RU2844473C1 - Compounds gpr52 modulators - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1):

(1) or a pharmaceutically acceptable salt thereof, in which: X is N or CR⁵; Y is N or CR⁶; R¹ is H, C_1-6 alkyl, optionally substituted with OH or 1–6 fluorine atoms, C_3-6 cycloalkyl, optionally substituted with OH or 1–6 fluorine atoms, in which, when C_1-6 alkyl or C_3-6 cycloalkyl group is not substituted with OH, one C_1-6 atom of the alkyl or C_3-6 cycloalkyl group can be optionally substituted with an O atom, which is not bonded directly to N or is bonded to a carbon atom which is directly bonded to N; or R¹ is bonded with R² to form 5-membered ring which is optionally substituted with OH or 1–6 fluorine atoms; R² is H or C_1-3 alkyl optionally substituted with OH or 1–6 fluorine atoms; or R² is connected to R¹ to form 5-membered ring which is optionally substituted with OH or 1–6 fluorine atoms; R⁴, R⁵ and R⁶ are independently selected from H, CN, halogen, C_1-6 alkyl, optionally substituted with OH or 1–6 fluorine atoms, C_3-6 cycloalkyl and C_1-6 alkoxy; R³ is a group of formula: ; ; or ; L is CH₂ or CHOH; group: is: ; R⁸, R⁹ and R¹⁰ are independently selected from H, halogen or C_1-3 alkyl, optionally substituted with 1–6 fluorine atoms, as well as to a pharmaceutically acceptable salt and a pharmaceutical composition.

EFFECT: novel compounds are obtained, which can be used as G-protein related receptor 52 (GPR52) modulators for the treatment or prevention of diseases, in which GPR52 receptors are involved, or in which modulation of GPR52 receptors may be preferable.

32 cl, 1 dwg, 5 tbl, 59 ex

Description

This application relates to novel compounds and their use as modulators of G protein-coupled receptor 52 (GPR52). The compounds described in this application may be useful for the treatment or prevention of diseases in which GPR52 receptors are involved or in which modulation of GPR52 receptors may be advantageous. The application is also directed to pharmaceutical compositions comprising these compounds and to the manufacture and use of these compounds and compositions for the prevention or treatment of diseases in which GPR52 receptors are involved or in which modulation of GPR52 receptors may be advantageous.

LEVEL OF TECHNOLOGY

G protein-coupled receptor 52 (GPR52) is a constitutively active Gs-coupled orphan receptor that is highly expressed in the striatum and cerebral cortex. In the striatum, GPR52 is expressed exclusively on dopamine D2 medium spiny neurons, and in the cerebral cortex it is found on cortical pyramidal neurons expressing dopamine D1 receptors (Komatsu et al, 2014, PLoS One 9:e90134). Based on its localization and functional connectivity, GPR52 is proposed to play a role in modulating frontostriatal and limbic dopamine and may therefore be useful for the treatment of neuropsychiatric disorders. GPR52 agonists are considered to be particularly important for the treatment of schizophrenia, where they are thought to indirectly improve cognitive function and negative symptoms by enhancing D1 signaling, but alleviate positive symptoms by inhibiting D2-mediated signaling in the striatum.

GPR52 agonists can be used to treat psychiatric disorders associated with dysfunction of the mesolimbic and mesocortical pathways. Examples include the treatment of positive, negative, and cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder, anxiety disorders (generalized anxiety disorder, obsessive-compulsive disorder, panic disorder), bipolar disorder, addiction/impulse control disorders, and autism spectrum disorders. 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. Expression of GPR52 in the pituitary and hypothalamus suggests the utility of GPR52 modulators in pituitary and hypothalamic diseases, and there is preclinical evidence (Xiong et al, 2016, WO 2016/176571) that GPR52 agonists may be useful for the treatment of hyperprolactinaemia.

WO 2019/053090 discloses diphenyl compounds as growth factor pathway activators.

INVENTION

The present invention provides compounds having activity as modulators of G protein-coupled receptor 52 (GPR52).

Accordingly, the invention provides a compound of Formula (1):

or its salt, in which:

X represents N or CR ⁵ ;

Y represents N or CR ⁶ ;

R ¹ is H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, in which when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with an O atom that is not directly bonded to N or is attached to a carbon atom that is directly bonded to N; or R ¹ is joined to R ² to form a 4-, 5-, 6- or 7-membered ring that is optionally substituted with OH or 1-6 fluorine atoms;

R ² is H or C _1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms; or R ² is joined to R ¹ to form a 4-, 5-, 6- or 7-membered ring which is optionally substituted with OH or 1-6 fluorine atoms;

R ⁴ , R ⁵ and R ⁶ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which, when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with O;

R ³ is a group of the formula:

in which each A is independently N or CR ⁷ ;

L is _CH2 or CHOH;

each B represents independently N, CR ⁸ , CR ⁹ or CR ¹⁰ ;

R ⁷ is selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms;

R ⁸ , R ⁹ and R ¹⁰ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl group may be optionally substituted with a heteroatom selected from O, N, S and their oxidized forms.

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 in the manufacture of medicaments. The compounds or medicaments can be used to treat, prevent, ameliorate, control or reduce the risk of diseases or disorders in which GPR52 receptors are 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 GPR52 receptors may be advantageous. The compounds of the present invention can be useful for the treatment of mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stress-related disorders; disruptive, impulsive, or conduct disorders; sleep-wake disorders; substance use disorders; addictive disorders; behavioral disorders; hypofrontality; tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway disorders; underactivity in the striatum; cortical dysfunction; neurocognitive dysfunction; or conditions or symptoms related thereto.

The compounds of the present invention may be useful for the treatment of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addictive/impulse control disorders, autism spectrum disorders, 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 dyskinesia, myoclonus, mirror movement syndrome, paroxysmal kinesiogenic dyskinesia, restless legs syndrome, spasms, stereotypic movement disorder, stereotypy, tic disorder, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or drug-induced psychotic disorder, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or drug-induced bipolar and related disorders associated with another medical condition bipolar and related disorders due to separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder associated with another medical condition, anxiety disorders, delirium, major neurocognitive disorder, minor neurocognitive disorder, amnesia, dementia, dyspraxia, stereotypic movement disorder, post-stroke effect, dentato-rubro-pallido-Lewis atrophy, decreased emotional expression, abulia, alogia, and asociality.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to new compounds. The invention also relates to the use of the new compounds as GPR52 receptor modulators. The invention further relates to the use of the new compounds in the manufacture of medicinal products for use as GPR52 modulators. The compounds of the present invention can be used as GPR52 agonists. The compounds or medicinal products can be used to treat, prevent, alleviate, control or reduce the risk of diseases or disorders in which GPR52 receptors are involved. The compounds or medicinal products can be used to treat, prevent, alleviate, control or reduce the risk of diseases or disorders in which modulation of GPR52 receptors may be advantageous.

The invention further relates to compounds, compositions and medicinal products which may be useful for treating mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; prolactin-related disorders; trauma- or stress-related disorders; disruptive, impulsive or conduct disorders; sleep-wake disorders; substance use disorders; addictive disorders; behavioural disorders; hypofrontality; tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathway disorders; underactivity in the striatum; cortical dysfunction; neurocognitive dysfunction or conditions or symptoms associated with them.

The invention provides a compound of Formula (1):

or its salt, in which:

X represents N or CR ⁵ ;

Y represents N or CR ⁶ ;

R ¹ is H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, in which when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with an O atom that is not directly bonded to N or is attached to a carbon atom that is directly bonded to N; or R ¹ is joined to R ² to form a 4-, 5-, 6- or 7-membered ring that is optionally substituted with OH or 1-6 fluorine atoms;

R ² is H or C _1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms; or R ² is joined to R ¹ to form a 4-, 5-, 6- or 7-membered ring which is optionally substituted with OH or 1-6 fluorine atoms;

R ⁴ , R ⁵ and R ⁶ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which, when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with O;

R ³ is a group of the formula:

in which each A is independently N or CR ⁷ ;

L is _CH2 or CHOH;

each B represents independently N, CR ⁸ , CR ⁹ or CR ¹⁰ ;

R ⁷ is selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms;

R ⁸ , R ⁹ and R ¹⁰ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl group may be optionally substituted with a heteroatom selected from O, N, S and their oxidized forms.

Also provided is the compound of Formula (1a):

or its salt, in which:

X represents N or CR ⁵ ;

Y represents N or CR ⁶ ;

R ¹ is H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, in which one atom of C _1-6 alkyl or C _3-6 cycloalkyl may be optionally substituted with O; or R ¹ is joined to R ² to form a 4-, 5-, 6- or 7-membered ring which is optionally substituted with OH or 1-6 fluorine atoms;

R ² is H or C _1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms; or R ² is joined to R ¹ to form a 4-, 5-, 6- or 7-membered ring which is optionally substituted with OH or 1-6 fluorine atoms;

R ⁴ , R ⁵ and R ⁶ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with OH or 1-6 fluorine atoms, wherein when the C _1-6 alkyl group is not substituted with OH, any one atom of the C _1-6 alkyl group may be optionally substituted with O;

R ³ is a group of the formula:

in which each A is independently N or CR ⁷ ;

L is _CH2 or CHOH;

each B represents independently N, CR ⁸ , CR ⁹ or CR ¹⁰ ;

R ⁷ is selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms;

R ⁸ , R ⁹ and R ¹⁰ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl group may be optionally substituted with a heteroatom selected from O, N, S and their oxidized forms.

In the compounds herein, X may be N, CH, _CCH3 , or _CCH2OH . X may be N. X may be ^CR5 . X may be CH. X may be _CCH3 . X may be _CCH2OH .

In the compounds herein, Y may be N, CH, _CCH3 , or _CCH2OH . Y may be N. Y may be ^CR6 . Y may be CH. Y may be _CCH3 .

In the compounds of the present description, X can be N and Y can be ^CR5 . X can be N and Y can be N. X can be ^CR5 and Y can be ^CR6 . X can be ^CR5 and Y can be N. At least one of X and Y can be N. The ring containing X and Y can be selected from a pyrrole, pyrazole and 1,2,3-triazole ring system. The ring containing X and Y can be a pyrrole ring system. The ring containing X and Y can be a pyrazole ring system. The ring containing X and Y can be a 1,2,3-triazole ring system.

In the compounds of the present description, R ¹ can be H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, in which, when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with an O atom that is not directly bonded to N or attached to a carbon atom that is directly bonded to N. R ¹ can be H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with O. R ¹ may be attached to R ² to form a 4-, 5-, 6-, or 7-membered ring which is optionally substituted with OH or 1-6 fluorine atoms. R ¹ may be attached to R ² to form a 4-, 5-, 6-, or 7-membered ring. R ¹ may be H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, or C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms. R ¹ may be H, C _1-6 alkyl, or C _3-6 cycloalkyl. R ¹ may be selected from: H, methyl, oxetanyl, CH ₂ CH ₂ OH and CH ₂ CH ₂ OCH ₃ , or R ¹ may be attached to R ² to form a 5-membered ring. R ¹ may be attached to R ² to form a pyrrolidine ring. R ¹ may be H. R ¹ may be C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms. R ¹ may be C _3-6 cycloalkyl optionally substituted with 1-6 fluorine atoms. R ¹ may be C _1-6 alkyl optionally substituted with 1-6 fluorine atoms. R ¹ may be C _3-6 cycloalkyl optionally substituted with 1-6 fluorine atoms. R ¹ may be C _1-6 alkyl. R ¹ may be C _3-6 cycloalkyl. R ¹ may be methyl. R ¹ may be oxetanyl. R ¹ may be CH ₂ CH ₂ OH. R ¹ may be CH ₂ CH ₂ OCH ₃ .

In the compounds of the present description, R ² can be H or C _1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms. R ² can be attached to R ¹ to form a 4-, 5-, 6- or 7-membered ring, which is optionally substituted with OH or 1-6 fluorine atoms. R ² can be H or methyl, or can be attached to R ¹ to form a 5-membered ring. R ² can be H or methyl. R ² can be attached to R ¹ to form a 5-membered ring. R ² can be attached to R ¹ to form a pyrrolidine ring. R ² can be H. R ² can be methyl.

In the compounds of the present description, R ⁴ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which, when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with O. R ⁴ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which, when C _1-6 the alkyl group is not substituted by OH, any one atom of the C _1-6 alkyl group may be optionally substituted with O. R ⁴ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms. R ⁴ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms. R ⁴ may be selected from H, CN, halogen, C _1-6 alkyl and C _1-6 alkoxy. R ⁴ may be selected from: H, methyl, methoxy, Cl, CHF ₂ , CF ₃ , ethyl, CN, cyclopropyl, CH ₂ OH and CH ₂ OCH ₃ . R ⁴ may be H. R ⁴ may be methyl.

In the compounds of the present description, R ⁵ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which, when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with O. R ⁵ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which, when C _1-6 the alkyl group is not substituted with OH, any one atom of the C _1-6 alkyl group may be optionally substituted with O. R ⁵ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms. R ⁵ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms. R ⁵ may be selected from H, CN, halogen, C _1-6 alkyl and C _1-6 alkoxy. R ⁵ may be selected from H, methyl and CH ₂ OH. R ⁵ may be H. R ⁵ may be methyl.

In the compounds of the present specification, R ⁶ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with O. R ⁶ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which when C _1-6 the alkyl group is not substituted with OH, any one atom of the C _1-6 alkyl group may be optionally substituted with O. R ⁶ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms. R ⁶ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms. R ⁶ may be selected from H, CN, halogen, C _1-6 alkyl and C _1-6 alkoxy. R ⁶ may be selected from H, methyl and CH ₂ OH. R ⁶ may be H. R ⁶ may be methyl.

In the compounds in the present description, R ³ may be a group of the formula:

in which each A is independently N or CR ⁷ ;

L is _CH2 or CHOH;

each B represents independently N, CR ⁸ , CR ⁹ or CR ¹⁰ ;

R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms.

In the compounds herein, A may be N or CH. A may be N. A may be ^CR7 . A may be CH. Each A may be CH; or one A may be N and each remaining A may be ^CR7 . Each A may be CH; or one A may be N and each remaining A may be CH.

In the compounds herein, L may be _CH2 . L may be CHOH.

In the compounds herein, B may be N. B may be ^CR8 , ^CR9 , or ^CR10 . B may be CH. Each B may be ^CR8 , ^CR9 , or ^CR10 . Each B may be CH.

R ⁷ may be selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms. R ⁷ may be selected from H, F, CHF ₂ and CF ₃ . R ⁷ may be H.

R ⁸ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl group may be optionally substituted with a heteroatom selected from O, N, S and their oxidized forms. R ⁸ may be selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms. R ⁸ may be selected from H, F, CHF ₂ and CF ₃ . R ⁸ may be H. R ⁸ may be F. R ⁸ may be CHF ₂ . R ⁸ may be CF ₃ .

R ⁹ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl group may be optionally substituted with a heteroatom selected from O, N, S and their oxidized forms. R ⁹ may be selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms. R ⁹ may be selected from H, F, CHF ₂ and CF ₃ . R ⁹ may be H. R ⁹ may be F. R ⁹ may be CHF ₂ . R ⁹ may be CF ₃ .

R ¹⁰ may be selected from H, CN, halogen, C _1-6 alkyl optionally substituted with 1-6 fluorine atoms, and C _1-6 alkoxy optionally substituted with 1-6 fluorine atoms, in which one atom of the C _1-6 alkyl group may be optionally substituted with a heteroatom selected from O, N, S and their oxidized forms. R ¹⁰ may be selected from H, halogen, CN and C _1-3 alkyl optionally substituted with 1-6 fluorine atoms. R ¹⁰ may be selected from H, F, CHF ₂ and CF ₃ . R ¹⁰ may be H. R ¹⁰ may be F. R ¹⁰ may be CHF ₂ . R ¹⁰ may be CF ₃ .

R ⁸ , R ⁹ and R ¹⁰ may be independently selected from H, F, CHF ₂ and CF ₃ .

R ³ can be:

or ;

in which L and B are as defined above.

In the compounds in this description, the group:

may represent:

;

in which R ⁸ , R ⁹ and R ¹⁰ are as defined above.

In the compounds in this description, the group:

may represent:

or .

The compound may be a compound of formula (2a):

or a salt thereof, in which X, Y, R ³ and R ⁴ are as defined above.

The compound may be a compound of formula (3a), (3b), (3c) or (3d):

or a salt thereof, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above.

The compound may be a compound of formula (4a), (4b), (4c), (4d), (4e) or (4f):

or a salt thereof, in which X, Y, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ and R ¹⁰ are as defined above.

The compound may be a compound of formula (5a), (5b), (5c) or (5d):

or a salt thereof, in which R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above.

The compound may be a compound of formula (6a), (6b), (6c), (6d), (6e) or (6f):

or a salt thereof, in which X, Y, R ⁴ , R ⁸ , R ⁹ and R ¹⁰ are as defined above.

The compound may be a compound of formula (7a), (7b), (7c), (7d), (7e) or (7f):

or a salt thereof, in which X, Y, R ¹ , R ² and R ⁴ are as defined above.

The connection may be selected from the group consisting of:

or its salts.

The connection may be selected from the group consisting of:

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-4-carboxamide;

2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-2 H -1,2,3-triazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1 H -pyrazole-3-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy-1 H -pyrazole-4-carboxamide;

2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2 H -1,2,3-triazole-4-carboxamide;

2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-2 H -1,2,3-triazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1 H -pyrazole-4-carboxamide;

1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1 H -pyrazole-3-carboxamide;

(1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- 1H -pyrazol-4-yl)(pyrrolidin-1-yl)methanone;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N ,3-dimethyl-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N, N ,3-trimethyl-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- N -(oxetan-3-yl)-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-hydroxyethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-methoxyethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide;

3-(difluoromethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1 H -pyrazole-4-carboxamide;

3-ethyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide;

3-cyano-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide;

3-cyclopropyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H - pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N ,5-dimethyl-1 H -pyrazole-3-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N, N -dimethyl-1 H -pyrazole-3-carboxamide;

(1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazol-3-yl)(pyrrolidin-1-yl)methanone;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(oxetan-3-yl)-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-hydroxyethyl)-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-methoxyethyl)-1 H -pyrazole-3-carboxamide;

1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1H - pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)- N ,3-dimethyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide;

1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)- N ,3-dimethyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-3-carboxamide;

1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1 H -pyrazole-4-carboxamide;

1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)- N -methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1 H -pyrazole-3-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)- N -methyl-1 H -pyrazole-3-carboxamide;

1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1 H -pyrazole-3-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl- 1H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl-1 H -pyrazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1 H -pyrazole-3-carboxamide;

1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -methyl-1 H -pyrazole-3-carboxamide;

2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-2 H -1,2,3-triazole-4-carboxamide;

1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N ,4-dimethyl-1 H -pyrazole-3-carboxamide;

2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N ,5-dimethyl-2 H -1,2,3-triazole-4-carboxamide;

1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxamide

or their salts.

Further embodiments of the 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 a GPR52 receptor agonist. The compounds of the present invention can be used as GPR52 modulators. The compounds of the present invention can be used as GPR52 agonists. General references to Formula (1) in the specification include all compounds of Formula (1) and Formula (1a).

The compounds of the present invention can be used to treat mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stress-related disorders; disruptive, impulsive, or conduct disorders; sleep-wake patterns disorders; substance use disorders; addictive disorders; behavioral disorders; hypofrontality; tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway disorders; underactivity in the striatum; cortical dysfunction; neurocognitive dysfunction or conditions or symptoms associated with them.

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, addictive/impulse control disorders, autism spectrum disorders, 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 dyskinesia, myoclonus, mirror movement syndrome, paroxysmal kinesiogenic dyskinesia, restless legs syndrome, spasms, stereotypic movement disorder, stereotypy, tic disorder, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or drug-induced psychotic disorder, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or drug-induced bipolar and related disorders associated with another medical condition, separation-induced bipolar and related disorders anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorder associated with another medical condition, anxiety disorders, delirium, major neurocognitive disorder, minor neurocognitive disorder, amnesia, dementia, dyspraxia, stereotyped movement disorder, post-stroke effect, dentato-rubro-pallido-Lewis atrophy, decreased emotional expression, abulia, alogia, and asociality.

