculated from residuals of statistical models. Example 1 was compared to D-amphetamine by Williams test. As shown in FIG. 1, treatment with Example 1 caused a reduction in D-amphetamine-induced hyperlocomotion responses, reaching statistical significance at 10 mg / kg but not at 1 or 3 mg / kg. FTBMT showed a trend toward a reduction in D-amphetamine-induced hyperlocomotion responses, but did not reach statistical significance.

[0482] Subchronic PCP-induced reversal learning deficits in rats Subchronic treatment with PCP in rats results in long-term neurobiological changes and dysfunction in a range of behaviors related to neuropsychiatric disorders. The deficit in cognitive flexibility after subchronic PCP treatment was demonstrated using a reverse learning paradigm (Neuropharmacology, 2017, 142, 41). The ability of Example 1 to attenuate subchronic PCP-induced cognitive deficits was assessed to be comparable to the D1 receptor agonist SKF-38393 in female Lister Hooded rats.

[0483] Adult female Lister Hooded rats were housed in groups of 5 under standard laboratory conditions with a 12-hour light:dark cycle with lights on at 07:00 and food restricted to 90% of free-feeding body weight. Testing was performed during the light phase. Rats were first trained to press the left / right lever for food reward in the presence or absence of a visual cue and then to respond to the opposite contingency. The reverse learning task was introduced as follows. A full 30-minute operant training session was performed one day before each reverse task session to ensure stable responding. In the first task, animals were first exposed to a process in which the contingency (cue location of the working lever) was the same as in the operant training session for 5 minutes. This was followed by a 2-minute rest period, signaled by turning off the lights in the housing area. In the following 5 minutes (reverse task), the contingency was reversed. Responses made on the correct and incorrect levers were recorded. Animals underwent several of these reversal learning task sessions before drug testing began to ensure they obtained a stable level of performance in both phases of the task. Generally, 4-6 sessions were required before this was achieved, and animals required approximately 6 weeks of training in total to reach this point. At this stage, training was stopped and rats were treated with PCP (2 mg / kg, IP, or vehicle 0.9% saline, IP) for 7 days, followed by a washout period of at least 7 days.

[0484] On the day of testing, rats were randomly assigned to six treatment groups (n=8-10 per group) and received acute treatment with Example 1 (3, 10 and 30 mg / kg, PO), SKF-38393 (6 mg / kg, IP), or vehicle. Example 1 was dissolved in 10% DMAC, 10% Solutol (kolliphor H515) and 80% water and administered in a volume of 5 ml / kg by oral route 2 hours before testing. SKF-38393 was dissolved in 0.9% NaCl and administered in a volume of 1 ml / kg IP 60 minutes before testing. In the initial phase, the reward contingency was the same as the previous day, and in the reverse phase, the reward contingency was reversed. Animals received one reverse session after the first phase (initial phase), i.e., initial phase for 5 minutes, rest for 2 minutes, and reverse phase 1 for 5 minutes, at the end of the test. Rats are randomized using a Microsoft Excel 2010 random number generator into a crossover design whereby each rat within a cage receives a different treatment both during and between experiments.

[0485] Data are presented as the mean (+SEM) of total number of lever presses and percentage of correct responses (+SEM). Percentage of correct responses data were used to determine whether there was a significant effect of drug on response accuracy, and these data were arcsine transformed prior to analysis. Statistical significance was estimated at P<0.05 and measured as follows: One-way ANOVA (IBM SPSS Statistics 22) was performed to detect main effects of drug treatment in the initial and reverse tasks. If significant effects were detected, post-hoc LSD t-tests were performed to compare treatment groups with appropriate controls in the reverse phase of testing.

[0486] Subchronic PCP treatment produced a significant (P<0.001) deficit in reversal learning, as measured by a significant and selective reduction in the percentage of correct responses in the reversal phase of the test, with early-phase performance unaffected. Treatment with 10 and 30 mg / kg (but not 3 mg / kg) of Example 1, as well as the positive control compound SKF-38393, significantly (P<0.05 to P<0.001) reversed the deficit compared to the vehicle-treated subchronic PCP group (Figure 2). There was no significant effect of Example 1 or SKF-38393 on the total number of lever presses (Figure 3), indicating that any cognitive enhancing effects occurred without having a reduction in motivation or motor control. [Brief description of the drawings]

