GB2610812A

GB2610812A - Novel compounds

Info

Publication number: GB2610812A
Application number: GB2113016.6A
Authority: GB
Inventors: Teall Martin; Bürli Roland; Brice Nicola
Original assignee: Cerevance Inc
Current assignee: Cerevance Inc
Priority date: 2021-09-13
Filing date: 2021-09-13
Publication date: 2023-03-22
Also published as: GB202113016D0

Abstract

Compounds for treating nicotinic acetyl choline receptor a6 disorders Compounds of formula (I), wherein: R1 is halo, cyano, hydroxyl, C1-5 alkyl or haloalkyl, C3-5 cycloalkyl or halocycloalkyl, -O-(C1-5 alkyl or haloalkyl), -O-(C3-5 cycloalkyl or halocycloalkyl), -NH-(C1-5 alkyl or haloalkyl), -NH-(C3-5 cycloaklyl or halocycloalkyl), -N(C1-5 alkyl or cycloalkyl)2, -N(C1-5 alkyl)(C1-5 haloalkyl), -N(C3-5 cycloalkyl or halocycloalkyl)2, -N(C3-5 cycloalkyl)(C3-5 halocycloalkyl); R2 is C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, halocyclopropyl; R3 is H, C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, halocyclopropyl; R4 is bond, C1-3 alkylene, C1-3 haloalkylene; R5 is a 4-7 membered saturated heterocycle which contains one or two nitrogen ring atoms, optionally one oxygen ring atom, and the heterocycle may be substituted; m is 1-3. Also provided is a process for the preparation of a compound of formula (I). Also provided is a pharmaceutical composition comprising a compound of formula (I). A compound of formula (I) may be for use in therapy, for use in treating or preventing a disease, disorder, or condition that has dysregulation of a dopamine, that has dysregulation of noradrenaline, that has dysregulation of serotonin. A compound of formula (I) may be for use in treating or preventing a movement disorder such as tremor, dystonia, dyskinesia, Parkinson’s, Huntington’s, or psychiatric disorder such as schizophrenia, bipolar disorder, or an addition disorder.

Description

NOVEL COMPOUNDS

Field of the Invention

The present invention relates to 5-phenyl-pyrazole-3-carboxamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with nicotinic acetylcholine receptor a6 (nAChRa6) activity.

Background of the Invention

Acetylcholine is one of the principle neurotransmitters in the central nervous system (CNS) and mediates its effects via two classes of receptors. The first class is the muscarinic family of 0-protein coupled receptors, of which there are five known members, Ml, M2, M3, M4 and MS. The second class of receptors are the nicotinic ligand gated ion channels. These nicotinic receptors are expressed throughout the CNS and have been shown to have a modulatory effect on nearly all neurotransmitter systems examined, including dopamine. The receptors are cation-selective pentamcrs that belong to the same ligand gated ion channel superfamily as GABAa and 5HT3 receptors. In the CNS, nicotinic receptors are composed from a set of 12 different alpha (a) and beta (13) subunits (a2-10 and f32-4). Each receptor pentamer consists of 2 or 3 a subunits with 13 subunits (e.g. (a4)3(1:32)2, (a6)7(132)3, (0)2(134)3, a4a6133(132)2) (Le et al, J Neurobiol 53: 447-456 2002). The one exception is a7, which can form a homopentamer. The different subunit compositions give rise to different biophysical and pharmacological profiles which make them suitable drug targets depending on subunit composition (Wells, Front Biosci 13: 5479-5510 2008; Campling et al, PLUS One 8: e79653 2013).

Nicotinic receptors can be found throughout the CNS, with the a4f32 being the most abundant heteroreceptor (Wada et al, J Comp Neurol 284: 314-335 1989). In contrast to other subunits, the a6 subunit expression is restricted to mid brain regions, such as the dopaminergic neurons of the substantia nigra (SN) and ventral Wgmental area (VTA), as well as noradrenergic neurons of the locus coeruleus (LC). These brain regions are important in movement disorders and psychiatric disorders such as addiction (Quik et al, Biochem Pharm 82: 873-882 2011; Engle et al, 1\4°1 Pharmacol 84: 393-406 2013). The a6 subunit has also been detected in the superior colliculus (Mackey et al, J Neurosci 32: 10226-10237 2012; Allen Brain Atlas www.brain-map.org), a region important for integrating sensory information into movement, particularly eye movement. The a6 subunit has been shown to heteromultimize with both f32 and f33 subunits and potentially other a subunits such as a3 and a4 (Miller and Gold. Neuropharmacol 56: 237-246 2009 for review).

The dopaminergic neurons from the VTA and SN project to the striatum, where they release dopamine in response to a reward signal or for locomotor control respectively. Control of this release is lost in movement disorders such as tremor, dystonia. Parkinson's lo disease and Huntington's disease, and psychiatric disorders including schizophrenia, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD). Tourettes syndrome and addictions (Klein et al. Cellular and Molecular Neurobiol 39: 31-59 2019; Collins-Praino et al, Front Sys( Neurosci 4: 492011; Bao et al, J Neurochem 114: 178-191 2010; Rice et al. Neurosci 198: 112-137 2011; Jakel and Maragos, TiNS 23: 239-is 245 2000; Howes et al, Biol Psychiatry 81: 9-20 2017; Castellanos and Tannock, Nat Rev Neurosci 3: 617-628 2002; Maia and Conceicao, Biol Psychiatry 84: 332-344 2018; Nutt et al, Nat Rev Neurosci 16: 305-312 2015).

The a6 containing receptors are pre-synaptically located on the dopaminergic neurons that project into the striatum. Their functional effect is to potentiate dopamine release in response to acetylcholine released from local cholinergic intemeurons (Ztaou and Amalric, Neurochem Int 126: 1-10 2019; de Kloest et al, Biochem Pharmacol 97: 425-438 2015; Aosaki et al, Geriatr Gerontol Int S148-157 2010). In the non-human primate striatal synaptosome preparation, a6 containing receptors mediate 80% of dopamine release compared to only 20% by the a4 containing nAChR population (Quik et al, Biochemical Pharm, 82: 873-882 2011 for review). Therefore, modulators specific for the nicotinic a6 subunit would have therapeutic potential in disorders that have dysrcgulation of dopamine as a key pathological mechanism. Similarly, a6 containing receptors in the locus coeruleus (LC) and superior colliculus have been shown to modulate firing patterns of the noradrenergic and GABAergic neurons, respectively (Lena et al, PNAS 96: 12126-12131 1999; Mackey et al, J Neurosci 32: 10226-10237 2012), which has a consequence on noradrenaline release. The a6 containing receptors are also expressed in other discrete regions that contain monoaminergic neurons including the serotonergic neurons of the raphe nuclei. Similarly to the dopaminergic neurons, modulation of the nicotinic receptor can modulate the excitability of these neurons and therefore the release of serotonin (Galindo-Charles et al, Synapse 62(8): 601-615 2008).

Movement disorders Previous studies have shown the important role of nicotinic receptors in mechanisms of Parkinson's disease. The observation that nicotine appears to have neuroprotective properties led to investigation into the possible efficacy of nicotinic agonists such as TC8831, which is an agonist for both a4132 and a6f32 and shows efficacy in the macaque MPTP model (Johnston et al, Neuropharmacology 73: 337-347 2013). One hypothesis is that the agonists desensitize die receptors, therefore acting as functional antagonists. This is supported by Bordia et al (JPET 333: 929-938 2010) who showed in 6-0HDA lesioned rats that were then chronically treated with L-DOPA to induce dyskinesias, that (1) chronic nicotine closing is efficacious at reducing the abnormal involuntary movements (ATMs), a pre-clinical correlate of dyskinesias, whereas acute nicotine has no effect, and (2) the nAChRa6 antagonist, mecamylamine, could reduce the AIMs score when dosed alone.

Other studies using genetically manipulated mice have extended this hypothesis by showing that chronically dosed nicotine reversed dyskinesia in WT mice and not transgenic gain-of-function (a6 L9S) mice, in which the receptor shows little desensitization (Bordia et al, Neuroscience 295: 187-197 2015). Furthermore, nAChRa6 knockout (KO) mice show improvement in 6-0HDA/L-DOPA induced AIMs (reduced AIMs score) compared to WT mice. This reduction in the AIMs score seen in the KO mice was comparable to WT mice chronically treated with nicotine (Quik et al, Neuropharm 63: 450-459 2012). Although dyskinesias are often associated with Parkinson's disease, other diseases and medications also have dyskinesia as a symptom or side effect, for example, tardive dyskinesia in schizophrenia. Similar to L-DOPA induced dyskinesias, these other dyskinesias are a result of aberrant dopamine release. Indeed, pre-clinical models of tardive dyskinesia show that chronic nicotine administration reduces the dyskinesia. The molecular mechanism of this was shown to include the reduction in the a6 subunit expression (Bordia et al, JPET 340: 612-619 2012) which is a similar consequence as an a6 antagonist. This hypothesis is supported by further work by Bordia et al (Exp Neurol 286: 32-39 2016) in which the nicotinic receptor antagonist, mecamylamine, reduced haloperidol induced dyskinesias.

Tremor is the most prevalent movement disorder and can be a symptom of many underlying disorders including Parkinson's disease. Tremors can be subdivided into groups depending on characteristics such as amplitude, frequency or etiology. Categories of tremor can include resting tremor, essential tremor, drug induced tremor, dystonic tremor or psychogenic tremor. Resting tremor is seen in approximately 75% of Parkinson's patients and is poorly treated with existing medication. The monoaminergic neurons have been implicated in resting tremor (Dirkx et al. Brain 140: 721-734 2017; Isaias et al, Front Hum Neurosci, vol 5, article 179, 2012; Qamhawi et al, Brain 138: 2964-2973 2015) and all express the a6 subunit. Furthermore, tremor dominant Parkinson's patients have less noradrenergic neuronal loss in the locus coeruleus (LC) than non-tremor dominant Parkinson's patients, which leads to an imbalance of available neurotransmitter release in key brain regions such as the striatum and the thalamus with more noradrenaline being released. Further evidence for this comes from the observation that tremor is exacerbated in stressful situations when the locus coeruleus (LC) is activated and more noradrenaline is released (Zach et al, CNS Neurosci and Ther 23: 209-215 2017). An agent, such as a nicotinic a6 subunit antagonist that reduces noradrenaline release, should therefore improve symptoms of resting tremor (Lena et al, PNAS 96(21): 12126-12131 1999).

Dystonia is another movement disorder that can either be a symptom of Parkinson's and other diseases, or a syndrome in the absence of other diseases such as the DYT1 dystonia that is caused by mutations in the TOR1A gene. A common feature is an increase in dopamine release and abnormal striatal cholinergic transmission (Zimmerman et al, Front Syst Neurosci 11: 43 2017). Therefore, an a6 antagonist would reduce the dopamine tone and improve symptoms.

Huntington's disease is a fatal neurodegenerative disorder caused by a poly-glutamine expansion in the Huntington's gene (Htt). The symptoms of the disease are characterised by progressive motor, cognitive and psychiatric decline. Post-mortem analysis shows a loss of neurons in the striatum, particularly the acetylcholinergic interneurons in this region which leads to dysregulation of this system. In a study looking at the effect of varenicline, a non-specific nicotinic receptor ligand that readily desensitizes the a6 subunit, it has been shown to improve symptoms of Huntington's disease, including cognitive ability (McGregor et al, Neuropsychiatric Diseases and Treatment 12: 2381-2386 2016).

Psychiatric disorders Many of the symptoms of psychiatric disorders are caused by abnormal monoaminergic tone. For instance, schizophrenia, psychosis, psychotic disorder and schizoaffective disorder have hyperdopaminergic tone that is principally caused by increase in presynaptic capacity (McCutcheon et al, World Psychiatry 19: 15-33 2020). Therefore, a molecule that can reduce the release of dopamine could have efficacy in these disorders. Antagonists of a6 reduce the release of evoked dopamine via pre-synaptic mechanisms (Wickham et al, Psychopharm 229: 73-82 2013; Wang eta!, J Neurochem 129: 315-327 2014) and so have the potential to be efficacious in schizophrenia and related disorders.

io Lack of impulse control is a symptom of several psychiatric disorders including ADHD, schizophrenia, bipolar disorder, ASD including Fragile X, and addiction. Impulse behaviour is stimulated, in part, by increased dopamine release in the nucleus accumbens (Cole and Robbins, Behav Brain Res 33: 165-179 1989; Patti] et al, Psychopharmaeology 1991: 587-598 2007). Activation of nicotinic receptors by nicotine or varenicline has been Is shown to induce impulsive behaviours when administered acutely (non-desensitizing) but not chronically (desensitizing) (Tsutsui-Kimura et al. Psychophannacology 209: 351-359 2010). Both of these agonists activate a6 containing receptors when administered acutely, which would potentiate dopamine release. Therefore, an a6 antagonist that inhibits dopamine release would have utility in treating impulse control symptoms in a range of psychiatric disorders.

Tourettes syndrome (TS) is a neurodevelopmental disorder defined by characteristic involuntary movements, tics, with both motor and phonic components. Tourette,s syndrome is considered a disorder of the basal ganglia and, in particular, a striatal dysfunction (Ganos et al, Neurosci Biobehav Rev 37: 1050-1062 2013; Tremblay et al, Mov Disord 30: 1155- 1170 2015). This concept is based on the response of tics to treatment with dopamine antagonists, the occurrence of tics in diseases with unequivocal striatal pathology, and evidence from structural and functional imaging studies implicating basal ganglia associated neurocircuits (Worbe et al, Mov Disord 30: 1179-1183 2015). Currently, dopamine D2 receptor antagonists are the only treatments approved by the US Food and Drug Administration for tics, but they are not recommended as first line treatment due to their adverse side-effect profile (Eddy et al, Ther Adv Neurol Disord 4(1): 25-45 2011). Taken together, a striatal based mechanism that regulates synaptic dopamine output may have therapeutic utility in treating the symptoms of Tourettes syndrome.

Addiction disorders, including substance use disorder, alcohol use disorder, binge eating, and gambling disorder, all follow a similar pathology. Whatever the addictive stimuli, the addictive behaviour is caused by abnormal release of dopamine from VTA neurons projecting to the nucleus accumbens in what has been termed the 'reward pathway'. In normal circumstances dopamine is released from these neurons in response to natural rewards such as food, social interaction or sex. However, in the addicted brain the pathway is hyperstimulated by the addictive substance or behaviour and is not stimulated by natural rewards. This leads to the feeling of craving. Agents that can decrease this hyperstimulation of the pathway and normalise dopamine transmission, reverse addictive io behaviours in pre-clinical models (Volkow et al, Nat Rev Neurosci 18: 741-752 2017).

Antagonists of the nAChRa6 subunit decrease dopamine release from synaptosomes of neurons originating in the VTA and projecting into the nucleus accumbens (Gotti et al, I Neurosci 30(15): 5311-5325 2010). Furthermore, multiple genetic studies have linked the nAChRa6 gene to increased risk of addictions including nicotine (Won et al. Psychiatry Investig 11(3): 307-312 2014; Wang et al, Hum Genet 133: 575-586 2014; Brunzell, Nicotine & Tobacco Res 14(11): 1258-1269 2012), cocaine (Sadler et al, Sci Rep 4: 4497 2014) and alcohol (Hoft et al, Genes Brain Behav 8: 631-637 2009).

Bipolar disorder is a complex psychiatric disorder with patients experiences both episodes of mania and depression. It is thought that the balance between acetylcholine and the catecholamines norepinephrine and dopamine determine these episodes with a hypercholinergic state during bipolar depression and increased functional catecholamines during bipolar mania (Enkhuzien et al, Eur J Pharmacol 753: 114-126 2015). The a6 subunit is expressed on the pre-synaptic terminals of both dopamine and norepinephrine neurons and modulates neurotransmitter release (Gotti et al, I Neurosci 30(15): 5311-5325 2010; Azam et al FASEB J. 24: 5113-5123 2010). Therefore, an antagonist of a6 could restore levels of catecholamines and reduce symptoms of bipolar mania. Similarly, antagonising the excess cholinergic tone during bipolar depression using a specific a6 antagonist could reduce the effects of the excess acetylcholine which would shift towards a less depressive state. Indeed, drugs currently used to treat depression such as SSRIs are nicotinic receptor antagonists (Hennings et al, Brain Res 759: 292-294 1997; Shytle et al, Mol Psychiatry 7: 525-535 2002).

There is a need for treatment of the above conditions and others described herein with compounds that are nAChRa6 antagonists. The present invention provides antagonists of nAChRa6.

Summary of the Invention

A first aspect of the present invention provides a compound of formula (I): 0 R4--R5

NH R2

Formula (I) io or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: m is 1, 2 or 3; each RI is independently selected from halo, cyano, hydroxyl, Ci-05 alkyl, Ci-05 haloalkyl, C3-05 cycloalkyl, C3-Cs halocycloalkyl, -0-(CI-05 alkyl), -0-(Ci-05 haloalkyl), -0-(C3-05 cycloalkyl), -0-(C3-05 halocycloalkyl), -NH-(Ci-05 alkyl), -NH-(Ci-05 haloalkyl), -NH-(C3-05 cycloalkyl), -N1-1-(C3-05 halocycloalkyl), -N(Ci-05 alky1)2, -N(Ci-05 alkyl)(Ci-05 haloalkyl), -N(Ci-05 haloalky1)2, -N(C3-05 cycloalky1)2, -N(C3-05 cycloalkyl)(C3-05 halocycloalkyl), or -N(C3-05 halocycloalky1)2; R2 is Ci-C3 alkyl, Ci-C3 haloalkyl, cyclopropyl or halocyclopropyl; R3 is hydrogen, Ci-C3 alkyl, Ci-C3 haloalkyl, cyclopropyl or halocyclopropyl; R4 is a bond. Ci-C3 alkylene, or Ci-C3 haloalkylene; and R5 is a 4-, 5-, 6-or 7-membered, saturated heterocycle, wherein the heterocycle contains one or two nitrogen ring atoms and optionally one oxygen ring atom, and wherein the heterocycle is optionally substituted.

In the context of the present specification, unless otherwise stated, an substituent group or an "alkyl" moiety in a substituent group (such as an alkoxy group) may be linear or branched.

Examples of Ci-05 alkyl groups/moieties include methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-1-butyl, 2-meth y1-3-butyl, and 2,2-di meth y1-1 -propyl.

The term "hydrogen" encompasses -EH, 2H (D) and 3H (T). Therefore, for the avoidance of doubt, it is noted that, for example, the terms "alkyl" and "methyl" include, for example, trideuteriomethyl.

A "cycloalkyl" substituent group or a "cycloalkyl" moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 6 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

A "haloalkyl" substituent group or a "haloalkyl" moiety in a substituent group refers to an alkyl group or moiety in which one or more, e.g. one, two, three, four or five, hydrogen atoms are replaced independently by halogen atoms, i.e. by fluorine, chlorine, bromine or iodine atoms. Examples of haloalkyl groups/moieties include fluoromethyl, ditluoromethyl, trifluoro methyl and 2,2,2-trifluoroethyl.

The term "oxo" refers to an oxygen atom doubly bonded to the carbon atom to which it is attached to form the carbonyl of a ketone or aldehyde.

The term "halogen" includes fluorine, chlorine, bromine and iodine. In one embodiment, halogen is fluorine.

When any chemical group or moiety in formula (I) is described as substituted, it will be appreciated that the number and nature of substituents will be selected so as to avoid sterically undesirable combinations.

Further, it will he appreciated that the invention does not encompass any unstable ring or other structures or any 0-0 or S-S bonds.

hi one embodiment, each RI is independently selected from halo, cyano, hydroxyl, Ci-05 alkyl, Ci-C3 haloalkyl, cyclopropyl, halocyclopropyl, -0-(Ci-C3 alkyl), -0-(C -C3 haloalkyl), -0-(cyclopropyl), -0-(halocyclopropyl), -NH-(C -C3 alkyl), -NH-(Ci-C3 haloalkyl), -NH-(cyclopropyl), -NH-(halocyclopropyl), -N(Ci-C3 alky1)2, -N(Ci-C3 alkyl)(C1-C3 haloalkyl), -N(Ci-C3 haloalky1)2, -N(cyclopropy1)2, -N(cyclopropyl)(halocyclopropyl) or -N(halocyclopropy1)2. In another embodiment, each * RI is independently selected from fluoro, chloro, bromo, iodo, cyano, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent yl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, cyclopropyl, monofluorocyclopropyl, dill uorocyclopropyl, triIiuorocyclopropyh tetralluorocyclopropyl, pen tafl uorocyclopropyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, rnonofluoromethoxy, difluoromethoxy, trifluorome,thoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, cyclopropoxy, monofluorocyclopropoxy, difluorocyclopropoxy, trifluorocyclopropoxy, tetrafluorocyclopropoxy or pentafluorocyclopropoxy. In another embodiment, each RI is independently selected from fluoro, chloro, cyano, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, npropoxy, iso-propoxy or trifluoromethoxy. In another embodiment, each RI is independently selected from fluoro, chloro, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, iso-propoxy or trifluoromethoxy. In another embodiment, each RI is independently selected from fluoro, chloro, hydroxyl, methyl, trifluoromethyl, or methoxy. In another embodiment, each R1 is independently selected from fluor°, chloro, methyl, trifluoromethyl, or methoxy.

In one embodiment, m is 1 or 2.

In one embodiment, in is I. When m is 1, the single substituent R.1 can be in the 2-, 3-or 4-position. In one embodiment, m is 1 and R' is in the 4-position.

In one embodiment, m is 2. When m is 2, the two substituents RI can be in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-positions. hi one embodiment, m is 2 and the two substituents R1 are in the 2,4-, 2,5-or 3,4-positions. In another embodiment, m is 2 and the two substituents are in the 2,4-or 2,5-positions. In another embodiment, m is 2 and the two substituents RI are in the 2,4-positions.

In one embodiment, R2 is methyl, ethyl, n-propyl, iso-propyl, monofluoromethyl, difl uoro methyl, tri fluoro meth yl mo not] uoroethyl, di fluoroethyl, trifluoroeth yl tetrafluoroethyl, pentafluoroethyl, cyclopropyl, monofluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, tetrafluorocyclopropyl Or pentafluorocyclopropyl. In another embodiment. R2 is methyl, ethyl, n-propyl, iso-propyl or cyclopropyl. In another embodiment. R2 is methyl or ethyl. In another embodiment, R2 is methyl.

In one embodiment, R3 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, monofluoromethyl, difluoromethyl, trifluorotnethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, cyclopropyl, monofluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, tetrafluorocyclopropyl Or pentafluorocyclopropyl. In another embodiment, R3 is hydrogen, methyl, ethyl, n-propyl, iso-propyl or cyclopropyl. In another embodiment, R3 is hydrogen, methyl or ethyl. In another embodiment, R3 is hydrogen or methyl. In another embodiment, le is hydrogen.

In one embodiment, R4 is a bond, -CH2-, -CH20-12-, -CHMe-CI-In-or -CH2-CHMe-, each of which may optionally be substituted with one, two or three halogens (particularly fluorine). In another embodiment. R4 is a bond, -CH2-, -CH2CH2-, -CHMe-CH2-or -CH/-CHMe-. In another embodiment, R4 is a bond, -CH2Cli2-. In another embodiment, R4 is a bond or -CH2-.

In one embodiment, R5 is an azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl. isothiazolidinyl, piperidinyl, piperazinyl, perhydropyridazinyl, perhydropyrimidinyl, morpholinyl, thiomorpholinyl, 1,2-oxazinanyl, 1,3-oxazinanyl, 1,2-thiazinanyl, 1,3-thiazinanyl, azepanyl or diazepanyl group, each of which may optionally be substituted. In another embodiment, R5 is an azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, perhydropyridazinyl, perhydropyrimidinyl, morpholinyl, 1,2-oxazinanyl, 1,3-oxazinanyl, azepanyl or diazepanyl group, each of which may optionally be substituted. In another embodiment. R5 is an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepanyl group, each of which may optionally he substituted. In another embodiment, R5 is a pyrrolidinyl, piperidinyl or morpholinyl group, each of which may optionally be substituted. In another embodiment. R5 is a pyrrolidinyl or piperidinyl group, each of which may optionally be substituted. In another embodiment R5 is an optionally substituted pyrrolidinyl group.

In one embodiment, R. is substituted with one, two or three substituents independently selected from halo, cyano, hydroxyl. Ci-C3 alkyl, Ci-C3 haloalkyl, cyclopropyl, halocyclopropyl, -0-(Ci-C3 alkyl), -0-(Ci-C3 haloalkyl), -0-(cyclopropyl), -0-(halocyclopropyl), -NH-(Ci-C3 alkyl), -NH-(Ci-C3 haloalkyl), -NH-(cyclopropyl).

-NH-(halocyclopropyl), -N(Ci-C3 alky1)2, -N(Ci-C3 alkyl)(Ci-C3 haloalkyl), -N(Ci-C3 haloalky1)2, -N(cyclopropyl)2, -N(cyclopropyl)(halocyclopropyl), -N(halocyclopropy1)2, or C i-C4 alkylene, wherein one -CH2-in the C1-Ca alkylene group may optionally be replaced by -0-, -NH-, -N(Ci-C3 alkyl)-, or -N(Ci-C3 haloalkyl)-.

1 5 In another embodiment, R5 is substituted with one, two or three substituents independently selected from halo, cyano, hydroxyl, CI-C3 alkyl, CI-C3 haloalkyl, cyclopropyl, halocyclopropyl, -0-(Ci-C3 alkyl), -0-(Ci-C3 haloalkyl), -0-(cyclopropyl). -0-(halocyclopropyl), or Ci-C4 alkylene, wherein one -CH2-in the C1-C4 alkylene group may optionally be replaced by -0-, -NH-or -N(Ci-C3 alkyl)-. In another embodiment. R5 is substituted with one, two or three substituents independently selected from halo, cyano, hydroxyl, Cl-C3 alkyl. Cl-C3 haloalkyl. cyclopropyl, halocyclopropyl. -0-(Ci-C3 alkyl). haloalkyl), -0-(cyclopropyl), or -0-(halocyclopropyl).

In another embodiment, R5 is substituted with one, two or three substituents independently selected from halo, hydroxyl, Ci-C3 alkyl, Ci-C3 haloalkyl, cyclopropyl, halocyclopropyl or Ci-C4 alkylene, wherein one -CH, in the Ci-C4 alkylene group may optionally be replaced by -0-, -NH-or -N(Ci -C3 alkyl)-. In another embodiment, R5 is substituted with one, two or three substituents independently selected from halo, hydroxyl. Ci-C3 alkyl, Ci-C3 haloalkyl, cyclopropyl or halocyclopropyl.

In another embodiment, R5 is substituted with one or two substituents independently selected from halo, hydroxyl, CI-C3 alkyl, cyclopropyl or CI-Ca alkylene, wherein one -CH,-in the Ci-C4 alkylene group may optionally be replaced by -0-, -NH-or -N(Ci-C3 alkyl)-. In another embodiment, R5 is substituted with one or two substituents independently selected from halo, hydroxyl, Ci-C3 alkyl or cyclopropyl.

In another embodiment, R5 is substituted with one or two substituents independently * selected from fluoro, chloro, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CHMe-CH2-, -CH2-CHMe-, -CHMe-CH2CH2-, -CH2-CHMe-CH2-, -CH2CH2-CHMe-, -0-CH2-, -CH2-0-, -0-CH2CH2-, -CH2-0-CH2-, -CH2CH2-0-, -(NH)-CH2-, -CH2-(NH)-, -(NH)-CH2CH2-, -CH2-(NH)-CH2-, -CH2CH2-(NH)-. -(NMe)-CH2-, -CH2-(NMe)-, -(NMe)-CH2CH2-, -CH2-(NMe)-CH2-, or -CH2CH2-(NMe)-. In another embodiment, R5 is substituted with one or two substituents independently selected from fluoro, chloro, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, -CH2-, -CH2CH2-, -CH2CH2CH2-or -CH2-0-CH2-. In another embodiment, R5 is substituted with one or two substituents independently selected from fluor°, chloro, hydroxyl, methyl, ethyl, n-propyl, iso-propyl or cyclopropyl. In another embodiment, R5 is substituted with one or two substituents independently selected from fluoro, chloro, methyl, ethyl, n-propyl, iso-propyl or cyclopropyl.

In another embodiment, R5 is substituted with one or two substituents independently selected from fluoro, hydroxyl, methyl, ethyl, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2-0-CF12-. In another embodiment, Rs is substituted with one or two substituents independently selected from Iluoro, hydroxyl, methyl or ethyl. In another embodiment, R5 is substituted with one or two substituents independently selected from fluoro, methyl or ethyl. Tn another embodiment, R5 is substituted with one or two substituents independently selected from methyl or ethyl.

R5 may be substituted with Ci-C4 alkylene, wherein one -CH2-in the Ci-C4 alkylene group may optionally be replaced by -0-, -NH-, -N(CI-Cs alkyl)-, or -N( haloalkyl)-. In one embodiment, R5 is a piperidinyl group substituted with -CH2CH2-, for example an 8-azabicyclo[3.2. floctanyl group (such as an 8-methyl-8-azabicyclo[3.2.1 Joctanyl group), or a quinuclidinyl group. In another embodiment, R5 is a piperidinyl group substituted with -CTI2CH2CH2-, for example a 9-azabicyclo[3.3.1]nonanyl group (such as a 9-methyl9-azabicyclo[3.3.1]nonanyl group). In another embodiment, Rs is a piperidinyl group substituted with -CH2-, for example a 1-azabicyclor.2.11heptanyl group. In one embodiment, R5 is not substituted with Ci-C4 alkylene.

R5 may be substituted with one, two or three substituents on a ring nitrogen atom and/or on a ring carbon atom. In one embodiment. R5 is substituted with only one substituent, wherein the substituent is on a ring nitrogen atom.

hi one embodiment, R5 is a pyrrolidinyl or piperidinyl group, each of which may optionally be substituted with one or two substituents independently selected from fluor°, hydroxyl, o methyl or ethyl. In another embodiment, R5 is a pyn-olidinyl or piperidinyl group, each of which may optionally be substituted with one or two substituents independently selected from fluor°, methyl or ethyl. In another embodiment. R5 is a pyrrolidinyl or piperidinyl group, each of which may optionally be substituted with one or two substituents independently selected from methyl or ethyl. In another embodiment, R5 is a piperidinyl group substituted with a methyl or ethyl group on the ring nitrogen atom. In another embodiment. R5 is a piperidinyl group substituted with a methyl group on the ring nitrogen atom (i.e. 1 -methylpiperidi n-2-yl, 1 -methylpiperid n-3-y1 or 1 -methylpiperidi n-4-y1).

In one specific embodiment of the first aspect, the present invention provides a compound of formula (I), wherein each R1 is independently selected from fluor°, chloro, cyano, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, iso-propoxy or trifluoromethoxy; m is 1 or 2; R2 is methyl, ethyl, n-propyl, iso-propyl or cyclopropyl; R3 is hydrogen, methyl, ethyl, n-propyl, iso-propyl or cyclopropyl; R1 is a bond, -CH2-or -CH2CH2-; and is an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepanyl group, each of which may optionally be substituted with one, two or three substituents independently selected from halo, hydroxyl, CI -C3 alkyl, Ci -C3 haloalkyl, cyclopropyl, halocyclopropyl or CI -C4 alkylene, wherein one -CH2-in the C1-C4 alkylene group may optionally be replaced by -0-, -NH-or -N(CI-C3 alkyl)-.

In another specific embodiment of the first aspect, the present invention provides a compound of formula (I), wherein each RI is independently selected from fluor°, chloro, hydroxyl, methyl, ethyl, npropyl, iso-propyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, iso-propoxy or trifluoromethoxy; m is 1 or 2; R2 is methyl or ethyl; R3 is hydrogen, methyl or ethyl; R4 is a bond, -CH2-or -CH2CH2-; and R5 is a pyn-olidinyl, piperidinyl or morpholinyl group, each of which may optionally he substituted with one or two substituents independently selected from fluor°, chloro, hydroxyl, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, -CH2-, -CH2CH2-, -CH2CH2CH2-or -CH/-0-CH2-.