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, addictive/impulse control disorders, autism spectrum disorders, 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.

DEFINITIONS

The following definitions apply in this application unless otherwise stated.

As used herein, the term "GPR52 modulator" refers to any compound that binds to 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.

The term "treatment" in relation to the use of any of the compounds described in this application, including the compounds of Formula (1), is used to describe any form of intervention where the compound is administered to a subject suffering from, or at risk for, or potentially at risk of, the disease or disorder in question. Thus, the term "treatment" encompasses both preventive (prophylactic) treatment and treatment that produces measurable or detectable symptoms of the disease or disorder.

The term "effective therapeutic amount" (e.g., in relation to methods of treating a disease or condition) refers to the amount of a compound that is effective to produce the desired therapeutic effect. For example, if the condition is pain, then an effective therapeutic amount is an amount sufficient to provide the desired level of pain relief. The desired level of pain relief may be, for example, complete elimination of pain or a decrease in the severity of pain.

Terms such as "alkyl", "cycloalkyl", "alkoxy" and "halo" are all used in their standard meaning (e.g. as defined in the IUPAC Gold Book) unless otherwise indicated. "Optionally substituted" when applied to any group means that the said group may, if desired, be substituted by one or more substituents which may be the same or different.

Examples of replacement of carbon atoms by a heteroatom include replacement of a carbon atom in the -CH ₂ -CH ₂ -CH ₂ - chain with oxygen or sulfur to produce an ether -CH ₂ -O-CH ₂ - or a thioether -CH ₂ -S-CH ₂ -, replacement of a carbon atom in a CH ₂ -C≡CH group with nitrogen to produce a nitrile (cyano) group CH ₂ -C≡N, replacement of a carbon atom in a -CH ₂ -CH ₂ -CH ₂ - group with C=O to produce a ketone CH ₂ -C(O)-CH ₂ -, replacement of a carbon atom in a -CH ₂ -CH=CH ₂ group with C=O to produce an aldehyde CH ₂ -C(O)H, replacement of a carbon atom in a -CH ₂ -CH ₂ -CH ₃ group with O to produce an alcohol CH ₂ -CH ₂ -CH ₂ OH, replacement of a carbon atom in a -CH ₂ -CH ₂ -CH ₃ with O to give the ether CH ₂ -O-CH ₃ , replacing a carbon atom in the -CH ₂ -CH ₂ -CH ₃ group with S to give the thiol CH ₂ -CH ₂ -CH ₂ SH, replacing a carbon atom in the -CH ₂ -CH ₂ -CH ₂ - group with S=O or SO ₂ to give the sulfoxide -CH ₂ -S(O)-CH ₂ - or the sulfone -CH ₂ -S(O) ₂ -CH ₂ -, replacing a carbon atom in the -CH ₂ -CH ₂ -CH ₂ - chain with C(O)NH to give the amide -CH ₂ -CH ₂ -C(O)-NH-, replacing a carbon atom in the -CH ₂ -CH ₂ -CH ₂ - chain with nitrogen to give the amine -CH ₂ -NH-CH ₂ - and replacing a carbon atom in the -CH ₂ -CH ₂ -CH ₂ - chain with C(O)O to give the complex ester (or carboxylic acid) -CH ₂ -CH ₂ -C(O)-O-. Each such replacement must leave at least one carbon atom of the alkyl group.

To the extent that any of the compounds disclosed have chiral centers, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. The invention described herein pertains to all crystalline forms, solvates and hydrates of any of the disclosed compounds, whether or not prepared in this manner. To the extent that any of the compounds disclosed herein have acidic or basic centers, such as carboxylates or amino groups, then all salt forms of said compounds are included in the present description. When used in pharmaceuticals, a salt should be considered a pharmaceutically acceptable salt.

Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by standard methods, for example, by reacting the compound in free acid or free base form with one or more equivalents of the corresponding acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of said solvent or said medium using standard methods (e.g., under vacuum, freeze drying or filtration). Salts may also be obtained by replacing the counterion of the compound in salt form with another counterion, for example, using a suitable ion exchange resin.

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

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

Also included are any solvates of the compounds and their salts. Preferred solvates are those formed by incorporating into the solid state structure (e.g., crystal structure) of the compounds of the invention molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or solvent mixture containing the solvating solvent. Whether or not a solvate has formed in any given case can be determined by subjecting crystals of the compound to analysis using well-known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

Solvates may be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and the methods used to prepare 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.

The term "pharmaceutical composition" in the context of this invention means a composition containing an active agent and further containing one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, carriers, preservatives, fillers, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the route of administration and the dosage forms. The compositions may have the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, wafers, granules, capsules and suppositories, as well as liquid preparations for injection, including liposomal preparations.

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

Therapeutic dosages may vary depending on the needs of the patient, the severity of the condition being treated, and the compound being administered. Determination of the appropriate dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with lower dosages, which are less than the optimal dosage of the compound. The dosage is then increased in small increments until the optimal effect under the given conditions is achieved. For convenience, the total daily dosage may be divided and, if desired, administered in portions throughout the day.

The effective dose of the compound will, of course, vary depending on the nature of the severity of the condition being treated and on the particular compound and the route of administration. The selection of suitable dosages is within the skill of the art without undue burden. In general, the daily dose range may be from about 10 μg to about 30 mg per kg body weight of humans and non-human animals, preferably from about 50 μg to about 30 mg per kg body weight of humans and non-human animals, for example from about 50 μg to about 10 mg per kg body weight of humans and non-human animals, for example from about 100 μg to about 30 mg per kg body weight of humans and non-human animals, for example from about 100 μg to about 10 mg per kg body weight of humans and non-human animals, and most preferably from about 100 μg to about 1 mg per kg body weight of humans and non-human animals.

PHARMACEUTICAL COMPOSITIONS

Although the active compound can be administered alone, it is preferably presented as a pharmaceutical composition (e.g., formulation).

Accordingly, in some embodiments of the invention there is provided a pharmaceutical composition comprising at least one compound of Formula (1), as defined above, together with at least one pharmaceutically acceptable excipient.

The composition may be a tablet composition.

The composition may be a capsule composition.

The pharmaceutically acceptable excipient(s) can be selected, for example, from carriers (e.g., a solid, liquid or semi-solid carrier), 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 improvers, coating agents, release rate regulators (e.g., polymers or waxes that delay or postpone release), binders, disintegrants, buffering agents, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, tonicity adjusting agents, thickeners, flavoring agents, sweeteners, pigments, plasticizers, taste-masking agents, stabilizers or any other excipients commonly used in pharmaceutical compositions.

As used herein, the term "pharmaceutically acceptable" means compounds, materials, compositions and/or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject (e.g., a human subject) without undue toxicity, irritation, allergic reaction or other problems or complications consistent 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.

Pharmaceutical compositions containing compounds of Formula (1) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, U.S.A. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.

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

Tablet compositions may contain a unit dose of the active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, for example, lactose, sucrose, sorbitol or mannitol; and/or a sugar-free diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or a derivative thereof such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose and starches such as corn starch. Tablets may also contain such conventional ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrating agents (e.g., swelling cross-linked polymers such as cross-linked carboxymethylcellulose), lubricating agents (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (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 herein.

Tablets may be designed to release the drug either upon interaction with stomach fluids (immediate-release tablets) or to release it in a controlled manner (controlled-release tablets) over an extended period of time or in a specific area of the gastrointestinal tract.

The pharmaceutical compositions typically comprise from about 1% (w/w) to about 95%, preferably % (w/w) of the active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (e.g. as defined above) or a combination of such excipients. Preferably, the compositions comprise from about 20% (w/w) to about 90% (w/w) of the active ingredient and from 80% (w/w) to 10% of a pharmaceutical excipient or a combination of excipients. The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical compositions according to the invention may be, for example, in the form of a unit dosage form such as ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow improvers and/or 0-99% (w/w) fillers and/or bulking agents (depending on the dose of the drug). They may also contain 0-10% (w/w) polymeric binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Sustained-release tablets also typically contain 0-99% (w/w) polymers that control (e.g. delay) release (depending on the dose). Film coatings of tablets or capsules typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) water for injection (WFI) (depending on dose and if lyophilized). Intramuscular depot formulations may also contain 0-99% (w/w) oils.

Pharmaceutical formulations may be presented to the patient in "patient packs" containing the entire course of treatment in one package, usually a blister pack.

The compounds of Formula (1) are typically presented in unit dosage form and, as such, typically contain a sufficient amount of the compound to provide the desired level of biological activity. For example, the formulation may contain from 1 nanogram to 2 grams of the active ingredient, such as from 1 nanogram to 2 milligrams of the active ingredient. Within these ranges, particular subranges of the compound are from 0.1 milligram to 2 grams of the active ingredient (more commonly from 10 milligrams to 1 gram, such as from 50 milligrams to 500 milligrams) or from 1 microgram to 20 milligrams (for example, from 1 microgram to 10 milligrams, such as from 0.1 milligram to 2 milligrams of the active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, such as from 50 milligrams to 1 gram, such as from 100 milligrams to 1 gram of the active compound.

The active compound will be administered to a patient in need of such treatment (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of compound to be administered may be determined by the treating physician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference to the following examples shown in Table 1.

Table 1 - Examples

Example 1
Example 2
Example 3
Example 4
Example 5
Example 6
Example 7
Example 8
Example 9
Example 10
Example 11
Example 12
Example 13
Example 14
Example 15
Example 16
Example 17
Example 18
Example 19
Example 20
Example 21
Example 22
Example 23
Example 24
Example 25
Example 26
Example 27
Example 28
Example 29
Example 30
Example 31
Example 32
Example 33
Example 34
Example 35
Example 36
Example 37
Example 38
Example 39
Example 40
Example 41
Example 42
Example 43
Example 44
Example 45
Example 46
Example 47
Example 48
Example 49
Example 50
Example 51
Example 52
Example 53
Example 54
Example 55
Example 56
Example 57
Example 58
Example 59

OBTAINING COMPOUNDS OF THE INVENTION

Compounds of Formula (1) can be prepared according to synthetic methods known to a person skilled in the art. The invention also provides a method for preparing a compound defined by Formula (1) above. In cases where the intermediates are commercially available, they are identified by their registry number (CAS) in Table 3, and in cases where they are not commercially available, the synthesis of the intermediates using standard transformations is described in detail in the present application. Commercial reagents were used without further purification.

General techniques

Room temperature (RT) refers to approximately 20-27°C. ^1H NMR spectra were typically recorded at 400 MHz at ambient temperature unless otherwise stated. Chemical shift values are expressed in parts per million (ppm), i.e., (δ)-values. Standard abbreviations or combinations of them are used for NMR signal multiplicities, e.g., s=singlet, br=broad, d=doublet, t=triplet, k=quartet, qv=quintet or p=pentet, g=heptet, dd=doublet of doublets, dt=doublet of triplets, m=multiplet. Coupling constants are reported as J values measured in Hz. NMR and mass spectroscopy results have been corrected for background peaks. Chromatography refers to column chromatography carried out using silica or C18 silica and carried out under positive pressure conditions (flash chromatography).

LCMS methods

LCMS experiments were performed using electrospray conditions under the following conditions (Solvents: A1=0.1% TFA in _H2O :MeCN (95:5); A2=5 mM ammonium acetate in _H2O ; A3=2.5 L _H2O +2.5 mL 28% ammonia in _H2O solution; A4=0.1% _HCO2H in _H2O :MeCN (95:5); A5=10 mM _NH4HCO3 in _H2O ; A6=0.2% ₂₈ % ammonia in _H2O ; A7=0.1% TFA in _H2O ; A8=50 mM ammonium acetate pH 7.4; 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% ammonia in _H2O solution. LCMS data are reported as 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).

Method 1. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Zorbax XDB C18, 5 μm; 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.

Method 2. Instruments: Waters Acquity UHPLC, Waters 3100 PDA detector, SQD; Column: Acquity BEH C-18, 1.7 μm, 2.1×100 mm; Gradient [time (min)/solvent B2 to A2 (%)]: 0.00/2, 2.00/2, 7.00/50, 8.50/80, 9.50/2, 10.0/2; Injection volume 1 μl; Detection wavelength 214 nm; Column temperature 30°C; Flow rate 0.3 ml/min.

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

Method 4. Instruments: Waters Acquity UHPLC, Waters 3100 PDA detector, SQD; Column: Acquity BEH C-18, 1.7 μm, 2.1×100 mm; Gradient [time (min)/solvent B2 to 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 from 0.6 ml/min to 3.20 min, then 0.8 ml/min.

Method 5. Instruments: Waters Acquity UHPLC, Waters 3100 PDA detector, SQD; Column: Acquity HSS-T3, 1.8 μm, 2.1×100 mm; Gradient [time (min)/solvent B2 in A7 (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90, 8.00/90, 9.00/10, 10.00/10; Injection volume 1 μl; Detection wavelength 214 nm; Column temperature 30°C; Flow rate 0.3 ml/min.

Method 6. Instruments: Hewlett Packard 1100 with G1315A DAD, Micromass ZQ; Column: Phenomenex Gemini-NX C18, 3 μm, 2.0 x 30 mm; Gradient [time (min)/solvent B3 to A3 (%)]: 0.00/2, 0.10/2, 2.5/95, 3.5/95; Injection volume 1 μl; UV detection from 230 to 400 nM; Column temperature 45°C; Flow rate 1.5 ml/min.

Method 7. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Zorbax eclipse plus C18, 1.8 μm, 2.1×50 mm; Gradient [time (min)/solvent B2 in A4 (%)]: 0.0/05, 0.25/05, 2.5/100, 3.0/100, 3.1/05, 4.0/05; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25°C; Flow rate 0.8 mL/min.

Method 8. Instruments: Agilent Technologies 1260 LC with Chemstation software, diode array detector, Agilent 6120 quadrupole MS with APCI and ES source; Column: Phenomenex Gemini-NX C18, 3 μm, 2×30 mm; Gradient [time (min)/solvent B3 to 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.

Method 9. Instruments: Agilent Technologies 1260 LC with Chemstation software, diode array detector, Agilent 6120 quadrupole MS with APCI and ES source; Column: Phenomenex Gemini-NX C18, 3 μm, 2×30 mm; Gradient [time (min)/solvent B3 to A3 (%)]: 0.00/2, 0.10/2, 8.40/95, 10.0/95, 10.1/2, 12.0/2; Injection volume 0.5 μL; UV detection 190-400 nm; Column temperature 40°C; Flow rate 1.5 mL/min.

Method 10. Instrumentation: Waters Acquity H-Class UHPLC MS system with MassLynx software, photodiode array detector (PDA), QDa mass detector with electrospray ionization source; Column: Phenomenex Gemini-NX C18, 3 μm, 2.1×50 mm; Gradient [time (min)/solvent B2 in A8 (%)]: 0.00/0, 1.3/100, 1.55/100, 1.6/0, 3.0/0; Injection volume 1 μL; UV detection 200-500 nm; Column temperature 40°C; Flow rate 0.5 mL/min.

Method 11. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Waters XBridgeC8 3.5 μm, 4.6 x 50 mm; Gradient [time (min)/solvent B1 to A1 (%)]: 0.0/5, 2.5/95, 4.0/95, 4.5/5, 6.0/5; Injection volume 1 μL; UV detection from 210 to 400 nM; Column temperature 25°C; 1.5 mL/min.

Method 12. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Atlantis dC18 5 μm, 4.6 x 50 mm; Gradient [time (min)/solvent B2 to A1 (%)]: 0.0/5, 2.5/95, 4.0/95, 4.5/5, 6.0/5; Injection volume 1 μL; UV detection from 210 to 400 nM; Column temperature 25°C; 1.5 mL/min.

Method 13. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Waters XBridgeC8 3.5 μm, 4.6 x 50 mm; Gradient [time (min)/solvent B2 to A5 (%)]: 0.0/10, 4.0/95, 5.0/95, 5.5/10, 7.0/10; Injection volume 1 μL; UV detection from 210 to 400 nM; Column temperature 25°C; 1.2 mL/min.

Method 14. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Acquity BEH C18 1.7 μm, 2.1 x 50 mm; Gradient [time (min)/solvent B2 to 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 from 210 to 400 nM; Column temperature 25°C; 0.8 mL/min.

Method 15. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 SL quadrupole MSD; Column: Acquity BEH C8 1.7 μm, 2.1 x 50 mm; Gradient [time (min)/solvent B2 to 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 from 210 to 400 nM; Column temperature 25°C; 0.8 mL/min.

GCMS methods

GCMS data are presented in the following format: mass ion, electrospray mode (positive or negative), retention time.

Method 1. Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30 m x 250 μm x 0.25 μm); Inlet Temperature: 250°C; Split Ratio: 75:1; Oven Temperature: 50°C, Retention Time: 3 min; Ramp 1: 40°C/min to 300°C, Retention Time: 2 min; Detector Temperature: 310°C; Column Flow: 2 mL/min; Air Flow: 300 mL/min; _H2 Flow: 40 mL/min; Assist Gas (He) Flow: 25 mL/min; Source Temperature: 230°C.

Method 2. Instrument: Agilent GCMS 7890B; Column: HP-5ms UI (30 m x 250 μm x 0.25 μm); Inlet Temperature: 250°C; Split Ratio: 75:1; Oven Temperature: 120°C, Retention Time: 1 min; Ramp 1: 40°C/min to 300°C, Retention Time: 4 min; Detector Temperature: 310°C; Column Flow: 2 mL/min; Air Flow: 300 mL/min; _H2 Flow: 40 mL/min; Assist Gas (He) Flow: 25 mL/min; Source Temperature: 230°C.

Methods of MS

Method 1 : Data obtained on either a Waters QDA or Waters SQD instrument after 4-6 minutes of running through an UPLC column using buffer.

Preparative HPLC methods

See the LCMS Methods section for solvent conditions.

Method 1. Instrumentation: Gilson semi-preparative HPLC system - 321 pump/171 diode array detector/GX-271 liquid handler; Column: Phenomenex Gemini-NX C18, 5 μm, 30 x 100 mm; Gradient 12.5 min, solvent B2 to A6 (%) varies depending on the individual run (see method examples for details).

Method 2. Instruments: Waters 2767 Autoclean; Column: X Bridge Shield 10 µm 19×250 mm; Gradient 20 min, solvent B2 to A2 (%) varies depending on the individual run (see method examples for details).

Method 3. Instruments: Agilent Technologies 1260 Infinity II Series LC/6125 quadrupole MSD; Column: Waters XBridge C8, 5 µm, 19×150 mm; Gradient [time (min)/solvent B2 to A5 (%)]: 0.0/10, 15/95, 18/95, 19/10, 21/10.

Abbreviations

water = water DAST = (diethylamino)sulfur trifluoride dba = dibenzylideneacetone DXM = dichloromethane Dess-Martin = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIPEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMF-DMA = N,N-dimethylformamide dimethyl acetal DMSO = dimethyl sulfoxide dppf = 1,1'-ferrocenediyl-bis(diphenylphosphine) ER = electrospray EtOAc = ethyl acetate EtOH = ethanol h = watch) HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide IPS = isopropyl alcohol l = liter ZH = liquid chromatography LCMS = liquid chromatography, mass spectrometry MeCN = acetonitrile MeOH = methanol min = minute(s) MS = mass spectrometry NMP = 1-methyl-2-pyrrolidinone NMR = nuclear magnetic resonance Peter.ether = petroleum ether pin = pinacolato CT = room temperature RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TFUK = trifluoroacetic acid THF = tetrahydrofuran

The prefixes n- , vtor- , iso- , t- and tert- have their usual meanings: normal, secondary, iso and tertiary.

SYNTHESIS OF INTERMEDIATES

Preparation of substituted fluoropyridine intermediates

The route to the synthesis of Intermediate 1, using the example of obtaining Intermediate 1, 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

PdCl ₂ (dppf).DCM (284 mg, 0.38 mmol) was added to a degassed solution of (2-fluoropyridin-4-yl)boronic acid (1.3 g, 7.77 mmol), potassium carbonate (3.2 g, 22.3 mmol) and 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.3 g, 9.30 mmol) in 1,4-dioxane (20 mL)/water (5 mL) and the resulting reaction mixture was heated at 90 °C for 1 h. The reaction mixture was partitioned between water (70 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (50 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in petroleum ether to give 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a brown oil (1.8 g, 86%). Data are presented in Table 2 .