[0487] [Figure 1] Effects of acute treatment with Example 1 (1, 3 and 10 mg / kg, PO) and risperidone (0.6 mg / kg, SC) on D-amphetamine-induced hyperlocomotion activity. Significant differences relative to D-amphetamine are indicated as *p<0.05, **p<0.01, ***p<0.001. [Diagram 2] Effects of acute treatment of Example 1 (3, 10 and 30 mg / kg, PO, 2 hours before testing) and SKF-38393 (6 mg / kg, IP, 60 minutes before testing) in subchronic PCP (scPCP)-treated rats (2 mg / kg, IP twice daily for 7 days followed by at least 7 days of washout period) on performance in a reversal learning task. Data are presented as mean ± sem of % correct responses (n = 8-10) and analyzed by ANOVA and post-hoc Student's t-test. Significant reduction in correct response rate in the reversal phase compared to vehicle group, **P<0.01, ***P<0.001. Improved response compared to scPCP alone in the reversal phase, #P<0.05 to ###P<0.001. [Diagram 3]Effect of acute treatment with Example 1 (3, 10 and 30 mg / kg, PO, 2 hours prior to testing) and SKF-38393 (6 mg / kg, IP, 60 minutes prior to testing) in subchronic PCP (scPCP)-treated rats (2 mg / kg, IP twice daily for 7 days followed by a washout period of at least 7 days) on performance in a reversal learning task. Data are presented as the mean total number of lever presses, with correct responses indicated by clear bars and incorrect responses indicated by shaded bars (n=8-10).

Claims

1. Formula (1): 【Chemistry 1】 or a salt thereof, X is N or CR ２ and Y is N, NR ３ , or C.R. ２ and Z is N or NR ３ and where Y and Z are either NR, but not both. ３ and Q is -CR ４ R ５ -, -CR ４ R ５ CR ６ R ７ -, -CR ４ R ５ CR ６ R ７ CR ８ R ９ -, -CR ４ R ５ CR ６ R ７ O-, -OCR ４ R ５ --and--OCR ４ R ５ CR ６ R ７ - selected from R １ is H, C optionally substituted with 1 to 6 fluorine atoms １～６ Alkyl, the group -C(R １４ ) ２ C(R １８ ) ２ OR １７ or a group -C(R １４ ) ２ C(R １９ ) ２ OH, where each R １４ are independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, R １７ C optionally substituted with 1 to 6 fluorine atoms １～３ alkyl, and each R １８ are independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, and each R １９ are independently H or C optionally substituted with 1 to 6 fluorine atoms. １～３ alkyl, R １７ and one R １４ may be taken together to form an oxolane or oxetane ring, R ２ is H; halo; CN; OH or C optionally substituted with 1 to 6 fluorine atoms. １～６ Alkyl; C optionally substituted with OH or 1 to 6 fluorine atoms １～６ alkoxy; or C optionally substituted with OH or 1 to 6 fluorine atoms ３～６ cycloalkyl; １～６ Alkyl, C １～６ Alkoxy, or C ３～６ One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and oxidized forms thereof; R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ is H and C １～３ independently selected from alkyl, R 3 is a group represented by the formula: 【Chemistry 2】 wherein each A is independently N or CR 10 ; L is selected from CH2, CHD, CD2, CHF, CF2, C=O, CHOH, O, and NH; R 10 is selected from H, halo, and C 1-3 alkyl optionally substituted with 1 to 6 fluorine atoms; W is (i) a 6-membered optionally substituted aryl or heteroaryl ring; or (ii) an optionally substituted 9-10 membered heterobicyclic ring system, wherein one or more rings are aromatic; or a group selected from the group consisting of

2. 2. The compound of claim 1, or a salt thereof, wherein W is a 6-membered optionally substituted aryl or heteroaryl ring.