A second aspect of the present invention provides a compound selected from: 5-(4-Methoxypheny1)-1-methyl-N-((l-methylpiperidin-2-yemethyl) -1H-pyrazole-3-carboxamide; (R)-5-(4-Methoxypheny1)-1-methyl-N-((l-methylpiperidin-2-y1)methyl) -1H-pyrazole-3-carboxamide; (S)-5-(4-Methoxypheny1)-1-methyl-N-((l-methylpiperidin-2-yemethyl) -1H-pyrazole-3-carboxamide; 5-(4-Methoxyphen y1)-1 -methyl-N-C -methylpiperidin-4-y1)-1H-pyrazole-3-carboxami de; 5-(4-Methoxypheny1)-1 -methyl-N-(2-( 1 -methylpiperidi n-2-ypethyl)-1 H-pyrazo le-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(241-melhylpiperidin-3-y1)ethyl) -1H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(2-(1-methylpynolidin-2-yl)ethyl) -1H-pyrazole-3-carboxamide; 544-Methoxyphen yl)-1 -methyl-N-(2-( 1 -methylpyrrol i di n-3-yl)eth y1)-1 H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N4(1-methylpyrrolidin-3-yl)methyl) -1H-pyrazole-3-carboxamide; 544-Methox yphen yl)-1 -methyl-N-(1 -meth yl pyn-ol idin-3-y1)-1 H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide; (R)-5-(4-Methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxam i de; (S)-5-(4-Methoxypheny1)-1-methyl-N-( 1-methylpiperidin-3-y1)-1H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-((1-methylpyrrolidin-2-yl)methyl) -1H-pyrazole-3-carboxamide; (R)-5-(4-Methoxypheny1)-1-methyl-N-((1-methylpynolidin-2-yl)methyl) -1H-pyrazole-3-carboxamide; (S)-5-(4-Methox yphen y1)-1 -methyl-N-(( 1 -meth yl pyn-ol idi n-2-yl)meth yl)-1 H-pyrazole-3-carboxam i de; 1-Methyl-N-(quinuclidin-3-y1)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(8-methy1-8-az abicyclo [3.2.1]oct an-3-y1)-1H-pyrazole3-carboxamide; Is N-(1 -A zabieyel o [2.2.1 Jheptan-3-y1)-5-(4-m ethoxyphen y1)-1 -methyl-1 H-pyrazol 0-3-carboxamide; 5-(4-Methoxyphen y1)-1 -methyl-N-(9-methyl -9-azabi cyclo [3.3. 1 nonan-3-y1)-1 1-f-pyraz6le3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(2-morpholinoethyl) -1H-pyrazole-3-carboxamide; 1-Methyl-N-(1-methylpiperidin-4-y1)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide; 1 -Methyl-N-((1 -tnethylpiperidin-2-yOmethyl)-5-(4-(trifluoromethyl)pheny1)-1 H-pyrazole3-carbox am ide; (R)-1-Methyl-N4(1-methylpiperidin-2-yl)methyl)-5-(4-(trifluoromethyl) pheny1)-111-25 pyrazole-3-carboxamide; (S)-1 -M ethyl-N-(( 1 -methylpiperidi n-2-yl)methyl)-5-(4-(tri fl uoro methyl)pheny1)-1 Hpyrazole-3-carboxamide; 1-Methyl-N-(2-(1-methylpiperidin-3-yflethyl)-5 -(4-(trifluoromethyl)pheny1)-1H-p yrazole3-carbox am ide; 1-Methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-(4-(nifluoromethyl)pheny1) -111-pyrazole-3-carboxamide; 1-Methyl-N-(( 1-methylpyrrolidin-2-yl)methyl)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole3-carbo x amide; (R)-1-Methyl-N-((1-methylpyrrolidin-2-yOmethyl)-544-(trifluoromethyl) phenyl)-1Hpyrazole-3-carboxamide; (S)-1 -M ethyl-N-(( 1 -methylpyrroli di n-2-yl)m ethyl)-544-(tritluoro methyl)phen y1)-1 Hpyrazole-3-carboxamide; 1-Methyl-N4(1-methylpiperidin-3-yl)methyl)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole3-carboxamide; (R)-1-Methyl-N4(1-methylpiperidin-3-yl)methyl)-5-(4-(trifluoromethyl) pheny1)-1Hpyrazole-3-carboxamide; (S)-1 -M eth yl-N-(( 1 -me(hyl pi peridi n-3-yl)meth yl)-5-(4-(tri fluoromethyl)phen y1)-IN-pyrazole-3-carbox amide; 1 -Methyl-N-(1 -methylpiperidi n-3-y1)-5-(4-(trifluorornethyl)pheny1)-1 H-pyrazole-3-cuboxamide; (R)-1-Methyl-N-(1-methylpiperidin-3-y1)-544-(trifluoromethyppheny1) -1H-pyrazole-3-carboxamide; (S)-I -Methyl-N-( 1 -meth ylp iperidi n-3-y1)-544-(tri fluoromethyl)phen y1)-1 H-pyrazol 0-3-carboxamide; 1 -M eth yl-N-(24 1 -meth ylp iperidi n-2-yl)ethyl)-544-(tritluoromethyl)phenyfl-1 H-pyrazole3-carboxamide; (R)-1-Methyl-N-(2-( 1-methylpiperidin-2-yflethyl)-5-(44trifluoromethyl)pheny1)-1H20 pyrazole-3-carboxamide; (S)-1 -Methyl-N-(2-( 1 -meth yl piped din-2-yl)eth yl)-544-(tri fluoromethyl)phenyl)-1 Hpyrazo le-3-carbox amide; 1 -Methyl-N-(2-(1 -methylpyrrol idi n-3-yflethyl)-544-(trifluoromethyflpheny1)-1 Hpyrazole-3-carboxamide; 1-Methyl-N4( 1-methylpyrrolidin-3-yl)methyl)-544-(trifluoromethyl)pheny1)-1H-pyrazole- 3-carbox am ide; N-((1-Ethylpiperidin-2-yl)methyl)-1-methyl-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide; 1 -M eth yl-N4 1 -methylpyrroli di n-3-y1)-544-(tri fluoro meth yl)pheny1)-1 H-pyrazole-3-carboxamide; 1-Methyl-N4piperidin-2-ylmethyl)-5-(4-(trifluoromethyflpheny1) -1H-pyrazole-3-carboxamide; 1-Methyl-N-(8-methy1-8-az abicyclo [3.2.1]oetan-3-y1)-5-(4-(trifluoromethyl)pheny1)-1Hpyrazole-3-carboxamide; N-(1 -A zabi cycl o [2.2.1 Jheptan-3-y1)-1 -meth y1-5-(4-(tri fluoromethy)phcny1)-1 H-pyrazolc3-carboxamide; 5-(4-Isopropylpheny1)-1-methyl-N-(1-methylpiperidin-4-y1) -1H-pyrazole-3-carboxamide; 5-(4-Isopropylpheny1)-1-methyl-N-(( 1-methylpiperidin-2-yl)methyl)-1H-pyrazole-3-earboxamide; 5-(2-Fluoropheny1)-1 -methyl-N-((1-methylpiperidin-2-yemethyl)-1H-pyrazole-3-carboxamide; 5-(2,5-Dime(h ylphen y1)-1 -methyl -N-(( 1 -meth ylpi peri din-2-yl)me(h yl)-1 H-pyrazole-3-carboxam i de; (R)-5-(2,5-Dimethylpheny1)-1-methyl-N-((1-methylpiperidin-2-yemethyl) -1H-pyrazole-3-carboxamide; (S)-5-(2,5 -Dimethylpheny1)-1-methyl-N-(( 1-methylpiperidin-2-yl)methyl)-1H-pyrazole-3-carboxam ide; 5-(3-Fluoropheny1)-1 -methyl-N((1-methylpiperidin-2-yemethyl)-1H-pyrazole-3-carboxam i de; 5-(4-Fluoropheny1)-1 -methyl-N((1-methylpiperidin-2-yemethyl)-1H-pyrazole-3-carboxamide; 5-(4-Chloropheny1)-1-methyl-N4(1-methylpiperidin-2-yemethyl) -1H-pyrazole-3-carboxamide; 5-(4-Chlorophcny1)-1 -methyl-N-((1 -methylpiperidin-4-y1) methyl)-1 H-pyrazole-3-carboxam i de; 5-(4-Chloropheny1)-1-methyl-N-( (1-methylpiperidin-3-yl)methy1)-1H-pyrazole-3-carboxamide; 5-(4-Chloro-3-fluoropheny1)-1 -methyl-N-(1 -methylpipeddi n-3 -y1)-1 H-pyrazolc-3-carboxamide; 5-(3-Fluoro-4-methoxypheny1)-1-methyl-N-(1-methylpipericlin-3 -y1)-1H-pyrazole-3-carboxam i de; 5-(3-Chloro-4-fluoropheny1)-1-methyl-N-(( 1-methylpiperidin-4-yl)methyl)-1H-pyrazole-3-carboxamide; 5-(3-Chloro-4-fluoropheny1)-1-methyl-N4(1-methylpiperidin-3-yl)methyl) -1H-pyrazole-3-carboxamide; 5-(3-Fluoro-4-methoxypheny1)-1-methyl-N((1-methylpiperidin-4-yl)methyl) -1Hpyrazole-3-carboxamide; 5-(3-Fluoro-4-methoxypheny1)-1 -methyl-N-(( 1 -methylpiperidi n-3 -y1) methyl)-1Hpyrazale-3-carboxamide; 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-((1-methylpiperidin-4-yl)methyl) -1Hpyrazole-3-carboxamide; 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-(24 1-methylpyrrolidin-2-yflethyl)-111-pyrazole-3-carboxamide; 5-(2-F1 uoro-4-me(hoxypheny1)-1 -methyl-N-(( 1 -methy1piperidin-2-yl)me(hy1)-I H-io pyrazole-3-carbox amide; 5-(2-Fluoro-4-methoxypheny1)-1 -methyl-N-(1 -methylpiperidi n-3 -y1)-1 H-pyrazole-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole3-carboxamide; (R)-5-(2-Fluoro-4-(tritluoro methyl)ph en y1)-1 -methyl-N-(1 -methylpiperidi n-3-y1)-1H- pyrazale-3-carboxamide; (8)-542-Fluoro-4-(tritluoro tnethyl)pheny1)-I -methyl -N-( I -rnethylpiperi di n-3-y1)-1 Hpyrazale-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(( 1-methylpiperidin-2-yl)methyl)-1H-pyrazole-3-carboxamide; 5-(2-F1 uoro-4-(tri Iluorometh yl)phen y1)-1 -methyl -N-(2-( I -meth yl pyn-oli di n-2-yl)ethyl)-1 ftpyrazo le-3-carbox amide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1 -methyl -N-(2-( I -tnethylpiperidin-2-ypethyl)-1 H -pyrazole-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-3-yl)methyl)-1H-pyrazole-3-carbox amide; (R)-5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N4 (1-methylpiperidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; (8)-542-Fluoro-4-(tritluoro tnethyl)pheny1)-I -methyl -N-(( I -methylpiperidi n-3-yl)tneth y1)- 1H-pyrazole-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-4-yl)methyl)-1Hpyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide; (R)-5-(2-Chloro-4-methoxypheny1)-1 -methyl-N-(1 -methylp iperidi n-3-y1)-1H-pyrazole-3-carboxamidc; (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-( (1 -methylpyrrolidin-3-yl)methyl)-111-pyrazole-3-carboxamide; (R)-5-(2-Chloro-4-metho x yphen y1)-1 -methyl-N-(( 1 -meth ylp yrrolidin-3-y1)methyl)-1 Fi-io pyrazole-3-carbox amide; (S)-5-(2-Chloro-4-methox yphen yI)-1 -meth yl -N-(( 1 -methylpyrrolidin-3-y1) meth yI)-1 Hpyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(( 1 -methylpiperidin-3 -yl)methyl)-1Hpyrazole-3-carboxamide; (R)-5-(2-Chloro-4-methoxypheny1)-1 -methyl-N-(( 1 -tnethylp iperi di n-3-y1) methyl)-1 H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methox yphen y1)-1 -meth yl -N-(( 1 -methylpiperidin-3-y1) methyl)-1 Flpyrazole-3-carboxamide; 5-(2-Chloro-5-(trifluoromethyepheny1)-1-methyl-N4 1-methylpiperidin-3-y1)-1H-pyrazole20 3-carboxamide; (R)-5-(2-Chloro-5-(tri Iluoromethyl)phen yl)-1 -meth yl-N-( 1 -meth ylpi peridi n-3-y1)-1 Hpyrazo le-3-carbox amide; (S)-5-(2-Chloro-5-(trifluoro methy Op hen yI)-1 -methyl-N-(1 -methylpiperidi n-3-y1)-1 Hpyrazole-3-carboxamide; 5-(2-Chloro-5-(trifluoromethyl)pheny1)-1-methyl-N-((1 -methylp yrrolidin-3-yl)methyl)- 1 H-pyrazole-3-carboxami de; (R)-5-(2-Chloro-5-(tritluoromethyl)pheny1)-1-methyl-N-((1 -methylpyrrolidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-5-(tritluoro methyl)ph en y1)-1 -methyl-N-(( 1 -meth ylpyrrol idi n-3-30 yl)methy1)-1H-pyrazole-3-carboxamide; 5-(2-Chloro-5-methoxypheny1)-1-methyl-N-( 1 tethylpiperidin-3 -y1)-1H-pyrazole-3-carboxamide; (R)-5-(2-Chloro-5-methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-5-methox yphen y1)-1 -methyl-N-(1-tnethylpiperi di n-3-y1)-1 H-pyrazol 0-3-carboxamide; 5-(2-Chloro-5-methoxypheny1)-1-methyl-N-((1 -methylpyrrolidin-3-yl)methyl)-1Hpyrazole-3-carboxamide; (R)-5-(2-Chloro-5-methoxypheny1)-1-methyl-N-(( 1-methylpyrrolidin-3-yl)methyl)-1Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-5-methoxyphen y1)-1 -methyl -N-(( 1 -meth ylpyn-olidin-3-yl)meth y1)-1 H-io pyrazole-3-carbox amide; methyl-N-( 1-methylpiperidi n-4-y1)-5-(4-(trifluoromethyppheny1)-1 H-pyrazole-3-carboxamide; 1,4-Dimethyl-N4(1-methylpiperidin-2-yl)methyl)-5-(4-(trifluoromethyl) pheny1)-1Hpyrazole-3-carboxamide; Is 1 -Ethyl-N-( 1 -methylpyrrol idi n-3-y1)-5-(4-(trifluoro tnethyl)phen y1)-1 H-pyrazole-3-carboxamide; 1 -Ethyl-5-(4-methoxyph eny1)-N-( 1 -methylpyrrol idi n-3-y1)-1 H-pyrazol e-3-earbox am i de; 5-(2-Methoxy-4-(trifluoromethy1)pheny1)-1-methy1-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-carboxamide; 5-(2-Methoxy-4-(trifluoromethyl)pheny1)-1-methyl-N4 (1-methylpiperidin-2-yl)methyl)- 1 H-pyrazole-3-carboxami de; 5-(2-Methoxy-4-(trifluoromethyl)phenyl)-1 -methyl-N-((1 -methylpipexidi n-4-y1) methyl)-1 H-pyrazole-3-carboxamide; 5-(2-Methoxy-4-(trifluoromethy1)pheny1)-1-methyl-N-( (1-methylpiperidin-3-yl)methyl)-25 1H-pyrazole-3-carboxamide; 5-(2-Chloro-4-rnethox yphen y1)-1 -methyl-N-(( 1 -meth ylpyrrol idi n-2-y1) meth y1)-1Hpyrazole-3-carboxamide; (R)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(( 1-methylp yrrolidin-2-yl)methyl)-1Hpyrazole-3-carbox amide; S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-( ( 1-methylpyrrolidin-2-yemethyl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methoxypheny1)-4-ethyl-1 -methyl-N-(1-methylpiperidin-3-y1)-1Hpyrazole-3-carbox amide; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((1 -methylpiperidin-2-yl)methyl)-1Hpyrazole-3-carboxamide; (R)-5-(2-Chloro-4-methoxypheny1)-1 -methyl-N-(( 1-tnethylp iperi di n-2-yl)methyl)-1 Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((l-methylpiperidin-2-y1) methyl)-1Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methoxypheny1)-1,4-dimethyl-N-( 1-methylpiperidin-3 -y1)-1H-pyrazole3-carboxamide; 5-(2-Chloro-4-(trilluorometh yl)phen y1)-1 -methyl-N-(1 -meth yl piperidin-3-y1)-1 H-p yrazole-o 3-carboxamide; (R)-5-(2-Ch loro-4-(trifluoromethyl)pheny1)-1 -methyl-N-(1 -methylpipexidi n-3-yI)-1Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-carboxamide; 5-(2-Chloro-4-(tritluoro tnethyl)pheny1)-1 -methyl-N-(( 1 -rnethylpyrrolidin-3-yl)rnethyl)- 1H-pyrazole-3-carboxamide; (R)-5-(2-Chloro-4-(tri fluor° methyl)phenyl)-1 -methyl-N-(( 1 -methylpyrroli di n-3-yflmethyl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-(trifluoromethyepheny1)-1-methyl-N-(( 1-methylpyrrolidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; 5-(2-F1 uoro-4-((ri Iluorometh yl)phen y1)-1-methyl -N-(( 1 -meth yl pyrroli din-3-yl)m ethyl)-1 ftpyrazo le-3-carbox amide; (R)-5-(2-Fluoro-4-(trifluorennethyppheny1)-1 -methyl-N-(( 1 -methylpyrrolidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(0 -methylp yrrolidin-3-yemethyl)- 1 H-pyrazole-3-carboxami de; (S)-5-(2-Fluoro-4-(tritluoromethyl)pheny1)-1-(methyl-d3)-N4 1-(methyl-d3)piperidin-3-y1)-1H-p yrazole-3-c arboxamide; (S)-5-(2-Chloro-4-(rnethoxy-d3)phenyl)-1 -(methyl-d3)-N-( 1 -(methyl-d3)piperi di n-3-y1)- 1H-pyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-N-(1,3-dimethylpiperidin-3-y1)-1 -methyl-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(piperidin-3-y1) -1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methox yphen y1)-1 -meth yl -N-( 1 -(meth yl -d3)p iperidi n-3 -y1)-1 I-1-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-(methoxy-d3)pheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1Hpyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-N-(4,4-difluoropiperidin-3-y1) -1-methyl-1H-pyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-N-(4.4-dilluoro-1 -meth yl piperi clin-3-y1)-1-methyl-1 H-pyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-N-(4,4-difluoropyrrol idi n-3-yI)-1-methyl-1 H-pyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3)-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(tritluoro tnethyl)pheny1)-1 - 1-0 -(methyl-d3)piperidi n-3-y1)-1 H-pyrazole-3-carboxamide; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.

A third aspect of the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, wherein the process comprises reacting a compound of formula (H)

OH R2

Formula (H) or a salt thereof, with a compound of formula (M). H2N-R4-R5, wherein m, R1, R2, R3, R4 and R5 are as defined according to the first aspect of the present invention; and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (I) into another compound of formula (I); removing any protecting groups; forming a pharmaceutically acceptable salt.

The above process may conveniently be carried out by combining the pyrazole-3-carboxylic acid of formula (II) with the amine of formula (III) in the presence of a coupling reagent such as (1) HATU with DIPEA or triethylamine (e.g. in THF or dichloromethane e.g. at 0°C to room temperature), or (2) EDC and HOAt with triethylamine (e.g. in dichloromethane e.g. at room temperature). Alternatively. the pyrazole-3-carboxylic acid of formula (II) may be converted into an acid chloride, for example, by using oxaly1 chloride (e.g. in dichloromethane optionally with DMF e.g. at 0°C to room temperature); and combining the acid chloride with the amine of formula (In) in the presence of a base such as triethylamine (e.g. in dichloromethane or DMF or a mixture thereof e.g. at 0°C to room temperature).

The amines of formula (III) arc known compounds or may be prepared according to processes known in the art. The pyrazole-3-carboxylic acids of formula (II) are known compounds or may be prepared according to the general reaction scheme depicted in Figure 1.

OH base

diethyl oxalate, base Figure 1 R3 (VI) Me0-NHMe (CH2R3)MgBr R3

N

(1316 R2 (II) The benzoic acids of formula (IV) are known compounds or may be prepared according to processes known in the art. They may be converted into the amides of formula (V) by using N,O-dimethyl hydroxylamine, for example, in the presence of a coupling reagent such as EDC and HOAt with DIPEA (e.g. in DMF e.g. at room temperature). The amides of formula (V) may be converted into the ketones of formula (VI), for example, by using a Grignard reagent (such as (CH2R3)MgBr) (e.g. in diethyl ether e.g. at -10°C to room temperature). The ketones of formula (VI) may be converted into the triketones of formula (VII) by using diethyl oxalate in the presence of a base such as (1) LiHMDS (e.g. in diethyl ether e.g. at -80°C to room temperature), or (2) n-BuLi (e.g. in diethyl ether e.g. at -80°C to room temperature), or (3) NaH (e.g. in DMF or THE e.g. at 0-50°C). The triketones of formula (VII) may he converted into the pyrazole-3-carboxylic esters of formula (VIII) by using a hydrazine H2N-NHR2 (such as methylhydrazine or ethylhydrazine) or a salt thereof (such as a sulphate or hydrochloride salt) (e.g. in ethanol e.g. at room temperature to 90°C). The pyrazole-3-carboxylic esters of formula (VIII) may he converted into the pyrazole-3-carhoxylic acids of formula (II) by using a base, for example, lithium hydroxide (e.g. in water and THF optionally with an alcohol such as methanol or ethanol e.g. at room temperature).

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as phenol, hydroxyl or amino groups in the reagents may need to he protected by protecting groups. Thus, the preparation of the compounds, salts, solvates and prodrugs of the present invention may involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups.

The protection and deprotection of functional groups are described, for example, in Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973); 'Greene's Protective Groups in Organic Synthesis', 4th edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (2007); and 'Protecting Groups', 3rd edition, P.J. Kocienski, Thieme (2005).

The compounds of formula (I) may be converted into a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi-formate, hydrochloride, hydrobromi de, benzenes ul phon ate (besyl ate), saccharin (e.g. monosaccharin), trilluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy2-naphthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt. In one embodiment of the invention, the compounds of formula (I) are in the form of a hydrochloride salt.

A salt of a compound of formula (I) may also be formed between a protic acid functionality (such as a carboxylic acid group) of a compound of formula (I) and a suitable cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium In one embodiment of the invention, the salt is a mono-or di-sodium salt or a mono-or di-potassium salt.

Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form another embodiment of the present invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.

hi one embodiment of the present invention, therapeutically inactive prodrugs are provided. Prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of formula (I). Generally, the prodrugs are pharmacologically inert chemical derivatives that can he converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds of formula (T) can he administered as a prodrug to increase the activity, hioavailahility, or stability of the compound of formula (I) or to otherwise alter the properties of the compound of formula (I). Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound. The present invention also encompasses salts and solvates of such prodrugs as described above.

Where the compounds, salts, solvates and prodrugs of the present invention are capable of existing in stereoisomeric forms, it will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) and mixtures thereof. The use of tautomers and mixtures thereof also forms an embodiment of the present invention. The compounds, salts, solvates and prodrugs of the present invention may contain at least one chiral centre. The compounds, salts, solvates and prodrugs may therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, salts, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a "substantially enantiomerically pure" isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight. Enantiomerically pure isomers are particularly desired.

The compounds, salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to 12C, 13C, 1H, 2H (D), 14N, 15N, 160, 170, 180, 19F and 1271, and any radioisotope including, but not limited to "C, 14C, 2, (T), 13N, 150, 18F, 1231, 1241, 1251 and 1311. Therefore, the term -hydrogen", for example, encompasses 1H, 2H 1;, 12r (D) and 31-1 (T). Similarly, carbon atoms are to be understood to include nc, t..,. --C and 14C, nitrogen atoms are to be understood to include 13N, 14N and 15N, oxygen atoms are to be understood to include 150 160 170 and ts 0, fluorine atoms are to be understood to -, include 18F and 19F, and iodine atoms are to be understood to include 121 1241 125 1 1271 and 1311.

In one embodiment, the compounds, salts, solvates and prodrugs of the present invention may be isotopically labelled. As used herein, an -isotopically labelled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature. Any of the compounds, salts, solvates and prodrugs of the present invention can be isotopically labelled, for example, any of examples 1 to 78. In particular, 5-(2,5-dimethylpheny1)-1-methyl-N-((l-meth ylpiperi di n-2-yl)methyl)-1 H-pyrazole-3 -carbox am ide of example 34 may be isotopically labelled.

hi one embodiment, the compounds, salts, solvates and prodrugs of the present invention may bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds, salts, solvates or prodrugs, or may be introduced by coupling the compounds, salts, solvates or prodrugs to chelating moieties capable of binding to a radioactive metal atom. Such radiolabelled versions of compounds, salts, solvates and prodrugs may be used, for example, in diagnostic imaging studies.

hi one embodiment, the compounds, salts, solvates and prodrugs of the present invention may be tritiated, i.e. they contain one or more 'II (T) atoms. Any of the compounds, salts, solvates and prodrugs of the present invention can be tritiated, for example, any of examples 1 to 78. In particular, 5-(2,5-dimethy1p1ieny1)-1-methyl-N-((l-methylpiperidin-2-In yl)methyl)-1H-pyrazole-3-carboxamide of example 34 may be tritiated.

The compounds, salts, solvates and prodrugs of the present invention may be amorphous or in a polymorphic form or a mixture of any of these, each of which is an embodiment of the present invention.

The compounds, salts, solvates and prodrugs of the present invention have activity as pharmaceuticals and may be used in treating or preventing a disease, disorder or condition that has dysregulation of dopamine, noradrenaline or serotonin as a key pathological mechanism.

Therefore, a fourth aspect of die present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, for use in therapy, in particular for use in treating or preventing a movement disorder such as tremor, dystonia, dyskinesia, Parkinson's disease, or Huntington's disease; or a psychiatric disorder such as schizophrenia, psychotic disorder, psychosis, schizoaffective disorder, bipolar disorder (including bipolar I, bipolar II, bipolar mania, and bipolar depression), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) including Fragile X syndrome, Tourettes syndrome, or an addiction disorder (including substance or drug dependence, alcohol dependence, nicotine dependence, binge eating, and gambling disorder). In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, for use in treating or preventing Parkinson's disease, tremor, Tourettes syndrome, or an addiction.

A fifth aspect of the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, for the manufacture of a medicament for treating or preventing a movement disorder such as tremor, dystonia, dyskinesia. Parkinson's disease, or Huntington's disease; or a psychiatric disorder such as schizophrenia, psychotic disorder, psychosis, schizoaffective disorder, bipolar disorder (including bipolar I, bipolar H. bipolar mania, and bipolar depression), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) including Fragile X syndrome, Tourettes syndrome, or an addiction disorder (including substance or drug dependence, alcohol dependence, nicotine dependence, binge eating, and gambling disorder). In one embodiment, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, for the manufacture of a medicament for treating or preventing Parkinson's disease, tremor, Tourettes syndrome, or an addiction.

A sixth aspect of the present invention provides a method of treating or preventing a movement disorder such as tremor, dystonia, dyskinesia, Parkinson's disease, or Huntington's disease; or a psychiatric disorder such as schizophrenia, psychotic disorder, psychosis, schizoaffective disorder, bipolar disorder (including bipolar I, bipolar TE, bipolar mania, and bipolar depression), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) including Fragile X syndrome, Tourettes syndrome, or an addiction disorder (including substance or drug dependence, alcohol dependence, nicotine dependence, binge eating, and gambling disorder); the method comprising administering a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, to a patient in need thereof. In one embodiment, the present invention provides a method of treating or preventing Parkinson's disease, tremor, Tourettes syndrome, or an addiction, the method comprising administering a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, to a patient in need thereof.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing die disorder or condition or those in the prodromal phase of a disorder.

The terms "treat", "treatment" and "treating" include improvement of the conditions described herein. The terms "treat", "treatment" and "treating" include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms "treat", "treatment" and "treating" are intended to include therapeutic as well as prophylactic treatment of such conditions.

As used herein the terms "disease", "disorder" and "condition" relate to any unhealthy or abnormal state. The terms "disease, disorder or condition that has dysregulation of dopamine as a key pathological mechanism", "disease, disorder or condition that has dysregulation of noradrenaline as a key pathological mechanism" and "disease, disorder or condition that has dysregulation of serotonin as a key pathological mechanism" includes diseases, disorders and conditions in which the modulation of the receptor a6 (nAChRa6) may provide a therapeutic benefit, examples of which include: (1) Movement disorders: such as tremor, dystonia, dyskinesia. Parkinson's disease, and Huntington's disease; and (.2) Psychiatric disorders: such as schizophrenia, psychotic disorder, psychosis, schizoaffective disorder, bipolar disorder (including bipolar I. bipolar II, bipolar mania, and bipolar depression), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) including Fragile X syndrome, Tourettes syndrome, and an addiction disorder (including substance or drug dependence, alcohol dependence, nicotine dependence, binge eating, and gambling disorder).

Schizophrenia is a debilitating psychiatric disorder characterised by a combination of negative symptoms (such as social withdrawal, anhedonia, avolition and apathy) and positive symptoms (including hallucinations, delusions and paranoia) as well as marked cognitive deficits (such as impairment of executive function). The executive function (EF) has been defined as "a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place. EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states" (Oreliana and Slachevsky, Front Psychiatry, 2013, vol 4, article 35).

Accordingly, the present invention also provides a method of treating or preventing a negative symptom, a positive symptom and/or a cognitive deficit associated with a psychiatric disorder, especially schizophrenia, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (ng/kg) to 100 micrograms per kilogram body weight (pg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (ug/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof may be used on their own, but will generally be administered in the form of a pharmaceutical composition in which the active ingredient is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

Therefore, a seventh aspect of the present. invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

The invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to the first aspect of the present invention, with a pharmaceutically acceptable adjuvant, diluent or carrier.

Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, -Pharmaceutics -The Science of Dosage Form Design", M.E. Au1ton, Churchill Livingstone, 1988.

Pharmaceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, pol yvi n ylpyrrol i done, cellulose-based substances, polyethylene glycol. sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylenc-block polymers, polyethylene glycol and wool fat.

The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathccal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may he in the form of a sterile injectable preparation, for o example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.

Among the acceptable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage foloi including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch.

When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.

The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered by nasal aerosol io or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.05 to 80% by weight, still more preferably from 0.10 to 70% by weight, and even more preferably from 0.10 to 50% by weight of active ingredient, all percentages by weight being based on total composition.

The compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof) may also be administered in conjunction with other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated. The compound of the invention or the pharmaceutical composition or formulation comprising the compound of the invention may be administered simultaneously with, separately from or sequentially to the one or more other therapeutic agents. The compound of the invention and the one or more other therapeutic agents may be comprised in the same pharmaceutical composition or formulation, or in separate pharmaceutical compositions or formulations. The one or more other therapeutic agents may be selected from the following: (i) anti-addiction drugs including, for example, acamprosate, disulfiram, naltrexone and nalmefene for alcohol dependency, and venlafaxine, 2abapentin, modafinil, topiramate, vigabatrin and baclofen for drug, particularly cocaine, addiction, and equivalents and pharmaceutically active isomer(s) and/or metabolite( s) thereof; (ii) antidepressants including, for example, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone" itnipramine, ipsapirone, maprotilinc, nortriptyline, nefazodone, pai-oxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, and vortioxetine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (iii) antipsychotics including, for example, am i sulpri de, aripiprazole, asenapi ne, benzisoxidil, bifeprunox, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapinc, divalproex, duloxetinc, eszopiclone, fluphenazine, haloperidol, iloperidone, lamotrigine, loxapine, lurasidone, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, quetiapine, risperidone, scrtindole, sulphide, suproclonc, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, zicronapine, and ziprasidone, and equivalents and pharmaceutically active isomer(s) and/or met abolite(s) thereof; (iv) anxiolytics including, for example, azapirones, benzodiazepines, barbiturates, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof. Example anx iol ytics include adi nazol aryl, al nespirone, alprazol am, balezepam, bentazepam, bromazepam, brotizolam, buspironc, clonazepam, clorazepatc, chlordiazepoxidc, cyprazepam, diazepam, diphenhydramine, estazolam, fcnobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lomaetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, prazosin, quatepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uklazepam, and zolazepam, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (y) anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, levetiracetam, and gabapentin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (vi) Parkinson's therapies including, for example. L-dopa, ropinirole, pramipexole, apomorphine, monoamine oxidase type B (MAO-B) inhibitors such as deprenyl, selegiline and rasagiline, catechol-O-methyl transferase (COMT) inhibitors such as entacapone and tolcapone, adenosine A-2 inhibitors, dopamine re-uptake inhibitors. NMDA antagonists, nicotine agonists, dopamine agonists, and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (vii) mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (viii) stimulants including, for example, methylphenidatc, amphetamine, and modafinil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (ix) mGluR5 modulators including, for example, basimglurant, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; and (X) non-stimulant behaviour modifiers including, for example, atomoxetine, clonidine, and guanfacine, and equivalents and pharmaceutically active i so mer(s) and/or metabolite(s) thereof; and (xi) muscle relaxants including, for example, Botulinum toxin, baclofen and anti-30 muscarinic compounds such as trihexyphenidyl, benztropinc, biperiden, atropine, procyclidinc, orphenadrine, and scopolamine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof.

Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.

Examples

The present invention will now be further explained by reference to the following illustrative examples, in which the starting materials and reagents used are available from commercial suppliers or prepared via literature procedures.

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K, 298.2K or 293K unless otherwise stated; the chemical shifts (8) are reported in parts per million Spectra were recorded using a BrukerTm 400 AVANCE instrument fitted with a 5mm BB F() probe with instrument controlled by Bruker TopSpin 2.1 software, or a Bruker 400 AVANCE-III HD instrument fitted with a 5mm BBO smart probe or a 5mm BBFO probe with instrument controlled by Bruker TopSpin 3.5 software, or a Bruker 400 AVANCE-I11 instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker Topspin 3.0 software, or a Bruker 300MHz AVANCE II instrument fitted with a 5mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software, or 5mm BBFO probe controlled by Bruker Topspin 3.2 software.

Reactions were monitored using one or more of the following: * Agilent 1290 infinity II UPLC coupled with 6130 quadrupole LCMS; Chromatographic Conditions: Mobile Phase A: 0.1% FA in H20; Mobile Phase B: 0.1% FA in ACM; Column: Acquity UPLC BEH C18 (50mm x 2.1mm) 1.7pm; Column Temp: 40°C; Sample Temp: RT; Detection (mu): 220; Flow Rate: 0.7 mUmin; Analysis Time: 4.2 min. Measured Mass Range: 100 to 1500 * Dionex Ultima 3000 UHPLC Coupled with Thermo Scientific LCQ Fleet Ion Trap; Chromatographic Conditions: Mobile Phase A: 10 mM Ammonium Formate in Water: ACN (95:5); Mobile Phase B: 10 mNI Ammonium Formate in Water: ACM (5:95); Column: XBridge BEH C18 (50mm x 3.0mm) 2 5pm; Column Temp: 40°C; Sample Temp: RT; Detection (nm): 220; Flow Rate: 0.7 mL/min; Analysis Time: 4.2 mm; Measured Mass Range: 100 to 1500 * Waters ACQUITY UPLC H-Class with single quadrupole LCMS; Chromatographic Conditions: Mobile Phase A: 0.1% FA in F20; Mobile Phase B: 0.1% FA in ACN; Column: Acquity UPLC BEH C18 (50mm x 2.1mm) 1.7p m; Column Temp: 40°C; Sample Temp: RT; Detection (nm): 220; Flow Rate: 0.7 mL/min; Analysis Time: 4.2 min. Measured Mass Range: 100 to 1500 Purity was assessed using one or more of the following: * Ultra Performance Liquid Chromatography (UPLC) with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a WatersTm Acquity UPLC system equipped with Acquity UPLC BEH, HSS or HSS T3 C18 columns (2.1mm id x 50mm long) operated at 50 or 60°C. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% FA, 0.1% TFA or 0.025% ammonia. Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using atmospheric pressure ionisation.

* UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using Shimadzulm Nexera X2 UPLC controlled by Lab Solution software equipped with Acquity UPLC BEH, HSS or HSS T3 C18 columns (2.1mm id x 50mm long) operated at 50°C. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% FA, 0.1% TFA or 0.025% ammonia. Mass spectra were recorded with a Shimadzu single quadrupole mass spectrometer using DU IS ionisation.

Compounds were purified using Grace purifier, Buchi Reveler's X2 flash purification system or Biotage using normal phase chromatography on silica, using Reveleris SRC flash cartridges, InterchimTm PuriFlash cartridges or KinesisTm Telos silica cartridges, or on basic silica using Biotage KP-NH cartridges, or by reverse phase chromatographic methods using Reveleris RP flash cartridges or by Biotage lsolute SCX-2 or PhenomenexTm Strata ABW catch-release cartridges, or by preparative high performance liquid chromatography (HPLC).

Preparative HPLC was performed using Agilent Technologieslm 1100 Series system or a Waters autopurification LC/MS system typically using Waters (19 mm id x 250 mm long) C18 columns such as XBri&elm or SunFireTm 5 pm materials at RT. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1% FA or 0.1% ammonia, unless otherwise stated.

Super Critical Fluid Chromatography (SFC) chiral separations were performed on a Waters SFC investigator system, using a flow rate of 60 g to 120 g/min, temperature of RT to 40°C and a pressure of 100 bar. Mobile phases typically consisted of supercritical CO2 and a polar solvent such as acetonitrile, methanol, ethanol or isopropanol. Column type and eluent are detailed for individual examples. Columns: Chiralcel OJ-H (250*21mm, 5pm), Chiralpak-IG (250*30mm, 5pm), Chiralpak-IE (250*30mm, 5pm), Chiralpak-AD-H (250*30mm, 5pm), Chiralcel OX-H (250*21mm, 5pm), YMC SC (250*30mm, 5pm), Chiralpak AS-H (250*30mm, 5pm), R,R Whelk-01 (250*30mm, 5p m), Chrornega chiral CCO (250*30mm, 5pm), Chromega Chiral CCA (250*30mm, 5pm), Chiralpak IA (250*30mm 5pm), Lux Cellulose-02 (250*30mm, 5pm), Chiralpak OD-H (250*30mm, 5pm); Detection: 200nm to 400nm; Sample Diluent: Acetonitrile, Methanol; Injection: 0.1m1 to 5m1; Isocratic Ratio: 5% to 50% of mobile phase.

Room temperature', as used in the present specification, means a temperature in the range from about 18°C to about 25°C.

Abbreviations ACN: Acetonitrile DAST: Diethylaminosulphur trifluoride DCM: Dichloromethanc DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diisobut ylaluminium hydride DIPEA: N,N-Diisopropylethylamine DMF: Dimethylformamide DMP: Dess-Martin Periodinane EDC: 1-Ethy1-3-(3-di meth yl ami nopropyl)carbodi m ide Et0Ac: Ethyl acetate FA: Formic acid h: hours HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 b]pyridinium 3-oxid hexafluorophosphate HOAt: I-Hydroxy-7-azahenzotriazole HOBt: 1-Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography MeOH: Methanol min: minutes NaH: Sodium hydride nt: Not tested Pd2(dha)3: Tris(dihenzylideneacetone)dipalladium(0) pet ether: Petroleum ether RT: Room temperature T3P: Propylphosphonic anhydride TEA: Triethylamine THE: Tetrahydrofuran TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride Intermediates Standard synthetic approach The pyrazole-3-carhoxylic acid reaction intermediates can he prepared according to the general reaction scheme depicted in Figure 1.

Intermediate I: 5-(4-Methoxypheny1)-1-methy1-1H-pyrazole-3-carhoxylic acid

OH

3 steps Step 1: To a stirred solution of LiHMDS (1M in hexane, 39.9 nil. 0.039 mol) in diethyl ether (166 nil) at -78°C under nitrogen was added 1-(4-methoxyphenyl)ethanone (6 g.

0.039 mol) in diethyl ether (33 ml) dropwise. The reaction mixture was stirred at -78°C for 30 min. Diethyl oxalate (5.84 2, 0.039 mol) in diethyl ether (33 ml) was then added dropwise. The solution was slowly allowed to warm to RT and stirred at RT for 2h. A solid began to form, stirring was discontinued, and the mixture allowed to settle overnight. The solid was filtered to afford the lithium enolate of ethyl 4-(4-methoxypheny1)-2,4-dioxobutanoate (9.5 g, 95%, pale yellow solid).

111 NMR 400 MHz, DMSO-d6: 6 15.2 (s, 1H), 7.81 (t, J = 2.00 Hz, 2H), 6.96 (s, 1H), 6.40 (s, 2H), 4.14 (q, J = 6.80 Hz, 2H), 3.80 (s, 3H), 1.25 (t, J = 7.20 Hz, 3H). MS ES': 251.06.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(4-methoxypheny1)-2,4-dioxobutanoate (9.5 g, 0.036 mol) in ethanol (330 ml), tnethylhydrazine sulphate (7.99 g, 0.055 mol) was added under nitrogen and stirred for 16h at RT. After reaction completion (monitored by TLC), ethanol was removed under reduced pressure to give crude product. The crude product was purified by Grace purifier using a gradient elution of 2-4% ethyl acetate in pet ether to afford ethyl 3-(4-tnethoxypheny1)-1-tnethy1-1H-pyrazole-5-carboxylate (2 g) and 20-25% ethyl acetate in pet ether to afford ethyl 544-methox ypheny1)-1-methy1-1H-pyrazole-3 -carboxyl ate (5.4 g, 54%, white solid).

1H NMR 400 MHz, CDC13: 6 7.43-7.33 (m, 2H), 6.98-6.99 (m, 2H), 6.80 (s, 1H), 4.42 (q, J = 7.20 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 1.25 (t, J = 6.80 Hz, 3H). MS ES': 261.12.

Step 3: To a stirred solution of ethyl 5-(4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylate (5.4 g, 0.020 mol) in a mixture of THF (50 nil) and water (20 ml), lithium hydroxide monohydrate (1.74 g, 0.0415 mol) was added and stirred for 16h at RT. After the reaction was complete, solvents were removed under reduced pressure to give a residue which was acidified with HC1 and extracted with ethyl acetate (2 x 100 mL) The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (4 g, 83%, off-while solid).

11-1 NMR 400 MHz, DMSO-d6: 6 12.65 (s, 1H), 7.54-7.49 (m, 2H), 7.07-7.05 (m, 2H), 6.76 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H). MS ES': 232.99.

Intermediate 2: 1-Methyl-5-(4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylic acid F3C F3C OH Step 1: To a stirred solution of LiHMDS (1M in hexane, 79.7 ml, 79.72 mmol) in diethyl ether (300 ml) at -78°C was added 1-(4-(trifluoromethyl)phenyl)ethanone (15 g. 79.72 mmol) in diethyl ether (50 ml) dropwise. The reaction mixture was stirred at -78°C for 1.5h. To the reaction mixture was added diethyl oxalate (11.62 g 79 72 mmol) in diethyl ether (50 ml) at -78°C dropwise. The reaction mixture was stirred at RT for 16h. The reaction was monitored by LCMS. The reaction mixture was concentrated at 35°C, diluted with pet ether. filtered and the solid washed with pet ether. The solid was dried under high in vacuum to obtain the lithium enolate of ethyl 4-(4-(trifluoromethyl)phenyI)-2,4-dioxobutanoate (24 g, 98%, off-white solid).

11-INMR 400 MHz, DMSO-d6: 6 8.00 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 6.45 (s, I H), 4.15 4 J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 31-1). MS ES*: 289.08.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(4-(trifluoromethyl)pheny1)- 2,4-dioxobutanoate (3 g, 10.41 mmol) in ethanol (110 ml), methylhydrazine sulphate (2.26 g, 15.6 mmol) was added under nitrogen and stirred for 16h at RT. After the reaction was complete (monitored by TLC), ethanol was removed under reduced pressure to give crude product, which was purified by Grace purifier using a gradient elution of 10-15% ethyl acetate in pet ether to afford ethyl 5-(4-(trilluoromethyl)pheny1)-1-methyl-I H-pyrazole-3-carboxylate (800 mg, 17%, white solid).

1HNMR 400 MHz, DMSO-d6: 67.76 (d, J = 8.00 Hz, 2H), 7.56 (d, J = 8.00 Hz, 2H), 7.26 (s, 1H), 4.44 (t, J = 7.20 Hz, 2H), 3.98 (s, 3H), 1.42 (t, J = 7.20 Hz, 3H). MS ES': 299.8.

Step 3: To a stirred solution of ethyl 5-(4-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole- 3-carboxylate (0.8 g, 0.0026 mol) in a mixture of THF (10 ml) and water (4 ml), lithium hydroxide monohydrate (0.338 g, 0.008 mol) was added and stirred for 16h at RT. After the reaction was complete, solvents were removed under reduced pressure to give a residue which was acidified with HC1 and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (620 mg, 83%, off-while solid).

NMR 400 MHz, DMSO-d6: S 12.78 (s, 114), 7.83-7.85 (in, 414), 6.97 (s, 11-1), 3.96 (s, 3H). MS ES': 271.1.

Intermediate 3: 5-(2-Chloro-4-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid CI 0 OH 5 steps Step 1: To a stirred solution of 2-chloro-4-methoxybenzoic acid (100 g 53 76 mmol) in in DMF (50 ml), D1PEA (28.5 nil, 161.29 mmol) was added, then after 10 min N,O-di methyl hydroxylamine (5.3 g, 53.76 mmol), EDC.HC1 (15.5 g, 80.64 mmol) and HOBt (7.4 g, 53.76 mmol) were added. The reaction mixture was stirred for 16h at RT. The reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate, washed with cold water twice and then with sodium bicarbonate solution and concentrated. The crude product was purified by column chromatography on silica gel (100-200 mesh), by gradient elution of 5-6% of ethyl acetate in pet ether to obtain 2-chloro-N,4-dimethoxy-Nmethylbenzamide (12.0 g, 93%, pale yellow solid).

111 NMR 400 MHz, CDC13: 5 7.27 (d, I = 6.8 Hz, 1H), 6.94 (s, 1H), 6.84-6.82 (in, 1H), 3.54 (br s, 3H), 3.32 (br s, 6H). MS ES': 230.

Step 2: 2-Chloro-N,4-dimethoxy-N-methylbenzamide (11 0 g 48 03 mmol) was dissolved in diethyl ether (80 ml) and cooled to -10°C. CH3MgBr (3M in diethyl ether) (18 ml, 48.04 mmol) was added and the reaction mixture was stin-ed for 4h at RT. The reaction was monitored by LCMS. The reaction mixture was cooled and quenched with 1N HC1 (50 ml), diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with gradient elution of 5-6% of ethyl acetate in pet ether to obtain 1-(2-chloro-4-methoxypheny)ethanone (8.5 g, 81%, colourless liquid). 1H NMR 400 MHz, CDC13: 6 7.69 (d, I = 8.4 Hz, 1H), 6.95 (d, I = 2.8 Hz, 1H), 6.95-6.84 (m, 1H), 3.86 (s, 3H), 2.65 (s, 6H). MS ES': 185.11.