The route to the synthesis of Intermediate 2, using the example of obtaining Intermediate 2, 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

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 (2×100 mL). The organic layers _were combined, dried ( _Na2SO4 ) and the solvent was removed in vacuo to give 4-fluoro-2-(tributylstannyl)pyridine as a yellow liquid (14.3 g, crude). 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(PPh ₃ ) 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 (2×100 mL). The combined organic layers _were washed with brine, dried ( _Na2SO4 ) and the solvent was removed in vacuo . The residue was purified by flash column gradient chromatography eluting with 5-10% EtOAc in hexane to give 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a light yellow liquid (400 mg, 6.4% over two steps).

Data in table 2 .

The route to the synthesis of Intermediate 3, using the example of obtaining Intermediate 6, 2-fluoro-6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

Sn ₂ Me ₆ (600 mg, 1.94 mmol) was added to a stirred solution of 2-bromo-6-fluoropyridine (340 mg, 1.94 mmol) in 1,4-dioxane (20 mL) at RT followed by the addition of PdCl ₂ (dppf) (150 mg, 0.19 mmol) and the reaction mixture was heated at 100 °C for 15 h. 1-(Bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (500 mg, 1.94 mmol) and PdCl ₂ (dppf) (150 mg, 0.19 mmol) were then added and the reaction mixture was heated at 100 °C for 15 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography with a gradient, eluting with a 0-5% gradient. EtOAc in petroleum ether to give 2-fluoro-6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a white semi-solid (400 mg, 75%). Data in Table 2 .

Preparation of substituted hydrazinyl intermediates

The route to the synthesis of Intermediate 4, using the example of obtaining Intermediate 3, 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine

Hydrazine hydrate (0.17 mL, 3.52 mmol) was added to a stirred solution of 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 300 mg, 1.17 mmol) in EtOH (10 mL) and the resulting reaction mixture was heated at 60 °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 (50 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo to give 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine as a brown oil (350 mg, 100%). Data are in Table 2 .

Intermediate 13, 4-(3-(difluoromethyl)-5-fluorobenzyl)-2-hydrazinylpyridine

The title compound (110 mg, crude) was prepared in two steps from (2-fluoropyridin-4-yl)boronic acid (145 mg, 1.03 mmol), 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (Intermediate 12, 200 mg, 1.03 mmol), PdCl ₂ (dppf) DCM (84 mg, 0.103 mmol), and K ₂ CO ₃ (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 using the methods of Intermediate 1 and Intermediate 3. After completion of step 2, the title compound was isolated as a yellow gum by partitioning between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo . The crude product was used in the next step without further purification. Data are in Table 2 .

The route to the synthesis of Intermediate 5, using the example of obtaining Intermediate 14, 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine

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 RT. The residual zinc was allowed to settle and the pale green DMF supernatant was transferred via cannula to 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 and then filtered through celite and washed with EtOAc (600 mL). The filtrate was washed with brine (3 x 300 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-5% EtOAc in petroleum ether to give 4-chloro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a yellow semi-solid (8 g, 33%).

LCMS (Method 1) : m/z 290.1 (ES+), at 2.65 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.49 (d,J= 5.2 Hz, 1H), 7.83-7.79 (m, 1H), 7.61-7.41 (m, 4H), 4.23 (s, 2H).

Step 2. Hydrazine hydrate (20 g, 415 mmol) was added to a stirred solution of 4-chloro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (8 g, 27.68 mmol) in IPA (100 mL) in a sealed tube and the reaction mixture was heated at 110 °C for 72 h. The solvent was removed in vacuo and the residue was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine (200 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo to give 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine as a yellow gum (5 g, 63%). Data are in Table 2 .

Preparation of intermediates of substituted azole carboxylic acids

The route to the synthesis of Intermediate 6, using the example of obtaining Intermediate 4, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylic acid

Step 1. A mixture of methyl 3-methyl-1 H -pyrazole-4-carboxylate (150 mg, 1.07 mmol) and 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 2, 292 mg, 1.07 mmol) was heated at 130 °C for 16 h to give methyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylate as a white to off-white solid (400 mg, 95%).

LCMS (Method 4) : m/z 394.3 (ES+), at 2.38 min.

Step 2. NaOH (83 mg, 2.03 mmol) in water (1 mL) was added to a solution of methyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylate (400 mg, 1.02 mmol) in THF (2 mL) and MeOH (1 mL). The reaction mixture was heated at 50 °C for 2 h. The solvent was removed in vacuo and the residue was treated with water (25 mL). The resulting solid was filtered and dried under vacuum to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- 1H- pyrazole-4-carboxylic acid as a white to off-white solid (400 mg, 95%). Data in Table 2 .

The route to the synthesis of Intermediate 7, using the example of obtaining Intermediate 5, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-3-carboxylic acid

Step 1. A mixture of methyl 1 H -pyrazole-3-carboxylate (100 mg, 0.79 mmol) and 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 217 mg, 0.79 mmol) was heated at 120 °C for 48 h. The reaction mixture was diluted with 5% MeOH in DCM and the solvent was removed in vacuo to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-3-carboxylate as a brown semi-solid (220 mg, 73%).

LCMS (Method 4) : m/z 378.3 (ES+), at 2.36 min.

Step 2. A solution of sodium hydroxide (63 mg, 1.58 mmol) in water (2 mL) was added to a solution of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-3-carboxylate (200 mg, 0.52 mmol) in MeOH (10 mL) and the reaction mixture was heated at 80 °C for 16 h. The solvent was removed in vacuo and the residue was acidified with aq. NaHSO ₄ (20 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was washed with heptane (10 mL) and Et ₂ O (10 mL) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-3-carboxylic acid as a white to off-white solid (190 mg, 99%). Data in Table 2 .

Intermediate 7, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1 H -pyrazole-3-carboxylic acid

The title compound (180 mg, 68%) was prepared in two steps from ethyl 4-methyl- 1H- pyrazole-3-carboxylate (100 mg, 0.64 mmol) and 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 177 mg, 0.64 mmol) heated at 130 °C for 16 h; and a solution of NaOH (73 mg, 1.82 mmol) in water (1.5 mL) in MeOH (5 mL) heated at 80 °C for 2 h using the methods of Intermediate 5. After completion of step 2, the title compound was isolated as a white solid by acidifying with aq. NaHSO ₄ (20 mL) and extracting the aqueous layer with EtOAc (3×30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . Data are presented in Table 2 .

Intermediate 8, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-3-carboxylic acid

The title compound (200 mg, 69%) was prepared in two steps from methyl 1H -pyrazole-3-carboxylate (100 mg, 0.79 mmol) and 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 2, 217 mg, 0.79 mmol) heated at 130 °C for 16 h; and a solution of NaOH (153 mg, 3.81 mmol) in water (1.5 mL) in MeOH (6 mL) heated at 80 °C for 4 h using the methods of Intermediate 5. After completion of step 2, the title compound was isolated as a pink solid by acidifying with aq. NaHSO ₄ (20 mL) and extracting the aqueous layer with EtOAc (3×30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . Data are presented in Table 2 .

The route to the synthesis of Intermediate 8, using the example of obtaining Intermediate 9, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-3-carboxylic acid

Step 1. A mixture of methyl 5-methyl- 1H- pyrazole-3-carboxylate (100 mg, 0.71 mmol), 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 195 mg, 0.71 mmol), and cesium carbonate (232 mg, 0.71 mmol) was heated at 140 °C for 16 h. The reaction mixture was diluted with 10% MeOH in DCM, filtered, and the solvent was removed in vacuo to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl- 1H- pyrazole-3-carboxylate as a yellow solid (130 mg, crude). The crude product was used in the next step without further purification.

LCMS (Method 4) : m/z 394.0 (ES+), at 2.32 min.

Step 2. The title compound (100 mg, crude) was prepared from methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl- 1H- pyrazole-3-carboxylate (100 mg, 0.33 mmol) in MeOH (4 mL) and a solution of NaOH (53 mg, 1.32 mmol) in water (1 mL) heated at 80 °C for 16 h using the methods of Intermediate 5, step 2. The title compound was isolated as a yellow semi-solid by acidifying with aq. NaHSO ₄ (20 mL) and extracting the aqueous layer with EtOAc (2×30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . Data are listed in Table 2 .

The route to the synthesis of Intermediate 9, using the example of obtaining Intermediate 15, 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxylic acid

Step 1. Hydrazine hydrate (5.69 g, 114 mmol) was added to a stirred solution of 4-bromo-2-fluoropyridine (2 g, 11.4 mmol) in IPA (100 mL) at RT and the resulting reaction mixture was heated at 100 °C for 16 h. The residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 4-bromo-2-hydrazinylpyridine as a brown solid (1.5 g, 70%).

LCMS (Method 1) : m/z 187.9 (ES-), at 0.41 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 7.85 (d,J=5.2 Hz, 1H), 7.72 (s, 1H), 6.92 (d,J=1.6 Hz, 1H), 6.71 (dd,J=5.4, 2.0 Hz, 1H), 4.21 (s, 2H).

Step 2. 4-Bromo-2-hydrazinylpyridine (520 mg, 2.77 mmol) and acetic acid (0.053 mL, 0.922 mmol) were added to a solution of ethyl 2-(ethoxymethylene)-3-oxobutanoate (343 mg, 1.84 mmol) in EtOH (20 mL) at RT and the reaction mixture was further heated at 80 °C for 15 h. The solvent was removed in vacuo . The residue was triturated with 10% aq. _NaHCO3 solution (15 ml), filtered and dried under vacuum to give ethyl 1-(4-bromopyridin-2-yl)-3-methyl- 1H- pyrazole-4-carboxylate as a white to yellowish or grayish solid (300 mg, 35%).

LCMS (Method 1) : m/z 310.0 (ES+), at 2.64 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.47 (d,J= 5.2 Hz, 1H), 8.10 (s, 1H), 8.07 (d,J= 1.6 Hz, 1H), 7.78 (dd,J= 5.4, 1.6 Hz, 1H), 4.27 (k,J= 7.2 Hz, 2H), 4.25 (s, 3H), 1.31 (t, J= 6.8 Hz, 3H).

Step 3. Potassium acetate (285 mg, 2.90 mmol) and pin ₂ B ₂ (246 mg, 0.97 mmol) were added to a stirred solution of ethyl 1-(4-bromopyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxylate (300 mg, 0.97 mmol) in 1,4-dioxane (5 mL), followed by the addition of PdCl ₂ (dppf).DCM (39.5 mg, 0.048 mmol) and the resulting reaction mixture was heated at 110 °C for 16 h. The solvent was removed in vacuo to give (2-(4-(ethoxycarbonyl)-3-methyl-1 H -pyrazol-1-yl)pyridin-4-yl)boronic acid as a brown semi-solid (300 mg, crude). The crude product was used in the next step without further purification.

LCMS (Method 11) : m/z 276.1 (ES+), at 1.75 min.

Step 4. _K2CO3 (160 mg, 1.156 mmol) and _PdCl2 (dppf).DCM (31.5 mg, 0.039 mmol) were added to a solution of (2-(4-(ethoxycarbonyl)-3-methyl- 1H -pyrazol-1 _- yl)pyridin-4-yl)boronic acid (254 mg, 0.925 mmol) and 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (Intermediate 12, 150 mg, 0.771 mmol) in 1,4-dioxane (10 mL) at RT and the resulting reaction mixture was heated at 110 °C for 15 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The organic layer was separated, dried ( _Na2SO4 ) and the solvent was removed in vacuo . The residue was purified by flash column chromatography with a gradient eluting _with 0-30% EtOAc in petroleum ether to give ethyl 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl- 1H -pyrazole-4-carboxylate as a white to off-white solid (60 mg, 17%).

LCMS (Method 11) : m/z 390.0 (ES+), at 2.93 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.48 (d,J= 5.1 Hz, 1H), 8.06 (d,J= 5.7 Hz, 1H), 7.77 (s, 1H), 7.46-7.41 (m, 3H), 7.32 (d, J= 8.4 Hz, 1H), 7.03 (t,J= 55.5 Hz, 1H), 4.27-4.25 (m, 2H), 4.20 (s, 2H), 2.81 (s, 3H), 1.38-1.28 (m, 3H).

Step 5. LiOH (11.07 mg, 0.462 mmol), water (0.5 mL), and MeOH (0.5 mL) were added to a solution of ethyl 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxylate (60 mg, 0.15 mmol) in 1,4-dioxane (3 mL) at RT and the resulting reaction mixture was stirred at RT for 15 h. The solvent was removed in vacuo . The residue was acidified with 1.5 N HCl (5 mL) to pH ~6 and the aqueous layer was extracted with EtOAc (15 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl- 1H- pyrazole-4-carboxylic acid as a white to off-white solid (40 mg, 72%). Data in Table 2 .

Intermediate 16, 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1 H -pyrazole-3-carboxylic acid

The title compound (60 mg, 6%) was prepared in four steps from 4-bromo-2-fluoropyridine (1.5 g, 8.52 mmol) and methyl 1 H -pyrazole-3-carboxylate (1.6 g, 12.78 mmol) heated at 145 °C for 16 h; potassium acetate (261 mg, 2.66 mmol), pin ₂ B ₂ (248 mg, 0.97 mmol), and PdCl ₂ (dppf).DCM (36.2 mg, 0.04 mol) in 1,4-dioxane (20 mL) heated at 100 °C for 16 h; K ₂ CO ₃ (213 mg, 1.54 mmol), PdCl ₂ (dppf).DCM (21 mg, 0.026 mmol) and 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (Intermediate 12, 100 mg, 0.51 mmol) in 1,4-dioxane (10 ml) heated at 110°C for 15 h; and a solution of NaOH (26.6 mg, 0.664 mmol) in water (0.5 mL) in THF (1 mL) and MeOH (1 mL) stirred at RT for 1 h using the methods of Intermediate 4, step 1, Intermediate 15, steps 3 and 4, and Intermediate 4, step 2. After completion of step 4, the title compound was isolated as a white to off-white solid by acidifying with 1.5 N HCl (5 mL) to pH~6 and extracting the aqueous layer with EtOAc (15 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . Data are in Table 2 .

The route to the synthesis of Intermediate 10, using the example of obtaining Intermediate 17, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxylic acid

Step 1. 4-(3-Fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine (Intermediate 3, 4.69 g, 16.5 mmol) was added to a stirred solution of ethyl 2-methyl 4-oxo-4,5-dihydrofuran-3-carboxylate (Intermediate 10, 2.8 g, 16.5 mmol) in ethanol (50 mL) at RT, followed by the addition of a catalytic amount of acetic acid (0.094 mL, 1.65 mmol) and the resulting reaction mixture was heated at 80 °C for 16 h. Upon cooling, the precipitated solid was filtered, washed with EtOH (2×10 mL) and dried under vacuum to give ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxylate as a white solid (1.95 g, 27%).

LCMS (Method 1) : m/z 438.0 (ES+), at 2.80 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.48 (d,J= 7.2 Hz, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.61-7.59 (m, 2H), 7.43 (d, J= 6.4 Hz, 1H), 5.27 (t,J= 9.2 Hz, 1H), 5.01 (d,J= 8.8 Hz, 2H), 4.29-4.27 (m, 4H), 2.42 (s, 3H), 1.32 (t, J= 9.6 Hz, 3N).

Step 2. Lithium hydroxide monohydrate (1.07 g, 44.5 mmol) was added to a stirred solution of ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxylate (1.95 g, 4.45 mmol) in THF (10 mL), MeOH (10 mL), and water (5 mL), and the resulting reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo . The resulting residue was dissolved in water (30 mL), acidified with 2 N HCl to pH ~2, and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were separated, washed with brine (30 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H- pyrazole-4-carboxylic acid as a white solid (1.81 g, 99%). Data in Table 2 .

Intermediate 18, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxylic acid

The title compound (230 mg, 26%) was prepared in two steps from 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine (Intermediate 14, 600 mg, 2.10 mmol), ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate (Intermediate 10, 430 mg, 2.52 mmol), and acetic acid (0.120 mL, 2.10 mmol) in EtOH (20 mL) heated at 80°C for 16 h; and LiOH (109 mg, 4.57 mmol), water (1 mL), MeOH (1 mL), and 1,4-dioxane (20 mL) stirred at RT for 16 h using the methods of Intermediate 17, step 1 and Intermediate 15, step 5. After completion of Step 2, the title compound was isolated as a pale yellow solid by removing the solvent in vacuo , acidifying with 1.5 N HCl (5 mL) to pH~6, and partitioning between water (10 mL) and EtOAc (15 mL). The organic layer was separated, dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo . Data are in Table 2 .

Intermediate 19, 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxylic acid

The title compound (1.1 g, 76%) was prepared in two steps from 4-(3-(difluoromethyl)-5-fluorobenzyl)-2-hydrazinylpyridine (Intermediate 13, 1.0 g, 3.74 mmol), ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate (Intermediate 10, 0.638 g, 3.74 mmol), and acetic acid (0.021 mL, 0.374 mmol) in EtOH (30 mL) heated at 80°C for 16 h; and LiOH (0.756 g, 31.6 mmol), water (5 mL), MeOH (20 mL) and THF (20 mL) stirred at RT for 16 h using the methods of Intermediate 17. After completion of Step 2, the title compound was isolated as a white solid by removing the solvent in vacuo , dissolving in water (50 mL) and acidifying with 2N HCl to pH~2. The aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine (50 mL), dried ( _Na2SO4 ) and the solvent _removed in vacuo . Data are in Table 2 .

The route to the synthesis of Intermediate 11, using the example of obtaining Intermediate 20, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxycarbonyl)-1 H -pyrazole-4-carboxylic acid

Step 1. 2-Fluoro-6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 6, 0.8 g, 2.93 mmol) and methyl 4-formyl- 1H -pyrazole-3-carboxylate (0.677 g, 4.39 mmol) were heated at 145 °C for 16 h. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with brine (50 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-40% EtOAc in petroleum ether to give methyl 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-formyl- 1H- pyrazole-3-carboxylate as a brown liquid (0.66 g, 50%).

LCMS (Method 14) : m/z 408.0 (ES+), at 2.11 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 10.29 (s, 1H), 9.12 (s, 1H), 8.05 (t, J= 10.8 Hz, 1H), 7.88 (d,J= 10.8 Hz, 1H), 7.69-7.67 (m, 2H), 7.53-7.48 (m, 2H), 4.31 (s, 2H), 3.95 (s, 3H).

Step 2. Sodium dihydrogen phosphate (0.147 g, 1.23 mmol) in water (5 mL) was added to a stirred solution of methyl 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-formyl-1 H -pyrazole-3-carboxylate (0.25 g, 0.61 mmol) in DMSO (30 mL) at RT followed by the addition of sodium chlorite (0.222 g, 2.46 mmol) in water (5 mL) at 0 °C over 30 min. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (50 mL), acidified with 1 N HCl to pH ~5 and extracted with DCM (50 mL). The organic layer was removed and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with brine (30 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo . The residue was purified by flash column gradient chromatography eluting with 0-45% EtOAc in petroleum ether to give 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxycarbonyl)-1H - pyrazole-4-carboxylic acid as a white solid (0.17 g, 65%). Data are in Table 2 .

The route to the synthesis of Intermediate 12, using the example of obtaining Intermediate 21, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1 H -pyrazole-3-carboxylic acid

Step 1. 2-Fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 1 g, 3.66 mmol) and methyl 4-formyl- 1H -pyrazole-3-carboxylate (0.846 g, 5.49 mmol) were heated at 145 °C for 16 h. The reaction mixture was purified by gradient flash column chromatography eluting with 0-20% EtOAc in petroleum ether to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-formyl- 1H -pyrazole-3-carboxylate as a white to off-white solid (970 mg, 65%).