3. Formula (1b): 【Chemistry 3】 The compound of claim 1 or a salt thereof, Q is -CR ４ R ５ -, -CR ４ R ５ CR ６ R ７ -, -CR ４ R ５ CR ６ R ７ CR ８ R ９ -, -CR ４ R ５ CR ６ R ７ O-, -OCR ４ R ５ --and--OCR ４ R ５ CR ６ R ７ - selected from R １ is H, C optionally substituted with 1 to 6 fluorine atoms １～６ Alkyl, the group -C(R １４ ) ２ C(R １８ ) ２ OR １７ or a group -C(R １４ ) ２ C(R １９ ) ２ OH, where each R １４ are independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, R １７ C optionally substituted with 1 to 6 fluorine atoms １～３ alkyl, and each R １８ are independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, and each R １９ are independently H or C optionally substituted with 1 to 6 fluorine atoms. １～３ alkyl, R １７ and one R １４ may be taken together to form an oxolane or oxetane ring, R ２ is H; halo; CN; OH or C optionally substituted with 1 to 6 fluorine atoms. １～６ Alkyl; C optionally substituted with OH or 1 to 6 fluorine atoms １～６ alkoxy; or C optionally substituted with OH or 1 to 6 fluorine atoms ３～６ cycloalkyl; １～６ Alkyl, C １～６ Alkoxy, or C ３～６ One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and oxidized forms thereof; R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ is H and C １～３ independently selected from alkyl, R ３ is the formula: 【Chemistry 4】 where each A is independently N or CR １０ and L is CH ２ , C.H.D., C.D. ２ , C.H.F., C.F. ２ , C═O, CHOH, O, and NH; Each B is independently N, CR １１ , C.R. １２ , C.R. １３ , C.R. １５ , or C.R. １６ and R １０ is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, R １１ , R １２ , R １３ , R １５ , and R １６ H, CN, SF ５ , halo, C optionally substituted with 1 to 6 fluorine atoms １～６ Saturated hydrocarbon groups (wherein １～６ One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S and their oxidized forms), OC, optionally substituted with 1 to 6 fluorine atoms; １～６ Alkyl, SO optionally substituted with 1 to 6 fluorine atoms ２ C １～６ alkyl, optionally substituted with 1 to 6 fluorine atoms, or CF ３ C optionally substituted with ３～６ cycloalkyl.

4. Formula (2a), (2b), (2c), (2d), (2e), (2f) or (2g): 【Chemistry 5】 2. The compound of claim 1, which is a compound of the formula:

5. Formula (11a): 【Chemistry 6】 2. The compound of claim 1, which is a compound of the formula:

6. R ３ But the formula: 【Chemistry 7】 wherein each A is independently N or CR １０ and L is CH ２ , C.H.D., C.D. ２ , C.H.F., C.F. ２ , C═O, CHOH, O, and NH; Each B is independently N, CR １１ , C.R. １２ , C.R. １３ , C.R. １５ , or C.R. １６ and R １０ is H, halo, and C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, R １１ , R １２ , R １３ , R １５ , and R １６ H, CN, SF ５ , halo, C optionally substituted with 1 to 6 fluorine atoms １～６ Saturated hydrocarbon groups (wherein １～６ One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S and their oxidized forms), OC, optionally substituted with 1 to 6 fluorine atoms; １～６ Alkyl, SO optionally substituted with 1 to 6 fluorine atoms ２ C １～６ alkyl, optionally substituted with 1 to 6 fluorine atoms, or CF ３ C optionally substituted with ３～６ 6. The compound according to claim 1 , wherein the aryl group is independently selected from aryl, arylalkyl, arylsulfonyl, arylsulfur ...

7. R ３ but, 【Chemistry 8】 7. The compound of claim 6, selected from the group consisting of:

8. L is CH ２ 8. The compound according to claim 1 , wherein:

9. Base: 【Chemistry 9】 but, 【Chemistry 10】 9. The compound according to any one of claims 6 to 8, or a salt thereof, selected from the group consisting of:

10. Q is -CH ２ CH ２ --, --CH ２ CH ２ CH ２ --, --CH ２ --, --OCH ２ --, --CH ２ CH ２ O-, -CH(CH ３ ) CH ２ - and -CH ２ CH (CH ３ 10. The compound according to any one of claims 1 to 9, or a salt thereof, selected from the group consisting of:

11. Q is -CH ２ CH ２ The compound according to claim 10, or a salt thereof, wherein

12. Formula (13a), (13b), (13c), (13d), (13e), (13f), (13g), (13h), (13i), or (13j): 【Chemistry 11】 or a salt thereof, R １ is H, C optionally substituted with 1 to 6 fluorine atoms １～６ Alkyl, the group -C(R １４ ) ２ C(R １８ ) ２ OR １７ or a group -C(R １４ ) ２ C(R １９ ) ２ OH, where each R １４ are independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, R １７ C optionally substituted with 1 to 6 fluorine atoms １～３ alkyl, and each R １８ are independently H, F, or C optionally substituted with 1 to 6 fluorine atoms; １～３ alkyl, and each R １９ are independently H or C optionally substituted with 1 to 6 fluorine atoms. １～３ alkyl, R １７ and one R １４ may be taken together to form an oxolane or oxetane ring, R ２ is H; halo; CN; OH or C optionally substituted with 1 to 6 fluorine atoms. １～６ Alkyl; C optionally substituted with OH or 1 to 6 fluorine atoms １～６ alkoxy; or C optionally substituted with OH or 1 to 6 fluorine atoms ３～６ cycloalkyl; １～６ Alkyl, C １～６ Alkoxy, or C ３～６ One atom of the cycloalkyl group may be replaced by a heteroatom selected from O, N, S, and oxidized forms thereof; R １１ , R １２ , R １３ , R １５ , and R １６ H, CN, SF ５ , halo, C optionally substituted with 1 to 6 fluorine atoms １～６ Saturated hydrocarbon groups (wherein １～６ One atom of the saturated hydrocarbon group may be replaced by a heteroatom selected from O, N, S and their oxidized forms), OC, optionally substituted with 1 to 6 fluorine atoms; １～６ Alkyl, SO optionally substituted with 1 to 6 fluorine atoms ２ C １～６ alkyl, optionally substituted with 1 to 6 fluorine atoms, or CF ３ C optionally substituted with ３～６ cycloalkyl.

13. Formula (6a): 【Chemistry 12】 2. The compound of claim 1, which is a compound of the formula:

14. R １ is H, methyl, -CH ２ CH ２ OCH ３ , or -CH ２ CH ２ 14. The compound according to any one of claims 1 to 13, or a salt thereof, wherein R is 0-OH.

15. R ２ H, methyl, F, Cl, CN, CF ３ , and C.H. ２ 15. The compound of any one of claims 1 to 3, or 12 to 14, or a salt thereof, wherein:

16. R ２ is H or methyl, or a salt thereof.

17. R １１ , R １２ , R １３ , R １５ , and R １６ H, CN, F, Cl, methyl, isopropyl, cyclopropyl, CF ３ , C.F. ２ H, O.C.F. ２ H, OMe, and 【Chemistry 13】 17. The compound according to any one of claims 3 to 16, or a salt thereof, independently selected from:

18. R １１ , R １２ , R １３ , R １５ , and R １６ H, F, and CF ３ 18. The compound of claim 17, or a salt thereof, independently selected from:

19. 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 5-methyl-1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-5-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one, 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridazin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridazin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-{4-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridin-2-yl}-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chlorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,5-difluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-fluoro-3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,4,5-trifluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-methylbenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-methyl-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(2-fluoro-3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(2-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,5-dichlorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-((4-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)-5-(trifluoromethyl)benzonitrile, 1-(2-(3,5-bis(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(fluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(difluoro(3-fluoro-5-(trifluoromethyl)phenyl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)methyl-d ２ ) pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-6-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one, 1-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 5-methyl-2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 2-(4-(3-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(2H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,7-dihydropyrazolo[4,3-d][1,2]oxazin-4(5H)-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)methyl-d)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-7-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-cyclopropyl-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-methoxy-3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyrimidin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-methoxy-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3,5-difluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(benzo[b]thiophen-5-ylmethyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-methoxy-4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(pentafluoro-λ ６ -sulfanyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-(difluoromethoxy)-3-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,4-difluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4,5-difluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(quinolin-3-ylmethyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(benzo[b]thiophen-2-ylmethyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3,5-difluoro-4-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-isopropylbenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((5-fluoro-6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(1-(trifluoromethyl)cyclopropyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-methyl-1-(2-(3,4,5-trifluorobenzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-methyl-1-(2-(3-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-5-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-(difluoromethoxy)-3-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(5-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-3-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((6-fluoro-5-methylpyridin-3-yl)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4,5-difluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-fluoro-5-((4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)benzonitrile, 1-(2-(3,4-difluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-chloro-4-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethoxy)-5-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(4-chloro-3,5-difluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((5-fluoro-6-methoxypyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-(difluoromethoxy)pyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 3-fluoro-5-((4-(4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)methyl)benzonitrile, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,3]triazolo[4,5-c]azepin-4(1H)-one, 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-2,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one, 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(5-(3-fluoro-5-(trifluoromethyl)phenoxy)pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-methoxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-methoxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(2-hydroxyethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(3-(3-fluoro-5-(trifluoromethyl)benzyl)phenyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-6,7-dihydro-2H-pyrazolo[4,3-f][1,4]oxazepin-4(5H)-one, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(hydroxymethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, 1-(4-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-2-yl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one, or its salt 2. The compound of claim 1 selected from the group consisting of:

20. The compound of claim 1, 【Chemistry 14】 2. The compound of claim 1, 21. The compound of claim 1, 【Chemistry 15】 2. The compound of claim 1, 22. The compound of claim 1, 【Chemistry 16】 2. The compound of claim 1, 23. The compound of claim 22, 【Chemistry 17】 2. The compound of claim 1 , 24. The compound comprising: 【Chemistry 18】 2. The compound of claim 1 , 25. The compound comprising: 【Chemistry 19】 2. The compound of claim 1 , 26. The compound of claim 1, 【Chemistry 20】 2. The compound of claim 1 , 27. The compound comprising: 【Chemistry 21】 2. The compound of claim 1 , 28. The compound comprising: 【Chemical 22】 2. The compound of claim 1 , 29. The compound comprising: 【Chemistry 23】 2. The compound of claim 1 , 30. The compound comprising: 【Chemistry 24】 2. The compound of claim 1 , 31. The compound of claim 30, 【Chemistry 25】 2. The compound of claim 1 , 32. The compound of claim 1, 【Chemistry 26】 2. The compound of claim 1 , 33. The compound comprising: 【Chemical 27】 2. The compound of claim 1 , 34. A salt of a compound defined in any one of claims 20 to 33.

35. A pharma- ceutically acceptable salt of a compound defined in any one of claims 20 to 33.

36. 36. A compound according to any one of claims 1 to 35, or a salt thereof, having GPR52 receptor modulator activity.

37. 37. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 36 or a salt thereof, and a pharma- ceutically acceptable excipient.

38. The composition of claim 37 for use as a GPR52 receptor agonist.

39. The composition of claim 37 for use in medicine.

40. 38. The composition of claim 37 for use in treating a psychiatric disorder; a neuropsychiatric disorder; a neurodegenerative disorder; a psychiatric disorder; a cognitive disorder; a neurocognitive disorder; an extrapyramidal disorder; a movement disorder; a motility disorder; a hyperkinetic disorder; catatonia; a mood disorder; an anxiety disorder; an obsessive-compulsive disorder (OCD); an autism spectrum disorder; a depressive disorder; a hypothalamic disorder; a pituitary disorder; a prolactin-related disorder; a trauma or stressor-related disorder; a disruptive impulse control or conduct disorder; a sleep-wake disorder; a substance-related disorder; an addictive disorder; a behavioral disorder; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesencephalic or nigrostriatal pathway; reduced activity in the striatum; cortical dysfunction; neurocognitive dysfunction; or a condition or symptom related thereto.

41. The disorder or symptom is schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, Chinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, nonfunctioning tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and related movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia, myoclonus, mirror movement disorder, paroxysmal kinesigenic dyskinesia, restless legs syndrome, spasms, stereotypy movement disorder, stereotypy, tics, tremors, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or medication-induced psychosis, delusions, hallucinations, disorganized thinking, severely disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or medication-induced bipolar and related disorders, bipolar disorder due to another medical condition, 41. The composition for use of claim 40, wherein the anxiety disorder is selected from: anxiety disorder, selective mutism, specific phobia, social anxiety disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder caused by another medical condition, delirium, severe neurocognitive disorder, mild neurocognitive disorder, amnesia, dementia, developmental coordination disorder, stereotypy, post-stroke effects, dentatorubral-pallidoluysian atrophy, decreased emotional expressiveness, amotivation, allogy, and antisocialism.

42. 41. The composition for use according to claim 40, wherein the disorder or condition is selected from schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorder, autism spectrum disorder, psychosis, neurocognitive disorder, delirium, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD).

Images