Step 3: To a stirred solution of LiHMDS OM in hexane, 40 ml) in diethyl ether (150 ml) at -78°C was added 1-(2-chloro-4-tnethoxyphenyflethanone (7.5 g, 40.62 trunol) in diethyl ether (50 ml) dropwise. The reaction mixture was stirred at -78°C for 1.5h. To the reaction mixture was added diethyl oxalate (5.9 g) in diethyl ether (50 ml) at -78°C dropwise. The reaction mixture was stirred at RT for 5h. The reaction was monitored by LCMS. The reaction mixture was concentrated at 35°C, diluted with pet ether, and the solid filtered and washed with pet ether. The solid was dried under reduced pressure to afford the lithium enolate of ethyl 4-(2-chloro-4-methoxypheny1)-2,4-dioxobutanoate (10 g. 85%. pale yellow solid).

NMR 400 MHz, DMSO-d6: 67.38 (d, :1= 4.8 Hz, 111), 6.99 (s, 1H), 6.95-6.87 (m, 111). 5.97 (s, 1H), 4.12 (q, J = 6.80 Hz, 2H), 3.79 (s, 3H), 1.22 (t, J = 6.80 Hz, 311). MS ES': 285.05.

is Step 4: To a stirred solution of the lithium enolate of ethyl 4-(2-chloro-4-methoxypheny1)- 2,4-dioxobutanoate (10 g, 1 eq) in ethanol (250 ml) was added methylhydrazine sulphate (7.5 g, 1.5 eq). The reaction mixture was stirred at RT for 16h. Then the reaction mixture was concentrated under high vacuum to yield crude product. The crude compound was purified by column chromatography using ethyl acetate: pet ether (30:70) as an eluent to afford ethyl 5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylate (5 g, 50%, yellow solid).

NMR 400 MHz, DMSO-d6: 6 7.43 (d, J = 8.40 Hz, 1H), 7.25 (s, 111), 7.06 (dd, J = 2.40, 8.60 Hz, 111), 6.77 (s, 111), 4.28 (q, J = 6.80 Hz, 211), 3.85 (s, 3H), 3.70 (s. 311), 1.30 (t, J = 6.80 Hz, 3H). MS ES': 295.08.

Step 5: To a stirred solution of ethyl 5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole3-carboxylate (5 g, 1 eq) in THF: ethanol: water (3:1:1) was added lithium hydroxide monohydrate (2.2 2, 3 eq). The reaction mixture was stirred at RT for 16h. Then the reaction mixture was concentrated under high vacuum, acidified with IN 1-IC1 solution and extracted with 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford the title compound (4.8 g, 95%, off-white solid).

1H NMR 400 MHz, DM5O-d6: 6 12.07 (s, 1H), 7.44 (d, J = 9.60 Hz, 1H), 7.24 (s, 1H), 7.07 (d, J = 8.00 Hz, 1H), 6.71 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H). MS ES: 267.0.

Intermediate 4: 5-( 2-Fluoro-4 -(trifluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH F3C F3C Step 1: To a stirred solution of LiHMDS (1M in hexane, 14.5 ml. 14.55 mmol) in diethyl ether (60 ml) at -78°C was added 1-(2-fluoro-4-(trifluoromethyl)phenyeethanone (3 g.

14.55 mmol) in diethyl ether (10 ml) dropwise. The reaction mixture was stirred at -78°C for 1.5h. To the reaction mixture was added diethyl oxalate (1.19 ml, 14.55 mmol) in diethyl ether (10 ml) at -78°C dropwise. The reaction mixture was stirred at RT for 16h. The reaction was monitored by LCMS. The reaction mixture was concentrated at 35"C. diluted with pet ether, and the solid filtered and washed with pet ether. The solid was dried under reduced pressure to yield the lithium enolate of ethyl 4-(2-fluoro-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (3.1 g, 75%, pale yellow solid). MS ES': 307.

Step 2: To a stirred solution of the lithium cnolatc of ethyl 4-(2-fluoro-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (3.1 g, 10 12 mmol) in ethanol (60 nil) was added methylhydrazine sulphate (2.14g. 15.18 mmol). The reaction mixture was stirred at RT for 16h. Then the reaction mixture was concentrated under high vacuum to yield crude product. The crude compound was purified by column chromatography using ethyl acetate: pet ether (30:70) as an eluent to yield ethyl 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylate (1.4 g, 50%, yellow solid).

11-1 NMR 400 MHz, CDC13: 6 7.53-7.55 (m. 1H), 7.26 (s, 2H), 6.93 (s, 1H), 4.43-4.45 (m, 2H), 3.90 (s, 3H), 1.42 (t, J = 7.20 Hz, 3H). MS ES': 317.

Step 3: To a stirred solution of ethyl 5-(2-tluoro-4-(tritluoromethyl)pheny1)-1-methyl-1Hpyrazolc-3-carboxylate (1.4 g, 4.42 mmol) in THF: methanol: water (3:1:1) was added 30 lithium hydroxide monohydrate (558 mg, 13.2 mmol) The reaction mixture was stirred at RT for 16h. Then the reaction mixture was concentrated under high vacuum, acidified with 1N HC1 solution and extracted with 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to yield the title compound (1.1 g, 56%, off-white solid).

II-1 NMR 400 MHz, DMSO-d6: 6 12.82 (s, 1H), 7.94 (d, J = 9.60 Hz, 1H), 7.83 (d, J = 7.60 Hz, 1H), 7.76 (d, J = 8.00 Hz, 1H), 6.94 (s, 1H), 3.85 (s, 3H). MS ES: 289.

Intermediate 5: 5-(4-Isopropylpheny1)-1-methy1-1H-pyrazole-3-carboxylic acid

OH

Step 1: To a stirred solution of LiHMDS (1M in hexane, 18.5 ml, 0.0185 mol) in diethyl ether (80 ml) at -78°C under nitrogen, was added 1-(4-isopropylphenyl)ethanone (3 2, 0.0185 mol) in diethyl ether (15 ml) dropwise. The reaction mixture was stirred for 30 min at -78°C. Diethyl oxalate (2.70 g, 0.0185 mot) in diethyl ether (15 ml) was then added clropwise. The solution was slowly allowed to warm to RT for 2h. A solid began to form.

The stirring was discontinued, and the reaction mixture was allowed to settle overnight. The solid was filtered to afford the lithium enolate of ethyl 4-(4-isopropylpheny1)-2,4-dioxobutanoate (3.5 g, 73%, pale yellow solid).

II-1 NMR 400 MHz, DMSO-d6: 57.76 (d, J = 8.40 Hz, 2H), 7.29 (d, J = 8.00 Hz, 2H), 6.41 (ti, 1H), 4.15 (q, J = 7.20 Hz, 2H), 2.49-2.50 (m, 1H), 1.20-1.22 (m, 9H). MS ES*: 263.1.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(4-isopropylpheny1)-2,4-dioxobutanoate (3.5 g, 0.013 mol) in ethanol (110 ml), methylhydrazine sulphate (2.88 g, 0.02 mol) was added under nitrogen and stirred for 16h at RT. After the reaction was complete, ethanol was removed under reduced pressure to give crude product, which was purified by Grace purifier using a gradient elution of 10-15% ethyl acetate in pet ether to afford ethyl 5-(4-isopropylpheny1)-1-methyl-1H-pyrazole-3-carboxylate (2.1 2, 58%, while solid).

1H NMR 400 MHz, DMSO-d6: 6 7.30 (d, J = 8.40 Hz, 4H), 6.83 (s, 1H), 4.43 (q, J = 7.20 Hz, 2H), 3.96 (s, 3H), 2.97 (t, J = 6.80 Hz, 1H), 1.41-1.40 (m, 3H), 1.30 (s, 6H). MS ES': 273.1.

Step 3: To a stirred solution of ethyl 5-(4-isopropylpheny1)-1-methy1-1H-pyrazole-3-carboxylate (2.1 g, 7.72 mol) in a mixture of THE (20 ml) and water (7 ml), lithium hydroxide monohydrate (0.972 g, 23.16 mol) was added and stirred for 16h at RT. After the reaction was complete, solvents were removed under reduced pressure to give a residue, which was acidified with IN HC1 and extracted with ethyl acetate (2 x 50 mL).

io The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (1.7 g, 94%, white solid).

1H NMR 400 MHz, DMSO-d6: 6 12.67 (s, 1H), 7.49 (d, J = 8.00 Hz, 2H), 7.39 (d, J = 8.00 Hz, 2H), 6.80(s. 1H), 3.90 (s, 3H), 2.96-2.94 (m, 1H), 1.24 (s, 6H). MS ES": 245.18.

Intermediate 6: 5-(2-Fluoropheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH Step 1: 1-(2-Fluorophenypethanone (1 g, 7.2 mmol) and diethyl oxalate (1.26 g, 17.4 mmol) were dissolved in DMF (20 mL) and cooled to 0°C, then NaH (56% in oil) (0.576 g, 14.4 mmol) was added. The reaction mixture was stirred at 0°C for 10 min, then stirred at RT for 30 min and heated to 40°C for lh. The reaction mixture was quenched with ice cold water, acidified with 6N HC1 (25 mL) and extracted with ethyl acetate (3 x 30 mL) The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure. The crude product was purified by Grace purifier eluting with 20% ethyl acetate in pet ether to afford ethyl 4-(2-fluoropheny1)-2,4-dioxobutanoate (1 g, 58%, brown solid). 1H NMR 400 MHz, DMSO-d6: 6 15.23 (s, 1H), 7.98 (t, J = 6.00 Hz, 1H), 7.94-7.95 (m, 114), 7.31-7.31 (m, 1H), 7.20-7.21 (m, In), 6.96 (s, In), 4.41 (t, J = 6.80 Hz, 2H), 1.42 (t, J = 3.20 Hz, 3H). MS ES': 239.14.

Step 2: Ethyl 4-(2-fluoropheny1)-2,4-dioxobutanoate (1 g 4 mmol) and methylhydrazine sulphate (0.864 g, 6 mmol) in ethanol (20 mL) were heated to 80°C for lit The reaction mixture was evaporated under reduced pressure The crude product was purified by Grace purifier using 23% ethyl acetate in pet ether to afford ethyl 5-(2-fluoropheny1)-1-methyl1H-pyrazole-3-carboxylate (1 g, 96%, light brown oil) NMR 400 MHz, DMSO-d6: 6 7.48 (t, J = 6.00 Hz, 1H), 7.38 (t, J = 5.60 Hz, 1H), 7.247.24 (m, 2H), 6.88 (s, 1H), 4.43 (q, J = 6.80 Hz, 2H), 3.88 (s, 3H), 1.42 (t, J = 6.80 Hz, 3H). MS ES': 249.01.

Step 3: Ethyl 5-(2-11uoropheny1)-1-methy1-1H-pyrazole-3-carboxylate (1 2, 4 mmol) was dissolved in THE (10 mL), Me0H (5 mL) and water (2.5 mL) and lithium hydroxide monohydrate (0.33 g, 8 mmol) was added. The reaction mixture was stirred at RT for 16h. Solvent was evaporated, and the residue was acidified with 6N HC1 (12 mL) and extracted with 10% Me0H/DCM (2 x 30 mL) The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure to obtain the title compound (0.6 g, 67%, white solid).

111 NMR 400 MHz, DMSO-d6: 6 12.75 (s, IF1), 7.59-7.59 (m, 2H), 7.54-7.56 (m, 2H), 6.84 (s, 1H), 3.80 (s, 3H). MS ES': 220.1.

Intermediate 7: 5-(2,5-Dimethylpheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH Step 1: To a stirred solution of LiHMDS (1M in hexane, 15.9 nil, 10.135 mmol) in diethyl ether (80 ml) at -78°C under nitrogen, was added 1-(2,5-dimethylphenypethanone (1.5 g, 10.135 mmol) in diethyl ether (40 ml) dropwise and stirred for 30 mm at -78°C. Diethyl oxalate (2.33 g, 10.135 mmol) in diethyl ether (15 ml) was added dropwise. The solution was then allowed to warm to RT and stirred at RT for 2h. A solid began to form. The stirring was discontinued, and the mixture allowed to settle overnight. The solid was filtered to afford the lithium enolate of ethyl 4-(2,5-dimethylpheny1)-2,4-dioxobutanoate (2.0 g, 90%, pale yellow solid).

II-1 NMR 400 MHz, DMSO-d6: 57.23 (s, 1H), 7.08 (s, 2H), 5.90 (s, 1H), 4.12 (q, J = 7.20 Hz, 2H), 2.23-2.27 (m, 6H), 1.22 (t, J = 6.80 Hz, 3H). MS ES-: 247.18.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(2,5-dimethy1pheny1)-2,4-dioxobutanoate (2.0 g,11.3 mmol) in ethanol (70 ml), methylhydrazine sulphate (2.443 2, 16.95 mmol) was added under nitrogen and stirred for 16h at RT. After the reaction was complete, ethanol was removed under reduced pressure to give crude product, which was purified on Grace purifier using a gradient elution of 10-15% ethyl acetate in pet ether to afford ethyl 5-(2,5-dim ethylphen y1)-1-meth y1-1H-pyrazole-3-carbox yl ate (1.0 g, 72%, io white solid).

111 NMR 400 MHz, DM5O-d6: 5 7.21-7.19(m, 2H), 7.01 (s, 1H), 6.74 (s, 1H), 4.44 (t, J = 6.80 Hz, 2H), 3.72 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H), 1.42 (t, J = 7.20 Hz, 3H). MS ES': 259.14.

Step 3: To a stirred solution of ethyl 5-(2,5-dimethylpheny1)-1-tnethyl-1H-pyrazole-3-carboxylate (1.0 g 3 4 mmol) in a mixture of THE (10 ml) and water (4 ml), lithium hydroxide monohydrate (0.428 g, 10.2 rnmol) was added and stirred for 16h. After the reaction was complete, solvents were removed under reduced pressure to give a residue, which was acidified with HC1 and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.8 2, 92%, white solid). 111 NMR 400 MHz, DMSO-d6: 5 12.58 (s, 1H), 7.20-7.22Q, 2H), 7.11 (s, 1H), 6.67 (s, 1H), 3.71 (s, 3H), 2.31 (s, 3H), 2.08 (s, 3H). MS ES': 231.19.

Intermediate 8: 5-(3-Fluoropheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH Step 1: 1-(3-Huorophenyl)ethanone (1 g, 7.2 mmol) and diethyl oxalate (1.26 g, 17.4 mmol) were dissolved in DMF (20 mL) and cooled to 0°C. Then NaH (56% in oil) (0.576 g, 14.4 mmol) was added. The reaction mixture was stirred at 0°C for 10 min, then stirred at RT for 30 min and then heated to 40°C and stirred for lh. The reaction mixture was quenched with ice cold water, acidified with 6N HC1 (25 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure. The crude product was purified by Grace purifier eluting with 20% ethyl acetate in pet ether to afford ethyl 4-(3-fluoropheny1)-2,4-dioxobutanoate (1 g, 58%, brown solid).

111NMR 400 MHz, DMSO-d6: 6 15.01 (s, 1H), 7.79 (d, J = 1.20 Hz, 1H), 7.77 (t, J = 0.80 Hz, 1H), 7.50-7.51 (m, 1H), 7.31-7.31 (m, 1H), 7.04 (s, 1H), 4.41 (q, J = 7.20 Hz, 2H), 1.48 (t, J= 2.80 Hz, 3H). MS ES: 239.06. 1)

Step 2: Ethyl 4-(3-fluorophenyI)-2,4-dioxobutanoate (1 g, 4 mmol) and methylhydrazine sulphate (0.864 g, 6 mmol) in ethanol (20 mL) were heated to 80°C for lh. Solvent from the reaction mixture was evaporated under reduced pressure. The crude product was purified by Grace purifier using 23% ethyl acetate in pet ether to give ethyl 5-(3-I s fluorophen y1)-1 -methyl -1H-pyrazole-3-carboxylate (1g, 96%, light brown liquid).

1H NMR 400 MHz, DMSO-d6: 67.76-7.75 (m, 1H), 7.16-7.20 (m, 1H), 7.12-7.13 (m, 2H), 6.87 (s, 11-1), 4.43 4 J = 7.20 Hz, 2H), 3.97 (s, 3H), 1.42 (t, J = 7.20 Hz, 3H). MS ES': 249.10.

Step 3: Ethyl 5-(3-fluoropheny1)-1-methy1-1H-pyrazole-3-carboxylate (1 g 4 mmol) was dissolved in THE (10 mL), Me0H (5 mL) and water (2.5 mL) and lithium hydroxide monohydrate (0.33 g, 8 mmol) was added. The reaction mixture was stirred at RT for 16h. Solvent was evaporated, and the residue was acidified with 6N HCI (12 mL) and extracted with 10% Me0H/DCM (2 x 30 mL) The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure to obtain the title compound (0.6 g, 67%, white solid).

1H NMR 400 MHz, DMSO-d6: 5 12.73 (s, 1H), 7.57 (d, J = 2.00 Hz, 1H), 7.48-7.50 (m, 1H), 7.44-7.44 (m, 1H), 7.32-7.33 (m, 1H), 6.90 (s, 1H), 3.94 (s, 3H). MS ES±: 221.06.

Intermediate 9: 5-(4-Fluoropheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH Step 1: 1-(4-Fluorophenyeethanone (1 g, 7.2 mmol) and diethyl oxalate (1.26 g, 17.4 mmol) were dissolved in DMF (20 mL) and cooled to 0°C. Then NaH (56% in oil) (0.576 g, 14.4 mmol) was added. The reaction mixture was stirred at 0°C for 10 min, then stirred at RT for 30 min and finally heated to 40°C for lh. The reaction mixture was quenched with ice cold water, acidified with 6N HC1 (25 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure. The crude product was purified by Grace purifier eluting with 20% ethyl io acetate in pet ether to yield ethyl 4-(4-fluoropheny1)-2,4-dioxobutanoate (1 g, 58%, brown solid).

1H NMR 400 MHz, DMSO-d6: 6 15.24 (s. 1H), 8.04 (dd. J= 2.00. 4.20 Hz, 2H), 7.48 (dd, J= 2.0 Hz, 4.2 Hz, 2H), 7.04(s, 1H), 4.41 (q, J= 3.20 Hz, 2H), 1.44 (t, J= 2.00 Hz, 3H). MS ES': 239.06.

Step 2: Ethyl 4-(4-tluoropheny1)-2,4-dioxobutanoate (1 g, 4 mmol) and methylhydrazine sulphate (0.864 g, 6 mmol) in ethanol (20 mL) were heated to 80°C for 1h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by Grace purifier using 23% ethyl acetate in pet ether to obtain ethyl 5-(4-fluoropheny1)-1-methyl- 1H-pyrazole-3-carboxylate (1 g, 96%, light brown liquid).

1H NMR 400 MHz, DMSO-d6: 6 7.42-7.42 (m, 2H), 7.19-7.20(m, 2H), 6.86(s, 1H), 4.46 (q, J = 7.20 Hz, 2H), 3.96 (s, 3H), 1.44 (t, J = 7.20 Hz, 3H). MS ES': 249.10.

Step 3: Ethyl 5-(4-fluoropheny1)-1-methyl-1H-pyrazole-3-carboxylate (1 g 4 mmol) was dissolved in THE (10 mL) Me0H (5 mL) and water (2.5 mL) and lithium hydroxide monohydrate (0.33 g, 8 mmol) was added. The reaction mixture was stirred at RT for 16h. Solvent was evaporated, and the aqueous layer was acidified with 6N HC1 (12 mL) and extracted with 10% Me0H/DCM (2 x 30 mL). The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure to obtain the title compound (0.6 g, 67%, white solid).

1H NMR 400 MHz, DMSO-d6: 6 12.80 (bs, 1H), 7.47 (m 2H), 7.20-7.21 (m, 2H), 6.88 (s, 1H), 3.94 (s, 3H). MS ES±: 221.06.

Intermediate 10: 5-(4-Chloropheny1)-1-methyl-1H-pyrazole-3-carboxylic acid 3 steps CI OH

CI

Step 1: 1-(4-Chlorophenypethanone (4 g, 25.87 mmol) was dissolved in DMF (20 m1). Then under stirring and cooling at 0°C, NaH (1.24 2, 31.044 mmol) was added portionwise and stirred for 30 min. Then diethyl oxalate (5.67 g 38 80 mmol) was added under cooling lc) and stirred at RT for lh. The reaction mixture was heated at 45-50°C for lhr. Then the reaction mixture was quenched with ice, neutralised with 1N HC1 and extracted with ethyl acetate. The organic layer was washed thoroughly with water, dried over sodium sulphate and concentrated. The crude product was subjected to column purification on 100-200 mesh silica gel, eluting with 18% ethyl acetate in pet ether to afford ethyl 4-(4-chloropheny1)-2,4-dioxobutanoate (1.9 g, 29%, pale yellow solid).

11-1 NMR 400 MHz, DMSO-d6: 6 15.24(s, In), 7.51 (d, J= 6.80 Hz, 21-1), 7.44(d. J= 2.1 Hz, 2H), 7.02 (s, 1H), 4.40 (q, J = 3.20 Hz, 2H), 1.46 (t, J = 2.00 Hz, 3H). MS ES': 255.03.

Step 2: To a stirred solution of ethyl 4-(4-chloropheny1)-2,4-dioxobutanoate (1.5 g, 5.89 mmol) in ethanol (20 ml), methylhydrazine sulphate (1.27 g, 8.83 mmol) was added and stirred at 60°C for lh. Solvent was evaporated, and the residue subjected to column purification on 100-200 mesh silica gel using 10% ethyl acetate in pet ether as eluent to afford ethyl 5-(4-chloropheny1)-1-methy1-1H-pyrazole-3-carboxylate (0.9 g, 57%, pale yellow solid).

1H NMR 400 MHz, DMSO-d6: 6 7.48 (d, J = 6.80 Hz, 2H), 7.39 (d, J = 2.00 Hz, 2H), 6.90 (s, 1H), 4.45 (q, J= 7.20 Hz, 2H), 3.94(s. 3H), 1.45 (t, J= 7.20 Hz, 3H). MS ES': 265.07.

Step 3: To a stirred solution of ethyl 5-(4-chloropheny1)-1-methy1-1H-pyrazole-3-carboxylate (0.8 g, 3.02 mmol) in THF (20 ml) and water (2 ml), lithium hydroxide monohydrate (0.37 g, 9.06 mmol) was added and stirred at RT for 16h. Solvent was evaporated under reduced pressure, and the residue was acidified with 2N HC1 and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated to afford the title compound (700 mg, 97%, pale yellow solid).

1HNMR 400 MHz, DM5O-d6: 6 7.48 (d, J= 6.80 Hz, 2H), 7.38 (d, J = 2.00 Hz, 2H), 6.91 (s, 1H), 3.96 (s, 3H). MS ES': 237.04.

Intermediate 11: 5-(4-Chloro-3-fluoropheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH

CI

Step 1: To a stirred solution of 1-(4-chloro-3-fluorophenyl)ethanone (2 g, 11 6 rmnol) in diethyl ether (15 nil), LiHMDS (1M in hexane, 12 ml) was added dropwise over a period of 1 h at -78°C. The reaction mixture was stirred at -78°C for 30 min. Then diethyl oxalate (2.54 g, 17.4 mmol) was added dropwise and stirred at -78°C to RT for 16h. After complete conversion, the precipitate from the reaction mixture was filtered, washed with diethyl ether and dried under vacuum to yield the lithium enolatc of ethyl 4-(4-chloro-3-fluoropheny1)-2,4-dioxobutanoate (3 g, 93%, off-white solid). MS ES: 273.28.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(4-chloro-3-fluoropheny1)- 2,4-dioxobutanoate (3 2, 11.02 mmol) in ethanol (25 ml) was added methylhydrazine sulphate (2.37 g) and heated to reflux for 2h. Solvent was evaporated, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The resulting compound was subjected to esterification in ethanol using a catalytic amount of H2SO4 at 80°C for 16h.

After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with Na2CO3 solution. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by flash column chromatography with amine silica (DAVISIL), using ethyl acetate: pet ether (2:8) as eluent to yield ethyl 5-(4-chloro- 3-fluoropheny1)-1-methy1-1H-pyrazole-3-carboxylate (0.6 g, 19%, off-white solid).

11-1 NMR 400 MHz, DMSO-d6: 57.76-7.72 (m, 2H), 7.49-7.47 (m, 1H), 7.00 (s, 1H), 4.29 (q, J = 7.20 Hz, 2H), 3.96 (s, 3H), 1.30 (t, J = 7.20 Hz, 3H). MS ES: 283.16.

Step 3: To a stirred solution of ethyl 5-(4-chloro-3-fluoropheny1)-1-methyl-1H-pyrazole-3-carboxylate (0.6 g, 2.12 mmol) in a mixture of THF: H20 (4:1) (15 ml) was added lithium hydroxide monohydrate (0.44 g, 10.63 mmol) and stiffed overnight at RT. The reaction mixture was concentrated under reduced pressure, acidified with 1N HC1 and extracted with a mixture of methanol and DCM (1:9). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield the title compound (0.49 g, 89%, white solid).

II-1 NMR 400 MHz, DMSO-d6: 6 12.76 (s, 1H), 7.76-7.72 (m, 2H), 7.48-7.46 (m, 1H), 6.94 (s, 1H), 3.94 (s, 3H). MS ES': 255.15.

Intermediate 12: 5-(3-Fluoro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid 3 steps OH Step 1: 1-(3-Fluoro-4-methoxyphenyeethanone (2 g 11 89 mmol) in diethyl ether (20 nil) was treated with LiHMDS (1M in hexane, 11.8 nil, 1 eq) dropwise at -78°C and stirred for 30 mm. Diethyl oxalate (2.6g, 1.5 eq) was added. The reaction mixture was warmed to RT and stirred for 1611. The precipitated solid was filtered and dried to obtain the lithium enolate of ethyl 4-(3-fluoro-4-methoxypheny1)-2,4-dioxobutanoate (3 g, 92%, pale yellow solid).

11-1 NMR 400 MHz, DMSO-d6: 6 15.23 (bs, 1H), 7.67 (d, J = 8.40 Hz, 1H), 7.59 (dd, J = 1.60, 12.60 Hz, 1H), 7.17-7.19 (m, 1H), 6.38 (s, 1H), 3.90 (s, 3H), 4.15 (q, J = 7.20 Hz, 2H), 1.25 (t, J = 7.20 Hz, 3H). MS ES': 269.07.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(3-fluoro-4-methoxypheny1)-2,4-dioxobutanoate (3 g, 10.94 mmol) in ethanol (15 ml), methylhydrazine sulphate (2.5 g. 16.41 mmol) was added and stirred at RT for 16h. Solvent was evaporated, and the solid was subjected to column purification on 100-200 silica mesh using pet ether and ethyl acetate to obtain ethyl 5-(3-fluoro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylate (1.55 g, 51%, pale yellow solid).

NMR 400 MHz. DMSO-d6: 67.53 (d, J= 2.00 Hz, 1H). 7.44 (dd, J= 1.20, 46.00 Hz, 1H), 7.27-7.30 (m, 1H). 6.89 (s, 1H), 3.90 (s, 6H), 4.15 (q, J = 7.20 Hz, 2H), 1.25 (t, J = 7.20 Hz, 3H). MS ES: 279.11.

Step 3: To a stirred solution of ethyl 5-(3-fluoro-4-inethoxypheny1)-1-methyl-1H-pyrazole3-carboxylate (1.5 g, 5.39 mmol) in THF (20 ml) and water (5 ml), lithium hydroxide monohydrate (0.71 g, 16.17 mmol) was added and stirred at RT for 16h. The solvent was io evaporated under reduced pressure. Then the residue was acidified with 2N HC1 and extracted using DCM. The organic layer was dried over sodium sulphate and concentrated to afford the title compound (1.33 g, 98%, pale yellow solid).

II-1 NMR 400 MHz, DMSO-d6: 6 12.68 (bs, 1H), 7.50 (d, J = 12.40 Hz, 1H), 7.31-7.35 (m, 1H), 7.28 (d, J= 8.40 Hz, 1H), 6.81 (s, 1H), 3.90 (s, 6H). MS ES: 251.08.

Intermediate 13: 5-(3-Chloro-4-fluoropheny1)-1-methyl-1H-pyrazole-3-carboxylic acid

OH

Step 1: To a stirred solution of 1-(3-chloro-4-fluorophenypethanone (2 g, 11 6 mmol) in diethyl ether (15 ml), Li HMDS (12 ml) was added dropwise at -78°C over a period of lh.

The reaction mixture was stirred at -78°C for 0.5h. Diethyl oxalate (2.54 g, 17.4 mmol) was added dropwise at -78°C and allowed to stir at -78°C for lh and gradually allowed to warm to RT. After complete conversion, the reaction mixture was filtered. The precipitate obtained was washed with diethyl ether and dried under high vacuum to obtain the lithium enolate of ethyl 4-(3-chloro-4-fluoropheny1)-2.4-dioxobutanoate (3 g, 95%. off-white solid).

1+1 NMR 400 MHz, DMSO-d6: 6 12.68 (bs, 1H), 7.95-7.93 (dd, J = 7.6 Hz and 2.0 Hz, 111), 7.86-7.82 Om 1H), 7.45 (t, J= 9.2 Hz, 1H), 6.38 (s, 111), 4.17 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). MS ES': 273.07.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(3-chloro-4-fluoropheny1)-2,4-dioxobutanoate (3 g, 11 mmol) in ethanol (25 ml) was added methylhydrazine sulphate (2.37 g) and stirred overnight at RT. After completion of the reaction, solvent was evaporated under reduced pressure, and the residue purified by flash column chromatography, using ethyl acetate: pet ether (2:8) as eluent to afford ethyl 5-(3-chloro4-Iluoropheny1)-1-methyl-1H-pyrazole-3-carboxylate (2 g, 64%, off-while solid).

1-1-1 NMR 400 MHz, DMSO-d6: 6 7.89-7.87 (dd, J = 7.6 Hz and 2.0 Hz, 1H), 7.65-7.55 (m, 2H), 6.96 (s, 1H), 4.29 (q, J = 6.8 Hz, 2H), 3.93 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H). MS ES': 283.11.

Step 3: To a stirred solution of ethyl 5-(3-chloro-4-fluorophenyI)-1-methyl-1H-pyrazole-3-caitoxylate (1 g, 3.54 mmol) in THF: water (4:1) (15 ml), lithium hydroxide monohydrate (0.44 g) was added and stirred overnight at RT. After the complete conversion of ester to acid, the reaction mixture was concentrated under reduced pressure. The residue obtained was acidified with IN HC1 and extracted with DCM containing methanol (9:1). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give the title compound (U.S g, 89%, white solid).

1H NMR 400 MHz, DMSO-d6: 6 12.73 (s, 1H), 7.88-7.85 (dd, J = 7.2 Hz and 2.0 Hz, 1H), 7.63-7.55 (m, 2H), 6.90 (s, 1H), 3.91 (s, 3H). MS ES': 254.9.

Intermediate 14: 5-(2-Fluoro-4-methoxypheny1)-1-meth y1-IH-pyrazole-3-carboxylic acid 3 steps OH Step 1: To a stirred solution of LiHMDS (29.7 ml, 29.75 mmol) in diethyl ether (60 ml) at -78°C, was added 1-(2-fluoro-4-methoxyphenyl)ethanone (5 g, 29.75 mmol) in diethyl ether (10 ml) dropwise. The reaction mixture was stirred at -78°C for 1.5h. To the reaction mixture was added diethyl oxalate (4.04 ml) in diethyl ether (10 ml) at -78°C dropwise. The reaction mixture was stirred at RT for 16h. The reaction mixture was concentrated at 35°C. The solid obtained was filtered, washed with pet ether and dried under reduced pressure to yield the lithium enolate of ethyl 4-(2-11uoro-4-methoxypheny1)-2,4-dioxobutanoate (7.5 g, 92%, pale yellow solid).

NMR 400 MHz, DMSO-d6: 6 15.20 (bs, 111), 8.19 (d. J= 5.60 Hz, 111), 7.86-7.90(m, 1H), 7.78-7.84 (m, 1H). 6.89 (s, 1H), 3.93 (s, 3H), 4.15 (q, J = 7.20 Hz, 2H), 1.25 (t, J = 7.20 Hz, 3H). MS ES': 269.07.

Step 2: To a stirred solution of the lithium cnolate of ethyl 4-(2-fluoro-4-methoxyphenye2,4-dioxobutanoate (7.5 g, 27 37 mmol) in ethanol (60 nil) was added methylhydrazine sulphate (6.8 g). The reaction mixture was stirred at RT for 16h and then concentrated io under high vacuum to yield crude product. The crude compound was pun i lied by column chromatography with ethyl acetate: pet ether (30:70) as eluent to yield ethyl 5-(2-fluoro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylate (1.4 g, 18%, yellow solid).

1H NMR 400 MHz, DMSO-d6: 6 7.46 (t, J = 8.80 Hz, 1H), 7.05 (dd, J = 2.40, 12.40 Hz, 1H), 6.94 (d, J = 2.40 Hz, 1H), 6.81 (s, 1H), 4.28 (q, J = 7.20 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 1.29 (t, J= 7.20 Hz, 314). MS ES*: 279.12.

Step 3: To a stirred solution of ethyl 5-(2-fluoro-4-methoxypheny1)-1-methy1-1H-pyrazole3-carboxylatc (1.4 g, 5.03 mmol) in THF: methanol: H20 (3:1:1) was added lithium hydroxide monohydrate (558 mg). The reaction mixture was stirred at RT for 16h. Then the reaction mixture was concentrated under high vacuum, acidified with IN HC1 solution and extracted with 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to yield the title compound (1.1 g, 87%, off-white solid).

11-1 NMR 400 MHz, DMSO-d6: 6 12.74 (bs, 1H), 7.45 (t, J = 8.80 Hz, 1H), 7.04 (dd, J = 2.40, 12.40 Hz, 1H), 6.93 (dd, J = 2.40, 8.80 Hz, 1H), 6.75 (s, 1H), 3.84 (s, 3H), 3.77 (s, 314). MS ES*: 251.09.

Intermediate 15: 5-(2-Chloro-5-(trilluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid CI 0 3 steps OH F3C CF3 Step 1: To a stirred solution of 1-(2-chloro-5-(trifluoromethyl)phenyDethanone (2.2 2, 9.9 mmol) in THE, was added NaH (0.28 g, 17.5 mmol) portionwise at 0°C. After 10-15 min, diethyl oxalate (1.34 ml) was added dropwisc at 0°C. The reaction mixture was stirred at RT for 16h. Then the reaction was quenched with ice and the solvent was evaporated. The residue was extracted with ethyl acetate. The organic layer was washed with brine solution, and dried over sodium sulphate to obtain ethyl 4-(2-chloro-5-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (1.55 g, 53%, pale yellow oil).

11-1 NMR 400 MHz, DMSO-d6: 6 15.20 (bs. 1H), 8.20 (d, J = 5.60 Hz, 1H), 7.89-7.90 (m, 1H), 7.68-7.74 (m, IH), 6.89 (s, IH), 4.10 (q, J= 7.20 Hz, 2H), 1.29 (t, J = 7.20 Hz, 3H). MS ES: 323.03.

Step 2: To a stirred solution of ethyl 4-(2-chloro-5-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (0.84 g, 2.6 mmol) in ethanol, was added methylhydrazine sulphate (0.56 g, 3.4 mmol) at RT. The reaction mixture was stirred at RT for 8h. The solvent was removed, and the crude product was purified by column chromatography using 230-400 silica, to obtain ethyl 5-(2-chloro-5-(trifluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylate (0.13 g, 15%, pale yellow oil).

1H NMR 400 MHz, DMSO-d6: 6 7.66-7.61 (m, 3H), 6.88 (s. 1H), 4.44 (q, J = 7.20 Hz, 2H), 3.81 (s, 3H). 1.42 (t, J = 7.20 Hz. 3H). MS ES*: 333.05.

Step 3: To a stirred solution of ethyl 5-(2-chloro-5-(trifluorometh yeplien y1)-1 -meth yl -1 Hpyrazole-3-earboxylate (0.13 8.0.39 mmol) in a mixture of methanol and THF, was added a solution of lithium hydroxide monohydrate (0.22 g, 1.0 mmol) in water. The reaction mixture was stirred at RT for 3-4h. The solvent was evaporated, and the residue acidified with 1M HO. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulphate and concentrated to obtain the title compound (0.1 g, 77%, off-white solid).

1H NMR 400 MHz, DMSO-d6: 6 12.79 (bs, 1H), 7.91-7.93 (m, 3H), 6.88 (s, 1H), 3.73 (s, 3H). MS ES: 305.02.

Intermediate 16: 5-(2-Chloro-5-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid

CI OH N,N

Step 1: To a stirred solution of 1-(2-chloro-5-methoxyphenyl)ethanone (3 g 16 25 mmol) in diethyl ether (60 ml) was added LiHMDS (I M. 13.8 ml, 16.25 mmol) at -78°C. After lh, diethyl oxalate (2.37 g. 16.25 mmol) was added and stirred at RT for 16h. The solvent io was evaporated, and the crude product, the lithium enolate of ethyl 4-(2-chloro-5-methoxypheny1)-2,4-dioxobutanoate, was carried forward to the next step without further purification (5.2 g, quantitative, pale yellow solid). MS ES': 285.61.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(2-chloro-5-methoxypheny1)- 2,4-dioxobutanoate (5.2 2, 16.3 mmol) in ethanol was added methylhydrazine sulphate (3.52 g, 24.45 mmol) at RT and stirred at 90°C for 2h. The reaction mixture was concentrated under vacuum. The crude product was purified by Grace purifier using a gradient elution of 20% ethyl acetate in pet ether to afford ethyl 5-(2-chloro-5-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylate (1.4 g, 29%, yellow solid).

1H NMR 400 MHz, DMSO-d6: 57.55 (d, J = 8.80 Hz, 1H). 7.13 (dd. J = 2.80, 9.00 Hz, 1H), 7.09 (d, J = 3.20 Hz, 1H). 6.83 (s, 1H), 4.26-4.28 (rn, 2H), 3.80 (s. 3H). 3.73 (s, 3H). 1.28-1.30 (m, 3H). MS ES': 295.17.

Step 3: To a stirred solution of ethyl 5-(2-chloro-5-methoxypheny1)-1-methyl-1H-pyrazole- 3-carboxylate (1.1 g, 3.73 mmol) in Me0H: THE: water (3:1:1) was added lithium hydroxide monohydrate (0.428 g, 10.2 mmol) at RT and stirred for 16h. The reaction mixture was concentrated under vacuum, acidified with 1N HC1 solution and extracted using 10% methanol in DCM. The organic layer was washed with brine solution and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was used for the next step without further purification (0.95 2, 96%, pale yellow solid).

NMR 400 MHz, DMSO-d6: 8 12.73 (s, 1H), 7.55 (d, J = 8.80 Hz, 1H), 7.11-7.12 (m, 2H), 6.77 (s, 1H), 3.80 (s, 3H), 3.72 (s, 3H). MS ES': 267.14.

Intermediate 17: 1,4-Dimethy1-5-(4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylic acid 3 steps OH F3C F3C io Step 1: To a stirred solution of LiHMDS (1M in hexane. 9 ml 10 89 mmol) in diethyl ether at -78°C under nitrogen, 1-(4-(trifluoromethyl)phenyepropan-1-one (2 g 9 9 mmol) in diethyl ether (15 ml) was added dropwise and stirred for 30 mm at -78°C. Diethyl oxalate (1.44 g, 10.89 mmol) in diethyl ether (15 ml) was added dropwise. The solution was then slowly allowed to warm to RI and stirred at RI for 2h. A solid began to form. The stifling was discontinued, and the mixture was allowed to settle overnight. The solid was filtered and dried to afford the lithium enolate of ethyl 3-methy1-2,4-dioxo-4-(4-(trifluoromethyl)phenyl)butanoate (2.2 g, 67%, pale yellow solid). MS ES-: 301.0.