LCMS (Method 12) : m/z 408.0 (ES+), at 2.77 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 10.28 (s, 1H), 9.10 (s, 1H), 8.50 (d, J= 4.8 Hz, 1H), 8.04 (s, 1H), 7.68 (s, 1H), 7.63-7.55 (m, 2H), 7.49 (d, J= 4.8 Hz, 1H), 4.29 (s, 2H), 3.96 (s, 3H).

Step 2. NaOH (95 mg, 2.38 mmol), water (1 mL), and MeOH (1 mL) were added to a stirred solution of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-formyl-1 H -pyrazole-3-carboxylate (970 mg, 2.38 mmol) in 1,4-dioxane (20 mL) and the resulting reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo . The resulting residue was acidified with 1.5 N HCl to pH ~6 and partitioned between water (10 mL) and EtOAc (15 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-formyl- 1H -pyrazole-3-carboxylic acid as a white to off-white solid (800 mg, 85%).

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 9.07 (s, 1H), 8.53 (s, 1H), 8.48 (d, J= 7.2 Hz, 1H), 7.94 (s, 1H), 7.67-7.63 (m, 3H), 7.37 (d, J= 4.8 Hz, 1H), 4.67 (s, 2H). 1 exchange proton is not observed.

Step 3. _NaBH4 (231 mg, 6.10 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-formyl- 1H- pyrazole-3-carboxylic acid (800 mg, 2.03 mmol) in THF (20 mL) and the resulting reaction mixture was stirred at RT for 1 h. The reaction mixture was neutralized with 1 N HCl (10 mL) and the aqueous layer was extracted with 20% MeOH in DCM (20 mL). The organic layer was separated, dried ( _Na2SO4 ) and the solvent was removed in vacuo _. The residue was purified by preparative HPLC (Method 3) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1H - pyrazole-3-carboxylic acid as a white solid (100 mg, 12%). Data in Table 2 .

Intermediate 22, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1 H -pyrazole-3-carboxylic acid

The title compound (35 mg, 15%) was prepared in three steps from 2-fluoro-6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 6, 0.8 g, 2.93 mmol) and methyl 4-formyl- 1H- pyrazole-3-carboxylate (0.677 g, 4.39 mmol) heated at 145 °C for 16 h; LiOH.H ₂ O (8.8 mg, 0.37 mmol), water (0.2 mL), MeOH (2 mL), and THF (2 mL) stirred at RT for 2 h; and NaBH ₄ (0.024 g, 0.636 mmol) in MeOH (10 mL) added at 0 °C and stirred at RT for 24 h using the methods of Intermediate 21, step 1, Intermediate 17, step 2, and Intermediate 21, step 3. After completion of step 3, the title compound was isolated as a yellow gum by removing the solvent in vacuo and dissolving in water (30 mL). The aqueous layer was extracted with 20% MeOH in DCM (5 x 20 mL). The combined organic layers were washed with brine (50 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo . Data are in Table 2 .

The route to the synthesis of Intermediate 13, using the example of obtaining Intermediate 23, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylic acid

Steps 1 and 2. Ethyl 1-(2-bromo-5-methylpyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylate (300 mg, 46%) was prepared in two steps from 2-bromo-4-fluoro-5-methylpyridine (400 mg, 2.11 mmol) and hydrazine hydrate (1.06 mL, 21.1 mmol) in IPA (10 mL) heated at 100°C for 16 h; and ethyl 2-(ethoxymethylene)-3-oxobutanoate (157 mg, 0.85 mmol) and acetic acid (25 mg, 0.42 mmol) in EtOH (5 mL) heated at 80 °C for 15 h using the methods of Intermediate 15, steps 1 and 2. After completion of step 2, the product was isolated as a white to off-white solid by partitioning between water (15 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo .

LCMS (Method 13) : m/z 324.0 (ES+), at 2.22 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.55 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 4.30-4.24 (m, 2H), 2.39 (s, 3H), 2.03 (s, 3H), 1.30 (t, J= 6.8 Hz, 3H).

Step 3. Sn ₂ Me ₆ (455 mg, 1.39 mmol) and Pd(PPh ₃ ) ₄ (53.5 mg, 0.046 mmol) were added to a solution of ethyl 1-(2-bromo-5-methylpyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylate (300 mg, 0.93 mmol) in 1,4-dioxane (10 mL) and the resulting reaction mixture was heated at 110 °C for 15 h. The solvent was removed in vacuo . The residue was triturated with petroleum ether (10 ml) and dried in vacuo to give ethyl 3-methyl-1-(5-methyl-2-(trimethylstannyl)pyridin-4-yl)-1H - pyrazole-4-carboxylate as a brown semi-solid (300 mg, crude). The crude product was used in the next step without further purification.

LCMS (Method 1) : m/z 410.0 (ES+), 1.38 min.

Step 4. Pd( _PPh3 ) ₄ (33.7 mg, 0.029 mmol) was added to a solution of ethyl 3-methyl-1-(5-methyl-2-(trimethylstannyl)pyridin-4-yl)-1H - pyrazole-4-carboxylate (286 mg, 0.70 mmol) and 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (150 mg, 0.58 mmol) in 1,4-dioxane (10 mL), and the resulting reaction mixture was heated at 110°C for 15 h. The solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in petroleum ether to give ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl- 1H- pyrazole-4-carboxylate as a yellow gum (20 mg, 7%).

LCMS (Method 1) : m/z 422.0 (ES+), at 2.73 min.

Step 5. The title compound (30 mg, crude) was prepared from ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl- 1H- pyrazole-4-carboxylate (20 mg, 0.047 mmol) in 1,4-dioxane (3 mL) and sodium hydroxide (5.69 mg, 0.142 mmol), water (0.5 mL), and MeOH (0.5 mL) stirred at RT for 15 h using the methods of Intermediate 15, Step 5. The title compound was isolated as a white to off-white solid by acidifying with 1.5 N HCl (5 mL) to pH ~6 and extracting the aqueous layer with EtOAc (15 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed under vacuum . Data in Table 2 .

The route to the synthesis of Intermediate 14, using the example of obtaining Intermediate 24, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1 H -pyrazole-3-carboxylic acid

Step 1. 2-Fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 300 mg, 1.10 mmol) and dimethyl 1 H -pyrazole-3,5-dicarboxylate (202 mg, 1.10 mmol) were heated at 140 °C for 16 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine (2 x 30 mL), dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in petroleum ether to give dimethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-3,5-dicarboxylate as a white solid (200 mg, 41%).

LCMS (Method 11) : m/z 437.9 (ES+), at 2.86 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.44 (d,J= 6.8 Hz, 1H), 7.85 (s, 1H), 7.67-7.51 (m, 4H), 7.41 (s, 1H), 4.26 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H).

Step 2. _K2CO3 (90 mg, 0.652 mmol) was added to a stirred solution _of dimethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-3,5-dicarboxylate (190 mg, 0.434 mmol) in MeOH (2 mL) and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (30 mL) and acidified with 2N HCl (5 mL) to pH~2. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give a mixture of regioisomers of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxycarbonyl)-1H - pyrazole-5-carboxylic acid and 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(methoxycarbonyl)-1H - pyrazole-3-carboxylic acid as a white gum (140 mg, 76%).

LCMS (Method 15) : m/z 423.9 (ES+), at 1.78 and 1.81 min.

Step 3. _BH3.THF (1 M in THF, 1.65 mL, 1.65 mmol) was added to a stirred solution of a mixture of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxycarbonyl)-1H - pyrazole-5-carboxylic acid and 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(methoxycarbonyl)-1H - pyrazole-3-carboxylic acid (0.140 g, 0.33 mmol) in THF (3 mL) at 0 °C and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched by dropwise addition of MeOH (4 mL) at 0 °C and stirred at RT for 1 h. The solvent was removed under The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in petroleum ether to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H - pyrazole-3 - carboxylate (Isomer 1, 30 mg, 22%) and methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl) -1H- pyrazole-5-carboxylate (Isomer 2, 22 mg, 16%) as white solids.

Isomer 1:

LCMS (Method 11) : m/z 409.9 (ES+), at 2.74 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.45 (d,J= 4.8 Hz, 1H), 7.93 (s, 1H), 7.67 (s, 1H), 7.62-7.56 (m, 2H), 7.40 (d, J= 4.8 Hz, 1H), 6.91 (s, 1H), 5.52 (t, J= 6.0 Hz, 1H), 4.90 (d,J= 6.0 Hz, 2H), 4.27 (s, 2H), 3.86 (s, 3H).

Isomer 2:

LCMS (Method 1) : m/z 410.0 (ES+), at 2.25 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.37 (d,J= 4.8 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.62-7.57 (m, 2H), 7.40 (d, J= 4.8 Hz, 1H), 6.90 (s, 1H), 5.31 (t, J= 4.4 Hz, 1H), 4.86 (d,J= 5.6 Hz, 2H), 4.23 (s, 2H), 3.73 (s, 3H).

Step 4. Lithium hydroxide monohydrate (13 mg, 0.305 mmol) was added to a stirred solution of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H - pyrazole-3-carboxylate (Isomer 1 from the previous step) (25 mg, 0.061 mmol) in THF (0.4 mL), MeOH (0.4 mL) and water (0.16 mL) and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (30 mL) and acidified with 2N HCl (5 mL) to pH ~2. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H - pyrazole-3-carboxylic acid as a white solid (20 mg, 82%). Data in Table 2 .

Preparation of substituted ketoester intermediates

The route to the synthesis of Intermediate 15, using the example of obtaining Intermediate 10, ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate

Sodium ethoxide (7.84 g, 115 mmol) was added to a suspension of ethyl 3-oxobutanoate (10 g, 76.8 mmol) in toluene (50 mL) at 0 °C and the reaction mixture was stirred at RT for 1 h. MeCN (20 mL) and 2-chloroacetyl chloride (6.15 mL, 38.4 mmol) were added and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was acidified with 6 N aq. H ₂ SO ₄ (60 mL), the organic layer was removed and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-10% EtOAc in petroleum ether to give ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate as a yellow liquid (2.8 g, 21%). Data are in Table 2 .

The route to the synthesis of Intermediate 16, using the example of obtaining Intermediate 11, methyl 2-acetyl-4-methoxy-3-oxobutanoate

Acetyl chloride (0.533 g, 6.84 mmol) and pyridine (1.08 g, 13.69 mmol) were added to a stirred solution of methyl 4-methoxy-3-oxobutanoate (1 g, 6.84 mmol) and magnesium chloride (0.646 g, 6.84 mmol) in DCM (10 mL) at RT and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between water (100 mL) and DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-10% EtOAc in petroleum ether to give methyl 2-acetyl 4-methoxy-3-oxobutanoate as a yellow liquid (1 g, 77%). Data are given in Table 2 .

Preparation of substituted benzyl chloride intermediates

The route to the synthesis of Intermediate 17, using the example of obtaining Intermediate 12, 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene

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 RT for 3 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH ~7 and the reaction mixture was partitioned between water (100 mL) and EtOAc ( ₅₀ mL). The organic layer was separated, dried ( _Na2SO4 ) and the solvent was removed in vacuo to give methyl 3-fluoro-5-(hydroxymethyl)benzoate as a colorless liquid (1.12 g, 43%).

GCMS (Method 1) : m/z 184.0 (ES+), at 7.34 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 7.79 (s, 1H), 7.55 (d, J= 12.8 Hz, 1H), 7.43 (d,J= 12.8 Hz, 1H), 5.49 (t,J= 7.6 Hz, 1H), 4.58 (d,J= 7.6 Hz, 2H), 3.87 (d,J= 2.4 Hz, 3H).

Step 2. Dess-Martin periodinane (2.3 g, 5.54 mmol) was added to a solution of methyl 3-fluoro-5-(hydroxymethyl)benzoate (510 mg, 2.77 mmol) in DCM (10 mL) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo . The residue was purified by flash column gradient chromatography eluting with 0-30% EtOAc in hexane to give methyl 3-fluoro-5-formylbenzoate as a white solid (410 mg, 81%).

GCMS (Method 1) : m/z 182.0 (ES+), at 6.76 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 10.08 (d,J= 2.4 Hz, 1H), 8.33 (d,J= 1.6 Hz, 1H), 8.05-8.04 (m, 2H), 3.92 (s, 3H).

Step 3. DAST (0.44 mL, 3.37 mmol) was added to a solution of methyl 3-fluoro-5-formylbenzoate (410 mg, 2.25 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. The reaction mixture was neutralized with 10% NaHCO ₃ (20 mL) to pH ~7 and the reaction mixture was partitioned between water (100 mL) and DCM (50 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by flash column gradient chromatography eluting with 0-30% EtOAc in hexane to give methyl 3-(difluoromethyl)-5-fluorobenzoate as a colorless liquid (400 mg, 87%).

GCMS (Method 2) : m/z 204.0 (ES+), at 2.36 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 7.99 (s, 1H), 7.89 (d, J= 11.2 Hz, 1H), 7.80 (d,J= 11.2 Hz, 1H), 7.35-6.98 (m, 1H), 3.91 (s, 3H).

Step 4. LiAlH ₄ (2.0 M in THF, 0.45 mL, 0.90 mmol) was added to a solution of methyl 3-(difluoromethyl)-5-fluorobenzoate (390 mg, 1.81 mmol) in THF (10 mL) at 0 °C and the reaction mixture was stirred at RT for 1 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH ~ 7 and then partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give (3-(difluoromethyl)-5-fluorophenyl)methanol as a colorless liquid (230 mg, 72%).

GCMS (Method 2) : m/z 176.0 (ES+), at 6.36 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 7.39 (s, 1H), 7.32-7.29 (m, 3H), 5.46 (d, J= 6.4 Hz, 1H), 4.57 (t,J= 6.4 Hz, 2N).

Step 5. Thionyl chloride (3 mL, 43.2 mmol) was added to a solution of (3-(difluoromethyl)-5-fluorophenyl)methanol (170 mg, 0.96 mmol) in chloroform (10 mL) at RT and the reaction mixture was heated at 65 °C for 12 h. The reaction mixture was neutralized with 10% NaHCO ₃ (20 mL) to pH ~7, then partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene as a colorless liquid (170 mg, crude). The crude product was used in the next step without further purification. Data are in Table 2 .

Table 2 - Table of intermediates

Intermediate Name Structure Data 1 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine LCMS (Method 1): m/z 274.0
(ES+), at 2.54 min.
^1H NMR: (400 MHz, DMSO- _d6 ) δ: 8.17 (d, J= 4.4 Hz, 1H), 7.61 (s, 3H), 7.29 (d, J= 1.2 Hz, 1H), 7.16 (s, 1H), 4.17 (d, J= 3.6 Hz, 2H). 2 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine LCMS (Method 2): m/z 274.1
(ES+), at 6.26 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 8.54 (dd, J= 9.1, 5.7 Hz, 1H), 7.60-7.45 (m, 3H), 7.36 (dd, J= 10.2, 2.5 Hz, 1H), 7.20 (ddd, J= 8.6, 5.7, 2.5 Hz, 1H), 4.24 (s, 2H). 3 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine LCMS (Method 1): m/z 286.2
(ES+), at 1.37 min.
^1H NMR: (400 MHz, DMSO- _d6 ) δ: 7.88 (d, J= 5.2 Hz, 1H), 7.53-7.44 (m, 3H), 7.36 (s, 1H), 6.57 (s, 1H), 6.45-6.44 (m, 1H), 4.07 (s, 2H), 3.95 (s, 2H). 4 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazole-4-carboxylic acid LCMS (Method 4): m/z 380.3
(ES+), at 1.67 min.
¹ H NMR: Not registered. 5 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid LCMS (Method 4): m/z 366.0
(ES+), at 1.76 min.
¹ H NMR: Not registered. 6 2-fluoro-6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine LCMS (Method 7): m/z 274.0
(ES+), at 2.48 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 7.94 (d, J= 1.2 Hz, 1H), 7.55-7.48 (m, 3H), 7.33 (d, J= 6.4 Hz, 1H), 7.03 (t, J= 7.2 Hz, 1H), 4.19 (s, 2H). 7 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1H-pyrazole-3-carboxylic acid LCMS (Method 4): m/z 380.2
(ES+), at 1.83 min.
¹ H NMR: Not registered. 8 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-3-carboxylic acid LCMS (Method 8): m/z 366.2
(ES+), at 0.67 min.
¹ H NMR: Not registered. 9 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxylic acid LCMS (Method 4): m/z 380.4
(ES+), at 1.75 min.
¹ H NMR: Not registered. 10 ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate LCMS (Method 11): m/z 171.0
(ES+), at 1.94 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 4.78 (s, 2H), 4.17 (k, J= 3.6 Hz, 2H), 2.50 (s, 3H), 1.22 (t, J= 9.6 Hz, 3H). 11 methyl 2-acetyl-4-methoxy-3-oxobutanoate LCMS (Method 1): m/z 187.1
(ES-), at 1.41 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 4.49 (s, 2H), 3.88 (s, 3H), 3.47 (s, 3H), 2.42 (s, 3H). 1 exchangeable proton is not observed. 12 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene GCMS (Method 2): m/z 193.9
(ES+), at 2.25 min.
¹ H NMR: Not registered. 13 4-(3-(difluoromethyl)-5-fluorobenzyl)-2-hydrazinylpyridine LCMS (Method 11): m/z 267.9
(ES+), at 3.00 min.
¹ H NMR: Not registered. 14 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine LCMS (Method 1): m/z 286.1
(ES+), at 1.19 min.
^1H NMR: (400 MHz, DMSO- _d6 ) δ: 7.95 (d, J= 6.0 Hz, 1H), 7.56-7.21 (m, 4H), 6.59 (d, J= 1.6 Hz, 1H), 6.51-6.49 (m, 1H), 4.15 (s, 2H), 3.99 (s, 2H). 15 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxylic acid LCMS (Method 11): m/z 362.1
(ES+), at 2.23 min.
^1H NMR: (400 MHz, DMSO- _d6 ) δ: 12.57 (s, 1H), 8.47 (d, J= 5.1 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.46-7.40 (m, 3H), 7.32 (d, J= 9.3 Hz, 1H), 7.03 (t, J= 55.8 Hz, 1H), 4.20 (s, 2H), 2.74 (s, 3H). 16 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid LCMS (Method 11): m/z 348.0
(ES+), at 2.55 min.
^1H NMR: (300 MHz, DMSO- _d6 ) δ: 13.10 (s, 1H), 8.68 (d, J= 2.4 Hz, 1H), 8.44 (d, J= 4.8 Hz, 1H), 7.93 (s, 1H), 7.46-7.30 (m, 4H), 7.03 (t, J= 55.8 Hz, 1H), 6.95 (d, J= 2.4 Hz, 1H), 4.23 (s, 2H). 17 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid LCMS (Method 12): m/z 410.0
(ES+), at 2.49 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 8.46 (d, J= 6.8 Hz, 1H), 7.84 (s, 1H), 7.66-7.55 (m, 3H), 7.41 (d, J= 6.8 Hz, 1H), 5.01 (s, 2H), 4.24 (s, 2H), 2.44 (s, 3H). 2 exchangeable protons are not observed. 18 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid LCMS (Method 1): m/z 410.0
(ES+), at 2.03 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 8.65 (d, J= 7.2 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J= 12.4 Hz, 2H), 4.81 (s, 2H), 4.32 (s, 2H), 3.57 (s, 1H), 2.41 (s, 3H). 1 exchangeable proton is not observed. 19 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid LCMS (Method 1): m/z 392.0
(ES+), at 2.48 min.
¹ H NMR: (300 MHz, DMSO-d ₆ ) δ: 8.40 (d, J= 5.1 Hz, 1H), 7.74 (s, 1H), 7.45-7.41 (m, 2H), 7.32-7.30 (m, 2H), 7.03 (t, J= 55.5 Hz, 1H), 4.92 (d, J= 8.1 Hz, 2H), 4.18 (s, 2H), 2.38 (s, 3H). 2 exchangeable protons are not observed. 20 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxycarbonyl)-1H-pyrazole-4-carboxylic acid LCMS (Method 1): m/z 424.0
(ES+), at 2.50 min.
^1H NMR: (400 MHz, DMSO- _d6 ) δ: 13.08 (s, 1H), 8.96 (s, 1H), 8.02 (t, J= 7.6 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.69-7.65 (m, 2H), 7.55 (d, J= 8.4 Hz, 1H), 7.47 (d, J= 7.2 Hz, 1H), 4.31 (s, 2H), 3.88 (s, 3H). 21 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxylic acid LCMS (Method 1): m/z 396.0
(ES+), at 2.01 min.
¹ H NMR: (300 MHz, DMSO-d ₆ ) δ: 8.53 (s, 1H), 8.43 (d, J= 4.8 Hz, 1H), 7.94 (s, 1H), 7.66-7.59 (m, 3H), 7.37 (d, J= 4.8 Hz, 1H), 4.66 (s, 2H), 4.26 (s, 2H). 2 exchangeable protons are not observed. 22 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxylic acid LCMS (Method 11): m/z 395.9
(ES+), at 2.52 min.
¹ H NMR: Not registered. 23 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl-1H-pyrazole-4-carboxylic acid LCMS (Method 1): m/z 394.0
(ES+), at 2.24 min.
¹ H NMR: (400 MHz, DMSO-d ₆ ) δ: 8.65 (s, 1H), 8.04 (s, 1H), 7.59 (s, 1H), 7.55-7.51 (m, 2H), 7.53 (s, 1H), 4.28 (s, 2H), 2.34 (s, 3H), 2.05 (s, 3H). 1 exchangeable proton is not observed. 24 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H-pyrazole-3-carboxylic acid LCMS (Method 12): m/z 396.0
(ES+), at 2.22 min.
^1H NMR: (400 MHz, DMSO- _d6 ) δ: 13.03 (s, 1H), 8.44 (d, J= 5.2 Hz, 1H), 7.91 (d, J= 0.4 Hz, 1H), 7.66 (s, 1H), 7.61-7.55 (m, 2H), 7.39-7.38 (m, 1H), 6.86 (s, 1H), 5.48 (t, J= 6.4 Hz, 1H), 4.89 (d, J= 5.6 Hz, 2H), 4.26 (s, 2H).

SYNTHESIS OF EXAMPLES

Typical methods for obtaining examples, using the example of obtaining the examples given below in Methods 1-15.

Method 1:

Example 1, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-4-carboxamide

1 H- pyrazole-4-carboxamide (49 mg, 0.44 mmol) was added to a solution of 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 30 mg, 0.11 mmol) and triethylamine (0.12 mL, 0.88 mmol) in NMP (2 mL) and the resulting reaction mixture was heated at 150 °C for 4 days. The reaction mixture was partitioned between EtOAc (2 mL) and water (4 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×3 mL), the combined organic layers were dried (phase separator) and the solvent was removed in vacuo . The residue was purified by flash gradient chromatography eluting with 12-100% EtOAc in iso- hexane to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-4-carboxamide as a white solid (7 mg, 17%). Data in Table 3 .

Method 2:

Example 3, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-4-carboxamide

Step 1. A solution of methyl 1H -pyrazole-4-carboxylate (92 mg, 0.73 mmol), 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 200 mg, 0.73 mmol), and _Na2CO3 (155 mg, 1.46 mmol) in DMSO (3 mL) was heated at 120 °C for 12 h. _The reaction mixture was poured into water (20 mL), and the aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were combined and the solvent was removed in vacuo to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-4-carboxylate as a brown semi-solid (210 mg, 76%).

LCMS (Method 4) : m/z 380.1 (ES+), at 2.38 min.

Step 2. A solution of sodium hydroxide (68 mg, 1.66 mmol) in water (1 mL) was added to a solution of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-4-carboxylate (210 mg, 0.55 mmol) in THF (2 mL) and MeOH (2 mL) and the reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo and the residue was acidified with aq. NaHSO ₄ (20 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-4-carboxylic acid as a white to off-white semi-solid (180 mg, 90%).

LCMS (Method 4) : m/z 366.0 (ES+), at 1.71 min.

Step 3. 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-4-carboxylic acid (180 mg, 0.49 mmol), DIPEA (0.26 mL, 1.47 mmol) and methylamine (10 mL, 2 M in THF) were stirred in DCM (2.00 mL) at 0 °C for 10 min and T3P (0.9 mL, 1.47 mmol, 50% solution in EtOAc) was added at 0 °C. The reaction mixture was stirred at RT for 16 h. To the reaction mixture was added aq. NaHCO ₃ (10 mL) and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl) -N- methyl- 1H- pyrazole-4-carboxamide as a white to off-white solid (6 mg, 3%). Data in Table 3 .

Method 3 :

Example 6, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl-1 N -pyrazole-4-carboxamide

Step 1. A mixture of methyl 3,5-dimethyl-1 H -pyrazole-4-carboxylate (100 mg, 0.64 mmol) and 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 177 mg, 0.65 mmol) was heated in a reaction vessel at 135 °C for 16 h and then at 150 °C for 24 h. The reaction mixture was dissolved in 5% MeOH in DCM (10 mL) and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 14-20% EtOAc in hexane to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl- 1H- pyrazole-4-carboxylate as a white solid (90 mg, 34%).

LCMS (Method 4) : m/z 408.4 (ES+), at 2.45 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 8.41 (d,J= 5.0 Hz, 1H), 7.66 (s, 1H), 7.28 (s, 1H), 7.23-7.01 (m, 3H), 4.04 (s, 2H), 3.86 (s, 3H), 2.86 (s, 3H), 2.49 (s, 3H).

Step 2. NaOH (36 mg, 0.88 mmol) was added to a stirred solution of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl- 1H -pyrazole-4-carboxylate (0.12 g, 0.295 mmol) in THF (4 mL), MeOH (4 mL), and water (2 mL). The reaction mixture was heated at 80 °C for 16 h. The solvent was removed in vacuo and the residue was acidified with aq. NaHSO ₄ (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was triturated with _Et2O (10 mL) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl- 1H -pyrazole-4-carboxylic acid (100 mg) as a white solid.

LCMS (Method 4) : m/z 394.3 (ES+), at 1.88 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 12.47 (s, 1H), 8.43 (d, J= 5.0 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.62-7.55 (m, 2H), 7.38 (d, J= 6.0 Hz, 1H), 4.21 (s, 2H), 2.74 (s, 3H), 2.37 (s, 3H).

Step 3. DIPEA (0.14 mL, 0.76 mmol) and HATU (116 mg, 30 mmol) were added successively to a mixture of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl-1 H -pyrazole-4-carboxylic acid (100 mg, 0.25 mmol) in DMF (2 mL). After stirring at RT for 10 min, NH ₄ Cl (68 mg, 1.27 mmol) was added and the resulting mixture was stirred at RT for 20 min. The reaction mixture was diluted with water and the resulting solid was filtered and washed with water (50 mL). The solid was dried under vacuum and then triturated with Et ₂ O (20 mL) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl- 1H- pyrazole-4-carboxamide (11 mg, 11%) as a white solid. Data in Table 3 .

Method 4 :

Example 7, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-4-carboxamide

Step 1: A solution of methyl 3-oxobutanoate (2.00 g, 17.2 mmol) and DMF-DMA (3.08 g, 25.8 mmol) in toluene was heated at 80 °C for 2.5 h. The solvent was removed in vacuo to give methyl (2 E )-2-[(dimethylamino)methylidene]-3-oxobutanoate as a brown semi-solid (2.90 g, crude). The crude product was used in the next step without further purification.

Step 2. Methyl (2 E )-2-[(dimethylamino)methylidene]-3-oxobutanoate (2, 180 mg, 1.05 mmol) and AcOH (2 mL) were added to a stirred solution of 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine (Intermediate 3, 150 mg, 0.526 mmol) in EtOH. The reaction mixture was heated at 90 °C for 2 h. The solvent was removed in vacuo and the residue was purified by flash gradient chromatography eluting with 20-30% EtOAc in hexane to give methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl- 1H -pyrazole-4-carboxylate as a white to off-white to grayish solid (200 mg, crude). The crude product was used in the next step without further purification.

LCMS (Method 4) : m/z 394.0 (ES+), at 2.51 min.

Step 3. Sodium hydroxide (62.5 mg, 1.53 mmol) was added to a solution of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl- 1H- pyrazole-4-carboxylate (200 mg, 0.508 mmol) in MeOH (4 mL) and the reaction mixture was heated at 80 °C for 5 h. The solvent was removed in vacuo and the residue was acidified with aq. NaHSO ₄ (20 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was triturated with _Et2O (10 mL) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl- 1H -pyrazole-4-carboxylic acid as a brown solid (150 mg, crude). The crude product was used in the next step without further purification.

LCMS (Method 4) : m/z 380.3 (ES+), at 1.76 min.

Step 4. HATU (301 mg, 0.791 mmol) and DIPEA (0.37 mL, 1.98 mmol) were added to a solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-4-carboxylic acid (150 mg, 0.395 mmol) in DMF (5 mL) at 0 °C. The reaction mixture was stirred for 15 min at the same temperature and ammonium chloride (106 mg, 1.98 mmol) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with ice water (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine, dried ( _Na2SO4 ) _, and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-10% MeOH in DCM to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl- 1H- pyrazole-4-carboxamide as a white to off-white solid (30 mg, 20%). Data are given in Table 3 .

Method 5 :

Example 11, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy-1 H -pyrazole-4-carboxamide

Step 1. Ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy- 1H -pyrazole-4-carboxylate (36 mg, 46%) was prepared from 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (50 mg, 0.18 mmol), ethyl 3-methoxy- 1H -pyrazole-4-carboxylate (62 mg, 0.37 mmol), and triethylamine (0.15 mL, 1.10 mmol) in NMP (1.8 mL) heated at 160 °C for 26 h using the methods of Procedure 1. The residue was purified by flash column chromatography with a gradient eluting with 0-100% EtOAc in iso- hexane to give the product.

LCMS (Method 6) : m/z 424.2 (ES+), at 2.45 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 9.12 (s, 1H), 8.56 (dd, J= 5.6, 0.6 Hz, 1H), 7.96 (dd,J= 2.2, 0.6 Hz, 1H), 7.76 (dd,J=5.6, 2.3 Hz, 1H), 7.59 (td,J= 1.5, 0.8 Hz, 1H), 7.57-7.50 (m, 2H), 4.30-4.20 (m, 4H), 4.00 (s, 3H), 1.29 (t, J= 7.1 Hz, 3N).

Step 2. Ammonium hydroxide solution (28% in _H2O , 3 mL) was added to a suspension of ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy- 1H- pyrazole-4-carboxylate (15 mg, 0.04 mmol) in MeOH (1.5 mL). The reaction mixture was heated at 50 °C for 16 h. Additional ammonium hydroxide solution (28% in H ₂ O, 1 mL) was added and the reaction mixture was heated at 80 °C for 3 h. The solvent was removed in vacuo , the residue was dissolved in a solution of NH ₃ in 1,4-dioxane (0.5 M, 3 mL), and the reaction mixture was heated at 90 °C for 16 h. Ammonium hydroxide solution (28% in H ₂ O, 1 mL) was added and the reaction mixture was heated at 100 °C for 4 h. The solvent was removed in vacuo and the residue was dissolved in a solution of NH ₃ in MeOH (7 N, 2.5 mL) and 1,4-dioxane (1 mL). The reaction mixture was heated at 100 °C for 18 h. Lithium methoxide (18 mg, 0.47 mmol) and additional NH ₃ in MeOH (7 N, 2.5 mL) were added and the reaction mixture was heated at 100 °C for 68 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Method 1, 5-95% gradient) to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy-1 H -pyrazole-4-carboxamide (3 mg, 18%). Data are in Table 3 .

Method 6 :

Example 12, 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2 N -1,2,3-triazole-4-carboxamide

Step 1. Methyl 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl- 2H- 1,2,3-triazole-4-carboxylate (30 mg, 42%) was prepared from 4-fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 2, 50 mg, 0.18 mmol) and methyl 5-methyl- 1H -1,2,3-triazole-4-carboxylate (31 mg, 0.22 mmol) heated at 160 °C for 72 h using the methods of Procedure 3, step 1. The residue was purified by flash column chromatography with a gradient eluting with 0-50% EtOAc in iso -hexane to give the product.

LCMS (Method 6) : m/z 395.1 (ES+), at 2.47 min.

¹ H NMR: (400 MHz, CDCl₃) δ: 8.61 (dd,J= 5.5, 0.7 Hz, 1H), 7.94-7.75 (m, 2H), 7.30 (td, J= 1.6, 0.8 Hz, 1H), 7.13 (tt,J= 8.7, 2.1 Hz, 2H), 4.19 (s, 2H), 3.93 (s, 3H), 2.55 (s, 3H).

Step 2. Methyl 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2 H -1,2,3-triazole-4-carboxylate (23 mg, 0.06 mmol) was added to a solution of NH ₃ in MeOH (7 N, 1.6 mL) and a solution of sodium methoxide in MeOH (0.4 M, 0.16 mL, 0.06 mmol). The reaction mixture was heated at 65 °C for 18 h. The solvent was removed in vacuo and the residue was purified by flash gradient chromatography eluting with 0-100% DCM/MeOH/2 M NH ₃ in MeOH (89:10:1) in DCM to give 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2 H -1,2,3-triazole-4-carboxamide as a white solid (17 mg, 77%). Data are in Table 3 .

Method 7 :

Example 14, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1 H -pyrazole-4-carboxamide

Step 1. Ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy- 1H- pyrazole-4-carboxylate (44 mg, 28%) was prepared from 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 1, 100 mg, 0.37 mmol) and ethyl 3-methoxy- 1H- pyrazole-4-carboxylate (62 mg, 0.37 mmol) heated at 160 °C for 29 h using the methods of Procedure 3, step 1. The residue was purified by flash column chromatography with a gradient eluting with 0-10% MeOH in DCM to give the product.

LCMS (Method 6) : m/z 424.1 (ES+), at 2.63 min.

¹ H NMR: (400 MHz, CDCl₃) δ: 8.87 (s, 1H), 8.32 (dd, J= 5.0, 0.7 Hz, 1H), 7.71 (dt,J= 1.6, 0.7 Hz, 1H), 7.30 (dd,J= 1.9, 1.1 Hz, 1H), 7.24 (d, J= 8.3 Hz, 1H), 7.09 (d,J= 8.8 Hz, 1H), 6.96 (ddd, J= 5.1, 1.5, 0.7 Hz, 1H), 4.32 (k,J= 7.1 Hz, 2H), 4.10 (s, 2H), 4.09 (s, 3H), 1.35 (t, J= 7.1 Hz, 3H).

Step 2. A solution of NH ₃ in MeOH (7 N, 2.9 mL) was added to ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1 H -pyrazole-4-carboxylate (44 mg, 0.10 mmol) and the reaction mixture was heated at 80 °C for 72 h. The solvent was removed in vacuo and the residue was purified by flash gradient chromatography eluting with 0-10% MeOH in DCM to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1 H -pyrazole-4-carboxamide as a white solid (7 mg, 17%). Data are in Table 3 .

Method 8 :

Example 16, (1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazol-4-yl)(pyrrolidin-1-yl)methanone

DIPEA (0.09 mL, 0.52 mmol) was added to a solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylic acid (Intermediate 4, 50 mg, 0.13 mmol) and pyrrolidine (28 mg, 0.39 mmol) in DCM (1.3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and to it was added T3P (0.16 mL, 0.26 mmol, 50% solution in EtOAc). The reaction mixture was stirred at RT for 16 h. Water (5 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers _were dried ( _Na2SO4 ) and the solvent was removed in vacuo . The residue was purified by preparative HPLC (Method 2, 10-80% gradient) to give (1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- 1H -pyrazol-4-yl)(pyrrolidin-1-yl)methanone as a white solid (15 mg, 27%). Data in Table 3 .

Method 9 :

Example 20, 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-hydroxyethyl)-3-methyl-1 H -pyrazole-4-carboxamide

DIPEA (0.09 mL, 0.52 mmol) and HATU (62 mg, 0.26 mmol) were added successively to a stirred solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylic acid (Intermediate 4, 50 mg, 0.13 mmol) in DMF (2 mL) at 0 °C. After 10 min, 2-aminoethan-1-ol (16 mg, 0.26 mmol) was added at 0 °C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with ice-water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were combined, washed with brine (50 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by preparative HPLC (Method 2, 20-80% gradient) to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl) -N- (2-hydroxyethyl)-3-methyl- 1H -pyrazole-4-carboxamide as a white solid (5 mg, 9%). Data are given in Table 3 .

Method 10 :

Example 22, 3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide

Step 1. 4-Fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 2, 150 mg, 0.55 mmol) and ethyl 3-chloro- 1H- pyrazole-4-carboxylate (125 mg, 0.71 mmol) were combined and then heated at 150 °C for 30 min. The reaction mixture was allowed to cool to RT and purified by flash gradient chromatography eluting with 0-80% EtOAc in iso- hexane to give ethyl 3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H - pyrazole-4-carboxylate (180 mg, 77%).

LCMS (Method 8) : m/z 428.2 (ES+), at 1.85 min.

¹ H NMR: (400 MHz, CDCl₃) δ: 8.69 (dd,J= 5.6, 0.6 Hz, 1H), 8.10 (s, 1H), 7.61 (dd, J= 2.2, 0.7 Hz, 1H), 7.51 (dd,J= 5.6, 2.2 Hz, 1H), 7.37 (tt,J= 1.4, 0.7 Hz, 1H), 7.26-7.16 (m, 2H), 4.37 (k, J= 7.1 Hz, 2H), 4.28 (s, 2H), 1.40 (t, J= 7.1 Hz, 3N).

Step 2. Ethyl 3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H - pyrazole-4-carboxylate (180 mg, 0.42 mmol) was dissolved in EtOH (5 mL). Sodium hydroxide (1 N in water, 2 mL, 2.0 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was partitioned between EtOAc (30 mL) and 1 N HCl (20 mL). The organic layer was separated, dried (MgSO ₄ ) and the solvent was removed in vacuo . The residue was dissolved in DMF (5 mL). HATU (481 mg, 1.26 mmol), ammonium chloride (68 mg, 1.26 mmol) and DIPEA (0.22 ml, 1.26 mmol) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was separated, washed with water (30 ml), brine (20 ml), dried (MgSO ₄ ) and the solvent was removed in vacuo . The residue was purified by flash gradient chromatography eluting with 0-8% MeOH in DCM. The residue was further purified by preparative HPLC (Method 1 - gradient 35-65%) to give 3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H - pyrazole-4-carboxamide as a white solid (74 mg, 44%). Data in Table 3 .

Method 11 :

Example 39, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide

DIPEA (3.06 mL, 17.68 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H -pyrazole-4-carboxylic acid (Intermediate 17, 1.81 g, 4.42 mmol) and ammonium chloride (0.354 g, 6.63 mmol) in DMF (50 mL), followed by the addition of HATU (3.36 g, 8.84 mmol) and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried ( _Na2SO4 ) and the solvent was removed in vacuo . The residue was purified by flash column chromatography with a gradient eluting _with 0-85% EtOAc in petroleum ether. The title compound was dissolved in MeOH (35 mL) and heated to reflux. The resulting clear solution was allowed to cool to RT and stood undisturbed for 48 h. The recrystallized solid was filtered, washed with MeOH (2×10 mL) and dried in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H -pyrazole-4-carboxamide as a white crystalline solid (0.52 g). The recrystallization process was repeated from the remaining mother liquor to obtain an additional 0.208 g of material. Overall yield was 0.728 g, 40%. Data are in Table 3 .

Method 12 :

Example 40, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide

HATU (0.11 g, 0.293 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H -pyrazole-4-carboxylic acid (Intermediate 17, 0.06 g, 0.15 mmol) and 2-aminoethan-1-ol (0.012 g, 0.22 mmol) in DMF (3 mL) at 0 °C, followed by the addition of DIPEA (0.038 mg, 0.29 mmol) and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated and washed with brine (50 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by flash column chromatography with a gradient eluting with 0-50% EtOAc in petroleum ether to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl) -N- (2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl- 1H -pyrazole-4-carboxamide as a white solid (18 mg, 27%). Data are in Table 3 .