Step 2: To a stirred solution of the lithium enolate of ethyl 3-methy1-2,4-dioxo-4-(4- (trifluoromethyl)phenyl)butanoate (1.5 g, 4.96 mmol) in ethanol (50 ml), methylhydrazine sulphate (1.13 g, 5.96 mol) was added under nitrogen and stirred for 16h. Ethanol was removed under reduced pressure to give crude product. which was purified by Grace purifier using a gradient elution of 2-4% ethyl acetate in pet ether to afford ethyl 1,4-dimethy1-5-(4-(t3i uoromethyl)pheny1)-1H-pyrazolc-3-carboxylatc (0.51 g, 33%, white solid).

11-1 NMR 400 MHz, DMSO-d6: 6 7.78 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.22 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). MS ES: 313.1.

Step 3: To a stirred solution of ethyl 1,4-dimethy1-5-(4-(trifluoromethyppheny1)-1H30 pyrazolc-3-carboxylate (0.5 g, 1 6 mmol) in a mixture of THF (10 ml) and water (5 ml), lithium hydroxide monohydrate (0.202 2, 4.8 mmol) was added and stirred for 16h. The solvents were evaporated under reduced pressure to give a residue, which was acidified with HC1 and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (420 mg, 92%, white solid). MS ES: 285.1.

Intermediate 18: 1-Ethy1-5-(4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylic acid 3 steps OH F3C F3C io Step 1: To a stirred solution of the lithium cnolate of ethyl 4-(4-(trifluoromethyl)phenye- 2,4-dioxobutanoate (Intermediate 2, Step 1) (1 g, 3.47 mmol) in ethanol (35 ml), ethylhydrazine hydrochloride (0.048 g, 5.1 mmol) was added under nitrogen and stirred for 16h at RT. Ethanol was evaporated under reduced pressure to give crude product, which was purified by Grace purifier using a gradient elution of 10-15% ethyl acetate in pet ether Is to afford ethyl 1-ethy1-5-(4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylate (800 m2, 74%, white solid).

1HNMR 400 MHz, DMSO-d6: 6 7.75 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 6.86 (s, 1H), 4.43 (q, J = 7.2 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.45-1.39 (m, 6H). MS ES': 313.1.

Step 2: To a stirred solution of ethyl 1-ethy1-5-(4-(tritluoromethyl)pheny1)-1H-pyrazole-3-carboxylate (0.8 g 2 7 mmol) in a mixture of THE (10 ml) and water (4 ml), lithium hydroxide monohydrate (0.338 g, 8 mmol) was added and stirred for 16h at RT. Solvents were evaporated under reduced pressure to give a residue which was acidified with HC1 and extracted with ethyl acetate (2 x 40 mL) The combined organic layer was washed with n5 brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (620 mg, 83%, off-white solid).

1H NMR 400 MHz, DMSO-d6: 6 12.79 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 6.91 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.35-1.31 (t, J = 7.2 Hz, 3H). MS ES': 285.1.

Intermediate 19: 1-Ethy1-5-(4-methoxypheny1)-1H-pyrazole-3-carboxylic acid 2 steps OH Step 1: To a stirred solution of the lithium enolate of ethyl 4-(4-methoxypheny1)-2,4-dioxobutanoate (Intermediate 1, Step 1) (1.2 g, 4.68 mmol) in ethanol (20 nil), ethylhydrazine hydrochloride (0.315 g, 3.6 mmol) was added under nitrogen and stirred for 16h at RT. Ethanol was removed under reduced pressure to give crude product, which was purified by Grace purifier using a gradient elution of 2-4% ethyl acetate in pet ether to afford ethyl 1-ethyl-5-(4-methoxypheny1)-1H-pyrazole-3-carboxylate (640 mg, 50%, white solid). MS ES': 275.1.

Step 2: To a stirred solution of ethyl 1-ethy1-5-(4-methoxypheny1)-1H-pyrazole-3-carboxylate (0.63 g, 2.30 mmol) in a mixture of THE (10 ml) and water (5 ml), lithium hydroxide monohydrate (0.2759 g, 6.56 mmol) was added and stirred for 16h. Solvents were removed under reduced pressure to give a residue, which was acidified with HC1 and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (520 mg, 92%, white solid). MS ES': 247.1.

Intermediate 20: 5-(2-Methoxy-4-(tritluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxyl ic acid 3 steps OH F3C F3C Step 1: To a stirred solution of 1-(2-methoxy-4-(trifluoromethy1)phenyeethanone (3 g, 13.8 mmol) in diethyl ether (60 ml) was added LiHMDS (1M in hexane, 13.8 ml, 13.8 mmol) at -78°C and stirred for lh. Then diethyl oxalate (2.01 g, 13.8 mmol) was added and stirred at RT for 16h. Complete evaporation of ether gave crude product, the lithium enolate of ethyl 4-(2-methoxy-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate which was carried forward to the next step without further purification (5.2 2, quantitative, pale yellow solid). MS ES': 319.21 Step 2: To a stirred solution of the lithium enolate of ethyl 4-(2-methoxy-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (5.2 g, 16.3 mrnol) in ethanol was added methylhydrazine sulphate (3.52 g, 24.45 mmol) at RT and stirred at 90°C for 2h. The reaction mixture was concentrated under high vacuum. The crude product was purified by Grace purifier using a gradient elution of 20% ethyl acetate in pet ether to afford ethyl 5- (2-methoxy-4-(trilluoromethyl)pheny1)-1-methyl -1H-p yrazole-3-carbo x yl ate (1.4 g, 50%, yellow solid).

11-1 NMR 400 MHz, CDC13: 6 7.38 (d, J = 8.0 Hz,1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.82 (s, 1H), 4.43 (q, J = 6.8 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). MS ES: 329.17.

Step 3: To a stirred solution of ethyl 5-(2-methoxy-4-(trifluoromethyl)pheny1)-1-methyl1H-pyrazole-3-carboxylate (1.1 g, 3.21 mmol) in Me0H: THE: water (3:1:1) was added lithium hydroxide monohydrate (0.428 g, 10.2 mmol) and stirred at RT for 16h. The reaction mixture was concentrated under high vacuum, acidified with 1N HC1 solution and extracted with 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was used for the next step without further purification (0.95 g, 80%, pale yellow solid).

11-1 NMR 400 MHz, DMSO-d6: 6 12.68 (bs, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.47-7.42 (m, 2H), 6.76 (s, 1H), 3.91 (s, 3H), 3.71 (s, 3H). MS ES*: 301.18.

Intermediate 21: 5-(2-Chloro-4-methoxypheny1)-4-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid CI 0 CI 0 Step 1: To a stirred solution of 2-chloro-N,4-dimethoxy-N-methylbenzamide (Intermediate 3, Step 1) (1.1 g, 4.8 mmol) in diethyl ether (50 ml) at 0°C, propyl magnesium bromide solution (2M, 5 ml) was added and stirred at RT for 6h. The reaction mixture was cooled, quenched with 1N HC1 (50 ml) and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using a gradient elution of 56% ethyl acetate in pet ether to give 1-(2-chloro-4-methoxyphenyl)butan-1-one (0.5 g, 55%, colourless liquid). MS ES': 230.

Step 2: 1-(2-Chloro-4-methoxyphenyl)butan-1 -one (5 g, 23.6 mmol) was dissolved in diethyl ether (100 ml) and cooled to -75°C. n-BuLi (18 ml) was added at -75°C and stirred for 40 min Then diethyl oxalate (3.45 g, 23.6 mmol) was added at -75°C. The reaction mixture was stirred at -75°C for 8h, quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (3 x 30m1). The combined organic layer was dried with sodium sulphate and concentrated under vacuum to obtain ethyl 3-(2-chloro-4-methoxybenzoy1)-2-oxopentanoate (5 g, 68%, pale yellow gum). MS ES-: 311.39.

Step 3: Ethyl 3-(2-chloro-4-methoxybenzoy1)-2-oxopentanoate (5 g, 15.98 mmol) was dissolved in ethanol (10 m1). Methylhydrazine sulphate (3.46 g, 24 mmol) was added and stirred at 80°C for 3h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3 x 30m1). The combined organic layer was dried over sodium sulphate and concentrated under vacuum. The crude product was purified on Grace purifier to obtain ethyl 5-(2-chloro-4-methoxypheny1)-4-ethyl-l-methyl-1H-pyrazole-3-carboxylate (1 g, 19%, pale yellow gum).

1H NMR 400 MHz, DM50-d6: 6 7.37 (d, J = 8.40 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.09- 7.07 (m, 114), 4.28 (q, J = 7.2 Hz, 211), 3.86 (s, 314), 3.60 (s, 31-1), 2.51-2.36 (in, 211), 1.30 (t, J = 7.20 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H). MS ES': 323.24.

Step 4: Ethyl 5-(2-chloro-4-methoxypheny1)-4-ethyl-1-methyl-IH-pyrazole-3-carboxyl ate (1 g, 3.4 mmol) was dissolved in THF: water: Me0H (3:1:1) and lithium hydroxide monohydrate (10.2 mmol) was added. The reaction mixture was stirred at RT for 2h, and then concentrated under vacuum. The residue was dissolved in water, acidified with 1N HC1 and extracted with ethyl acetate (3 x 20m1). The combined organic layer was dried over sodium sulphate and concentrated under vacuum. The solid obtained was washed with pentane to give the title compound (700 mg, 58%, off-white solid).

NMR 400 MHz, DMSO-d6: 6 12.58 Ow s, 11-1), 7.37 (d, J = 8.8 Hz, 11-1), 7.27 (d, J = 2.4 Hz, 1H), 7.10-7.07 (m, 1H), 3.86 (s, 3H), 3.59 (s, 3H), 2.51-2.37 (m, 2H), 0.94 (t, J = 7.20 Hz, 3H). MS ES: 295.21.

Intermediate 22: 5-(2-Chloro-4-methoxypheny1)-1.4-dimethy1-1H-pyrazole-3-carboxylic acid CI 0 Step 1: 2-Chloro-N,4-dimethoxy-N-methylbenzamide (Intermediate 3, Step 1) (2.5 g, 10.88 mmol) was dissolved in diethyl ether (80 ml) and cooled to -10°C. Ethyl magnesium bromide solution (1M in THE. 16 ml) was added and stirred for 4h at RT. The reaction mixture was cooled, quenched with IN HC1 (50 ml) and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure.

The crude product was purified by column chromatography using a gradient elution with 5-6% ethyl acetate in pet ether to give 1-(2-chloro-4-methoxyphenyl)propan-1-one (2.5 g, 83%, colourless liquid).

IFI NMR: 400 MHz, DMSO-d6: 6 7.70 (s, 1H), 7.10 (dd, J = 2.40 Hz, 1H), 7.02 (dd, J = 2.40 Hz, 1H), 3.84 (s. 3H). 2.90-2.92 (m, 2H). 1.05 (t, J = 1.20 Hz, 3H).

Step 2: To a stirred solution of LiHMDS (14 ml) in diethyl ether (60 ml) at -78°C was added 1-(2-chloro-4-methoxyphenyl)propan-1-one (2 5 g 12 58 mmol) in diethyl ether (10 ml) dropwise. The reaction mixture was stirred at -78°C for 1.5h. To the reaction mixture was added diethyl oxalate (1.8 ml) in diethyl ether (10 nil) at -78°C dropwise. The reaction mixture was stirred at RT for 16h, and then concentrated at 35°C. The residue was diluted with pet ether. The solid obtained was filtered, washed with pet ether, and dried under reduced pressure to yield the lithium enolate of ethyl 4-(2-chloro-4-methoxypheny1)-3-methy1-2,4-dioxobutanoate (3.2 g, 85%, pale yellow solid). MS ES': 298.99.

Step 3: To a solution of the lithium enolate of ethyl 4-(2-chloro-4-methoxypheny1)-3-methy1-2,4-dioxobutanoate (3.2 g, 10.71 mmol) in ethanol (20 ml) was added methylhydrazine sulphate (2.9 g, 16.07 mmol) and the reaction mixture was stirred at 80°C for 3h. The reaction mixture was concentrated under high vacuum to yield crude product, which was purified by column chromatography using ethyl acetate: pet ether (30:70) as eluent to yield ethyl 5-(2-chloro-4-methoxypheny1)-1,4-dimethy1-1H-pyrazole-3-carboxylate (0.5 g, 15%, yellow solid).

NMR: 400 MHz, DM5O-d6: 6 7.39 (s, 1H), 7.27 (dd, J = 2.40 Hz, 1H), 7.09 (dd, J = 2.80 Hz, 1H), 4.25-4.27 Om 2H), 3.86 (s, 3H), 3.62 (s. 3H), 1.75 (s, 3H), 1.30 (t, J = 7.20 Hz, 3H).

Step 4: To a stirred solution of ethyl 5-(2-chloro-4-methoxypheny1)-1,4-dimethy1-1HPYrazole-3-carboxylate (0.5 2, 1.62 mmol) in THF: Me0H: H20 (3:1:1) (5 mL), lithium hydroxide monohydrate (0.2 g, 4.86 mmol) was added. The reaction mixture was stirred at is RT for 16h, concentrated and acidified with 2N HO. The solid obtained was collected by filtration and dried under high vacuum to give the title compound (0.45 g, 99%, off-white solid). ES MS*: 281.18.

Intermediate 23: 5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid CI 0 3 steps OH F3C F3C Step 1: To a stirred solution of LiHMDS (1M solution in THE, 24.3 ml, 24 3 mmol) in diethyl ether (60 ml) at -78°C was added 1-(2-ehloro-4-(trilltioromethypphenypetharame (5 g, 24.3 mmol) in diethyl ether (40 ml) dropwise. The reaction mixture was stirred at -78°C for 1.5h. Diethyl oxalate (3 5 g 24 3 mmol) in diethyl ether (10 ml) at -78°C was added dropwise. The reaction mixture was allowed to stir at RT for 16h, concentrated at 35°C and triturated with pet ether. The solid obtained was filtered and dried under reduced pressure to yield the lithium enolate of ethyl 4-(2-chloro-4-(trifluoromethyppheny1)-2,4-dioxobutanoate (6 g, 75%, pale yellow solid). MS ES': 323.15.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(2-chloro-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (6 g, 18.63 mmol) in ethanol (60 ml) was added methylhydrazine sulphate (4.02 g, 27.95 mmol) and the reaction mixture was allowed to stir at 80°C for 3h. The reaction mixture was concentrated under high vacuum and subjected to esterification by refluxing in ethanol in the presence of catalytic sulphuric acid. Solvent was evaporated from the reaction mixture. The residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using ethyl acetate: pet ether (10:90) as eluent to yield ethyl 5-(2-chloro- 4-(trifluoromethyl)pheny1)-1-methyl-IH-pyrazole-3-carboxylate (2.8 g, 48%, pale yellow gum).

1H NMR 400 MHz, DMSO-d6: 6 8.12 (d, J = 0.80 Hz, 1H), 7.89 (d, J = 1.20 Hz, 1H), 7.79 (d, J = 8.00 Hz, 1H), 6.93 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 1.30 (t, J = 7.2 Hz, 31-1). MS ES: 333.19.

Step 3: To a stirred solution of ethyl 5-(2-chloro-4-(tritluoromethyl)pheny1)-1-methyl-1Hpyrazole-3-carboxylate (6 g, 18.63 rminol) in THE: methanol: H20 (3:1:1) was added lithium hydroxide monohydratc (2.34 g, 55.9 mmol) The reaction mixture was stirred at RT for 16h, concentrated under high vacuum, acidified with IN HC1 solution and extracted with 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound (5.5 g, 86%, off-white solid).

11-1 NMR 400 MHz, DMSO-d6: 6 12.80 (s, 1H), 8.12 (s, 1H), 7.88 (dd, J = 1.20 Hz and 8.0 Hz, 1H), 7.79 (d, J = 8.00 Hz, 1H), 6.87 (s, 1H), 3.74 (s, 3H). MS ES: 305.10.

Intermediate 24: 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3) -1H-pyrazole-3-carboxylic acid 4 steps OH Step 1: A stirred solution of LiHMDS (1.4M in THF, 48.5 mmol) in diethyl ether (80 nil) at -78°C was treated dropwise with 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethan-1-one (10.0 g, 48.5 mmol), allowed to stir for 30 min, and treated with a solution of diethyl oxalate (7.08 g, 48.5 mmol in diethyl ether, 5 m1). The resultant reaction mixture was allowed to warm to RT and stirred at for 18h. The precipitate was collected by filtration and washed with diethyl ether (3 x 25 ml) to obtain a yellow solid (14.8 2, 97%). HPLC: 2.23 min, 92.01%. MS ES': 307.01.

Step 2: A stirred solution of (4-ethoxy-1-(2-11uoro-4-(trilluoromethyl)phenyl)-1,3,4-th trioxobutan-2-yl)lithium (14.8 g, 47.41 mmol) in Et0H was treated with hydrazine hydrate (3.50 g, 71.1 mmol) and allowed to stir at RT for 16h. The mixture was concentrated under reduced pressure and the residue purified by column chromatography (on Davisil, 4-20% Et0Ac in petrol ether) to afford ethyl 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1H-pyrazole3-carboxylate (10g. 70%) as an off-while solid.

1H NMR (400 MHz, DMSO-d6): 6 14.49 (s, III), 8.20-8.00 (m, 11-1), 7.90-7.70 (m, 7.22 (s, 1H), 4.38-4.29 (m, 2H), 1.35-1.32 (m, 3H). HPLC: 2.14 min, 99.3%. MS ES': 303.15.

Step 3: A stirred solution of ethyl 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylate (10.0 g, 33.1 mmol) in THF (100 ml) was treated with NaH (1.98 g, 49.6 mmol) at 0°C followed by addition of methyl iodide-d3 (2.8 ml, 39.7 mmol) under atmosphere. The mixture was allowed to stir at RT for 16h, cooled to 0°C, treated with chilled 1120 and diluted with Et0Ac. The layers were separated and the organic layer dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by column chromatography (on Davisil, 5-70% Et0Ac in petrol ether) gave isomer 1, ethyl 5- (2-fluoro-4-(tri fluoro meth yl)pheny1)-1-(methyl -d3)-1H-pyrazole-3-carboxyl ate (6.2 g, 59%) and isomer 2, ethyl 3-(2-11uoro-4-(trif1uoromethy1)pheny1)-1-(methyl-d3) -1Hpyrazole-5-carboxylate (1.1 2, 10.4%) as off-white solids.

Isomer 1: Ili NMR (400 MHz, DMSO-d6): 57.94 (d, J = 9.6 Hz, 111), 7.84 (d, J = 7.6 Hz, 3o 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). HPLC: 2.11 min, 99.7%. MS ES': 320.11.

Step 4: A solution of ethyl 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3) -1Hpyrazole-3-carboxylate (1.40g. 4.38 mmol) in THF/Me0H/H20 (20 ml, 1:2:1) was treated with LiOH*1-120 (552 mg, 13.2 mmol), stirred at RT for 2h and evaporated. The residue was acidified to pH 4 with 1M citric acid and extracted with Et0Ac (50 m1). The layers were separated and the organic layer dried (Na9SO4) and concentrated under reduced pressure to afford the title compound (1.10g. 86%) as a while solid.

II-1 NMR (400 MHz, DMSO-d6): 6 12.8 (br s, 1H), 7.93 (d, J = 10.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H). HPLC: 1.75 min, 91.9%. MS ES': 292.06.

Examples

Example 1: 5-(4-Methoxypheny1)-1-methyl-N-((1-methylpiperidin-2-yl)methyl) -1Hpyrazole-3-carboxamide

N

To a stirred solution of 5-(4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 1) (0.25 g, 1.07 mmol) in THF (5 mL) and (1-methylpiperidin-2-yl)methanamine (0.151 g, 1.2 mmol) under nitrogen, were added HATU (0.627 g, 1.65 mmol) and DIPEA (0.425 g, 3.3 mmol) and stirred at RT for 16h. Saturated sodium carbonate solution was then added to the reaction mixture and the product was extracted with ethyl acetate (2 x 25 mL) The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. The crude product was purified by Grace purifier using a gradient elution of 5-8% methanol in DCM to afford the title compound (65 mg, 18%) as a white ns solid.

NMR (400 MHz, DMSO-d6) 6 7.67 (t, J= 5.6 Hz, 1H), 7.49 (q, J = 2.9 Hz, 2H), 7.07 (q, J = 3.0 Hz, 2H), 6.68 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.48 (t, J = 3.3 Hz, 1H), 3.22 (d, J =5.0 Hz, 11-1), 2.77 (t, J=5.8 Hz, 11-1), 2.23 (s, 3H), 2.01 (in, J =4.6 Hz, 21-1), 1.66 (q, J = 3.8 Hz, 1H), 1.54 (m, J = 6.9 Hz, 2H), 1.42 (m, J = 4.7 Hz, 1H), 1.23 (m, J = 4.8 Hz, 2H). MS ES': 343.30.

The enantiomers were separated by SFC-prep. Preparative SFC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acctonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example 1A: Isomer 1

1H NMR (400 MHz, DMSO-d6) 6 7.69(s, 1H), 7.49 (d. J= 8.5 Hz, 2H). 7.07 (d, J= 8.5 Hz, 2H), 6.68 (s, 1H), 3.82 (s, 3H), 3.84 (s, 3H), 3.46 (q, J= 3.3 Hz, 1H), 3.26 (q, J= 6.3 Hz, 1H), 2.79(d, J = 11.0 Hz, 1H). 2.25 (s, 311), 2.05 (d, J = 8.8 Hz, 211). 1.67 (m, 1= 19.8 Hz, 111). 1.55 (m, J = 19.8 Hz, 3H), 1.25 (q, J = 10.6 Hz, 2H). SORia120589: +41.26 (0.1% in chloroform). MS ES*: 343.35.

is Example IB: Isomer 2 1H NMR (400 MHz, DMSO-d6) 6 7.68 (s, 1H), 7.49 (d. J = 8.8 Hz, 2H). 7.07 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 3.8 (s, 311). 3.84 (s, 3H). 3.46 (in. J = 3.3 Hz, 111), 3.24 (q, J = 6.2 Hz, 1H). 2.78 (d, J = 10.7 Hz, 1H). 2.24 (s, 3H). 2.0214, J = 22.7 Hz, 2H), 1.66 (t, J = 5.8 Hz, 111). 1.49 (m, J = 19.0 Hz, 3H), 1.23 (m, J = 10.9 Hz, 2H). SOR1a1205s9: -33.12 (0.1% in chloroform). MS ES*: 343.37.

Example 2: 5-(4-Methoxypheny1)-1-methyl-N-(1-rnethylpiperidin-4-y1) -1H-pyrazolc-3-carboxamide C) / k "N n5 To a stirred solution of 5-(4-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 1) (0.25 2, 1.07 mmol) in THF (5 mL) and 1-methylpiperidin-4-amine (0.135 g,1.17 mmol) under nitrogen, were added HATU (0.627 g 1 65 mmol) and D1PEA (0.425 g, 3.3 mmol) and stirred at RT for 16h. Saturated sodium carbonate solution was added and the product extracted with ethyl acetate (2 x 30 inL) The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. The crude product was purified by Grace purifier using a gradient elution of 5-8% methanol in DCM to afford the title compound (55 mg, 17%) as a white solid.

NMR (400 MHz, DMSO-d6) 57.91 (d, J= 8.1 Hz, 1H), 7.49 (q, J= 2.9 Hz, 2H), 7.07 (q, J= 2.9 Hz, 2H), 6.68 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.83 (d, J= 10.5 Hz, 2H), 2.24 (s, 3H), 2.11 (s, 2H), 1.69 (in, J = 6.9 Hz, 4H). MS ES': 329.42.

Example 3: 5-(4-Methoxyphenyl)-1-methyl-N-(2-(1-methylpiperidin-2-yl)ethyl)-1H-th pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(4-mettioxypheny1)-1-methyl-IH-pyrazole-3-carboxylic acid (Intermediate 1) (0.2 g, 0.861 mmol) and 2-(1-methylpiperidin-2-y1) ethanamine (0.19 2, 1.29 mmol) to afford the title compound (0.185 2, 60%) as a pale Is yellow solid.

1-H NMR (400 MHz, DMSO-d6) 59.16 (m, J= 31.3 Hz, 1H), 7.49 (t, J= 4.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.69 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 2.92 (q, J = 33.7 Hz, 8H), 1.76 (m, J= 69.3 Hz, 8H). MS ES': 357.38.

Example 4: 5-(4-Methox ypheny1)-1-methyl-N-(2-(1-methylpiperidin-3-yeethyl) -1H-pyrazolc-3-carboxamide

N

Prepared as desciibcd for Example 1 using 5-(4-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 1) (0.2 g, 0.861 mmol) and 2-(1-methylpiperidin-3-y1) ethanamine (0.19 2, 1.29 mmol) to afford the title compound (0.150 2, 49%) as an off-white solid.

IFI NMR (400 MHz, DMSO-d6) 68.09 (t, J= 5.9 Hz, 111), 7.49 (q, J= 2.9 Hz, 211), 7.07 (q, J = 2.9 Hz, 2H), 6.66 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.24 (q, J = 6.7 Hz, 2H), 2.69 (m, J = 10.2 Hz, 2H), 2.14 (s, 3H), 1.81 (t. J = 10.3 Hz, 1H), 1.71 (d, J = 12.7 Hz, 1H), 1.48 (m, J= 8.9 Hz, 6H), 0.83 (t, J= 10.5 Hz, 1H). MS ES: 357.38.

Example 5: 5-(4-Methoxypheny1)-1-methyl-N-(2-(1-methylpyrrolidin-2-yflethyl) -1Hpyrazole-3-carboxamide Prepared as described for Example 1 using 5-(4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate I) (0.2 g, 0.861 mmol) and 2-(1-methylpyn-olidin-2-y1) ethanamine (0.17 g, 1.29 mmol) to afford the title compound (0.070 g, 23%) as an off-white solid.

1-14 NMR (400 MHz, DMSO-d6) 6 8.20 (q, J = 6.8 Hz, 1H), 7.50 (q, J = 2.9 Hz, 2H), 7.07 4 J= 2.9 Hz, 2H), 6.67 (s. IH). 3.87 (s, 3H). 3.82 (s, 3H), 3.26 (n. J= 4.1 Hz. 2H), 3.03 (s, 1H), 2.30 (s, 5H), 2.00 (m, J = 7.0 Hz, 1H). 1.88 (m, J = 3.8 Hz, 1H). 1.67 (t, J = 6.3 Hz, 2H), 1.46 (q. J = 6.8 Hz, 2H). MS ES': 343.35.

Example 6: 5-(4-M ethox ypheny1)-1-methyl-N-(2-(1-meth ylpyrrol idi n-3-yl)ethyl)-1 H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 1) (0.2 g, 0.861 mmol) and 2-(1-methylpyrrolidin-3-y1) ethanamine (0.17 g, 1.29 mmol) to afford the title compound (0.045 g, 15%) as an off-white solid.

1H NMR (400 MHz, CDC13) 87.33 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.94 (t, J = 5.6 Hz, 1H), 6.77 (s, 1H), 3.86 (d, J= 1.9 Hz, 6H), 3.43 (q, J= 6.9 Hz, 2H), 2.790. J= 8.2 Hz, 1H), 2.61 (t, J= 7.3 Hz, 1H), 2.47 (d, J= 6.2 Hz. 1H). 2.35 (s. 3H), 2.29 (t, J= 8.1 Hz, 1H). 2.18 (t. J = 8.0 Hz, 1H), 2.08 (m, J = 2.7 Hz, 1H), 1.71 (m. J = 3.5 Hz, 2H). 1.49 (m, J= 3.0 Hz, 1H). MS ES': 343.32.

Example 7: 5-(4-Methoxypheny1)-1-methyl-N-((1-methylpyrrolidin-3-y1)methyl) -1Hpyrazole-3-carboxamide io Prepared as described for Example 1 using 5-(4-tnethoxypheny1)-1-methyl-lH-pyrazole-3-carboxylic acid (Intermediate 1) (0.15 g, 0.645 mmol) and (1-methylpyrrolidin-3-y1) methanamine (0.10g, 0.967) to afford the title compound (0.050 g. 24%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) 87.78-7.70 (m, 1H), 7.49 (d, J= 8.8 Hz. 2H), 7.07 (d. J = 8.8 Hz, 2H), 6.68 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.55-3.45 (m, 1H), 3.15-3.05 (m, 1H), 3.00-2.92 (m, 1H), 2.35-2.30 (m, 1H), 2.28 (s, 3H), 2.15-2.10 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.55 (m, 3H). MS ES': 329.2.

Example 8: 5-(4-Methoxypheny1)-1-methyl-N-(1-methylpyrrolidin-3-y1)-1H-pyrazole-3-20 carboxamide Prepared as described for Example 1 using 5-(4-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate I) (0.2 g, 0.861 mmol) and 1-methylpyrrolidin-3-amine (0.163 g, 1.63 mmol) to afford the title (0.030 g, 12%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 8 7.88 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.07 (d, J= 8.7 Hz, 2H), 6.69 (s, 1H), 4.38 (q, J= 3.2 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.62 (m, J = 7.8 Hz, 2H), 2.38 (m, J= 6.0 Hz, 2H), 2.25 (s, 3H), 2.14 (m, J = 4.6 Hz, 1H), 1.73 (q, J= 4.3 Hz, 1H). MS ES: 315.31.

Example 9: 5-(4-Methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-ye-1H-pyrazole-3-, carboxamide cN

NN

Prepared as described for Example 1 using 5-(4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate I) (0.2 g, 0.861 mmol) and 1-methylpiperidin-3-amine (0.15g. 1.29 mmol) to afford die title compound (0.09 g, 32%) as an off-white solid.

'LH NMR (400 MHz, DMSO-d6) 6 7.74 (d, J = 8.0 Hz, 1H), 7.49 (q, J = 2.9 Hz, 2H), 7.07 (t, J= 4.4 Hz, 2H), 6.69(s, 1H), 3.97(t, J= 3.9 Hz, 1H), 3.87 (s, 3H), 3.82(s, 3H), 2.60(d, J= 8.1 Hz, 1H), 2.45(d, J= 7.2 Hz, 1H), 2.20(s, 5H), 1.64(d, J= 5.2 Hz, 2H), 1.49(m, J = 7.1 Hz, 2H). MS ES': 329.31.

The enantiomers were separated by SFC-prep. Preparative SFC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example 9A: Isomer 1

111 NMR (400 MHz, DMSO-d6) 6 7.71 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.69 (s, 1H), 3.95 (t, J = 4.0 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.58 (s, 1H), 2.40(s. 1H), 2.17 (s, 3H), 2.08 (s, 2H), 1.62 (d, J = 5.2 Hz, 2H), 1.48 (m, J = 7.0 Hz, 2H).

Example 9B: Isomer 2

11-1 NMR (400 MHz, DMSO-d6) 67.72 (d. J = 8.4 Hz, 1H). 7.49 (q. J= 2.9 Hz, 2H). 7.07 (q, J = 2.9 Hz, 2H), 6.69 (s. 1H), 3.95 (t, J = 3.9 Hz, 1H). 3.87 (s. 3H), 3.82 (s, 3H), 2.56 (d, J = 9.9 Hz, 1H), 2.39 (s, 1H), 2.17 (s, 3H), 2.09 (s, 2H), 1.62 (s, 2H), 1.49 (q, J = 6.8 Hz, 2H).

Example 10: 5-(4-Methoxypheny1)-1-methyl-N-(( 1-methylpynolidin-2-yl)methyl)-1Hpyrazole-3-carboxamide Prepared as described for Example 1 using 5-(4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate I) (0.25 g, 1.07 mmol) and (1-methylpyrrolidin-2-yl)methanamine (0.135 g, 1.17 mmol) to afford the title compound (65 fig. 17%) as a io white solid.

IF1 NMR (400 MHz, DMSO-d6) 6 7.83 (s, 1H), 7.49 (q, J = 2.9 Hz, 2H), 7.07 (q, J = 2.9 Hz, 2H), 6.68 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.50 (m, J= 3.4 Hz, 1H), 3.11 (d, J= 63.3 Hz, 21-1), 2.37 (s, 5H), 1.84 (s, 1H). 1.64 (t, J = 7.9 Hz, 3H). MS ES*: 329.32.

Example 10A: Isomer 1 IF1 NMR (400 MHz, DMSO-d6) 6 7.75 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 3.84 (d, J = 20.3 Hz, GH), 3.48 (m, J= 3.4 Hz, 1H), 3.12 (m, J= 6.0 Hz, 1H), 2.97 (d, J = 3.1 Hz, 1H), 2.30 (s, 4H), 2.14 (d, J = 8.2 Hz, 1H), 1.80 (m, J = 4.5 Hz, 1H), 1.58 (m, J = 6.5 Hz, 3H).

Example 10B: Isomer 2 1-11 NMR (400 MHz, DMSO-d6) 6 7.74 (s, 1H), 7.49 (q. J = 2.9 Hz, 2H). 7.07 (q, J = 2.9 Hz, 2H), 6.68 (s, 1H). 3.84 (d, J = 20.1 Hz, GH), 3.48 (m, J = 3.4 Hz, 1H). 3.12 (m, J = 4.8 Hz, 1H), 2.96 (q, J= 5.0 Hz, 1H), 2.30 (s, 4H), 2.12 (t, J= 8.5 Hz, 1H), 1.80 (m, J= 4.5 Hz, 1H), 1.58 (m, J= 5.8 Hz, 3H).

Example 11: 1-Methyl-N-(quinuclidin-3-y1)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-s carboxamide F3C Prepared as desciibed for Example 1 using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.2 g, 0.861 mmol) and quinuclidin-3-amine (0.097 g, 1.29 mmol) to afford the title compound (0.09 g, 34%) as an off-white solid.

It) NMR (400 MHz, DMSO-d6) ö 8.03 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.83 (d, J= 8.2 Hz, 2H), 6.92 (s, 1H), 3.96 (m, 4H), 3.07 (m, J = 4.2 Hz, 1H), 2.89 (m, J = 3.8 Hz, 1H), 2.66 (m, J= 4.9 Hz, 4H), 1.80 (m, J= 7.6 Hz, 2H), 1.57 (m, J= 3.6 Hz, 2H), 1.30 (m, = 3.9 Hz, 1H). MS ES*: 379.35.

Example 12: 5-(4-Methoxypheny1)-1-methyl N (8 methyl-8-azabicyclor3.2.1loctan-3-y1)- 1H-pyrazole-3-carboxami de

N

Prepared as described for Example 1 using 5-(4-tnethoxypheny1)-1-methy1-IH-pyrazole-3-carboxyl i c acid (Intermediate I) (0.15 g, 0.6 m mol) and 8-methy1-8-azabicyclor3.2.1loctan-3-amine (0.083 2, 0.66 mmol) to afford the title compound (121 mg, 63%) as a white solid. The product obtained was a mixture of diastereomers.

1HNMR (400 MHz, DMSO-d6, normalised) 6 7.80 (d, I = 8.8 Hz, 1H), 7.52-7.45 (m, 2H). 7.08-7.04 (m. 2H). 6.68 (s, 1H), 4.15-4.05 (m, 1H). 4.00-3.92 (tn. 1H), 3.87 (s, 3H). 3.80 (s, 3H), 3.20-3.00 (m, 2H), 2.15 (s, 3H), 2.10-1.90 (m, 3H), 1.70-1.62 (m, 3H), 1.58-1.50 (m, 1H). MS ES': 355.34.

Example 13: N-(1-Azabicyclo[2.2.1]heptan-3-y1)-5-(4-methoxypheny1) -1-methy1-1Hpyrazole-3-carboxamide Prepared as described for Example 1 using 5-(4-tnethoxypheny1)-1-methy1-IH-pyrazole-3- carboxylic acid (Intermediate 1) (0.15 g, 0.6 mmol) and 1-azabicyclo[2.2.1]heptan-3-amine (0.083 g, 0.66 mmol) to afford the title compound (75 mg, 39%) as a white solid.

11-1 NMR (400 MHz, DMSO-d6) 5 7.96 (d, J = 6.8 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.07 (d, J= 8.7 Hz. 2H), 6.69 (s. 1H), 3.87 (s. 3H), 3.82 (s, 3H), 3.55 (d, J= 3.5 Hz, 1H), 2.75 (t, I = 8.9 Hz, 1H), 2.58 (q, J = 6.7 Hz, 3H), 2.43 (d, J = 4.4 Hz, 1H), 2.31 (d, 1= 11.1 Hz, io 1H), 2.13 (d, J = 9.5 Hz. 1H). 1.50 (m, J = 5.6 Hz, 1H), 1.08 (t, J = 11.7 Hz, 1H). MS ES+: 327.32.

Example 14: 5-(4-M ethox yphen y1)-1-methyl-N-(9-methy1-9-azab cyclo[3.3.1 J non an-3-y1)-1H-pyrazole-3-calboxamide To a stirred solution of 5-(4-methoxypheny1)-1-methyl-1H-pyrazole-3-cuboxylic acid (Intermediate 1) (0.15 2, 0.646 mmol) in DCM (5 mL) at 0°C, oxalyl chloride (0.164 2, 0.129 mmol) was added under nitrogen. After stirring at 0°C for 5 min, the reaction mixture was stirred at RT for 1 hr. Solvents were removed under reduced pressure to give a residue, which was dissolved in DMF (5 mL) under nitrogen at 0°C. 9-Methy1-9-azabicyclo13.3.1inonan-3-amine (0.109 g, 0.71 mmol) and triethylamine (0.195 g, 0.193 mmol) were added and stirred at RT for 16h. Saturated sodium bicarbonate solution was added and the product extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. The crude product was purified

IN 1,N

by Grace purifier using a gradient elution of 5-8% methanol in DCM to afford the title compound (55 mg, 17%) as a pale brown solid.

IFI NMR (400 MHz, DMSO-d6) 87.77 (d, J= 9.1 Hz, 1H), 7.48 (q, J= 2.9 Hz, 2H), 7.07 (q, J = 2.9 Hz, 2H), 6.67 (s, 1H), 4.30 (m, J = 4.3 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.95 (d, J= 11.0 Hz, 2H), 2.40 (s, 3H), 2.11 (m, J= 6.0 Hz, 3H), 1.88 (m, J= 4.3 Hz, 2H), 1.46 (m, J= 8.1 Hz, 3H), 0.89 (d, J= 12.4 Hz, 2H). MS ES': 369.24.

Example 15: 5-(4-Methoxypheny1)-1-methyl-N-(2-morpholinoethyl) -1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 544-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 1) (0.25 g, 1.07 mmol) and 2-morpholinoethanamine (0.154 g, 1.18 mmol) to afford the title compound (50 mg, 17%) as a white solid.

11-1 NMR (400 MHz, DMSO-d6) 6 7.99 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.8 Is Hz, 2H), 6.68 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.58 (s, 4H), 3.37 (s, 2H), 2.41 (s, 6H).

MS ES': 345.42.

Example 16: 1-Methyl-N-(1-methylpiperidin-4-y1)-5-(4-(trifluoromethyl)pheny1) -1Hpyrazole-3-carboxamide Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.2 g, 0.7 mmol) and 1-methylpiperidin-4-amine (0.092 g, 0.8 mmol) to afford the title compound (120 mg, 44%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.94 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.82 (d, J= 8.2 Hz, 2H), 6.89(s, 1H), 3.94(s, 3H), 3.72(m, J= 7.0 Hz, 1H), 2.74(d, J= 11.4 Hz, 21-0, 2.15 (s, 3H). 1.93 (d, J= 2.4 Hz, 2H). 1.66 (q. J= 6.2 Hz, 4H). MS ES': 367.17.