Method 13 :

Example 47, 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1 H -pyrazole-4-carboxamide

Step 1. DIPEA (0.279 mL, 1.61 mmol) was added to a stirred solution of 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxycarbonyl)-1H - pyrazole-4-carboxylic acid (Intermediate 20, 0.17 g, 0.40 mmol) and ammonium chloride (0.021 g, 0.40 mmol) in DMF (30 mL), followed by the addition of HATU (0.305 g, 0.80 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice water (30 mL). The precipitated solid was filtered, washed with water (2×20 mL) and dried under vacuum to give methyl 4-carbamoyl-1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-3-carboxylate as a white solid (0.165 g, 97%).

LCMS (Method 1) : m/z 423.0 (ES+), at 2.26 min.

¹ H NMR: (400 MHz, DMSO-d ₆) δ: 9.02 (s, 1H), 9.00 (s, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.84 (d,J= 7.6 Hz, 1H), 7.66 (s, 1H), 7.61 (d,J= 8.8 Hz, 1H), 7.56-7.54 (m, 2H), 7.46 (d, J= 7.2 Hz, 1H), 4.32 (s, 2H), 3.90 (s, 3H).

Step 2. Sodium borohydride (0.076 g, 2.01 mmol) was added to a stirred solution of methyl 4-carbamoyl-1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazole-3-carboxylate (0.17 g, 0.40 mmol) in MeOH (30 mL) at 0 °C. The reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo . The residue was dissolved in water (40 mL) and extracted with DCM (40 mL). The organic layer was removed and the aqueous layer was extracted with DCM (40 mL). The combined organic layers were separated and washed with brine (50 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by gradient flash column chromatography eluting with 0-58% EtOAc in petroleum ether to give 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1H - pyrazole-4-carboxamide as a white solid (0.112 g, 70%). Data in Table 3 .

Method 14 :

Example 53, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl-1 N -pyrazole-4-carboxamide; Example 39, 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide

Step 1. 4-(3-Fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine (Intermediate 3, 1.5 g, 5.26 mmol) and acetic acid (0.03 mL, 0.526 mmol) were added to a stirred solution of methyl 2-acetyl 4-methoxy-3-oxobutanoate (Intermediate 11, 0.99 g, 5.26 mmol) in EtOH (15 mL) and the resulting reaction mixture was heated at 90 °C for 16 h. The residue was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by flash column chromatography with a gradient eluting with 0-30% EtOAc in petroleum ether to give a mixture of regioisomers of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxymethyl)-5-methyl- 1H -pyrazole-4-carboxylate and methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(methoxymethyl)-3-methyl- 1H -pyrazole-4-carboxylate as a red gum (0.25 g, 10%).

LCMS (Method 1) : m/z 438.0 (ES+), at 2.64 min.

Step 2. _BBr3 (1 M in DCM, 5.72 mL, 5.72 mmol) was added to a stirred solution of a mixture of methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(methoxymethyl)-5-methyl- 1H -pyrazole-4-carboxylate and methyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(methoxymethyl)-3-methyl- 1H- pyrazole-4-carboxylate (0.25 g, 0.572 mmol) in DCM (5 mL) at 0 °C and the resulting reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo . The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried ( _Na2SO4 ) and the solvent was removed in vacuo . The residue was dissolved in THF (2 mL), MeOH (2 mL) and water (0.5 mL), lithium hydroxide monohydrate (41 mg, 0.99 _mmol ) was added and the resulting reaction mixture was stirred at RT for 3 h. The solvent was removed in vacuo . The residue was dissolved in water (30 mL) and acidified with 2 N HCl to pH~2. The aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give a mixture of regioisomers of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl- 1H -pyrazole-4-carboxylic acid and 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H -pyrazole-4-carboxylic acid as a white to off-white solid (0.2 g, crude). The crude product was used in the next step without further purification.

LCMS (Method 11) : m/z 409.9 (ES+), at 2.36 and 2.40 min.

Step 3. HATU (0.279 g, 0.735 mmol) was added to a stirred solution of a mixture of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl- 1H -pyrazole-4-carboxylic acid and 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H- pyrazole-4-carboxylic acid (0.2 g, 0.49 mmol) and NH ₄ Cl (0.033 g, 0.62 mmol) in DMF (5 mL), followed by the addition of DIPEA (0.21 mL, 0.12 mmol) at 0 °C and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo . The residue was purified by preparative HPLC (Method 3) to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl- 1H -pyrazole-4-carboxamide (Example 53, 11 mg, 5%) and 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl- 1H -pyrazole-4-carboxamide (Example 39, 22 mg, 11%) as white solids. Data are in Table 3 .

Method 15 :

Example 59, 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxamide

Step 1. 4-Fluoro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (Intermediate 2, 300 mg, 1.10 mmol) and ethyl 3-methyl-1 H -pyrazole-4-carboxylate (169 mg, 1.10 mmol) were heated at 150°C for 5 days. The residue was purified by gradient flash column chromatography eluting with 0-80% EtOAc in iso- hexane to give ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- 1H- pyrazole-4-carboxylate (Product 1, 150 mg, 34%) and ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-3-methyl- 1H- pyrazole-4-carboxylate (Product 2, 300 mg, 65%).

Product 2:

LCMS (Method 8) : m/z 422.2 (ES+), at 1.92 min.

Step 2. Sodium hydroxide (1 N in water, 2 mL, 2.0 mmol) was added to a solution of ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxylate (300 mg, 0.71 mmol) in EtOH (5 mL) and the reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (30 mL) and 1 N HCl (20 mL). The organic layer was separated, dried (MgSO ₄ ) and the solvent was removed in vacuo . The residue was dissolved in DMF (5 mL). HATU (814 mg, 2.14 mmol), ammonium chloride (114 mg, 2.14 mmol) and DIPEA (0.37 ml, 2.14 mmol) were added and the reaction mixture was stirred at RT for 3 h. The reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was separated, washed with water (30 ml), brine (20 ml), dried (MgSO ₄ ) and the solvent was removed in vacuo . The residue was purified by flash column chromatography eluting with 0-8% MeOH in DCM to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzoyl)pyridin-4-yl)-3-methyl- 1H- pyrazole-4-carboxamide and 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl- 1H -pyrazole-4-carboxamide (Example 59). The resulting 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl- 1H -pyrazole-4-carboxamide was further purified by preparative HPLC (Method 1, 25-50% gradient) to give a white solid (33 mg, 12%). Data are in Table 3 .

Additional examples obtained using the above techniques are detailed in Table 3.

Table 3 - Table of examples

Ave. No. Name Intermediate/method ¹ H NMR LCMS 1 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide Intermediate 1 and CAS: 437701-80-9
Method 1 (400 MHz, DMSO-d ₆ ) δ: 9.11 (d, J= 0.8 Hz, 1H), 8.43 (dd, J= 5.1, 0.7 Hz, 1H), 8.12 (d, J= 0.7 Hz, 1H), 7.91 (dd, J= 1.6, 0.8 Hz, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.63-7.52 (m, 2H), 7.36 (dd, J=5.1, 1.5 Hz, 1H), 7.23 (s, 1H), 4.24 (s, 2H). m/z 365.6 (M+H)+ (ES+), at 4.15 min, 96%
(Method 3) 2 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 437701-80-9
Method 1 (400 MHz, Methanol-d ₄ ) δ: 8.88 (s, 1H), 8.59 (d, J= 5.6 Hz, 1H), 8.17 (s, 1H), 7.88 (d, J= 2.0 Hz, 1H), 7.76 (dd, J= 5.6, 2.2 Hz, 1H), 7.49 (s, 1H), 7.37 (dd, J= 9.4, 2.1 Hz, 1H), 7.31 (dd, J= 8.7, 2.1 Hz, 1H), 4.31 (s, 2H). 2 exchangeable protons are not observed. m/z 363.3 (MH)- (ES-), 365.2 (M+H)+ (ES+), at 3.75 min, 100%
(Method 3) 3 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide Intermediate 1 and CAS: 51105-90-9
Method 2 (400 MHz, DMSO-d ₆ ) δ: 9.06 (s, 1H), 8.43 (d, J= 5.1 Hz, 1H), 8.31 (d, J= 4.8 Hz, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.63-7.53 (m, 2H), 7.36 (dd, J= 5.1, 1.4 Hz, 1H), 4.23 (s, 2H), 2.74 (d, J= 4.5 Hz, 3H). m/z 379.2 (M+H)+ (ES+), at 5.84 min, 94%
(Method 2) 4 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-2H-1,2,3-triazole-4-carboxamide Intermediate 1 and CAS: 4967-77-5
Method 3 (400 MHz, DMSO-d ₆ ) δ: 8.52 (d, J= 5.0 Hz, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 8.05 (d, J= 1.3 Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.64-7.54 (m, 2H), 7.50 (dd, J= 5.0, 1.5 Hz, 1H), 4.27 (s, 2H). m/z 366.1 (M+H)+ (ES+), at 5.50 min, 97%
(Method 2) 5 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 1 and CAS: 23170-45-8
Method 3 (400 MHz, DMSO-d ₆ ) δ: 9.15 (s, 1H), 8.39 (d, J= 5.1 Hz, 1H), 7.88 (s, 1H), 7.79-7.47 (m, 4H), 7.31 (d, J= 5.2 Hz, 1H), 7.08 (s, 1H), 4.22 (s, 2H), 2.44 (s, 3H). m/z 379.2 (M+H)+ (ES+), at 5.91 min, 99%
(Method 2) 6 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide Intermediate 1 and CAS: 25016-18-6
Method 3 (400 MHz, DMSO-d ₆ ) δ: 8.41 (d, J= 5.0 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.60-7.52 (m, 2H), 7.32 (d, J= 6.0 Hz, 1H), 7.24 (s, 2H), 4.20 (s, 2H), 2.63 (s, 3H), 2.32 (s, 3H). m/z 393.2 (M+H)+ (ES+), at 5.69 min, 99%
(Method 2) 7 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxamide Intermediate 3 and CAS: 105-45-3
Method 4 (400 MHz, DMSO-d ₆ ) δ: 8.45 (d, J= 5.0 Hz, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.70-7.52 (m, 4H), 7.39 (dd, J= 5.2, 1.4 Hz, 1H), 7.10 (s, 1H), 4.22 (s, 2H), 2.77 (s, 3H). m/z 379.1 (M+H)+ (ES+), at 5.67 min, 99%
(Method 2) 8 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 4 and CAS: 12125-02-9
Method 9 (400 MHz, DMSO-d ₆ ) δ: 9.00 (s, 1H), 8.58 (d, J= 5.6 Hz, 1H), 7.81 (d, J= 1.9 Hz, 1H), 7.59-7.56 (m, 2H), 7.53 (d, J= 9.1 Hz, 2H), 7.47 (s, 1H), 7.18 (s, 1H), 4.28 (s, 2H), 2.42 (s, 3H). m/z 379.2 (M+H)+ (ES+), at 4.98 min, 99%
(Method 5) 9 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-3-carboxamide Intermediate 5 and CAS: 12125-02-9
Method 9 (400 MHz, DMSO-d ₆ ) δ: 8.63 (d, J= 2.6 Hz, 1H), 8.42 (d, J= 5.1 Hz, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.65-7.46 (m, 4H), 7.40-7.24 (m, 1H), 6.89 (d, J= 2.6 Hz, 1H), 4.23 (s, 2H). m/z 365.2 (M+H)+ (ES+), at 5.77 min, 97%
(Method 2) 10 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1H-pyrazole-3-carboxamide Intermediate 7 and CAS:
12125-02-9
Method 9 (400 MHz, DMSO-d ₆ ) δ: 8.44 (d, J= 1.1 Hz, 1H), 8.39 (d, J= 5.1 Hz, 1H), 8.02 (d, J= 1.4 Hz, 1H), 7.69-7.49 (m, 4H), 7.38 (s, 1H), 7.28 (dd, J= 5.1, 1.5 Hz, 1H), 4.21 (s, 2H), 2.26 (s, 3H). m/z 379.1 (M+H)+ (ES+), at 6.24 min, 99%
(Method 2) 11 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 478968-48-8
Method 5 (400 MHz, Methanol-d ₄ ) δ: 8.66 (s, 1H), 8.44 (dd, J= 5.8, 0.6 Hz, 1H), 7.75 (dd, J= 2.2, 0.6 Hz, 1H), 7.62 (dd, J= 5.7, 2.2 Hz, 1H), 7.41 (td, J= 1.6, 0.8 Hz, 1H), 7.35-7.26 (m, 1H), 7.26-7.16 (m, 1H), 4.20 (s, 2H), 4.05 (s, 3H). 2 exchangeable protons are not observed. m/z 395.2 (M+H)+ (ES+), at 3.92 min, 100%
(Method 3) 12 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2H-1,2,3-triazole-4-carboxamide Intermediate 2 and CAS: 60419-70-7
Method 6 (400 MHz, Methanol-d ₄ ) δ: 8.53 (dd, J = 5.6, 0.7 Hz, 1H), 7.97 (dk, J = 2.2, 0.7 Hz, 1H), 7.86 (dd, J = 5.6, 2.1 Hz, 1H), 7.39 (ct, J = 1.3, 0.6 Hz, 1H), 7.31-7.25 (m, 1H), 7.24-7.16 (m, 1H), 4.22 (d, J = 8.1 Hz, 2H), 2.48 (s, 3H). 2 exchangeable protons are not observed. m/z 380.1 (M+H)+ (ES+), at 4.25 min, 100%
(Method 3) 13 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-2H-1,2,3-triazole-4-carboxamide Intermediate 1 and CAS: 60419-70-7
Method 6 (400 MHz, Methanol-d ₄ ) δ: 8.37 (dd, J= 5.1, 0.7 Hz, 1H), 7.96 (dk, J= 1.3, 0.7 Hz, 1H), 7.40 (s, 1H), 7.33-7.19 (m, 3H), 4.16 (d, J= 8.4 Hz, 2H), 2.50 (s, 3H). 2 exchangeable protons are not observed. m/z 380.1 (M+H)+ (ES+), at 4.13 min, 98%
(Method 3) 14 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1H-pyrazole-4-carboxamide Intermediate 1 and CAS: 478968-48-8
Method 7 (400 MHz, Methanol-d ₄ ) δ: 8.77 (s, 1H), 8.24 (dd, J= 5.1, 0.7 Hz, 1H), 7.67 (dk, J= 1.5, 0.7 Hz, 1H), 7.37 (dd, J= 1.8, 1.0 Hz, 1H), 7.31-7.18 (m, 2H), 7.06 (ddd, J= 5.1, 1.4, 0.7 Hz, 1H), 4.11 (s, 2H), 4.02 (s, 3H). 2 exchangeable protons are not observed. m/z 395.2 (M+H)+ (ES+), at 4.52 min, 100%
(Method 3) 15 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1H-pyrazole-3-carboxamide Intermediate 6 and CAS: 6076-12-6
Method 6 (400 MHz, Methanol-d ₄ ) δ: 8.27 (k, J= 0.9 Hz, 1H), 7.88-7.69 (m, 2H), 7.44 (dk, J= 1.6, 0.8 Hz, 1H), 7.37-7.26 (m, 1H), 7.21 (dd, J= 8.7, 2.2 Hz, 1H), 7.19-7.12 (m, 1H), 4.16 (s, 2H), 2.24 (d, J= 0.9 Hz, 3H).
2 exchange protons are not observed. m/z 379.1 (M+H)+ (ES+), at 4.94 min, 100%
(Method 3) 16 (1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazol-4-yl)(pyrrolidin-1-yl)methanone Intermediate 4 and CAS: 123-75-1
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.88 (s, 1H), 8.55 (d, J= 5.6 Hz, 1H), 7.93 (d, J= 2.0 Hz, 1H), 7.74 (dd, J= 2.0 Hz, 5.6 Hz, 1H), 7.57 (s, 1H), 7.52 (d, J= 9.2 Hz, 2H), 4.27 (s, 2H), 3.63 (t, J= 6.0 Hz, 2H), 3.45 (t, J= 6.0 Hz, 2H), 2.37 (s, 3H), 1.83-1.88 (m, 4H). m/z 433.2 (M+H)+ (ES+), at 5.27 min, 97%
(Method 5) 17 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N,3-dimethyl-1H-pyrazole-4-carboxamide Intermediate 4 and CAS: 593-51-1
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.94 (s, 1H), 8.58 (d, J= 5.6 Hz, 1H), 8.01 (k, J= 4.5 Hz, 1H), 7.83 (d, J= 2.1 Hz, 1H), 7.59 (k, J= 2.5 Hz, 2H), 7.53 (d, J=9.2 Hz, 2H), 4.28 (s, 2H), 2.74 (d, J= 4.5 Hz, 3H), 2.43 (s, 3H). m/z 393.2 (M+H)+ (ES+), at 5.01 min, 100%
(Method 5) 18 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N,N,3-trimethyl-1H-pyrazole-4-carboxamide Intermediate 4 and CAS: 124-40-3
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.83 (s, 1H), 8.56 (d, J= 5.6 Hz, 1H), 7.91 (d, J= 2.1 Hz, 1H), 7.71 (dd, J= 5.6, 2.2 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J= 9.3 Hz, 2H), 4.27 (s, 2H), 3.06 (br.s, 3H), 3.00 (br.s, 3H), 2.30 (s, 3H). m/z 407.1 (M+H)+ (ES+), at 5.06 min, 98%
(Method 5) 19 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-N-(oxetan-3-yl)-1H-pyrazole-4-carboxamide Intermediate 4 and CAS: 21635-88-1
Method 8 (400 MHz, DMSO-d ₆ ) δ: 9.05 (s, 1H), 8.77 (d, J= 6.7 Hz, 1H), 8.60 (d, J= 5.6 Hz, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.69-7.57 (m, 2H), 7.54 (d, J= 9.2 Hz, 2H), 5.08-4.88 (m, 1H), 4.79 (t, J= 6.9 Hz, 2H), 4.53 (t, J= 6.3 Hz, 2H), 4.29 (s, 2H), 2.42 (s, 3H). m/z 435.2 (M+H)+ (ES+), at 5.02 min, 98%
(Method 5) 20 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-hydroxyethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 4 and CAS: 141-43-5
Method 9 (400 MHz, DMSO-d ₆ ) δ: 9.04 (s, 1H), 8.59 (d, J= 5.6 Hz, 1H), 8.02 (t, J= 5.6 Hz, 1H), 7.84 (d, J= 2.1 Hz, 1H), 7.58 (k, J= 2.4 Hz, 2H), 7.53 (d, J= 9.2 Hz, 2H), 4.75 (t, J= 5.5 Hz, 1H), 4.28 (s, 2H), 3.49 (k, J= 6.0 Hz, 2H), 3.29 (k, J= 6.0 Hz, 2H), 2.43 (s, 3H). m/z 423.2 (M+H)+ (ES+), at 5.29 min, 99%
(Method 2) 21 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-methoxyethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 4 and CAS: 109-85-3
Method 8 (400 MHz, DMSO-d ₆ ) δ: 9.03 (s, 1H), 8.59 (d, J= 5.6 Hz, 1H), 8.10 (t, J= 5.4 Hz, 1H), 7.84 (d, J= 2.2 Hz, 1H), 7.59 (k, J= 2.5 Hz, 2H), 7.53 (d, J= 9.2 Hz, 2H), 4.29 (s, 2H), 3.44 (dd, J= 6.1, 4.0 Hz, 2H), 3.39 (k, J= 5.2 Hz, 2H), 3.28 (s, 3H), 2.43 (s, 3H). m/z 437.2 (M+H)+ (ES+), at 5.19 min, 96%
(Method 5) 22 3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 1393667-83-8 and 12125-02-9
Method 10 (400 MHz, DMSO-d ₆ ) δ: 9.16 (s, 1H), 8.63 (dd, J= 5.6, 0.6 Hz, 1H), 7.90 (dd, J= 2.3, 0.6 Hz, 1H), 7.66 (dd, J= 5.6, 2.2 Hz, 1H), 7.59 (tt, J= 1.5, 0.7 Hz, 1H), 7.58-7.43 (m, 4H), 4.30 (s, 2H). m/z 399.2 (M+H)+ (ES+), at 1.41 min, 98%
(Method 8) 23 3-(difluoromethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 151733-96-9 and 12125-02-9
Method 10 (400 MHz, DMSO-d ₆ ) δ: 9.18 (t, J = 1.4 Hz, 1H), 8.68 (dd, J = 5.5, 0.6 Hz, 1H), 7.90 (dd, J = 2.2, 0.7 Hz, 1H), 7.80 (s, 1H), 7.65 (dd, J = 5.6, 2.2 Hz, 1H), 7.60 (tt, J = 1.6, 0.7 Hz, 1H), 7.56-7.49 (m, 2H), 7.43 (t, J = 53.7 Hz, 1H), 4.34 (s, 2H). 1 exchangeable proton is not observed. m/z 415.2 (M+H)+ (ES+), at 1.43 min, 100%
(Method 8) 24 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 155377-19-8 and 12125-02-9
Method 10 (400 MHz, DMSO-d ₆ ) δ: 9.24 (k, J= 1.1 Hz, 1H), 8.69 (dd, J= 5.6, 0.6 Hz, 1H), 7.93 (dd, J= 2.2, 0.6 Hz, 1H), 7.80 (s, 1H), 7.70 (dd, J= 5.5, 2.2 Hz, 1H), 7.60 (tt, J= 1.6, 0.8 Hz, 1H), 7.57-7.41 (m, 3H), 4.34 (s, 2H). m/z 433.2 (M+H)+ (ES+), at 1.50 min, 100%
(Method 8) 25 3-ethyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 73981-23-4 and 12125-02-9
Method 10 (400 MHz, CDCl ₃ ) δ: 8.62 (dd, J= 5.6, 0.6 Hz, 1H), 8.35 (d, J= 0.4 Hz, 1H), 7.55 (dd, J= 2.2, 0.7 Hz, 1H), 7.47 (dd, J= 5.6, 2.1 Hz, 1H), 7.36 (tk, J= 1.5, 0.7 Hz, 1H), 7.24-7.14 (m, 2H), 5.68 (s, 2H), 4.24 (s, 2H), 2.96 (d, J= 7.5 Hz, 2H), 1.36 (t, J= 7.5 Hz, 3H). m/z 393.2 (M+H)+ (ES+), at 3.95 min, 91%
(Method 9) 26 3-cyano-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 119741-57-0 and 12125-02-9
Method 10 (400 MHz, DMSO-d ₆ ) δ: 9.29 (s, 1H), 8.72 (dd, J= 5.6, 0.6 Hz, 1H), 7.95 (dd, J= 2.2, 0.7 Hz, 1H), 7.90 (s, 1H), 7.68 (dt, J= 5.4, 2.7 Hz, 2H), 7.60 (dk, J= 1.7, 0.8 Hz, 1H), 7.58-7.49 (m, 2H), 4.34 (s, 2H). m/z 390.2 (M+H)+ (ES+), at 3.83 min, 100%
(Method 9) 27 3-cyclopropyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 119741-57-0 and 12125-02-9
Method 10 (400 MHz, DMSO-d ₆ ) δ: 8.96 (s, 1H), 8.57 (dd, J= 5.6, 0.6 Hz, 1H), 7.74 (dd, J= 2.2, 0.6 Hz, 1H), 7.57 (td, J= 1.5, 0.8 Hz, 1H), 7.56-7.42 (m, 3H), 7.22 (s, 1H), 4.28 (s, 2H), 2.65 (tt, J= 8.2, 5.2 Hz, 1H), 1.00-0.86 (m, 4H). 1 exchangeable proton is not observed. m/z 405.2 (M+H)+ (ES+), at 4.10 min, 100%
(Method 9) 28 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N,5-dimethyl-1H-pyrazole-3-carboxamide Intermediate 1 and CAS: 4027-57-0 and 74-89-5
Method 10 (400 MHz, _CDCl3 ) δ: 8.40 (dd, J= 5.1, 0.8 Hz, 1H), 7.70 (dt, J= 1.4, 0.7 Hz, 1H), 7.31 (d, J= 2.4 Hz, 2H), 7.10 (d, J= 9.2 Hz, 1H), 7.06-7.02 (m, 1H), 6.71 (q, J= 0.8 Hz, 1H), 4.11 (s, 2H), 2.99 (s, 3H), 2.67 (d, J= 0.8 Hz, 3H). 1 exchangeable proton is not observed. m/z 393.3 (M+H)+ (ES+), at 1.74 min, 96%
(Method 10) 29 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-3-carboxamide Intermediate 8 and CAS:
12125-02-9
Method 9 (400 MHz, DMSO-d ₆ ) δ: 8.72 (d, J= 2.6 Hz, 1H), 8.61 (d, J= 5.6 Hz, 1H), 8.03 (d, J= 1.7 Hz, 1H), 7.85-7.81 (m, 2H), 7.57 (s, 1H), 7.54-7.50 (m, 3H), 6.95 (d, J= 2.6 Hz, 1H), 4.28 (s, 2H). m/z 365.2 (M+H)+ (ES+), at 5.41 min, 99%
(Method 2) 30 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxamide Intermediate 9 and CAS:
12125-02-9
Method 9 (400 MHz, DMSO-d ₆ ) δ: 8.43 (d, J= 5.2 Hz, 1H), 7.94 (s, 1H), 7.56 (d, J= 8.8 Hz, 2H), 7.66 (s, 2H), 7.38-7.32 (m, 2H), 6.64 (s, 1H), 4.21 (s, 2H), 2.58 (s, 3H). m/z 379.2 (M+H)+ (ES+), at 1.72 min, 99%
(Method 10) 31 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-1H-pyrazole-3-carboxamide Intermediate 5 and CAS: 593-51-1
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.64 (d, J= 2.6 Hz, 1H), 8.43 (d, J= 5.1 Hz, 1H), 8.34 (d, J= 5.1 Hz, 1H), 8.00 (s, 1H), 7.67-7.50 (m, 3H), 7.33 (d, J= 5.1 Hz, 1H), 6.88 (d, J= 2.6 Hz, 1H), 4.24 (s, 2H), 2.80 (d, J= 4.7 Hz, 3H). m/z 379.1 (M+H)+ (ES+), at 6.33 min, 100%
(Method 5) 32 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N,N-dimethyl-1H-pyrazole-3-carboxamide Intermediate 5 and CAS: 124-40-3
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.62 (d, J= 2.6 Hz, 1H), 8.42 (d, J= 5.1 Hz, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.58 (t, J= 9.9 Hz, 2H), 7.33 (dd, J= 5.1, 1.5 Hz, 1H), 6.79 (d, J= 2.6 Hz, 1H), 4.24 (s, 2H), 3.25 (s, 3H), 3.02 (s, 3H). m/z 393.2 (M+H)+ (ES+), at 6.19 min, 99%
(Method 2) 33 (1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone Intermediate 5 and CAS: 123-75-1
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.61 (d, J= 2.7 Hz, 1H), 8.42 (d, J= 5.1 Hz, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.59 (d, J= 9.3 Hz, 2H), 7.34 (dd, J= 5.1, 1.5 Hz, 1H), 6.86 (d, J= 2.5 Hz, 1H), 4.26 (s, 2H), 3.85 (t, J= 6.7 Hz, 2H), 3.51 (t, J= 6.8 Hz, 2H), 1.89 (dk, J= 23.0, 6.8 Hz, 4H). m/z 419.2 (M+H)+ (ES+), at 6.49 min, 100%
(Method 2) 34 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(oxetan-3-yl)-1H-pyrazole-3-carboxamide Intermediate 5 and CAS: 21635-88-1
Method 8 (400 MHz, DMSO-d ₆ ) δ: 9.07 (d, J= 6.8 Hz, 1H), 8.66 (d, J= 2.6 Hz, 1H), 8.44 (d, J= 5.0 Hz, 1H), 8.05 (s, 1H), 7.62 (s, 1H), 7.57 (t, J= 10.6 Hz, 2H), 7.32 (dd, J= 5.2, 1.5 Hz, 1H), 6.93 (d, J= 2.6 Hz, 1H), 5.04 (g, J= 7.1 Hz, 1H), 4.77 (t, J= 6.9 Hz, 2H), 4.65 (t, J= 6.4 Hz, 2H), 4.26 (s, 2H). m/z 421.2 (M+H)+ (ES+), at 5.99 min, 100%
(Method 2) 35 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide Intermediate 5 and CAS: 141-43-5
Method 9 (400 MHz, DMSO-d ₆ ) δ: 8.65 (d, J= 2.7 Hz, 1H), 8.43 (d, J= 5.1 Hz, 1H), 8.24 (t, J= 5.8 Hz, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.60-7.49 (m, 2H), 7.32 (dd, J= 5.1, 1.5 Hz, 1H), 6.91 (d, J= 2.6 Hz, 1H), 4.78 (t, J= 5.5 Hz, 1H), 4.25 (s, 2H), 3.52 (k, J= 6.0 Hz, 2H), 3.36 (t, J= 6.1 Hz, 2H). m/z 409.2 (M+H)+ (ES+), at 5.66 min, 98%
(Method 2) 36 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide Intermediate 5 and CAS: 109-85-3
Method 8 (400 MHz, DMSO-d ₆ ) δ: 8.65 (d, J= 2.7 Hz, 1H), 8.43 (d, J= 5.0 Hz, 1H), 8.30 (t, J= 5.4 Hz, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.60-7.49 (m, 2H), 7.32 (dd, J= 5.1, 1.5 Hz, 1H), 6.91 (d, J= 2.6 Hz, 1H), 4.25 (s, 2H), 3.52-3.40 (m, 4H), 3.28 (s, 3H). m/z 423.2 (M+H)+ (ES+), at 6.20 min, 99%
(Method 2) 37 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 15 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.45 (d, J= 4.8 Hz, 1H), 8.12 (s, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.45-7.42 (m, 4H), 7.32 (d, J= 8.8 Hz, 1H), 7.03 (t, J= 55.6 Hz, 1H), 4.19 (s, 2H), 2.78 (s, 3H). m/z 360.9 (M+H)+ (ES+), at 2.38 min, 99%
(Method 11) 38 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1H-pyrazol-3-carboxamide Intermediate 16 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.64 (d, J= 1.8 Hz, 1H), 8.43 (d, J= 3.9 Hz, 1H), 8.02 (d, J= 0.6 Hz, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.43-7.32 (m, 4H), 7.03 (t, J= 55.8 Hz, 1H), 6.95 (d, J= 2.4 Hz, 1H), 4.20 (s, 2H). m/z 347.0 (M+H)+ (ES+), at 2.47 min, 99%
(Method 11) 39 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 17 and CAS: 12125-02-9
Method 11;
or:
Intermediates 3 and 11 and CAS: 12125-02-9
Method 14 (400 MHz, DMSO-d ₆ ) δ: 8.44 (d, J= 6.8 Hz, 1H), 7.80 (s, 1H), 7.66-7.55 (m, 4H), 7.42-7.37 (m, 2H), 5.63 (t, J= 8.4 Hz, 1H), 4.91 (d, J= 8.4 Hz, 2H), 4.23 (s, 2H), 2.36 (s, 3H). m/z 409.0 (M+H)+ (ES+), at 2.08 min, 97%
(Method 1) 40 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 17 and CAS: 141-43-5
Method 12 (400 MHz, DMSO-d ₆ ) δ: 8.44 (d, J= 5.2 Hz, 1H), 8.08 (t, J= 5.6 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.62-7.58 (m, 2H), 7.39 (d, J= 1.2 Hz, 1H), 5.62 (t, J= 6.4 Hz, 1H), 4.89 (d, J= 6.4 Hz, 2H), 4.74 (t, J= 5.6 Hz, 1H), 4.24 (s, 2H), 3.53-3.52 (m, 2H), 3.34-3.30 (m, 2H), 2.34 (s, 3H). m/z 453.0 (M+H)+ (ES+), at 2.08 min, 95%
(Method 13) 41 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 18 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.64 (dd, J= 5.4, 1.6 Hz, 1H), 7.74 (s, 1H), 7.63-7.61 (m, 2H), 7.55-7.53 (m, 2H), 7.45 (s, 1H), 7.39 (s, 1H), 5.89 (t, J= 3.6 Hz, 1H), 4.65 (d, J= 5.2 Hz, 2H), 4.31 (s, 2H), 2.37 (s, 3H). m/z 409.0 (M+H)+ (ES+), at 1.77 min, 96%
(Method 11) 42 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 18 and CAS: 141-43-5
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.63 (d, J= 5.6 Hz, 1H), 7.94 (t, J= 5.2 Hz, 1H), 7.74 (s, 1H), 7.64-7.63 (m, 2H), 7.55-7.53 (m, 2H), 5.87 (t, J= 4.4 Hz, 1H), 4.75 (t, J= 4.4 Hz, 1H), 4.63 (d, J= 5.2 Hz, 2H), 4.31 (s, 2H), 3.52 (k, J= 5.6 Hz, 2H), 3.37-3.33 (m, 2H), 2.35 (s, 3H). m/z 453.0 (M+H)+ (ES+), at 1.99 min, 99%
(Method 11) 43 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-N,3-dimethyl-1H-pyrazole-4-carboxamide Intermediate 17 and CAS: 74-89-5
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.44 (d, J= 4.8 Hz, 1H), 7.97 (d, J= 4.8 Hz, 1H), 7.81 (s, 1H), 7.67-7.56 (m, 3H), 7.38 (d, J= 5.2 Hz, 1H), 5.58 (t, J= 6.4 Hz, 1H), 4.87 (d, J= 6.4 Hz, 2H), 4.24 (s, 2H), 2.78 (d, J= 4.8 Hz, 3H), 2.34 (s, 3H). m/z 422.9 (M+H)+ (ES+), at 2.29 min, 99%
(Method 11) 44 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 19 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.44 (d, J= 5.2 Hz, 1H), 7.78 (s, 1H), 7.53-7.50 (m, 1H), 7.46-7.43 (m, 3H), 7.37-7.31 (m, 2H), 7.03 (t, J= 55.2 Hz, 1H), 5.64 (t, J= 6.4 Hz, 1H), 4.91 (d, J= 6.4 Hz, 2H), 4.20 (s, 2H), 2.37 (s, 3H). m/z 391.0 (M+H)+ (ES+), at 1.88 min, 97%
(Method 1) 45 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-N,3-dimethyl-1H-pyrazole-4-carboxamide Intermediate 15 and CAS: 74-89-5
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.45 (d, J= 5.2 Hz, 1H), 8.09 (s, 2H), 7.74 (s, 1H), 7.45-7.31 (m, 4H), 7.03 (t, J= 55.6 Hz, 1H), 4.19 (s, 2H), 2.78 (s, 3H), 2.74 (d, J=4.6 Hz, 3H). m/z 374.9 (M+H)+ (ES+), at 2.45 min, 99%
(Method 11) 46 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-N-methyl-1H-pyrazole-3-carboxamide Intermediate 16 and CAS: 74-89-5
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.66 (d, J= 2.8 Hz, 1H), 8.44 (d, J= 4.8 Hz, 1H), 8.35-8.34 (m, 1H), 7.99 (s, 1H), 7.44-7.37 (m, 2H), 7.33-7.32 (m, 2H), 7.17 (t, J= 58.0 Hz, 1H), 6.89 (s, 1H), 4.23 (s, 2H), 2.80 (d, J= 4.0 Hz, 3H). m/z 361.0 (M+H)+ (ES+), at 2.56 min, 93%
(Method 11) 47 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-4-carboxamide Intermediate 20 and CAS: 12125-02-9
Method 13 (400 MHz, DMSO-d ₆ ) δ: 9.15 (s, 1H), 8.12 (s, 1H), 7.97 (t, J= 8.0 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.63-7.55 (m, 3H), 7.49 (s, 1H), 7.33 (d, J= 7.2 Hz, 1H), 5.77 (m, 1H), 4.66 (d, J= 4.4 Hz, 2H), 4.29 (s, 2H). m/z 394.9 (M+H)+ (ES+), at 2.18 min, 98%
(Method 1) 48 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-N-methyl-1H-pyrazole-4-carboxamide Intermediate 20 and CAS: 74-89-5
Method 13 (400 MHz, DMSO-d ₆ ) δ: 9.11 (s, 1H), 8.59 (s, 1H), 7.97 (t, J= 8.4 Hz, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.63-7.56 (m, 3H), 7.33 (d, J= 7.6 Hz, 1H), 5.75 (t, J= 6.0 Hz, 1H), 4.67 (d, J= 6.0 Hz, 2H), 4.30 (s, 2H), 2.79 (d, J= 3.2 Hz, 3H). m/z 409.0 (M+H)+ (ES+), at 2.27 min, 98%
(Method 1) 49 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxamide Intermediate 21 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.42 (d, J= 5.2 Hz, 1H), 8.04 (s, 1H), 7.83 (s, 1H), 7.61-7.55 (m, 4H), 7.32 (d, J= 4.8 Hz, 1H), 5.27 (t, J= 6.0 Hz, 1H), 4.64 (d, J= 6.0 Hz, 2H), 4.23 (s, 2H). m/z 395.0 (M+H)+ (ES+), at 2.06 min, 99%
(Method 1) 50 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-N-methyl-1H-pyrazole-3-carboxamide Intermediate 21 and CAS: 74-89-5
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.52 (s, 1H), 8.44-8.39 (m, 2H), 8.01 (s, 1H), 7.60-7.53 (m, 3H), 7.31 (d, J= 5.2 Hz, 1H), 5.26 (t, J= 5.6 Hz, 1H), 4.65 (d, J= 6.0 Hz, 2H), 4.24 (s, 2H), 2.81 (s, 3H). m/z 409.1 (M+H)+ (ES+), at 2.34 min, 100%
(Method 11) 51 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxamide Intermediate 22 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.00 (t, J= 8.0 Hz, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.60-7.54 (m, 3H), 7.37 (d, J= 7.2 Hz, 1H), 5.26 (t, J= 6.0 Hz, 1H), 4.65 (d, J= 5.2 Hz, 2H), 4.29 (s, 2H). m/z 394.9 (M+H)+ (ES+), at 2.57 min, 98%
(Method 11) 52 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 23 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO- _d6 ) δ: 8.60 (s, 1H), 8.15 (s, 1H), 7.63 (s, 1H), 7.58-7.52 (m, 3H), 7.47 (s, 1H), 7.11 (s, 1H), 4.26 (s, 2H), 2.33 (s, 3H), 2.02 (s, 3H). m/z 393.0 (M+H)+ (ES+), at 2.22 min, 95%
(Method 11) 53 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl-1H-pyrazole-4-carboxamide Intermediates 3 and 11 and CAS: 12125-02-9
Method 14 (400 MHz, DMSO-d ₆ ) δ: 8.44 (d, J= 6.4 Hz, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65-7.56 (m, 3H), 7.39-7.36 (m, 2H), 5.99 (t, J= 7.2 Hz, 1H), 4.58 (d, J= 7.2 Hz, 2H), 4.23 (s, 2H), 2.72 (s, 3H). m/z 409.0 (M+H)+ (ES+), at 2.00 min, 99%
(Method 1) 54 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1H-pyrazole-3-carboxamide Intermediate 24 and CAS: 12125-02-9
Method 11 (400 MHz, DMSO-d ₆ ) δ: 8.43 (d, J= 4.8 Hz, 1H), 8.02 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.58 (d, J= 9.2 Hz, 2H), 7.45 (s, 1H), 7.34 (d, J= 5.2 Hz, 1H), 6.83 (s, 1H), 5.49 (t, J= 6.0 Hz, 1H), 4.89 (d, J= 6.0 Hz, 2H), 4.23 (s, 2H). m/z 395.0 (M+H)+ (ES+), at 2.20 min, 100%
(Method 11) 55 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide Intermediate 2 and CAS: 15366-34-4 and 74-89-5
Method 10 (using MeOH in step 2, part i) (400 MHz, CDCl ₃ ) δ: 8.64 (dd, J= 5.5, 0.7 Hz, 1H), 8.01 (d, J= 2.6 Hz, 1H), 7.56 (dd, J= 2.2, 0.6 Hz, 1H), 7.49 (dd, J= 5.6, 2.2 Hz, 1H), 7.37 (tk, J= 1.4, 0.7 Hz, 1H), 7.21 (ddk, J= 9.1, 1.3, 0.6 Hz, 2H), 7.04 (d, J= 2.6 Hz, 1H), 6.96 (s, 1H), 4.26 (s, 2H), 3.03 (d, J= 5.0 Hz, 3H). m/z 379.4 (M+H)+ (ES+), at 1.64 min, 100%
(Method 10) 56 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-2H-1,2,3-triazole-4-carboxamide Intermediate 1 and CAS: 1084802-21-0 and 74-89-5
Method 10 (using MeOH in step 2, part i) (400 MHz, CDCl ₃ ) δ: 8.56 (dd, J= 5.1, 0.7 Hz, 1H), 8.32 (s, 1H), 7.96 (dk, J= 1.4, 0.7 Hz, 1H), 7.29 (tt, J= 1.6, 0.7 Hz, 1H), 7.26 (dd, J= 5.7, 1.4 Hz, 1H), 7.19 (ddt, J= 5.0, 1.3, 0.6 Hz, 1H), 7.10 (dt, J= 9.0, 1.8 Hz, 1H), 7.01 (s, 1H), 4.15 (s, 2H), 3.02 (d, J= 5.0 Hz, 3H). m/z 380.3 (M+H)+ (ES+), at 1.64 min, 100%
(Method 10) 57 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N,4-dimethyl-1H-pyrazole-3-carboxamide Intermediate 1 and CAS: 6076-12-6 and 74-89-5
Method 10 (using MeOH in step 2, part i) (400 MHz, CDCl ₃ ) δ: 8.34 (dd, J= 5.1, 0.7 Hz, 1H), 8.33 (k, J= 0.9 Hz, 1H), 7.78 (dk, J= 1.5, 0.7 Hz, 1H), 7.29 (tk, J= 1.4, 0.7 Hz, 1H), 7.26-7.21 (m, 1H), 7.12-7.06 (m, 1H), 7.00 (ddd, J= 5.0, 1.3, 0.7 Hz, 1H), 6.96 (d, J= 4.0 Hz, 1H), 4.09 (s, 2H), 3.00 (d, J= 5.0 Hz, 3H), 2.41 (d, J= 1.0 Hz, 3H). m/z 393.2 (M+H)+ (ES+), at 4.54 min, 100%
(Method 9) 58 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N,5-dimethyl-2H-1,2,3-triazole-4-carboxamide Intermediate 1 and CAS: 60419-70-7 and 74-89-5
Method 10 (using MeOH in step 2, part i) (400 MHz, CDCl ₃ ) δ: 8.54 (dd, J= 5.0, 0.7 Hz, 1H), 7.91 (dk, J= 1.4, 0.7 Hz, 1H), 7.29 (dk, J= 1.6, 0.8 Hz, 1H), 7.28-7.23 (m, 1H), 7.14 (ddd, J= 5.1, 1.4, 0.7 Hz, 1H), 7.13-7.06 (m, 1H), 7.00 (s, 1H), 4.14 (s, 2H), 3.00 (d, J= 5.0 Hz, 3H), 2.68 (s, 3H). m/z 394.3 (M+H)+ (ES+), at 1.69 min, 97%
(Method 10) 59 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1H-pyrazole-4-carboxamide Intermediate 2 and CAS: 85290-78-4 and 12125-02-9
Method 15 (400 MHz, DMSO-d ₆ ) δ: 9.10 (d, J= 0.6 Hz, 1H), 8.57 (dd, J= 5.5, 0.6 Hz, 1H), 8.01 (dt, J= 2.3, 0.6 Hz, 1H), 7.67 (tt, J= 1.5, 0.7 Hz, 1H), 7.63-7.60 (m, 1H), 7.60-7.53 (m, 2H), 7.51 (s, 1H), 7.18 (s, 1H), 6.68 (s, 1H), 5.91 (s, 1H), 2.44 (s, 3H). m/z 395.2 (M+H)+ (ES+), at 1.21 min, 100%
(Method 8)