Example 17: 1-Methyl-N-(0-methylpiperidin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl) -1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.2 g, 0 7 mmol) and (1-methylpiperidin-2-10 yl)methanamine (0.092 g, 0.8 mmol) to afford the title compound (60 mg, 24%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 67.88 (d. J = 8.3 Hz, 2H). 7.83 (d. J= 8.3 Hz, 2H). 7.76 (s. 1H), 6.89 (s, 1H), 3.95 (s. 3H). 3.47 (rn, J = 3.3 Hz, 1H), 3.27 (d, J = 5.5 Hz, 1H), 2.78 (d, J= 11.4 Hz, 1H), 2.25 (s, 3H), 2.04 (d, J= 10.8 Hz, 2H), 1.66(d. J= 12.1 Hz, 1H), Is 1.50(m, J= 15.8 Hz, 3H), 1.25(q, J= 10.6 Hz, 2H). MS ES': 381.32.

The enantiomers were separated by SEC-prep. Preparative SEC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example 17A: Isomer 1 1H NMR (400 MHz, DMSO-d6) 6 7.85 (d. J = 8.2 Hz, 2H). 7.78 (d. J = 8.1 Hz, 2H). 7.76 ns (s, 1H), 6.76 (s, 1H), 3.91 (s, 3H), 3.52 (s, 2H), 3.19 (d, J= 15.8 Hz, 3H), 2.92 (d, J= 10.9 Hz, 1H). 2.80 (d, J = 6.9 Hz, 1H), 2.47 (d, J = 11.7 Hz, 1H), 1.70 (d, J = 25.3 Hz, 1H), 1.57 (d, J= 11.8 Hz, 1H), 1.48 (s, 1H), 1.29 (q, J= 10.5 Hz, 2H), 1.06 (d, J= 1.6 Hz, 1H).

Example 17B: Isomer 2 NMR (400 MHz, DMSO-d6) ö 7.88 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.76 (s, 1H), 6.89 (s, 1H), 3.95 (s, 3H), 3.48 (m, J= 3.3 Hz, 1H), 3.26 (q, J= 4.4 Hz, 1H), 2.79 (d, J= 10.4 Hz, 1I-0, 2.25 (s, 3H), 2.06 (s, 2H), 1.59 (tn, J= 11.6 Hz, 31-I), 1.41 (d. J = 11.2 Hz, 1H), 1.23 (m, J = 10.9 Hz, 2H).

Example 18: 1-Methyl-N-(2-(1-methylpiperidin-3-yl)ethyl)-5-(4-(trilluoromethyl)phenyl) -1H-pyrazole-3-carboxamide F 3C Prepared as described for Example 1 using 1-methy1-5-(4-(trifluoromethyl)phcnyl)-1H10 pyrazole-3-carboxylic acid (Intermediate 2) (0.15 g, 0.55 mmol) and 2-(1-methylpiperidin-3-yl)ethanamine (0.12 g, 0.605 mmol) to afford the title compound (0.035 mg, 16%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 3 8.17 (t, J = 5.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 3.94 (s, 3H), 3.25 (q, J = 6.7 Hz, 2H), 2.68 (1, J = 15.3 Hz, 2H), 2.12 (s, 3H), 1.730. J= 18.3 Hz, 2H), 1.48 (m, J= 8.7 Hz, 6H), 0.81 (d, J= 7.5 Hz, Ill). MS ES': 395.1.

Example 19: 1-Methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-(4-(trifluoromethyl) phenyl) -1H-pyrazole-3-carboxamide Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethy1)pheny1)-1Hpyrazolc-3-carboxylic acid (Intermediate 2) (0 2 g 0 7 mmol) and 2-(1-methylpyrrolidin3-yflethanamine (0.092 g, 0.8 mmol) to afford the title compound (30 mg, 22%) as a white solid.

11-1 NMR (400 MHz, DMSO-d6) 6 8.20 (s, 1H), 7.85 (q, J = 10.0 Hz, 4H), 6.88 (s, 1H), 3.94 (s, 3H), 3.21 (d, J = 6.5 Hz, 2H), 2.64 (q, J = 6.9 Hz, 1H), 2.44 (d, J = 8.4 Hz, 1H), 2.32 (q, J = 7.6 Hz, 11-1), 2.20 (s. 3H), 1.99 (m, J = 8.0 Hz, 3H), 1.55 (t, J = 7.0 Hz, 2H). 1.33 (q, J = 6.7 Hz, 1H). MS ES': 381.1.

Example 20: 1-Methyl-N-((1-methylpynolidin-2-yemethyl)-5-(4-(trifluoromethyl)phenyl) -1H-pyrazole-3-carboxamide F3C NrciN Prepared as described for Example 1 using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1H- pyrazole-3-carboxylic acid (Intermediate 2) (0.15 g 0 55 mmol) and (1-methylpyrrolidin- 2-yl)methanamine (0.12 g, 0.605 mmol) to afford the title compound (0.035 mg, 16%) as an off-white solid. MS ES': 367.26.

Example 20A: Isomer 1 NMR (400 MHz, DMSO-d6) 6 7.88 (d. J = 8.3 Hz, 2H). 7.83 (d. J = 8.2 Hz, 3H). 6.89 (s, 1H), 3.94 (s, 3H), 3.49 (m, J = 3.4 Hz, 1H), 3.13 (m, J = 4.0 Hz, 1H), 2.96 (q, J = 4.8 Hz, 1H). 2.30(s, 4H), 2.13 (q, J= 8.6 Hz, 1H), 1.80(m, J= 3.5 Hz, 1H), 1.58 (m, J= 4.6 H7, 3H).

Example 20B: Isomer 2 H NMR (400 MHz, DMSO-d6) 6 7.88 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.2 Hz, 3H), 6.89 (s, 114), 3.94 (s. 3H), 3.49 (in, J= 3.4 Hz. 1H), 3.14 (m, J= 4.9 Hz, 114), 2.974 J= 4.8 Hz, 1H). 2.31 (s. 4H), 2.14 (d, J = 8.4 Hz, 1H), 1.79 (m, J = 4.4 Hz, 1H), 1.59 (m, J = 5.1 Hz, 3H).

Example 21: 1-Methyl-N-((l-methylpiperidin-3-yl)methyl) 5 (4 (trifluoromethyl)pheny1)-1H-pyrazole-3-carboxami de F3C Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.15 g 0 55 mmol) and (1-methylpiperidin3-yl)methanamine (0.11 g, 0.605 mmol) to afford the title compound (0.100 g, 50%) as pale brown solid.

4-1 NMR (400 MHz, DMSO-d6) 68.20 (t, J= 6.0 Hz, IF1), 7.88 (d, J= 8.3 Hz, 21-1), 7.83 (d, J = 8.3 Hz, 2H), 6.89 (s, 1H), 3.94 (s, 3H), 3.12 (m, J = 5.6 Hz, 2H), 2.63 (m, J = 8.5 Hz, 2H), 2.11 (s, 3H), 1.81 (m, J= 5.2 Hz, 2H), 1.59 (t, J= 10.2 Hz, 3H), 1.39(q, J= 8.8 Hz, 1H), 0.88 (d. J = 9.2 Hz, 1H). MS ES': 381.2.

Example 2IA: Isomer 1 11-1 NMR (400 MHz, DMSO-d6) 68.20 (t, J= 6.1 Hz. 1H), 7.88 (d. J= 8.4 Hz, 2H), 7.83 (d, I = 8.2 Hz, 2H). 6.89 (s, 1H), 3.94 (s, 3H), 3.12 (m, I = 5.1 Hz, 2H). 2.63 (m, J = 8.6 Hz, 2H), 2.11 (s, 3H), 1.81 (q, J= 7.2 Hz, 2H), 1.590. J= 10.4 Hz, 3H), 1.41 (m, J= 5.1 Hz, 1H), 0.88 (q. J = 10.4 Hz, 1H).

Example 21B: Isomer 2 NMR (400 MHz, DMSO-d6) 68.16 (t, J= 5.7 Hz, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 3.94 (s, 3H), 3.12 (in, J = 7.1 Hz, 2H), 2.62 (m, J = 8.7 Hz, 2H), 2.12 (s. 3H), 1.81 (in, J= 6.7 Hz, 2H), 1.60 (t, J= 10.0 Hz, 3H), 1.41 (q, J= 3.9 Hz, 1H), 0.89 (d, J = 9.0 Hz, 1H).

Example 22: 1-Methyl N (1 methylpiperidin 3 yl) 5 (4 (trilluoromethyl)pheny1)-1Hpyrazole-3-carboxamide F3C cN---- Prepared as desciibed for Example 1 using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylic acid (Intermediate 2) (0.2 g 0 7 mmol) and 1-methylpiperidin-3-amine (0.092 g, 0.8 mmol) to afford the title compound (120 mg, 48%) as a white solid. 11-1 NMR (400 MHz, DMSO-d6) 6 8.29(s, 1H), 7.89 (d, J= 8.3 Hz, 2H), 7.83 (d, J= 8.3 Hz, 2H), 6.93 (s, 1H), 4.13 (s, 1H), 3.96 (s, 3H), 3.16 (s, 2H), 2.67 (s, 5H), 1.74 (q, J = lo 26.9 Hz, 4H). MS ES: 367.99.

Example 22A: Isomer 1 1I-1 NMR (400 MHz, DMSO-d6) 37.88 (d, J= 8.3 Hz, 2H), 7.81 (1, J= 10.0 Hz, 3H), 6.90 (ti, 1H). 3.94(s, 4H), 2.58 (d, J= 9.4 Hz. 1H), 2.42 (d, J= 7.5 Hz, I H), 2.17 (s, 3H), 2.09 (s, 2H), 1.63 (d, J = 6.0 Hz, 2H). 1.49 (t, J = 8.5 Hz, 2H).

Example 22B: Isomer 2 NMR (400 MHz, DMSO-d6) 37.88 (d, J = 8.3 Hz, 2H). 7.81 J = 9.7 Hz, 3H). 6.90 (s, 1H). 3.94 (s. 4H), 2.59 (s. 1H), 2.44 (s. 1H), 2.17 (s, 3H), 2.09 (s, 2H), 1.63 (d, J = 5.8 Hz, 2H), 1.48 (d. J = 8.2 Hz, 2H).

Example 23: 1-Methyl-N4241-methylpiperidin-2-yDethyl)-544-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethyppheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.2 g, 0.7 mmol) and 2-(1-methylpiperidin2-yflethanarnine (0.092 g, 0.8 mmol) to afford the title compound (70 mg, 35%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 8.37 (t, J = 5.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.83 (d, J= 8.2 Hz, 2H), 6.89 (s, 1H), 3.95 (s, 3H), 3.19 (d, J= 9.8 Hz, 3H), 2.79 (t, J= 6.4 Hz, 2H), 2.65 (q, J= 6.3 Hz, 3H), 1.92 (m, J= 10.3 Hz, 2H), 1.67 (m, J= 8.7 Hz, 41-1), 1.38 (t, J = 9.8 Hz, 2H). MS ES': 395.34.

The enantiomers were separated by SEC-prep. Preparative SEC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 emin; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example 23A: Isomer 1 -LH NMR (400 MHz, DMSO-d6) 6 8.24 (t, J = 5.9 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.82 (d, J= 8.2 Hz, 2H), 6.87 (s, 1H), 3.94 (s, 3H), 3.26 (t, J= 7.8 Hz, 2H), 2.77 (d, J= 11.3 Hz, 1H), 2.21 (s, 3H), 1.98 (t, J= 12.3 Hz, 2H), 1.65 (m, J= 8.5 Hz, 4H), 1.46 (t, J= 15.0 Hz, 2H), 1.25 (m, J = 7.7 Hz, 2H).

Example 23B: Isomer 2 1I-1 NMR (400 MHz. DMSO-d6) 6 8.24 (t, J = 5.7 Hz, 1H). 7.88 (d. J = 8.3 Hz. 2H), 7.82 (d, J= 8.2 Hz, 2H). 6.87 (s. 1H), 3.94(s. 3H). 3.26(q, J= 5.1 Hz, 2H). 2.78 (d, J= 10.4 Hz, 1H), 2.22(s, 3H), 2.01 (d, J= 9.8 Hz, 2H), 1.66(m. J= 9.1 Hz, 4H), 1.46 (t, J= 15.2 Hz, 2H), 1.26 (m, J= 8.3 Hz, 2H).

Example 24: 1-Methyl-N-(2-(1-methylpyrrolidin-3-yl)ethyl)-5-(4-(trifluoromethyl) phenyl) -1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1 H5 pyrazolc-3-carboxylic acid (Intermediate 2) (0.15 g, 0.55 mmol) and 241-methylpyn-olidin-3-ypethanamine (0.12 g, 0.605 mmol) to afford the title compound (0.035 M2, 16%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 68.27 (t, J= 5.9 Hz, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 6.87 (s, 1H), 3.94 (s, 3H), 3.26 (m, J = 4.7 Hz, 2H), 2.93 (m, J = 3.1 Hz, 1H), 2.20 (s, 3H), 2.04 (m, J = 4.0 Hz, 2H), 1.88 (m, J = 4.5 Hz, 2H), 1.61 (m, J = 4.2 Hz, 2H), 1.43 (m, J= 4.3 Hz, 2H). MS ES': 381.32.

Example 25: 1-Meth yl-N-((l-methylpyrrol idi n-3-y1) methyl)-5-(4 -(tri fl uoro methyl)phenyl) -1H-pyrazole-3-carboxainide F 3 C -CN Prepared as described for Example 1 using 1-methy1-5-(4-(trifluoromethyl)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.15 g 0 55 mmol) and (1-methylpyrrolidin3-yl)methanamine (0.10 g, 0.825 nunol) to afford the title compound (83 mg, 41%) as a pale yellow solid.

1E1 NMR (400 MHz, DMSO-d6) 68.27 (t, J= 5.8 Hz, 11-1), 7.88 (d, J= 8.3 Hz, 211), 7.83 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 3.94 (s, 3H), 3.21 (m, J = 6.2 Hz, 2H), 2.39 (m, J = 6.8 Hz, 4H), 2.26 (t, J= 3.9 Hz, 1H), 2.21 (s, 3H), 1.82 (t, J= 4.4 Hz, 1H), 1.46 (t, J = 6.3 Hz, 1H). MS ES': 367.1.

Example 26: N-((l-Ethylpiperidin-2-yl)methyl)-1-methyl-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethyppheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.2 g 07 mmol) and (1-ethylpiperidin-2-yl)methanamine (0.138 g, 0.8 mmol) to afford the title compound (140 mg, 71%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.85 (m, J = 7.6 Hz, 5H), 6.89 (s, 1H), 3.94 (s, 3H), 3.46 (m, J = 3.3 Hz, 1H), 3.26 (q, J = 4.3 Hz, 1H), 2.73 (m, J = 6.5 Hz, 2H), 2.53 (d, J = 7.3 Hz, 2H), 2.24 (q, J = 7.0 Hz, 1H), 1.58 (m, J= 7.6 Hz, 3H), 1.32 (in, J = 7.8 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H). MS ES': 395.41.

Example 27: 1-Methyl-N-(1-methylpynolidin-3-y1)-5-(4-(trifluoromethyl)pheny1) -1Hpyrazole-3-carboxamide F 3C Prepared as described for Example I using 1-methy1-5-(4-(tri fluoromethyl)pheny1)-1 H- pyrazolc-3-carboxylic acid (Intermediate 2) (0 2 g 0 7 mmol) and 1-methylpyrrolidin-3-amine (0.097 g, 0.8 mmol) to afford the title compound (52 mg, 39%) as a white solid.

11-1 NMR (400 MHz, DMSO-d6) 6 7.98 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 6.91 (s, 1H), 4.38 (m, J = 3.9 Hz, 1H), 3.94 (s, 3H), 2.63 (m, J = 4.2 Hz, 2H), 2.40(m, J= 5.4 Hz, 2H), 2.25(s, 3H), 2.13 (in, J= 4.3 Hz, 11-1), 1.74(m. J= 4.0 Hz, 1H). MS ES': 353.32.

Example 28: 1-M ethyl-N-(piperi di n-2-ylmethyl)-5-(4-(tri fluoro meth yl)phenyl)-1 pyrazolc-3-carboxamidc OH two steps F3C F3C Step 1: To a stirred solution of 1-methy1-5-(4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylic acid (Intermediate 2) (0.4 g, 1.5 mmol) in THF (5 mL), tert-butyl 2-(aminomethyl)piperidine-1 -carboxylate (0.35 g, 1.6 mmol) was added under nitrogen. HATU (0.84 g, 2.2 mmol) and DIPEA (0.59 g, 4 6 mmol) were then added and stirred at RT for 16h. The reaction mixture was diluted with water and extracted with DCM (2 x 30 mL) The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. The crude product was purified by Grace ptuffier using a gradient elution of 5-8% methanol in DCM to afford tert-butyl 2-( (1 -methyl-5-(4-(trifluoromethyepheny1)-1H-p yrazole-3-carboxamido)methyl)piperidine-1 -carboxylate (0.5 g, 68%) as a white solid. MS ES': 367.34.

Step 2: To a stirred solution of tert-butyl 24(1-methy1-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido) methyl)piperidine-1-carboxylate (0.5 g, 1.1 mmol) in 1,4-dioxane (5 nth) cooled to 0°C. was added HO in 1,4-dioxane and stirred for 2h at RT. Saturated sodium bicarbonate solution was added and the product extracted with ethyl acetate (2 x 20 mL) The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product, which was purified by Grace purifier using a gradient elution of 5-8% methanol in DCM to afford the title compound (0.21 g, 53%) as a white solid.

11-1 NMR (400 MHz, DMSO-d6) 5 8.02 (t, J = 5.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.83 (d, J= 8.2 Hz, 2H). 6.90(s, 1H), 3.95 (s. 3H), 3.18(m. J= 6.1 Hz, 2H). 2.93 (d. J= 11.2 Hz, 1H). 2.59 (t, J = 3.9 Hz, 1H). 2.46 (t, J = 5.8 Hz, 1H), 2.10 (s. 1H), 1.74 (d, J = 17.2 Hz, 1H), 1.52 (q, J= 13.3 Hz, 2H), 1.27 (t, J= 8.7 Hz, 2H), 1.04 (m, J= 5.3 Hz, 1H). MS ES': 367.33.

Example 29: 1-Methyl-N-(8-methy1-8-azahicyclo[3.2.1.1octan-3-y1)-5-(4- (trifluoromethyl) 30 pheny1)-1H-pyrazole-3-cmboxamide F3C Prepared as described for Example I using 1-methy1-5-(4-(trifluoromethy1)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 2) (0.1 g 04 mmol) and 8-methy1-8-azabicyclo[3.2.1joctan-3-amine (0.062 g.0.4 mmol) to afford the title compound (0.070 g, 50%) as a white solid. The product obtained was a mixture of diastercomers.

1H NMR (400 MHz, DMSO-d6, normalised) 6 7.92 -7.86 (m, 2H), 7.85-7.80 (m, 2H), 7.54 (d, J = 6.8 Hz, 1H), 6.90 (s, 1H), 4.15-4.05 (m, 1H), 4.02-3.95 (m, 1H), 3.95 (s, 3H), 3.203.02 (m, 2H), 2.15 (s, 3H), 2.10-1.90 (m, 3H), 1.85-1.63 (m, 3H), 1.60-1.50 (m, 1H). MS ES': 393.37.

Example 30: N-(1-Azabicyclo[2.2.1]heptan-3-y1)-1-methy1-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide F3C Prepared as described for Example 1 using 1-methyl-5-(4-(trifluoromethyl)phenyl)-1H- Is acid (Intermediate 2) (0.2 g, 0.74 mmol) and 1-azabicyclo[2.2.1]heptan-3-amine (0.097 g, 0.81 mmol) to afford the title compound (0.188 g, 84%) as an off-white solid.

-1H NMR (400 MHz, DMSO-d6) 6 8.05 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.82 (d, J= 8.2 Hz, 2H), 6.91 (s, 1H), 3.94 (s, 3H), 3.56 (q, J= 5.7 Hz, 1H), 2.76(m. J= 3.1 Hz, 1H), 2.58 (m, J= 5.0 Hz, 3H), 2.43 (d, J= 4.6 Hz, 1H), 2.31 (m, J= 3.7 Hz, 1H), 2.13 (d, J = 9.6 Hz, 1H), 1.50(m, J= 5.6 Hz, 1H), 1.09(q, J = 7.7 Hz, 1H). MS ES': 365.15.

Example 31: 5-(4-Isopropylpheny1)-1-methyl-N-(1-methylpiperidin-4-y1) -11J-pyrazolc-3-carboxamide Prepared as described for Example 1 using 5-(4-isopropylpheny1)-1-methy1-1H-pyrazole3-carboxylic acid (Intermediate 5) (0.2 g, 0 7 mmol) and 1-methylpiperidin-4-amine (0.102 g, 0.9 nunol) to afford the title compound (120 mg, 44%) as a white solid.

NMR (400 MHz, DMSO-d6) 6 7.88 (d, J = 8.2 Hz, 1H), 7.48 (q, J = 2.8 Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 6.72(s, 1H), 3.89 (s, 3H), 3.72 U. J =3.1 Hz, 1H), 2.96 (m, J= 6.9 Hz, 1H), 2.76 (d, J= 11.0 Hz, 2H), 2.18 (s, 3H), 1.98(s, 2H), 1.66(m. J= 6.8 Hz, 4H), 1.24 (d, J= 6.9 Hz, 6H). MS ES*: 341.1.

Example 32: 5-(4-Isopropylpheny1)-1-methyl-N-((1-methylpiperidin-2-y1)methyl) -1Hpyrazole-3-carboxamide Prepared as described for Example I using 5-(4-isopropylpheny1)-1-methy1-1H-pyrazo1e3-carboxylic acid (Intermediate 5) (0.2 2, 0.7 mmol) and (1-methylpiperidin-2-yl)methanamine (0.102g. 0.9 mmol) to afford the title compound (120 mg, 44%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.69 0, J = 5.6 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 6.72 (s, 1H), 3.89 (s, 3H), 3.46 (m, J = 3.3 Hz, 1H), 3.25 (m, J = 4.9 Hz, 1H), 2.96 (t, J = 6.9 Hz, 1H), 2.78 (d, J = 11.4 Hz, 11-1), 2.23 (s, 3H), 2.02 (m, J = 5.8 Hz, 2H), 1.66 (1, J = 6.1 Hz, 1H), 1.54 (q, J = 11.4 Hz, 2H), 1.43 (d, J = 3.6 Hz, 1H), 1.24 (d, J= 6.9 Hz, 8H). MS E51': 355.36 Example 33: 5-(2-Fluoropheny1)-1-methyl-N-0 1-methylpiperidin-2-yl)methyl)-1H-pyrazole-3-carboxamide Prepared as described for Example I using 5-(2-fluoropheny1)-1-tnethyl-1H-pyrazole-3-carboxylic acid (Intermediate 6) (0.25 g, 11 mmol) and (1-methylpiperidin-2-ye methanamine (0.1549 g, 1.21 mmol) to afford the title compound (66 mg. 17%) as a light brown solid.

11-1 NMR (400 MHz, DMSO-d6) 6 7.74 (t. J = 5.5 Hz, 1H), 7.57 (m. J = 2.6 Hz, 2H), 7.39 (m, J= 3.4 Hz, 2H), 6.76(s, 1H), 3.79 (d, J= 1.0 Hz, 3H), 3.47 (m, J= 3.3 Hz, 1H), 3.25 (m, J= 4.1 Hz. 1H), 2.78(d, J= 11.5 Hz, 1H), 2.24(s, 3H), 2.02 (m, J= 4.6 Hz, 2H), 1.66 (t. J = 5.9 Hz, 1H), 1.50 (m, J = 7.9 Hz, 3H). 1.23 (m, J = 5.6 Hz, 2H). MS ES*: 331.38.

Example 34: 5-(2,5-Dimethylpheny1)-1-methyl-N4(1-methylpiperidin-2-y1)methyl) -1Hpyrazole-3-carboxamide Prepared as described for Example I using 5-(2,5-climethylpheny1)-1-methy1-1 H-pyrazole3-carboxylic acid (Intermediate 7) (0.2 g, 0.65 mmol) and (1-methylpiperidin-2-y1) methanamine (0.107 g, 0.7 mmol) to afford the title compound (85 mg, 52%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.71 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 4.4 Hz, 1H), 7.10 (s, IFI), 6.59 (s, In). 3.64 (s, 3H), 3.46 (m, J = 3.3 Hz, 1H), 3.27 (s, 11-I).

2.79 (d, I = 8.2 Hz. 1H), 2.31 (s. 6H), 2.08 (s, 5H), 1.53 (m, I = 12.3 Hz, 4H), 1.26 (q. J = 9.8 Hz, 2H). MS ES*: 341.29.

Example 35: 5-(3-Fluoropheny1)-1-methyl-N-((1-methylpiperidin-2-y1)methyl) -1Hpyrazole-3-carboxamide N(N Prepared as described for Example I using 5-(3-fluorophenyI)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 8) (0.25 g, 11 mmol) and (1-methylpiperidin-2-ye methanamine (0.1549 g, 1.21 mmol) to afford the title compound (83 mg, 22%) as an off-s white gum. The product obtained was subjected to formation of the hydrochloride salt by stirring a solution of the product in dioxane (10 mL) with 4N HCI (2 ml) in dioxane at RT for 2h. Solvent was evaporated from the reaction mixture on a rotavapor, and the residue was subjected to lyophilization to afford the HC1 salt of the title compound as an off-white solid.

111 NMR (400 MHz, DMSO-d6) (at 90°C) 6 10.59 (d, J = 95.7 Hz, 1H), 8.20 (s, 1H), 7.54 (m, J= 3.2 Hz, 1H), 7.36(m, J= 1.7 Hz, 2H), 7.26(m, J= 2.3 Hz, 1H), 6.86(s, 1H), 3.90 (s, 3H), 3.76 U. J= 5.0 Hz, 1H), 3.57 (m, J= 6.1 Hz, 1H), 3.37 (d, J= 12.0 Hz, 1H), 3.18 (d. J = 25.8 Hz, 1H), 2.94 (d, J = 19.5 Hz. 1H). 2.86 (s, 3H), 1.82 (m, J = 22.1 Hz, 5H). 1.48 (t, J= 12.0 Hz, 1H). MS ES': 331.19.

Example 36: 5-(4-Fluoropheny1)-1-methyl-N-((1-meth ylpiperi di n-2-yl)methyl)-1 H-pyrazole-3-carboxamide Prepared as described for Example l using 5-(4-tluoropheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 9) (0.25 g, 11 mmol) and (1-methylpiperidin-2-y1) methanamine (0.1549 g, 1.21 mmol) to afford the title compound. The product obtained was subjected to formation of the TFA salt by stirring the compound in the presence of trifluoroacetic acid in dioxane and subsequent lyophilization to afford the title compound as TFA salt (94 mg, 25%) as a white solid.

NMR (400 MHz, DMSO-d6) 8 9.36 (s, 1H), 8.33 (s, 11-1), 7.63 (m, J = 2.8 Hz, 2H), 7.37 (t, J = 8.8 Hz, 2H), 6.80 (s, 1H), 3.90 (s, 3H), 3.52 (d, J = 4.8 Hz, 2H), 2.78 (s, 6H), 1.59 (m, 1= 13.5 Hz, 6H). MS ES': 331.40.

Example 37: 5-(4-Chloropheny1)-1-methyl-N-01-methylpiperidin-2-yl)methyl) -1Hpyrazolc-3-carboxamide

CI

Prepared as described for Example 1 using 5-(4-chloropheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 10) (0.15 g, 0.63 mmol) and (1-methylpiperidin-2-y1) methanamine (0.11 g, 0.95 mmol) to afford the title compound (0.023 g, 10%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 67.71 (t, J = 5.1 Hz, 1H), 7.60 (d, J = 4.4 Hz, 4H), 6.79 (s, 1H), 3.90 (s, 3H), 3.46 (m, I = 3.3 Hz, 1H), 3.25 (in, I = 4.9 Hz, 1H), 2.78 (d, I = 11.5 Hz, 1H), 2.23 (s, 3H), 2.01 (t, J= 11.6 Hz, 2H), 1.59 (m, J= 7.0 Hz, 3H), 1.39(m, J= 6.0 Hz, 2H), 1.194 J = 5.0 Hz, 1H). MS ES': 347.32.

Example 38: 5-(4-Chloropheny1)-1-methyl-N-01-methylpiperidin-4-yl)methyl)-1H15 pyrazole-3-carboxamide

CI

Prepared as described for Example 1 using 5-(4-chloropheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 10) (0.15 g, 0.63 mmol) and (1-methylpiperidin-4-y1) methanamine (0.11 g, 0.95 mmol) to afford the title compound (0.024 g, 11%) as an off-white solid.

11-1 NMR (400 MHz, DMSO-d6) 68.12 (t, J= 6.0 Hz, 1H), 7.59 (d, J= 4.2 Hz, 4H), 6.78 (s, 1H), 3.89 (s, 3H), 3.11 (t, J= 6.5 Hz, 2H), 2.73 (d, J= 11.4 Hz, 2H), 2.13 (s, 3H), 1.78 (t, J= 10.8 Hz, 2H), 1.59 (d, J= 12.5 Hz, 2H), 1.49 (m, J= 3.7 Hz, 1H), 1.15 (m, J = 6.0 Hz, 2H). MS ES': 347.1.

Example 39: 5-(4-Chloropheny1)-1-methyl-N-01-methylpiperidin-3-yl)methyl) -1Hpyrazole-3-carboxamide

CI

Prepared as described for Example 1 using 5-(4-chloropheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 10) (0.2 g, 1 eq) and (1-methylpiperidin-3-yl)methanamine (0.15 g, 1.5 eq) to afford the title compound (0.046 g, 21%) as an off-white solid.

1-H NMR (400 MHz, DMSO-d6) 68.16 (t, J= 6.1 Hz, 1I-1), 7.61 (q, J= 4.5 Hz, 411), 6.79 (s, 1H), 3.90 (s, 3H), 3.11 (q, J = 7.4 Hz, 2H), 2.61 (t, J = 9.7 Hz, 2H), 2.11 (s, 3H), 1.81 (q, J = 7.1 Hz, 2H), 1.59 (t, J = 10.1 Hz, 3H), 1.39(m, J= 6.6 Hz, 1H), 0.87(d, J= 9.4 Hz, 1H). MS ES': 347.34.

Example 40: 5-(4-Chloro-3-fluoropheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -114-pyrazole-3-carboxamide

CN N,N Cl

Prepared as described for Example 1 using 5-(4-chloro-3-fluoropheny1)-1-methy1-1Hpyrazole-3-carboxylic acid (Intermediate 11) (0.20 g, 0.787 mmol) and I -methylpiperidin-3-amine (0.098 g, 0.866 mmol) to afford the title compound (0.130 g, 47%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 6 7.77 (d, J = 7.6 Hz, 1H), 7.74-7.70 (m, 2H), 7.47-7.44 (dd. J = 1.2 Hz and 8.0 Hz, 1H), 6.87 (s, 1H), 3.96 (hr s, 1H), 3.93 (s, 3H), 2.60-2.53 (m, 1H), 2.45-2.35 (m, 1H), 2.17 (s, 3H), 2.15-2.03 (m, 2H), 1.67-1.55 (m, 2H), 1.53-1.44 (in, 2H). MS ES': 351.35.

Example 41: 5-(3-Fluoro-4-methoxyphen y1)-1-methyl-N-(1-methyl p peridi n-3 -y1)-1Hpyrazolc-3-carboxamide

N

Prepared as described for Example I using 5-(3-fluoro-4-methoxypheny1)-1-methy1-1Hpyrazole-3-carboxylic acid (Intermediate 12) (0.2 g) and (1-methylpiperidin-3-y1) methanamine (0.15 g) to afford the title compound. The product obtained was subjected to MCI salt formation to afford the title compound as MCI salt (0.1 g, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 10.26 (s, 1H), 8.52-8.35 (m, 1H), 7.53-7.48 (dd. J = 2.0 Hz and 12.0 Hz, 1H), 7.38-7.28 (in, 2H), 6.93-6.78 (m, 1H), 4.45-4.18 (m, 1H), 3.91 (m, 6H), 3.45-3.35(m, 2H), 2.95-2.75(m, 5H), 1.95-1.75(m, 3H), 1.65-1.55 (m, 1H). MS ES': 347.56.

Example 42: 5-(3-Chloro-4-fluoropheny1)-1-methyl-N-((1-methylpiperidin-4-yl)methyl) -1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 1H- acid (Intermediate 13) (0.2 2, 0.79 mmol) and (1-methylpiperidin- 4-yl)methanamine (0.120 g, 0.94 mmol) to afford the title compound (0.13 g, 45%) as an off-white solid.

II-1 NMR (400 MHz, DMSO-d6) 68.13 (t, J= 6.1 Hz, 1H), 7.86 (q, J= 3.0 Hz, 1H), 7.58 (m, J= 4.3 Hz, 2H), 6.81 (s, 1H), 3.89 (s, 3H), 3.11 (t, J= 6.5 Hz, 2H), 2.72 (d, J= 11.5 Hz, 2H), 2.12(s, 31-1), 1.77 (t, J= 10.7 Hz, 21-1), 1.58 (d, J= 12.7 Hz, 2H), 1.484 J= 3.7 Hz, 1H), 1.16(m, J= 5.5 Hz, 2H). MS ES': 365.15.

Example 43: 5-(3-Chloro-441 uoropheny1)-1-methyl-N-((l-methylpiperi di n-3-yl)meth y1)-1H-pyrazole-3-carboxamide

CI

Prepared as described for Example 1 using 5-(3-c h I oro-4-fluorophen yI)-1-methyl -1 Hpyrazole-3-carboxylic acid (Intermediate 13) (0.2 g, 0.78 mmol) and (1-methylpiperidin3-yl)methanamine (0.120 2, 0.93 mmol) to afford the title compound (0.1 2, 48%) as a white solid.

NMR (400 MHz, DMSO-d6) 6 8.16 (t, J = 6.0 Hz, 1H), 7.86 (q, J = 3.0 Hz, 1H), 7.58 (m, J = 4.7 Hz, 2H), 6.82 (s, 1H), 3.90 (s, 3H), 3.12 (m, J = 7.2 Hz, 2H), 2.62 (q, J = 10.3 Hz, 2H), 2.11 (s, 3H), 1.81 (t, J= 10.4 Hz, 2H), 1.59 (1, J= 10.3 Hz, 3H), 1.40 (q, J= 3.9 Hz, 1H), 0.87 (d, J =9.0 Hz, 1H). MS ES: 365.46.

Example 44: 5-(3-Fluoro-4-methoxypheny1)-1-methyl-N-((1-methylpiperidin-4-yl)methyl) -1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(3-fluoro-4-methoxypheny1)-1-methy1-1H- pyrazole-3-carboxylic acid (Intermediate 12) (0.2 g, 0.8 mmol) and (1-methylpiperidin-4-yl)methanamine (0.11 2, 1.2 mmol) to afford the title compound (0.118 2, 41%) as a pale yellow solid.

NMR (400 MHz, DMSO-d6) 68.10 (t, J= 6.1 Hz, 1H), 7.49 (q, J= 4.8 Hz, 1H), 7.35 (m, J= 2.7 Hz, 1H), 7.29 (t, J= 8.7 Hz, 1H), 6.73 (s, 1H), 3.89 (d, J= 5.8 Flt, 6H), 3.11 (1, J= 6.5 Hz, 2H), 2.72(d, J= 11.4 Hz, 2H), 2.12(s, 3H), 1.77 (m, J = 5.7 Hz, 2H), 1.58 (d, J= 12.8 Hz, 2H), 1.48 (q, J = 3.6 Hz, 11-1), 1.16 (tn, J = 5.5 Hz, 2H). MS ES: 361.10.

Example 45: 5-(3-Fluoro-4-methox yphcn y1)-1-meth yl-N-((l-meth ylpiperi di n-3-yl)methyl)-1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(3-fluoro-4-methoxypheny1)-1-methy1-1Hpyrazole 3 carboxylic acid (Intermediate 12) (0.20 2 079 mmol) and (1-methylpiperidin3-yl)rnethanamine (0.130 g, 0.96 rnmol) to afford the title compound (110 mg, 38%) as a white solid.

IFI NMR (400 MHz, DMSO-d6) 58.13 (t, J= 6.1 Hz, 1H), 7.49 (q, J= 4.8 Hz, 1H), 7.36 (m, J= 2.7 Hz, 1H), 7.290. J= 8.7 Hz, 1H), 6.73 (s, 1H), 3.90(d. J= 4.5 Hz, 6H), 3.11 (q, J = 7.4 Hz, 2H), 2.65 (q, J = 5.5 Hz, 2H), 2.11 (s, 3H), 1.80 (q, J = 9.3 Hz, 2H), 1.59 (t, J = 10.6 Hz, 3H), 1.39 (q, J= 8.3 Hz, 1H), 0.87(q. J= 10.6 Hz, 1H). MS ES': 361.20.

Example 46: 5-(2-E1 uoro-4-methox yphen yl)-1-meth yl-N-((l-meth yl piped din-4-yl)methyl)-1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(2-fluoro-4-methoxypheny1)-1-methy1-1Hpyrazole-3-carboxylic acid (Intermediate 14) (0.12 g) and (1-methylpiperidin-4-yl)methanamine (0.11 g) to afford the title compound (0.120g. 95%) as an off-white solid.

The product obtained was subjected to HC1 salt formation using 4N HC1 in clioxane and was subsequently lyophilized to give an off-white solid.

NMR (400 MHz, DMSO-d6) 6 9.52 (s, 1H), 8.33 (t, J = 6.1 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.04 (q, J = 4.9 Hz, 1H), 6.94 (q, J = 3.7 Hz, 1H), 6.69 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.39 (d, J= 11.3 Hz, 2H), 3.15 (q, J= 5.6 Hz, 2H), 2.87 (q, J= 11.2 Hz, 2H), 2.71 (d, J= 4.4 Hz, 3H), 1.81 (t, J= 12.7 Hz, 3H), 1.384 J= 13.0 Hz, 21-1). MS ES': 397.20.

Example 47: 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-(2-(1-methylpyrrolidin-2-yflethyl) -1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(2-fluoro-4-methoxypheny1)-1-methy1-1Hpyrazole 3 carboxylic acid (Intermediate 14) (0.25 g) and 2-0-methylpyrrolidin-2-yflethanamine (0.125 g) to afford the title compound (0.18 g, 45%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 8.25 (t, J = 5.7 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.04 (q, J= 4.9 Hz, 1H), 6.94 (q, J= 3.7 Hz, 1H), 6.67 (s, 1H), 3.84(s, 3H), 3.76(d, J= 0.8 Hz, 3H), 3.26 (q, J= 5.3 Hz, 2H), 3.03 (s, 1H), 2.10 (m, J= 30.3 Hz, 7H), 1.67 (s, 2H), 1.46(d. J = 4.6 Hz, 2H). MS ES': 361.20.

Example 48: 5-(2-F1 uoro-4-methox yphen yl)-1-meth yl-N-((l-meth yl piped din-2-yl)meth y1)-1H-pyrazole-3-carbo x amide Prepared as described for Example I using 5-(2-11uoro-4-methoxypheny1)-1-methy1-1Hpyrazole-3-carboxylic acid (Intermediate 14) (0.12 g 077 mmol) and (1-methylpiperidin2-yl)methanamine (0.120 g, 0.93 mmol) to afford the title compound (0.120 g, 95%) as an off-white solid. The product obtained was subjected to HC1 salt fo -illation and was subsequently lyophilized to give an off-white solid.