BIOLOGICAL ACTIVITY

Functional cAMP assay of GPR52 agonist

HEKf suspension cells were infected for 24 h with 0.1% v/v human GPR52 expressing BacMam virus, a modified baculovirus designed to express mammalian genes. Following BacMam infection, cells were pelleted by centrifugation (335 g, 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 spotted onto proxy plates (PerkinElmer) using a LabCyte ECHO acoustic pipette. Frozen cells were thawed and resuspended in assay stimulation buffer (Cisbio) containing 0.5 mM 3 -isobutyl -1-methylxanthine (IBMX, Sigma) to reach a density of 2000 cells per well. 10 μl of cells were added to the assay plates using a Multidrop Combi reagent dispenser (ThermoFisher) before centrifugation (335 g, 1 min). Cells were incubated with compounds at 37°C for 30 min before addition of cAMP detection reagents (HiRange cAMP kit, Cisbio), which were 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 3-(2-(3-chloro-5-fluorobenzyl)benzo[b]thiophen-7-yl)-N-(2-methoxyethyl)benzamide (compound 7m in J. Med. Chem ., 2014, 57 , 5226) maximal responses (100%) and fit to a 4-parameter logistic fit to obtain the agonist pEC ₅₀ and maximal responses, which are presented in Table 4 below.

Table 4 - pEC data ₅₀ GPR52

Ex. No. pEC ₅₀ average E _max (%) Ex. No. pEC ₅₀ average E _max (%) 1 6.9 90 31 7.7 87 2 6.3 90 32 6.7 75 3 6.5 86 33 6.9 87 4 6.5 84 34 6.2 77 5 7.8 94 35 6.4 83 6 7.9 97 36 6.9 87 7 6.9 93 37 7.1 96 8 7.7 96 38 7.7 93 9 7.0 85 39 8.2 101 10 7.1 83 40 8.6 101 11 6.6 86 41 7.5 98 12 7.3 95 42 7.5 100 13 7.4 93 43 8.0 101 14 7.5 95 44 8.4 101 15 7.1 92 45 6.7 91 16 7.5 93 46 7.3 88 17 8.0 93 47 6.3 52 18 7.1 92 48 5.8 36 19 7.8 99 49 7.2 93 20 7.8 96 50 8.0 82 21 7.4 96 51 6.3 83 22 7.8 96 52 7.0 100 23 7.6 87 53 7.1 97 24 7.6 91 54 7.1 92 25 8.0 99 55 6.9 83 26 7.0 87 56 7.0 84 27 7.6 97 57 8.5 87 28 7.5 95 58 7.8 92 29 5.9 86 59 6.7 79 30 6.8 93

Pharmacokinetic profiling

The pharmacokinetic profiles of Example 39 were evaluated in male Sprague-Dawley rats by intravenous (iv) and oral ( oral , p/o) routes of delivery. The pharmacokinetic data (means ± standard deviations) for Example 39 of the invention are detailed in Table 5.

Methods : For pharmacokinetic analysis, groups of three male Sprague-Dawley rats weighing between 200 and 230 g were administered a single dose of Example 39 IV or PO using the doses, dose volumes, and vehicles listed in Table 5. Post-dose, blood samples were collected at multiple time points (pre-dose at 2 min, 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, 12 h, and 24 h for IV administration and pre-dose at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h for PO administration) via serial tail vein bleeding and centrifugation to separate plasma for LC-MS/MS analysis. WinNonlin v8.2 statistical software (Pharsight Corporation, California, USA) was used to obtain pharmacokinetic parameters using non-compartmental analysis.

Penetration into the brain

Plasma and brain exposure were determined to assess the penetration of Example 39 into the brain following i.v. administration. The unbound brain to plasma ratio (K _p,uu ) was calculated as detailed in Table 5 after experimental determination of binding in rat plasma and brain homogenate.

Methods . To assess brain penetration, male Sprague-Dawley rats (n=3) were administered a single 1 mg/kg dose (containing 10% DMAC+10% Solutol HS15+80% saline) intravenously. Animals were sacrificed 10 min after dosing and brains were removed, homogenized with 2 volumes (w/v) of 50 mM sodium phosphate buffer (pH 7.4) and analyzed by LC-MS/MS. Blood samples were collected at the same time point by tail vein bleeding, centrifuged and plasma analyzed by LC-MS/MS.

To allow calculation of the unbound brain to plasma ratio (Kp, uu), binding of test compound in rat plasma and brain homogenate was performed using rapid equilibrium dialysis (RED). Test compound prepared in DMSO (final 1 μM, 0.2% DMSO) was added to (i) undiluted male Sprague Dawley rat plasma and (ii) rat brain tissue homogenized with 2 volumes (w/v) sodium phosphate buffer (pH 7.4) and dialyzed against phosphate buffer for 5 h at 37°C. After incubation, the contents of each plasma/brain and buffer compartment were removed and mixed with equal volumes of dialyzed buffer or plasma/brain control to maintain matrix similarity for the assay. The proteins were then precipitated by adding acetonitrile containing the analytical internal standard (which allowed the ratio of the test compound to the internal standard to be obtained), centrifuged and the supernatant removed for analysis by LC-MS/MS. The fraction of unbound substance (F _u ) in plasma and brain was calculated using the following formula, then used to adjust the total plasma and brain concentrations to obtain K _{p, uu} :

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

To correct for dilution in the brain binding assay:

Undiluted F _u , brain = (1/dilution factor)/((1/diluted F _u )) - 1) + (1/dilution factor)

Where the dilution factor = 4

Table 5 - Caffeine-induced locomotor activity in rats

IV pharmacokinetics in rats (n=3) Dose (mg/kg) Dose volume (ml/kg) Carrier Clearance (ml/min/kg) Example 39 1 5 10% DMAC+10% Solutol HS15+80% saline solution 8.8±1.1 P/O pharmacokinetics in rats (n=3) Dose (mg/kg) Dose volume (ml/kg) Carrier Bioavailability (%) Example 39 3 5 10% DMAC+10% Solutol HS15+80% water 77.4±14.9 IV penetration into the brain in rats, 10 min (n=3) Dose (mg/kg) Dose volume (ml/kg) Carrier K _{p, uu} Example 39 1 5 10% DMAC+10% Solutol HS15+saline solution 0.42±0.08

Caffeine, a nonselective adenosine receptor antagonist, is a psychostimulant that increases locomotor activity in rodents primarily by blocking _A2A receptors ( Br. J. Pharmacol. , 2000, 129 , 1465). These receptors are densely expressed at the terminals of GABAergic striatopallidal neurons of the indirect pathway of the basal ganglia, which coexpress dopamine D2 receptors ( J. Comp. Neurol. , 1998, 401 , 163; J. Comp. Neurol. , 2001, 431 , 331). Tonic activation of _A2A receptors decreases the affinity of D2 receptors for dopamine, and antagonism of _A2A receptors facilitates dopaminergic signaling ( Curr. Pharm. Des. , 2008, 14 , 1468). A number of antipsychotic drugs have been shown to block caffeine-induced hyperlocomotion ( Pharmacol. Biochem. Behav. , 1994, 47 , 89; Naunyn-Schmiedeberg's Arch. Pharmacol. , 2016, 389 , 11).

Male Sprague-Dawley rats (200-250 g) were group housed on a 12 h light/dark cycle (lights on at 07:00), at an ambient temperature of 21 ± 2 °C, and with standard pelleted chow and water ad libitum . The study was conducted in the light phase. On the day of the experiment, the animals were habituated to the locomotor cages for a period of 60 minutes. They were then orally administered vehicle or Example 39 (0.1, 0.3, 1, and 3 mg/kg) and returned to the appropriate locomotor cage. Example 39 was formulated in vehicle containing 10% DMAC, 10% Solutol (Kolliphor HS15), and 80% water (v/v/v). Sixty minutes later, the animals were subcutaneously administered vehicle (saline) or caffeine (15 mg/kg). Locomotor activity was assessed over a 2-h period following caffeine ingestion. Data are back-transformed means adjusted for between-treatment differences in activity during the 30 min prior to treatment with test compound or vehicle (n=10-12). Analysis was performed using a general linear model with treatment, cohort, and patient as factors. SEM was calculated from the residuals of the statistical model. Example 39 was compared to caffeine using the Williams test.

As shown in Figure 1, treatment with Example 39 compound caused a dose-dependent reduction in caffeine-induced hyperlocomotor response, reaching statistical significance at 1 and 3 mg/kg.

Brief description of the drawings

Figure 1 : Effect of acute treatment with Example 39 (0.1, 0.3, 1 and 3 mg/kg, p.o.) on caffeine-induced hyperlocomotor activity. Significant differences compared to caffeine are presented as *p<0.05, **p<0.01, ***p<0.001.

Claims (128)

1. Compound of Formula (1): (1); or a pharmaceutically acceptable salt thereof, in which: X represents N or CR ⁵ ; Y represents N or CR ⁶ ; R ¹ is H, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl optionally substituted with OH or 1-6 fluorine atoms, in which when the C _1-6 alkyl or C _3-6 cycloalkyl group is not substituted with OH, one atom of the C _1-6 alkyl or C _3-6 cycloalkyl group may be optionally substituted with an O atom that is not directly bonded to N or is attached to a carbon atom that is directly bonded to N; or R ¹ is joined to R ² to form a 5-membered ring that is optionally substituted with OH or 1-6 fluorine atoms; R ² is H or C _1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms; or R ² is joined to R ¹ to form a 5-membered ring which is optionally substituted with OH or 1-6 fluorine atoms; R ⁴ , R ⁵ and R ⁶ are independently selected from H, CN, halogen, C _1-6 alkyl optionally substituted with OH or 1-6 fluorine atoms, C _3-6 cycloalkyl and C _1-6 alkoxy; R ³ is a group of the formula: ; ; ; ; or ; L is _CH2 or CHOH; group: represents: ; R ⁸ , R ⁹ and R ¹⁰ are independently selected from H, halogen or C _1-3 alkyl optionally substituted with 1-6 fluorine atoms. 2. The compound of claim 1, wherein R ¹ is selected from: H, methyl, oxetanyl, CH ₂ CH ₂ OH and CH ₂ CH ₂ OCH ₃ or wherein R ¹ is joined to R ² to form a 5-membered ring. 3. A compound according to claim 1 or 2, wherein R ² is H or methyl or is joined to R ¹ to form a 5-membered ring. 4. The compound according to claim 1, which is a compound of formula (2a): (2a); or a pharmaceutically acceptable salt thereof. 5. A compound according to any one of claims 1 to 4, wherein X is N, CH, _CCH3 or _CCH2OH . 6. A compound according to any one of claims 1 to 5, wherein Y is N, CH or CCH ₃ . 7. A compound according to any one of claims 1 to 6, wherein R ⁴ is selected from: H, methyl, methoxy, Cl, CHF ₂ , CF ₃ , ethyl, CN, cyclopropyl, CH ₂ OH and CH ₂ OCH ₃ . 8. A compound according to any one of claims 1 to 4, wherein R ⁵ and R ⁶ are independently selected from H, methyl and CH ₂ OH. 9. The compound according to claim 1, which is a compound of formula (3a), (3b), (3c) or (3d): or a pharmaceutically acceptable salt thereof. 10. A compound according to any one of claims 1 to 9, wherein L is CH ₂ . 11. A compound according to claim 1, which is a compound of formula (4b), (4c), (4d), (4e) or (4f): or a pharmaceutically acceptable salt thereof. 12. A compound according to any one of claims 1 to 11, wherein R ⁸ , R ⁹ and R ¹⁰ are independently selected from H, F, CHF ₂ and CF ₃ . 13. The compound according to claim 1, wherein the group: represents: or . 14. The compound according to claim 1, which is selected from the group consisting of: 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-4-carboxamide; 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-2 H -1,2,3-triazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3,5-dimethyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1 H -pyrazole-3-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy-1 H -pyrazole-4-carboxamide; 2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2 H -1,2,3-triazole-4-carboxamide; 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-2 H -1,2,3-triazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1 H -pyrazole-4-carboxamide; 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1 H -pyrazole-3-carboxamide; (1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- 1H -pyrazol-4-yl)(pyrrolidin-1-yl)methanone; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N ,3-dimethyl-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N,N ,3-trimethyl-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl- N -(oxetan-3-yl)-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-hydroxyethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-methoxyethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide; 3-(difluoromethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1 H -pyrazole-4-carboxamide; 3-ethyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide; 3-cyano-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-4-carboxamide; 3-cyclopropyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H - pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N ,5-dimethyl-1 H -pyrazole-3-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N,N -dimethyl-1 H -pyrazole-3-carboxamide; (1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H - pyrazol-3-yl)(pyrrolidin-1-yl)methanone; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(oxetan-3-yl)-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-hydroxyethyl)-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-methoxyethyl)-1 H -pyrazole-3-carboxamide; 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-1H - pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)- N ,3-dimethyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1 H -pyrazole-4-carboxamide; 1-(4-{[3-(difluoromethyl)-5-fluorophenyl]methyl}pyridin-2-yl)- N ,3-dimethyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)- N -methyl-1 H -pyrazole-3-carboxamide; 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-1 H -pyrazole-4-carboxamide; 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)- N -methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1 H -pyrazole-3-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)- N -methyl-1 H -pyrazole-3-carboxamide; 1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-(hydroxymethyl)-1 H -pyrazole-3-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methylpyridin-4-yl)-3-methyl- 1H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-(hydroxymethyl)-5-methyl-1 H -pyrazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-1 H -pyrazole-3-carboxamide; 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)- N -methyl-1 H -pyrazole-3-carboxamide; 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N -methyl-2 H -1,2,3-triazole-4-carboxamide; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N ,4-dimethyl-1 H -pyrazole-3-carboxamide; 2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)- N ,5-dimethyl-2 H -1,2,3-triazole-4-carboxamide; 1-(2-((3-fluoro-5-(trifluoromethyl)phenyl)(hydroxy)methyl)pyridin-4-yl)-3-methyl-1 H -pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1, wherein the compound is: . 16. The compound of claim 1, wherein the compound is: . 17. The compound of claim 1, wherein the compound is: . 18. The compound of claim 1, wherein the compound is: . 19. The compound of claim 1, wherein the compound is: . 20. The compound of claim 1, wherein the compound is: . 21. The compound of claim 1, wherein the compound is: . 22. The compound of claim 1, wherein the compound is: . 23. The compound of claim 1, wherein the compound is: . 24. The compound of claim 1, wherein the compound is: . 25. A pharmaceutically acceptable salt of a compound according to any one of claims 15 to 24. 26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 25, having GPR52 receptor modulator activity. 27. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 25 for use as a GPR52 receptor agonist. 28. A pharmaceutical composition having GPR52 receptor agonist activity, comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-25 and a pharmaceutically acceptable excipient. 29. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 25 or a composition according to claim 28 for use in medicine as a GPR52 receptor agonist. 30. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 25 or a composition according to claim 28 for use in the treatment of mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stress-related disorders; disruptive, impulsive, or conduct disorders; sleep-wake patterns disorders; substance use disorders; addictive disorders; behavioral disorders; hypofrontality; tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway abnormalities; decreased activity in the striatum; cortical dysfunction; neurocognitive dysfunction, or conditions or symptoms associated with them. 31. The compound or composition for use according to claim 30, wherein the disorder or symptom 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, addictive/impulse control disorders, autism spectrum disorders, psychosis, anhedonia, anxiety 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 dyskinesia, myoclonus, mirror movement syndrome, paroxysmal kinesiogenic dyskinesia, restless legs syndrome, spasms, stereotypic movement disorder, stereotypy, tic disorder, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or drug-induced psychotic disorder, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal movement behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or drug-induced anxiety disorder, bipolar and related disorders associated with another medical condition, bipolar and related disorders, separation-induced anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or drug-induced anxiety disorder associated with another medical condition, anxiety disorders, delirium, major neurocognitive disorder, minor neurocognitive disorder, amnesia, dementia, dyspraxia, stereotypic movement disorder, post-stroke effect, dentato-rubro-pallido-Lewis atrophy, decreased emotional expression, abulia, alogia, and asociality. 32. A compound or composition for use according to claim 31, wherein the disorder or symptom 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, addictive/impulse control disorders, autism spectrum disorders, 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).