11-1 NMR (400 MHz, DMSO-d6) 6 9.90-9.70 (m, 1H), 8.55 (t, J = 6.2 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.08-7.02 (dd, J = 2.8 Hz, 12.4 Hz, 1H), 6.95-6.92 (dd, J = 2.4 Hz and 8.4 Hz, 1H), 6.75 (d, J= 4.6 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.65-3.15 (m, 4H), 3.05-2.95 (m, 11-I), 2.90-2.70 (m, 314), 1.95-1.40 (m, 6I1). MS ES*: 361.1.

Example 49: 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-(1 lethylpiperidin-3-y1)-114-pyrazole-3-carboxamide Prepared as described for Example I using 5-(2-11uoro-4-methoxypheny1)-1-methy1-1H- pyrazole-3-carboxylic acid (Intermediate 14) (0.12 g, 0.48 mmol) and 3-amino-1-methylpiperidine (0.065 g, 0.58 mmol) to afford the title compound (0.120 g, 95%) as an off-while solid. The product obtained was subjected to HC1 salt fo -illation and was subsequently lyophilized to give an off-white solid 1H NMR (400 MHz, DMSO-d6) 6 9.94 (s. 1H), 8.40 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.06-7.03 (dd, J = 2.4 Hz and 12.0 Hz, 1H), 6.96-6.93 (dd, J = 2.4 Hz and 8.4 Hz, 1H), 6.73 (s, 1H), 4.30-4.10 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.45-3.30 (m, 2H), 3.002.80 (in, 5H), 1.90-1.55 (m, 4H). MS ES': 383.18.

Example 50: 5-(2-E1 uoro-4-(trilluorometh yl)phen y1)-1-methyl-N-( 1-meth yl piperidin-3-y1)-1H-pyrazol e-3-c arbo xami de F3C Prepared as described for Example 1 using 5-(2-fluoro-4-(trilluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 4) (0.2 g, 0.69 mmol) and 1-methylpiperidin-3-amine (0.088 g, 0.75 mmol) to afford the title compound (0.063 g, 38%) as an off-white solid 1T1 NMR (400 MHz, DMSO-d6) 87.94 (d, J= 9.1 Hz, 1H). 7.79 (m, J= 6.2 Hz. 3H). 6.88 (d, J = 0.5 Hz, 1H), 3.98 (t. J = 4.1 Hz, 1H), 3.83 (d, J = 1.0 Hz, 3H). 2.61 (s. 2H), 2.14 (t. J = 23.3 Hz, 5H), 1.65 (d. J = 6.0 Hz, 2H). 1.50(i, J = 9.1 Hz, 2H). MS ES': 385.

The enantiomers were separated by SEC-prep. Preparative SEC Conditions: Column/dimensions: LUX Cellulose-2 (30tnna x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example 50A: Isomer 1 11-INMR (400 MHz, DMSO-d6) 87.94 (d, J = 9.20 Hz, 1H), 7.82 (t, J = 7.20 Hz, 1H), 7.77 (d, J = 1.20 Hz, 1H), 7.75 (d, J = 1.20 Hz, 1H), 6.88 (s, 1 H), 3.97-3.97 (m, 1H), 3.83 (s. 3H), 2.51-2.61 (m, 1H). 2.49-2.50 (m. 1H), 2.09-2.11 (m. 5H). 1.65 (d, I = 6.00 Hz, 2H), 1.48-1.50 (m, 2H). SORIct120589: +10.30 (0.1% in acetonitrile). Off-white solid. MS ES': 385.37.

Example 50B: Isomer 2 NMR (400 MHz, DMSO-d6) 6 7.94 (d, J = 9.20 Hz, 1H), 7.82 (t, J = 7.20 Hz, 1H), 7.77 (d, J = 1.20 Hz, 1H), 7.75 (d, J = 1.20 Hz, 1H), 6.88 (s, 1H), 3.97-3.97 (m, 1H).3.83 (s, 3H), 2.51-2.61 (in, 1H). 2.49-2.50 (m. 1H), 2.09-2.11 (m. 5H). 1.65 (d, I = 6.00 Hz, 2H), 1.48-1.50 (m, 2H). White solid. MS ES: 385.38.

Example 51: 5-(2-Fluoro-4-(trilluoromethyl)phen y1)-1-methyl-N-((1-meth yl piped din-2-yl)methyl)-1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 4) (0.2 g, 0.69 mmol) and (1-methylpiperidin-2-yl)methanamine (0.098 2, 0.75 mmol) to afford the title compound (0.140 g, 56%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 6 7.94 (d, J = 8.9 Hz, 1H), 7.79 (m, J = 5.4 Hz, 3H), 6.87 (d, J = 0.6 Hz, 1H), 3.83 (d, J = 1.0 Hz, 3H), 3.47 (m, J = 3.3 Hz, 1H), 3.24 (t, J = 5.6 Hz, 1H), 2.77 (d, J = 11.6 Hz, 1H), 2.24 (s, 3H). 2.04 (m, J = 4.6 Hz, 2H), 1.54 (m, J = 8.6 Hz, 4H), 1.23 (in, J = 5.5 Hz, 211). MS ES': 399.

Example 52: 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(2- (1-methylpyrrolidin2-yDethyl)-1H-pyrazole-3-carboxamide F3C Prepared as described for Example 1 using 5-(2-11uoro-4-(trilluoromethyl)pheny1)-1- methy1-1H-pyrazole-3-carboxylic acid (Intermediate 4) (0.2 2, 0.69 mmol) and 2-(1-methylpyrrolidin-2-ypethanamine (0.109 g, 0.75 mmol) to afford the title compound (0.130 g, 42%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 68.30 (t, J= 5.8 Hz, 11-1), 7.93 (d, J= 9.5 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 6.85 (s, 1H), 3.83 (d, J = 0.8 Hz, 3H), 3.26 (m, J = 4.5 Hz, 2H), 2.93 (q, J = 4.2 Hz, 1H), 2.20 (s, 3H), 2.04 (m, J = 4.4 Hz, 2H), 1.89 (q, J = 16.9 Hz, 2H), 1.61 (m, J= 5.0 Hz, 2H), 1.42(n, J= 3.5 Hz, 2H). MS ES': 399.

Example 53: 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(2- (1-methylpiperidin2-yl)eth yl)-1H-p yrazole-3-carbo x amide F3C MI Prepared as described for Example 1 using 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 4) (0.2 2, 0.69 mmol) and 2-(1-methylpiperidin-2-yl)ethanamine (0.108 g, 0.75 mmol) to afford the title compound (0.130 g, 45%) as an off-white solid.

Is 11-1 NMR (400 MHz, DM5O-d6) 6 8.26 (t, J = 5.9 Hz, 1H), 7.93 (d, J= 10.0 Hz, 1H), 7.82 (t, J= 7.5 Hz, 1H), 7.76 (d, J= 8.0 Hz, 11-1), 6.84 (s, 11-1), 3.82 (d, J = 0.8 Hz. 31-1), 3.28 (d. J = 2.4 Hz, 2H), 2.75 (d, J = 11.0 Hz, 1H), 2.18 (s, 3H), 1.94 (m, J = 10.3 Hz, 2H), 1.65 (m, J = 5.0 Hz, 4H), 1.46(m, J = 7.3 Hz, 2H), 1.24(n, J = 4.9 Hz, 2H). MS ES': 413.

Example 54: 5-(2-Fluoro-4-(trifl uoro meth yl)phen y1)-1-meth yl-N-((l-meth yl p peri di n-3-yl)methyl)-1H-pyrazolc-3-carboxamidc F3C To a stirred solution of 5-(2-fluoro-4-(trifluoromethyl)phcny1)-1-methyl-1H-pyrazolc-3-carboxylic acid (Intermediate 4) (1.0 g, 3.47 mmol) in THE (25 mL), D1PEA (2 mL, ns 10.41 mmol) and HATU (2.1 g, 5.5 mmol) were added and stirred at RT for 15 min. Then (1-methylpiperidin-3-yl)methanamine (0.721 g, 5.5 mmol) was added and stirred at RT for 16h under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (3 x 30 mL) The organic layer was washed with ice cold water (3 x 30 ml), dried over sodium sulphate and concentrated under vacuum. The crude product obtained was purified by prep HPLC using ammonium bicarbonate buffer.

The enantiomers were separated by SEC-prep. Preparative SEC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total io Flow: 90.0 emin; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example MA: Isomer 1

NMR (400 MHz, DMSO-d6) 6 8.23 (t, J = 6.0 Hz, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.83 OM 1H). 7.76 (d, J= 8.0 Hz, I H), 6.86 (s, IF1), 3.83 (s, 311), 3.20-3.05 (m, 21-1), 2.70-2.55 (m, 211), 2.11 (s, 3H), 1.85-1.70 (m, 2H), 1.65-1.55 (m, 3H), 1.55-1.35 (m, 1H), 0.92-0.85 (m, 1H). MS ES': 399.29.

Example 54B: Isomer 2 II-1 NMR (400 MHz, DMSO-d6) 6 8.24 (t, J = 6.0 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.83 (d, J= 7.6 Hz. I H), 7.76 (d, J= 7.6 Hz, 1H). 6.86 (s. 1H), 3.83 (s. 3H), 3.20-3.05 (m, 2H). 2.70-2.55 (m, 2H), 2.11 (s. 3H), 1.85-1.70 (m, 211), 1.65-1.55 (m, 311), 1.48-1.35 (m, 11-I). 0.98-0.80 (m, 111). MS ES: 399.25.

Example 55: 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-4-yl)methyl)-1H-pyrazole-3-carboxamide F 3 C Prepared as described for Example l using 5-(2-11uoro-4-(trilluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 4) (0.2 g, 0.69 namol) and (1-methylpiperidin-4-yl)methanamine (0.098 2, 0.75 mmol) to afford the title compound (0.120 g, 38%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 68.21 (t, J= 6.1 Hz, 11-1), 7.93 (d, J= 9.9 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 6.86 (s, 1H), 3.83 (d, J = 0.8 Hz, 3H), 3.12 (t, J= 6.5 Hz, 2H), 2.72(d, J= 11.4 Hz, 2H), 2.12(s, 3H), 1.78 (1, J= 10.6 Hz, 2H), 1.59 (d, J= 12.5 Hz, 2H), 1.49 (m, J= 3.7 Hz, 1H), 1.15 (m, J= 5.7 Hz, 2H). MS ES': 399.

Example 56: 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1Hpyrazole-3-carboxamide

CI

NN

To a stirred solution of 5-(2-chloro-4-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 3) (1.2 g, 4.5 mmol 1 eq) in THE (10 mL) was added D1PEA (1.41 g, 2.5 eq) and HATU (2.488 g, 1.5 eq) and after 5 min, 1-methylpiperidin-3-amine (0.6 g, 1.2 eq). The reaction mixture was stirred at RT for 16h. Solvent was evaporated under vacuum. Aqueous sodium bicarbonate solution was added, and the product was extracted with a solution of 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield crude product, which was purified by reverse phase column chromatography to afford the title compound (1 g, 61.3%) as an off-white solid.

111 NMR (400 MHz, DMSO-d6) 6 7.77 (d, J = 8.40 Hz, 1H), 7.41 (d. J = 8.40 Hz, 1H).

7.24 (d, J = 2.80 Hz, 1H), 7.05 (dd, J = 3.70, Hz, 1H), 6.65 (s, 1H), 3.96 (t, J = 3.90 Hz, 1H), 3.85 (s, 3H). 3.67 (s. 3H), 2.58 (d, J = 9.60 Hz, 1H). 2.41 (s, 1H), 2.17 (s, 5H). 1.63 (d, J= 5.60 Hz, 2H), 1.51-1.44 (m, 2H). MS ES': 363.15.

The enantiomers were separated by SEC-prep. Preparative SEC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30)C; UV: 230 nm; Solubility: Methanol.

Example 56A: Isomer 1 NMR (400 MHz, DMSO-d6) S 7.77 (d, J = 8.00 Hz, 1H), 7.41 (d, J = 8.40 Hz, 1H), 7.24 (d, J = 2.80 Hz, 1H), 7.06 (dd, J = 8.80 Hz, 1H), 6.65 (s, 1H), 3.96 (t, J = 8.00 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 2.51-2.49 (m, 1H), 2.41 (s, 1H), 2.18 (s, 3H), 2.08 (d, J = 6.40 Hz, 2H), 1.63 (d, J = 5.60 Hz, 2H), 1.52-1.45 (m, 2H). SOR1/4120589: +7.36 (0.1% in acetonitrile). MS ES': 363.28. Off-white solid. Chiral HPLC: LUX Cellulose-2 (4.6mm x 250mm) 5am column, 0.2% methanolic ammonia in methanol, 5.16 mm RT.

io Example 56B: Isomer 2 NMR (400 MHz, DMSO-d6) 5 7.77 (d, J = 8.00 Hz, 1H), 7.41 (d, J = 8.40 Hz, 1H), 7.24 (d, J = 2.80 Hz, 1H), 7.06 (dd, J = 8.80 Hz, 1H), 6.65 (s, 1H), 3.96 (t, J = 8.00 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 2.51-2.49 (m, 1H), 2.41 (s, 1H), 2.18 (s, 3H), 2.08 (d, J = 6.40 Hz, 2H), 1.63 (d, J = 5.60 Hz, 2H), 1.52-1.45 (m, 2H). SORM20589: -9.84 (0.1% in acetonitrile). MS ES': 363.28. Off-white solid. Chiral HPLC: LUX Cellulose-2 (4.6mtn x 250mm) 5am column, 0.2% methanolic ammonia in methanol, 6.2 mm RT.

Example 57A: (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazolc-3-carboxamide (s) N

CI

N

To a stirred solution of 5-(2-chloro-4-methoxypheny1)-1-methyl -IH-pyrazole-3-carboxyl c acid (Intermediate 3) (0.4 g, 1.5 mmol, 1 eq) in THF (10 mL) was added DIPEA (0.47 g, 2.5 eq) and HATU (0.829g. 1.5 eq) and after 5 mm, (S)-1-methylpiperidin-3-amine (0.2 2, 1.2 eq). The reaction mixture was stirred at RT for 16h. Solvent was evaporated under vacuum. Aqueous sodium bicarbonate solution was added and the product was extracted with a solution of 10% methanol in DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield crude product, which was purified by reverse phase column chromatography to afford the title compound (0.45 g, 83%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.76 (d, J = 8.00 Hz, 1H), 7.41 (d, J = 8.40 Hz, 1H), 7.24 (d, J = 2.40 Hz, 1H), 7.05 (dd, J = 2.40 Hz and 8.4 Hz, 1H), 6.65 (s, 1H), 3.96 (m, Hi), 3.85 (s, 31-1), 3.67 (s, 3H), 2.65-2.52 (m, 11-1), 2.45-2.41 (m, 114), 2.17 (s, 3H), 2.172.14 (m, 2H), 1.70-1.62 (m, 2H), 1.60-1.40 (m, 2H). MS ES': 363.15. SOR[a]20589: +14.05 (0.1% in acetonitrile). Chiral HPLC: LUX Cellulose-2 (4.6mm x 250mm) 5pm column, 0.2% methanolic ammonia in methanol, 5.09 min RT. The isomer was identical to Example 56A (isomer 1).

Example 57B: (R)-5-(2-Chl oro-4-metho x yphen yl)-1-meth yl-N-(1-meth yl piperidin-3-y1)- 1H-pyrazole-3-carboxamide methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 3) (0.2 g, 0.75 mmol) in DCM (2 ml) at 0°C. One drop of DMF was added to the reaction mixture and allowed to stir at RT for 3h. After total conversion of acid to acid chloride, solvent was evaporated from the reaction mixture on a rotavapor. In a separate flask, (R)-1-methylpiperidin-3-amine (0.100 g, 1.21 mmol) was taken in DCM (3 ml), cooled to 0°C, triethylamine (0.202 g, 2.75 mmol) was added followed by the addition of a DCM solution of the synthesized acid chloride. The reaction mixture was stirred at RT for 16h, quenched with ice cold water and extracted with DCM (2 x 10 ml). The combined organic layer was dried with sodium sulphate and evaporated under reduced pressure. The crude product obtained was purified on Grace purifier using a gradient elution of 70-75% methanol in water to afford the title compound (0.07 g, 26%) as a white solid.

NMR (400 MHz, DMSO-d6) 6 1.44-1.51 (m, 2E1), 1.63 (d, J = 6.00 Hz, 2E1), 2.09 (s, 2H), 2.17 (s, 3H), 2.40 (s, 1H), 2.57 (d, J = 10.00 Hz, 1H), 3.67 (s, 3H), 3.85 (s, 3H), 3.96 (s, 1H), 6.64 (s, 1H), 7.06 (dd, J = 2.40, 8.40 Hz, 1H), 7.24 (d, J = 2.28 Hz, 1H), 7.41 (d, J = 8.40 Hz, 1H), 7.76 (d, J = 8.40 Hz, 1H). MS ES': 363.0. SORE ai2o589: -8.34 (0.1% in acetonitrile). Chiral HPLC: LUX Cellulose-2 (4.6mm x 250mm) 5pm column, 0.2% (R) N Oxalyl chloride (0.202 g,

CI

N N

2.2 mmol) was added to a solution of 5-(2-chloro-4-methanolic ammonia in methanol, 6.08 min RT. The isomer was identical to Example 56B (isomer 2).

Example 58: 5-(2-Chloro-4-methoxyphenyl)-1 -methyl-N-(( 1-methylpyrrolidin-3-yl)methyl)-1H-pyrazole-3-carboxamide To a stirred solution of 5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 3) (1.25 2, 4.68 mmol, 1 eq) in THF (10 ml), HATU (2.6 g, 1.5 eq) and DIPEA (1.8 g, 2.5 eq) were added, followed by (1-methylpyrrolidin-3-yl)methanamine io (0.58 g, 1.1 eq). The reaction mixture was stirred overnight at RT. After completion of the reaction, the solvent was evaporated under reduced pressure, water was added and the product was extracted with ethyl acetate (2 x 100 mL) The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by reverse phase column chromatography to afford the title compound (0.6 g, 35%) as an off-white solid. The product obtained was converted into the HC1 salt.

NMR (400 MHz, DMSO-d6) 6 8.23 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 7.07 (q. J = 3.7 Hz, 1H), 6.66 (s, 1H), 3.84 (s, 311), 3.68 (s, 3H), 3.603.45 (m, 2H), 3.35 (m, 211), 3.15-3.00 (m, 2H), 2.80 (m, 3H), 2.65 (m, 1H), 2.15-1.95 (m, 111), 1.85-1.60 (m, 1H). MS ES: 363.15.

The enantiomers were separated by SEC-prep. Preparative SFC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Solubility: Methanol.

Example 58A: Isomer 1 1H NMR (400 MHz, DMSO-d6) 6 8.23 (t, J = 5.9 Hz. 1H), 7.42 (d. J = 8.6 Hz, 1H), 7.24 (d, J= 2.5 Hz, 1H), 7.06 (q, J= 3.7 Hz, 1H). 6.63 (s, 111). 3.85 (s, 311). 3.67 (s, 3H), 3.19 (q, J= 6.2 Hz, 2H), 2.35 (m, J= 5.2 Hz, 5H), 2.21 (s, 3H), 1.83 (m, J= 4.5 Hz, 1H), 1.45 (m, J = 4.3 Hz, 1H). MS ES: 363.1. SORIct120589: -6.92 (0.1% in methanol). Off-white solid.

Example 58B: Isomer 2 NMR (400 MHz, DMSO-d6) 5 8.23 (t, J = 5.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 7.06 (q, J = 3.7 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 3.19 (q, J= 6.2 Hz, 2H), 2.35 (m, J= 5.2 Hz, 5H), 2.21 (s, 3H), 1.83 (m, J= 4.5 Hz, 1H), 1.45 (m, J = 4.3 Hz. 1H). MS ES': 363.0. SORica20589: +9.32 (0.1% in methanol). Off-white io solid.

Example 59: 5-(2-Ch1oro-4-methoxypheny1)-1-methyl-N-((1-methylpiperidin-3-yl)methyl) -1H-pyrazole-3-carboxamide Me0 Prepared as described for Example 1 using 5-(2-chloro-4-methoxypheny1)-1-methy1-1H- pyrazole-3-carboxylic acid (Intermediate 3) (1.58, 5.703 mmol) and (1-methylpiperidin3-yl)methanamine (1.1 g, 8.551 mmol) to afford the title compound. The product obtained was purified by preparative HPLC in basic condition and the enantiomers were separated by SFC to afford the title compound (367 mg of isomer 1 and 240 mg of isomer 2) as off-white solids.

Example 59A: Isomer 1 II-INMR (400 MHz, DMSO-d6) 58.16 (d, J = 6.00 Hz, 1H), 7.42 (d, I = 8.40 Hz, 1H), 7.24 (d, J = 2.40 Hz, 1H), 7.07-7.05 (dd, J = 2.4 Hz and 8.4 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 3.15-3.05 (m, 2H), 2.70-2.55 (m. 2H), 2.13 (s, 3H), 1.85-1.70 (m, 2H), 1.65- 1.55 (m. 3H), 1.45-1.35 (m, 1H). 0.95-0.70 (m. 1H). MS ES': 377.32. SOR[a]20mo: +14.74 (0.1% in methanol).

Example 59B: Isomer 2 1H NMR (400 MHz, DMSO-d6) 58.17 (d, J = 6.00 Hz, 1H), 7.42 (d, J = 8.80 Hz, 1H), 7.24 (d, J = 2.40 Hz, 1H), 7.07-7.05 (dd, J = 2.4 Hz and 8.4 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 3.67 (s, 311), 3.18-3.05 (m, 214), 2.72-2.60 (m, 211), 2.15 (s, 314), 1.90-1.75 (m, 211), 1.701.55 (m, 3H), 1.45-1.35 (m, 1H), 0.95-0.85 (m, 1H). MS ES': 377.1. SOR[a]20589: -12.20 (0.1% in methanol).

Example 60: 5-(2-Chloro-5-(trifluoromethyl)pheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide cN F3C To a stirred solution of 5-(2-chloro-5-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 15) (0.20 g 0 7 mmol) in THF (15 mL) were added DIPEA (0.27 g, 1.75 mmol) and HATU (0.38 2 1 0 mmol) followed by 1-methylpiperidin-3-amine (0.09 g, 0.8 mmol) at RT. The reaction mixture was stirred at RT for 12h. After completion of the reaction, the solvent was evaporated on a rotavapor. The residue was diluted with IS water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated. The crude product was purified by prep HPLC using ammonium bicarbonate buffer to afford the title compound (0.15 g, 76%) as an off-white solid.

The enantiomers were separated by SEC-prep. Preparative SEC Conditions: Column/dimensions: LUX Cellulose-2 (30tnna x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 nm; Methanol.

Example 60A: Isomer 1 1E1 NMR (400 MHz, DMSO-d6) 67.93 (d, J= 2.2 Hz, 311), 7.82 (d, J= 8.4 Hz, 111), 6.81 (s, 111), 3.97 (t, J= 4.1 Hz, 111), 3.71 (s, 311), 2.58 (d, J= 9.8 Hz, 1H), 2.41 (s, 1H), 2.17 (s, 3H), 2.08 (d, J = 1.9 Hz, 2H), 1.64 (t, J = 4.2 Hz, 2H), 1.49 (m, J = 5.8 Hz, 2H). MS ES: 401.13.

Example 60B: Isomer 2 1I-1 NMR (400 MHz, DMSO-d6) 5 7.92(d, J= 2.2 Hz, 3H), 7.82 (d, J= 8.4 Hz, 1H), 6.81 (s, 1H), 3.97 (t, J= 4.1 Hz, 1H), 3.71 (s, 3H), 2.58 (d, J= 9.8 Hz, 1H), 2.41 (s, 1H), 2.17 (s, 3H), 2.08 (d, J = 1.9 Hz, 2H), 1.64 (t. J = 4.2 Hz, 2H), 1.49 (m, J = 5.8 Hz, 2H). MS ES': 401.13.

o Example 61: 5-(2-Chloro-5-(tri uluoromethyl)phenyl)-1-meth yl-N-((l-methylp yrroli din-3-yl)methyl)-1H-pyrazole-3-carboxamide F3C To a stirred solution of 5-(2-chloro-5-(tritluoromethyl)pheny1)-1-methyl-IH-pyrazole-3-carboxylic acid (Intermediate 15) (0.40 g, 1.3 mmol) in THE (20 mL) was added DIPEA Is (0.51 g, 3.9 mmol) and HATU (0.74 g 1 95 mmol) followed by (1-methylpyrrolidin-3-y1) methanamine (0.16 g, 1.43 mmol) at RT. The reaction mixture was stirred at RT for 12h. After completion of the reaction, the solvent was evaporated on a rotavapor. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2 x 15 mL) The combined organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by prep HPLC using ammonium bicarbonate buffer to afford the title compound (0.15 g, 29%) as a white solid.

The individual isomers obtained were subjected to salt formation to afford the hydrochloride salts as white solids.

Example 61A: Isomer 1 NMR (400 MHz, DMSO-d6) 5 10.14 (s, 1H), 8.53 (t, J = 5.9 Hz, 1H), 7.94 (s, 3H), 6.82 (s, 1H), 3.72 (s, 3H), 3.54 (s, 2H), 3 12 (s, 4H), 2.80 (s, 4I1), 1.92 (d, J = 122.2 Hz, 211). MS ES': 438.0.

Example 61B: Isomer 2 11-1 NMR (400 MHz, DMSO-d6) 5 10.18 (s, 1H), 8.53 (t, J = 5.9 Hz, 1H), 7.94 (s, 3H), 6.82 (s. 1H), 3.72 (s, 311), 3.54 (s, 4H). 3.06 (s, 211). 2.80 (s, 411), 2.07 (s, 1H), 1.81 (s. 111). MS ES': 438.0.

Example 62: 5 -(2-Chloro-5-methoxypheny1)-1-methyl-N-(1-methylpiperidin-3 -y1)-1H-I s pyrazole-3-carboxamidc c\N To a stirred solution of 5-(2-chloro-5-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 16) (0.15 g, 0.56 mmol) in THF (5 mL) was added 1-methylpiperidin3-amine (0.062 g, 0.55 mmol) followed by DIPEA (0.193 ml, 1 5 mmol) and HATU (0.285 2, 0.75 mmol) at 0)C and stirred at RT for 16h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate (2 x 10 m1). The combined organic layer was dried over sodium sulphate, filtered and evaporated. The crude product was purified by Grace purifier using a gradient elution of 80-90% aqueous ammonium bicarbonate solution in methanol to afford the title compound (0.13 g, 64%) as an off-white ns solid.

The enantiomers were separated by SFC-prep. Preparative SFC Conditions: Column/dimensions: LUX Cellulose-2 (30mm x 250mm) 5pm; % CO2: 75%; % co-solvent: 25% (0.1% 7M methanolic ammonia in acetonitrile (7): methanol (3)); Total Flow: 90.0 g/min; Back Pressure: 100 bar; Temperature: 30°C; UV: 230 mu; Solubility: Methanol.

The individual isomers obtained were subjected to salt formation to afford the hydrochloride salts as off-white solids.

Example 62A: Isomer 1 1I-1 NMR (400 MHz, DMSO-d6) (at 90°C) 6 10.20 (s, 1H), 8.00 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H). 7.11 (d. J = 8.8 Hz, 1H). 7.01 (s, 1H), 6.70 (s. 1H). 4.24 (s, 1H), 3.81 (s. 3H).

3.70 (s, 3H), 3.40 (t, J = 14.2 Hz, 2H), 2.78 (s, 5H), 1.78 (q, J = 34.7 Hz, 4H). MS ES': 400.0. SOR[a]20589: -6.84 (0.1% in methanol).

Example 62B: Isomer 2 1H NMR (400 MHz, DMSO-d6) (at 90°C) 6 10.06 (s, 1H), 8.02 (s, 1H), 7.51 (d, J = 8.9 is Hz, 11-1), 7.11 (d. J= 8.8 Hz, 1H). 7.01 (s. 1H), 6.71 (s, 1H), 4.24(d, J= 8.1 Hz. 1H), 3.81 (s, 3H), 3.70 (s, 3H). 3.39 (t, J = 11.2 Hz, 2H), 2.78 (s, 5H), 1.78 (q, J = 35.8 Hz, 4H). MS ES': 400.0. SORkt120589: +6.48 (0.1% in methanol).

Example 63: 5-(2-Chloro-5-methoxypheny1)-1-methyl-N-((1-methylpyrrolidin-3-yl)methyl) -1H-pyrazole-3-carboxamide To a stirred solution of 5-(2-chloro-5-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 16) (27, 0.15 g, 0.56 mmol) in THF (5 mL) was added (1-methylpyrrolidin-3-yOmethanatnine (0.07 g, 0.55 mmol) followed by DIPEA (0.193 MI_ 1.5 mmol) and HART (0.285 g, 0.75 mmol) at 0°C and stin-ed at RT for 16h. The reaction mixture was quenched with ice cold water, extracted with ethyl acetate (2 x 10 ml), dried over sodium sulphate, filtered and evaporated. The crude product was purified by Grace purifier using a gradient elution of 80-90% aqueous ammonium bicarbonate solution in methanol to afford the title compound (0.12 g, 59%) as an off-white solid.

The individual isomers obtained were subjected to salt formation to afford the hydrochloride salts as pale brown solids.

Example 63A: Isomer 1 II-INMR (400 MHz, DMSO-d6) (at 90°C) 6 10.41 (d, J = 26.7 Hz, 1H), 8.13 (s, 1H), 7.51 (d, J= 8.9 Hz, 1H), 7.10 (d, J= 8.8 Hz, 1H), 7.01 (s, 1H), 6.68 (s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.54 (d, J = 18.4 Hz, 2H), 3.39 (d, J = 18.6 Hz, 2H), 3.12 (s, 2H), 2.80 (s, 4H), Is 2.12 (d, J = 42.5 Hz, 1H), 1.81 (d, J = 58.6 Hz, 11-1). SORkte0589: -10.12 (0.1% in methanol). MS ES': 363.3.

Example 63B: Isomer 2 11-1 NMR (400 MHz, DMSO-d6) (at 90°C) 6 10.21 (s, 1H). 8.13 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.01 (s, 1H), 6.68 (s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.57 (s. 2H). 3.37 (s. 2H). 3.13 (s, 2H), 2.81 (s, 4H), 2.11 (t. J= 26.3 Hz. 1H), 1.81 (d, J= 61.5 Hz, 1H). SOR[o.]20589: +10.5 (0.1% in methanol). MS ES: 363.1.

Example 64: 1,4-Dimethyl-N-(1-methylpiperidin-4-y1)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide Q. I Prepared as described for Example 1 using 1,4-dimethy1-5-(4-(tritluoromethyl)pheny1)-1H-pyrazole-3-carboxyl ic acid (Intermediate 17) (0.27 g, 0.95 mmol) and 1-methylpiperidin-4-amine (0.132 g 114 mmol) to afford the title compound (180 mg, 48%) as a white solid.

NMR (400 MHz, DMSO-d6) 67.91 (d, J= 8.2 Hz, 2H), 7.79 (d, J= 8.3 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 3.72 (m, J = 4.3 Hz, 1H), 2.73 (d, J = 11.7 Hz, 2H), 2.15 (d, J= 4.8 Hz, 6H), 1.93 (m, J= 5.1 Hz, 2H), 1.65 (m, J= 5.5 Hz, 4H). MS ES: 381.36.

Example 65: 1,4-Dimethyl-N-((1-methylpiperidin-2-ypmethyl)-5-(4-(trifluoromethyl) phenyl)-1H-pyrazole-3-carboxamide F3C u) Prepared as described for Example 1 using 1,4-dimethyl-5-(4-(trifluoromethyl)pheny1)- 1H-pyrazole-3-carboxylic acid (Intermediate 17) (0.27 g, 0.95 mmol) and (1-methylpiperidin-2-yl)methanamine (0.132 g. 1.14 mmol) to afford the title compound (180 mg. 48%) as a white solid.

NMR (400 MHz, DMSO-Do) 67.91 (d, J= 8.2 Hz, 2H), 7.70 (d, J= 8.0 Hz, 2H), 7.63 Is (t, J = 5.5 Hz, 1H), 3.78 (s, 3H), 3.46 (m, J = 3.3 Hz, 1H), 3.24 (m, J = 4.8 Hz, 1H), 2.78 (d, J= 11.3 Hz, 1H), 2.24(s, 3H), 2.16(s, 3H), 2.03 (m, J= 5.3 Hz, 2H), 1.67 (t, J= 5.9 Hz, 1H), 1.55 (m, J = 8.7 Hz, 2H), 1.42 (q, J = 5.2 Hz, 1H), 1.24 (m, J = 5.2 Hz, 2H). MS ES': 395.37.

Example 66: 1-Ethyl-N-(1-methylpyrro1i di n-3-y1)-5-(4-(tri fluoro meth yl)phenyl)-1 pyrazole-3-carboxamide F3C 2- Prepared as described for Example 1 using 1-ethy1-5-(4-(trif1uoromethy1)pheny1)-1Hpyrazole-3-carboxylic acid (Intermediate 18) (0.2 g, 0.7 mmol) and 1-methylpyrrolidin-3-amine (0.108 g, 0.8 mmol) to afford the title compound (72 mg, 48%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.96 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 6.86 (s, 1H), 4.39 (m, J = 3.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.63 (m, J = 3.7 Hz, 2H), 2.39 (m, J= 6.7 Hz, 211), 2.26 (s, 311), 2.15 (in, J = 4.7 Hz, 111), 1.75 (m, J = 4.6 Hz, 1H), 1.34 (t, J = 7.2 Hz, 3H). MS ES': 367.33.

Example 67: 1-Ethyl-5-(4-methoxypheny1)-N-(1-methylpyrrolidin-3-y1) -1H-pyrazole-3-carboxamide

NN

Prepared as described for Example 1 using 1-ethyl-5-(4-methoxypheny1)-1H-pyrazole-3-lc) carboxylic acid (Intermediate 19) (0.2 g, 0.7 mmol) and 1-methylpyrrolidin-3-amine (0.102 g, 0.9 mmol) to afford the title compound (130 mg, 65%) as a white solid.

1H NMR (400 MHz, DMSO-d6) 6 7.92 (d, J = 7.7 Hz, 1H), 7.42 (q, J = 2.9 Hz, 2H), 7.07 (q, J= 2.9 Hz, 2H), 6.65 (s, 111), 4.40 (m, J= 2.4 Hz, 111), 4.14 (q, J= 7.2 Hz, 211), 3.82 (s, 3H), 2.70 (q, J = 7.7 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 2.16 (m, I = 4.7 Hz, 1H), 1.76 (d, J= 6.0 Hz, 1H), 1.32 (1, J= 7.2 Hz, 3H). MS ES: 329.35.

Example 68: 5-(2-Methoxy-4-(trifluoromethyepheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide F30 Q Prepared as desciibed for Example 1 using 5-(2-methoxy-4-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 20) (0.15 g, 0 5 mmol) and 1-methylpiperidin-3-amine (0.062 g, 0.55 mmol) to afford the title compound (0.13 g, 38%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 6 7.75 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.43 (d, I = 7.8 Hz, 1H), 6.69 (s, 1H), 3.96 (t, J = 4.0 Hz, 1H), 3.91 (s, 3H), 3.70 (s, 3H), 2.57 (d, J = 9.4 Hz, 1H), 2.40 (s, 1H), 2.17 (s, 3H), 2.09 (s, 2H), 1.63 (d, J = 5.7 Hz, 2H), 1.49 (m, J= 4.5 Hz, 2H). MS ES±: 397.

Example 69: 5-(2-Methoxy-4-(thfluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-2-yl)methyl)-1H-pyrazole-3-carboxamide F3C Prepared as described for Example 1 using 5-(2-methoxy-4-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 20) (0.15 g, 0.5 mmol) and (1-methylpiperidin-2-yl)methanamine (0.07 g, 0.55 mmol) to afford the title compound (0.12 g, 65%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 5 7.70 (t, J = 5.6 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H). 7.43 (d, J= 7.9 Hz. 1H), 6.68 (s, 1H), 3.91 (s, 3H). 3.70 (s, 3H), 146 (m. J= 3.3 Hz, 1H), 3.24 4] = 4.5 Hz, 1H), 2.78 (d, J = 11.5 Hz, 1H), 2.23 (s, 3H), 2.02 (iii, J = 3.9 Hz, 2H), 1.66(t. J= 6.1 Hz, 1H), 1.49 (m, J= 7.8 Hz, 3H), 1.23 (m, J= 4.7 Hz, 2H). MS ES': 411.

Example 70: 5-(2-Methoxy-4-(thfluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-4-y1)methyl)-1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 5-(2-methoxy-4-(tritluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 20) (0.15 g 0 5 rmnol) and (1-methylpiperidin-4-yl)methanamine (0.062 g,0.55 mmol) to afford the title compound (0.13 g, 68%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 6 8.13 (t, J = 6.1 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.44 0, J= 8.8 Hz, 2H), 6.67 (s, 1H), 3.91 (s, 3H), 3.69 (s, 3H), 3.11 (t, J= 6.5 Hz, 2H), 2.72 (d, J= 11.3 Hz, 2H). 2.12 (s, 3H), 1.77 (t, J = 10.6 Hz, 2H). 1.59 (d, J= 12.4 Hz, 2H), 1.49 (m, J = 3.7 Hz, 1H), 1.15 (m, J = 5.6 Hz, 2H). MS ES': 411.

Example 71: 5-(2-Methoxy-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-3-yl)methyl)-1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 5-(2-methoxy-4-(tritluoromethyl)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 20) (0.15 g 0 5 rmnol) and (1-methylpiperidin-3-yl)methamunine (0.062 g. 0.55 mmol) to afford the title compound (0.06 g, 42%) as an off-white solid.

11-1 NMR (400 MHz, DMSO-d6) 68.16 (t, J= 6.0 Hz. 111), 7.56 (d. J= 7.7 Hz, 1H), 7.44 (t. J = 8.8 Hz, 2H), 6.68 (s, 1H). 3.91 (s, 3H), 3.70 (s, 3H), 3.11 (q, I = 7.2 Hz, 2H), 2.63 (q, J= 11.3 Hz, 2H), 2.12 (s, 3H), 1.78 (t, J= 10.5 Hz, 2H), 1.590. J = 10.3 Hz, 3H), 1.41 (m, J= 6.0 Hz, 1H), 0.88 (q, J= 10.5 Hz, 1H). MS ES': 411.

Example 72: 5-(2-Chloro-4-methoxyphenyI)-1-methyl-N-01-tnethylpyrrolidin-2-yl)methyl) -1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(2-chloro-4-methoxypheny1)-1-methy1-1Hpyrazole-3-carboxylic acid (Intermediate 3) (1.2 g, 4 49 mmol) and (1-methylpyrrolidin2-yl)methanamine (0.85 g, 7.41 mmol) The product obtained was purified by preparative HPLC to afford the title compound (910 mg, 56%) as a pale yellow gum. The isomers were separated by SEC to obtain 300 ing of each isomer as a pale yellow gum.

The individual isomers obtained were subjected to salt formation to afford the hydrochloride salts. 4N HC1 in 1,4-dioxane was added to a solution of each individual isomer (0.3 g) in 1,4-dioxane (10 mL) at 0°C, and stirred for 2h. All solvent was evaporated, and the residue was triturated with diethyl ether and dried under vacuum to obtain isomer 1 (250 mg, 82%) and isomer 2(160 mg, 49.2%), both as pale yellow solids.

CI Me0

Example 72A: Isomer 1 1H NMR (400 MHz, DMSO-c16) 6 9.91 (s, 1H), 8.61 (s, 1H), 7.42 (d, J = 8.80 Hz, 1H), 7.25 (d, J = 2.40 Hz. 1H). 7.08-7.05 (dd, J = 8.8 Hz and 2.8 Hz, 1H), 6.72 (s, 1H). 3.85 (s, 3H), 3.69 (s, 3H), 3.65-3.51 (m, 4H), 3.12-3.02 (m. 1H), 2.88 (s, 3H). 2.20-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.75 (m, 2H). MS ES: 400.46. SORNI20589: +11.36 (0.1% in methanol).

Example 72B: Isomer 2 1H NMR (400 MHz, DMSO-d6) 6 9.72 (s. 1H), 8.61 (s, 1H). 7.42 (d. = 8.80 Hz. 1H).

7.25 (d, J = 2.40 Hz, 1H), 7.08-7.05 (dd, J = 2.4 Hz and 8.8 Hz, 1H), 6.71 (s, 1H), 3.85 (s, 3H), 3.70 (s, 3H), 3.64 (t, J = 5.60 Hz, 2H), 3.51-3.57 (n, 2H), 3.12-3.02 (m, 1H), 2.90 (d, J = 4.80 Hz. 3H), 2.15-2.10 (m, 1H), 2.00-1.92 (m, 1H), 1.90-1.75 (m, 2H). MS ES': 400.46.

Example 73: (S)-5-(2-Chl oro-4-methoxyphen y1)-4-ethyl -1-m ethyl-N-(1-methylp iperidi n- 3-y1)-1H-pyrazolc-3-carboxamidc Prepared as described for Example 1 using 5-(2-chloro-4-methoxypheny1)-4-ethyl-lmethyl-1H-pyrazole-3-carboxylic acid (Intermediate 21) (0.3 g, 1.35 mmol) and (S)-1-methylpiperidin-3-amine (0.304 g, 1.6 mmol). The product obtained was purified by preparative HPLC to obtain the title compound (0.297 g, 58%) as an off-white solid.

NMR (400 MHz, DMSO-d6) 6 7.68 (d, J = 8.4 Hz, 1H), 7.35-7.32 (dd, J = 2.4 Hz and 8.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.09-7.06 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 4.05-3.95 (m, 1H), 3.85 (s, 3H), 3.57 (s, 3H), 2.62-2.52 (m, 111), 2.50-2.35 (in, 3H), 2.25-2.10 (m, 5H).

1.70-1.40 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H). MS ES': 391.31.

Example 74: 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((1-methylpiperidin-2-yl)methyl) -1H-pyrazole-3-carboxamide

CI / "NN Me0

Prepared as described for Example 1 using 5-(2-chloro-4-methoxypheny1)-1-methy1-1Hpyrazole-3-carboxylic acid (Intermediate 3) (1.5 g, 5.703 mmol) and (1-methylpiperidin2-yl)methanamine (1.1 g, 8.551 mrnol). The product obtained was purified by preparative HPLC in basic condition and the isomers were separated by SFC to obtain the title compound (494 fig of isomer 1 and 308 mg of isomer 2, 50%), both as yellow solids.

Example 74A: Isomer 1 111 NMR (400 MHz, DMSO-d6) 6 7.71 (d, J = 5.60 Hz. 1H), 7.42 (d, J = 8.40 Hz. 1H).

7.24 (d, J = 2.40 Hz, 1H). 7.07-7.05 (dd, J = 2.4 Hind 8.4 H7, 1H), 6.64 (s, 1H). 3.85 (s, 3H), 3.68 (s. 3H). 3.46-3.43 (m. 1H), 3.30-3.24 (m. 1H), 2.77 (d, J = 11.60 Hz, 1H), 2.24 (s, 3H), 2.08-1.97 (m, 2H), 1.70-1.35 (m, 4H), 1.30-1.12 (m, 2H). MS ES*: 377.33. SOR1/4.120589: +34.36 (0.1% in methanol).

Example 74B: Isomer 2 IFI NMR (400 MHz, DMSO-d6) 57.71 (d, J = 5.60 Hz, 111), 7.42 (d, J = 8.40 Hz, Ill), 7.24 (d, J = 2.40 Hz, 1H), 7.07-7.05 (dd, J = 2.4 Hz mid 8.4 Hz, 1H), 6.64 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.46-3.43 (m, 1H), 3.30-3.20 (in, 1H), 2.78 (d, J = 11.60 Hz, 1H), 2.25 (s, 3H), 2.10-1.98 (m, 2H), 1.70-1.35 (m, 4H), and 1.30-1.15 (m, 2H). MS ES': 377.33.

S OR [a] 20580: -27.76 (0.1% in methanol).

Example 75: (S)-5-(2-Ch loro-4-methoxypheny1)-1,4-di methyl -N-(1-methylpiperidin-3-y1)-1H-pyrazole-3-calboxamide Prepared as described for Example 1 using 5-(2-chloro-4-methoxypheny1)-1,4-dimethyl1H-pyrazole-3-carboxylic acid (Intermediate 22) (0.4 g, 1 eq) and (S)-1-methylpiperidin3-amine (0.24 g, 1.1 eq). The crude product was purified by reverse phase column (S) N

CI Me0

chromatography in Grace purifier using a gradient elution of 50-60% methanol in aqueous ammonium bicarbonate solution to give the title compound (0.15 g, 34%) as an off-while solid.

1H NMR (400 MHz, DMSO-d6) 6 7.65 (d, J = 8.40 Hz, 1H), 7.35-7.32 (dd, J = 1.60 Hz, 8.40 Hz, 1H), 7.26 (d, J = 2.40 Hz, 1H), 7.09-7.06 (dd. J = 2.40 Hz, 8.40 Hz, 1H), 4.053.95 (m, 1H), 3.85 (s, 3H), 3.57 (s, 3H), 2.62-2.52 (m, 1H), 2.50-2.35 (m, 3H), 2.14-2.16 (m, 5H), 2.00 (s, 3H), 1.36-1.52 (m, 2H). MS ES*: 377.85.

Example 76: 5-(2-Chloro-4-(trilluorometh yl)pheny1)-1-meth yl-N-(1-meth yl piped din-3-y1)-1H-p yrazole-3-carbo xami de F3C Prepared asas described for Example 1 using 5-(2-chloro-4-(trifluoromethyl)pheny1)-1-methyl-1 H-pyrazole-3-carboxylic acid (Intermediate 23) (1.2 g, 3.94 mmol) and 1-methylpiperidin-3-amine (0.67 2, 5.90 mmol) The product obtained was purified by prep Is HPLC using ammonium bicarbonate buffer and the isomers were separated by SFC to obtain isomer 1 (360 mg) and isomer 2 (410 mg), both as white solids (total yield 0.77 2, 49%).

Example 76A: Isomer 1 1H NMR (400 MHz, DMSO-d6) 6 8.12 (s, 1H), 7.89 (d, J = 8.00 Hz, 1H), 7.87-7-76 (m, 211), 6.80 (s, 111), 3.97-3.96 (m, 11-1), 3.73 (s, 311), 2.65-2.51 (in, 111), 2.50-2.40 (m, 111), 2.17 (s, 3H), 2.17-2.10 (m, 2H), 1.60-1.51 (m, 2H), 1.49-1.46 (m, 2H). MS ES': 401.70.

Example 76B: Isomer 2 1H NMR (400 MHz, DMSO-d6) 6 8.12 (s, 1H), 7.89 (d, J = 8.00 Hz, 1H), 7.87-7-76 (m.

2H), 6.80 (s, 1H), 4.05-3.96 (m, 1H), 3.75 (s, 3H), 2.60-2.51 (m, 1H), 2.52-2.40 (m, 1H), 2.20(s. 3H), 2.20-2.10 (m, 2H), 1.66-1.55 (in, 2H), 1.49-1.44 (m, 2H). MS ES': 401.70.

Example 77: 5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (l-methylpyrrolidin-3-y1)methyl)-1H-pyrazole-3-carboxamide F3C Prepared as described for Example I using 5-(2-chloro-4-(trifluoromethyl)pheny1)-1- methy1-1H-pyrazole-3-carboxylic acid (Intermediate 23) (1.2 g, 3.94 mmol) and (1-methylpyrrolidin-3-ypmethanamine (0.67 g, 5.90 mmol) The product obtained was purified by prep HPLC using ammonium bicarbonate buffer and the isomers were separated by SEC to obtain isomer 1 (377 mg) and isomer 2 (300 mg), both as off-white solids (total yield 0.677 g, 43%).

Example 77A: Isomer 1 11-1 NMR (400 MHz, DMSO-d6) 6 8.12 (s, 1H), 7.89-7-82 (m, 2H), 7.78 (d, J = 8.0 Hz, 111), 6.79 (s, 114), 3.73 (s, 314), 3.55-3.45 (m, 111), 3.18-3.10 (in, 114), 3.00-2.90 (m, 1H). 2.37-2.30 (m, 1H), 2.30 (s, 3H), 2.15-2.10 (m, 1H), 1.85-1.75 (m, 114), 1.65-1.50 (m, 311).

MS ES: 401.41. SOR[a]20589: -74.30(0.1% in methanol).

Example 77B: Isomer 2 111 NMR (400 MHz, DMSO-d6) 6 8.12 (s, 1H), 7.89-7.82 (m, 2H), 7.78 (d, J = 8.0 Hz, 111), 6.79 (s, 111), 3.75 (s, 311), 3.52-3.42 (m, 1H), 3.18-3.10 (m, 1H), 3.00-2.90 (m, 1H), 2.38-2.30 (m. 1H), 2.29 (s. 3H), 2.15-2.08 (m, 1H), 1.85-1.75 (m, 1H). 1.65-1.50 (m, 3H).

MS ES+: 401.41. SOR[ct]20589: +71.78 (0.1% in methanol).

Example 78: 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (l-methylpyrrolidin-3-y1)methyl)-1H-pyrazole-3-carboxamide Prepared as described for Example 1 using 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 4) (1.2 g, 4.16 [name and (1-methylpyn-olidin-3-yl)methanamine (0.71 g, 6.25 mmol) The product obtained was purified by prep HPLC using ammonium bicarbonate buffer and the isomers were separated by SFC to obtain isomer 1 (490 mg) and isomer 2 (307 m2), both as off-while solids (total yield 0.797 g, 50%).

s Example 78A: Isomer 1 1H NMR (400 MHz, DMSO-d6) 57.94 (d, J = 9.60 Hz, 2H), 7.83 (t, J = 7.20 Hz, 1H), 7.76 (d, J = 8.00 Hz, 1H), 6.88 (s, 1H), 3.84 (s. 3H), 3.55-3.45 (m, 1H), 3.20-3.00 (m, 2H). 2.45-2.20 (m, 5H), 1.92-1.80 (m, 1H), 1.70-1.55 (m, 3H). MS ES': 385.36. SOR[a.]20589: +39.80 (0.1% in methanol).

Example 78B: Isomer 2 NMR (400 MHz, DMSO-d6) 5 7.94 (d, J = 9.60 Hz, 2H), 7.83 (t, J = 7.60 Hz, 1H), 7.76 (d, J = 7.60 Hz, 1H), 6.88 (s, 1H), 3.84 (s, 3H), 3.55-3.50 (m, 1H), 3.20-3.00 (m, 2H), 2.45-2.20 (m, 5H), 1.92-1.80 (m, 1H), 1.70-1.60 (m, 3H). MS ES": 385.32. SOR1/4.120589: -22.02 (0.1% in methanol).

Example 79: (S)-5-(2-tluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3)-N-(1-(methyld3) piperidin-3-y1)-1H-pyrazole-3-carboxamide C F 3 D3 Step 1: To a stirred solution of LiHMDS (1M in hexane, 14.5 mL, 14.55 mmol) in diethyl ether (60 nth) at -78°C was added dropwise 1-(2-f1uoro-4-(trifluoromethyl)phenye ethanone (3.00 g, 14.5 mmol) in diethyl ether (10 mL) The mixture was stirred at -78°C for 1.5 h, treated dropwise with diethyl oxalate (1.19 mL, 14.55 mmol) in diethyl ether (10 ml) at -78°C and stirred at RT for 16 h. The mixture was evaporated at 35°C and the residue diluted with petrol ether. The solids were filtered and washed with petrol ether and dried under reduced pressure to yield the lithium enolate of ethyl 4-(2-fluoro-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (3.1 g, 75%) as a pale yellow solid. MS ES': 307.

Step 2: To a stirred solution of the lithium enolate of ethyl 4-(2-fluoro-4-(trifluoromethyl)pheny1)-2,4-dioxobutanoate (1.3 g, 4.2 rnmol) in ethanol (10 mL) was added AcOH (1 mL) and hydrazine hydrate (0.17 g 5 46 mmol) dropwise and the mixture was stirred at RT for 16 it The solvent was evaporated and the resulting residue (ethyl 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxylate) was used in the next step without any further purification.

Step 3: To a stirred solution of ethyl 54241 uoro-4-(trifluorometh yl)phen y1)-1H-pyrazole- 3-carboxylate (2.0 g, 6.6 mmol) in DMF (15 mL) was added K2CO3 (1.2 g, 8.7 mmol) followed by CD3I (1.0 g, 6.9 mmol). The mixture was stirred at RT for 16 h, quenched with ice FLO and extracted with Et0Ac (2 x 30 mL) The organic layer was washed with cold H20, brine, dried over Na2504 and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography in reverse phase to obtain ethyl 5-(2-fl uoro-4-(triti uoro methyl)pheny1)-1-(meth yl -d3)-1 H-pyrazole-3-carboxyl ate (0.08 g, 8%) as a pale yellow gummy mass.

NMR (401 MHz, DMS0): 7.56-7.49 (m, 3H), 6.93 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 5.4 Hz, 3H). MS ES': 320.34.

Step 4: A stirred solution of ethyl 5-(2-fluoro-4-(tfifluoromethyl)pheny1)-1-(methyl-d3)- 1H-pyrazole-3-carboxylate (80 mg, 0.25 mmol) in THF:MeOH:H20 (3:2:1, 3 mL) was treated with lithium hydroxide monohydrate (40 mg, 0.75 mmol) and stirred at RT for 16 h. The solvent was evaporated and an aq. solution of citric acid was added to the residue to adjust the pH to 4. The mixture was extracted with a solution of 10% Me0H in DCM (15 mL) The organic layer was dried over Na2504 and evaporated to obtain 5-(2-fluoro-4- (trifluoromethyl)pheny1)-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid (0.07 g, 96%) as a pale yellow solid.

11-1 NMR (401 MHz, DM50): 6 12.82 (br s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.76-7.70 (m, 1H), 6.94 (s, 1H); MS ES': 292.33.

Step 5: A stirred solution of 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3) -1Hpyrazole-3-carboxylic acid (0.08 g, 0.273 mmol) in THE (5 mL) was treated with tert-butyl (S)-3-aminopiperidine-1 -carboxylate (0.066 g, 0.33 mmol) followed by DIPEA (0.071 2, 0.55 mmol) and HATU (0.16 g, 0.41 mmol) at 0°C, stirred at RT for 16 h and quenched with ice cold H20. The mixture was extracted with Et0Ac (2 x 10 mL), dried over Na2SO4 and concentrated. The crude compound was purified by column chromatography on 230400 mesh silica gel (30-40% Et0Ac in petrol ether) to afford tert-butyl (S)-3-(5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3) -1H-pyrazole-3-carboxamido)piperidine-1-carboxylate (0.08 g, 63%) as a pale yellow gummy mass.

1-1-1 NMR (401 MHz, DM50): 7.95-7.92 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.80 -7.77 (m, 1H), 7.75-7.70 (m, 1H), 6.89 (s, 1H), 3.85-3.60 (m, 3H), 2.95-2.75 (m, 2H), 1.90-1.78 (m, 2H), 1.75-1.60(m. 2H), 1.35(s. 9H). MS ES': 474.32, 374.48 IM-Bocr.

Step 6: A solution of tert-butyl (S)-3-(5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-(methyld3) -1H-pyrazole-3-carboxamido)piperidine-1-carboxylate (0.08 g 022 mmol) in DCM (5 mL) was treated with 4M solution of HC1 in dioxane (0.5 mL) stirred at RT for 5 h and evaporated. The residue was dissolved in Me0H (5 mL), treated with basic resin, stirred for 30 min at RT and filtered. The filtrate was evaporated to obtain (S)-5-(2-tluoro-4- (trifluoromethyl)pheny1)-1-(methyl-d3)-N-(piperidin-3-y1) -1H-pyrazole-3-carboxamide (0.075 g, 95%) as a pale yellow solid.

1H NMR (401 MHz, DMS0): 8.26 (d, I = 8.0 Hz, 1H), 7.94 (d, I = 10. 0 Hz, 1H), 7.847.77 (m, 2H), 6.89 (s, 1H), 4.09 (s, 2H), 3.10 (in, 1H), 2.85-2.75 (m, 1H), 2.65-2.70 (m, 2H), 1.80-1.70 (m, 2H), 1.70-1.60 (m, 2H). MS ES': 374.44.

Step 7: A solution of (S)-5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3)-N(piperidin-3-y1) -1H-pyrazole-3-carboxamide (0.08 g, 0.21 mmol) in DMF (6 mL) was treated with K2CO3 (0.039 g, 0.28 nunol) followed by CD3I (0.031 g, 0.21 mmol) and stirred at RT for 2.5 h. The mixture was treated with ice H20 and extracted with Et0Ac (2 x 10 nth). The organic layer was washed with cold I-120, followed by brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by column chromatography in reverse phase and further purified by prep HPLC to obtain the title compound (0.03 g, 37%) as an off-white solid.

1H NMR (401 MHz, DMS0): 67.94 (d, I = 9.9 Hz, 1H), 7.82 (m, 2H), 7.76 (d, I = 8.1 Hz, 1H), 6.88 (s, 1H), 3.97-3.95 (in. 1H), 2.58 (d, I = 9.8 Hz, 1H), 2.41 (hr s, 1H), 2.07 (hr s, 2H), 1.68-1.58 (m, 2H), 1.55-1.40 (n, 2H). Chiral HPLC: 1.03 mm 99.92%. MS ES': 391.27.

Example 80: (8) 5 (2 chloro 4 (methoxy d3)phenyl) 1 (methyl d3) N (1 (methyl-d3)piperidin-3-y1)-1H-pyrazole-3-carboxamide CD30 CD3 Step 1: A solution of 1-(2-chloro-4-hydroxyphenyl)ethanone (1.70 g, 9 96 mmol) in DMF (50 mL) was treated with K2CO23 (1.79 g, 12.9 mmol) and Cl/II (1.73 g, 11.9 mmol), stirred at RT for 2 h, diluted with Eln0 and extracted with Et0Ac (2 x 30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain crude 1-(2-ch1oro-4-(methoxy-d3)pheny1)ethanone (1.57 g 8 4 mmol) as an off-white sticky solid, which was used for the next step without further purification. MS ES': 188.02.

Step 2: A solution of 1-(2-chloro-4-(methoxy-d3)phenyl)ethanone (1.87 2, 10 mmol) in dry THF at -78°C was treated dropwise with LiHMDS (1M in THF, 12 mL), stirred for 1 h at -78 'C, treated with diethyl oxalate (1.75 g, 12 mmol) and allowed to warm to RT and stirred for 16 h. The solvent was evaporated and the residue triturated with diethyl ether to obtain the lithium enolate of ethyl 4-(2-chloro-4-(methoxy-d3)pheny1)-2,4-dioxobutanoate (5 g. crude) which was used for the next step without further purification. MS ES': 288.16 Step 3: A solution of the lithium enolate of ethyl 4-(2-chloro-4-(methoxy-d3)phenyI)-2,4-dioxobutanoate (5 g, 10 mmol) in Et0H (40 mL) was treated with hydrazine hydrate (2.5 mL) and AcOH (5 mL) and refluxed at 90°C for 1 h. The solvent was evaporated and the resulting residue purified by flash column chromatography to obtain ethyl 5-(2-chloro-4- (methoxy-d3)pheny1)-1H-pyrazole-3-carboxylate (1.59 g, 56%) as a pale yellow solid. MS ES: 284.12.

Step 4: A solution of ethyl 5-(2-chloro-4-(methoxy-d3)pheny1)-1H-pyrazole-3-carboxylate (1.59 g 5.6 mmol) in DMF (50 mL) was treated with K2CO3 (1.54 g, 11 2 mmol) and CD3I (1.06g. 7.28 mmol), stirred at RT for 2 h, diluted with 1-1/0 and extracted with Et0Ac (2 x 10 mL) The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography (50% Et0Ac in petrol ether) to obtain ethyl 5-(2-chloro-4-(methoxy-d3)pheny1)-1-(methyl-d3)-1H-pyrazole-3-carboxylate (0.340 g, 20%) as a pale yellow solid.

11-1 NMR (401 MHz, DM50): 5 7.71 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 5.6 Hz, 1H), 7.006.80 (m. 1H), 6.88-6.85 (dd. J = 2.8, 8.8 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.40 (t. J = 7.2 Hz, 3H). MS ES': 301.17.

Step 5: A solution of ethyl 5-(2-chloro-4-(metho x y-d3)ph en yl)-1-(methyl-d3)-H-pyrazo le-3-carboxy late (0.34 g, 1.1 mmol) in THF:H20:Et0H (2:1:1, 8 mL) was treated with lithium hydroxide monohydrate (0.092 g 2 2 mmol), stirred at RT for 16 h and concentrated in vacuo. The aqueous residue was acidified with 1.5M aq. HC1 and extracted with 10% Me0H in DCM (2 x 20 mL) The combined organic layer was dried over is Na2SO4 and concentrated under reduced pressure to give 5-(2-chloro-4-(methoxy-d3)pheny1)-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid (0.26, 84%), which was used for the next step without any further purification.

1H NMR (401 MHz, DMS0): 6 7.24 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.926.89 (dd, J = 2.4, 8.4 Hz, 1H), 6.84 (s, 1H); MS ES': 273.11.

Step 6: The title compound was prepared as described for Example 79 using 5-(2-chloro4-(methoxy-d3)pheny1)-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid (0.260 g, 0.953 mmol) and tert-butyl (S)-3-aminopiperidine-1-carboxylate (0.229 g, 1.114 mmol). The crude title compound was purified by preparative HPLC (Column: x-bridge C18 (30mm x 150mm) 5mm; Mobile phase A: 10 naM ammonium bicarbonate in H20; Mobile phase B: ACN; How rate: 18 mlimin; THF + Me0H) to obtain the title compound (0.08 g, 30%) as an off-white solid.

-EH NMR (401 MHz, DMS0): 57.76 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.6 Hz, 1H), 7.24 (d, J= 2.5 Hz, 111), 7.06 (dd, J= 2.8, 8.4 Hz, 1H), 6.64(s. 1H), 3.96 (t, J= 4.0 Hz, 1H), 2.57 3o (d, J = 9.3 Hz, 1H), 2.40 (hr s, 1H), 2.08 (br s, 2H), 1.68-158 (m, 2H), 1.55-1.40 (m, 2H).

MS ES': 372.28.

Example 81: 5-(2-chloro-4-methoxypheny1)-N-(1,3-dimethylpiperidin-3-y1) -1-methy1-1Hpyrazole-3-carboxamide CH30 Step 1: Prepared as described for Example 1 using 5-(2-chloro-4-methoxypheny1)-1- methy1-1H-pyrazole-3-carboxylic acid (Intermediate 3) (0.300 g, 1.12 mmol) and tertbutyl 3-amino-3-methylpiperidine-1-carboxylate (0.241 g, 1.1 mmol). The crude material was purified by reverse phase column chromatography by gradient elution of ay. ammonium bicarbonate in Me0H to afford tert-butyl 3-(5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxamido) -3-methylpiperidine-l-carboxylate (0.520 g, 95%) as a pale yellow gummy solid. MS ES': 485.36 [M + Na]+, 363.29 [M-Boc]t Step 2: A solution of tert-butyl 3-(5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxamido) -3-methylpiperidine-1-carboxylate (0.50 g, 1.08 mmol) in Et0Ac was treated at RT with 4M HO in Et0Ac (8 mL) and stirred for 16 h. The mixture was evaporated, treated with H/0 and 1M NaOH. then extracted with DCM (3 x 10 mL). The combined organic layer was first washed with sat. NaHCO3 solution (2 x 15 mL) and brine solution (2 x 10 mL) and then dried over anhydrous Na2SO4 and evaporated. The crude residue (5-(2-chloro-4-methoxypheny1)-1-methyl-N-(3-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide, 0.38 g, 96%) was used for the next step without further purification. MS ES: 363.21 Step 3: A solution of 5-(2-chloro-4-methoxypheny1)-1-methyl N (3 methylpiperidin-3-y1)-11-1-pyrazole-3-carboxamide (0.38 g, 1.07 mmol) in DCM (10 mL) at 0-5 °C was treated with DIPEA (0.270 g, 2 13 mmol), stirred for 15 min, then treated dropwise with methyl iodide (0.152 2, 1.01 mmol), and stirred at RT for 16 h. The mixture was diluted with DCM, added H/0 and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography followed by chiral SFC separation to afford the individual enantiomers of the title compound (total yield: 0.24 g, 61%) as gummy solids.

Example 81A: Isomer 1 II-1 NMR (401 MHz, DMS0): 6 8.00-7.24 (m, 3H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 2.67 (m, 3H), 2.45-2.15 (m, 3H), 2.10-0.90 (m, 8H). Chiral HPLC: 3.88 mm, 99.95%. MS ES': 377.66.

Example 8IB: Isomer 2 1-1-1 NMR (401 MHz, DMS0): 6 7.90-7.15 (m, 3H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H), 6.62 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.05-2.65 (m, 3H), 2.45-2.15 (m, 3H), 1.95-1.05 (m, 8H). Chiral HPLC: 5.07 mm. 99.71%. SOR: -13.9, (c 0.1, Me0H); MS ES': 377.66.

Example 82: (S)-5-(2 chloro-4-methoxypheny1)-1-methyl-N-(piperidin-3-y1) -1H-pyrazole-3-carboxamide CH30 Step 1: Prepared as described for step 1 of Example 79 using 5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (Intermediate 3) (0.5 g, 1.87 mmol) tert-butyl (S)-3-aminopiperidine-1-carboxylate (0.375 g, 1.87 mmol). The crude was purified on automated purification system (GRACE) using Davisil silica and Et0Ac: petrol ether (40:60) as eluent to give tert-butyl (S)-3-(5-(2-chloro-4-methoxypheny1)-1-methy1-1H-pyrazole-3-carboxamido) piperidine-l-carboxylate (0.58 g, 70%) as a while solid.

1H NMR (401 MHz, DMS0): 6 7.22 (d, J = 8.4 Hz, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 6.90- 6.87 (m, 1H), 6.77 (s, 1H), 4.12 (Fr s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 3.65 (m, 1H), 3.42 s, 3H), 1.95-1.90 (m, 1H), 1.76-1.72 (m, 2H), 1.58 (m, 1H), 1.46 (s, 9H). MS ES': 471.181M + Nar, 349.261M-Bocr.

Step 2: A solution of tert-butyl (S)-3-(5-(2-chloro-4-methoxypheny1)-1-methy1-1Hpyrazole-3-carboxamido) piperidine-1-carboxylate (0.67 2, 1.48 mmol) in Et0Ac (10 mL) at 0°C was treated with 4M 1-ICI in Et0Ac (2 nth), stirred at RT for 16 11, evaporated, and diluted with DCM. The solution was treated with aq. sat. NaHCO3 solution to bring the pH to 8 and extracted with DCM. The combined organic layer was dried over Ma2604 and concentrated under reduced pressure. The residue was triturated with n-pentane and dried under reduced pressure to obtain the title compound (0.387 g, 85%) as a white solid.

11-1 NMR (401 MHz, DMS0): 6 7.81 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.07-7.04 (dd, J = 2.4, 8.4 Hz, 1H), 6.64 (s. 1H), 3.85 (s, 3H), 3.84-3.80 (m, 1H), 3.67 (s, 3H), 2.90-2.86 (m, 1H), 2.75-2.70 (m, 1H), 2.50-2.45 (m, 2H), 1.78-1.70 (m, 1H), 1.65-1.50 (m, 2H), 1.45-1.35 (m, 1H). Chiral HPLC: 1.37 min, 98.95%. MS EY: 349.22.

Example 83: (S)-5-(2-chloro-4-methoxypheny1)-1-methyl N (1 (methyl-d3)piperidin-3-I s y1)-1H-pyrazole-3-carboxamide CI C D3 / ,1\1 CH30 At 0°C. a solution of (S)-5-(2-chloro-4-methoxypheny1)-1-methyl-N-(piperidin-3-y1) -1Hpyrazole-3-carboxamide (Example 82, 0.387 g 111 mmol) in DCM (10 mL) was treated with D1PEA (0.215 g, 1.66 mmol) followed by CD31 (0.161 g, 1.11 mmol) The mixture was allowed to warm to RT, stirred overnight, diluted with DCM (20 mL) and washed with H20 (2 x 15 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on automated instrument on Davisil silica using Me0H and DCM as eluent. The product was further triturated with n-pentane and dried in vacuo to obtain the title compound (0.174 g, 43%) as a pale yellow solid.

11-1 NMR (401 MHz, DMS0): 6 7.82 (br s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.07-7.04 (dd. J = 2.4, 8.4 Hz, 1H), 6.65 (s. 1H), 3.98 (hr s, 1H), 3.85 (s, 3H). 3.67 (s. 3H), 2.70-2.58 Om 2H), 2.25-2.05 (m, 2H), 1.72-1.62 (m, 2H). 1.58-1.40 (m, 2H). Chiral HPLC: 2.01 min. 97.04%. MS ES': 366.32.

Example 84: (S)-5-(2-chloro-4-(methoxy-d3)pheny1)-1-methyl-N-0-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide CD30 Step 1: A solution of 1-(2-chloro-4-hydroxyphenyl)ethanone (0.40 g, 2.4 mmol) in DCM (10 mL) at 0°C was treated with imidazole (0.49 g, 7.2 mmol) DMAP (0.014 g, 0.12 mmol), followed by dropwise addition of a solution of TBDMS-Cl (0.43 g, 2 88 mmol) in DCM (3 mL). The mixture was allowed to warm to RT, stirred for 4 h, treated with HA) lo and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated. The product obtained was passed through a pad of silica gel and concentrated to obtain 1-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyBethanone (0.50 g, 76%) as a pale yellow thick liquid.

NMR (401 MHz, DM50): 5 7.59 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.77-is 6.74 (m, 1H), 2.62 (s. 3H), 0.97 (s, 9H), 0.22 (s, 6H). MS ES': 285.26.

Step 2: A solution of 1-(4-((ten-butyldimethylsilyl)oxy)-2-chlorophenyeethanone (0.50 g. 1.8 mmol) in dry THF at -78°C was treated dropwise with LiHMDS (1M in THF, 2.2 mL, 2.2 mmol) stirred for 1 h at -78°C, treated with diethyl oxalate (0.32 2 2 2 mmol) and allowed to stir at RT for 16 h. The solvent was evaporated and the resulting residue (lithium enolate of ethyl 4-(4-((ten-butyldimethylsilyfloxy)-2-chlorophenyl)-2,4-dioxobutanoate) niturated with diethyl ether, dried in vacuo and used for the next step (0.5 g, 74%). MS ES: 385.30.

Step 3: A stirred solution of the lithium cnolatc of ethyl 4-(4-((tertbutyldimethylsilyl)oxy)-2-chloropheny1)-2,4-dioxobutanoate (0.5 g, 1.3 mmol) in DOH (10 mL) was treated with methyl hydrazine sulphate (0.2 g, 1.43 mmol) and retluxed at 90°C for 1 h. The solvent was evaporated and the resulting crude purified by flash column chromatography to yield ethyl 5-(4-((tert-butyldimethylsilyfloxy)-2-chloropheny1) -1-methyl-1H-pyrazole-3-carboxylate (0.25 g, 49%) as a colourless solid.

IFI NMR (401 MHz, DM50): 6 7.16 (d, J = 8.4 Hz, 111), 7.00 (d, J = 2.4 Hz, 1H), 6.836.80 (dd, J = 2.4, 8.4 Hz, 1H), 6.80 (s, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.00 (s, 9H), 0.26 (s, 6H). MS ES': 395.29.

Step 4: A stirred solution of ethyl 5-(4-((tert-butyldimethylsilyfloxy)-2-chloropheny1) -1-methyl-1H-pyrazole-3-carboxylate (025 g 06 mmol) in dry DCM (8 mL) at 0°C was treated with tetrabutyl ammonium fluoride solution (1M in THE. 1.27 mmol) and stirred at RT for 2 h. The solvent was evaporated and the residue diluted with DCM, and washed with H20 and brine. The organic layer was dried over Na2SO4, evaporated and purified by flash column chromatography to obtain ethyl 5-(2-chloro-4-hydroxypheny1)-1-methy1-1Hpyrazole-3-carboxylate (0.13 2, 73%) as a colourless solid. MS ES': 281.36.

Step 5: A solution of ethyl 5-(2-chloro-4-hydroxypheny1)-1-tnethyl-1H-pyrazole-3-carboxylate (0.3 g, 11 mmol) in DMF (10 mL) under N2 was treated with sodium hydride (60% in oil, 67 mg, 1.65 mmol), stirred for 10 min at RT, cooled 0°C and treated dropwise with a DMF solution of CD3I (172 mg, 1.21 mmol) The mixture was stirred at RT for 1 h, quenched with H20 and extracted with Et0Ac (3 x 25 mL). The combined organic layer was dried over Na2504 and concentrated. The crude obtained was purified by silica gel column chromatography (15% Et0Ac in petrol ether) to afford ethyl 5-(2-chloro-4-(methoxy-d3)pheny1)-1-methyl-1H-pyrazole-3-carboxylate (0.20 g, 63%) as a colourless solid. MS ES': 298.37.

Step 6: A solution of ethyl 5-(2-chloro-4-(methoxy-d3)pheny1)-1-methy1-1H-pyrazole-3-carboxylate (0.2 g, 0.7 mmol) in THF, Et01-1 and H20 (2:1:1, 8 mL) was treated with lithium hydroxide monohydrate (0.12g. 2 8 mmol), stirred at RT for 16 h and concentrated in vacuo. The residue was acidified with 1.5M HC1 and extracted with 10% Me0H in DCM (2 x 20 mL). The combined organic layer was dried over Na/SO4 and evaporated to give crude 5-(2-chloro-4-(methoxy-d3)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (0.10 g, 55%) as a pale yellow solid, which was used for the next step without further purification. MS ES': 270.27.

Step 7: Prepared as described for step 1 of Example 79 using 5-(2-chloro-4-(methoxyd3)pheny1)-1-methy1-1H-pyrazole-3-carboxylic acid (0.1 2 0 4 mmol) and (S)-1-methylpiperidin-3-amine (0.05 g, 0.44 mmol). The crude obtained was further purified by silica gel column chromatography to afford the title compound (0.013 g, 6.5%) as pale brown solid.

1I-1 NMR (401 MHz, DMS0): 57.77 (d, J = 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.07-7.04 (dd, J = 2.8, 8.8 Hz, 1H), 6.64 (s, 1H), 4.05-3.92 (m, 1H), 3.67 (s, 3H), 2.65-2.50 (m, 1H), 2.45-2.35 (m, 1H), 2.17 (s, 3H), 2.15-2.00 (m, 2H), 1.70-1.58 (m, 2H), 1.55-1.40 (m, 2H). Chiral HPLC: 1.99 min. 98.61%. MS ES': 366.44.

Example 85: 5-(2-chloro-4-methox ypheny1)-N-(4,4-difluoropiperidi n-3-y1)-1-methyl -111-pyrazole-3-carboxamide CH30 Is Step 1: Prepared as described for step 1 of Example 79 using 5-(2-chloro-4- methoxypheny1)-1-methy1-11-1-pyrazole-3-carboxylic acid (Intermediate 3) (0.3 g. 1.1 mmol) and tert-butyl 3-amino-4,4-difluoropiperidine-1-carboxylate (0.28 g, 1.21 mmol). Crude was purified by column chromatography with Davisil silica by gradient elution of 20-22% of Et0Ac in petrol ether to afford tert-butyl 3-(5-(2-chloro-4-methoxypheny1)-1-meth y1-11-1-pyrazole-3 -carbox am ido)-4,4-difl uoropiperidi ne-l-carbox yl ate (0.45 g, 70%) as an off-white solid.

II-1 NMR (400 MHz, DMS0): 5 8.00 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H), 6.74 (s, 1H), 4.45-4.30 (m, 111), 3.85 (br s. 5H), 3.69 (s, 3H), 3.25-3.00 (tn. 2H), 2.30-1.95 (m. 2H). 1.42 (s, 9H). Chiral HPLC: 2.14 mm (49.82%) & 2.43 mm (50.18%). MS ES': 483.32.

Step 2: Prepared as described for step 2 of Example 79 using tert-butyl 3-(5-(2-chloro-4-methoxypheny1)-1-methyl-IH-pyrazole-3-carboxamido)-4. 4-difluoropiperidine-1-carboxylate (0.4 g. 0.8 mmol) in Et0Ac (10 inL) and 4M HCI in Et0Ac (0.4 mL, 2.4 mmol) The crude material was washed with n-pentane and dried in high vacuum to afford the title compound (0.3 g, 98%) as a yellow solid.

1T1 NMR (400 MHz, DMS0): 6 7.81 (d, J= 9.6 Hz, 1H). 7.42 (d, J= 8.8 Hz, 1H), 7.25 (d. J = 2.8 Hz, 1H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H), 6.72 (s, 1H), 4.40-4.25 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 2.95-2.82 (m, 2H), 2.80-2.60 (m, 2H), 2.15-2.00 (m, 1H), 1.98-1.80 (m, 1H). Chiral HPLC: 2.65 min (50 12%) & 5.33 mm (49.88%). MS ES': 385.0.

Example 86: 5-(2-chloro-4-methoxypheny1)-N-(4,4-difluoro-1-methylpiperidin-3-y1) -1-methyl-IH-pyrazole-3-carboxamide CH30 Prepared as described for step 3 of Example 79 using 5-(2-chloro-4-methoxypheny1)-N(4,4-difluoropiperidin-3-y1) -1-methyl-IH-pyrazole-3-carboxamide (Example 85, 0.2 g, 0.5 mmol) and Mel (0.06 mg, 0.45 mmol) The crude material was washed with n-pentane, dried under high vacuum and subjected to SFC-Prep to afford the individual enantiomers of the title compound (0.15 g, 75%) as an off-white solid.

Example 86A: Isomer 1 II-1 NMR (400 MHz, DMS0): 6 7.75 (d, J = 9.5 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H), 6.73 (s, 1H), 4.50-4.35 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 2.70-2.50 (m, 2H), 2.50-2.35 (m, 2H), 2.27 (s. 3H), 2.20-1.95 (m, 2H). Chiral HPLC: 7.04 min, 99.77%. MS ES': 399.23.

Example 86B: Isomer 2 1H NMR (400 MHz, DMS0): 6 7.75 (d, J = 9.5 Hz, 1H). 7.42 (d, J = 8.6 Hz, 1H), 7.25 (d.

J = 2.5 Hz, 1H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H). 6.73 (s, 1H), 4.50-4.35 (m, 1H). 3.85 (s, 3H), 3.69 (s, 3H), 2.70-2.50 (m, 2H), 2.50-2.35 (m, 2H), 2.27 (s, 3H), 2.18-1.98 (m, 2H). Chiral HPLC: 8.58 min, 99.28. MS ES*: 399.23.

Example 87: 5-(2-chloro-4-methoxypheny1)-N-(4,4-difluoropyrrolidin-3-y1) -1-methy1-1Hpyrazole-3-carboxamide C H 3 0 Step I: Prepared as described for step I of Example 79 using 5-(2-chloro-4-methoxypheny1)-1-methyl-1H-pyrazole-3-carboxylic acid (Intermediate 3) (0.4 g, 1.5 mmol) and tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (0.4 g 1 8 mmol) in DMF (10 mL). The resulting crude solid was purified by column chromatography on silica gel (0-40% Et0Ac in petrol ether) to provide tert-butyl 4--(2-chIoro-4-methoxyphenyl)-io 1-methy1-1H-pyrazole-3-carboxamido)-3,3-difluoropyrrolidine-1-carboxylate (0.69 g. 97%) as a white solid.

1HNMR (DMSO-d6, 400 MHz): 6 8.57 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.08-7.05 (dd, J = 2.8, 8.8 Hz, 1H), 6.73 (s, 111), 5.05-4.95 (m, 111). 3.85 (s, 3H), 3.80-3.65 (m, 6H), 3.55-3.45 (m, 1H), 1.42 (s, 9H). MS ES': 471.26.

Step 2: A solution of tert-butyl 4-(5-(2-chloro-4-methoxypheny1)-1-methy1-114-pyrazolc-3-carboxamido)-3, 3-difluoropyrrolidine-l-carboxylate (0.6 g, 1 3 mmol) in DCM (10 mL) was treated with TFA (10 mL), stirred at RT for 3 h and evaporated. The residue was diluted with DCM and washed with sat. sodium bicarbonate solution (2 x 30 mL) The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by flash chromatography (0-10% McOH in DCM) to afford the title compound (450 mg, 95%) as a grey solid.

IHNMR (DMSO-d6, 400 MHz, 90 "C): 69.37 (br s, 2H), 8.71 (d, J= 8.9 Hz, 1H), 7.43 (d, J = 8.6 Hz, 11-1), 7.26 (d, J = 2.6 Hz, I H), 7.09-7.06 (dd, J = 2.4, 9.2 Hz, I H), 6.73 (s, I H).

5.07-4.98 (m, 1H), 3.85-3.65 (m, 9H), 3.62-3.52 (m, 1H). Chiral HPLC: 21.72 min (50.04%) & 2.02 min (49.96%). MS ES': 371.24.

Example 88: (S)-5-(2-fl uoro-4-(tri fluoro meth yl)pheny1)-I -(methyl-d3)-N-(1-methylpiperidin-3-y1)-1H-pyrazolc-3-carboxanaide A solution of 5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3) -1H-pyrazolc-3-carboxylic acid (Intermediate 24) (100 mg, 0.343 mmol) in Cl-12C12 (10 ml) was treated with EDC*HC1 (99 mg, 0.52 mmol) HOBt (9.3 mg, 0.069 mmol) and Et3N (0.18 ml, 1.37 mmol) and stirred for 15 min at RT, cooled to 0°C, treated with (S)-1-methylpiperidin-3-amine dihydrochloride (77 mg, 0.42 mmol) and stirred for 16h at RT. The mixture was diluted with CH2C12 (10 ml), washed with cold H20 (3 x 5 ml), dried (Na2SO4) and evaporated. Purification of the residue by column chromatography (on Davisil, 0-40% Et0Ac in petrol ether) gave the title compound (55 mg, 41%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6): 6 7.94 (d, J = 10.0 Hz, 1H), 7.84-7.80 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 4.00-3.92 (m, 1H), 2.65-2.55 (m, 1H), 2.50-2.40 (m, 1H), 2.18 (s, 3H), 2.15-2.05 (m, 2H), 1.68-1.60 (m, 2H), 1.55-1.40 (m, 2H). HPLC: 3.33 min, 99.6%. Chiral purity: 1.97 min, 99.59%. MS ES: 388.43.

Example 89: (S)-5-(2-11uoro-4-(trilluoromethyl)pheny1)-1-methyl-N-(1-(methyl-d3) piperidin-3-y1)-1H-pyrazole-3-carboxamide

NH

--CDS

\ N Nt CF3 Step 1: A solution of 5-(2-11uoro-4-(trilluorometh yl)phen y1)-1-meth yl -1H-pyrazole-3-carboxylic acid (Intermediate 4) (0.77 g, 2.67 mmol) in CH2C12 (20 ml) was treated with EDC*HC1 (0.77 2, 4.01 mmol), DMAP (0.49 g. 4.01 mmol) and Et3N (0.544 g, 5.34 mmol), stirred for 15 min at RT, cooled to 0°C, treated with (S)-1-Boc-piperidin-3-amine (0.800 g, 4.01 mmol) and stirred for 16h at RT. The mixture was diluted with C1-12C12 (10 ml), washed with cold H20 (3 x 5 ml), dried (Na2SO4) and evaporated. Purification of the residue (on Davisil, 0-40% Et0Ac in petrol ether) gave tert-butyl (S)-3-(5-(2-fluoro-4- (trifluoromethyl)pheny1)-1-methyl-1H-pyrazole-3-carboxamido) piperidine-l-carboxylate (1.0 g, 78%) as an off-white solid.

1-1-1 NMR (400 MHz, DMSO-d6): 8 8.00 Ow s, 11-1), 7.94 (d, J = 10.0 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 3.83 (s, 3H), 3.80-3.78 (m, 3H), 3.00- 2.78 (m, 2H), 1.83-1.80 (m, 1H), 1.68-1.60 (m, 2H), 1.40 (s, 9H), 1.40-1.39 (m, 1H).

HPLC: 2.23 min, 96.2%.

Step 2: A solution of tert-butyl (S)-3-(5-(2-fluoro-4-(trifluoromethyl)pheny1) -1-methy1-1Hpyrazole-3-carboxamido)piperidine-1-carboxylate (1.0 g, 2.10 mmol) in 4M HO in 1.4-dioxane (15 ml) was stirred at RT for 4h and evaporated. The residue was dissolved in Me0H (10 ml), treated with Amberlite resin (2.0 g) and stirred for lh. The mixture was filtered and the filtrate concentrated under reduced pressure to obtain (S)-5-(2-fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(piperidin-3-y1) -1H-pyrazole-3-carboxamide (0.79 2, 100%) as a sticky solid.

11-1 NMR (400 MHz, DMSO-d6): 87.93 (d, J= 10.0 Hz, 1H), 7.87-7.80 (m, 2H). 7.76 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 3.83 (s, 3H), 3.84-3.80 (m, 1H), 2.90-2.88 (m, 1H), 2.87-2.86 (m, 1H), 2.50-2.46 (m, 21-1), 1.75-1.72 (in, 11-1), 1.60-1.52 (m, 2H), 1.44-1.40 (m, 11-1). HPLC: 1.52 min, 99.4%. MS ES': 371.13.

Step 3: A solution of (S)-5-(2-fluoro-4-(trifluoromethyfipheny1)-1-methyl-N-(piperidin-3-y1) -1H-pyrazole-3-carboxamide (250 mg, 0.670 mmol) in CH2C12 (5 ml) was treated with DIPEA (0.24 mL, 1.34 mmol), stirred for 5 min at RT, treated with methyl iodide-d3 (0.04 mL, 0.60 mmol) and allowed to stir for 2h. The mixture was concentrated under reduced pressure and the residue purified by prep. HPLC (X bridge C18, 19 x 250 mm; mobile phase A: 10 m_M ammonium bicarbonate in H20, mobile phase B: CH3CN; gradient 20100% B; flow rate: 17m1/min) to obtain the title compound (75 mg, 29%) as an off-white solid.

NMR (400 MHz, DMSO-d6): 6 7.94 (d, J = 10.0 Hz, 1H), 7.84-7.80 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H). 4.00-3.90 (in, 1H), 3.83 (s, 3H), 2.62-2.52 (m, 111), 2.50-2.40 (m, 1H), 2.12-2.02 (m, 2H), 1.68-1.58 (m, 2H), 1.55-1.40 (m, 2H). HPLC: 3.34 min, 99.58%. Chiral purity: 1.63 min, 99 81%. MS ES': 388.18.

Biological efficacy of compounds of the invention The IC50 values for the compounds of the Examples are shown in Table I. The ability of the test compounds to inhibit nicotine stimulated nAChRa6 activity was determined in a fluorescence-based calcium assay. Compound activity was determined using a HEK cell line stably expressing a human nAChRa6-a3 chimera, in addition to 132 and 133v2735 subunits (as in Capelli et al, Br J Pharmacol, 2011, vol 163(2), pages 313-329). In this cell line, nicotine stimulated an increase in intracellular calcium concentration, io measured as an increase in fluorescence when cells were incubated with a calcium sensitive dye. Test compounds were pre-incubated with cells prior to nicotine stimulation to detect any reduction in the magnitude of the nicotine response.

The day prior to the assay, compounds were serially diluted in DMSO (200x final assay concentration (FAC)), in 384-well plates which were then stored in the dark at room temperature (RT) until use. Cells were seeded at 20 k/well in black, poly-D-lysine coated, clear bottom 384-well plates and incubated for 4h at 37°C, followed by overnight incubation at 30°C. The following day, the DMSO compound plate was diluted 1:20 (10x FAC) in assay buffer (HEPES buffered saline solution with 10 mM HEPES, 0.1% bovine serum albumin, 1 mM probenecid). A nicotine solution was prepared in assay buffer (7x FAC) and dispensed into a 384-well plate. The growth media was removed from the cell plate, replaced with 53 pl calcium dye/well (Calcium 5; Molecular Devices) and the plate incubated at 30°C for 45 min. Test compounds were then added to the cells (7 1_11 of 10x FAC) and incubated for 10 mM, after which nicotine ECRU (10 pl of 7x FAC) was added and changes in fluorescence measured using a FLIPR plate reader (Molecular Devices).

Compound activity was examined using a 10-point, half-log concentration-response range and each concentration was tested in duplicate wells. Responses were calculated as changes in relative fluorescence units (max-min) and IC50 values were derived from this data using a four-parameter curve fit.

Results

Table 1

Example ICso (nM) Example ICso (nM) Example ICso (nM) 1 133 28 113 61 nt IA 245 29 135 61A 929 1B 125 30 131 61B 1426 2 620 31 162 62 nt 3 116 32 78 62A 335 4 522 33 1087 62B 380 75 34 37 63 nt 6 1103 35 239 63A 2273 7 181 36 773 63B 1926 8 400 37 102 64 187 9 101 38 188 65 101 9A 194 39 205 66 93 9B 230 40 248 67 902 218 41 249 68 123 10A 183 42 228 69 129 10B 149 43 189 70 181 11 168 44 1088 71 117 12 320 45 711 72A 98 13 951 46 644 72B 95 14 148 47 240 73 86 1115 48 114 74A 87 16 113 49 102 74B 81 17 57 50 62 75 110 17A 103 50A 110 76A 83 17B 75 SOB 76 76B 76 18 92 51 116 77A nt 19 97 52 113 77B nt 72 53 86 78A nt 20A 81 54A 113 78B nt 20B 70 54B 156 79 81 21 105 55 157 80 89 21A 134 56 88 81A 154 21B 162 56A/57A 76 81B 146 22 107 56B/57B 75 82 78 22A 98 58 nt 83 105 22B 75 58A 253 84 72 23 90 58B 192 85 88 Example ICso (n1M) Example ICso (nM) Example IC59 (nM) 23A 66 59 nt 86A 94 23B 53 59A 170 86B 115 24 137 59B 195 87 661 105 60 nt 88 93 26 86 60A 298 89 109 27 132 60B 314 In vivo efficacy: tacrine studies Resting tremor is one of the classic symptoms of Parkinson's disease. These characteristic tremors can be modelled pharmacologically in preclinical models using cholinomimetics such as the acetylcholine esterase inhibitor, tacrine (5 mg/kg, i.p.) (Salamone et al, Prog Neurobiol 56: 591-611 1998) to induce tremulous jaw movement behaviours. These tremulous jaw movements are thought to arise from an imbalance between cholinergic and in dopamincrgic neurotransmission and are thought to mimic the imbalances in neurotransmission resulting from the dopamine loss seen in Parkinson's disease (Aosaki et al, Geriatr Gerontol Int 10: s148-s157 2010). These tremors can be reversed by agents increasing the dopamine tone, such as dopamine agonists (Salarnone et al, Bchav Brain Res 156: 173-179 2005).

The objective of these studies was to evaluate the effects of oral administration of Example Compounds on tremulous jaw movements induced by tacrine in male Sprague-Dawley rats. Animals were administered vehicle (0.5% methylcellulose, p.o.) or Example Compound (across a range of doses; 10 ing/kg, p.o. data shown) 15 to 60 minutes prior to behavioural testing (n=10/group). Tacrine (5 mg/kg, i.p.) was administered to all animals immediately before behavioural assessment commenced. For each animal the latency to the first tremulous jaw movement and the total duration of the tremulous jaw movements post tacrine administration were recorded.

Example % Decrease from vehicle or percentage relative to vehicle (100%), (mean ± SEM) 57A 28.5+ 6.3** 79 88.4 + 8.6 Illustrative data shown is percentage attenuation of tacrine-induced tremulous jaw movements relative to vehicle (100%). Each compound shown was tested at 10 mg/kg p.o. Statistical significance was assessed using an unpaired student's t-test vs vehicle * p<0.05, "p<0.001.

It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit io of the invention, which is defined by the following claims only.

Claims

Claims A compound of formula (I): R4---R5NH R2Formula (I) or a pharmaceutically acceptable salt, solvate or prodru2 thereof, wherein: m is 1, 2 or 3; each RI is independently selected from halo, cyano, hydroxyl, Ci-05 alkyl, Ci-05 haloalkyl, C3-05 cycloalkyl. C3-Cs halocycloalkyl, -0-(Ci -Cs alkyl), -0-(Ci -05 haloalkyl).-0-(C3-Cs cycloalkyl), -0-(C3-Cs halocycloalkyl), -NH-(C -Cs alkyl), -NH-(C -05 haloalkyl), -NH-(C3-05 cycloalkyl), -NH-(C3-05 halocycloalkyl), -N(Ci-05 alky1)2, -N(Ci-05 alky1)(Ci-05 haloalkyl), -N(Ci-05 haloalky1)2, -N(C3-05 cycloalky1)2. -N(C3-05 cycloalkyl)(C3-Cs halocycloalkyl), or -N(C3-05 halocycloalky1)2; R2 is Ci-C3 allcyl, Ci-C3 haloalkyl, cyclopropyl or halocyclopropyl; is R3 is hydrogen, Ci-C3 alkyl, Ci-C3 haloalkyl, cyclopropyl or halocyclopropyl; R4 is a bond. Ci-C3 alkylene, or Ci-C3 haloalkylenc; and R5 is a 4-, 5-, 6-or 7-membered, saturated heterocycle, wherein the heterocycle contains one or two nitrogen ring atoms and optionally one oxygen ring atom, and wherein the heterocycle is optionally substituted.
2. A compound as claimed in claim 1, wherein m is 1 or 2.
3. A compound as claimed in claim 1 or 2, wherein each R1 is independently selected from halo, cyano, hydroxyl, CI-Cs alkyl. CI-03 haloalkyl, cyclopropyl, halocyclopropyl, -0-(C 1-C3 alkyl), -0-(CI-C1 haloalkyl). -0-(cyclopropyl). -0-(halocyclopropyl).-NH-(Ci-C3 alkyl), -NH-(Ci-C3 haloalkyl). -NH-(cyclopropyl), -NH-(halocyclopropyl), -N(Ci-C3 alky1)2, -N(Ci-C3 alkyl)(Ci-C3 haloalkyl), -N(Ci-C3 haloalky1)2, -N(cyclopropyl)2. -N(cyclopropyl)(halocyclopropyl) or -N(halocyclopropyl)2.
4. A compound as claimed in any one of the preceding claims, wherein R2 is methyl, ethyl, n-propyl, iso-propyl, monotluoromethyl difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, cyclopropyl, monofluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, tetrafluorocyclopropyl or pentafluorocyclopropyl.
5. A compound as claimed in any one of the preceding claims, wherein R3 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, mono II uorometh yl difluoromethyl, tn uoromethyl, monolluoroethyl, di 11 uoroeth yl, trill uoroethyl, tetralluoroeth yl, pentafluoroethyl, cyclopropyl, monofluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, tetrafluorocyclopropyl or pentafluorocyclopropyl.
6. A compound as claimed in any one of the preceding claims, wherein R4 is a bond, -CH/-, -CH2C12-, -Cl2CH2C1±-, -ClMe-C1-12-or -C1-12-CIMc-.
7. A compound as claimed in any one of the preceding claims, wherein R5 is an azetidinyl, pyrrolidinyl, pyrazolidinyl, hnidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, perhydropyridazinyl, perhydropyrimidinyl, morpholinyl, thiommpholinyl, 1,2-oxazinanyl, 1,3-oxazinanyl, 1,2-thiazinanyl, 1,3-thiazinanyl, azepanyl or cliazepanyl group, each of which may optionally be substituted.
8. A compound as claimed in any one of the preceding claims, wherein R5 is substituted with one, two or three substituents independently selected from halo, cyano, hydroxyl, C -C 3 alkyl, C -Cs haloalkyl, cyclopropyl, h al ocyclopropyl, -0-(C -Cs alkyl), -0-(CI-Cs haloalkyl), -0-(cyclopropyl), -0-(halocyclopropyl), -NH-(CI-Cs alkyl), -NH-(Ci-C3 haloalkyl), -NH-(cyclopropyl), -NH-(halocyclopropyl), -N(Ci-C3 alky1)2, -N(CI-Cs alkyl)(Ci-Cs haloalkyl), -N(Ci-Cs haloalky1)2, -N(cyclopropy1)2, -N(cyclopropyl)(halocyclopropyl), -N(halocyclopropy1)2, or CI -C4 alkylene, wherein one -CH2-in the CI -C4 alkylene group may optionally be replaced by -0-, -NH-, -N(Ci -Cs alkyl)-, or -N(Ci-C3 haloalkyl)-.
9. A compound as claimed in claim 1, wherein the compound is selected from: 5-(4-Methoxypheny1)-1-methyl-N-((1-methylpiperidin-2-yl)methyl) -1H-pyrazole-3-carboxam i de; (R)-5(4-Methoxypheny1)-1-methyl-N4( 1 methylpiperidin-2-yl)methyl)-1H-pyrazole-3-carboxamide; (S)-544-Methoxypheny1)-1-methyl-N-((1-methylpiperidin-2-y1)methyl) -1H-pyrazole-3-carboxamidc; 5-(4-Methoxypheny1)-1-methyl-N-(1-methylpiperidin-4-y1) -1H-pyrazole-3-carboxamide; 5(4-Me(hoxyphen yl)-1 -methyl-N-(24 1 -meth ylpiperidi n-2-yl)eth yl)-1 H-pyrazole-3- 1 carboxamide; 5-(4-MethoxyphenyI)-1 -methyl-N-(2-( 1 -me,thylpiperidi n-3-ypethyl)-1 H-pyrazo le-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl) -1H-pyrazole-3-carboxamide; 5-(4-Methoxyphen y1)-I -methyl-N-(2-( 1 -methylpyrrol i di n-3-yl)eth y1)-1 H-pyrazole-3-carboxamidc; 5-(4-Methoxyphen y1)-I -methyl-N4( 1 -methylpyrrol idi n-3-yl)meth y1)-1 H-pyrazol e-3-carboxamidc; 5-(4-Methoxypheny1)-1-methyl-N41-methylpyrrolidin-3-y1) -1H-pyrazolc-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole-3-carboxamide; (R)-5-(4-M etho x yphen y1)-1-methyl-N-( 1 -meth ylpi peridin-3-y1)-1 H-pyrazole-3-carboxamide; (S)-5(4-Methoxypheny1)-1 -methyl-N-( 1-methylpiperidi n-3-yI)-1 H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N-((1-methylpyrrolidin-2-yl)methyl) -1H-pyrazole-3-carboxam i de; (R)-5-(4-Methoxypheny1)-1-methy1-N-((1-methy1pyno1idin-2-y1)methy1) -1H-pyrazole-3-carboxamide; (S)-5-(4-Methoxypheny1)-1 -methyl-N4( 1 -methylpyrrol idi n-2-yl)methyl)-1 H-pyrazole-3-carboxamidc; 1-Methyl-N4quinuclidin-3-y1)-544-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide; 5-(4-Methoxypheny1)-1-methyl-N48-methy1-8-az abicyclo [3.2.1]octan-3-y1)-1H-pyrazole3-carbo x amide; N-(1-Azabicyclo[2.2.1]heptan-3-y1)-5 -(4-methoxypheny1)-1-methyl-1H-pyrazole-3-earboxamide; 5-(4-Methoxyphen y1)-1 -methyl-N-(9-methyl -9-azabi eyelo [3.3. 1 nonan-3-y1)-1 H-p yrazole3-carboxamidc; 5-(4-Methoxypheny1)-1-methyl-N-(2-morpholinoethyl) -1H-pyrazole-3-carboxamide; 1-Methyl-N-(1-methylpiperidin-4-y1)-5-(4-(trilluoromethyl)pheny1) -1H-pyrazole-3-carboxamide; 1-Methyl-N-(( 1-methylpiperidin-2-yemethyl)-5 -(4-(trifluoromethyl)pheny1)-1H-pyrazole3 -carho x amide; (R)-1 -Meth yl-N-(( 1 -meth ylpi peridi n-2-y1)meth yl)-5-(4-(trilluoromethyl)pfien y1)-111-pyrazo Ic-3-carbox amide; (S)-1-Methyl-N-((1-methylp peridin-2-yl)methyl)-5-(4-(tr fluoromethyl)pheny1)-1Hpyrazole-3-carboxamide; 1-Methyl-N-(2-(1-methylpiperidin-3-yl)ethyl) 5 (4 (trifluoromethyl)pheny1)-1H-pyrazole- 3-earbox amide; 1-Methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5-(4-(ttifluoromethyl) pheny1)-1Hpyrazole-3-earbox amide; 1-Methyl-N-(( 1-methylpyrrolidin-2-yl)methyl)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole3-carboxamide; (R)-1-Methyl-N4(1-methylpyrrolidin-2-yl)methyl)-5-(4-(trifluoromethyl) pheny1)-1H-pyrazole-3-earbox amide; (S)-1 -Methyl-N-(0 -methylpyrrolidi n-2-y Om ethyl)-5-(4-(trifluoromethyl)pheny1)-1 Hpyrazo le-3-carbox amide; 1-Methyl-N-(( 1-methylpiperidin-3-yemethyl)-5 -(4-(trifluoromethyl)pheny1)-1H-pyrazole- 3-carboxamide; (R)-1 -Methyl-N-(( 1 -methylpiperidi n-3-yl)meth y1)-5-(4-(tri fl uoro meth yl)pheny1)-1Hpyrazole-3-carboxamide; (S)-1-Methyl-N-((1-methylpiperidin-3-yl)methyl)-5-(4-(trifluoromethyl) pheny1)-1Hpyrazole-3-earbox amide; 1-Methyl-N-(1-methylpiperidin-3-y1)-5-(4-(trifluoromethyepheny1) -1H-pyrazole-3-earboxamide; (R)-1-Methyl-N-(1-methylpiperidin-3-y1)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-earboxamide; (5)-1-Methyl-N41-methylpiperidin-3-y1)-544-(trifluoromethyl)pheny1) -1H-pyrazole-3-carboxamide; 1-M eth yl-N-(241-meth ylp iperidi n-2-yl)ethyl)-544-(tritl uoro methyl)phen y1)-1H-pyrazole3-carboxamide; (R)-1-Methyl-N4241-methylpiperidin-2-yl)ethyl)-5-(44trifluoromethyl) phenyl)-1Hpyrazole-3-carboxamide; (S)-1-Methyl-N-(2-(1-methylpiperidin-2-yflethyl)-544-(trifluoromethyl) phenye-1Hpyrazole-3-carboxamide; 1-M eth yl-N-(241-meth ylp yrrol idi n-3-yl)eth yl)-5-(4-((rifIuorometh yl)phen y1)-1 /-pyrazole-3-carbox amide; 1-Methyl-N4(1-tnethylpyrrol idi n-3-y1)methyl)-5-(4-(trifluoromethyl)pheny1)-1H-pyrazo le3-carboxamide; N-((1-Ethylpiperidin-2-yl)methyl)-1-methyl-5-(44trifluoromethyl)phenyl) -1H-pyrazole-3-carboxamide; Is I-Methyl-N-(1-methylpyrroli di n-3-y1)-544-(tri tluoro meth yl)pheny1)-1H-pyrazole-3- carboxamide; 1-M eth yl-N4piperidi n-2-ylniethyl)-5(4-(trifluoro tnethyl)pheny1)-1/1-pyrazole-3-carboxamide; 1-Methyl-N-(8-methy1-8-az abicyclo [3.2.1]octan-3-y1)-544-(trifluoromethyl)pheny1)-1H-pyrazole-3-carboxamide; N-(1-Azahicyclor 2.2.1 Jhep(an-3-y1)-1-methy1-544-((rill uorometh yl)phen y1)-1H-p yrazole3-carbox am ide; 5-(4-isopropylpheny1)-1-rnethyl-N-(1-methylpiperidin-4-y1) -1H-pyrazole-3-carboxamide; 5-(4-Isopropylpheny1)-1-methyl-N-(( 1-methylpiperidin-2-yl)methyl)-1H-pyrazole-3-carboxamide; 5-(2-Fluorophen y1)-1 -methyl-N4(1-methylpiperidi n-2-yemethyl)-1H-pyrazole-3-carboxamide; 5-(2,5-Dimethylpheny1)-1-methyl-N4(1-methylpiperidin-2-y1)methyl) -1H-pyrazole-3-carboxam i de; 30 (R)-5-(2,5-Dhnethylpheny1)-1-methyl-N-((1-methylpiperidin-2-yemethyl) -1H-pyrazole-3-carboxamide; (S)-5-(2,5-Dimethylpheny1)-1-methyl-N4(1-methylpiperidin-2-yl)methyl) -1H-pyrazole-3-carboxamide; 5-(3-Fluoropheny1)-1-methyl-N-((1-methylpiperidin-2-yl)methyl) -1H-pyrazole-3-carboxamide; 5-(4-Fluorophen y1)-1 -methyl-N-((l-methylpiperidi n-2-yemethyl)-1H-pyrazole-3-carboxamidc; 5-(4-Chloropheny1)-1-methyl-N-((1-methylpiperidin-2-yl)methyl)-1H-p yrazole-3-carboxamide; 5-(4-Chlorophcny1)-1-mcthyl-N-((1-mcthylpiperidin-4-y1)methyl) -1H-pyrazolc-3-carboxamide; 5-(4-Chlorophen y1)-1-meth yl-N-((l-meth ylpiperi din-3-yl)meth yl)-1H-p yrazol e-3-o carboxamide; 5-(4-Ch loro-3-fluoropheny1)-1-methyl-N-(1-methylpiperidi n-3 -y1)-1H-pyrazole-3-carboxamide; 5-(3-Fluoro-4-methoxypheny1)-1-methyl-N-(1-methylpipericlin-3 -y1)-1H-pyrazole-3-carboxamide; 5-(3-Chloro-4-fluoropheny1)-1-methyl-N-((l-methylpiperidin-4-y1)methyl) -1H-pyrazole-3- carboxamidc; 5-(3-Chloro-4-fluoropheny1)-1-methyl-N-((l-methylpiperidin-3-y1)methyl) -1/1-pyrazole-3-carboxamidc; 5-(3-Fluoro-4-methoxypheny1)-1-methyl-N-((1-methylpiperidin-4-y1)methyl) -111-pyrazole-3-carboxamide; 5-(3-F1 uoro-4-me(hox ypheny1)-1-meth yl-N-((l-methylpi peridi n-3 -yl)me(hyl)-1Hpyrazo le-3-carbox amide; 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-((l-methylpiperidi n-4-y1) methyl)-1Hpyrazole-3-carboxamide; 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl) -1H-pyrazole-3-carbox amide; 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N4(1-methylpiperidin-2-yflmethyl) -1Hpyrazole-3-carboxamide; 5-(2-Fluoro-4-methoxypheny1)-1-methyl-N-(1-meth ylpiperi di n-3 -yl)-1H-pyrazole-3-carboxamidc; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(1-mcthylpiperidin-3-y1) -1H-pyrazolc3-carboxamide; (R)-5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(tritluorotnethyl)pheny1)-I -methyl-N-(1 -tnethylpiperi di n-3-y1)-1 Hpyrazale-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-2-yl)methyl)-1Hpyrazole-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(24 1-methylpyrrolidin-2-yl)cthyl)-1Hpyrazole-3-carboxamide; 5-(2-F1 uoro-4-((ri Iluorometh yl)phen y1)-1-methyl -N-(2-( 1 -meth yl piperi din-2-yl)eth yl)-IN-pyrazole-3-carbox amide; 5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1 -methyl -N-((1-methylpiperidi n-3-yl)mcthyl)-1 Hpyrazole-3-carboxamide; (R)-5-(2-Fluoro-4-(trifluoromethyl)pheny1) -1-methyl-N41-methylpiperidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(tritluorotnethyl)pheny1)-I -methyl -N-(( 1 -methylpiperidi n-3-yl)tneth y1)- 1H-pyrazolc-3-carboxamide; 5-(2-Fluoro-4-(tri tluorometh yl)phenyl)-1-methyl -N-(( 1 -methylpiperidi n-4-yl)methyl)-1 Hpyrazale-3-carboxamide; 5-(2-Chloro-4-Incthoxypheny1)-1-Incthyl-N-( 1 tethylpiperidin-3 -y1)-1H-pyrazolc-3-20 carboxamide; (R)-5-(2-Chloro-4-metho x yphen y1)-1 -methyl-N-( 1 -me(h ylpi peridi n-3-y1)-1 H-pyrazole-3-carboxam i de; (S)-5-(2-Ch loro-4-methoxyphcny1)-1 -methyl-N-(1-tnethylpiperidi n-3-y1)-1 H-pyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((1 -methylpyrrolidin-3-yl)methyl)-1H- pyrazolc-3-carbox amide; (R)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((1-methylpyrrolidin-3-yl) methyl)-1Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methox yphen y1)-1 -methyl -N-(( 1 -meth ylpyrrol idi n-3-y1) meth y1)-IN-pyrazolc-3-carboxamide; 5-(2-Chloro-4-Incthoxypheny1)-1-Incthyl-N-( (1 -methylpiperidin-3 -yl)methyl)-111pyrazole-3-carboxamide; (R)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-( (1-methylpiperidin-3-yOmethyl)-1Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methox yphen y1)-1-meth yl -N-((l-methylpiperidi n-3-y1) methyl)-1Hpyrazale-3-carboxamide; 5-(2-Chloro-5-(trifluoromethyl)pheny1)-1-methyl-N-(1-methylpiperidin-3-y1) -1H-pyrazole3-carhoxamide; (R)-5-(2-Chloro-5-(trifluoromethyl)pheny1)-1-methyl-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-carboxamide; (S)-5-(2-Chloro-5-(trilluorome(h yl)ph en yl)-1-meth yl-N-(1-meth yl piperidi 11-3-y1)-1 io pyrazole-3-carbox amide; 5-(2-Chloro-5-(trifilloromethyl)pheny1)-1-methyl-N-(( I -rnethylpyrrol idi a-3-y') methyl)-1H-pyrazole-3-carboxamide; (12)-5-(2-Chloro-5-(trifluoromethyl)pheny1)-1-methyl-N( (1-methylpyrrolidin-3-yOmethyl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-5-(tritluoro methyl)ph en y1)-1-methyl-N-((1-meth ylpyrrol idi n-3-yflmethy1)-1H-pyrazole-3-carboxamide; 5-(2-Chloro-5-rnethox yphen y1)-1-methyl-N-(1-m ethylpi peri di n-3 -y1)-1H-pyrazole-3-carboxamide; (R)-5-(2-Chloro-5-methoxypheny1)-1-methyl-N-( 1 tethylpiperidin-3-y1)-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-5-methoxyphen y1)-1-methyl-N-( 1-meth yl piped din-3-y1)-1H-pyrazol e-3-carboxam i de; 5-(2-Ch loro-5-rnethox yphenyI)-1-methyl-N-(( I -methylpyrrol idi n-3-y1) methyl)-1 Hpyrazole-3-carboxamide; (12)-5-(2-Chloro-5-methoxypheny1)-1-methy1-N-((1-methylp yrrolidin-3-yOmethyl)-1H-pyrazole-3-carbox amide; (S)-5-(2-Chloro-5-methoxypheny1)-1-methyl-N4 (1-methylpyrrolidin-3-yemethyl)-1Hpyrazole-3-carboxamide; 1,4-Di methyl-N-(1-tnethylp iperi di n-4-y1)-5-(4-(trill uoro methyl)pheny1)-1H-pyrazole-3-carboxamide; 1,4-Dimethyl-N-((1-methylpiperidin-2-yemethy1)-5-(4-(trifluoromethyl) pheny1)-111/pyrazole-3-carboxamide; 1-Ethyl-N-(1-methylpyrrolidin-3-y1)-5-(4-(trifluoromethyl)pheny1) -1H-pyrazole-3-earboxamide; 1-Ethy1-5-(4-methoxypheny1)-N-(1-methylpyrrol idi n-3-y1)-1H-pyrazol e-3-earbox am i de; 5-(2-Methoxy-4-(trifluoromethyl)pheny1)-1-methyl-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-earboxamide; 5-(2-Methoxy-4-(trifluoromethyl)pheny1)-1-methyl-N41-methylpiperidin-2-y1) methyl)-1H-pyrazole-3-carboxamide; 5-(2-Methoxy-4-(trifluoromethyl)pheny1)-1-methyl-N4 (1-methylpiperidin-4-yl)methyl)-1H-pyrazole-3-earboxami de; 5-(2-Me(hoxy-4-(trilluoromethyl)pheny1)-1-methyl-N-( (1-methylpiperidin-3-y1)methy1)- 1H-pyrazole-3-earboxamidc; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-( (1 -methylpyrrolidin-2-yl)methyl)-111-pyrazole-3-earboxamide; (R)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((1-methylp yrrolidin-2-yl)methyl)-1H-Is pyrazole-3-earbox amide; (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-( ( 1-methylpyrrolidin-2-yemethyl)-11-/-pyrazole-3-earbox amide; (S)-5-(2-Chloro-4-methoxypheny1)-4-ethyl-1-methyl-N- (1-methylpiperidin-3-y1)-111-pyrazole-3-earboxamide; 5-(2-Chloro-4-methoxypheny1)-1-methyl-N-((1 -methylpiperidin-2-yl)methyl)-1H-pyrazole-3-earbox amide; (R)-5-(2-Ch loro-4-metho x yphenyI)-1-methyl-N-((1 -methylpiperidin-2-yOmethyl)-1 Hpyrazo Ic-3-carbox amide; (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-( ( 1-methylpiperidin-2-yemethyl)-11-1-pyrazole-3-earboxamide; (S)-5-(2-Chloro-4-methoxypheny1)-1,4-di methyl-N-(1-meth ylpiperi di n-3 -yl)-1H-pyrazole3-carboxamide; 5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N-( 1-methylpiperidin-3-y1)-1H-p yrazole3-cal-box am ide; (R)-5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N- (1-methylpiperidin-3-y1)-1Hpyrazole-3-earboxamide; (S)-5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N (1-methylpiperidin-3-y1)-1Hpyrazole-3-earbox amide; 5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpyrrolidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; (R)-5-(2-Chloro-4-(tri tl uoro methyl)pheny1)-1 -methyl-N-(( 1 -methylpyrroli di n-3-yl)methy1)-1H-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-(trifluoromethyl)pheny1)-1-methyl-N-( (1-methylpyrrolidin-3-yl)methyl)-1H-pyrazole-3-carboxamide; 5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(( 1-methylpyrrolidin-3-yl)methyl)-1Hpyrazole-3-carboxamide; (R)-5-(2-Fluoro-4-(trilluorometh yl)ph en yl)-1 -methyl-N-(( 1 -meth yl pyn-ol idin-3-o yl)meth y1)-1 H-pyraz6le-3-carbo x amide; (S)-5-(2-Fluoro-4-(trifluoro methy Opheny1)-I -methyl -N-(( 1 -methy lpyrro I idi n-3-y I) meth yl)-1H-pyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-(methyl-d3)-N-(1-(methyl-d3) piperidin-3-y1)-1H-p yrazole-3-c arboxamide; (S)-5-(2-Chloro-4-(meth oxy-d3)phenyl)-1 -(methyl-d3)-N-( 1 -(methyl-d3)piperi di n-3-y1)- 1H-pyrazole-3-carboxamide; 5-(2-Chloro-4-rnethox yphen y1)-N-( 1,3-di methylpiperidi n-3-y1)-1 -methyl-11-1-pyrazole-3-carboxamide; (S)-5-(2-Chloro-4-methoxypheny1)-1-methyl-N-(piperidin-3-y1) -1H-pyrazole-3-20 carboxamide; (S)-5-(2-Chloro-4-methoxyphen y1)-1 -methyl -N-( 1 -(meth yl -d3)pi peridin-3 -y1)-1 Hpyrazo le-3-carbox amide; (S)-5-(2-Ch loro-4-(methoxy-d3)phenyl)-1-methyl -N-(1 -methylpiperidi n-3-yI)-1 Hpyrazole-3-carboxamide; 5-(2-Chloro-4-methoxypheny1)-N-(4,4-difluoropiperidin-3 -y1)-1-methy1-1H-p yrazole-3-carboxam i de; 5-(2-Chloro-4-methoxypheny1)-N-(4,4-ditluoro-1 -methylpiperidin-3-y1)-1-methyl-1Hpyrazole-3-carboxamide; 5-(2-Chloro-4-rnethox yphen y1)-N-(4,4-ditl uoropyrrol i di n-3-y1)-1-methyl -11-1-pyrazole-3-30 carboxamide; (S)-5-(2-Fluoro-4-(trifluoromethyepheny1)-1-(methyl-d3)-N-( 1-methylpiperidin-3-y1)-1Hpyrazole-3-carboxamide; (S)-5-(2-Fluoro-4-(trifluoromethyl)pheny1)-1-methyl-N-(1-(methyl-d3) piperidin-3-y1)-1Hpyrazole-3-carboxamide; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.
10. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of the preceding claims, wherein the process comprises reacting a compound of formula (II)OHFormula (II) or a salt thereof, with a compound of formula (III), H2N-R4-R5, wherein m, RI, R2, R3, R4 and R5 are as defined in any one of the preceding claims; and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (I) into another compound of formula (I); removing any protecting groups; forming a pharmaceutically acceptable salt.
11. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of claims 1 to 9, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.
12. A compound of formula (I) or a pharmaceutically acceptable salt. solvate or prodrug thereof, as claimed in any one of claims 1 to 9, for use in therapy.
13. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of claims 1 to 9, for use in treating or preventing a disease, disorder or condition that has dysregulation of dopamine as a key pathological mechanism.
14. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of claims 1 to 9, for use in treating or preventing a disease, disorder or condition that has dysregulation of noradrenaline as a key pathological mechanism.
IS. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of claims I to 9, for use in treating or preventing a disease, disorder or condition that has dysregulation of serotonin as a key pathological mechanism.
16. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or Is prodrug thereof, as claimed in any one of claims I to 9, for use in treating or preventing a movement disorder such as tremor, dystonia, dyskinesia, Parkinson's disease, or Huntington's disease; or a psychiatric disorder such as schizophrenia, psychotic disorder, psychosis, schizoaffective disorder, bipolar disorder (including bipolar I, bipolar H. bipolar mania, and bipolar depression), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) including Fragile X syndrome, Tourettes syndrome, or an addiction disorder (including substance or drug dependence, alcohol dependence, nicotine dependence, binge eating, and gambling disorder).